Comparison of Hyper-CVAD Plus Ofatumumab to Hyper-CVAD Plus Rituximab in Patients with Newly Diagnosed Philadelphia Chromosome-Negative CD20-Positive B-Cell Acute Lymphoblastic Leukemia: A Propensity Score Analysis

Introduction:

Outcome of patients (pts) with CD20-positive B-cell acute lymphoblastic leukemia (B-ALL) has significantly improved with hyper-CVAD (HCVAD) in combination with rituximab with 3-year OS 65% (Thomas et al Blood 2009). Ofatumumab is an anti-CD20 monoclonal antibody with higher capacity of promoting complement-dependent cytotoxicity compared to rituximab. The aim of this study is to compare the outcome of pts with CD20-positive B-ALL who received HCVAD plus ofatumumab (HCVAD-O) or HCVAD plus rituximab (HCVAD-R) therapy.

Methods:

We reviewed 69 adult pts with newly diagnosed, Philadelphia chromosome (Ph)-negative, CD20-positive B-ALL who were treated with HCVAD-O at our institution between 8/2011 and 5/2017. HCVAD therapy consisted of 4 alternating cycles of hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, plus high-dose methotrexate (MTX) / cytarabine (AraC) with 8 intrathecal injections of MTX/AraC. Ofatumumab was administered at 300mg IV as first dose, and 2000mg IV subsequently. The maintenance phase consisted of 30 cycles of 6-MP, MTX, vincristine, and prednisone (POMP) with 4 intensification courses (high-dose MTX plus L-asparaginase and HCVAD+O) on courses 6-7 and 18-19. Overall survival (OS) was calculated from the start date of treatment to the date of death, or last follow-up. We performed a comparison of survival between pts treated with HCVAD-O and a cohort of 153 historical-control pts treated with HCVAD with or without rituximab between 11/2002 and 7/2012. Historical-control pts were treated with HCVAD alone (N=58) if CD20 expression was 1-19% or HCVAD-R (N=95) if CD20 expression was ≥20%. To adjust for baseline differences of pts characteristics between the cohorts, we performed inverse probability of treatment weighing (IPTW) using propensity scores calculated from pts baseline characteristics. Covariates for the calculation of propensity scores included age, performance status, white blood cell count at diagnosis, the positivity of CD20 expression and adverse-risk cytogenetics (KMT2A-rearrangement, complex karyotype or low-hypodiploidy / near triploidy).

Results:

The median follow-up for HCVAD-O cohort and historical-control cohort was 44 months (95% CI: 41-53) and 133 months (95% CI: 115-141), respectively. There was no difference in baseline characteristics between HCVAD-O cohort and historical-control cohort (Table 1). The 5-year OS rates were 65% and 51% in HCVAD-O cohort and historical-control cohort, respectively. With the IPTW analysis, the HCVAD-O regimen was associated with better outcome compared with the historical HCVAD/HCVAD-R regimen (HR, 0.74; 95% CI, 0.55-0.99, p = 0.047) (Figure 1). The treatment effect was similar regardless of the level of CD20 positivity, although not statistically significant among each subgroup (CD20 ≥20%, HR 0.73, 95% CI, 0.52-1.04, p = 0.09; CD20 1-19%, HR, 0.68; 95% CI, 0.39-1.20, p = 0.18).

Conclusions:

The combination of HCVAD plus ofatumumab is highly effective and seems to have offered better outcome than did HCVAD plus rituximab therapy in pts with Ph-negative CD20-positive B-ALL. Additional novel monoclonal/bispecific antibody constructs targeting CD19 and CD22 are expected to further improve the outcome.