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Several research and market developments in the past 5 years could influence front-line and subsequent-line strategies in chronic myeloid leukaemia. These developments include the increased availability of effective and safe generic imatinib at affordable prices, studies showing that doses of tyrosine kinase inhibitors (TKIs) lower than the approved dose are effective and less toxic, studies showing that dose-adjusted ponatinib therapy at a reduced dose is effective and substantially safer than approved doses, and the approval of asciminib as third-line therapy in 2021. With the availability of an affordable generic imatinib, all patients with chronic myeloid leukaemia globally should be able to access a lifetime supply. The availability of reduced-dose schedules of generic second-generation TKIs, which are less toxic and produce faster deep molecular response than imatinib, might make them more appealing to use as front-line therapy. In the subsequent-line setting, the role of different TKIs as second, third, and later lines of therapy depends on the evolving front-line use. Dose-adjusted ponatinib schedules have shown better efficacy and safety with long-term follow-up. Ponatinib is the favoured therapy for patients with second-generation-TKI resistance or chronic myeloid leukaemia with 944C→T (Thr315Ile)-mutated BCR-ABL1. Studies of asciminib are needed in larger numbers of patients and with longer follow-up than has been done previously to better assess its comparative efficacy, safety, and survival data (vs ponatinib). The role of third-generation TKIs as second-line therapy following front-line resistance to second-generation TKIs needs to be evaluated. New and mature data with TKI therapy in chronic myeloid leukaemia are producing observations that encourage continuous discussion of the optimal treatment recommendations and frameworks in chronic myeloid leukaemia.

Ponatinib plus Hyper-CVAD yields a five-year overall survival of 73% in patients with Philadelphia-positive acute lymphoblastic leukemia. Ponatinib dose intensity is associated with increased incidence of adverse effects (AEs), including vascular events. Ponatinib combined with azole antifungals may further increase the risk of AEs due to increased ponatinib exposure. We reviewed 53 patients who received ponatinib with intensive (

Chronic lymphocytic leukaemia (CLL) rarely presents in adolescent and young adult (AYA) patients (patients aged 15-39 years). Disease characteristics and outcomes of AYA patients with CLL are not well understood, particularly in the era of novel oral targeted therapies. We analysed outcomes of 227 AYA patients with CLL diagnosed in the last two decades and evaluated at our institution. Median time to first treatment (TTFT) was 2·2 years, and five- and 10-year overall survival (OS) were 90% and 78%, respectively. Pre-treatment elevated beta 2-microglobulin, advanced Rai stage, del(11q) or del(17p) by FISH, unmutated IGHV and CD38 positivity were associated with both shorter TTFT and OS. Within the subgroup of patients who received oral targeted therapy at any time, del(11q) or del(17p) and complex karyotype were associated with shorter OS. First-line treatment choice was significantly associated with time to second treatment (P < 0·001). Patients harbouring del(11q) or del(17p) experienced shorter time to Richter transformation and were more likely to undergo an allogeneic stem cell transplant. There was a significant association between age and both OS and time to Richter transformation. Our study is the first analysis of AYA patients with CLL with a large number of patients treated with oral targeted therapies.

Advances in our understanding of cancer biology have enabled drug development to progress towards better targeted therapies that are both more effective and safer owing to their lack of off-target toxicities. In this regard, antibody-drug conjugates (ADCs), which have the potential to combine the selectivity of therapeutic antibodies with the cytotoxicity of highly toxic small molecules, are a rapidly developing drug class. The complex and unique structure of an ADC, composed of a monoclonal antibody conjugated to a potent cytotoxic payload via a chemical linker, is designed to selectively target a specific tumour antigen. The success of an ADC is highly dependent on the specific properties of its components, all of which have implications for the stability, cytotoxicity, pharmacokinetics and antitumour activity of the ADC. The development of therapeutic ADCs, including gemtuzumab ozogamicin and inotuzumab ozogamicin, provided great knowledge of the refinements needed for the optimization of such agents. In this Review, we describe the key components of ADC structure and function and focus on the clinical development and subsequent utilization of two leukaemia-directed ADCs - gemtuzumab ozogamicin and inotuzumab ozogamicin - as well as on the mechanisms of resistance and predictors of response to these two agents.

Objective Acute myeloid leukemia (AML) is primarily a disease of older adults. These patients may not be candidates for intensive treatment, and there has been an ongoing need for treatment options for this group. We review the use of glasdegib, a hedgehog-pathway inhibitor available for use in combination with low-dose cytarabine (LDAC). Data Sources: PubMed and relevant congress abstracts were searched using the term “glasdegib”. In addition, based on our experience with glasdegib, we considered treatment aspects of particular relevance to pharmacists and advanced practitioners. Data Summary: In a randomized phase II study, the combination of glasdegib plus LDAC demonstrated superior overall survival versus LDAC alone (hazard ratio 0.51, 80% confidence interval 0.39–0.67, p = 0.0004). The trial reported adverse events (AEs) of special relevance for older patients, such as hematologic events, gastrointestinal toxicity, and fatigue, as well as AEs associated with Hh-pathway inhibitors (alopecia, muscle spasms, dysgeusia). Educating patients about typical AEs can facilitate adherence as well as early AE identification and proactive management. For LDAC, which is a long-established therapy in AML, various stages of delivery need consideration, with attention to individual circumstances. Practical measures such as dispensing a longer supply can reduce the number of return clinic visits, providing a meaningful difference for many patients. Conclusions Pharmacists and advanced practitioners play important roles in treatment with glasdegib plus LDAC. Ultimately, framing plans for treatment delivery within the individual circumstances of each patient may enable them to stay on therapy longer, giving them the greatest potential to achieve benefit.

The advent of BCR–ABL1 tyrosine kinase inhibitors has revolutionized the treatment and prognosis of chronic myeloid leukemia. Life expectancy for patients with chronic phase chronic myeloid leukemia now nears that of the healthy population; however, optimal outcomes require continuous tyrosine kinase inhibitor administration, which can impact patient quality of life. Consequently, the concept of treatment-free remission has been explored in patients achieving and sustaining a deep molecular response. Heterogeneous data exist with multiple tyrosine kinase inhibitors; however, nilotinib is currently the only therapy that has been approved by the US Food and Drug Administration for treatment-free remission. The decision to pursue treatment-free remission is one that relies heavily on both patient- and disease-related factors. Herein, we will discuss relevant considerations to be made when determining an optimal candidate for treatment-free remission.

Acute myeloid leukaemia (AML) is a heterogeneous disease in which prognosis is determined by cytogenetic and molecular aberrations as well as patient-related factors, including age, prior haematologic disorders, and comorbidities. Despite the diverse disease biology, the standard of care for remission induction therapy has changed very little since its inception in 1973. Next generation sequencing has helped to increase our knowledge of the disease pathogenesis, allowing us to develop targeted and possibly more effective treatment options. Seven new agents have been approved for the treatment of AML since 2017, all of which are directed toward a specific molecular subtype or patient population. With the advent of these therapies, a more optimal, patient-specific approach rather than the historical 'one-size fits all' model can be utilised. This review will discuss the role of these novel therapies in the remission induction setting.

Recent treatment advances in both acute myeloid leukemia and acute lymphoblastic leukemia have drastically improved outcomes for these diseases, but central nervous system (CNS) relapses still occur. Treatment of CNS disease can be challenging due to the impermeability of the blood-brain barrier to many systemic therapies.The diagnosis of CNS leukemia relies on assessment of clinical symptoms, cerebrospinal fluid sampling for conventional cytology and/or flow cytometry, and neuroimaging. While treatment of CNS leukemia with systemic or intrathecal chemotherapy and/or radiation can be curative in some patients, these modalities can also lead to serious toxicities. In the modern era, prophylaxis with intrathecal chemotherapy is the most important strategy to prevent CNS relapses in high risk patients. Accurate risk stratification tools and the use of risk-adapted prophylactic therapy are imperative to improving the outcomes of patients with acute leukemias and preventing the development of CNS leukemia.

