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Second- and third-generation tyrosine kinase inhibitors (TKI) play an important role in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). However, data on feasibility and efficacy of using these drugs for persisting or relapsed Ph + ALL after allogeneic stem cell transplantation (alloSCT) are scarce. Based on the EBMT Acute Leukemia Working Party registry, we evaluated the use of second-/third-generation TKI in 140 patients with Ph + ALL, suffering from measurable residual disease (MRD, n = 6), molecular relapse (MRel, n = 23), or hematological relapse (HRel, n = 111) following alloSCT. Treatment included dasatinib in 104, nilotinib in 18, or ponatinib in 18 patients. Forty-nine patients received TKI monotherapy, while 91 received additional treatment. Toxicity of second-/third-generation TKI post alloSCT was comparable to pretransplant use and could be managed with dose reduction or temporary discontinuation. Response rates were 71% (overall) and 61% (following TKI monotherapy). For the entire cohort, 2- and 5-year overall survival (OS) was 49% and 33%, respectively. OS was comparable among patients treated for persisting MRD/MRel and HRel. Among patients treated with TKI monotherapy, 2- and 5-year OS was 38% and 33%, respectively. The data underscore that second-/third-generation TKI are important compounds for the management of active Ph + ALL post alloSCT.

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (CD8+ PCAETL) is a rare disease characterized by aggressive clinical course and short survival. All available data are extracted from case reports and case series. The outcome is dismal and only two reported cases were cured after several lines of therapies including stem cell transplant. We herein present the case of a patient with CD8+ PCAETL who presented with rapidly progressive skin lesions and systemic symptoms. He was treated with aggressive multiagent chemotherapy comprising cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine (hyper-CVAD). The treatment resulted in durable complete remission with no evidence of disease recurrence after 58 months of follow-up. This is the first reported case of durable remission after first-line treatment.

Although novel agents have changed the treatment landscape of multiple myeloma (MM), cytotoxic chemotherapy regimens continue to have a role in aggressive or rapidly progressive disease. In such cases, our institution has utilized a hyperfractionated cyclophosphamide regimen (termed mCAD), similar to hyper-CVAD, in which vincristine is omitted or replaced with a proteasome inhibitor (PI), either bortezomib or carfilzomib. On occasion, doxorubicin is also omitted because of patient history and provider preference.We retrospectively reviewed the charts of adult patients with MM receiving mCAD regimens at our institution between 2012 and 2016 and analyzed utilization patterns, toxicity profiles, and clinical outcomes.A total of 131 patients received mCAD, including 9% for newly diagnosed MM (NDMM), 18% attempting to optimize response to frontline therapy (OPT-MM), and 73% for treatment of relapsed/refractory MM (RRMM). Renal dysfunction was common; 31% had estimated glomerular filtration rate 50 mL/min and 14% were dialysis dependent. The overall response rate was 83%, 63%, and 67% with a median progression-free survival of 17.4, 23.7, and 4.2 months, respectively, for NDMM, OPT-MM, and RRMM. Median overall survival was not reached for NDMM or OPT-MM, and was 15.2 months for RRMM. Most patients (90%) bridged to subsequent therapy, including 32% who proceeded to autologous transplantation. Hematologic, infectious, and cardiac toxicities were common and were similar to those expected for cytotoxic chemotherapy.mCAD regimens were safe and active across patient groups, including patients with renal dysfunction. Most patients were able to bridge to subsequent therapy.

Background Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with cytarabine and methotrexate (hyper-CVAD) is a commonly used regimen in adults with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL). Adult patients fit for pediatric-inspired protocols have an excellent outcome with chemotherapy alone. However, it is unclear whether patients receiving hyper-CVAD should undergo allogeneic hematopoietic cell transplantation (HCT) as postremission therapy. Our aim was to examine the role of HCT at first complete remission (CR1) in adult ALL/LBL after hyper-CVAD. Patients and Methods Adult patients with newly diagnosed ALL/LBL receiving frontline hyper-CVAD from 2008 to 2018 were identified and records retrospectively extracted. Results A total of 85 patients were identified and included for further analysis. The median (range) age was 23 (14-68) years, and 56 (66%) were male. A total of 24 (28%) had adverse cytogenetics, and 48 (56%) had at least one risk factor. All patients received hyper-CVAD as induction; induction failure was seen in 10 (12%). A total of 38 patients continued the hyper-CVAD course, while the remaining 47 received HCT in CR1. Three-year event-free survival (EFS) and overall survival for the entire cohort were 51.4% and 61.6%, respectively. Median follow-up of alive patients was 39.9 (3.8-123.8) months. At multivariable analysis for EFS, induction failure was associated with worse outcome (hazard ratio [HR], 4.8; 95% confidence interval [CI] 1.7-13.7; P = .003), whereas HCT in CR1 improved outcome (HR, 0.42; 95% CI 0.18-0.97; P = .044). Furthermore, HCT in CR1 was the only prognostic factor for overall survival (HR, 0.3; 95% CI 0.11-0.85; P = .023). Conclusion HCT at CR1 resulted in a favorable EFS and overall survival in ALL/LBL patients after hyper-CVAD frontline therapy. Given that hyper-CVAD is a widely used protocol for adult patients, further examination of this observation is warranted.

