Phase II Study Of The Hyper-CVAD Regimen In Combination With Ofatumumab As Frontline Therapy For Adults With CD-20 Positive Acute Lymphoblastic Leukemia (ALL)

The hyper-CVAD regimen is an effective frontline program 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 program in patients with CD20-positive ALL (≥20% expression by multicolor flow cytometry - FCI) improved outcome with 3-year CRD and OS rates by 68% and 65%, respectively. 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 complete remission duration (CRD) and overall survival rates.

In this phase II trial, pts with newly diagnosed ALL and pts 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 will 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

To date 17 pts with de novo ALL and 2 pts in complete remission (CR) previously treated (1 with prior cycle of hyper-CVAD and 1 post fludarabine-cytarabine based regimen) have received a median of 5 cycles (1-8) of therapy; 3 pts did not receive the full 8 planned courses of induction-consolidation. 8 pts are receiving maintenance in CR. Median age is 50 years (39–71). Median WBC at diagnosis was 5.5 x 10⁹/L (1 -189 x 10⁹/L). CD20 expression above 20% was found in 11 pts (58%), between 10 and 20% in 1 (5%) and below 10% in 7 (37%). 2 pts (11%) had concomitant CNS disease at diagnosis. Among the 15 pts with evaluable baseline cytogenetic analysis, 10 (67%) were abnormal. All but one pt (94%) achieved a CR after cycle 1; 1 pt died of septic shock and multiple organ failure at day 21 of cycle 1. All eighteen (100%) pts achieved minimal residual disease (MRD) negativity as assessed by FCI; of whom 12 (67%) achieved MRD negativity after induction. Median time to neutrophil and platelet recovery for cycle 1 was 19 and 23 days, and 16 and 22 days for subsequent cycles, respectively. Grade ≥ 3 toxicity included increase of LFT’s in 7 pts (37%), increase of bilirubin in 5(26%), thrombotic events in 1 (5%) and neuropathy in 1 (5%). Febrile neutropenia episodes during induction and consolidation cycles were reported at rates of 76% and 65%, respectively. With a median follow up of 8 months (1-23), 18 pts are alive and in CR; 1 pt has undergone an allogeneic stem cell transplant after cycle 3 by reason of a highly complex karyotype at diagnosis. The 1-year CRD and overall survival rates were 100% and 95% respectively.

The combination of hyper-CVAD with ofatumumab is safe and highly effective in pts with CD20-positive ALL.

Jabbour:GSK: Research Funding. Off Label Use: Ofatumumab in ALL. Faderl:Sanofi-Aventis: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Ravandi:Sunesis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Teva: Consultancy, Honoraria; Pfizer: Honoraria; Merck: Research Funding; Bayer/Onyx: Consultancy, Honoraria; EMD Serono: Research Funding; Medimmune: Research Funding; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria.