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Transplantation of umbilical cord blood (UCB) is an attractive alternative source of hematopoietic stem cells (HSCs). The unique properties of cord blood and its distinct immune tolerance and engraftment kinetics compared to bone marrow (BM) and peripheral blood progenitor cells, permit a wider disparity in human leukocyte antigen levels between a cord blood donor and recipient after an unrelated umbilical cord blood transplant (UCBT). In addition, it is readily available and has a lowered risk of graft-versus-host disease (GvHD), with similar long-term clinical outcomes, compared to BM transplants. However, the relatively low number of cells administered by UCB units, as well as the associated delayed engraftment and immune reconstitution, pose limitations to the wide application of UCBT. Research into several aspects of UCBT has been evaluated, including the ex vivo expansion of cord blood HSCs and the process of fucosylation to enhance engraftment. Additionally, UCB has also been used in the treatment of several neurodegenerative and cardiovascular disorders with varying degrees of success. In this article, we will discuss the biology, clinical indications, and benefits of UCBT in pediatric and adult populations. We will also discuss future directions for the use of cord blood.

Trogocytosis is an active process that transfers surface material from targeted to effector cells. Using multiple in vivo tumor models and clinical data, we report that chimeric antigen receptor (CAR) activation in natural killer (NK) cells promoted transfer of the CAR cognate antigen from tumor to NK cells, resulting in (1) lower tumor antigen density, thus impairing the ability of CAR-NK cells to engage with their target, and (2) induced self-recognition and continuous CAR-mediated engagement, resulting in fratricide of trogocytic antigen-expressing NK cells (NKsupTROG+/sup) and NK cell hyporesponsiveness. This phenomenon could be offset by a dual-CAR system incorporating both an activating CAR against the cognate tumor antigen and an NK self-recognizing inhibitory CAR that transferred a 'don't kill me' signal to NK cells upon engagement with their TROGsup+/supsiblings. This system prevented trogocytic antigen-mediated fratricide, while sparing activating CAR signaling against the tumor antigen, and resulted in enhanced CAR-NK cell activity.

Chimeric antigen receptor (CAR) T cells are a rapidly emerging form of cancer treatment, and have resulted in remarkable responses in refractory lymphoid malignancies. However, their widespread clinical use is limited by toxicity related to cytokine release syndrome and neurotoxicity, the logistic complexity of their manufacturing, cost and time-to-treatment for autologous CAR-T cells, and the risk of graft-versus-host disease (GvHD) associated with allogeneic CAR-T cells. Natural killer (NK) cells have emerged as a promising source of cells for CAR-based therapies due to their ready availability and safety profile. NK cells are part of the innate immune system, providing the first line of defence against pathogens and cancer cells. They produce cytokines and mediate cytotoxicity without the need for prior sensitisation and have the ability to interact with, and activate other immune cells. NK cells for immunotherapy can be generated from multiple sources, such as expanded autologous or allogeneic peripheral blood, umbilical cord blood, haematopoietic stem cells, induced pluripotent stem cells, as well as cell lines. Genetic engineering of NK cells to express a CAR has shown impressive preclinical results and is currently being explored in multiple clinical trials. In the present review, we discuss both the preclinical and clinical trial progress made in the field of CAR NK-cell therapy, and the strategies to overcome the challenges encountered.

The past decade has witnessed a revolution in the development of immune checkpoint inhibitors for the treatment of multiple tumor types, including genitourinary cancers. Immune checkpoint inhibitors have notably improved the treatment outcomes of patients with metastatic renal cell carcinoma and metastatic urothelial carcinoma. In prostate cancer, the role of immunotherapy with checkpoint inhibitors is not yet established except for microsatellite instability high (MSI-H) tumors. Other immunotherapeutic approaches that have been explored in these malignancies include cytokines, vaccines, and cellular therapy. Ongoing studies are exploring the use of immunotherapy combinations as well as combination with chemotherapy and targeted therapy in these types of tumors. The use of immunotherapy beyond the metastatic setting is an active area of research. Moreover, there is great interest in biomarker development to predict response to immunotherapy and risk of toxicity. This book chapter is a comprehensive review of immunotherapeutic approaches, both approved and investigational, for the treatment of renal cell carcinoma, urothelial carcinoma, and prostate cancer.

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: The combination of low-intensity therapy (mini-hyper-CVD) with inotuzumab ozogamicin with or without sequential blinatumomab is effective in patients with relapsed/refractory Philadelphia-chromosome negative acute lymphoblastic leukemia (ALL). The development of a prognostic model on the novel combination therapy may identify patients who requires additional or alternative therapies. Methods: Patients (pts) with relapsed/refractory Philadelphia chromosome-negative ALL who were treated with the combination of mini-hyper-CVD with inotuzumab ozogamicin plus/minus blinatumomab were analyzed. Briefly, the odd cycles of 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 anthracyclines. The 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. Inotuzumab ozogamicin 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. The protocol was amended to minimize the risk of veno-occlusive disease. Inotuzumab ozogamicin 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; blinatumomab was continuously infused over 28 days every 42-day cycle for 4 cycles. Backward multivariate Cox regression analysis was performed with a cutoff p value of 0.100 by univariate for variable selections from univariate to multivariate analysis. The optimal cutoffs were defined at the point with the most significant division by the log-rank test. CD22 expression was determined using multicolor flow cytometry analysis and reported as percentage of positive leukemic cells as a fraction of total gated events relative to internal control parameters. A new prognostic model was built based on identified prognostic factors by multivariate analysis. The developed prognostic model was planned to be validated with two independent dataset with salvage chemotherapy and inotuzumab single-agent. Results: We analyzed 96 pts enrolled on the clinical trial of mini-hyper-CVD + inotuzumab ozogamicin +/- sequential blinatumomab from February, 2013 to September, 2019 (Table 1). Overall, the median follow-up is 36 months (range, 0.1-87.5). The overall response rate was 80% with negative measurable residual disease rate of 83% overall (52% at response after induction therapy). Multivariate analysis showed the percentage of CD22 expression less than 70% (P Conclusion: The combination of low-intensity therapy with inotuzumab ozogamicin with or without sequential blinatumomab is highly effective. The presence of Ho-Tr, KMT2A rearrangement, or CD22 expression less than 70% confers poor outcome and identifies pts with poor-risk features who may be considered for alternative strategies such as CAR T-cells therapies and clinical trials. Disclosures Sasaki: Pfizer Japan: Consultancy; Otsuka: Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Kantarjian:Daiichi-Sankyo: Honoraria, Research Funding; Immunogen: Research Funding; Janssen: Honoraria; Oxford Biomedical: Honoraria; Abbvie: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Jazz: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ravandi:Celgene: Consultancy, Honoraria; Macrogenics: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria. Short:Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy. Kebriaei:Amgen: Other: Research Support; Jazz: Consultancy; Ziopharm: Other: Research Support; Pfizer: Other: Served on advisory board; Novartis: Other: Served on advisory board; Kite: Other: Served on advisory board. Jain:Verastem: 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; ADC Therapeutics: Research Funding; Pfizer: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: 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; Adaptive Biotechnologies: 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. Konopleva:Forty-Seven: Consultancy, Research Funding; AstraZeneca: Research Funding; Genentech: Consultancy, 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; Sanofi: Research Funding; Ablynx: Research Funding; Ascentage: Research Funding; Calithera: Research Funding; Amgen: Consultancy; Cellectis: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Kisoji: Consultancy; Eli Lilly: Research Funding; Agios: Research Funding; AbbVie: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding. Garcia-Manero:AbbVie: Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Amphivena Therapeutics: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; Novartis: Research Funding; Merck: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria. Champlin:Genzyme: Speakers Bureau; Actinium: Consultancy; Cytonus: Consultancy; Omeros: Consultancy; Takeda: Patents & Royalties; Johnson and Johnson: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees. Kadia:Astellas: Research Funding; Novartis: Honoraria; Cyclacel: Research Funding; Astra Zeneca: Research Funding; Incyte: Research Funding; Amgen: Research Funding; Ascentage: Research Funding; JAZZ: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cellenkos: Research Funding; Celgene: Research Funding; Pfizer: Honoraria, Research Funding; Pulmotec: Research Funding; Abbvie: Honoraria, Research Funding; Genentech: Honoraria, Research Funding. Rafei:United States Provisiona: Patents & Royalties: I have a filed patent. O'Brien:Sunesis: Research Funding; Gilead: Consultancy; Pharmacyclics: Research Funding; TG Therapeutics: Research Funding; Pfizer: Research Funding; Astellas: Consultancy; Amgen: Consultancy; Janssen Oncology: Consultancy; Vaniam Group LL: Consultancy; AbbVie: Consultancy; Verastem: Consultancy; Acerta: Research Funding; Regeneron: Research Funding; Vida Ventures: Consultancy; KITE: Research Funding; Celgene: Consultancy; Eisai: Consultancy; Juno Therapeutics: Consultancy; GlaxoSmithKline: Consultancy; Aptose Biosciences: Consultancy; Alexion: Consultancy. Jabbour:Adaptive Biotechnologies: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding.

