Selected Abstracts on Novel Therapies for Hematologic Malignancies


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Syed A. Abutalib, MD

Syed A. Abutalib, MD

THE 22ND CONGRESS of the European Hematology Association (EHA) was held in June in Madrid, drawing hematologists and allied professionals from every subspecialty of hematology from around the world. Among the extensive educational and scientific program, the EHA Congress provides a forum for presenting original unpublished data and sharing ideas for hematologic innovation as well as disseminating evidence-based knowledge of primary clinical relevance. 

Here are several abstracts selected from the proceedings of the 2017 EHA Congress, highlighting clinical trials on newer therapies for various types of hematologic malignancies. For full details of these study abstracts, visit https://learningcenter.ehaweb.org. 

Multiple Myeloma 

ABSTRACT S142: First-in-human multicenter study of bb2121 anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory multiple myeloma1 

Key Findings: A total of 11 patients had been infused with CAR T cells in the first 4 dose cohorts, and 9 patients had reached at least 1-month of follow-up. As of data cutoff, no dose limiting toxicities and no > grade 2 neurotoxicity or cytokine-release syndrome had been observed, although grade 1/2 cytokine-release syndrome was reported in 8 (73%) treated patients. All patients treated with doses of 15.0 107 or higher remained on study, and the overall response rate in the 9 evaluable patients is 100%, including 2 stringent complete remissions and 2 minimal residual disease–negative responses (stringent complete remissions and very good partial response). This particular CAR T-cell construct showed promising efficacy at dose levels above 5.0 107 CAR T cells. 

Practice Implications: These initial data support continued investigation of bb2121 anti-BCMA CAR T-cell therapy in relapsed/ refractory multiple myeloma. 

B-Cell Acute Lymphoblastic Leukemia 

ABSTRACT S479: Long-term survival of adult patients with B-cell acute lymphoblastic leukemia (ALL) after CD19 CAR (19-28Z) T-cell therapy2 

Key Findings: Of 51 adults with ALL received treatment, 20 were in a minimal residual disease cohort and 31 were in a morphologic cohort. Complete remission rates were 95% and 77%, respectively. However, median event-free and overall survival rates widely diverged among the 42 patients who achieved complete remission without minimal residual disease: not reached vs 6.3 months and not reached vs 17 months in the minimal residual disease (< 5% blasts) and morphologic cohorts (5% blasts), respectively. Subsequent allogeneic hematopoietic cell transplant (allo-HCT) in either cohort did not improve survival. Patients in the minimal residual disease cohort developed substantially less severe cytokine-release syndrome and neurotoxicity, and both toxicities significantly correlated with peak CAR T-cell expansion. No case of cerebral edema was observed. 

Practice Implications: Survival in relapsed B-cell ALL positively correlated with a low disease burden and did not appear to be enhanced by allo-HCT. These data strongly support the early (before morphologic relapse) incorporation of CD19 CAR T-cell therapy in B-cell ALL. 

Classical Hodgkin Lymphoma 

ABSTRACT S412: Extended follow-up of CheckMate 205: Nivolumab (Opdivo) for relapsed/refractory classical Hodgkin lymphoma after autologous HCT (auto-HCT)3 

Key Findings: In total, 243 patients were treated: 63 patients in cohort A (brentuximab vedotin [Adcetris]-naive), 80 patients in cohort B (brentuximab vedotin after auto-HCT), and 100 patients in cohort C (brentuximab vedotin before [n = 33], after [n = 58], or before and after [n = 9] auto-HCT). The overall response rate was 65% in cohort A, 68% in cohort B, and 73% in cohort C, with 29%, 13%, and 12% complete responses, respectively. The median duration of response was 20, 16, and 15 months in cohorts A, B, and C, respectively. The duration of response for patients with a complete response was 20 months for brentuximab vedotin–naive patients (cohort A) and at least 15 months for brentuximab vedotin–treated patients (cohorts B and C); the duration of response for patients with a partial response was 17 and at least 11 months, respectively. Median overall survival was not reached in any cohort. The most common drug-related serious adverse effects were infusion reactions (2%) and pneumonitis (1%). 

Clinical Implications: These data from CheckMate 205 confirm high and durable response rates to nivolumab therapy in patients with relapsed/refractory classical Hodgkin lymphoma after auto-HCT, regardless of prior brentuximab vedotin therapy. 

