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2783 Frontline Ofatumumab in Combination with Hyper-CVAD for Adult Patients with CD-20 Positive Acute Lymphoblastic Leukemia (ALL): Interim Result of a Phase II Clinical Trial

Acute Lymphoblastic Leukemia: Clinical Studies
Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Poster II
Sunday, December 4, 2016, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Koji Sasaki, MD1, Hagop M. Kantarjian, MD2, Farhad Ravandi, MD2, Naval Daver, MD2, Tapan M. Kadia, MD2, Rita B. Khouri2*, Yesid Alvarado, MD2, Jan A. Burger, MD, PhD2, Deborah A Thomas, MD2, Guillermo Garcia-Manero, MD2, Courtney D. DiNardo, MD, MSCE2, Naveen Pemmaraju, MD2, Nicholas J. Short, MD1, Heather Schroeder, RN2*, Rebecca Garris, MS2*, Prithviraj Bose, MD2, Nitin Jain, MD2, Kiran Naqvi, MD2*, William G. Wierda, MD, PhD2, Srdan Verstovsek2, Jorge E. Cortes, MD2, Marina Konopleva, MD, PhD2, Susan M. O'Brien, MD3 and Elias J. Jabbour, MD2

1Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA

Background: The hyper-CVAD regimen is an effective frontline regimen for de novo adult ALL. Expression of CD20 was identified as an adverse prognostic factor, associated with a higher incidence of relapse, lower 3-year complete remission duration (CRD) and lower 3-year overall survival (OS) rate. The addition of rituximab to the hyper-CVAD regimen in patients with CD20-positive ALL (≥20% expression by multicolor flow cytometry) improved outcome with 3-year CRD and OS rates of 68% and 65%, respectively (Deborah Thomas et al. J Clin Oncol 2010;28:3880-9). Ofatumumab (HuMax-CD20) targets a membrane proximal small-loop epitope on the CD20 molecule and was found to be more potent than rituximab in promoting complement-dependent cytotoxicity in vitro. Ofatumumab’s safety and efficacy has been proven in chronic lymphocytic leukemia. Therefore a combination of the hyper-CVAD regimen and ofatumumab may be associated with better response rates, higher 3-year CRD and overall survival rates. The aims of this study are to evaluate response rate, CRD, OS, and to assess the safety of this regimen.

Methods: Patients with newly diagnosed ALL (CD20 expression >1%) and patients who received one prior course of chemotherapy received 4 courses of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone; the odd courses 1, 3, 5, 7); ofatumumab was given on courses 1 and 3, and 4 courses of MTX-Ara-C (methotrexate-cytarabine; the even courses 2, 4, 6, 8); ofatumumab was given on courses 2 and 4. This treatment would be followed by POMP (6-mercaptopurine, MTX, VCR, prednisone) maintenance therapy for approximately 30 months, interrupted by intensifications months 6, 7 and 18, 19 with MTX/Pegylated asparaginase and hyper-CVAD-ofatumumab. Central nervous system prophylaxis with MTX and Ara-C was administered. When indicated local radiotherapy was administered in patients with bulky mediastinal disease.

Results: To date 55 patients with de novo ALL and 4 patients in complete remission (CR) previously treated (2 with one prior cycle of hyper-CVAD, 1 post fludarabine-cytarabine based regimen, 1 with cyclophosphamide and dexamethasone) have received a median of 8 cycles (1-8) of therapy. Median age was 41 years (18–71). Median WBC at diagnosis was 4.6 x 109/L (1 -202 x 109/L). CD20 expression above 20% was found in 37 patients (63%), between 10% and 20% in 5 (8%) and between 10% and 1% in 14 (24%). Two patients (5%) had concomitant CNS disease at diagnosis.  Among the 50 patients with evaluable baseline cytogenetic analysis, 29 (58%) were abnormal. All but one patient (98%) achieved a CR after cycle 1 (4 patients were in CR at the start); 1 patient died of septic shock and multiple organ failure at day 21 of cycle 1. Fifty-three (93%) patients achieved minimal residual disease (MRD) negativity as assessed by multicolor flow cytometry; of whom 34 (54%) achieved MRD negativity after induction. By binary logistic regression analysis, the lower CD20 levels was an adverse predictive factor for negative MRD at D21 (p=0.044); age at diagnosis did not affect negative MRD at D21 (p=0.604). Twenty-four (41%) patients did not receive full 8 cycles; 21 (36%) are receiving maintenance in CR; 9 (15%) in CR finished maintenance. 8 patients (14%) were referred to allogeneic stem cell transplantation (ASCT) due to complex karyotype (n=1), hyperdiploid karyotype (n=2), delay in achieving negative MRD (n=1), persistent MRD (n=2), and Philadelphia-like phenotype (n=2). Median time to neutrophil and platelet recovery for cycle 1 was 18 and 21 days after induction chemotherapy, respectively; 16 and 22 days after subsequent cycles, respectively. With a median follow up of 20 months (<1-58), 47 patients are alive; of them 43 in CR, 3 relapsed and 1 had molecular relapse only. Twelve (20%) patients died: 5 patients died post relapse and 1 post MRD relapse; 2 post ASCT; 1 post therapy related AML; 1 intracranial hemorrhage at C1D22; 1 sepsis at C3D17; and 1 sepsis on maintenance therapy C16D35. Eight (14%) patients have undergone ASCT. The 3-year CRD and OS rates were 78% and 68% respectively (Figure 1a).  The 3-year OS in patients with CD20 <20% and ≥20% were 82% and 64%, respectively (p=0.96) (Figure 1b). 

Conclusion: The combination of hyper-CVAD with ofatumumab is highly effective in patients with CD20-positive ALL.

Disclosures: Daver: Otsuka: Consultancy, Honoraria; Karyopharm: Honoraria, Research Funding; Sunesis: Consultancy, Research Funding; Kiromic: Research Funding; Ariad: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding. Burger: Pharmacyclics: Research Funding. DiNardo: Agios: Other: advisory board, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Novartis: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding. Pemmaraju: stemline: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria; Cellectis: Research Funding; Incyte: Consultancy, Honoraria. Jain: BMS: Research Funding; Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Infinity: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Novimmune: Consultancy, Honoraria; Abbvie: Research Funding; Celgene: Research Funding. Wierda: Abbvie: Research Funding; Acerta: Research Funding; Novartis: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Genentech: Research Funding. Verstovsek: CTI BioPharma Corp: Research Funding. Cortes: ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Konopleva: Calithera: Research Funding; Cellectis: Research Funding. O'Brien: Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

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