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: The outcome of patients with relapsed-refractory (R-R) acute lymphoblastic leukemia (ALL) is poor. Inotuzumab ozogamicin and blinatumomab are highly active single agents in R-R ALL. The combination of inotuzumab with low-intensity mini-hyper-CVD chemotherapy showed encouraging results in this patient population. The sequential addition of blinatumomab might optimize the efficacy of the regimen, reduce its toxicities, and further improve outcomes in R-R ALL. The aim of the analysis is to evaluate the efficacy and safety of inotuzumab ozogamicin plus low-intensity chemotherapy with or without blinatumomab in R-R ALL. Methods: Patients with relapsed-refractory Philadelphia chromosome-negative ALL were eligible. The mini-hyper-CVD (cycles 1, 3, 5, 7) were comprised of 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 anthracyclines. Even cycles (cycles 2, 4, 6, 8) were comprised of 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 the first 4 courses. Inotuzumab ozogamicin 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 67 pts were treated, an amendment was made to incorporate 4 cycles of blinatumomab after 4 cycles of mini-hyper-CVD + inotuzumab ozogamicin. Inotuzumab ozogamicin 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; blinatumomab was continuously infused over 28 days every 42-day cycle for 4 cycles. The decision to proceed with allogeneic hematopoietic cell transplantation (HCT) was based on the discretion of the treating physician after discussion with the patient. Results: From 2/2013 to 9/2019, 96 patients were enrolled and treated including 29 patients with mini-hyper-CVD + inotuzumab + blinatumomab. The median follow-up is 36 months (range, 0.1-87.5). Patient characteristics and outcome are summarized in Table 1. The median age was 37 years (range, 17-87), and 20% of patients had received prior HCT. The overall response rate was 80% (CR, 57%, CRp/CRi, 20%). These rates were 91% in salvage(S) 1 (primary refractory, 100%; CR1 duration 12 months, 94%) 61% inS2, and 57% in S3 or higher. Among 75 evaluable patients for minimal residual disease (MRD) assessment, 62 patients (83%) achieved negative MRD by multi-color flow cytometry with higher rates of MRD negativity in S1 (89%). Forty four patients (46%) received HCT. Three-year CR duration and overall survival (OS) rates were 32% and 33%, respectively (Figure 1). The 3-year OS rates for patients treated in S 1 and S 2+ were 42% and 13%, respectively (p=0.002). Historical comparison showed median OS of 13 months versus 6 months in hyper-CVD + inotuzumab ozogamicin +/- blinatumomab versus inotuzumab ozogamicin single agent, respectively (p Conclusion: The long-term follow-up of the combination of inotuzumab ozogamicin plus/minus blinatumomab with low-intensity mini-hyper-CVD chemotherapy continues to show promising results in patients with relapsed/refractory ALL. The risk of VOD can be minimized with a fractionated inotuzumab ozogamicin followed by blinatumomab schedule. Disclosures Sasaki: Novartis: Consultancy, Research Funding; Otsuka: Honoraria; Pfizer Japan: Consultancy; Daiichi Sankyo: Consultancy. Kantarjian:Aptitute Health: Honoraria; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Oxford Biomedical: Honoraria; Novartis: Honoraria, Research Funding; BMS: Research Funding; Delta Fly: Honoraria; Janssen: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Ascentage: Research Funding; Jazz: Research Funding; BioAscend: Honoraria; Abbvie: Honoraria, Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding. Ravandi:Macrogenics: Research Funding; Celgene: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria. Short:Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy. Kebriaei:Jazz: Consultancy; Amgen: Other: Research Support; Ziopharm: Other: Research Support; Pfizer: Other: Served on advisory board; Kite: Other: Served on advisory board; Novartis: Other: Served on advisory board. Jain:TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; ADC Therapeutics: Research Funding; Genentech: 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; BMS: Research Funding; Incyte: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: 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; Pharmacyclics: 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; 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. Konopleva:Ascentage: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Kisoji: Consultancy; Forty-Seven: Consultancy, Research Funding; Agios: Research Funding; Eli Lilly: Research Funding; Rafael Pharmaceutical: Research Funding; Calithera: Research Funding; Ablynx: Research Funding; AstraZeneca: Research Funding; Sanofi: Research Funding; Cellectis: 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; Amgen: Consultancy; Genentech: Consultancy, Research Funding. Garcia-Manero:Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Novartis: Research Funding; Amphivena Therapeutics: Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Champlin:Takeda: Patents & Royalties; Omeros: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy; Johnson and Johnson: Consultancy; Actinium: Consultancy; Genzyme: Speakers Bureau. Kadia:Genentech: Honoraria, Research Funding; Astellas: Research Funding; Cyclacel: Research Funding; Cellenkos: Research Funding; Astra Zeneca: Research Funding; JAZZ: Honoraria, Research Funding; Celgene: Research Funding; Pulmotec: Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding; BMS: Honoraria, Research Funding; Incyte: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Ascentage: Research Funding. Daver:Fate Therapeutics: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Research Funding; Pfizer: 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; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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; 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; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rafei:United States Provisiona: Patents & Royalties: I have a filed patent. O'Brien:Pharmacyclics: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Vida Ventures: Consultancy; Pfizer: Research Funding; Celgene: Consultancy; Eisai: Consultancy; KITE: Research Funding; Regeneron: Research Funding; Amgen: Consultancy; Vaniam Group LL: Consultancy; AbbVie: Consultancy; Verastem: Consultancy; Janssen Oncology: Consultancy; Gilead: Consultancy; Sunesis: Research Funding; Alexion: Consultancy; Aptose Biosciences: Consultancy; Juno Therapeutics: Consultancy; GlaxoSmithKline: Consultancy; Astellas: Consultancy. Jabbour:Takeda: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding.

The past decade has witnessed tremendous progress in the treatment of acute lymphoblastic leukaemia (ALL), primarily due to the development of targeted therapies, including tyrosine kinase inhibitors targeting BCR-ABL1 tyrosine kinase, monoclonal antibodies targeting cell surface antigens (CD19, CD20 and CD22), bispecific antibodies and chimeric antigen receptor T- cell therapy. A number of new therapies have been approved by the US Food and Drug Administration in the past 5 years, including blinatumomab in 2014, inotuzumab ozagamicin in 2017 and tisagenlecleucel in 2017 for relapsed/refractory ALL. This has led to tremendous improvement in long-term survival, of more than 50% in patients with precursor B-ALL [50-70% in patients with Philadelphia chromosome (Ph)-positive ALL)], 50-60% in T-ALL and 80% in mature B-ALL. Research is ongoing to optimize the benefit of targeted therapeutics with the goal of decreasing the use of cytotoxic therapies.

BCR-ABL1 tyrosine kinase inhibitors (TKIs) alone and with chemotherapy led to a dramatic increase in survival of chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemi...

Multiple myeloma (MM) is a B-cell malignancy characterized by the abnormal proliferation of clonal plasma cells in the bone marrow leading to end-organ manifestations. Despite the advancement in the therapy and care of patients with MM, relapse and resistance to standard therapy remain significant. The development of immunotherapy as a treatment modality for many types of cancers has led investigators to explore its use in MM in order to elicit myeloma-targeted immune responses, especially given that immune dysregulation is an underlying feature in the pathogenesis and progression of MM. In this concise review, we discuss the different advances in the immune-based therapy of MM, from immunomodulation, vaccines, to monoclonal antibodies, checkpoint inhibitors, adoptive T-cell therapies, and future promising therapies under investigation.