Follicular Lymphoma 

ABSTRACT S775: Immunotherapy with obinutuzumab (Gazyva) or rituximab (Rituxan) in 1,202 previously untreated patients with follicular lymphoma: Chemotherapy regimen analysis of GALLIUM study4 

Key Findings: After a median follow-up of 41.1 months, investigator-assessed progression-free survival remained superior for obinutuzumab chemotherapy relative to rituximab chemotherapy (hazard ratio [HR] = 0.68; 95% confidence interval: 0.54–0.87; P = .0016). 

Clinical Implications: In treatment-naive patients with follicular lymphoma, progression-free survival was superior with obinutuzumab chemotherapy relative to rituximab chemotherapy, with consistent effects across all chemotherapy regimens. Grade 3/4 and serious adverse events were more common with obinutuzumab chemotherapy. 

Myelodysplastic Syndromes 

ABSTRACT S487: Nivolumab or ipilimumab (Yervoy) with azacitidine in previously treated or untreated patients with myelodysplastic syndromes (MDS)5 

Key Findings: A total of 54 patients (86%) were evaluable for response and toxicity, including 21 treated with front-line azacitidine plus nivolumab as well as 15 and 18 patients treated with nivolumab or ipilimumab after failure to respond to hypomethylating agents, respectively. The stopping rule for toxicity was not met in any of the cohorts. Delays of therapy due to adverse events were required in nine patients: rash (one), adrenal insufficiency (one), colitis (one), thyroiditis (two), pneumonitis (three), and nephritis (one). Early 8-week mortality occurred in one patient due to a nonrelated intracranial hemorrhage. 

FEATURED ABSTRACTS FROM EHA CONGRESS

  • First-in-human study of bb2121 anti-BCMA CAR T-cell therapy for relapsed/ refractory multiple myeloma (Abstract S142)
  • CD19 CAR T-cell therapy for adults with B-cell ALL (Abstract 479)
  • Nivolumab for relapsed/refractory classical Hodgkin lymphoma after autologous hematopoietic transplant (Abstract S412)
  • Immunochemotherapy with obinutuzumab or rituximab in previously untreated follicular lymphoma (Abstract S775)
  • Nivolumab or ipilimumab with azacitidine in previously treated or untreated MDS (Abstract S487)
  • Venetoclax plus low-dose cytarabine in treatment-naive AML (Abstract S473)
  • Bosutinib vs imatinib in newly diagnosed CML (Abstract S425)

The overall response rate was 80% (13 of 21 patients) in the azacitidine plus nivolumab cohort, including 6 complete responses. The overall response rate was 0% and 30% (5 of 18 patients) in the nivolumab and ipilimumab arms, respectively. Therefore, the stopping rule for response was met on the nivolumab arm, and enrollment was stopped after patient 15. 

No differences in response were observed based on bone marrow expression of programmed cell death protein 1 (PD-1). 

Practice Implications: Preliminary results indicate that PD-1 blockade with nivolumab in combination with azacitidine in untreated higher-risk patients with MDS is associated with a tolerable safety profile and clinical activity. Single-agent ipilimumab is capable of inducing responses in previously treated patients with MDS. Single-agent nivolumab did not show clinical activity. 

Acute Myeloid Leukemia 

ABSTRACT S473: Venetoclax (Venclexta) plus subcutaneous low-dose cytarabine in treatment-naive patients with acute myeloid leukemia (AML) who are 65 years or older and unfit for conventional induction chemotherapy6 

Key Findings: In total, 61 patients, including 8 patients from a phase I trial, were treated with venetoclax at the recommended phase II dose (RP2D) of 600 mg (median age 74 years; Eastern Cooperative Oncology Group [ECOG] performance status of 1 or 2 70%; adverse karyotypes 31%; secondary AML 44%; prior hypomethylating agent 28%). Grade 3/4 adverse events were febrile neutropenia (34%), hypokalemia (15%), hypophosphatemia (13%), and hypertension (10%). No patient had clinical tumor-lysis syndrome, but one patient had laboratory tumor-lysis syndrome. The day 30- and day-60 mortality rates were 3% and 15%, respectively. The complete response with incomplete marrow recovery rate was 54% (33 of 61 patients; 21% complete response and 33% incomplete marrow recovery). The overall response rate was 61% (37 of 61 patients). Among response-evaluable patients, those achieving an objective response had longer survival than those who did not achieve an objective response. 

