Update of the Modified Hyper-CVAD Regimen with or without Rituximab as Frontline Therapy of Adults with Acute Lymphocytic Leukemia (ALL) or Lymphoblastic Lymphoma (LL).
Authors: Thomas Deborah A. , Kantarjian Hagop , Faderl Stefan , Koller Charles , Ravandi-Kashani Farhad , Beran Miloslav , O’Brien Susan 
Published: October 2019

The hyper-CVAD regimen is an effective therapy program for adult ALL and LL [Kantarjian, JCO18:547, 2000; Kantarjian, Cancer101:2788, 2004, Thomas, Blood104:1624, 2004]. Intensive chemotherapy with hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternates with high dose methotrexate and cytarabine every 21 days for 8 courses, followed by maintenance with POMP (6-mercaptopurine, methotrexate, VCR, prednisone). Historical CR rate was 92% with 3-year disease-free survival (DFS) rate of 38%. The regimen was modified in 1999 to address the following:

higher induction mortality in patients (pts) aged 60 years or older (17% vs 3%); possible benefit of early anthracycline intensification; worse survival with CD20 expression; and late relapses after completion of POMP therapy.

Newly diagnosed or primary refractory (1 course only) ALL or LL pts were treated on two sequential studies. Burkitt leukemia/lymphoma (BLL) and Philadelphia positive ALL pts were treated on separate protocols. From May 2000 to December 2001, 69 pts were treated with the modified regimen as detailed above (9 courses of intensive chemotherapy). Course 2 was eliminated from the second study, with an additional 124 pts were treated (8 courses of intensive chemotherapy). Results were reviewed by lineage (T-cell versus non T-cell), outcome after therapy with rituximab for CD20 positive ALL, and age. Overall CR rate of the group (n=190) was 91%. Median age of the T-lineage pts was 30 (range, 17–74) versus 43 (range, 15–83) for the non-T lineage pts. After a median follow-up of 30 months (range, 6–80), outcome appeared favorable for the younger group aged 30 years or less with 3-year DFS rates of 61% and 66%, and 3-year OS rates of 73% and 71% for non-T and T-lineage, respectively. When comparing outcome of non-T lineage CD20 positive ALL with historical experience, the addition of rituximab appeared to improve DFS rates (56% versus 35%, p=.06) but did not affect survival (62% versus 46%, p=0.23). A subset analysis showed that younger pts aged 30 or less with non T-lineage CD20 positive ALL treated with rituximab had superior outcomes compared with historical experience (DFS rates 62% versus 28%, p=.005; OS rates 73% versus 50%, p=.07). No such benefit of rituximab was observed for the elderly group, in contrast to data previously reported for BLL. Anthracycline intensification appeared to worsen outcome, particularly for T-lineage ALL. Rituximab may benefit subsets of CD20 positive ALL; alternative monoclonal antibodies should be explored. Further improvements in outcome may be achieved with incorporation of novel agents such as nelarabine for T-lineage ALL and sphingosomal VCR for elderly ALL.

Modifications to Hyper-CVAD Parameter Hyper-CVAD Modified Hyper-CVAD Laminar air flow rooms No For age [≥ 60yrs or poor PS Dose-intensive anthracycline No C2 Liposomal DNR & cytarabine Rituximab No For CD20 ≥ 20% Intrathecal CNS prophylaxis 4, 8 (16 BL) 6 or 8 (16 BL) POMP 24 months 30 months Intensifications Months 7, 11 Months 6, 7 & 18, 19