Background: The combination of low intensity therapy with mini-hyper-CVD and INO with or without Blina has led to significant improvement in survival and outcomes of pts with R-R ALL. ASCT following salvage therapy is considered standard of care in pts with R-R ALL. The aim of this study is to compare the outcomes of pts with R-R ALL treated with this combination followed by ASCT to those who did not receive subsequent ASCT. Methods: The chemotherapy was lower in intensity than conventional hyper-CVAD and referred to as mini-hyper-CVD (details in a separate abstract). INO was given on Day 3 of each of the first 4 courses at 1.8-1.3 mg/m2 for course 1 followed by 1.3-1.0 mg/m2 for subsequent courses. Following the enrollment of 67 pts, INO was reduced and fractionated into biweekly doses (0.6 mg/m2 and 0.3 mg/m2 during course 1 and 0.3 mg/m2 and 0.3 mg/m2 during subsequent courses), and Blina was added for up to 4 courses after INO therapy. The decision to proceed with ASCT was at the discretion of the treating physician and after discussion with the pt. Median time to ASCT was 4 months (range, 2 to 10 months). We performed a landmark analysis at 4 months and compared survival of pts on protocol who received ASCT and those who did not. We used a prognostic model to stratify pts into 2 categories: high- vs low-risk. This model relies on cytogenetics and CD22 expression to predict survival (detailed in another abstract). Pts with CD22 expression ≥70% and cytogenetics without KMT2A rearrangements, or low-hypodiploidy / near triploidy were considered low-risk disease. We compared the survival of pts who received ASCT to those who did not among each risk category. Results: Ninety-six pts with R-R ALL were treated. Forty-four pts (46%) with a median age of 34 years (range, 18 to 64 years) underwent ASCT (13 related donors; 16 match unrelated donors, 13 haploidentical, 2 cord stem cells). Of them, 35 (79%) underwent ASCT in Salvage 1 (S1). At the time of ASCT, all 44 pts were morphologic response (39 CR, 5 CRp), 38 among them (86%) in negative MRD status. To date, 19/44 pts (43%) remain alive in remission following ASCT [17 complete response (CR); 2 alive after relapse]. The remaining 25 pts (57%) died of vaso-occlusive disease (VOD; 2 pts), relapse (17 pts) or ASCT complications (6 pts). The median time from start of therapy to ASCT was 18 weeks (range 8 to 44 weeks); this median was 15 weeks (range: 8-44 weeks) for pts who received the original combination and 18 weeks (range: 9-31 weeks) for pts who received the weekly lower dose of INO followed by Blina. In a landmark analysis, the median OS for pts who received ASCT and those who did not was 35 months and 17 months, respectively. The 3-year OS rates were 48% (95% CI, 32%-63%) and 37% (95% CI, 19%-55%), respectively (p=0.4) (Figure 1). In pts who received ASCT in S1, the 3-year OS rate was 55.2% (95% CI, 36.7%-70.4%) with a median OS of 47 months. In univariate analysis of factors predicting survival, ASCT as a time-dependent variable was not associated with better survival [HR 0.775; 95% CI, 0.430-1.396; p=0.396]. VOD was observed in 7/44 pts (16%) who received subsequent ASCT versus 3/52 pts (6%) who did not and in 9/67 pts (13%; 22/67 received subsequent ASCT) treated with mini-hyper-CVD-INO compared with 1/29 pts (3%) treated with mini-hyper-CVD-INO-Blina (15/29 received a subsequent ASCT). This may be the result of lower dose schedules and distancing ASCT from last course of INO. For risk stratification, 82 pts were evaluable; 30 were considered high-risk. In low-risk pts, there was no difference in OS whether or not pts received ASCT (p=0.777). With a 4-month landmark analysis, the 3-year OS rates were 62% and 60% for pts who received ASCT and those who did not, respectively. Among the high-risk pts, the 1-year OS rates were 25% and 11% (p=0.14), respectively (Figure 2). Conclusions: The combination of mini-hyper-CVD and INO with or without Blina is very effective in pts with R-R ALL. ASCT ASCT should be potentially considered in pts with high-risk disease (KMT2A rearrangement, low-hypodiploidy / near triploidy, CD22 expression Disclosures Rafei: United States Provisiona: Patents & Royalties: I have a filed patent. Kantarjian:Ariad: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Astex: Research Funding; Pfizer: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Cyclacel: Research Funding; Jazz Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding. Sasaki:Daiichi Sankyo: Consultancy; Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Honoraria. Short:AstraZeneca: Consultancy; Amgen: Honoraria; Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding. Ravandi:Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Khouri:Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Kebriaei:Ziopharm: Other: Research Support; Novartis: Other: Served on advisory board; Kite: Other: Served on advisory board; Jazz: Consultancy; Amgen: Other: Research Support; Pfizer: Other: Served on advisory board. Champlin:Takeda: Patents & Royalties; Genzyme: Speakers Bureau; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy; Omeros: Consultancy; Johnson and Johnson: Consultancy; Actinium: Consultancy. Jain:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; ADC Therapeutics: Research Funding. Issa:Syndax: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celegene: Research Funding. Pemmaraju:Affymetrix: Other: Grant Support, Research Funding; Pacylex Pharmaceuticals: Consultancy; SagerStrong Foundation: Other: Grant Support; Incyte Corporation: Honoraria; Novartis: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria; Roche Diagnostics: Honoraria; Blueprint Medicines: Honoraria; DAVA Oncology: Honoraria; Samus Therapeutics: Research Funding; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Plexxikon: Research Funding. Kadia:JAZZ: Honoraria, Research Funding; Cyclacel: Research Funding; Amgen: Research Funding; Cellenkos: Research Funding; BMS: Honoraria, Research Funding; Ascentage: Research Funding; Abbvie: Honoraria, Research Funding; Astellas: Research Funding; Incyte: Research Funding; Pulmotec: Research Funding; Celgene: Research Funding; Genentech: Honoraria, Research Funding; Astra Zeneca: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria. Garcia-Manero:AbbVie: Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Onconova: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; H3 Biomedicine: Research Funding; Amphivena Therapeutics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. DiNardo:AbbVie: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; Takeda: Honoraria; Jazz: Honoraria; Syros: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Research Funding. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Thompson:Pharmacyclics: Research Funding; Genentech: Consultancy; AbbVie: Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Janssen-Cilag: Honoraria. Konopleva:Cellectis: Research Funding; Calithera: Research Funding; AbbVie: Consultancy, Research Funding; Eli Lilly: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Kisoji: Consultancy; Genentech: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Sanofi: Research Funding; AstraZeneca: Research Funding; Forty-Seven: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Amgen: Consultancy; Ascentage: Research Funding; Ablynx: Research Funding; Rafael Pharmaceutical: Research Funding; Agios: Research Funding. O'Brien:Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy; Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding; Kite, Regeneron, Acerta: Research Funding. Jabbour:Amgen: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. OffLabel Disclosure: Blinatumomab Inotuzumab used in the setting of a clinical trial of a combination of mini-hyper-CVD + inotuzumab +/- blinatumomab in patients with acute lymphoblastic leukemia

Background: For patients (pts) with Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukemia (ALL), combination chemotherapy achieves complete remission rates of 80-90%; however, many pts ultimately relapse, leading to a cure rate of only 40-50%. Blinatumomab is highly effective in both the relapsed/refractory setting and for eradication of measurable residual disease (MRD). We hypothesized that early incorporation of blinatumomab in pts with newly diagnosed Ph-negative B-cell ALL would decrease the need for intensive chemotherapy, lead to deeper and more durable responses, and improve survival. Methods: Pts 14-59 years of age with newly diagnosed Ph-negative pre-B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤2 mg/dl and creatinine ≤2 mg/dl. Pts received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m2). Eight administrations of prophylactic IT chemotherapy were given in the first 4 cycles. Maintenance was with alternating blocks of POMP (given in maintenance cycles 1-3, 5-7, 9-11, and 13-15) and blinatumomab (given in maintenance cycles 4, 8, and 12). After 2 pts with high-risk features experienced early relapse prior to blinatumomab administration, for pts #10+ the protocol was amended so that pts with high-risk disease features (e.g. CRLF2+ by flow cytometry, complex karyotype, KMT2A rearranged, low-hypodiploidy/near triploidy, TP53 mutation, or persistent MRD) started blinatumomab after 2 cycles of hyper-CVAD. Results: 39 pts have been treated, 34 of whom are evaluable for efficacy (5 too early for assessment). 6 pts were in complete remission (CR) at enrollment and unevaluable for morphologic response. Pt characteristics of the 34 evaluable pts are summarized in Table 1. Median age was 36 years (range, 17-59 years). At least one high-risk feature was present in 19 pts (56%), including TP53 mutation in 27%, CRLF2+ in 20%, and an adverse-risk karyotype in 26%. 82% of pts received ofatumumab or rituximab. Among 28 pts with active disease at study entry, 100% achieved CR, with 82% achieving CR after the first cycle. MRD negativity by 6-color flow cytometry was achieved in 20/23 responding pts (87%) after 1 cycle and 33/34 pts (97%) overall. There were no early deaths, and the 60-day mortality rate was 0%. With a median follow-up of 22 months (range, 1-40 months), the 2-year continuous remission and OS rates were 79% and 86%, respectively (Figure 1). Overall, 5 pts (15%) relapsed, 12 (35%) underwent allogeneic SCT in first remission (including 1 additional pt who relapsed post-SCT), and 17 (50%) remain in continuous remission and are currently on treatment or have completed maintenance. All relapses occurred in pts with established poor-risk features, including 2 pts with KMT2A rearrangement, 2 pts with TP53 mutation (1 of whom was low hypodiploid), and 1 pt with baseline WBC count of 32 x 109/L. Two of these relapses occurred during hyper-CVAD cycles before the amendment allowing for earlier integration of blinatumomab for pts with high-risk disease features. Treatment was overall well-tolerated. Four pts developed grade 2-3 cytokine release syndrome (grade 2, n=3; grade 3, n=1) which resolved with corticosteroids and interruption of blinatumomab. Overall, 14 (41%) pts had a neurological AE of any grade due to blinatumomab. Only one pt discontinued blinatumomab due to blinatumomab-related adverse event (grade 2 encephalopathy and dysphasia). Conclusion: Sequential combination of hyper-CVAD and blinatumomab is highly effective as frontline treatment of Ph-negative B-cell ALL, with a CR rate of 100% and 97% of pts achieving MRD negativity. Survival data are promising with an estimated 2-year OS of 86%, which compares favorably to historical controls. This study continues to accrue pts. Disclosures Short: Astellas: Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding. Kantarjian:Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Oxford Biomedical: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; BMS: Research Funding; Adaptive biotechnologies: Honoraria; Abbvie: Honoraria, Research Funding; Sanofi: Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding. Ravandi:Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding. Kadia:Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cyclacel: Research Funding; Astellas: Research Funding; Cellenkos: Research Funding; Pfizer: Honoraria, Research Funding; Celgene: Research Funding; Pulmotec: Research Funding; Amgen: Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Incyte: Research Funding; JAZZ: Honoraria, Research Funding; Novartis: Honoraria; Astra Zeneca: Research Funding. Thompson:Pharmacyclics: Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Genentech: Consultancy; Janssen-Cilag: Honoraria; AbbVie: Research Funding. Alvarado:Tolero Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Sun Pharma: Research Funding; BerGenBio ASA: Research Funding; MEI Pharma: Research Funding; FibroGen: Research Funding. Jain:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Research Funding; ADC Therapeutics: Research Funding; Incyte: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Konopleva:Calithera: Research Funding; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Agios: Research Funding; AstraZeneca: Research Funding; Cellectis: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Eli Lilly: Research Funding; AbbVie: Consultancy, Research Funding; Ascentage: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Kisoji: Consultancy; Sanofi: Research Funding; Ablynx: Research Funding. Garcia-Manero:AbbVie: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding; H3 Biomedicine: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding. O'Brien:Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy; Kite, Regeneron, Acerta: Research Funding; Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding. Jabbour:Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding. OffLabel Disclosure: Blinatumomab - frontline therapy for ALL

