A Phase II Study of the Hyper-CVAD Regimen in Sequential Combination with Blinatumomab As Frontline Therapy for Adults with B-Cell Acute Lymphoblastic Leukemia (B-ALL)
Authors: Richard-Carpentier Guillaume , Kantarjian Hagop M. , Short Nicholas J , Ravandi Farhad , Ferrajoli Alessandra , Schroeder Heather M , Khouri Maria , Garcia-Manero Guillermo , Montalban Bravo Guillermo , Cortes Jorge E. , Jain Nitin , Konopleva Marina Y. , Takahashi Koichi , Sasaki Koji , Garris Rebecca E. , Jabbour Elias J. 
Published: October 2019

Abstract
Background
Multi-agent combination chemotherapy regimens for the treatment of ALL are considered a cancer success story in the pediatric setting. For adults, the same magnitude of success has not been realized using similar strategies. These regimens produce high complete remission (CR) rates of 80-90% but the cure rates are 40-50%. The incorporation of targeted agents (tyrosine kinase inhibitors and monoclonal antibodies) has improved survival and cure rates in adult ALL subsets. Blinatumomab, a bispecific T-cell engaging (BiTE) CD19-CD3 antibody, is effective in patients with relapsed/refractory disease and in patients with measurable residual disease (MRD). Better outcomes were obtained when blinatumomab was administered earlier in the course of the disease. We hypothesized that incorporating blinatumomab in sequential combination with Hyper-CVAD in previously untreated patients with ALL would improve the eradication of MRD, decrease the need for intensive chemotherapy, and improve survival.
Methods
Patients were eligible to participate in this phase 2 single-arm study if they were at least 14 years old, had newly diagnosed untreated Philadelphia-negative B-ALL or B-cell lymphoblastic lymphoma, had ECOG performance status (PS) of 0-3, and normal liver, kidney and cardiac function. Patients in CR after one prior course of chemotherapy were also eligible. Therapeutic regimen consisted of 4 alternating cycles of Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone, cycles 1 & 3) and high-dose methotrexate/cytarabine (cycles 2 & 4) followed by 4 consecutive cycles of blinatumomab (4 weeks every 6 week-cycle). All patients received 8 prophylactic intrathecal injections with methotrexate and cytarabine during the first 4 cycles of treatment. Additionally, patients with CD20+ ALL (≥ 1% cells) received a total of 8 doses of rituximab (375 mg/m2) or ofatumumab (2000 mg) during the hyper-CVAD cycles. Maintenance phase consisted of POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) on cycles 1-3, 5-7, 9-11 and 13-15 alternating with blinatumomab on cycles 4, 8 and 12. The primary outcome was relapse-free survival (RFS) and secondary outcomes were overall survival (OS), overall response rate and MRD negativity rate.
Results
To date, 17 patients were treated, three of them enrolled in CR after 1 cycle of Hyper-CVAD. Patient's characteristics are summarized in Table 1. Median age is 43 years (range, 20-59). All but one patient had CD20 expression. Six patients (35%) had TP53 mutations. Four patients (24%) had low hypodiploidy-near triploidy. One patient (6%) had CRLF2 overexpression.
All 14 evaluable patients achieved CR for an overall response rate of 100%. Minimal residual disease (MRD) negativity, assessed by 6-color multicolor flow, was achieved in 93% of the patients after one cycle of therapy. No early death within 6 weeks was reported. Patients have received a median of 4 cycles (1-4) of chemotherapy and 4 cycles (0-4) of blinatumomab. Two patients had early relapse during the Hyper-CVAD cycles after 2 and 4 cycles, respectively. Three patients underwent allogeneic stem cell transplantation (HSCT) (1 with histiocytic proliferation in the bone marrow, 1 with t(4;11) and 1 with CRLF2+ ALL). A total of 14 patients have initiated the blinatumomab phase. Nine patients received the total 8 courses of hyper-CVAD and blinatumomab and are currently receiving maintenance in CR.
The treatment was well tolerated. Grade 3-4 adverse events attributed to blinatumomab occurred in 2 patients (12%) and were manageable and reversible. One patient developed transient Grade 3 cytokine release syndrome and one had Grade 3 ataxia. Both recovered after holding blinatumomab therapy and dexamethasone administration. Treatment was resumed thereafter with no recurrence.
With a median follow up of 14 months (range, 3-20 months), 16 patients (94%) are alive (14 of them in first CR); one patient died after HSCT of a transplant-related complication. The 1-year RFS rate was 77% (95% CI 42-93%) (Figure 1A) and the 1-year OS rate was 90% (95% CI 47-99%) (Figure 1B).
Conclusion
The sequential combination of Hyper-CVAD and blinatumomab in newly diagnosed adult patients with B-ALL is safe and highly effective. These early results are favorable. The study continues to accrue patients.

Disclosures
Short: Takeda Oncology: Consultancy. Ravandi:Abbvie: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Jazz: Honoraria; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Sunesis: Honoraria. Cortes:Astellas Pharma: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Jain:BMS: Research Funding; ADC Therapeutics: Research Funding; BMS: Research Funding; Genentech: Research Funding; ADC Therapeutics: Research Funding; Servier: Research Funding; Astra Zeneca: Research Funding; Genentech: Research Funding; Verastem: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Infinity: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Cellectis: Research Funding; Incyte: Research Funding; Adaptive Biotechnologioes: Research Funding; Celgene: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Verastem: 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; Cellectis: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: 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; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: 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; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Stemline Therapeutics: Research Funding. Sasaki:Otsuka Pharmaceutical: Honoraria. Jabbour:Abbvie: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.