PURPOSE BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication of allogenic hematopoietic stem cell transplantation (AHSCT), particularly in recipients of alternative donor transplants, which are being performed in increasing numbers. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, without a definitive therapeutic option. METHODS We performed a clinical trial (ClinicalTrials.gov identifier: NCT02479698 ) to assess the feasibility, safety, and efficacy of administering most closely HLA-matched third-party BKV-specific cytotoxic T lymphocytes (CTLs), generated from 26 healthy donors and banked for off-the-shelf use. The cells were infused into 59 patients who developed BKV-HC following AHSCT. Comprehensive clinical assessments and correlative studies were performed. RESULTS Response to BKV-CTL infusion was rapid; the day 14 overall response rate was 67.7% (40 of 59 evaluable patients), which increased to 81.6% among evaluable patients at day 45 (40 of 49 evaluable patients). No patient lost a previously achieved response. There were no cases of de novo grade 3 or 4 graft-versus-host disease, graft failure, or infusion-related toxicities. BKV-CTLs were identified in patient blood samples up to 3 months postinfusion and their in vivo expansion predicted for clinical response. A matched-pair analysis revealed that, compared with standard of care, after accounting for prognostic covariate effects, treatment with BKV-CTLs resulted in higher probabilities of response at all follow-up timepoints as well as significantly lower transfusion requirement. CONCLUSION Off-the-shelf BKV-CTLs are a safe and effective therapy for the management of patients with BKV-HC after AHSCT.

In relapsed/refractory acute myeloid leukemia (AML), the prognostic impact of complete remission (CR) and measurable residual disease (MRD) negativity is not well established. We retrospectively analyzed 141 patients with relapsed/refractory AML who received first salvage therapy and had MRD assessed by multiparameter flow cytometry at the time of response. Patients who achieved CR with full hematologic recovery as best response vs those with incomplete hematology recovery had lower cumulative incidence of relapse (P = .01) and better relapse-free survival (P = .004) but not overall survival (P = .15); a similar trend was observed in patients who achieved MRD negativity vs those who were MRD positive (P = .01, P = .05, and P = .21, respectively). By multivariate analysis, CR and MRD negativity were each independently associated with lower cumulative incidence of relapse (P = .001 and P = .003, respectively) and better relapse-free survival (P < .001 and P = .02) but not overall survival. Patients who achieved CR with MRD negativity had the lowest rates of relapse and best survival (2-year overall survival rate, 37%), which was driven largely by lower rates of early relapse and an increased ability in this group to undergo hematopoietic stem cell transplantation (HSCT); however, post-HSCT outcomes were similar regardless of response to salvage chemotherapy. Overall, in patients with relapsed/refractory AML, CR with MRD negativity was associated with the best outcomes, supporting it as the optimal response in this setting.

The past decade has witnessed a revolution of immune checkpoint inhibitors in the treatment of multiple tumor types, including genitourinary cancers. Immune checkpoint inhibitors improved the treatment outcomes of patients with metastatic renal cell carcinoma and metastatic urothelial carcinoma. In prostate cancer, the role of immunotherapy with checkpoint inhibitors is not yet established, but clinical trials investigating their use are ongoing. Other immunotherapeutic approaches that have been explored in these malignancies include cytokines, vaccines, and cellular therapy. Ongoing studies are exploring the use of immunotherapy combinations as well as combination with chemotherapy and targeted therapy in these types of tumors. The use of immunotherapy beyond the metastatic setting is an active area of research. Moreover, there is a great interest in biomarker development to predict response to immunotherapy and risk of toxicity. This chapter is a comprehensive review of the immunotherapeutic approaches, both approved and investigational, for the treatment of renal cell carcinoma, urothelial carcinoma, and prostate cancer.

The past decade has witnessed a revolution of immune checkpoint inhibitors in the treatment of multiple tumor types, including genitourinary cancers. Immune checkpoint inhibitors improved the treatment outcomes of patients with metastatic renal cell carcinoma and metastatic urothelial carcinoma. In prostate cancer, the role of immunotherapy with checkpoint inhibitors is not yet established, but clinical trials investigating their use are ongoing. Other immunotherapeutic approaches that have been explored in these malignancies include cytokines, vaccines, and cellular therapy. Ongoing studies are exploring the use of immunotherapy combinations as well as combination with chemotherapy and targeted therapy in these types of tumors. The use of immunotherapy beyond the metastatic setting is an active area of research. Moreover, there is a great interest in biomarker development to predict response to immunotherapy and risk of toxicity. This chapter is a comprehensive review of the immunotherapeutic approaches, both approved and investigational, for the treatment of renal cell carcinoma, urothelial carcinoma, and prostate cancer.

Allogeneic hematopoietic stem cell transplantation (HSCT) reverses the bone marrow failure syndrome due to GATA2 deficiency. The intensity of conditioning required to achieve reliable engraftment and prevent relapse remains unclear. Here, we describe the results of a prospective study of HSCT in 22 patients with GATA2 deficiency using a busulfan-based conditioning regimen. The study included 2 matched related donor (MRD) recipients, 13 matched unrelated donor (URD) recipients, and 7 haploidentical related donor (HRD) recipients. MRD and URD recipients received 4 days of busulfan and 4 days of fludarabine. HRD recipients received low-dose cyclophosphamide for 2 days, fludarabine for 5 days, 2 to 3 days of busulfan depending on cytogenetics, and 200 cGy total body irradiation. MRD and URD recipients received tacrolimus and short-course methotrexate for graft-versus-host disease (GVHD) prophylaxis. HRD recipients received high-dose post-transplant cyclophosphamide (PTCy) followed by tacrolimus and mycophenolate mofetil. At a median follow-up of 24 months (range, 9 to 50), 19 of 22 patients were alive with reversal of the disease phenotype and correction of the myelodysplastic syndrome, including eradication of cytogenetic abnormalities. Three patients died: 1 from refractory acute myelogenous leukemia, 1 from GVHD, and 1 from sepsis. There was a 26% incidence of grades III to IV acute GVHD in the MRD and URD groups and no grades III to IV acute GVHD in the HRD cohort. Similarly, there was a 46% incidence of chronic GVHD in the MRD and URD cohorts, whereas only 28% of HRD recipients developed chronic GVHD. Despite excellent overall disease-free survival (86%), GVHD remains a limitation using standard prophylaxis for GVHD. We are currently extending the use of PTCy to the MRD and URD cohorts to reduce GVHD.