Background: The combination of INO with hyper-mini-CVD with or without blinatumomab offers a safe and effective treatment modality for pts with R-R ALL. However, the outcomes of some pts remain poor and the predictors of survival are not well understood. CA are frequently used as predictors of outcomes in leukemia. We present an exploratory analysis evaluating the relationship between baseline CA and outcome in pts with R-R ALL treated at our institution in a phase 2 study of INO in combination with mini-hyper-CVD with or without blinatumomab. Methods: Ninety-six pts with R-R ALL received low-intensity chemotherapy referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses). INO was given on Day 3 of each of the first 4 courses at 1.8-1.3 mg/m2 for course 1 followed by 1.3-1.0 mg/m2 for subsequent courses. From pt #68 onwards, INO was reduced and fractionated into biweekly doses (0.6 mg/m2 and 0.3 mg/m2 during course 1 and 0.3 mg/m2 and 0.3 mg/m2 during subsequent courses), and blinatumomab for up to 4 courses after INO therapy was added. By performing univariate and multivariate analyses of factors associated with survival, we identified 11q23 rearrangements and low hypodiploidy / near triploidy (Ho-Tr) as high-risk CA. Pts were categorized based on their CA as low-risk if they carry diploid, complex or other cytogenetics. Pts with 11q23 rearrangements and those with Ho-Tr were classified as having high-risk CA. Response rates and overall survival (OS) outcomes are compared between the two cytogenetic risk categories. Results: Pts characteristics are summarized in Table 1. Karyotype was diploid in 23 (24%) pts, complex in 12 (13%) pts, and other in 21 (22%) pts. Ten (10%) pts had Ho-Tr, 10 (10%) pts had KMT2A rearrangements, 3 (3%) pts had high hypertriploidy (HeH), 2 (2%) pts had near triploidy (Tt) and 15 (16%) pts had insufficient metaphases/ not determined karyotype. TP53 mutation was detected in a significantly higher proportion of pts with Ho-Tr (6 out of 7 tested pts or 86%) compared to pts with other cytogenetic abnormalities (10 out of 40 tested pts or 25%) (p=0.002). We performed univariate and multivariate analyses for the association of different cytogenetics with survival. By multivariate analysis, baseline cytogenetics independently associated with worse survival included Ho-Tr [HR= 18.262 (95% CI= 5.935-56.196); p Conclusion: Our analysis identified baseline KMT2A rearrangements and Ho-Tr as independent predictive of poor outcome in pts with R-R ALL treated with the combination therapy of INO with mini-hyper-CVD with or without blinatumomab. Pts with these poor-risk features should be considered for alternative strategies such as CAR T-cells therapies and clinical trials such as adding menin inhibitors to the regimen in pts with KMT2A rearrangement. Disclosures Rafei: United States Provisiona: Patents & Royalties: I have a filed patent. Kantarjian:BMS: Research Funding; AbbVie: Honoraria, Research Funding; Astex: Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Agios: Honoraria, Research Funding. Sasaki:Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Otsuka: Honoraria; Pfizer Japan: Consultancy. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Amgen: Honoraria. Ravandi:Celgene: Consultancy, Honoraria; Macrogenics: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Khouri:Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Kebriaei:Amgen: Other: Research Support; Novartis: Other: Served on advisory board; Ziopharm: Other: Research Support; Jazz: Consultancy; Pfizer: Other: Served on advisory board; Kite: Other: Served on advisory board. Jain:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Pfizer: Research Funding; Cellectis: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding. Verstovsek:Gilead: Research Funding; Genentech: Research Funding; CTI Biopharma Corp: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Celgene: Consultancy, Research Funding. Kadia:Pulmotec: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cellenkos: Research Funding; Cyclacel: Research Funding; Incyte: Research Funding; Ascentage: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Genentech: Honoraria, Research Funding. Garcia-Manero:Onconova: Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; H3 Biomedicine: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding. DiNardo:Takeda: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Syros: Honoraria; ImmuneOnc: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Agios: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Yilmaz:Pfizer: Research Funding; Pint Pharma: Honoraria; Daicho Sankyo: Research Funding. Konopleva:Agios: Research Funding; Calithera: Research Funding; Ablynx: Research Funding; Eli Lilly: Research Funding; Kisoji: Consultancy; Amgen: Consultancy; Forty-Seven: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Ascentage: Research Funding; Sanofi: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AstraZeneca: Research Funding; Cellectis: Research Funding. O'Brien:Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy; Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding; Kite, Regeneron, Acerta: Research Funding. Jabbour:BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding. OffLabel Disclosure: Blinatumomab and Inotuzumab as part of a clinical trial

Background: The combination of reduced-intensity chemotherapy with INO with or without blinatumomab improved survival of pts with R-R ALL compared to INO monotherapy. However, outcomes and survivals vary between pts and hence it is essential to investigate the predictors of response and survival in order to improve upon treatment selection in pts with R-R ALL. In the INO-VATE trial, patients with CD22 positivity of ≥90% had better outcomes in terms of duration of response and survival than those with Methods: The current analysis is based on a phase 2 study at our institution investigating the combination of low-intensity chemotherapy (mini-hyper-CVD) in combination with INO with or without blinatumomab in pts with R-R ALL. Briefly, pts with CD22-positive R-R ALL were treated with low-intensity chemotherapy compared to conventional hyper-CVAD and referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses). INO was given on Day 3 of each of the first 4 cycles at 1.8-1.3 mg/m2 for cycle 1 followed by 1.3-1.0 mg/m2 for subsequent cycles. The protocol was amended starting from pt #68 onwards to allow for the reduction of INO dose and its fractionation into biweekly doses (0.6 mg/m2 and 0.3 mg/m2 during cycle 1 and 0.3 mg/m2 and 0.3 mg/m2 during subsequent cycles), as well as the addition of blinatumomab for up to 4 cycles after INO therapy. Pts were categorized based on CD22 expression into 2 categories: those with 70% or greater expression of CD22 and those with less than 70% expression. The cutoff of CD22 at 70% was selected by the optimal cutoff finder (Budczies et al. PloS One 2012). The outcomes and survival of these pts were compared. Results: Ninety-six pts were enrolled, of whom 92 pts have available CD22 expression level for analysis. The median CD22 expression was 95% (range, 14% to 100%). Seventy-seven pts had a CD22 expression ≥ 70% (Table 1). The overall response rate (ORR) was 83% in pts with high CD22 expression compared to 67% in pts with low CD22 expression (p=0.142) with 61% complete remission (CR) in pts with high CD22 expression compared to 33% in pts with low expression (p=0.048). MRD negativity at the time of CR was achieved in 6 of 9 evaluable pts with low CD22 expression (67%) compared to 31 of 61 evaluable pts with high CD22 expression (51%) (p =0.374). Overall MRD was similar in both groups (80% vs 81% in low vs high CD22 expression) (Table 2). 4/15 (27%) pts in the low CD22 expression group proceeded to ASCT compared to 42/77 (55%) pts with high CD22 expression (p=0.048). At a median follow-up of 36 months (range, 4 to 88 months), the median OS is 17 months for pts with CD22 expression ³70% and 6 months for those with CD22 expression < 70% (p=0.0004). The estimated 3-year OS rates were 37% (95% CI, 26%-49%) and 7% (95% CI, 0.5%-26%), respectively. By multivariate analysis, baseline CD22 expression below 70% was independently associated with worse survival [HR= 4.669 (95% CI= 2.187-9.967); p Conclusions: Our analysis identified baseline low CD22 expression level of less than 70% as an independent predictive of poor outcome in pts treated with the combination of mini-hyper-CVD with INO with or without blinatumomab. Pts with poor risk features including low CD22 expression should be considered for alternative strategies such as CAR T-cells therapies directed at other tumor targets and clinical trials Disclosures Rafei: United States Provisiona: Patents & Royalties: I have a filed patent. Kantarjian:AbbVie: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Ariad: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Takeda: Honoraria; Cyclacel: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding. Sasaki:Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Honoraria; Daiichi Sankyo: Consultancy. Short:Amgen: Honoraria; Astellas: Research Funding; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding. Ravandi:Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Khouri:Pfizer: Research Funding; Bristol Myers Squibb: Research Funding. Kebriaei:Amgen: Other: Research Support; Ziopharm: Other: Research Support; Pfizer: Other: Served on advisory board; Kite: Other: Served on advisory board; Jazz: Consultancy; Novartis: Other: Served on advisory board. Jain:Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Incyte: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; BMS: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kadia:Cyclacel: Research Funding; JAZZ: Honoraria, Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte: Research Funding; Pulmotec: Research Funding; Cellenkos: Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding; Astellas: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Genentech: Honoraria, Research Funding; Novartis: Honoraria. Garcia-Manero:Onconova: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Amphivena Therapeutics: Research Funding. Burger:Gilead Sciences: Consultancy, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Speakers Bureau; TG Therapeutics: Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; AstraZeneca: Consultancy. DiNardo:Syros: Honoraria; Takeda: Honoraria; MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria; Jazz: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Bose:Kartos Therapeutics: Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer, Inc.: Research Funding; Promedior, Inc.: Research Funding; NS Pharma: Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding. Thompson:Janssen-Cilag: Honoraria; Pharmacyclics: Research Funding; AbbVie: Research Funding; Genentech: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding. Konopleva:Sanofi: Research Funding; Amgen: Consultancy; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Stemline Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Kisoji: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding; Ascentage: Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Research Funding; Calithera: Research Funding; Agios: Research Funding; Cellectis: Research Funding; Genentech: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Ablynx: Research Funding; AstraZeneca: Research Funding. O'Brien:Kite, Regeneron, Acerta: Research Funding; Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding; Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy. Jabbour:Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding. OffLabel Disclosure: Inotuzumab and Blinatumomab as part of a clinical trial

Background: The combination of low intensity therapy with InO improved outcome compared to intensive chemotherapy and to single agent InO in Salvage 1. The sequential addition of blina may allow the administration of weekly lower dose of InO and distancing allogeneic stem cell transplant (ASCT) from the last dose of InO, while deepening the minimal residual disease response. This will lead to less veno-occlusive disease (VOD) and better long-term efficacy. The aim of this study is to evaluate the outcome of pts in first relapse treated with this combination. Methods: The mini-hyper-CVD (cycles 1, 3, 5, 7) comprised cyclophosphamide (150 mg/m2 every 12 h on days 1-3), vincristine (2 mg flat dose on days 1 and 8), and dexamethasone (20 mg on days 1-4 and days 11-14) without anthracycline. Even cycles (cycles 2, 4, 6, 8) comprised methotrexate (250 mg/m2 on day 1) and cytarabine (0.5 g/m2 given every 12 h on days 2 and 3). Rituximab and intrathecal chemotherapy were given for first 4 courses. InO was originally given on day 3 of the first four cycles at the dose of 1.3-1.8 mg/m2 at cycle 1, followed by 1.0-1.3 mg/m2 in subsequent cycles. After 38 pts were treated, an amendment was made to incorporate 4 cycles of blina after 4 cycles of mini-hyper-CVD + InO. InO was given on days 2 and 8 at the dose of 0.6 and 0.3 mg/m2 at cycle 1, respectively, followed by days 2 and 8 at the dose of 0.3 and 0.3 mg/m2 at subsequent cycles; blina was continuously infused over 28 days every 42-day cycle for 4 cycles. The decision to proceed with ASCT was based on the discretion of the treating physician after discussion with the pt. Results: From 2/2013 to 9/2019, 65 pts were enrolled and received first salvage therapy including 27 pts with mini-hyper-CVD + InO + blina. Patient characteristics and outcome are summarized in Table 1. The median age at diagnosis was 39 years (range, 18-87). Among 65 pts, 8 (12%) pts had primary refractory disease; 25 (38%), CR1 duration less than 12 months. 7 (11%) pts had prior history of ASCT. The overall response rate was 91% (CR, 66%, CRp/CRi, 25%). These rates were 100% in pts with primary refractory disease (CR 100%); 84 % in pts with CR1 duration 12 months (CR 63%, CRi/CRp 31%) (Table 2). Among 56 evaluable pts for minimal residual disease (MRD) assessment at morphologic response and 57 overall, 57% of pts achieved negative MRD by multicolor flow cytometry at response and 88% overall. Among 59 who achieved remission, 26 (44%) relapsed, 35 (59%) underwent allogeneic SCT in CR2, and 6 (9%) died in CR/CRp. Overall, 6 pts (9%) developed VOD; 4 after subsequent ASCT. The rate of VOD was 5/38 (13%) in pts who did not receive blina. In contrast, only 1 case of VOD was observed among the 27 pts (4%) who received the weekly lower dose of InO and sequential addition of blina; this pt had VOD post ASCT in CR2. With a median follow-up of 36 months (range, 1-87 months), 27 pts (42%) were alive, 21 of whom (32%) were in CR and MRD negative status. The median CR duration (CRD) and overall survival (OS) were 13 and 16.5 months, respectively. The estimated 3-year CRD and OS rates were 25% and 42%, respectively. Using the IPTW analysis, compared to a similar historical cohort of pts treated with standard salvage chemotherapy (n=77), the mini-hyper-CVD + InO with or without blina (n=58) resulted in significantly improved survival (P Conclusion: The combination of InO with mini-hyper-CVD with or without blina is highly effective and shows improved outcome compared to intensive chemotherapy in pts with ALL in first relapse, with 3-year OS rate of 42%. The risk of VOD can be minimized with fractionated lower dose InO and sequential combination of blina. Disclosures Rafei: United States Provisiona: Patents & Royalties: I have a filed patent. Kantarjian:AbbVie: Honoraria, Research Funding; Ariad: Research Funding; Agios: Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; BMS: Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Amgen: Honoraria, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer Japan: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy, Research Funding. Short:Amgen: Honoraria; Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy. Ravandi:AstraZeneca: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Orsenix: Consultancy, Honoraria, Research Funding. Khouri:Pfizer: Research Funding; Bristol Myers Squibb: Research Funding. Kebriaei:Kite: Other: Served on advisory board; Pfizer: Other: Served on advisory board; Novartis: Other: Served on advisory board; Ziopharm: Other: Research Support; Jazz: Consultancy; Amgen: Other: Research Support. Jain:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Pfizer: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alvarado:Tolero Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; BerGenBio ASA: Research Funding; Sun Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; FibroGen: Research Funding; Daiichi-Sankyo: Research Funding; MEI Pharma: Research Funding. Kadia:BMS: Honoraria, Research Funding; Incyte: Research Funding; Amgen: Research Funding; Novartis: Honoraria; Cellenkos: Research Funding; Astra Zeneca: Research Funding; Genentech: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Ascentage: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Astellas: Research Funding; Celgene: Research Funding; Pulmotec: Research Funding. Garcia-Manero:Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; Merck: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Jazz Pharmaceuticals: Consultancy. Burger:TG Therapeutics: Research Funding, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Consultancy; Pharmacyclics, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau. DiNardo:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Novartis: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; MedImmune: Honoraria; Syros: Honoraria; Calithera: Research Funding. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yilmaz:Pfizer: Research Funding; Pint Pharma: Honoraria; Daicho Sankyo: Research Funding. Thompson:Adaptive Biotechnologies: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Research Funding; Janssen-Cilag: Honoraria; AbbVie: Research Funding. Konopleva:Agios: Research Funding; Sanofi: Research Funding; Cellectis: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Amgen: Consultancy; Stemline Therapeutics: Consultancy, Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Research Funding; Ablynx: Research Funding; Rafael Pharmaceutical: Research Funding; Kisoji: Consultancy; Eli Lilly: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding. O'Brien:Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding; Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy; Kite, Regeneron, Acerta: Research Funding. Jabbour:AbbVie: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding. OffLabel Disclosure: Inotuzumab Blinatumomab Used in combination with standard reduced intensity chemotherapy for the treatment of ALL

Background: Low-dose dasatinib was shown to be safe and effective in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). There is no randomized clinical trials to compare the outcome with the standard-dose dasatinib. The aim of this study is to compare responses and outcome of patients with newly diagnosed CML-CP treated with frontline dasatinib 50 mg/day with those who received standard-dose dasatinib 100 mg/day. Method: We analyzed 233 patients with newly diagnosed CML-CP who were treated with low-dose dasatinib 50 mg/day (N=83) or standard-dose dasatinib 100 mg/day (N=150). Responses criteria were previously defined. Failure-free survival (FFS) was calculated from the start date of therapy to the dates of treatment discontinuation for any reason except of treatment-free remission; event-free survival (EFS), to the date of any of the events while on study as defined in the IRIS study; transformation-free survival (TFS), to the date of transformation to accelerated or blastic phases or death during study; overall survival (OS), to the date of death from any cause at any time or date of last follow-up. Patients on low-dose dasatinib who had suboptimal response by European LeukemiaNet criteria had an option to increase the dose to 100 mg/day. Propensity score analysis with 1:1 matching was performed with the nearest neighbor matching method using calipers of width equal to 0.2. Multiple imputation was performed to minimize the bias. Propensity scores were calculated with logistic regression from baseline covariates including age, spleen size by examination, white blood cell count, hemoglobin, platelet count, percentage of basophils, percentage of blasts in peripheral blood and bone marrow, the presence of clonal evolution, and Sokal risk classification to minimize difference. Results: The overall median follow-up was 84 months: 24 months and 120 months for low-dose and standard-dose, respectively. Propensity score matching identified 77 patients in each cohort without significant baseline difference (Table 1). The 12-month major molecular response (MMR) rates were 82% and 76% for low-dose and standard-dose groups, respectively (P=0.136). The cumulative incidence of molecular response (MR)4, MR4.5, and complete molecular response (CMR) rates within 1 year were higher in the low-dose dasatinib group compared with the standard-dose group (63% and 43%, 53% and 37%, and 24% and 11% for each)(P Conclusions: The low-dose dasatinib is at least as effective as standard-dose dasatinib with better drug exposure, resulting in better outcome. Disclosures Sasaki: Otsuka: Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Pfizer Japan: Consultancy. Jabbour:Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding. Yilmaz:Daicho Sankyo: Research Funding; Pfizer: Research Funding; Pint Pharma: Honoraria. Bose:Promedior, Inc.: Research Funding; NS Pharma: Research Funding; Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Blueprint Medicines Corporation: Honoraria, Research Funding; Kartos Therapeutics: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding. Thompson:Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Janssen-Cilag: Honoraria; Genentech: Consultancy. Alvarado:Tolero Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; FibroGen: Research Funding; BerGenBio ASA: Research Funding; Jazz Pharmaceuticals: Research Funding; Sun Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding. Jain:TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Cellectis: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero:Celgene: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; H3 Biomedicine: Research Funding. Burger:BeiGene, Gilead, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Gilead, Janssen, Novartis, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company: Other: Travel/accomodations/expenses, Speakers Bureau. Borthakur:BioTherix: Consultancy; Treadwell Therapeutics: Consultancy; Nkarta Therapeutics: Consultancy; BioLine Rx: Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; Curio Science LLC: Consultancy; FTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BMS: Research Funding; AstraZeneca: Research Funding; Polaris: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding. Pemmaraju:Pacylex Pharmaceuticals: Consultancy; Blueprint Medicines: Honoraria; Plexxikon: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; DAVA Oncology: Honoraria; Samus Therapeutics: Research Funding; SagerStrong Foundation: Other: Grant Support; Affymetrix: Other: Grant Support, Research Funding; MustangBio: Honoraria; Incyte Corporation: Honoraria; Celgene: Honoraria; Daiichi Sankyo: Research Funding; LFB Biotechnologies: Honoraria; Novartis: Honoraria, Research Funding; Cellectis: Research Funding; Roche Diagnostics: Honoraria. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding. Kantarjian:Aptitute Health: Honoraria; BioAscend: Honoraria; Adaptive biotechnologies: Honoraria; BMS: Research Funding; Ascentage: Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oxford Biomedical: Honoraria; Janssen: Honoraria; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Delta Fly: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Immunogen: Research Funding.

Background Dasatinib, a potent Bcr-Abl tyrosine kinase inhibitor, is approved for the treatment of chronic-phase chronic myeloid leukemia (CML-CP) in the frontline and salvage settings. Notable side effects include pleural effusions and myelosuppression. Dasatinib at 50 mg daily has previously been reported to be active and better tolerated than the approved 100-mg daily dose. The aim of this study was to update the long-term follow-up results of dasatinib at 50 mg daily as frontline therapy for CML-CP. Methods Eighty-three patients with newly diagnosed CML-CP received dasatinib at 50 mg daily. Eligibility and response criteria were standards used in previous protocols. Results After a minimum follow-up of 12 months, 81 patients were evaluable. Two patients came off the study in less than 3 months. The rates of BCR-ABL1 transcript levels (International Standard) at ≤10% and ≤1% at 3 months were 96% and 77%, respectively. The cumulative rates for a complete cytogenetic response by 6 and 12 months were 77% and 95%, respectively. The cumulative rates for a major molecular response, a molecular response with a 4.0-log reduction, and a molecular response with a 4.5-log reduction by 12 months were 81%, 55%, and 49%, respectively. Twenty-one patients (25%) had treatment interruptions for a median of 13 days (range, 4-64 days). Five patients (6%) developed pleural effusions; 4 of these patients (80%) required a dose reduction. Two patients (2%) failed to achieve any cytogenetic or molecular response and were taken off the study. At a median follow-up of 24 months, none of the patients had disease transformation to an accelerated or blastic phase. The 2-year event-free and overall survival rates were 100%. Conclusions These updated results continue to support 50 mg of dasatinib daily as an effective and safe dose for early CML-CP.

Introduction: Blinatumomab is a first-in-class bispecific T-cell engager (BiTE) antibody that has demonstrated high response rates, including minimal or measurable residual disease (MRD) negativity...

Background The outcome of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. The combination of inotuzumab with low-intensity mini-hyper-CVD (mini-hyper-CVD; cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 × 4 doses) chemotherapy has shown encouraging results. The sequential addition of blinatumomab might improve outcome in patients with R/R ALL. Methods We used lower intensity chemotherapy, mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) compared to conventional hyper-CVAD. Results Ninety-six patients with a median age of 37 years (range, 18-87 years) were treated. Overall, 77 patients (80%) responded, 55 (57%) of whom achieved complete response. The overall measurable residual disease negativity rate among responders was 83%. Forty-four (46%) patients underwent later allogeneic stem cell transplantation. Veno-occlusive disease of any grade occurred in 10 (10%) patients. The rates were 13% with the original schedule and 3% with the use of lower-dose inotuzumab and sequential blinatumomab. With a median follow-up of 36 months, the median overall survival (OS) was 13.4 months, with 3-year OS rates of 33%. The 3-year OS rate for patients with CD22 expression ≥70% and without adverse cytogenetics (KMT2A rearrangements, low hypodiploidy/near triploidy) was 55%. Conclusion The combination of inotuzumab and low-intensity mini-hyper-CVD chemotherapy with or without blinatumomab shows sustained efficacy in patients with R/R ALL.

