A Single-Arm, Open-Label Phase 2 Pilot Study of Vyxeos (CPX-351) in Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia

Introduction: Vyxeos® is a liposomal formulation employing a 1:5 molar ratio of daunorubicin:cytarabine. Clinical trials in high risk acute myeloid leukemias demonstrated a significant benefit in CR rates and median OS, culminating in FDA approval August 2017. Emerging pediatric data suggest this benefit may extend to acute lymphoblastic leukemia (ALL). The following pilot trial was performed to better understand the activity and toxicity profile in adults with relapsed and refractory ALL. Methods: Adults with ALL or mixed phenotype leukemia were eligible if >5% lymphoblasts and/or extramedullary disease >1x1cm. Induction consisted of Vyxeos 100 units/m2 on days 1, 3 and 5. Those with clinical benefit could receive up to 3 cycles of consolidation delivered at 65 units/m2 on days 1 & 3 after recovery of neutrophils (>500 cells/uL) and platelets (>50,000 cells/uL). Response: 11 patients (pts) have been treated to date, with median age of 39y (22-74y), 9 male, and 3 Caucasian. Six pts had B-ALL, including 1 B-myeloid. Four of 5 T-ALL pts had early T-cell precursor (ETP) phenotype. NGS was available in 9 pts, and included TP53 mutation (n=4), and PH-like changes (n=2). Median prior lines of therapy was 3, with 7 pts showing primary refractory disease. Prior blinatumomab, inotuzumab, CAR-T cell therapy, and allogeneic transplant were noted in 5, 2, 1, and 3 pts. Pancytopenia was uniform during induction, with febrile neutropenia noted in 9 pts. One pt passed from pneumonia after moving to comfort measures in lieu of intubation 20 days after Vyxeos, and is non-evaluable for response. A second pt developed grade 3 sepsis. The remainder of infections were grade 1-2. One pt had grade 3 gastrointestinal bleed, and 3 pts had grade 1 spontaneous subdural bleeding. One pt developed recurrent pericarditis in setting of anterior mediastinal mass. One case of veno-occlusive disease was observed in a pt with prior allogeneic transplant and inotuzumab. Median time to ANC recovery was 33.5 days among 10 evaluable pts. Two pts with refractory disease failed to recover platelets; among the remaining pts, median time to platelet recovery was 30.5 days. Adverse events were uncommon during consolidation, and include foot cellulitis and myopericarditis, each in 1 pt. Among 10 evaluable pts, 3 achieved CR/CRi, including 2 ETP T-ALL and one B-ALL. Two pts with TP53 mutation demonstrated >50% blast reduction with hematologic recovery, allowing for prolonged time to subsequent therapy. Four pts received 1-3 cycles consolidation. One pt was bridged to donor leukocyte infusion. Responses were noted in only 2 pts after progression following Vyxeos, highlighting refractory status of those enrolled. Median PFS was 57 days (95%CI: 10, 105), time to next therapy 76 days (95%CI: 47, 105), and OS 223 days (95%CI: 144, 302). Conclusions Vyxeos in high-risk refractory adult ALL was overall well tolerated and active, with median OS of approximately 7.5 months in this pilot trial. Confirmation of benefit in a larger study is warranted, incorporating a second induction course and/or the addition of novel agents to further improve on remission rate and duration of response. Disclosures Shah: Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other; BeiGene: Consultancy, Honoraria; Acrotech/Spectrum: Honoraria; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Precision Biosciences: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Other: Expenses; Pfizer: Consultancy, Other: Expenses; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy. Chavez: Astra Zeneca: Research Funding; Novartis: Consultancy; Merck: Research Funding; Morphosys: Speakers Bureau; Adaptive Biotech: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Beigene: Speakers Bureau; Kite/Gilead: Consultancy; karyopharm: Consultancy; Epizyme: Speakers Bureau; Abbvie: Consultancy. Sokol: Dren Bio: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees. Lancet: Celgene/BMS: Consultancy; Millenium Pharma/Takeda: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy; BerGenBio: Consultancy; ElevateBio Management: Consultancy; Agios: Consultancy; Astellas: Consultancy; Jazz: Consultancy. OffLabel Disclosure: Vyxeos is being evaluated in the described trial for the treatment of relapsed or refractory acute lymphoblastic leukemia in adults.

Real-World Outcomes in Adolescents and Young Adults with Acute Lymphoblastic Leukemia without Access to Allogeneic Stem Cell Transplant

Introduction: Adolescents and young adult (AYA) patients (ages 15-39) with acute lymphoblastic leukemia (ALL) have inferior outcomes and increased treatment-related toxicity when compared to children. The use of pediatric-inspired protocols has resulted in improved outcomes in the AYA population but outcomes remain inferior to their pediatric counterparts. Hispanic patients with ALL also have inferior outcomes compared to non-Hispanic White patients. Real-world outcomes in AYA ALL patients without access to allogeneic transplant are not known, especially in Hispanic/Latino populations. Thus, in order to understand treatment outcomes with modern chemotherapy regimens in this high-risk population, we conducted a retrospective cohort analysis of all AYA ALL patients without access to allogeneic stem cell transplant at a large safety-net hospital. Methods: We conducted a retrospective single-center cohort analysis of ALL patients ages 18 to 39 treated at a large safety-net hospital in Dallas, TX between January 2010 and May 2021. All patients who received induction and consolidation at Parkland Health and Hospital System and did not receive an allogeneic stem cell transplant were included. We interrogated the database for demographic, laboratory, cytogenetic, and next-generation sequencing (using the Foundation Medicine platform) information as well as treatment outcomes and post-relapse therapy. Chemotherapy consisted of either Hyper-CVAD (+/- TKI) or the CALGB 10403 protocol. Data were stored in the RedCap database and SPSS analytical software was used to generate survival analysis and Kaplan-Meier plots. Results: We identified 54 AYA ALL patients during the designated time period, consisting of 36 males and 18 females. The median age of the cohort was 28 years, and 81% of patients were Hispanic. Twelve patients were Ph(+) and 42 patients were Ph(-); 11/12 Ph(+) patients received a TKI with induction and one patient received a TKI beginning with consolidation. Cytogenetic/FISH testing and next-generation sequencing (NGS) were performed in 42 (78%) and 13 (24%) patients respectively, with the most common aberrations noted in Table 1. Of note, NGS was not routinely performed before 2017 at our institution. Six of the 13 patients with NGS results available had Ph-like mutation signatures. The most common induction regimens used were CALGB 10403 (65%), Hyper-CVAD (15%), and Hyper-CVAD + TKI (20%). Forty-one of 49 patients (84%) with a documented day 30 bone marrow biopsy achieved a CR or CR with incomplete count recovery after induction which included 11/12 (92%) Ph(+) patients, 24/31 (77%) Ph(-) patients, and 6/6 (100%) Ph-like patients. Of the patients in CR or CRi at day 30, 27 (50%) were negative for minimal residual disease (MRD) by flow cytometry. Overall survival at 3 years for the entire cohort was 69%, and there was no statistical difference between Ph(+) and Ph(-) patients. Three-year OS was improved in patients who received Hyper-CVAD + TKI (78%) or CALGB 10403 (65%) compared to those who received Hyper-CVAD alone (59%) though this did not reach statistical significance (p=0.72). Conclusions: Our results underscore the ongoing outcomes disparities in the AYA and Hispanic populations, even with the use of modern pediatric-inspired and TKI-containing regimens. The 69% 3-year OS in our population is similar to that in the transplant-eligible AYA population and suggests a diminishing role for allogeneic transplant with current protocols. The high rate of Ph-like signatures on NGS in our population is consistent with the increased prevalence of these mutations in Hispanic ALL patients. Our study is limited as it is a retrospective analysis with a small sample size and represents the results of a single institution. Prospective studies are needed to determine the role of allogeneic transplant in Ph(+) and Ph-like AYA with ALL, and concerted efforts should be made to enroll Hispanic patients in these clinical trials given their high-risk biology and inferior outcomes. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Gilteritinib for Relapsed Acute Myeloid Leukaemia with FLT3 Mutation during the COVID-19 Pandemic: Real World Experience from the UK National Health Service

Background Early data suggest that patients undergoing salvage chemotherapy for relapsed or refractory (R/R) acute myeloid leukaemia (AML) have poor outcomes if infected with SARS-CoV-2, and nosocomial transmission has been a major problem worldwide. Gilteritinib is effective in R/R FLT3 mutated AML, is significantly less immunosuppressive and does not require hospital admission, however at the start of the pandemic this was not yet approved for routine use in all countries. In the United Kingdom, the National Health Service (NHS) made gilteritinib available as an emergency measure from late April 2020 to patients aged >16y with R/R FLT3 mutated AML, with the aim of reducing both mortality and healthcare resource use. We report a health-system-wide real world data collection for toxicity and patient outcomes across 27 NHS Hospitals. Methods Each patient was registered on a central NHS database, with clinicians certifying that their patient met the above criteria. Anonymised data were retrospectively collected by treating physicians. Gilteritinib dose, duration and toxicity information was requested for the first 4 cycles of therapy. Response definitions were as per European Leukaemia Network (ELN) guidelines. A total of 81 patients have been registered on the scheme, with outcomes reported here for those with follow-up information at a data cut on 1st August 2021. Results Fifty patients were included with a median age of 59y (range 19 - 77) and 50% male. The majority (83%) had an ECOG performance status of 0-1. AML was secondary to a previous haematological disorder in 12%, therapy-related in 4% and de novo in the remaining 84%. The disease was refractory to the last therapy in 38%. Most patients had previously received 1 (65%) or 2 (33%) lines of therapy, including intensive chemotherapy in a majority (86%). A FLT3 inhibitor had previously been administered to 45% and 35% were post allogeneic transplant. The FLT3 mutation was an internal tandem duplication (ITD) in 80% and tyrosine kinase domain (TKD) mutation in 22%. NPM1 mutations were detected in 34%. Next-generation sequencing results were available for 94% of patients, with mutations in IDH1 or IDH2 in 12.5%, ASXL1 in 2%, RUNX1 in 21% and no TP53 mutations. Patients spent a median 3.5 days in hospital in cycle 1, 0 days in cycles 2 and 3 and 1 day in cycle 4. In cycles 1, 2, 3 and 4, the median number of days of grade 4 neutropenia was 18, 7, 7.5, and 6.5 respectively, and the grade 4 thrombocytopenia was 2, 7, 0.5 and 0.5. The composite complete remission (CR) / CR with incomplete haematological recovery (CRi) rate was 27%. MRD data is being collected. The best response was morphological leukaemia free state (MLFS) in 4%, partial remission (PR) in 25% and refractory disease in 38%. The rate of combined CR/CRi did not differ in those with previous exposure to FLT3 inhibitors (23% vs 32%, p=0.6) or with past allogeneic transplant (29% vs 27%, p=0.3). There were no CR/CRi in patients with adverse cytogenetic risk. Median follow-up was 10.5 months (95%CI 7.3 - 12.3) with median overall survival (OS) 6.7 months (95%CI 4.5 - not reached). Mortality at day 30 was 0% and day 60 was 14%. 12-month overall survival was 38%. Patients who achieved a CR/CRi had a 12-month OS of 83%, and for PR this was 35%. Survival did not differ in those with previous FLT3 inhibitor exposure (HR 1.0, p>0.9) or allogeneic transplant (HR 0.63, p=0.3). Seven patients (14%) so far have been bridged with gilteritinib to allogeneic transplant. Conclusion Our data demonstrate that gilteritinib is well tolerated and clinically active in adults with relapsed FLT3 mutated AML. Importantly, during the COVID-19 pandemic, its availability has permitted the great majority of treatment to be delivered as an outpatient with significant resource saving at a time of critically constrained inpatient resources. Patients who achieve CR/CRi have good short-term outcomes and are able to proceed to a potentially curative allogeneic stem cell transplant. Figure 1 Figure 1. Disclosures Belsham: Celgene: Other: meeting attendance; Abbvie: Other: meeting attendance. Byrne: Incyte: Honoraria. Khan: Abbvie: Honoraria; Astellas: Honoraria; Takeda: Honoraria; Jazz: Honoraria; Gilead: Honoraria; Novartis: Honoraria. Khwaja: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Latif: Kite: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Speakers Bureau; Takeda UK: Speakers Bureau. Loke: Amgen: Honoraria; Daichi Sankyo: Other: Travel Support; Janssen: Honoraria; Novartis: Other: Travel Support; Pfizer: Honoraria. Munisamy: Jazz Pharmaceuticals: Speakers Bureau; Roche: Speakers Bureau. Murthy: Abbvie: Other: support to attend educational conferences.. Smith: Daiichi Sankyo: Speakers Bureau; Pfizer: Speakers Bureau; ARIAD: Honoraria. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dillon: Amgen: Other: Research support (paid to institution); Astellas: Consultancy, Other: Educational Events , Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Session chair (paid to institution), Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: educational events; Jazz: Other: Education events; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events.

Evaluating Venetoclax Treatment Duration When Combined with Hypomethylating Agents in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes

Background: Current literature recommends 28-day cycles of a hypomethylating agent (HMA) with continuous daily venetoclax (Ven) in select patients with newly diagnosed acute myeloid leukemia (AML). Key adverse events observed with azacitidine-Ven were grade ≥ 3 thrombocytopenia, neutropenia, and febrile neutropenia. Emerging data recommends HMA-Ven in relapsed/refractory (r/r) high-risk myelodysplastic syndrome (MDS) with a Ven duration ranging from 14-28 days of a 28-day cycle. Predominant grade ≥ 3 treatment emergent adverse events (TEAEs) also included cytopenias in this patient population. As the combination of HMA-Ven for patients with MDS and AML is increasingly utilized, practice variations in the initial duration of Ven requires evaluation. This study aims to characterize the safety profile with continuous or modified duration Ven after complete remission (CR), complete remission with incomplete hematologic recovery (CRi) or cycle 3 to further assess the safety profile of HMA-Ven due to treatment instead of disease. Methods: This is a retrospective, single center study of patients > 18 years of age with AML or MDS receiving HMA-Ven between December 1, 2017 - January 31, 2021. Patients were excluded if enrolled in an investigational protocol or received therapy at an outside hospital. To capture treatment-related neutropenia, thrombocytopenia, and other safety endpoints, patients were excluded if they received < 3 cycles of HMA-Ven, as cytopenias could be due to disease burden. Data was collected from day -21 until the completion of cycle 6 or last completed cycle. The primary end point was grade > 3 neutropenia for > 7 days. Secondary endpoints included grade > 3 anemia or thrombocytopenia for > 7 days, incidence of febrile neutropenia, antimicrobial use, dose interruption or delay, dose or duration modification, therapy discontinuation, and assessment of CR and CRi. Descriptive statistics were utilized to describe outcomes and safety endpoints were graded with the Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v.5.0). Results: 25 patients were included in analysis. The median age was 66 years (range 20-84) and 12% (n=3) had a diagnosis of MDS while 88% (n=22) had a diagnosis of AML. Most patients with AML had poor cytogenetic risk (n=18, 84%) and 28% (n=7) were treatment naïve. Prior therapies are outlined in Table 1. Ven was initiated with a 14-day duration in 60% (n=15) of patients, including 3 patients with MDS, 4 patients with r/r AML, and 4 patients with r/r AML with a prior allogeneic transplant. Many patients required a subsequent duration change of Ven throughout the evaluation period (n=13, 52%). Treatment delays of > 7 days occurred in 60% (n=15) of patients. 12 patients (48%) achieved CR or CRi and accounted for 45 evaluated cycles. Of the 12 patients, 4 started with 28-day ven, 1 with 21-day, and 7 with 14-day. Of the patients who achieved CR or CRi, there were 32 cycles with Ven 14-day durations, 7 cycles with 21-day duration, and 6 cycles of 28-day duration. Grade 3 or higher neutropenia for > 7 days was observed in 72% (n=23) of the 14-day durations and 100% of the 21-day and 28-day Ven durations. Grade 3 or higher thrombocytopenia and anemia was most common in the 28-day duration Ven at 83% (n=5) and 50% (n=3), respectively. Febrile neutropenia and treatment with antibiotic therapy had higher incidence of 67% (n=4) in the 28-day Ven duration. Most patients received treatment with antibiotic therapy (75%, n=9) and antifungal therapy (67%, n=8) after achieving CR or CRi on HMA-Ven. In those with newly diagnosed AML, 29% (n=2) and 57% (n=4) achieved CR and CRi respectively. 67% (n=2) of the MDS patients and 27% (n=4) of the r/r AML population achieved CRi. Of the 9 patients with prior HMA exposure, 2 patients achieved CRi. Conclusions: There was a high incidence of grade 3 or higher cytopenias, but a trend toward increased neutropenia, thrombocytopenia, febrile neutropenia, and infectious complications were observed in those receiving a 21-day or 28-day Ven duration after CR or CRi compared to those receiving a 14-day duration of Ven. Early decreased durations of Ven and further decreases outside the prescribing information after patients are in CR may be a reasonable and safe option for patients who are not likely to tolerate continuous Ven, such as those with prior MDS, r/r disease, or patients who have received prior allogeneic transplant. This requires further investigation. Figure 1 Figure 1. Disclosures Lei: AbbVie: Honoraria; Epizyme: Honoraria; Intervention Insights: Consultancy; Fresenius Kabi: Consultancy. Brunner: GSK: Research Funding; Agios: Consultancy; Keros Therapeutics: Consultancy; AstraZeneca: Research Funding; Aprea: Research Funding; Acceleron: Consultancy; Janssen: Research Funding; Takeda: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Fathi: Kite: Consultancy, Honoraria; Foghorn: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Trillium: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Blueprint: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Agios: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Morphosys: Consultancy, Honoraria; Ipsen: Consultancy, Honoraria. Signorelli: Bristol Myers Squibb: Consultancy; AbbVie: Honoraria.

Allogeneic Transplant and CAR-T Therapy After Autologous Transplant Failure in DLBCL: A Noncomparative Cohort Analysis

Allogeneic transplant (alloHCT) and chimeric antigen receptor modified (CAR) T-cell therapy are potentially cuarative options of diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous (auto) HCT. While the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic model can predict outcomes of alloHCT in DLBCL after autoHCT failure, corresponding models of CAR-T treatment in similar patient populations are not available. In this noncomparative registry analysis we report outcomes of DLBCL patients (≥18 years), undergoing a reduced intensity alloHCT or CAR-T therapy during 2012-2019, after a prior auto-HCT failure, and apply CIBMTR prognostic model to CAR-T recipients. 584 patients were included. The 1-year relapse, non-relapse mortality, overall survival (OS) and progression-free survival (PFS) for CAR-T treatment after autoHCT failure were were 39.5%, 4.8%, 73.4% and 55.7%, respectively. The corresponding rates in alloHCT cohort were 26.2%, 20.0%, 65.6% and 53.8%, respectively. The 1-year OS of alloHCT recipients classified as low-, intermediate- and high/very high-risk groups according to the CIBMTR prognostic score was 73.3%, 59.9%, and 46.3, respectively (p=0.002). The corresponding rates for low-, intermediate- and high/very high-risk CAR-T patients were 88.4%, 76.4%, and 52.8%, respectively (p<0.001). This registry analysis shows that both CAR-T and alloHCT can provide durable remissions in subset of DLBCL patients relapsing after a prior autoHCT. The simple, CIBMTR prognostic score can be used to identify patients at high risk of treatment failure after either procedure. Evaluation of novel relapse mitigations strategies after cellular immunotherapies are warranted in these high risk patients.