More effective therapies are emerging, with better toxicity profiles, and are being incorporated into modern treatment algorithms of chronic lymphocytic leukemia at various stages of the disease, including for patients harboring Del17p and/or aberrant TP53. Ibrutinib, an inhibitor of Bruton’s tyrosine kinase, has demonstrated impressive response rates in the relapsed/refractory setting, including in the setting of Del17p and/or TP53 mutations. Venetoclax, an inhibitor of BCL-2 known to play an important role in regulating cell death, has been approved recently for treatment of patients with chronic lymphocytic leukemia with Del17p who have received at least one prior therapy. Unfortunately, a cure remains unattainable unless eligible patients are offered an allogeneic hematopoietic cell transplant. However, hematopoietic cell allografting is limited by the availability of suitable donors and significant morbidity and mortality. Recent clinical practice recommendations by the American Society for Blood and Marrow Transplantation have relegated the role of transplantation to later stages of the disease. In patients with evidence of Richter syndrome, frontline consolidation allogeneic hematopoietic cell transplantation remains the most desirable approach owing to the limited activity of ibrutinib or other novel therapies. Further therapeutic advances would require enrolling these patients in large clinical trials that evaluate novel therapies alone or in combination with traditional chemotherapies or even in the setting of posttransplant consolidation/maintenance. Keywords: Allogeneic hematopoietic cell transplantation, CLL, Ibrutinib, Idelalisib, Venetoclax

Dasatinib is a small-molecule tyrosine kinase inhibitor used in the treatment of hematological malignancies. Pulmonary arterial hypertension (PAH) is a rare but known complication. The mainstay of treatment is cessation of Dasatinib, and while clinical improvement is rapid, complete hemodynamic resolution of pulmonary hypertension (PH) still remains exceedingly uncommon. We present a case of Dasatinib-induced PAH in a woman with chronic myeloid leukemia, who demonstrated rapid and complete clinical and hemodynamic resolution following treatment with combination pulmonary vasodilator therapy using an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor. This case suggests there may be an association between the use of targeted PH medication in combination and the complete resolution of dasatinib-associated PAH, but further investigation is required.

Acute graft versus host disease (aGVHD) remains the second leading cause of death following allogeneic hematopoietic stem cell transplant (AHSCT). Over the last five years, the progress in understanding the pathophysiology of this immune based-process helped redefine graft versus host reaction and opened new possibilities for novel preventive and therapeutic approaches. The evolution in the field of immunology widened the horizons for hematopoietic stem cell transplant leading to the availability of different stem cell sources for potential graft and incorporation of novel conditioning regimens. There is conflicting data about the impact of the graft source and the conditioning regimen used in the process of AHSCT on the incidence of aGVHD. Many studies have reported increased risk of chronic GVHD (cGVHD) and to a less extent aGVHD with the use of peripheral blood stem cell and bone marrow compared to umbilical cord stem cell. The conditioning regimen, either myeloablative, non-myeloablative or reduced intensity may have different impact on the incidence of GVHD. Several preventive modalities have been adopted by different transplant centers but, to date, there is no standardized regimen. As for treatment, immunosuppression using steroids remains the first line of intervention. Several novel therapeutic options are being investigated for treatment of steroid-refractory aGVHD including the use of mesenchymal stem cells, anti thymocyte globulin and extra corporeal photophoresis. This review discusses the pathophysiology, risk factors, clinical features, and advances in the diagnosis, prevention and treatment of aGVHD.

Context There are concerns that the use of immune checkpoint inhibitors (ICIs) after allogeneic stem cell transplant (allo-SCT) may increase the incidence of acute graft-versus-host disease (aGVHD). Objective We report our experience with ICIs used after allo-SCT in AML/MDS patients with a focus on the impact of post-transplant cyclophosphamide (PTCy). Methods We retrospectively analyzed 16 AML and 5 MDS patients who received nivolumab (n=16) or ipilimumab (n=5) for disease relapse after allo-SCT at our institution. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results Median age 54 years; 12 patients (57%) received PTCy. Transplantation characteristics were comparable between the two groups (PTCy vs no-PTCy), except for lower hematopoietic stem cell comorbidity index noted in the PTCy group (91% vs. 37.5%, P=.04). The PTCy group had shorter median time from allo-SCT to ICI initiation (5 vs. 26 months, P=.04). Over a median follow-up of 5.3 months, the frequency of grade 2–4 aGVHD was 19% in the entire cohort and was lower in PTCy group (16% vs 22%, P=0.7). All aGVHD cases were noted following nivolumab initiation. In patients who developed aGVHD, the median time from allo-SCT to ICI initiation was 4 months in PTCy group vs 9 months in the non-PTCy group (P=.17). Median time from ICI initiation to aGVHD was 24 days (range, 12–31) in the entire cohort and 22 days in PTCy group vs 16 days in non-PTCy (P=.31). After controlling for comorbidities and time from transplant to ICI initiation, we found that PTCy was significantly associated with a 90% reduced risk of aGVHD (HR= 0.1; 95% CI: 0.02–0.6; P=.01). No chronic GVHD or grade ≥2 immune-related adverse events were reported. The PTCy group had a significantly longer median PFS (22.4 vs. 5.2 months, P=.02) and a trend toward longer median OS (22.4 vs. 5.2 months, P=.08). Fourteen patients (67%) died, and no deaths were attributed to aGVHD. Conclusions The use of ICI for AML/MDS relapse after allo-SCT may be a safe and feasible option. PTCy appears to decrease the incidence of aGVHD in this cohort of patients.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) offers cure for a variety of conditions, in particular, but not limited to, hematologic malignancies. However, it can be associated with life-threatening complications, including graft-versus-host disease (GVHD) and infections, which are factors limiting its widespread use. Technical advances in the field of microbiome research have allowed for a better understanding of the microbial flora of the human intestine, as well as dissection of their interactions with the host immune system in allo-SCT and posttransplant complications. There is growing evidence that the commensal microbiome is frequently dysregulated following allo-SCT and that this dysbiosis can predispose to adverse clinical outcomes, especially including acute intestinal GVHD and reduced overall survival. In this review, we discuss the interactions between the microbiome and the components of the immune system that play a major role in the pathways leading to the inflammatory state of acute intestinal GVHD. We also discuss the microbiome-centered strategies that have been devised or are actively being investigated to improve the outcomes of allo-SCT patients in regard to acute intestinal GVHD.

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease with a bimodal distribution. The progresses made in understanding its biology led to the development of targeted therapies. In this review, we summarize the current and future approaches in management of adult ALL. Tyrosine kinase inhibitors (TKI) targeting BCR-ABL1 tyrosine kinase, monoclonal antibodies targeting cell surface antigens (CD19, CD20, and CD22), bispecific antibodies, and chimeric antigen receptor (CAR)-T therapy are breakthrough treatments. They resulted in FDA approvals of blinatumomab in 2014, inotuzumab ozagamicin in 2017, and tisagenlecleucel in 2017 for relapsed/refractory ALL. Currently, long-term survival is achieved in more than 50% of patients with precursor B-ALL (50-70% in patients with Philadelphia chromosome (Ph)-positive ALL), 50-60% T-ALL, and 80% mature B-ALL. Ongoing efforts exist to optimize therapeutic options in both the relapsed/refractory as well as the frontline settings. In the era of precision medicine, the future lies in using less cytotoxic and more targeted agents.

Myelodysplastic syndromes and acute myeloid leukemia are sporadic for the majority of cases affecting the elderly population. Inherited cases, however, do occur. Genetic predispositions to myeloid malignancies can be classified into three categories: familial cancer syndromes associated with increased risk of various malignancies including myelodysplasia and acute myeloid leukemia such as Li-Fraumeni syndrome and constitutional mismatch repair deficiency (CMMRD); germline mutations conferring a specific increased risk of myelodysplastic syndrome and acute myeloid leukemia such as mutations in ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72 genes; and finally primarily pediatric inherited bone marrow failure syndromes such as Fanconi anemia, dyskeratosis congenita, severe congenital neutropenia, Shwachman-Diamond syndrome and Diamond Blackfan anemia. The recognition of these germline syndromes is essential in the management and follow-up of patients. Herein, we review the conditions associated with hereditary myeloid leukemia with a special clinical focus on management and monitoring.

Background Proper approach to symptom control in cancer patients requires a good understanding of the prevalence of the various symptoms these patients have. Aim This study aims at assessing the Lebanese oncologists’ point of view concerning the symptom burden among cancer patients of Lebanon and comparing their opinions to the real complaints of patients themselves. Methods A cross-sectional study was conducted among a representative sample of the Lebanese medical oncologists. Thirty-six physicians filled out a questionnaire regarding their demographics as well as the symptom profile of their patients. Those results were compared to the ones obtained from our previous study about symptom profile as reported by patients. Results Fatigue was the symptom most our patients suffered from according to their physicians (64.167%). Also, a good percentage of physicians agreed that patients suffer from appetite loss, pain, weight loss, and nausea. When compared to the patients’ reports of their own symptoms, a statistically significant difference existed between the two profiles for the majority of symptoms (14 out of 19). Also, for the majority of symptoms, physicians were found to underestimate the percentage of patients suffering from each symptom. Conclusion This study shows that there is a statistically significant difference between the physicians’ and the patients’ perspectives on most of the common distressing symptoms. This entails more detailed questioning of the cancer patients about their distressing symptoms.

Beer potomania is a syndrome of hyponatremia associated with excessive beer drinking. Little or no salt content of beer results in marked reduction in the solute load to the kidney. This leads to impaired water clearance and dilutional hyponatremia. A 66-year-old man with history of alcoholism and alcoholic cardiomyopathy presented to the emergency room with tremors of his upper and lower extremities. He had a significant history of alcohol consumption, usually drinking 4 - 5 cans of beer per night for the past 34 years. In addition, he had consumed a fifth of a vodka bottle the day before presentation. He had a pattern of often skipping meals though was compliant with both his diuretics medications: furosemide 40 mg once daily and spironolactone 25 mg daily. On physical exam, he was euvolemic. Neurological exam revealed resting tremors of both his hands. Labs were remarkable for plasma sodium of 122, brain natriuretic peptide of 474, serum osmolality of 268, urine osmolality of 223, and urine sodium of 20. Patient was assessed to have moderate euvolemic hypotonic hyponatremia. The combination of euvolemic hyponatremia with history of excessive beer drinking made beer potomania very likely. His urine osmolality and urine sodium, however, were higher than expected in beer potomania. These could be explained by the two diuretics that the patient was taking. Patient was managed with fluid restriction, appropriate nutritional and sodium intake and withholding of his diuretics. Plasma sodium slowly corrected to 130 over the course of 3 days. This case illustrates the condition beer potomania, an infrequent cause of hyponatremia. Findings in hyponatremia do not always point in one direction, especially with the concomitant use of diuretics. Recognition of beer potomania is critical as it is associated with serious neurologic sequelae that should be part of counseling against alcohol abuse. J Endocrinol Metab. 2016;6(4):123-126 doi: http://dx.doi.org/10.14740/jem350e

Background Post-transplant lymphoproliferative disorders (PTLD) are a potentially fatal group of neoplasms arising in an immunodeficient environment. Although the cornerstone of treatment is reduced immunosuppression (RI), advanced cases often warrant treatment with chemoimmunotherapy. The chemoimmunotherapy regimen of dose-adjusted (DA)-EPOCH-R is superior to R-CHOP in HIV associated aggressive lymphomas, suggesting that it might also be favorable in the setting of PTLD. Methods We performed a retrospective analysis of patients with advanced monomorphic PTLD treated with first line DA-EPOCH-R in addition to RI at our institution from 2003-2016. Results Seven patients were included. Mean age was 51 and mean time from transplant to diagnosis was 71 months. Six of the seven patients received a kidney transplant, six had stage III or IV disease, six had tumors that were EBV positive, and six completed therapy. All six patients who completed therapy achieved a complete response. Mean PFS and OS were 46.6 and 52.6 months, respectively. Treatment was well-tolerated with no significant treatment related morbidity or mortality. Conclusions Our findings support several observations in the literature that DA-EPOCH-R is efficacious and well-tolerated for the treatment of advanced, monomorphic PTLD.

The V600 BRAF mutation has been described as a key mutation in the pathogenesis of classical hairy cell leukemia (c-HCL) cases without expression of a mutant immunoglobulin heavy chain (IgHV). Here we present a rare case of c-HCL with neither V600 BRAF mutation nor the aforementioned IgHV variant successfully treated with cladribine and review the current literature on its use in women of childbearing age/pregnancy., Highlights • This is a rare case of BRAF V600 mutation negative c-HCL with wild-type IgHV. • Unlike mutant BRAF HCL, The prognosis of wild-type BRAF in c-HCL is unknown. • In our experience, initial response to cladribine is similar to V600 BRAF c-HCL.

Background: Allogeneic hematopoietic stem cell transplantation (alloHCT) remains a curative approach for patients with AML/MDS. Still, up to 50 % of patients relapse after alloHCT. Immune checkpoint inhibitors (ICI) are being used in the post-transplant setting to reverse the immune dysfunction that contributes to AML/MDS relapse. However, a major concern with using ICI post alloHCT is the increased risk of graft versus host disease (GVHD). A variety of pre- and post- transplant factors can play a crucial role in exacerbating GVHD. We performed a retrospective analysis to report our experience with ICIs used after alloHCT in AML/MDS patients with a focus on the impact of post-transplant cyclophosphamide (PTCy). Methods: In this study, we included 16 AML and 5 MDS patients treated with single-agent anti-PD-1 (nivolumab, n=16) or anti-CTLA-4 (ipilimumab, n=5) for disease relapse after alloHCT at our institution. The primary outcome was acute GVHD (aGVHD) following ICI initiation post alloHCT. Secondary outcomes were progression-free survival (PFS) and overall survival (OS) that were estimated using the Kaplan-Meier method. Results: Median patient age was 54 years (range, 29-77 years). Patients received a median of 2 doses of ICI therapy (range, 1 to 12). The median time from alloHCT to ICI initiation was 9.1 months (range 1.3-134.4 months). All patients had received myeloablative conditioning regimens. Donors were matched related in 9 (43%), matched unrelated in 9 (43%), and haploidentical in 3 (14%). Stem cell source was peripheral blood stem cells in 14 (67%) and bone marrow in 7 patients (33%). Twelve patients (57%) received PTCy as GVHD prophylaxis (PTCy group). Transplantation characteristics were comparable between the two groups (PTCy vs no-PTCy), except for lower median score of hematopoietic stem cell comorbidity index in PTCy group (median score of 1 (range,0-3) vs. median score of 3 (range,1-5), P=.04), and a shorter median time from alloHCT to ICI initiation (5 vs. 26 months, P=.04) noted in PTCy group. Before initiation of ICI, 5 patients (24 %) had previously had GVHD. In the entire cohort, 4 patients (19 %) developed aGVHD following ICI initiation. All the 4 cases of aGVHD were reported following nivolumab initiation. Over a median follow up of 5.3 months, the frequency of grade 2-4 aGVHD was 19%. The frequency of grade 1 to 2 and grade 3 to 4 aGVHD were 9.5% and 9.5%, respectively, with a median time from initiation of nivolumab to onset of aGVHD of 24 days (range, 12-31 days), and a median time from alloHCT to nivolumab-related aGVHD of 188 days (range,109-419 days). The median number of nivolumab doses to aGVHD was 2 doses (range, 1-8 doses). No chronic GVHD or grade > 2 immune-related adverse events were reported. The frequency of grade 2-4 aGVHD was not influenced by stem cell source, donor type, age at transplant, and previous history of GVHD, but was affected by post-transplant GVHD prophylaxis. Specifically, patients receiving PTCy had a lower observed cumulative incidence of grade 2 to 4 aGVHD than patients who did not receive PTCy (16% vs 22%, P=.07). After controlling for comorbidities and time from transplant to ICI initiation, we found that PTCy was significantly associated with a 90% reduced risk of aGVHD (HR= 0.1; 95% CI: 0.02 - 0.6; P=.01). Of the 13 evaluable patients who received nivolumab, 4 patients (31%) had an objective response, including 3 patients achieving a complete response (CR) and 1 patient achieving a partial response. The other 9 patients (69%) had no response. Of the 5 patients who received ipilimumab, only 1 patient (20 %) achieved a CR. The other 4 patients (80%) had progression of disease. There was no significant difference between the clinical responses in patients who received PD-1 inhibitor versus CTLA-4 inhibitor (P= 0.65). Patients receiving PTCy had a significantly longer median PFS (22.4 vs. 5.2 months, P=.02), and a trend toward longer median OS (22.4 vs. 5.2 months, P=.08). Fourteen patients (67%) died, and no deaths were related to aGVHD. Conclusions: The use of ICI for AML/MDS relapse after alloHCT may be a safe and feasible option. PTCy appears to decrease the incidence of aGVHD in this cohort of patients. Given the small number of patients involved in our study, further investigations with a larger number of patients in prospective trials are needed to determine the magnitude of the of PTCy effect on reducing aGVHD after ICI. Disclosures Rafei: United States Provisiona: Patents & Royalties: I have a filed patent. Popat:Bayer: Research Funding; Novartis: Research Funding. Mehta:Kadmon: Research Funding; CSL Behring: Research Funding; Incyte: Research Funding. Konopleva:Amgen: Consultancy; Agios: Research Funding; Sanofi: Research Funding; Rafael Pharmaceutical: Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Cellectis: Research Funding; Calithera: Research Funding; Ablynx: Research Funding; Kisoji: Consultancy; Ascentage: Research Funding; Eli Lilly: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; AstraZeneca: Research Funding; Stemline Therapeutics: Consultancy, 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. Oran:Celgene: Consultancy; Arog Pharmaceuticals: Research Funding; ASTEX: Research Funding. Ravandi:Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Orsenix: Consultancy, Honoraria, Research Funding. Garcia-Manero:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amphivena Therapeutics: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; H3 Biomedicine: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Alousi:Incyte: Honoraria, Research Funding; Alexion: Honoraria; Therakos: Research Funding. Daver: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; 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; Daiichi Sankyo: 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. Champlin: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; Takeda: Patents & Royalties. Diab:Bristol Myers Squibb: Research Funding; Pfizer: Research Funding; Apexigen: Research Funding; Idera Therapeutics: Research Funding; Nektar Therapeutics: Research Funding.