Treatment of acute leukemia with intensive chemotherapy leads to an increased risk of myelosuppression. Luteinizing hormone (LH) blockade improves hematopoietic recovery in mice after radiation or chemotherapy, through protection of the hematopoietic stem cells which express the LH receptor. We hypothesized that LH blockade improves hematopoietic recovery following intensive chemotherapy in patients with leukemia. We conducted a retrospective analysis on pre-menopausal women with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) who received intensive chemotherapy and leuprolide given for abnormal uterine bleeding prevention or treatment. Given that leuprolide was more commonly administered in younger patients, we performed propensity score matching between the leuprolide (AML N=64; ALL N=49) and control groups (AML N=128; ALL N=98 patients). Patients with AML who received leuprolide had an additional increase of 13.8 x 109/L/year in their platelet count, and a 0.19 x 109/L/year increase in their lymphocyte count after chemotherapy compared to control (P=0.02; P=0.03 respectively). Those with ALL who received leuprolide had an additional increase of 0.37 x 109/L/year in their absolute neutrophil count (P=0.02). In AML, leuprolide was associated with higher long-term hemoglobin levels (P

Background Chimeric antigen receptor (CAR) T-cell therapy has been a major innovative breakthrough for hematologic malignancies. These therapies are associated with unique and potentially serious toxicities, including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity (ICANS), that require vigilance, prompt recognition, and appropriate management to ensure patient safety and optimal therapeutic benefit. We developed an online tool to give healthcare providers (HCPs) case-specific, evidence-based expert guidance on the management of adverse events (AEs) from CAR T-cell therapy. Here, we report an updated analysis comparing CAR T-cell toxicity management among HCPs using the tool vs the expert consensus recommendations.1 Methods In March 2019, 5 experts provided consensus guidance for the screening, prophylaxis, monitoring, and management of CRS and ICANS in patients considering or receiving CAR T-cell therapy. This information was used to build the interactive online tool. To use this tool, HCPs enter the AE of interest, the severity of the event,2 and their planned management approach. The HCPs were then shown the expert recommendation for that specific scenario. After viewing the expert recommendation, HCPs were asked if it affected their intended approach. Results Between May 2019 and July 2020, 282 HCPs entered 431 unique case scenarios into the tool. Of the entered cases, 56% were HCPs seeking expert recommendations on pretreatment screening and prophylaxis/monitoring strategies for patients not yet experiencing an AE. Of 188 cases entered for patients who received CAR T-cell therapy and experienced an AE, 67% were CRS and 33% were neurotoxicity/ICANS. Overall the planned toxicity management strategy of HCPs matched the expert recommendations in 57% of cases, with a similar rate of concordance for both CRS and ICANS events. There was no significant difference in concordance rates with expert recommendations by toxicity severity (figure 1) nor among HCPs who indicated they practiced at authorized centers vs those who did not (P = 0.7184). Among HCPs who answered the optional survey on the impact of the tool on their management plan, 30% indicated that the expert recommendations changed their approach. Conclusions These data suggest that many HCPs are challenged to optimally manage CAR T-cell therapy toxicities in concordance with expert recommendations. Use of an online tool providing easy access to evidence-based consensus expert recommendations may improve care and safety in patients treated with CAR T-cell therapy. A detailed analysis of the tool including planned management vs expert recommendations for each toxicity and grade will be presented. References Frigault MJ, Cartwright M, Marcello K, Quill T, DeAngelo DJ, Galinsky IA, Paul S, Park JH. Management of CAR T-Cell toxicities: concordance and divergence between healthcare providers and expert recommendations. Blood 2019:134:2199. Lee DW, Santomasso BD, Lock FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY, Eldjerou L, Gardner RA, Frey N, Curran KJ, Peggs K, Pasquini M, DiPersio JF, van den Brink MRM, Komanduri KV, Grupp SA, Neelapu SS. ASTCT Consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 2019;25:625–638.

Detection of minimal or measurable residual disease (MRD) in acute lymphoid leukemia (ALL) post induction or consolidation has significant prognostic and treatment implications. Persistence of MRD has shown to confer resistance to conventional chemotherapy and predicts for early relapse; therefore, it is regarded as an independent risk factor for poor outcomes. Assessment of MRD through various methods such as multiparameter flow cytometry (MFC), polymerase chain reaction (PCR), or next-generation sequencing (NGS) is important post induction, consolidation, and various other time points in therapy, as indicated, for early therapeutic intervention. Selection of MRD assay depends on its availability and expertise with the method, although each one has its own advantages and disadvantages. Recent development of MRD-directed therapies such as blinatumomab and inotuzumab ozogamicin (InO) has placed significant value on detecting MRD through these methods, as early treatment intervention with these therapies can potentially eradicate MRD and prolong survival. This chapter reviews and compares the different MRD assays, describes the prognostic implications of MRD, and discusses MRD-directed therapies.

The coronavirus disease 2019 (COVID-19) pandemic poses several challenges to the management of patients with leukemia. The biology of each leukemia and its corresponding treatment with conventional intensive chemotherapy, with or without targeted therapies (venetoclax, FLT3 inhibitors, IDH1/2 inhibitors, Bruton’s tyrosine kinase inhibitors), introduce additional layers of complexity during COVID-19 high-risk periods. The knowledge about COVID-19 is accumulating rapidly. An important distinction is the prevalence of “exposure” versus “clinical infectivity,” which determine the risk versus benefit of modifying potentially highly curative therapies in leukemia. At present, the rate of clinical infection is 30% in patients with cancer, careful consideration should be given to the risk of COVID-19 in leukemia. Instead of reducing patient access to specialized cancer centers and modifying therapies to ones with unproven curative benefit, there is more rationale for less intensive, yet effective therapies that may require fewer clinic visits or hospitalizations. Here, we offer recommendations on the optimization of leukemia management during high-risk COVID-19 periods.

Background Dasatinib is a potent BCR-ABL1 and Src family tyrosine kinase inhibitor. It is approved at a dose of 100 mg orally daily for the treatment of chronic myeloid leukemia in chronic phase (CML-CP). This dose schedule is associated with myelosuppression and pleural effusions. Anecdotal data suggest that lower doses may be as effective and less toxic. The aim of this study was to assess the efficacy and safety of a lower dose of dasatinib (50 mg daily) in patients with newly diagnosed CML-CP. Methods Seventy-five patients with newly diagnosed CML-CP received dasatinib 50 mg daily. The eligibility and response criteria were standards used in previous protocols. Results At a median follow-up of 9 months, 60 patients were evaluable for a response at 3 months. The rates of patients achieving BCR-ABL1 transcript levels ≤ 10% and ≤ 1% at 3 months by the International Standard were 93% and 72%, respectively. The rates of complete cytogenetic response by conventional cytogenetics or fluorescence in situ hybridization at 6 and 12 months were 86% and 88%, respectively. At 12 months, 79%, 71%, and 46% of the patients had achieved a major molecular response, a molecular response with a 4.0-log reduction, and a molecular response with a 4.5-log reduction, respectively. Nine patients had a dose interruption for ≤14 days. Only 1 patient developed a pleural effusion requiring a dose reduction to 20 mg. All patients remained alive and with no transformation so far. Conclusion Dasatinib 50 mg daily is active and well tolerated in patients with newly diagnosed CML-CP. It should be further explored as a new potential standard-of-care option for chronic myeloid leukemia. Cancer 2018;124:2740-2747. © 2018 American Cancer Society.

Romiplostim is a thrombopoietin receptor agonist approved for the treatment of immune thrombocytopenia purpura. When following FDA-approved romiplostim prescribing recommendations to withhold treatment for platelet counts above 400k/µL, some patients exhibit a precipitous decline in their platelet count potentially causing patient harm. We present two cases where stable platelet counts were achieved only through persistent weekly dosing of romiplostim despite platelet counts above 400k/µL on the day of administration. Therefore, continuous weekly dosing of romiplostim despite platelet count being above 400k/µL combined with twice weekly vigilant monitoring is an alternative method of romiplostim dosing that mitigates severe fluctuations in platelets. We also discuss important details, postulated mechanisms, and evidence-based mitigation strategies.

Background: Low-dose dasatinib was shown to be safe and effective in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). There is no randomized clinical trials to compare the outcome with the standard-dose dasatinib. The aim of this study is to compare responses and outcome of patients with newly diagnosed CML-CP treated with frontline dasatinib 50 mg/day with those who received standard-dose dasatinib 100 mg/day. Method: We analyzed 233 patients with newly diagnosed CML-CP who were treated with low-dose dasatinib 50 mg/day (N=83) or standard-dose dasatinib 100 mg/day (N=150). Responses criteria were previously defined. Failure-free survival (FFS) was calculated from the start date of therapy to the dates of treatment discontinuation for any reason except of treatment-free remission; event-free survival (EFS), to the date of any of the events while on study as defined in the IRIS study; transformation-free survival (TFS), to the date of transformation to accelerated or blast phases during study; overall survival (OS), to the date of death from any cause at any time or date of last follow-up. Patients on low-dose dasatinib who had suboptimal response by European LeukemiaNet criteria had an option to increase the dose to 100 mg/day. Propensity score analysis with 1:1 matching was performed with the nearest neighbor matching method using calipers of width equal to 0.2. Multiple imputation was performed to minimize the bias. Propensity scores were calculated with logistic regression from baseline covariates including age, spleen size by examination, white blood cell count, hemoglobin, platelet count, percentage of basophils, percentage of blasts in peripheral blood and bone marrow, the presence of clonal evolution, and Sokal risk classification to minimize difference. Results: Propensity score matching identified 77 patients in each cohort without significant baseline difference (Table 1). The overall median follow-up was 60 months: 48 months and 131 months for low-dose and standard-dose, respectively. The 12-month major molecular response (MMR) rates were 82% and 75% for low-dose and standard-dose groups, respectively (P=0.229). The cumulative incidence of molecular response (MR)4, MR4.5, and complete molecular response (CMR) rates within 1 year were higher in the low-dose dasatinib group compared with the standard-dose group (63% and 43%, 53% and 36%, and 46% and 33% for each)(P=0.009; P=0.031; P=0.060). The incidence of pleural effusion was 6% and 21% in the low-dose and standard-dose, respectively (P=0.016). The 4-year FFS rates were 89% and 77% in the low-dose dasatinib and standard-dose dasatinib, respectively (P=0.041) (Figure 1). The 4-year TFS rates were 100% and 100%, respectively (P=1.000); the 4-year EFS rates were 95% and 92%, respectively (P=0.556); the 4-year OS rates were 97% and 96%, respectively (P=0.781). Conclusions: The low-dose dasatinib is as effective as standard-dose dasatinib with less intolerance, resulting in favorable outcome. Figure 1 Figure 1. Disclosures Sasaki: Novartis: Consultancy, Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Ferrajoli: Janssen: Other: Advisory Board ; AstraZeneca: Other: Advisory Board, Research Funding; BeiGene: Other: Advisory Board, Research Funding. Bose: Incyte Corporation: Honoraria, Research Funding; Pfizer: Research Funding; Astellas: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Sierra Oncology: Honoraria; Kartos Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; NS Pharma: Research Funding; BMS: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Promedior: Research Funding. Thompson: Janssen: Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding. Alvarado: Sun Pharma: Consultancy, Research Funding; Jazz Pharmaceuticals: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding. Jain: ADC Therapeutics: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Janssen: Honoraria; Aprea Therapeutics: Research Funding; Pfizer: Research Funding; Beigene: Honoraria; Precision Biosciences: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Incyte: Research Funding; TG Therapeutics: Honoraria; Adaptive Biotechnologies: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Takahashi: GSK: Consultancy; Novartis: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy. Borthakur: GSK: Consultancy; Astex: Research Funding; Protagonist: Consultancy; University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pemmaraju: HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Roche Diagnostics: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy; CareDx, Inc.: Consultancy; Incyte: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Springer Science + Business Media: Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Aptitude Health: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; MustangBio: Consultancy, Other; Sager Strong Foundation: Other; Celgene Corporation: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Cortes: Sun Pharma: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Kantarjian: Precision Biosciences: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Taiho Pharmaceutical Canada: Honoraria; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Astra Zeneca: Honoraria; Daiichi-Sankyo: Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Aptitude Health: Honoraria; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria.