Burkitt leukemia/lymphoma (BL) and high-grade B-cell lymphoma (HGBL) have a high incidence of central nervous system (CNS) involvement, which is associated with poor prognosis. The hyper-cyclophosphamide, vincristine, Adriamycin, and dexamethasone plus rituximab (CVAD-R) regimen includes systemic and intrathecal CNS-directed therapy to treat and prevent CNS disease. We report here the long-term safety and efficacy of the hyper-CVAD-R regimen in adults with BL and HGBL, focusing on its efficacy to prevent CNS relapse. Among 79 adults (54 BL, 25 HGBL), the median age was 44 years (25% ≥60 years old), 73% had bone marrow (BM) involvement, and 28% had CNS involvement. The complete response rate was 91% (BL 96%; HGBCL 79%; P = .16). The 5-year relapse-free survival (RFS) and overall survival (OS) rates were 58% and 52%, respectively. The cumulative incidence of relapse (CIR) was 21% (BL 14%; HGBCL 37%, P = .06) and was associated with baseline BM (27% vs 0%; P = .02) and CNS (42% vs 12%; P < .01) involvement. In multivariate analyses, age and CNS involvement were independent predictors for OS and RFS. The 5-year CNS CIR was 6% (BL 4%; HGBL 11%; P = .31); 16% with baseline CNS involvement (P = .03). Our data support the use of hyper-CVAD-R in preventing CNS relapse, especially among high-risk patients with BM or CNS involvement.

Patients with high-risk aggressive B-cell lymphoma exhibit poor survival after R-CHOP. More intensive regimens yield higher rates of remission but also of complication. We investigated all 401 patients 70 years with high-risk (age-adjusted [aa] international prognostic index [IPI] ≥2, extranodal, or bulky) aggressive B-cell lymphoma hospitalized at Karolinska for urgent start of immunochemotherapy (129 R-Hyper-CVAD; 261 R-CHOP/R-CHOEP). Patients showed IPI 3-5 (70%), WHO PS ≥2 (49%), bulky disease (70%), extranodal (75%) and CNS (8%) involvement. Five-year overall/progression-free survival (OS/PFS) was better in patients who started R-Hyper-CVAD (84%/77%) compared with R-CHOP/R-CHOEP (66%/55%). Differences were independent in multivariable analysis, seen in all patient categories, and accentuated in extreme high-risk disease: R-Hyper-CVAD vs. R-CHOP/R-CHOEP showed 5-year PFS 69% vs.40% in aaIPI 3 and 88% vs. 38% in CNS involvement. For validation, survival was compared between the two Karolinska sites and calendar periods. Survival was superior 2006-2010 at the site that introduced R-Hyper-CVAD/R-MA 2006, identical at both sites 2011-2017 after the other site adopted R-Hyper-CVAD/R-MA 2011, and excellent 2018-2020 when R-Hyper-CVAD/R-MA use increased to 75% of patients. Despite considerable toxicity, also patients aged 61-69 years showed better survival with R-Hyper-CVAD/R-MA. This is the largest single-centre series of patients treated with R-Hyper-CVAD/R-MA, showing favourable outcome in high-risk aggressive B-cell lymphoma.

