Abstract
Background: The treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has been revolutionized with the introduction of tyrosine kinase inhibitors (TKIs) and the combination of these agents with chemotherapy. Blinatumomab is a bispecific anti-CD3/CD19 monoclonal antibody with clinical activity as single-agent in the relapsed/refractory (R/R) setting and independent of BCR-ABL1 mutational status, including T315I. The combination of blinatumomab with a TKI may further improve outcomes, including higher rate of eradication of minimal residual disease (MRD) without need for chemotherapy.
Methods: We evaluated the efficacy and safety of patients who received blinatumomab plus a TKI for relapsed/refractory (R/R) Ph+ ALL and chronic myeloid leukemia in lymphoid blast crisis (CML-LBC). Blinatumomab was administered at a standard dose of 9 mcg/day in the first week of the first cycle then the dose was escalated to 28 mcg/day by continuous infusion for 3 weeks and then 28 mcg/day for 4 weeks in the second cycle, repeated every 6 weeks with 4 weeks on and 2 weeks off. The TKI was administered concomitantly with blinatumomab, beginning on day 1 of the first cycle. Blinatumomab was given for up to 4 cycles in combination with a BCR-ABL TKI. Efficacy outcomes included overall response rate (ORR), MRD negativity and overall survival (OS).
Results: Thirteen patients with a median age of 61 years (range, 30-77) were treated, including 10 with R/R Ph+ ALL and 3 with CMP-LBC. The median number of prior chemotherapy regimens was 2 (range, 1-3) and median number of prior TKIs was 2 (range, 1-4). The TKIs used included: ponatinib 30 mg (n=8), dasatinib 100 mg (n=4) and bosutinib 300 mg (n=1). Six patients were treated for overt hematological disease and 7 were treated for positive MRD. Patient characteristics and response to therapy are shown in Table 1. Of the 6 patients with morphologic disease, 4 (67%) responded with 3 achieving complete remission and negative MRD by both flow cytometry (FC) and PCR (including one patient with T315I mutation). All 7 patients treated for positive MRD achieved negative MRD by flow cytometry and polymerase chain reaction after a median of one cycle (range, 1-2). The median number of administered cycles of blinatumomab was 2 (range, 1-4). Overall, the complete hematologic, cytogenetic and molecular response (CMR) rates were 57% (4/7), 75% (6/8), and 77% (10/13), respectively. Three patients in CMR underwent subsequent allogeneic stem cell transplantation, all of whom remain alive without relapse. Three cases of grade 2 cytokine release syndrome were observed and resolved with steroids. No cardiovascular events were encountered. With a median follow-up of 10 months, the median duration of remission was 8 months (range, 1-15.5+). The median OS was not reached; the estimated 1-year OS rate was 74% for all patients and 75% for the 8 patients treated with blinatumomab plus ponatinib.
Conclusions : The combination of blinatumomab with a TKI is safe and effective in patients with heavily pretreated R/R Ph+ leukemia. Prospective studies are currently ongoing.
Kantarjian: ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Delta-Fly Pharma: Research Funding. Daver: Karyopharm: Consultancy, Research Funding; Kiromic: Research Funding; Pfizer Inc.: Consultancy, Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Incyte Corporation: Honoraria, Research Funding; Jazz: Consultancy; Otsuka America Pharmaceutical, Inc.: Consultancy. Takahashi: Symbio Pharmaceuticals: Consultancy. DiNardo: Agios: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding. Burger: Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Cortes: BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; ImmunoGen: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Teva: Research Funding; Pfizer: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Jain: Novartis: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Verastem: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: 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. Wierda: Pharmacyclics: Consultancy, Honoraria, Research Funding; Juno: Research Funding; Kite: Research Funding; Genzyme: Consultancy, Honoraria; Janssen: Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Emergent: Consultancy, Honoraria, Research Funding; Karyopharm: Research Funding; Sanofi: Consultancy, Honoraria; The University of Texas MD Anderson Cancer Center: Employment; GSK/Novartis: Consultancy, Honoraria, Research Funding; Acerta: Research Funding. Jabbour: Bristol-Myers Squibb: Consultancy.