Introduction: There are no standard salvage options for patients (pts) with chronic myelomonocytic leukemia (CMML) after progressing on hypomethylating agents (HMA). Outcomes are especially poor after blast transformation (BT). Combination therapy with the BCL2 inhibitor venetoclax (VEN) has emerged as an efficacious treatment for pts with AML. To the best of our knowledge, the outcomes of VEN based therapies specifically in CMML, with or without BT, have not been reported. Methods: We retrospectively reviewed pts with CMML, both with and without BT, treated with VEN-based therapy at our institution from 2016 to present. Mutation testing at baseline (N=31) and loss of response was performed using an amplicon-based next-generation sequencing panel. Pts were stratified according to CPSS-Mol and whether VEN was given for chronic vs. transformed disease. Responses for CMML and CMML-BT were defined by IWG 2006 and ELN 2017 criteria, respectively. Cox proportional hazard regression and the Kaplan-Meir product limit method were used to study association of variables with survival. Overall survival was defined as the time from start of VEN therapy to death or last follow up and was not censored at date of transplant. Results: Thirty-two pts were identified: 17 CMML, 15 CMML-BT. Pt characteristics are shown in Figure 1A. The median age was 70 years in both groups; most pts were men with a PS of 0-1. The majority of pts treated for CMML had proliferative subtype (53%) and CPSS-Mol intermediate-2/high (76%) risk disease at diagnosis. Both groups were enriched for diploid karyotype (53 and 60%). Frequency of mutations prior VEN-based therapy are shown in Figure 1B; TET2 (71%), ASXL1 (55%), RUNX1 (45%), and NRAS (39%) were the most common. Forty-one percent (CMML) and 67% (BT) of pts had received ≥2 previous lines of therapy, and most (88% CMML, 87% BT) received VEN following HMA failure. The median per-cycle dosing of VEN was 100 mg x 14 days (CMML) and 200 mg x 21 days (BT). VEN was given in combination with HMA in 76% of the CMML group, whereas in the BT group it was partnered with HMA (47%), intensive chemotherapy (20%), or other agents (33%). Almost all pts were concurrently on a triazole antifungal. Forty-seven percent of pts in both groups required admission to hospital for infection and/or fever while on VEN. After a median of 1 (range 1-6 CMML, 1-16 BT) cycle in both groups, ORR was 59% (CR 0%, mCR 53%, PR 6%) in the CMML and 67% (CR/CRi 53%, MLFS 7%, PR 7%) in the BT group. Five out of the 7 pts in the BT group with CR/CRi responses and evaluable MRD by flow cytometry (sensitivity 0.01%) were MRD negative. Presence of a RAS pathway mutation was associated with lower likelihood of achieving CR (17% vs 83%, OR 5.5, 95% CI 0.92-33.2, p Conclusions: Combination therapy with venetoclax has activity in both CMML and secondary AML arising out of CMML, even in the challenging setting of relapsed/refractory disease post HMA failure. It appears particularly useful as a means to clear excess marrow blasts and to serve as a bridge to allogeneic SCT. Without a subsequent consolidative strategy, however, response durations are short. RAS pathway mutations were associated with lower likelihood of CR and often emerge at relapse. NPM1 mutations predict for CR and RUNX1 mutations are associated with a trend to higher ORR. The high incidence of neutropenic infections in this cohort suggests that venetoclax dosing should be carefully tailored to minimize myelosuppression. Figure 1 Disclosures DiNardo: ImmuneOnc: Honoraria; Calithera: Research Funding; Novartis: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Takeda: Honoraria; Syros: Honoraria; Jazz: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding. Konopleva:Amgen: Consultancy; Calithera: Research Funding; Rafael Pharmaceutical: Research Funding; Sanofi: Research Funding; Agios: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Stemline Therapeutics: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Kisoji: Consultancy; Cellectis: Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Ablynx: Research Funding; Forty-Seven: Consultancy, Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; Eli Lilly: Research Funding. Borthakur:Treadwell Therapeutics: Consultancy; Polaris: Research Funding; Xbiotech USA: Research Funding; Nkarta Therapeutics: Consultancy; BioTherix: Consultancy; BioLine Rx: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding. Sasaki:Otsuka: Honoraria; Daiichi Sankyo: Consultancy; Novartis: Consultancy, Research Funding; Pfizer Japan: Consultancy. Jabbour:Genentech: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding. Pemmaraju:Blueprint Medicines: Honoraria; Roche Diagnostics: Honoraria; Incyte Corporation: Honoraria; Novartis: Honoraria, Research Funding; DAVA Oncology: Honoraria; Celgene: Honoraria; Samus Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Plexxikon: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Cellectis: Research Funding; MustangBio: Honoraria; Pacylex Pharmaceuticals: Consultancy; SagerStrong Foundation: Other: Grant Support; Affymetrix: Other: Grant Support, Research Funding. Kadia:Pulmotec: Research Funding; Astra Zeneca: Research Funding; Cellenkos: Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Ascentage: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Celgene: Research Funding; JAZZ: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Cyclacel: Research Funding; Incyte: Research Funding. Ravandi:AstraZeneca: Consultancy, Honoraria; Macrogenics: Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding. Daver:Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Janssen: Honoraria; Oxford Biomedical: Honoraria; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Delta Fly: Honoraria; BioAscend: Honoraria; Aptitute Health: Honoraria; Adaptive biotechnologies: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding. Garcia-Manero:Bristol-Myers Squibb: Consultancy, Research Funding; AbbVie: Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Venetoclax for CMML

Introduction: Hypomethylating agents (HMA) are effective therapies in chronic myelomonocytic leukemia (CMML), with an overall and complete (CR) response rates that range from 40-75% and 19-40% between studies, respectively. HMA therapy is associated with an overall survival (OS) of 12-24 months. However, the rate of HMA failure is 50% and is associated with a poor prognosis with an OS of 4-7 months. Defining predictors of HMA failure and optimal management of these patients (pts) is essential. Methods: We studied 157 pts with CMML treated with HMA between May 2010 and April 2020, whose bone marrow samples were analyzed by target next-generation sequencing. We performed chart review to obtain treatment responses and analyze correlations between clinical, cytogenetic and molecular characteristics and HMA failure. Primary objective was to determined risk factors associated with HMA failure. Secondary objectives include overall response rates (ORR) by 2015 IWG response criteria for MDS/MPN, overall survival (OS) and transformation-free survival (TFS) after HMA failure for CMML. Results: A total of 95 pts had HMA failure (61%), 59 pts (38%) with primary failure and 36 pts (23%) with secondary failure, with median time to HMA failure of 11 months (mo) (9 mo primary failure vs. 21 mo for secondary failure). Seventy-one pts (75%) were >65 years, and most pts were male (72%) with 16% having proliferative CMML (MP-CMML). Most patients had a normal karyotype (57%). Baseline characteristics are listed in Table 1. The most frequent mutations at diagnosis were TET2 (53%), SRSF2 (48%) and ASXL1 (46%). We analyzed the risk factors associated with HMA failure by logistic regression analysis. Univariate analysis (UVA) showed a significant association of ASXL1 mutation and HMA failure (Odds ratio OR 2.26, P value = 0.016). There was a tendency towards higher risk of failure in pts with MP-CMML (OR 1.57, p= 0.065) and SRSF2 mutation (OR 2.05, P=0.084) (Figure 1). The most common somatic mutations at HMA failure were ASXL1 (55%), SRSF2 (44%), TET2 (43%) and NRAS (32%) (Figure 2). Emergence of previously not detected mutations occurred in 59% of pts and included: NRAS (14%), ASXL1 (9%) and IDH1 (8%), with 18% of pts having cytogenetic evolution. IDH1 mutation was significantly associated with CMML blast transformation (Figure 2). The rate of CMML blast transformation after HMA failure was 14%. Of the 73 pts with CMML after HMA failure 45 received therapy and were eligible for response. Therapies included HMA single agent (47%), HMA combination therapy (ruxolitinib, rigosertib or ipilimumab) (24%), chemotherapy (13%) and other investigational therapies (16%). Pts with CMML blast transformation were included in AML protocols, with high-intensity chemotherapy (35%) or low-intensity therapies (65%). Among pts with CMML after HMA failure, the ORR was 16%, with 13% mCR and 2% HI and 13% progression to AML (Table 2). There was no difference in the ORR by therapy, or type of HMA failure with 16% with HMA single agent, 18% with HMA combination and 17% after chemotherapy, and ORR was 12% for primary failure and 21% for secondary failure. Of the 6 pts (13%) that underwent HSCT, no patient relapse and 1 pt died from infection 6 months after HSCT. A total of 40 pts died (55%), 12 pts from infections (30%), 4 pts progressive disease (10%), 3 pts due to other malignancies (8%) and 1 pt from bleeding (3%). With a median follow up of 20 months, the OS was 11 months for CMML and 5 mo for CMML blast transformation (p=0.002) (Figure 3 A). The OS after HMA failure was 23 mo for primary failure (23 mo for 1ry failure with lack of HI and 6 mo for 1ry failure with no response or progressive disease) and 6 mo for secondary failure (p= 0.120). Risk factors associated with worse OS by UVA included cytogenetic clonal evolution (Figure 3B), male gender, anemia, RUNX1 and TP53 mutations. Hematologic stem cell transplant was associated with improved OS (NR vs 6 months, HR 0.08, p=0.017). Conclusions: HMA failure occurs in 60% of pts with CMML and is associated with ASXL1 mutations. Emergence of mutations at progression are common (59%) and more frequently involve the RAS pathway, IDH1 and ASXL1 mutations. The rate of AML transformation in CMML with HMA therapy is 14%. HMA failure is associated with poor prognosis, with an OS of 11 months. Cytogenetic evolution, anemia, RUNX1 and TP53 mutations are associated with worse OS in pts whose disease experiences HMA failure. Disclosures Sasaki: Pfizer Japan: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Honoraria. Kadia:Genentech: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Novartis: Honoraria; Astellas: Research Funding; Pulmotec: Research Funding; Cellenkos: Research Funding; Celgene: Research Funding; Amgen: Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ascentage: Research Funding; Incyte: Research Funding; Astra Zeneca: Research Funding. DiNardo:Calithera: Research Funding; Novartis: Consultancy; ImmuneOnc: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Syros: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Takeda: Honoraria. Konopleva:AstraZeneca: Research Funding; Ablynx: Research Funding; Amgen: Consultancy; AbbVie: Consultancy, Research Funding; Ascentage: Research Funding; Sanofi: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Forty-Seven: Consultancy, Research Funding; Eli Lilly: Research Funding; Rafael Pharmaceutical: Research Funding; Cellectis: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Agios: Research Funding; Calithera: Research Funding; Genentech: Consultancy, Research Funding; Kisoji: Consultancy. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ravandi:Astellas: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Pemmaraju:Plexxikon: Research Funding; AbbVie: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Blueprint Medicines: Honoraria; Celgene: Honoraria; Samus Therapeutics: Research Funding; DAVA Oncology: Honoraria; MustangBio: Honoraria; SagerStrong Foundation: Other: Grant Support; Affymetrix: Other: Grant Support, Research Funding; Incyte Corporation: Honoraria; Novartis: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Roche Diagnostics: Honoraria. Short:Amgen: Honoraria; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding. Issa:Syndax: Research Funding; Celegene: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Kantarjian:Aptitute Health: Honoraria; Delta Fly: Honoraria; Ascentage: Research Funding; BioAscend: Honoraria; Janssen: Honoraria; BMS: Research Funding; Immunogen: Research Funding; Adaptive biotechnologies: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Oxford Biomedical: Honoraria. Garcia-Manero:H3 Biomedicine: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Onconova: Research Funding; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Merck: Research Funding; Amphivena Therapeutics: Research Funding.