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

Introduction: Dasatinib monotherapy has demonstrated clinical activity in CML-LBC, however with limited duration of response and median overall survival (OS) Methods: We reviewed 81 pts (CML-LBC, N=19 and newly diagnosed Ph-positive ALL, N=62) who were treated with HCVAD+Dasa at our institution between 9/2006 and 3/2016. De novo CML-LBC cases without prior CML or relapsed CML-LBC cases were excluded. HCVAD+Dasa therapy consisted of 4 alternating cycles of HCVAD and high-dose methotrexate (MTX) / cytarabine (AraC) with 8 intrathecal injections of MTX/AraC. Dasa was administered 100mg daily on days 1-14 for course 1, and 70mg daily on courses 2 and onwards. The maintenance phase consisted of vincristine and steroids in addition to Dasa. Pts with CD20-positive disease received additional rituximab. Allogeneic stem cell transplant (allo-SCT) was offered at physician's discretion if matched donor was available. Complete cytogenetic remission (CCyR) was defined as the absence of Ph by karyotyping. Major molecular response (MMR) was defined as BCR-ABL1 transcripts Results: Among pts with CML-LBC, median age was 49 years (yrs) (range, 26-76). Initial CML diagnosis was as chronic phase (N=17, 89%), accelerated phase (N=1, 5%), or myeloid blast phase (N=1, 5%). Median time from initial CML diagnosis to LBC was 9.5 mos (range, 3-257). Seventeen (89%) pts were previously treated with TKIs (9 [47%] imatinib, 6 [32%] nilotinib, 1 [5%] imatinib and nilotinib, 1 [5%] imatinib and bosutinib), of which 7 (41%) were refractory to TKIs. The median duration of TKI therapy was 8.3 mos (range, 3.2-37). Two (11%) pts had not received any TKIs. One had undergone allo-SCT. At the time of CML-LBC, 9 (47%) pts were on imatinib, 7 (37%) with nilotinib, and 1 (5%) with bosutinib. At CML-LBC, 11 (58%) had abnormal karyotype, all with additional cytogenetic abnormalities (ACAs) in addition to Ph. ABL1 mutations were detected in 8 of 14 (57%) tested-pts, none with T315I. BCR-ABL1 transcript was p210 in all pts. In pts with Ph-positive ALL, 52 (84%) had abnormal karyotype, of which 10 (19%) had Ph only and 41 (79%) had Ph with ACAs. p210 and p190 were detected in 13 (21%) and 48 (77%) pts, respectively. Morphologic response (CR or CRi) rates were similar between pts with CML-LBC (90%) and Ph-positive ALL (96%), whereas pts with CML-LBC were less likely to obtain deeper molecular remission. CCyR was achieved in 94% vs 95% of pts with CML-LBC vs Ph-positive ALL, respectively (p = 1). MMR was achieved in 68% vs 95% of pts with CML-LBC vs Ph-positive ALL, respectively (p = 0.006). CMR was achieved in 53% vs 74% of pts with CML-LBC vs Ph-positive ALL, respectively (p = 0.093, Table 1). Nineteen pts received allo-SCT (CML-LBC, N=8 [42%]; Ph-positive ALL, N=11 [18%]). With a median follow-up of 133 mos (95% CI: 115-137), 20 (25%) pts relapsed and 50 (62%) died. Pts with CBL-LBC had similar survival outcome compared with pts with Ph-positive ALL (5-yr PFS 50% vs 44% [p = 0.75], 5-yr OS 61% vs 48% [p = 0.74], Figure 1). The 5-yr OS rates were 88 % and 37% for pts with CML-BC with or without allo-SCT (p = 0.019). In pts with Ph-positive ALL, there was no difference in outcome based on allo-SCT (p = 0.252, Figure 2). In pts with Ph-positive ALL, outcome was predicted by the achievement of CMR. The 5-yr OS rates were 63% and 25% (p = 0.002) for pts with CMR and MMR, respectively (Figure 3). By MVA, allo-SCT seemed to predict better OS in CML-LBC (HR 0.20, p = 0.057), whereas CMR predicted better OS in Ph-positive ALL (HR 0.37, p = 0.015) (Table 2). Conclusions: Outcome of CML-LBC has improved with HCVAD+Dasa therapy, particularly in pts who received subsequent allo-SCT. Further improvement can be obtained by the use of novel TKI and targeted agents. Disclosures Kantarjian: Oxford Biomedical: Honoraria; Janssen: Honoraria; Delta Fly: Honoraria; BioAscend: Honoraria; Aptitute Health: Honoraria; Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding. Ravandi:Macrogenics: Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding. Sasaki:Novartis: Consultancy, Research Funding; Otsuka: Honoraria; Pfizer Japan: Consultancy; Daiichi Sankyo: Consultancy. Jain: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; Cellectis: 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; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Research Funding; Adaptive Biotechnologies: 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; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Ablynx: Research Funding; Ascentage: Research Funding; Cellectis: Research Funding; Calithera: Research Funding; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Agios: Research Funding; AbbVie: Consultancy, Research Funding; Eli Lilly: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Sanofi: Research Funding; AstraZeneca: Research Funding; Rafael Pharmaceutical: 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; F. Hoffmann La-Roche: Consultancy, Research Funding. Short:Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy. DiNardo:Syros: Honoraria; MedImmune: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; ImmuneOnc: Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Takeda: Honoraria. Kadia:Abbvie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Astellas: Research Funding; JAZZ: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Pulmotec: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Cellenkos: Research Funding; Cyclacel: Research Funding; BMS: Honoraria, Research Funding; Astra Zeneca: Research Funding; Amgen: Research Funding; Ascentage: Research Funding; Novartis: Honoraria. Garcia-Manero:Merck: Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Novartis: Research Funding. Daver: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; Bristol-Myers Squibb: 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; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Issa:Celegene: Research Funding; Syndax: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Merus: Research Funding; Immunogen: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding. Jabbour:Pfizer: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding.