Practice Implications: Venetoclax plus low-dose cytarabine exhibited an acceptable safety profile and durable efficacy. The overall response rate highly correlated with overall survival, with better survival observed in responders compared with nonresponders. A planned phase III randomized trial has commenced (ClinicalTrials.gov identifier NCT03069352). 

Chronic Myeloid Leukemia 

ABSTRACT S425: Initial results with bosutinib (Bosulif) vs imatinib in newly diagnosed chronic myeloid leukemia (CML) from the BFORE trial7 

Key Findings: The primary endpoint of major molecular response rate at 12 months was significantly higher with bosutinib vs imatinib in the modified intent-to-treat population (47.2% vs 36.9%; P = .02) as well as in the intent-to-treat population of all randomized patients (46.6% vs 36.2%; P < .02). In the modified intent-to-treat population, time to major molecular response was shorter for bosutinib (hazard ratio [HR] = 1.34 based on cumulative incidence; P < .02). The rate of complete cytogenetic response by 12-months was also significantly higher with bosutinib than imatinib (77.2% vs 66.4%; P < .008), with time to complete cytogenetic response being shorter for bosutinib (HR = 1.38; P ≤ .001). The rate of BCR-ABL transcripts ≤ 10% international scale at 3 months was higher with bosutinib vs imatinib (75.2% vs 57.3%; P < .001); the rates of deep molecular response over time were also generally higher with bosutinib. Safety data for treated patients were consistent with the known safety profiles of bosutinib and imatinib. 

Practice Implications: Patients treated with bosutinib had significantly higher rates of 12-month major molecular response and complete cytogenetic response and achieved responses quicker than those treated with imatinib. The primary results from this study suggest bosutinib may be an important treatment option for patients with newly diagnosed chronic-phase CML. This multicenter phase III study is ongoing but not recruiting participants (ClinicalTrials.gov identifier NCT02130557). ■

DISCLOSURE: Dr. Abutalib reported no conflicts of interest. 

REFERENCES 

1. Lin Y, Berdeja J, Raje N, et al: First-in-human multicenter study of bb2121 anti-BCMA CAR T cell therapy for relapsed/refractory multiple myeloma: Updated results. 2017 EHA Congress. Abstract S142. Presented June 23, 2017. 

2. Park J, Riviere I, Wang X, et al: Durable long-term survival of adult patients with B-ALL after CD19 CAR (19-28Z) T cell therapy. 2017 EHA Congress. Abstract S479. Presented June 24, 2017. 

3. Engert A, Fanale M, Santoro A, et al: Nivolumab for relapsed/refractory classical Hodgkin lymphoma after autologous hematopoietic transplant: Full results after extended follow-up of the multicohort multicenter phase 2 CheckMate 205 trial. 2017 EHA Congress. Abstract S412. Presented June 24, 2017. 

4. Hiddemann W, Barbui AM, Albendea MAC, et al: Immunochemotherapy with obinutuzumab or rituximab in previously untreated follicular lymphoma in the randomized phase III GALLIUM study: Analysis by chemotherapy regimen. 2017 EHA Congress. Abstract S775. Presented June 25, 2017. 

5. Garcia-Manero G, Daver N, Montalban-Bravo G, et al: An update of phase II study of nivolumab or ipilimumab with azacitidine in patients with previously treated or untreated myelodysplastic syndromes. 2017 EHA Congress. Abstract S487. Presented June 24, 2017. 

6. Wei AH, Strickland SA, Roboz GJ, et al: Updated safety and efficacy results of phase 1/2 study of venetoclax plus low dose cytarabine in treatment-naive acute myeloid leukemia patients aged ≥ 65 years and unfit for standard induction therapy. 2017 EHA Congress. Abstract S473. Presented June 24, 2017. 

7. Brümmendorf TH, Gambacorti-Passerini C, Deininger M, et al: Bosutinib vs imatinib for newly diagnosed chronic myeloid leukemia: Initial results from the BFORE trial. 2017 EHA Congress. Abstract S425. Presented June 24, 2017. 



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