INTRODUCTION: Chronic myelomonocytic leukemia (CMML) is a clonal hematologic disorder characterized by clinical and prognostic heterogeneity. Hypomethylating agents (HMA), either alone or in combination, are common therapeutic drugs used to treat CMML. Here we characterize 165 patients (pts) with CMML and describe their outcomes after being treated with frontline HMA-based therapy METHODS: We retrospectively reviewed the medical records of pts with CMML treated with frontline HMA-based therapy at the University of Texas MD Anderson Cancer Center (MDACC) from 2013 to 2020. We characterized the pts according to the French-American-British (FAB) classification and the CMML-specific prognostic system (CPSS). Response to therapy was defined by IWG response criteria. Overall Survival (OS) was measured from the time of starting therapy until death or until the last follow up. Survival was not censored by transplant. Kaplan-Meir method was used to evaluate survival. For the statistical analysis, IBM SPSS statistic software version 26 was used. RESULTS: A total of 165 pts were identified. Pt characteristics are shown in Table 1. Median age was 71 years [range: 39-89]. One-hundred twenty pts were male (73%). Most of the patients had myelodysplastic (MD) CMML subtype (55%), and 122 pts (74%) were in the Int-2/High risk CPSS category. Most of the pts were treated with HMA single agent (Aza N= 51, decitabine N= 51, and guadecitabine N=17, total N=119). The median number of cycles of therapy was 6 (range 1-74). Overall response rate (ORR) for the whole cohort was 61%, and 51 pts (31%) achieved a best response of complete remission (CR). The median number of cycles to best response was 3 for both, Aza and decitabine. Within pts treated with HMA single agent (SA) the ORR was 60%, and CR rate of 34% vs 65% and 22% for pts treated with HMA combination therapy. Among pts treated with HMA SA (Table 2) the ORR was 47% for Aza, 68% for decitabine, and 70% for guadecitabine. The CR rate for decitabine was 43%, versus 22% for azacitidine. Patients in the low/int-1 CPSS risk categories had a combined ORR of 60.5% vs 61.5% for pts in the int-2/high risk categories (p=0.999). The CR rate for low/int-1 group was 33% and 30% for the int-2/high risk group (p=0.848). ORR were among pts with MD-CMML was 64% vs 58% in pts with MP-CMML (p=0.522) with CR rates of 34% and 27% (p=0.398), respectively. The median OS for the whole population was 30.1 months. Patients in the low/int-1 risk group had a median OS of 50.2 months vs 25.5 months for the pts in the int-2/high risk group (Figure 1) (p=0.003). The OS of pts with MD-CMML was 30.1 months vs 25 months for pts with MP-CMML (Figure 2) (p=0.026). The progression free survival for the whole group was 26.3 months. The PFS for MD-CMML pts was 31.4 months and for the MP-CMML group was 19 months (p= 0.005) (Figure 3), for the low/int-1 risk pts was 88.6 months, and for the int-2/high risk pts was 21.5 (p=0.0006) (Figure 4). The median OS for pts treated with azacitidine was 39.9 months, and for pts treated with decitabine was 25.7 months (p=0.208) (Figure 5). Patients with MD-CMML treated with azacitidine had a median OS of 30.8 months vs 42.6 months for pts treated with decitabine (p=0.345). The median OS for pts with MP-CML treated with Aza was 28.4 months vs 18 months on pts treated with decitabine (p=0.358). CONCLUSION: The HMAs are effective in treating CMML regardless of FAB subtype or CPSS risk group. There is no statistically significant difference in CR or OS based on HMA agent. No difference in OS was observed between HMA SA versus HMA in combination, even in the int-2/high risk group. Disclosures Sasaki: Otsuka: Honoraria; Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Kadia:Abbvie: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Astra Zeneca: Research Funding; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Ascentage: Research Funding; JAZZ: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cyclacel: Research Funding; Pulmotec: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Astellas: Research Funding; Incyte: Research Funding; Cellenkos: Research Funding. DiNardo:Notable Labs: Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Jazz: Honoraria; Novartis: Consultancy; Syros: Honoraria; Takeda: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria. Konopleva:Ascentage: Research Funding; Ablynx: Research Funding; Agios: Research Funding; Calithera: Research Funding; Eli Lilly: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Cellectis: Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Kisoji: Consultancy; Stemline Therapeutics: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Sanofi: Research Funding; Amgen: Consultancy; Forty-Seven: Consultancy, Research Funding; AstraZeneca: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ravandi:Amgen: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Macrogenics: Research Funding; Xencor: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding. Pemmaraju:Plexxikon: Research Funding; SagerStrong Foundation: Other: Grant Support; Pacylex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Celgene: Honoraria; Roche Diagnostics: Honoraria; Blueprint Medicines: Honoraria; AbbVie: Honoraria, Research Funding; Affymetrix: Other: Grant Support, Research Funding; Samus Therapeutics: Research Funding; Novartis: Honoraria, Research Funding; Incyte Corporation: Honoraria; MustangBio: Honoraria; DAVA Oncology: Honoraria; Daiichi Sankyo: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; LFB Biotechnologies: Honoraria. Short:Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy. Kantarjian:Agios: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Cyclacel: Research Funding; Astex: Research Funding; BMS: Research Funding; Ariad: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Daiichi-Sankyo: Research Funding. Garcia-Manero:Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Amphivena Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; Jazz Pharmaceuticals: Consultancy; Acceleron Pharmaceuticals: Consultancy, Honoraria; Novartis: Research Funding; Merck: Research Funding.

FLT3 mutations, characterized by an internal-tandem duplication or missense mutations in the tyrosine kinase domain, are observed in a third of patients with newly diagnosed acute myeloid leukemia. FLT3-ITD mutations are associated with high relapse rates and short overall survival with conventional chemotherapy. Several tyrosine kinase inhibitors targeting FLT3 have been developed in an effort to improve survival and therapeutic options. This review focuses on quizartinib, a second-generation FLT3 inhibitor that has demonstrated efficacy and safety as a single agent and in combination with chemotherapy. We discuss its clinical development as well as its place in the treatment of FLT3-mutated acute myeloid leukemia among the other FLT3 inhibtors currently available and its mechanisms of resistance.

Patients with relapsed or refractory acute lymphoblastic leukemia (R/R ALL) have dismal outcomes, with survival of less than 6 months, and treatment options in the salvage setting have been limited to conventional cytotoxic chemotherapy with minimal activity. Advances in the development of novel targeted therapies have significantly improved outcomes in R/R ALL. Blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor (CAR) T-cell therapy constitute new treatment modalities that are challenging the historical regimens and paving a new path for treating patients with R/R ALL.

Simple Summary CD123 is overexpressed in multiple hematologic malignancies. Advances in CD123-targeted therapies over the past decade have positioned this molecule as an integral biomarker in current practice. This review provides an overview of CD123 biology and in-depth discussion of clinical laboratory techniques used to determine CD123 expression in various hematolymphoid neoplasms. In addition, we describe various pharmacologic strategies and agents that are available or under evaluation for targeting CD123. Abstract CD123, the α chain of the interleukin 3 receptor, is a cytokine receptor that is overexpressed in multiple hematolymphoid neoplasms, including acute myeloid leukemia, blastic plasmacytoid dendritic cell neoplasm, acute lymphoblastic leukemia, hairy cell leukemia, and systemic mastocytosis. Importantly, CD123 expression is upregulated in leukemic stem cells relative to non-neoplastic hematopoietic stem cells, which makes it a useful diagnostic and therapeutic biomarker in hematologic malignancies. Varying levels of evidence have shown that CD123-targeted therapy represents a promising therapeutic approach in several cancers. Tagraxofusp, an anti-CD123 antibody conjugated to a diphtheria toxin, has been approved for use in patients with blastic plasmacytoid dendritic cell neoplasm. Multiple clinical trials are investigating the use of various CD123-targeting agents, including chimeric antigen receptor-modified T cells (expressing CD123, monoclonal antibodies, combined CD3-CD123 dual-affinity retargeting antibody therapy, recombinant fusion proteins, and CD123-engager T cells. In this review, we provide an overview of laboratory techniques used to evaluate and monitor CD123 expression, describe the strengths and limitations of detecting this biomarker in guiding therapy decisions, and provide an overview of the pharmacologic principles and strategies used in CD123-targeted therapies.