OBJECTIVE: The objective of this study was to determine the frequency of complete and partial remission after 2 courses of hyper CVAD regimen in newly diagnosed patients of acute lymphoblastic leukemia (ALL).MATERIAL AND METHODS: This study was conducted on 100 patients of ALL presenting to the oncology department of Jinnah Hospital, Lahore and fulfilling the inclusion criteria from 01-012016 to 30-12-2016. Patients were undergone treatment with hyper CVAD regimen according to the standard protocol. Complete or partial remission rate was checked after 2 session of hyper CVAD regimen. CT scan (chest and abdomen) was performed for confirmation of extramedullary disease. RESULTS: The mean age of study population was 35.68 ± 8.69 years. There were 48% male patients while female patients were 52%. Complete remission was present in 72% patients. Partial remission was present in 24% patients. There was no significant association between complete remission and age (p-value=0.497). No significant association was found between partial remission and age (p-value=0.103). Significant association was found between partial remission and complete remission with gender having p-value=0.001 and 0.01 respectively. CONCLUSION: The frequency of complete and partial remission after 2 courses of hyper CVAD regimen in newly diagnosed patients of ALL was 72% and 24% respectively. Effect modifiers have no significant influence except gender.

Adult T‐cell acute lymphoblastic leukemia (T‐ALL) is a heterogeneous group of acute leukemias that account for about one third of all cases of Philadelphia chromosome (Ph)‐negative ALL. Recently, a molecular classifier using the mutational status of NOTCH1, FBXW7, RAS, and PTEN (NFRP) has been shown to distinguish low‐ vs high‐risk groups in adult T‐ALL patients treated using the Berlin‐Frankfurt‐Münster ALL protocol. However, it is unknown if this molecular classifier can stratify adult T‐ALL patients treated with hyper‐CVAD ± nelarabine. We identified a relatively small cohort of 27 adults with T‐ALL who were uniformly treated with hyper‐CVAD ± nelarabine with available mutational analysis at time of diagnosis. The most commonly mutated genes in this group were NOTCH1 (52%), NRAS (22%), DNMT3A (19%), KRAS (15%), and TP53 (7%). The NFRP molecular classifier failed to stratify overall survival (OS; P = .84) and relapse‐free survival (RFS; P = .18) in this cohort. We developed a new stratification model combining K/NRAS and TP53 mutations as high‐risk factors and showed that mutations in these genes predicted poorer OS (P = .03) and RFS (P = .04). While the current study is limited by cohort size, these data suggest that the NFRP molecular classifier might not be applicable to adult T‐ALL patients treated with hyper‐CVAD ± nelarabine. RAS/TP53 mutation status, however, was useful in risk stratification in adults with T‐ALL., The NFRP (NOTCH1/FBXW7/RAS/PTEN) risk stratification is not optimal for T‐ALL patients treated with the hyper‐CVAD regimen. The new MDACC (TP53/RAS) risk stratification can identify high‐ and low‐risk groups in hyper‐CVAD‐treated patients.

Aggressive induction chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) is a standard option for the initial management of transplant-eligible mantle cell lymphoma (MCL).1-3 However, the optimal induction regimen before ASCT is unknown. Cytarabine-based induction achieves excellent response rates and higher rates of minimal residual disease (MRD) negativity compared with anthracycline-based induction regimens.4-6 While effective, most cytarabine-based induction regimens require inpatient hospitalization and are associated with significant hematologic and nonhematologic toxicities.4-6 Rituximab-bendamustine (RB) is a less intensive, outpatient-based chemoimmunotherapy regimen with excellent long-term efficacy and good tolerability in transplant-ineligible MCL patients.7-9 However, its role as a pretransplant induction strategy has not been formerly evaluated. S1106 is a randomized phase 2 multi-institutional clinical trial comparing induction R-hyper-CVAD (rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and methotrexate/cytarabine (RH) with RB followed by ASCT in newly diagnosed MCL patients. We previously reported that the 2-year progression-free survival (PFS) and overall survival (OS) were similar with either regimen. However, RH was more toxic than RB, had higher stem cell mobilization failure rates, and prompted protocol-specified early study closure.10 While premature closure limited the sample size, we demonstrated for the first time in a prospective setting that outpatient RB treatment can achieve excellent MRD negativity and could serve as an induction strategy worthy of further study. Given the increased survival of MCL patients,2 critical assessment of long-term efficacy and toxicity is needed. Here, we report the 5-year follow-up (FU) of the S1106 study.

The NOPHO ALL2008 is a population-based study using an unmodified pediatric protocol in patients 1-45 years of age with acute lymphoblastic leukemia. Patients with T-ALL were given a traditional pediatric scheme if fast responding (minimal residual disease (MRD) 0.1% day 29), or intensive block-based chemotherapy if slow responding (MRD 0.1% day 29). Both treatment arms included pediatric doses of high-dose methotrexate and asparaginase. If MRD ≥ 5% on day 29 or ≥0.1% after consolidation, patients were assigned to allogeneic hematopoietic stem cell transplantation. The 5-year overall survival of the 278 T-ALL patients was 0.75 (95% CI 0.69-0.81), being 0.82 (0.74-0.88) for patients 1.0-9.9 years, 0.76 (0.66-0.86) for those 10.0-17.9 years, and 0.65 (0.55-0.75) for the older patients. The risk of death in first remission was significantly higher in adults (12%) compared with the 1-9 years group (4%). The MRD responses in the three age groups were similar, and only a nonsignificant increase in relapse risk was found in adults. In conclusion, an unmodified pediatric protocol in patients 1-45 years is effective in all age groups. The traditional pediatric treatment schedule was safe for all patients, but the intensive block therapy led to a high toxic death rate in adults.

While promising results have been achieved in the treatment of childhood, the optimal initial treatment for adult acute lymphoblastic leukemia (ALL) has not yet been defined. Hyper-CVAD has become a widely used treatment for approximately 2 decades in the treatment of adult ALL. We conducted a retrospective analysis of 30 patients treated with Hyper-CVAD at two centers between 2014 and 2020. In all (n=30) patients treated with Hyper-CVAD, complete response (CR) rate was 86.7%, induction mortality was 10%, refractory disease was 3.3%, the median overall survival (OS) was 38 months (95% CI 7.78–68.2 months), the median disease-free survival (DFS) was 29 months (95% CI 9–49 months), the 2-year OS rate was 56.5%, and the 2-year DFS was rate 56.7%. For standard risk (n=12) ALL patients, the median OS was 20 months (95% CI 0–43 months), and median DFS was 7 months (95% CI 0–25 months). For high risk (n=18) ALL patients, the median OS was 38 months (95% CI 0–76 months), and median DFS was not reached. These results indicate that Hyper-CVAD regimen should be considered as an option for induction treatment of adult ALL patients who are newly diagnosed and eligible for allo-HSCT., Çocukluk çağı akut lenfoblastik lösemi (ALL) tedavisinde umut verici sonuçlar elde edilirken, yetişkin için optimal indüksiyon tedavisi henüz belirlenememiştir. Hyper-CVAD kemoterapi rejimi, yetişkin ALL tedavisinde yaklaşık yirmi yıldır yaygın olarak kullanılan bir tedavi haline gelmiştir. 2014 ve 2020 yılları arasında iki merkezde Hyper-CVAD rejimi ile tedavi edilen 30 hastanın retrospektif analizini gerçekleştirdik. Hyper-CVAD ile tedavi edilen hastalarda (n=30), tam yanıt oranı (TY) %86.7, indüksiyon mortalitesi %10, refrakter hastalık %3.3, medyan genel sağkalım (GS) 38 ay (%95 CI 7.78-68.2 ay), medyan hastalıksız sağkalım (HS) 29 ay (% 95 CI 9-49 ay), 2 yıllık GS oranı % 56.5 ve 2 yıllık HS oranı % 56.7 olarak saptadık. Standart risk (n=12) ALL hastalar için, medyan GS 20 ay (%95 CI 0-43 ay) ve medyan HS 7 ay (%95 CI 0-25 ay) saptadık. Yüksek riskli (n=18) ALL hastalar için, medyan GS 38 ay iken (%95 CI 0-76 ay), medyan HS’a ulaşılamadı. Bu sonuçlar, Hyper-CVAD rejiminin yeni tanı konmuş ve allojenik kök hücre transplantasyonu için uygun olan ALL hastalarının indüksiyon tedavisi için bir seçenek olarak değerlendirilmesi gerektiğini göstermektedir.

Background The outcome of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone plus ofatumumab hyper-CVAD + ofatumumab (hyper-CVAD + ofatumumab) has not been compared with the outcome of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone plus ofatumumab hyper-CVAD plus rituximab (hyper-CVAD + Rituximab) in Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) in a randomized clinical trial. Methods The authors compared the outcomes of 69 patients treated with hyper-CVAD + ofatumumab and 95 historical-control patients treated with hyper-CVAD + Rituximab. Historical-control patients were treated with hyper-CVAD + Rituximab if they had CD20 expression ≥ 20%. Ofatumumab (day 1 of course 1, 300 mg intravenously; subsequent doses, 2000 mg intravenously) was administered on days 1 and 11 of courses 1 and 3 and on days 1 and 8 of courses 2 and 4 for a total of 8 doses. A propensity score analysis with inverse probability of treatment weighting (IPTW) was performed to adjust for baseline covariates between groups. Results The median event-free survival with stem cell transplantation (SCT) censoring was 33 and 65 months with hyper-CVAD + Rituximab and hyper-CVAD + ofatumumab, respectively (crude P = .064; IPTW P = .054). The median overall survival with SCT censoring was 52 months and not reached, respectively (crude P = .087; IPTW P = .097). Conclusions Hyper-CVAD + ofatumumab was associated with better outcomes than hyper-CVAD + Rituximab among patients with newly diagnosed Philadelphia chromosome-negative ALL.

