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)

Background: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.

Methods: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

Results: To date 25 pts with de novo ALL and 3 pts in complete remission (CR) previously treated (2 with prior cycle of hyper-CVAD and 1 post fludarabine-cytarabine based regimen) have received a median of 7 cycles (1-8-) of therapy; 8 (29%) pts did not receive the full 8 planned courses of induction-consolidation. 16 (44%) pts are receiving maintenance in CR. One pt has finished all treatment. Median age is 46 years (32–71). Median WBC at diagnosis was 5.34 x 10⁹/L (1 -201 x 10⁹/L). CD20 expression above 20% was found in 17 pts (61%), between 10 and 20% in 1 (4%) and below 10% in 5 (18%). 3 pts (11%) had concomitant CNS disease at diagnosis. Among the 23 pts with evaluable baseline cytogenetic analysis, 14 (50%) were abnormal. All but one pt (96%) achieved a CR after cycle 1 (3 pts were in CR at the start); 1 pt died of septic shock and multiple organ failure at day 21 of cycle 1. All but one (96%) pts achieved minimal residual disease (MRD) negativity as assessed by FCI; of whom 17 (65%) achieved MRD negativity after induction. Two pts have undergone an allogeneic stem cell transplant (ASCT): due to the lack of MRD negativity achievement in one and a highly complex karyotype at diagnosis in the second. 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 11 pts (39%), increase of bilirubin in 6 (21%), thrombotic events in 1 (4%) and neuropathy in 1 (4%). Febrile neutropenia episodes during induction and consolidation cycles were reported at rates of 64% and 73%, respectively. With a median follow up of 15 months (1-35), 24 pts are alive and in CR. Four pts died: 1 at C1D22 of sepsis and intracranial bleed, 1 at C3D17 of sepsis and multiple organ failure; and 1 of relapse post ASCT; and 1 post salvage therapy for minimal residual disease relapse. The 1-year CRD and overall survival rates were 90% and 88% respectively.

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