Context Low-dose dasatinib was shown to be safe and effective in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). There are no randomized clinical trials to compare the outcome with the standard-dose dasatinib. Objective The aim of this study is to compare responses and outcome of patients with newly diagnosed CML-CP treated with frontline dasatinib 50 mg/day with those who received standard-dose dasatinib 100 mg/day. Design Propensity score analysis with 1:1 matching was performed with the nearest neighbor-matching method using calipers of width equal to 0.2. Setting MD Anderson Cancer Center. Patients or other participants We analyzed 233 patients with newly diagnosed CML-CP who were treated with low-dose dasatinib 50 mg/day (N=83) or standard-dose dasatinib 100 mg/day (N=150). Interventions Patients on low-dose dasatinib who had suboptimal response by European LeukemiaNet criteria had an option to increase the dose to 100 mg/day. Main outcome measures Responses criteria were previously defined. Failure-free survival (FFS) was calculated from the start date of therapy to the dates of treatment discontinuation for any reason except of treatment-free remission; event-free survival (EFS), to the date of any of the events while on study as defined in the IRIS study; transformation-free survival (TFS), to the date of transformation to advanced stage or death during study; overall survival (OS), to the date of death from any cause at any time or date of last follow-up. Results The overall median follow-up was 84 months: 24 months and 120 months for low-dose and standard-dose, respectively. Propensity score matching identified 77 patients in each cohort without significant baseline difference. The 12-month MMR rates were 82% and 76% for low-dose and standard-dose groups, respectively. The cumulative incidence of MR4, MR4.5, CMR rates within 1 year were higher in the low-dose dasatinib group compared with the standard-dose group (63% and 43%, 53% and 37%, and 24% and 11% for each). The 2-year FFS rates were 96% and 84%, respectively (P=0.011). The TFS, EFS, and OS rates were similar. Conclusions The low-dose dasatinib is at least as good as standard-dose dasatinib with better safety profile, resulting in better outcome.

Treatment of adult acute lymphoblastic leukemia (ALL) has largely relied on cytotoxic chemotherapy agents borrowed from successful treatment regimens of pediatric ALL. However, the high cure rates seen in pediatric ALL have not been replicated in adults. In recent years, the development of monoclonal antibodies targeting cell surface antigens, such as CD19 and CD20, have significantly improved outcomes when used alone or in combination with cytotoxic chemotherapy. With these novel agents come challenges in managing adverse events, understanding mechanisms of resistance and determining their optimal place in therapy alongside conventional chemotherapy and allogeneic stem cell transplant. Herein we discuss the above challenges with the next addition to the armamentarium of antileukemic agents, inotuzumab ozogamicin, an antibody–drug conjugate against CD22.

Background: Chimeric antigen receptor (CAR) T-cell therapy has been a major innovative breakthrough for hematologic malignancies with 2 currently FDA approved CAR T-cell products (tisagenlecleucel and axicabtagene ciloleucel) and several others in different stages of clinical investigation. However, these therapies are associated with unique safety profiles and potentially serious toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), that require vigilant monitoring and prompt recognition and management to ensure patient safety and optimal therapeutic benefit. We developed an online interactive decision support tool at www.clinicaloptions.com/carttool to give healthcare providers (HCPs) case-specific, evidence-based guidance from experts on the management of adverse events (AEs) due to CAR T-cell therapy. Here, we report a comparison of CAR T-cell toxicity management among HCPs using the tool vs the expert consensus recommendations in the tool. Methods: In March 2019, a panel of 5 experts provided consensus guidance for the screening, prophylaxis, monitoring, and management of CRS and ICANS in patients for which CAR T-cell therapy was either planned or started. This information was used to build the interactive online tool. To use the online tool, HCPs enter the AE that the patient is experiencing, either CRS or ICANS; the grade or severity of the event, per the American Society for Transplantation and Cellular Therapy consensus grading for CRS and ICANS (Lee DW, et al. Biol Blood Marrow Transplant. 2019;25:625-638); and their planned management approach. The HCPs were then shown the expert management recommendation for that specific AE scenario. After viewing the expert management recommendation, HCPs were asked if it impacted their intended management approach. Results: Between May and July 2019, 115 HCPs entered 166 unique case scenarios into the tool. The majority of cases (58%) entered were for patients who were planned for CAR T-cell therapy or who had started therapy without yet experiencing an AE, for which users received expert recommendations on pretreatment screening along with AE prophylaxis and monitoring. Of the 69 cases entered for patients who had received CAR T-cell therapy and were experiencing an AE, 71% were CRS and 29% were neurotoxicity/ICANS. The majority of CRS cases (67%) were intermediate grade (2/3) whereas the ICANS cases were evenly distributed across all grades (1-4). Overall the planned toxicity management strategy of HCPs matched the expert recommendations in 45% of cases, with the greatest discordance for CRS management, where the rate of agreement was 37% (Figure). The proportion of cases in which the planned management strategies of HCPs matched expert recommendations also varied by syndrome grade/severity between US and non-US HCPs. There was no concordance (0%) among US HCPs compared with non-US HCPs (60%) for grade 1 AEs, whereas greater concordance was found in the management of grade 2 and grade 3 AEs among US HCPs (67% and 57%, respectively) compared with non-US HCPs (43% and 44%, respectively; Figure). Of the 15 grade 1 AEs entered by users, only 5 came from US HCPs. Among the 48% of HCPs who answered the optional survey on the impact of the tool on their intended management plan, 48% indicated that the expert recommendations changed their approach, and 80% reported practicing at a treatment center authorized to administer CAR T-cell therapy. Conclusions: These data suggest that many HCPs are challenged to optimally manage toxicities related to CAR T-cell therapy and are not managing their patients in concordance with expert recommendations. Use of an online tool providing easy access to evidence-based consensus expert recommendations may improve patient care and safety in patients treated with CAR T-cell therapy. A detailed analysis of the tool, including case entries and planned management vs expert consensus recommendations for each toxicity and grade, will be presented. Figure. Planned Management of HCPs Compared With Expert Recommendations Figure Disclosures Frigault: Novartis: Patents & Royalties: Royalty; Arcellx, Celgene, Foundation Medicine, Kite/Gilead, Nkarta, Novartis, and Xenetic: Consultancy. DeAngelo:GlycoMimetics: Research Funding; Abbvie: Research Funding; Blue Print Medicines: Consultancy, Research Funding; Novartis: Consultancy, Patents & Royalties: Royalty, Research Funding; Celgene: Consultancy; Amgen: Consultancy; Shire: Consultancy; Jazz Pharmaceuticals Inc: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Takeda Pharmaceuticals: Consultancy. Galinsky:Pfizer Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Merus Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ABIM: Other: Member on specialty oncology board; AbbVie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Paul:Agios: Consultancy; Pfizer: Consultancy. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy.

Introduction: The addition of tyrosine kinase inhibitors to hyperfractionated cyclophosphamide, dexamethasone, vincristine, and doxorubicin alternating with high-dose methotrexate and cytarabine (HCVAD) for the treatment of Ph-positive ALL has significantly improved outcomes. However, with the increased median survival, an increased incidence of CNS relapses were documented over time, thus suggesting an increased risk among pts with Ph-positive disease (Ravandi et al, Cancer 2015).In order to reduce this incidence, treatment protocols for Ph-positive ALL were amended in 2012 to increase prophylactic IT chemotherapy from 8 to 12 at our institution. The aim of this study is to compare the incidence of CNS relapses in pts with Ph-positive ALL treated with 8 versus 12 ITs. Methods: We conducted a retrospective chart review of 156 pts with newly diagnosed Ph-positive ALL treated with Rituximab (R)± HCVAD plus imatinib (n=35), dasatinib (n=68), or ponatinib (n=53) between July 2001 and January 2019. Pts with CNS disease at initial diagnosis were excluded. Complete molecular response (CMR) at 3 months was defined as absence of a quantifiable BCR-ABL1 transcript. CNS relapse was identified by detection of blasts or rare atypical cells in the cerebrospinal fluid (CSF) in at least 2 successive evaluations and/or findings of leptomeningeal disease on imaging. Landmark analysis was performed at 6 months at the approximate time of completion of both systemic and IT therapy. Poor risk cytogenetic abnormality was defined as the presence of +der(22)t(9;22) and/or −9/9p in the absence of high hyperdiploidy (51‐65 chromosomes). CNS relapse-free survival (RFS) was defined from the start of therapy to the time of CNS relapse. Patients who died or relapsed in bone marrow were censored at the time of death and systemic relapse, respectively. Survival was assessed with and without the censoring of allogeneic stem cell transplantation (ASCT). Results: Pt characteristics are summarized in Figure A. One hundred and twelve pts (72%) received a median of 8 ITs (range, 2-8) and 44 pts (28%) received a median of 12 (range, 9-15). There were no statistically significant differences between groups in regards to baseline characteristics with the exception that more patients in the > 8 ITs cohort received ponatinib (66% vs 21%) and thus achieved a higher rate of 3-month CMR (70% vs 52%; p=0.04). CNS relapses were identified in 11 pts overall (7%, 4 treated with imatinib and 7 with dasatinib) and all of them received 8 or less prophylactic ITs (IT ≤8, 10% vs IT >8, 0%; p=0.023). The median follow-up of the entire population was 81 months, and 97 and 43 months for pts who received ≤8 and >8 ITs, respectively. The 3 and 6-year CNS RFS was 89% and 88% in pts with ≤8 ITs and 100% in pts with >8 Its, respectively (overall P=0.041; 3-yr CNS RFS P=0.049; 6-yr CNS RFS P=0.045) (Figure B). The outcomes remained statistically significant even after censoring for ASCT (P=0.048) (Figure C). In a multivariate analysis and after adjusting for the follow-up time, a median of 12 prophylactic IT chemotherapies was a prognostic factor significantly associated with a decrease rate of CNS relapses (P=0.03; HR=0.64 95%, CI: 0.43-0.96) (Figure D). Conclusion: In pts with newly diagnosed Ph-positive ALL, incorporation of 12 prophylactic IT chemotherapy in addition to systemic therapy is a very effective strategy to reduce the long-term incidence of CNS relapses. Figure Disclosures Paul: Pfizer: Consultancy; Agios: Consultancy. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Kadia:BMS: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; Celgene: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Garcia-Manero:Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Amphivena: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Ravandi:Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Kantarjian:BMS: Research Funding; Novartis: Research Funding; AbbVie: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding. Jabbour:AbbVie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding.