Outcomes Continue to Be Favorable for De Novo Philadelphia Chromosome Negative B-Lymphoblastic Leukemia (ALL) After Therapy with Hyper-CVAD (with or without Rituximab) Regimen

Abstract ³⁵⁷²

The hyper-CVAD regimen [Kantarjian, JCO 18: 547, 2000; Kantarjian, Cancer 101: 2788, 2004] includes intensive cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternating with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone) interrupted by early and late intensifications. The regimen was modified in 1999 to include use of laminar air flow rooms during the induction phase for patients (pts) aged 60 years or older. Therapeutic modifications included rituximab 375 mg/m² (Days 1 & 11 of hyper-CVAD, Days 1 & 8 of MTX-cytarabine for 8 total doses) for CD20 expression > 20% to counteract increased propensity for relapse [Thomas D, Blood 113: 6330, 2009], early anthracycline intensification with liposomal daunorubicin-cytarabine from 1999–2000 only [omitted thereafter owing to lack of benefit, Thomas D, Cancer 116: 4580, 2010], augmentation of CNS prophylaxis, and extension of maintenance POMP therapy from 24 to 30 months with additional early and late intensifications [details in Thomas D, JCO 28: 3830, 2010]. Overall, 216 pts with Ph negative B-lymphoblastic leukemia have been treated with the modified hyper-CVAD regimens. Median age was 46 years (range, 16–84). For the CD20 positive B-lymphoblastic subset treated with hyper-CVAD and rituximab 3-yr rates of CR duration (CRD) and survival (OS) were 66% and 57%. In the younger (age < 60 years) CD20-positive subset, rates of CRD and OS were superior compared with standard hyper-CVAD (69% v 38%; P <.001% and 71% v 47%, P =.003). Historical experience in 37 adolescent and young adult (AYA) subset aged 15 – 30 yrs with CD20 positive B-lymphoblastic leukemia (prior to shift to augmented BFM regimen as first line therapy) showed that the addition of rituximab improved 3-yr CRD rates from 26% to 60% (P =.001) and 3-yr OS rates from 47% to 70% (P =.05) compared with standard hyper-CVAD without rituximab. There were no significant differences in outcome for this AYA subset by regimen (standard or modified) for the CD20 negative groups (all 3-yr rates > 70%). Elderly pts aged 60 year or older with CD20 positive B-lymphoblastic leukemia treated with hyper-CVAD and rituximab, in contrast to the Burkitt experience, had outcomes which were similar to the historical experience with standard hyper-CVAD (rates of CRD 59% v 50%, P = NS and OS 23% v 32%, P = NS, respectively), despite high rates of negativity for minimal residual disease (MRD) by multiparameter flow cytometry (MFC) at CR, related mainly to deaths in CR during consolidation. MRD positivity by MFC after induction therapy with hyper-CVAD and rituximab was associated with a higher relapse rate and lower 3-yr CR duration rates compared with MRD negative status at the time of CR. Additional doses of rituximab were added to consolidation (Day 1 of cycles 5 – 8) and maintenance chemotherapy in order to potentially improve outcomes for the MRD positive subset. Upfront dose reductions of cyclophosphamide, doxorubicin, vincristine, dexamethasone and methotrexate have been implemented for all cycles of induction-consolidation phase for older age and/or poor performance status with reduction in rate of deaths in CR noted. Incorporation of pegylated asparginase (one dose of 2000 Units/m² with capping per cycle, 1000 Units/m² if older or poor performance status) during the induction-consolidation phase (“augmented hyper-CVAD”) was piloted as first line therapy in 19 pts aged 30 – 59 years of age, then omitted owing to excessive toxicity. Incorporation of rituximab into first line intensive chemotherapy such as the hyper-CVAD regimen appears beneficial for younger pts, prompting investigation of second generation anti-CD20 monoclonal antibodies such as ofatumumab and hyper-CVAD (regardless of CD20 expression owing to data showing upregulation of CD20 expression) for the younger subsets and inotuzumab (with or without rituximab) and “mini-hyper-CVAD” for the elderly group. Multivariate analysis of outcomes by risk groups (age/MRD status/CD20 expression) and the impact of the early/late intensifications during maintenance chemotherapy will be presented.