Background Dasatinib monotherapy has demonstrated modest clinical activity in chronic myeloid leukemia in lymphoid blastic phase (CML-LBP). The outcome of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) has dramatically improved with hyperfractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) in combination with tyrosine kinase inhibitors (TKIs). Methods The authors reviewed 85 patients (23 with CML-LBP and 62 with newly diagnosed Ph-positive ALL) who received hyper-CVAD plus dasatinib. Results In the CML-LBP cohort, 19 had prior chronic myeloid leukemia as chronic phase (n = 17; 74%), accelerated phase (n = 1; 4%), or myeloid blastic phase (n = 1; 4%); 4 (17%) presented with de novo CML-LBP. The BCR-ABL1 transcript was p210 in 22 patients (96%) and p190 in 1 patient (4%). In the Ph-positive ALL cohort, p210 and p190 transcripts were detected in 13 patients (21%) and 48 patients (77%), respectively. Patients with CML-LBP were less likely to achieve deep molecular remission than patients with Ph-positive ALL: the major molecular response (MMR) rates were 70% and 95%, respectively (P = .007), and the complete molecular response (CMR) rates were 55% and 74%, respectively (P = .16). Survival outcomes were similar for CML-LBP and Ph-positive ALL: the 5-year overall survival (OS) rates were 59% and 48%, respectively (P = .97). Allogeneic stem cell transplantation was associated with a better outcome in CML-LBP (5-year OS rate, 88% vs 57%; P = .04). In Ph-positive ALL, the outcome was driven by deeper molecular remission: the 5-year OS rates were 63% and 25% with CMR and MMR, respectively (P = .002). Conclusions The outcome of CML-LBP has improved with hyper-CVAD plus dasatinib therapy with survival comparable to that of Ph-positive ALL. Further improvement may be achieved with the use of novel TKIs and targeted agents.

Pediatric-inspired regimens (PIR) in adolescents and young adults with acute lymphoblastic leukemia have led to better long-term outcomes. In Latin America, the adolescent and young adult population has an increasing incidence of acute lymphoblastic leukemia with poor outcomes (5-year OS of approximately 20%) with traditional regimens.A retrospective cohort study was performed of adolescent and young adult acute lymphoblastic leukemia patients treated with PIR in two reference centers in Mexico City between March 2016 and June 2019, in which the primary endpoint was OS, compared to a historic cohort of patients treated with hyper-CVAD treated between February 2009 and June 2015.We compared 73 patients treated with PIR (46 and 27 received modified versions of the ALL-BFM 90 and CALGB C10403 regimens, respectively) and 173 patients treated with hyper-CVAD. Patients treated with PIR experienced higher 4-week complete response rates (79.5% vs. 64.2%; P = .02) and lower relapse rates (44.1% vs. 60.0%; P = .04). OS was significantly higher with PIR than with hyper-CVAD (24 months: 41.5% vs. 28.1%; P = .012). The benefit on OS for PIR was only significant for CALGB (24-month OS: 61.1% vs. 28.0%; P = .01) but not for BFM. In the multivariate analysis, hyperleukocytosis (hazard ratio [HR] = 1.90; 95% confidence interval [CI], 1.11-3.22; P = .02), autologous stem-cell transplantation (HR = 0.38; 95% CI, 0.17-0.86; P = .02), and 4-week complete response (HR = 0.43; 95% CI, 0.26-0.70; P .01) were independent prognostic factors. For the group of patients older than 20 years, only CALGB had an independent prognostic factor for OS (HR = 0.44; 95% CI, 0.20-0.97; P = .04).In terms of 4-week complete response, relapse rates, and OS, PIR provides benefits to Hispanic patients.

Summary Background The addition of rituximab to intensive chemotherapy improves outcomes in patients with B-cell acute lymphoblastic leukaemia. Ofatumumab is an anti-CD20 monoclonal antibody that binds to the small extracellular loop of CD20 and has greater in vitro complement-mediated cytotoxicity than rituximab. In this study, we assessed the activity and safety of ofatumumab in combination with chemotherapy in patients with Philadelphia chromosome (Ph)-negative CD20-positive B-cell acute lymphoblastic leukaemia. Methods This was a single-arm, phase 2 trial done at the MD Anderson Cancer Center (Houston, TX, USA). Patients with newly diagnosed, Ph-negative B-cell acute lymphoblastic leukaemia or lymphoblastic lymphoma with CD20 expression of at least 1% were eligible. Patients were treated with up to eight courses of the hyper-CVAD regimen (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) on courses 1, 3, 5, and 7 alternating with high-dose methotrexate and cytarabine on courses 2, 4, 6, and 8. Ofatumumab was administered on days 1 and 11 of courses 1 and 3 and on days 1 and 8 of courses 2 and 4 for a total of eight doses. The first dose of ofatumumab was 300 mg intravenously and all subsequent doses were 2000 mg intravenously. Patients received 30 courses of maintenance therapy with 6-mercaptopurine, vincristine, methotrexate, and prednisone (POMP), with four intensification courses (high-dose methotrexate plus L-asparaginase and hyper-CVAD plus ofatumumab on courses 6–7 and 18–19). The primary endpoints were event-free survival, overall response, and overall survival. All enrolled patients were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, NCT01363128. Findings Between Aug 26, 2011, and May 18, 2017, 69 patients (67 patients had B-cell acute lymphoblastic leukaemia and two had B-cell lymphoblastic lymphoma; median age 41 years [IQR 32-50]) were enrolled and treated, including 33 (48%) aged between 18 and 39 years. Nine (27%) of 33 patients had Ph-like acute lymphoblastic leukaemia. With a median follow-up of 44 months (26–53), 4-year event-free survival was 59% (95% CI 48–73); 69% (54–87) in adolescents and young adults aged 18–39 years. 4-year overall survival was 68% (58–81); 74% (60–91) in adolescents and young adults. The overall response rate was 98% (64 of 65 patients). The most common non-haematological grade 3 or 4 adverse events were infections (35 [54%] of 65 patients during induction and 53 [78%] of 68 patients during consolidation). Ten (14%) of 69 patients died in complete remission from sepsis (two [3%]), cardiac arrest (one [1%]), therapy-related acute myeloid leukaemia (two [3%]), and haematopoietic stem-cell transplantation complications (five [7%]). None of these deaths were considered related to ofatumumab treatment by the study investigators. Interpretation The combination of hyper-CVAD plus ofatumumab is safe and active in adults with Ph-negative CD20-positive B-cell acute lymphoblastic leukaemia. Modifications of this regimen with the addition of novel monoclonal and bispecific antibody constructs targeting CD19 and CD22 might further improve outcomes and allow reduction in the intensity and duration of chemotherapy. Funding Novartis.

