Ribera, Josep‐María

Abstract The past decade has witnessed remarkable advances in deciphering the pathophysiology of acute lymphoblastic leukemia (ALL) and in developing novel targeted therapies. Basic research and genomic mapping have identified new prognostic biomarkers, targets, and ALL subtypes (e.g., Philadelphia‐like ALL). The ongoing therapeutic revolution in ALL is driven by the addition to the treatment arsenal of therapies that target the ABL fusions, like the BCR::ABL1 tyrosine kinase inhibitors, as well as novel agents that target CD19 and CD22: the CD22 antibody–drug conjugate inotuzumab ozogamicin, the bispecific CD3/CD19 T‐cell engager antibody blinatumomab, and CD19 chimeric antigen receptor T‐cell therapies. These combinations have improved the long‐term survival rates in B‐cell ALL to 70%, and in Philadelphia chromosome‐positive ALL to 80%–90%. The desired goals are to achieve cure rates comparable to those in pediatric ALL and to reduce or eliminate the need for prolonged intensive/maintenance chemotherapy and associated toxicities.

Background: Minimal residual disease (MRD) is an established, prognostic indicator for patients with acute lymphoblastic leukemia (ALL), including Philadelphia chromosome-positive (Ph+) ALL. The objective of this study was to evaluate the association between MRD and long-term outcomes (event-free survival [EFS] and overall survival [OS]) in adult patients with Ph+ ALL receiving first-line therapy. Methods: A systematic literature review (SLR) was performed to identify eligible studies, including interventional and observational studies reporting survival outcomes by MRD status in adults ≥18 years of age with Ph+ ALL receiving first-line therapy. Key outcomes and data elements of interest were EFS, OS, and MRD or MRD-negative complete remission (CR) at end of induction (EOI). Aggregate study-level and individual patient data (IPD) meta-analyses were conducted. The IPD approach included a log-level MRD analysis to evaluate the concordance of deepening levels of molecular response with long-term EFS or OS in patients with CR and an analysis evaluating the utility of MRD-negative CR over CR alone. The analyses were conducted using frequentist and Bayesian approaches with fixed-effects and random-effects models. Kaplan-Meier method with log-rank tests was used for survival analysis. Where applicable, Cox regression method with and without adjustment for prognostic factors were applied. Results: The SLR identified 19 publications (18 unique studies), 10 (9 unique studies) of which had sufficient MRD and EFS/OS data. Nine studies (n=704) were included in the aggregate study-level analysis; 3 of the 9 studies (Phase II AP24534-11-001 [Jabbour et al. 2015], Phase II GIMEMAINCB 84344-201 [Martinelli et al. 2017], and Phase III GRAAPH-2005 RCT [Chalandon et al. 2015]) had IPD available. MRD was assessed by polymerase chain reaction in all 9 studies. Findings from the aggregate study-level meta-analysis demonstrated a significant long-term survival benefit (EFS and OS) in favor of patients with MRD-negative CR. This significant benefit was generally consistent across analysis types (base-case or sensitivity analyses), analytic models (fixed- or random-effects), and approaches (frequentist or Bayesian). Evidence from the IPD analysis, based on patients with CR, was mostly consistent with the aggregate study-level meta-analysis, supporting MRD-negative CR at the EOI as being predictive of EFS or OS. Log-level MRD analysis showed that patients who are in CR with deeper molecular response ( BCR::ABL1/ABL1 ≤0.01%) at EOI have significantly better long-term EFS and OS compared with patients with other levels of MRD (ie, BCR::ABL1/ABL1 >0.01%). This significant long-term survival benefit was also demonstrated in patients with MRD-negative CR ( BCR::ABL1/ABL1 ≤0.01%) at EOI compared with patients who were MRD-positive ( BCR::ABL1/ABL1 >0.01%) ( Table 1) or based on achievement of CR alone (regardless of BCR::ABL1/ABL1 values). Results from the IPD analysis standardized for outcome definition, with and without adjustment for prognostic factors (age, gender, white blood cell count at baseline, and stem cell transplant), were consistent with the findings from the log-level MRD analysis. The analysis showed a significant association between MRD-negative/MRD-negative CR status (ie, BCR::ABL1/ABL1 ≤0.01% threshold) at EOI with improved long-term EFS and OS. The results were significant for EFS in both the adjusted and unadjusted models. The OS results were significant only in the unadjusted model. Conclusions: These analyses indicate that a deeper molecular response at EOI results in better long-term EFS and OS; MRD-negative CR has a greater prognostic value than CR and is strongly associated with long-term EFS and OS in patients with Ph+ ALL. Acknowledgement: The authors acknowledge APHP, who provided the individualized patients data for the GRAAPH study.

