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

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.

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