Outcome after Detection of Minimal Residual Disease during Treatment with the Modified Hyper-CVAD Regimen with or without Rituximab in Newly Diagnosed Adult Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma (LL).
Authors: Thomas Deborah A. , Kantarjian Hagop M. , Jorgensen Jeffrey L. , Faderl Stefan , Cortes Jorge , Giles Francis , Garcia-Manero Guillermo , Wierda William , Ferrajoli Alessandra , Ravandi-Kashani Farhad , Asa Koller Charles , Beran Miloslav , Kornblau Steven M. , Andreeff Michael , Jones Dan , O’Brien Susan 
Published: October 2019

Abstract
The hyper-CVAD regimen is an effective program for adult ALL and LL [Kantarjian et al, Cancer101:2788, 2004, Thomas et al, Blood104:1624, 2004]. Hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternates with methotrexate and ara-C every 21 days for 8 courses, followed by POMP maintenance (6-MP, methotrexate, VCR, prednisone). Complete response (CR) rate was 92% with 3-year disease-free survival (DFS) rate of 38%. The regimen was modified to address the following issues: (1) higher induction mortality in patients (pts) aged ≥ 60 years (17% vs 3%); (2) longer DFS with early anthracycline intensification in other studies; (3) worse survival with CD20 expression (excluding Burkitt’s [BL] and LL); (4) CNS relapse rate of 6% and 1% in low and high risk pts, respectively; (5) late relapses after completion of POMP.
Modifications to Hyper-CVAD Parameter Hyper-CVAD Modified Hyper-CVAD Laminar air flow rooms No For age ≥ 60 yrs or poor PS Dose-intensive anthracyclines No C2 Liposomal DNR & ara-C Rituximab No For CD20 ≥ 20% Intrathecal CNS prophylaxis 4, 8 or 16 6 or 8 (16 BL) Maintenance (POMP) 24 months 30 months Intensifications (MTX, L-asparaginase) Months 7 & 11 Months 6,7 & 18,19 with hyper-CVAD
Newly diagnosed ALL or LL pts were treated on two sequential studies. BL and Ph-ALL pts were treated with other hyper-CVAD regimens. From May 2000 to December 2001, 69 pts received the modified regimen as above (9 courses of intensive therapy). Course 2 was eliminated from the second study, with an additional 113 pts treated (8 courses of intensive therapy). The median age for these 182 pts was 39 years (range, 15–83); 19% were ≥ 60 years old and 57% were males. Overall response rate was 90% (6 too early); 96% for the CD20+ group vs 86% for the CD20− group (p=.0.02). Induction mortality was 2%. The addition of rituximab for the CD20+ subgroup appeared to improve DFS compared with hyper-CVAD alone (83% vs 50%, p=.018), but not survival (OS) (72% vs 66%, p=0.327). The 2-yr OS rate for the elderly group was 22% vs 79% for their younger counterparts (p<0.001). In the latter study, minimal residual disease (MRD) was assessed by multiparameter flow cytometry (FC) at the time of CR as feasible. IgH by PCR, T-cell receptor (TCR) gamma and beta gene rearrangements by Southern or PCR, and cytogenetics (with FISH for 11q23 or others) were repeated if abnormal at diagnosis. TCR rearrangements were seen in 70% of pts with pre-B or CALLA immunophenotype. Of 83 evaluable pts, 20 (24%) were positive for MRD by FC at CR; 2-year DFS and OS rates were inferior compared with those negative for MRD by FC (58% vs 84%, p=0.02; 53% vs 73%, p=0.057). Alternative therapeutic strategies will be developed for the elderly pts and those with detectable MRD by FC at CR. Additional analysis of the latter subgroup, the other measures of MRD, and impact of MRD on outcome will be forthcoming.