Abstract Introduction: Current therapies for patients with r/r ALL who have had prior allogeneic hematopoietic stem cell transplantation (alloHSCT) have very poor outcomes. Improvements in the therapeutic options available for adult r/r ALL are required. Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct that redirects cytotoxic T cells to lyse CD19-positive B cells. The aim of the present analysis was to characterize a subset of patients with r/r ALL and prior alloHSCT before treatment with blinatumomab from a large confirmatory open-label, single-arm, multicenter phase 2 study (Topp MS et al Lancet Oncol 2015;16(1):57-66). Methods: Eligible patients (≥18 years) had Philadelphia chromosome-negative r/r ALL with 1 of the following negative prognostic factors: primary refractory, first relapse within 12 months of first remission, relapse within 12 months of alloHSCT, or second or greater salvage. Patients with active acute or chronic graft-versus-host disease (GvHD) were excluded. Patients were required to stop all immunosuppressive GvHD therapy within 2 weeks before starting blinatumomab. A total of 189 patients were enrolled and received blinatumomab by continuous intravenous infusion (4 weeks on/2 weeks off) for up to 5 cycles. The primary endpoint was complete remission or complete remission with partial hematologic recovery (CR/CRh) within the first 2 cycles. Secondary endpoints included overall survival (OS), relapse-free survival (RFS), and adverse events (AEs). Results: 64 (34%) patients had received alloHSCT before study enrollment; 10 patients had 2 prior alloHSCTs. Donor types primarily included 29 (45%) matched sibling and 31 (48%) unrelated, with 34 (59%) patients receiving myeloablative conditioning regimens (donor chimerism data were unavailable). Among those with prior alloHSCT, median age (range) was 32 (19-74) years. At baseline, 23 (36%) patients had 1 prior relapse, 24 (38%) had 2 prior relapses, and 17 (27%) had ≥3 prior relapses; 28 (44%) patients had relapsed post-alloHSCT. Of the 55 patients who had received previous salvage therapy, 38 (69%) had received salvage therapy after last alloHSCT and prior to blinatumomab. Median time (range) between the last alloHSCT and subsequent relapse was 6 (1-33) months. Median time from last prior alloHSCT to first dose of blinatumomab was 10 (3-40) months. Nineteen (30%) patients had a history of GvHD, and 42 (66%) had ≥50% bone marrow blasts at start of treatment as assessed by a central laboratory. Patients received blinatumomab for a median of 2 (1-5) cycles. Efficacy data are presented in Table 1. Overall, 45% (29/64; 95% confidence interval [CI], 33-58) of patients achieved CR/CRh within the first 2 cycles, with similar rates of remission also observed in the alloHSCT-naïve (42%; 52/125) group. With a median follow-up of 8.8 months, median (95% CI) OS was 8.4 (4.2-9.4) months for the 64 patients with prior alloHSCT treated with blinatumomab. Of the 29 responders (CR, n=18 and CRh, n=11), 22 (76%) had a minimal residual disease (MRD) response and 19 (66%) achieved a complete MRD response. Median RFS (95% CI) was 6.1 (5.0-7.7) months. 9/29 (31%) responders subsequently underwent another alloHSCT. In total, 56 (88%) patients had grade ≥3 treatment-emergent AEs, with the most frequent including neutropenia (22%), febrile neutropenia (20%), anemia (17%), and thrombocytopenia (14%). Six patients reported treatment-emergent GvHD (two grade ≥ 3) during blinatumomab treatment, 3 of whom had GvHD in skin. Eight patients had fatal treatment-emergent AEs, which included 1 due to gastrointestinal hemorrhage, 1 due to respiratory failure, and 6 due to infection/infestation; 1 of these (candida infection) was considered to be possibly related to treatment by the investigator. Of the subjects who had treatment-emergent fatal AEs, none were in remission at the time of death. Summary: In this heavily pretreated group of patients with r/r ALL and prior alloHSCT, single-agent blinatumomab was able to induce a CR/CRh rate of 45%, with an AE profile consistent with that previously reported. Post-alloHSCT patients who had relapsed performed equally as well as those without prior alloHSCT. To prolong remission in this poor outcome patient group, the addition of other immunotherapies to the treatment regimen may be considered for future investigations. Disclosures Stein: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Research Funding. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Goekbuget:Erytech: Consultancy; Gilead Sciences: Consultancy; Kite: Consultancy; Mundipharma: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bayer: Equity Ownership; Sanofi: Equity Ownership; GlaxoSmithKline: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Eusapharma/Jazz: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; SigmaTau: Consultancy, Honoraria, Research Funding. Bargou:Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Patents & Royalties: Patent for blinatumomab; University of Wuerzburg, Germany: Employment; GEMoaB GmbH: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rambaldi:Roche: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Celgene: Research Funding; Pierre Fabre: Honoraria. Zhang:Amgen: Employment, Equity Ownership. Zimmerman:Amgen: Employment, Equity Ownership. Forman:Mustang: Research Funding; Amgen: Consultancy.

Abstract Introduction: Guadecitabine (SGI-110) is a novel next-generation HMA administered as a small volume subcutaneous (SC) injection which results in extended decitabine exposure. Phase 2 studies have been conducted in TN-AML patients who were not candidates for intensive chemotherapy using two different doses and schedules of guadecitabine. We report here a comparative efficacy and safety analysis of the 5-day and 10-day regimens. Methods: TN-AML patients who were not candidates for intensive chemotherapy based on age (≥ 65 y), poor performance status (PS 2), comorbidities, or poor risk cytogenetics were enrolled in 2 separate treatment cohorts in the Phase 2 study. In the first cohort, patients were randomized (1:1) to either 60 mg/m2/d or 90 mg/m2/d on Days 1-5 (5-day regimen). In the second cohort, patients were treated with 60 mg/m2/d on Days 1-5 and Days 8-12 (10-day regimen) for up to 4 cycles, followed by 60 mg/m2/d Days 1-5 in subsequent cycles. Cycles were scheduled every 28 days for both regimes with dose reductions/delays allowed based on response and tolerability. Patients remained on treatment as long as they continued to benefit with no unacceptable toxicity. The primary endpoint was the composite Complete Response (CRc): Complete Response (CR) + CR with incomplete platelet recovery (CRp) + CR with incomplete neutrophil recovery (CRi) using modified International Working Group (IWG) criteria (Cheson et al, 2003). Secondary endpoints included overall survival (OS), and safety. Results: There was no difference in efficacy or safety between 60 and 90 mg/m2/d on the 5-day regimen (Yee et al, European Hematology Association meeting 2014, S647), so data are reported here for the two doses combined on the 5-day cohort. There were 51 patients treated in the 5-day regimen cohort and 52 treated with the 10-day regimen. There was no statistically significant difference in patient characteristics between the 2 regimens; median age 77.9 vs. 77.3 years ; male 59% vs. 65%; PS 2 or higher 35% vs. 40%; median BM blasts 40.0% vs. 49.5%; poor risk cytogenetics 46% vs. 43% for the 5-day and 10-day cohorts, respectively. Follow up of the 10-day cohort patients was shorter as it started after completion of enrolment of the 5-day cohort. The median follow up was 25.7 and 12.4 months and median number of cycles was 5 (range 1-26) and 3 (range 1-13) for the 5-day and 10-day cohorts, respectively. There was no significant difference in the primary efficacy endpoint, CRc, between the 2 regimens (p=0.43). CRc was achieved in 29/51 patients (57%) on the 5-day regimen (19 CR, 3 CRp, and 7 CRi) and in 25/52 patients (48%) on the 10-day regimen (16 CR, 5 CRp, and 4 CRi). Median OS was 10.5 and 8.7 months for the 5-day and 10-day cohorts, respectively (p=0.89). The 30, 60, and 90-day all-cause mortality rates were not statistically significant between the two cohorts: 5.9%, 15.7%, and 21.6% on the 5-day regimen and 1.9%, 17.3%, and 28.8% on the 10-day regimen. The most common Grade ≥3 AEs regardless of relationship to guadecitabine were: febrile neutropenia 59% vs. 60%, thrombocytopenia 47% vs. 38%, neutropenia 39% vs. 33%, anemia 27% vs. 19%, pneumonia 24% vs. 27%; and sepsis 12% vs. 19%, for the 5-day and 10-day cohorts respectively, none of which was statistically significant. Fifteen patients remain on treatment (5 from the 5-day cohort and 10 from the 10-day cohort). Conclusions: Guadecitabine is clinically active with a good safety profile in TN-AML patients not candidates for intensive chemotherapy. Unlike in relapsed/refractory AML, where the 10-day regimen of guadecitabine showed a trend toward improved efficacy (Roboz et al, Annals of Oncology 25 Supplement 4, 2014), there was no significant difference in either efficacy or safety between the 5-day and 10-day regimens in newly diagnosed AML patients. Guadecitabine 60 mg/m2/d SC Days 1-5 is currently being investigated in an 800-patient multicenter randomized phase 3 study in TN-AML patients unfit to receive intensive chemotherapy (ASTRAL-1 Phase 3 clinical trial: ClinicalTrials.gov reference NCT02348489). Disclosures Kropf: Teva Pharmaceuticals: Consultancy. O'Connell:Celgene: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Griffiths:Astex: Research Funding; Alexion Pharmaceuticals: Honoraria; Celgene: Honoraria. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Savona:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Rosenblat:Astex Pharmaceuticals, Inc.: Research Funding. Berdeja:Celgene: Research Funding; Onyx: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Array: Research Funding; Curis: Research Funding; Acetylon: Research Funding; MEI: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Takeda: Research Funding. Wilson:Astex Pharmaceuticals, Inc.: Employment. Lowder:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Issa:Janssen: Consultancy; Astex Pharmaceuticals, Inc.: Consultancy.