Monozygotic twins with GATA2 deficiency: same haploidentical-related donor, different severity of GvHD

Post-transfusion purpura is a rare transfusion-related complication that often goes undiagnosed. It is due to alloimmunization against platelet antigens which leads to acute profound thrombocytopenia following the transfusion of any platelet-containing product (red blood cells or platelets). It is commonly seen in multiparous women. Here, we report a case of post-transfusion purpura in a 56-year-old multiparous woman who developed acute thrombocytopenia seven days following a packed red blood cell transfusion. We will discuss the clinical presentation, diagnosis, workup and treatment of this rare disease. It is important to recognize this entity separately and to include it in the differential diagnosis of acute thrombocytopenia after a recent blood transfusion. Treatment for this condition consists of intravenous immunoglobulins, corticosteroids or plasmapheresis.

Background: A significant percentage of lung adenocarcinomas have a driver mutation. To date, there has been no assessment of the prevalence of such mutations in a Middle Eastern population. The present multicenter prospective study of formalin fixed paraffin embedded (FFPE) tissues from patients diagnosed with lung adenocarcinoma was performed to assess the prevalence of EGFR and ALK mutations in the Levant. Methods: Patients of Middle Eastern origin with lung adenocarcinomas at 10 sites in Lebanon, Jordan and Iraq were prospectively enrolled. Tumors were tested for EGFR by PCR and for EML4-ALK translocation by fluorescence in situ hybridization (FISH). Results: A total of 210 patients were enrolled, 139 (66.2%) males and 71 females (33.8%), with a mean age of 63.4 years. EGFR testing of 205 (97.6%) demonstrated the wild type in 173 (84.4%) and mutated forms in 32 (15.6%). Some 46.9% of EGFR positive patients were non-smokers and 62.5% were females as opposed to 22.4% and 33.8%, respectively, in the general population. As for the EML4-ALK translocation, testing in 157 (74.8%) cases gave negative results in 154 (98.1%), only 3 being positive (1.9%), 2 being females and 2 non-smokers. Conclusion: Our study established a 15.6% EGFR mutation rate in lung adenocarcinomas with ALK translocation mutations in only 1.9%, as compared to a 15-20% and 5%, respectively, in the Western literature.

Rituximab generally is a well-tolerated medication used in a variety of haematological and autoimmune conditions. The safety profile of the medication has been reviewed in the literature. Infusion reactions due to cytokine release are the most common side effects. With the increased use of rituximab, there is an increase incidence of cytopenias, most commonly thrombocytopenia and leucopenia. Coagulopathy is quite rare, reported previously in four cases in the literature. We highlighted the clinical course of a 39-year-old patient with precursor B-cell acute lymphoblastic leukaemia who was started on rituximab infusion. The patient developed a cytokine-release syndrome with haemodynamic instability, followed by rapid-onset cytopenias and disseminated intravascular coagulation abnormalities characterised by coagulopathy with fibrinolysis and mucocutaneous bleeding. The report is followed by a review of the literature. It is important to recognise rituximab-induced coagulopathy early as part of the differential diagnosis of thrombocytopenia and disseminated intravascular coagulation following rituximab administration.