Primary bone marrow lymphoma (PBML) is a rare clinical entity. Because of its rarity, there is no standard therapy defined. Prognosis in this disease is poor, and further studies for effective treatments are needed. In this report, we will discuss a patient with PBML who was treated with a hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine (hyper-CVAD) plus rituximab regimen with a favorable outcome. We believe this is the first reported use of this regimen in this type of lymphoma.

Introduction: In acute lymphoblastic leukemia (ALL) adolescents and young adults (AYA), there are benefits when using pediatric over adult treatment regimes. There is improved overall survival (OS), progression free survival (PFS) and reduced need for hematopoietic stem cell transplantation; all while having an acceptable toxicity profile. Yet, studies supporting this were largely performed in a western population (e.g., United Kingdom and United States) and thus may have had limited representation of the Asian population. Whether these results are generalizable and applicable to an Asian population is in question. MASPORE, a locally designed pediatric regiment based on BFM regimen, which has been used successfully in Singapore and Malaysia's AYA cohort since 2007. MASPORE protocol utilized PCR-based minimal residual disease (MRD) marker to risk stratify patients according to disease severity and used a 3- or 4-drug induction regimen depending on intermediate or high-risk stratification (L-asparaginase, Vincristine, Dexamethasone +/- daunorubicin). In contrast HyperCVAD does not use MRD to stratify or guide management. In this retrospective study performed in Singapore, we aim to demonstrate that MASPORE is an effective treatment option for AYA ALL in Asian population. Methods: Patient registries (IRB approved) spanning from January 2005 to June 2021 from three tertiary hospitals in Singapore were reviewed. ALL patients who were AYA, defined as less than 40 years of age, treated during this time were included and analyzed. Patients were treated with either the pediatric protocol MASPORE or with the adult protocol HyperCVAD. Patients who are Philadelphia positive were excluded from the MASPORE arm up to 2020. Patients' demographics, functional status, risk profile, adverse events, as well as the hematological response and transplant status were collected and analyzed with Pearson chi-square test. Kaplan Meier curve analysis were performed for OS and PFS with SPSS software. Results: In this retrospective study, 116 patients were analyzed. Among these patients 29 (25%) received MASPORE and 87 (75%) received HyperCVAD. The median age was 23 (range 18-40) for MASPORE arm vs 28 years (range 15-40) for the HCVAD arm. median follow-up time was 4.5 vs 10.8 years. Both groups were similar in gender, race, ECOG status, and ALL risk status at diagnosis. Likewise, both arms did not have differences in starting hematological parameters: hemoglobin, total white blood cell count, platelet count, absolute neutrophil count, and bone marrow blast percentages. Median time from diagnosis to treatment was 3 and 4 days for MASPORE and HyperCVAD arms respectively. There were increased adverse rates for patients in the MASPORE arm. They had more (13.8 vs 0.0%, p < 0.001) of which 75% of the pancreatitis were CTCAE grade 3/4, avascular necrosis (13.8 vs 2.2%, p = 0.016), cerebral venous thrombosis (13.8 vs 1.1%, p = 0.004) and other thrombosis (27.6 vs 5.7%, p = 0.004). For the MASPORE and HyperCVAD arms there was one induction death, one from sepsis and the other from pneumonia . Both arms managed to achieve complete response (CR) with equivalent rates (82.5 vs 80.5%, p = 0.752). However, there was less relapsed or refractory disease in those treated with MASPORE (10.3 vs 44.8%, p < 0.001). The 5- OS was better in the MASPORE versus the HyperCVAD arm (4.4 vs 3.7 years; p = 0.049). Likewise, the 5-year PFS was superior in the MASPORE arm (4.2 vs 3.2 years, p = 0.034). Furthermore, a smaller proportion of patients required consolidative stem cell transplant (13.8 vs 49.4%, p < 0.001). Conclusion: The pediatric-inspired protocol MASPORE achieved similar CR rates with OS and PFS benefit, reduced relapse rates, and less need for consolidative stem cell transplant. MASPORE serves as a viable treatment option when treating AYA patients with ALL. Larger prospective studies are needed to further explore its use. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background Ponatinib, a third-generation BCR-ABL1 tyrosine kinase inhibitor (TKI), + hyper-CVAD showed remarkable activity against Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), and may be superior to chemotherapy + earlier generation TKIs in terms of depth of remission, event-free survival (EFS), and overall survival (OS). However, this regimen's efficacy and tolerability have yet to be externally validated. Here, we summarize our real-world experience with ponatinib + hyper-CVAD for untreated Ph+ ALL and other Ph+ acute or blast phase leukemias. Methods We retrospectively analyzed all adults treated at the University of California, Davis (UCD) from March 2012 to May 2021 with ponatinib + hyper-CVAD upfront. The primary endpoints were 3-year OS and EFS. Secondary endpoints were complete molecular response (CMR), measurable residual disease (MRD) negativity by multiparameter flow cytometry (MFC), complete cytogenetic response (CCyR) rates, and adverse events (AEs). Time to event analyses were done via the Kaplan-Meier method. Patients alive were censored at their last follow-up date. Patients undergoing allogeneic hematopoietic cell transplant (HCT) after 6 months of achieving complete remission (CR) were censored at the time of HCT for the landmark analysis. Patients with missing data were excluded from the response analyses. Results We identified 13 Ph+ ALL patients who received ponatinib + hyper-CVAD for initial induction. The baseline characteristics for the Ph+ ALL patients are summarized in Table 1. The median follow-up was 16 months. The median number of hyper-CVAD cycles completed was 8 (range, 1-8) with ponatinib. Two patients proceeded to HCT in CR1, one at 3.5 months after starting induction, and due to difficulty controlling the patient's concurrent multiple myeloma prior to HCT and recovery from anti-neoplastic therapy, the second was delayed to 46 months after starting induction. The 3-year OS and EFS with ponatinib + hyper-CVAD were each 92% (95% confidence interval, 78.9-100) (Figure 1). Landmark analysis completed 6 months following CR showed a 3-year OS of 100% in patients treated with ponatinib + hyper-CVAD without HCT in first CR (CR1). The CMR, CCyR, and MRD-negativity by MFC rates with ponatinib were all 92.3% (12/13). The median time to CMR, CCyR, and MRD-negativity by MFC were 51 days, 22 days, and 53 days, respectively. Notable AEs with ponatinib include neutropenic fever (92%), bacterial infection (69%), transaminitis (38%), venous thromboembolism (31%), invasive fungal infection (15%), hemorrhage (15%), cerebrovascular accident (CVA) (15%), and tumor lysis syndrome (8%). One patient died during induction with ponatinib due to a bacterial infection. Two patients switched to a different TKI due to a CVA after 4 and 24 months. Only 2 patients did not complete 8 cycles of hyper-CVAD, due to death during induction (n=1) and proceeding to HCT after 3 cycles (n=1). As for similar Ph+ leukemias, 3 chronic myeloid leukemia with lymphoid blast crisis (CML-LBC), 1 CML with mixed phenotype blast crisis (CML-MPBC), and 1 with mixed phenotype acute leukemia (MPAL) were treated with ponatinib + hyper-CVAD. The MPAL patient achieved CMR within 55 days, while the CML-MPBC and 2 CML-LBC patients achieved CMR after HCT. The third CML-LBC patient is in CR with ongoing treatment. After median follow-up of 25 months, all 5 were alive, and only the MPAL patient relapsed 28 months after starting treatment and 1 year after HCT. Conclusion To our knowledge, this is the first report externally validating the efficacy and tolerability of ponatinib + hyper-CVAD for Ph+ ALL. We also show the feasibility of using this regimen in patients with Ph+ CML-LBC, CML-MPBC and MPAL. Despite the small sample size and retrospective nature, our study supports existing data demonstrating that this regimen challenges both the designation of Ph+ ALL as a high-risk disease and the trend to transplant in CR1. Our findings support that ponatinib + hyper-CVAD should be considered a standard of care for Ph+ ALL. Figure 1 Figure 1. Disclosures Kaesberg: Incyte: Speakers Bureau. Rosenberg: Takeda, Janssen: Speakers Bureau. Abedi: BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Speakers Bureau; Seattle Genetics: Speakers Bureau. Tuscano: Genentech, Pharamcyclics, Abbvie, BMS, Acrotech, Seattle Genetics, Takeda: Research Funding. Jonas: AbbVie, BMS, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Treadwell: Consultancy; 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, Treadwell: Research Funding; AbbVie: Other: Travel reimbursement. OffLabel Disclosure: Ponatinib is approved for Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. In this study, we described outcomes with ponatinib in combination with hyperCVAD in the frontline setting, which is off-label.