Sunitinib in relapsed or refractory diffuse large B-cell lymphoma: a clinical and pharmacodynamic phase II multicenter study of the NCIC Clinical Trials Group

There are limited effective therapies for most patients with relapsed diffuse large B-cell lymphoma (DLBCL). We conducted a phase II trial of the multi-targeted vascular endothelial growth factor receptor (VEGFR) kinase inhibitor, sunitinib, 37.5 mg given orally once daily in adult patients with relapsed or refractory DLBCL. Of 19 enrolled patients, 17 eligible patients were evaluable for toxicity and 15 for response. No objective responses were seen and nine patients achieved stable disease (median duration 3.4 months). As a result, the study was closed at the end of the first stage. Grades 3—4 neutropenia and thrombocytopenia were observed in 29% and 35%, respectively. There was no relationship between change in circulating endothelial cell numbers (CECs) and bidimensional tumor burden over time. Despite some activity in solid tumors, sunitinib showed no evidence of response in relapsed/refractory DLBCL and had greater than expected hematologic toxicity

Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12

PURPOSE: For patients with relapsed or refractory aggressive lymphoma, we hypothesized that gemcitabine-based therapy before autologous stem-cell transplantation (ASCT) is as effective as and less toxic than standard treatment. PATIENTS AND METHODS: We randomly assigned 619 patients with relapsed/refractory aggressive lymphoma to treatment with gemcitabine, dexamethasone, and cisplatin (GDP) or to dexamethasone, cytarabine, and cisplatin (DHAP). Patients with B-cell lymphoma also received rituximab. Responding patients proceeded to stem-cell collection and ASCT. Coprimary end points were response rate after two treatment cycles and transplantation rate. The noninferiority margin for the response rate to GDP relative to DHAP was set at 10%. Secondary end points included event-free and overall survival, treatment toxicity, and quality of life. RESULTS: For the intention-to-treat population, the response rate with GDP was 45.2%; with DHAP the response rate was 44.0% (95% CI for difference, -9.0% to 6.7%), meeting protocol-defined criteria for noninferiority of GDP (P = .005). Similar results were obtained in a per-protocol analysis. The transplantation rates were 52.1% with GDP and 49.3% with DHAP (P = .44). At a median follow-up of 53 months, no differences were detected in event-free survival (HR, 0.99; stratified log-rank P = .95) or overall survival (HR, 1.03; P = .78) between GDP and DHAP. Treatment with GDP was associated with less toxicity (P < .001) and need for hospitalization (P < .001), and preserved quality of life (P = .04). CONCLUSION: For patients with relapsed or refractory aggressive lymphoma, in comparison with DHAP, treatment with GDP is associated with a noninferior response rate, similar transplantation rate, event-free survival, and overall survival, less toxicity and hospitalization, and superior quality of life

Multicenter Validation of a Personalized Model to Predict Hypomethylating Agent Response in Myelodysplastic Syndromes (MDS)

Background While hypomethylating agents (HMAs) can improve cytopenias and even survival for MDS patients (pts), only 30-40% of pts respond to HMAs. Predicting response or resistance to therapy can improve pt outcomes, decrease cost and toxicities, and suggest alternative therapies when response is unlikely. No clinical or molecular model can reliability predict response or resistance to HMAs. We developed and validated a model to provide personalized predictions of response or resistance to HMAs during 12 weeks of treatment by monitoring changes in blood counts during therapy. Methods MDS pts treated with HMAs (azacitidine or decitabine) at Cleveland Clinic (314 pts) and the Moffit Cancer Center (100) and had their CBCs with differential monitored every 1-2 weeks in the first 12 weeks of therapy compromised the training cohort. The final model was externally validated in 80 MDS pts treated with HMAs at Sunnybrook hospital. Responses were defined per 2006 IWG criteria and pts with complete response (CR), marrow CR, partial response (PR), or hematologic improvement (HI) were considered responders. Time series analysis (analysis of serial changes in blood count parameters) using machine learning technology was used to develop the model, analogous to voice recognition algorithms such as Apple's Siri and Alexa, in which the sequence of words allows these algorithms to understand sentences. Changes in blood counts and monitoring the patterns of these changes during HMA therapy similarly can predict response/resistance to treatment. The area under the curve (AUC) was used to evaluate the performance of the final model. A feature importance algorithm was used to define the variables that most impacted the algorithm's decision for a given pt. Results For 494 included pts from all cohorts, the median age was 72 years (range: 40-94), 145 (29%) were female. Pts' IPSS-R scores at the time of treatment were: very low 4%; low 21%; intermediate 24%; high 21%; and very high 22%. Responses included: 56 (11%) complete remission (CR), 17 (3%) marrow CR, 6 (3%) partial remission (PR), and 143 (29%) hematologic improvement (HI). When trained exclusively on serial CBC values (adding other clinical or molecular values did not improve the model's performance), the model achieved an AUC of 0.82 in a cross-validated train/test schema and a similar AUC of 0.78 when it was applied to the Sunnybrook cohort. Feature importance algorithms identified improvements in hemoglobin from baseline between days 21-30 of therapy, improvement in platelets between days 51 and 60, changes in monocyte % between days 41 and 50, and changes in MCV and RDW between days 31 and 60 as predictors of response, Figure 1a. The model also can provide a personalized heatmap that summarizes the variables that impacted the response or resistance to HMAs and are specific for a given pt, Figure 1b, 1c. Conclusions We developed and externally validated a personalized prediction model that uses changes in blood counts during the initial 3 cycles of HMA therapy and can predict response or resistance to treatment with high accuracy. The model can provide personalized explanations of the variables that inform a given outcome. It can be used to develop novel clinical trial designs in which pts who are predicted not to respond within 3 cycles of HMA therapy can receive an investigational agent in addition to continuing HMA or change treatment entirely, whereas patients who are predicted to respond continue to receive HMA monotherapy. Disclosures Sallman: Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy; Celgene, Jazz Pharma: Research Funding. Buckstein:Celgene: Research Funding; Takeda: Research Funding; Celgene: Honoraria; Astex: Honoraria; Novartis: Honoraria. Brunner:Forty Seven, Inc: Consultancy; Biogen: Consultancy; Acceleron Pharma Inc.: Consultancy; Jazz Pharma: Consultancy; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Xcenda: Consultancy; GSK: Research Funding; Janssen: Research Funding; Astra Zeneca: Research Funding; Celgene/BMS: Consultancy, Research Funding. Mukherjee:Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees; Aplastic Anemia and MDS International Foundation: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squib: Honoraria; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EUSA Pharma: Consultancy. Komrokji:Abbvie: Honoraria; Agios: Speakers Bureau; BMS: Honoraria, Speakers Bureau; Jazz: Honoraria, Speakers Bureau; Incyte: Honoraria; Acceleron: Honoraria; Geron: Honoraria; Novartis: Honoraria. Maciejewski:Novartis, Roche: Consultancy, Honoraria; Alexion, BMS: Speakers Bureau. Sekeres:BMS: Consultancy; Pfizer: Consultancy; Takeda/Millenium: Consultancy. Nazha:Jazz: Research Funding; Incyte: Speakers Bureau; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee

Hematologic Improvement-Neutrophil and -Platelet in the MEDALIST Trial: Multilineage Data from a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept to Treat Anemia in Patients with Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions

Introduction: Lower-risk MDS is characterized by anemia and ineffective erythropoiesis leading to RBC transfusion dependence. Effective treatment for anemia remains an unmet medical need. Patients with MDS may also experience additional cytopenias that may complicate treatment and contribute to infections and bleeding events. Here, we report hematologic improvement (HI) outcomes for patients in the MEDALIST trial (ClinicalTrials.gov identifier: NCT02631070), a phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of luspatercept, a first-in-class erythroid maturation agent that binds select TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. Methods: Eligible patients in the MEDALIST trial were adults with anemia due to Very low-, Low-, or Intermediate-risk MDS with RS according to the Revised International Prognostic Scoring System; were refractory, intolerant, or ineligible to receive erythropoiesis-stimulating agents (ESAs); and required RBC transfusions. Patients received luspatercept (starting dose of 1.0 mg/kg and titration up to 1.75 mg/kg, if needed) or placebo subcutaneously every 3 weeks for ≥ 24 weeks. Platelet and neutrophil counts were assessed by the central laboratory. Secondary endpoints included HI-neutrophil (HI-N) and -platelet (HI-P) responses, using International Working Group 2006 criteria, over any consecutive 56-day period. Mean changes from baseline in platelets and neutrophils were also evaluated. Results*: A total of 94.8% patients in the luspatercept arm and 97.4% in the placebo arm had refractory cytopenia with multilineage dysplasia and RS at baseline. Mean neutrophil and platelet counts at baseline for patients in the luspatercept arm were 2.8 x 109/L and 259 x 109/L, respectively, and in the placebo arm were 2.7 x 109/L and 252 x 109/L, respectively. Neutropenia (< 1 x 109/L) was confirmed at baseline in 15 (9.8%) and 10 (13.2%) patients in the luspatercept and placebo arms, respectively. Fifty-one (33.3%) patients in the luspatercept arm and 22 (28.9%) in the placebo arm received granulocyte colony-stimulating factor in combination with ESAs prior to randomization. A total of 8 (5.2%) and 6 (7.9%) patients receiving luspatercept and placebo, respectively, had baseline thrombocytopenia (< 100 x 109/L); no patients received prior platelet transfusions. Fifteen (9.8%) and 10 (13.2%) patients in the luspatercept and placebo arms, respectively, were evaluable for HI-N (i.e. baseline neutrophils < 1 x 109/L); 3/15 (20%) of those receiving luspatercept and 1/10 (10%) of those receiving placebo achieved HI-N in Weeks 1-48. Among patients who were evaluable for HI-P (i.e. baseline platelets < 100 x 109/L), 5/8 (62.5%) of those receiving luspatercept and 2/6 (33%) of those receiving placebo achieved HI-P in Weeks 1-48 (Table). None of the luspatercept HI-P responders received platelet transfusions. Mean changes from baseline in neutrophils of 0.94 x 109/L with luspatercept and 0.04 x 109/L with placebo were observed at Week 15, with early increases reported for luspatercept by Day 8 (0.86 vs 0.08 x 109/L for placebo). Mean increases in neutrophils at Day 8 occurred in both luspatercept responders (by MEDALIST primary endpoint; 1.0 x 109/L) and non-responders (0.8 x 109/L). Mean changes from baseline in platelets of 29 x 109/L were observed with luspatercept and 0.9 x 109/L with placebo by Week 12, but early increases were observed with luspatercept by Day 8 (18 vs 3 x 109/L for placebo) and mean increases in platelets at Day 8 occurred in both luspatercept responders (21.4 x 109/L) and non-responders (16.5 x 109/L). No patients in either arm experienced grade 3 or 4 treatment-emergent thrombocytopenia. Treatment-related grade 3 or 4 neutropenia was reported in 1 (0.7%) patient receiving luspatercept and 1 (1.3%) patient receiving placebo. Conclusions: Although only a minority of patients were evaluable for HI-P/HI-N response based on entry criteria for the study, luspatercept treatment resulted in a mean increase from baseline in platelet and neutrophil counts in most patients overall vs placebo, regardless of response status. These improvements were observed early following treatment initiation and then stabilized. Luspatercept did not contribute to the worsening of cytopenias vs placebo. *Data cutoff: May 8, 2018. Disclosures Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Mufti:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Aprea: Research Funding. Buckstein:Takeda: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Santini:Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria. Díez-Campelo:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Finelli:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Ito:Celgene Corporation: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Rampersad:Celgene Corp: Employment, Equity Ownership. Sinsimer:Celgene Corporation: Employment, Equity Ownership. Linde:Fibrogen, Inc.: Equity Ownership; Abbott Laboratories, Inc.: Equity Ownership; Acceleron Pharma: Employment, Equity Ownership. Platzbecker:Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Komrokji:Alexion: Speakers Bureau; Incyte: Consultancy; Janssen: Consultancy; Agios: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Jazz: Speakers Bureau; DSI: Consultancy; Novartis: Speakers Bureau. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis

MDS-179: Clinical Benefit of Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS) and High Transfusion Burden (HTB) in the Phase 3 MEDALIST Study

Patients with LR-MDS and anemia who have HTB have very few treatment options and represent a patient population with significant clinical unmet need. To evaluate the clinical benefit of luspatercept in HTB patients with LR-MDS from the MEDALIST trial. Eligible patients were aged ≥18 years; had IPSS-R-defined LR-MDS with ring sideroblasts (RS); were refractory, intolerant, or unlikely to respond to erythropoiesis-stimulating agents (serum erythropoietin > 200 U/L); and had anemia requiring regular RBC transfusions. All patients provided informed written consent. 229 patients were randomized 2:1 to luspatercept (starting dose 1.0 mg/kg; titration up to 1.75 mg/kg allowed) or placebo subcutaneously every 3 weeks. HTB was defined as ≥6 RBC units transfused/8 weeks. 153 patients were randomized to luspatercept and 76 to placebo; 66 and 33 had HTB at baseline, respectively. As of 01 JULY, 2019, 23/66 (34.8%) and 12/66 (18.2%) luspatercept-treated HTB patients achieved a ≥50% and ≥75% reduction in RBC units transfused over at least 24 weeks compared to baseline, respectively, versus 3/33 (9.1%; P=0.0063) and 1/33 (3.0%; P=0.0363) HTB placebo patients. 6/66 (9.1%) luspatercept-treated HTB patients and 1/33 (3.0%) placebo-treated HTB patient achieved RBC-transfusion independence (RBC-TI) ≥ 8 weeks in Weeks 1–24 (P=0.2699). Median (range) time to achieve RBC-TI was 50.0 days (1.0–100.0) with luspatercept; median (range) duration of longest RBC-TI episode in luspatercept-treated patients was 42.6 weeks (8.4–81.1). Mean number of transfusion events in Weeks 1–24 was 9.2 for luspatercept-treated patients versus 12.4 in the placebo arm (hazard ratio [95% confidence interval] 0.794 [0.660–0.956]). 65/66 (98.5%) luspatercept- and 29/33 (87.9%) placebo-treated HTB patients reported ≥1 treatment-emergent adverse event (TEAE); 11/66 (16.7%) and 3/33 (9.1%) patients, respectively, reported ≥1 TEAE leading to discontinuation. 28/66 (42.4%) luspatercept- and 15/33 (45.5%) placebo-treated patients reported ≥1 serious TEAE. The incidence of grade 3–4 TEAEs in HTB patients was similar between treatment arms (53.0% for luspatercept vs 54.5% for placebo). HTB patients with LR-MDS with RS receiving luspatercept had clinically significant reductions in RBC transfusion burden and reduced number of transfusion events. Luspatercept was well tolerated in HTB patients, consistent with the overall study population