Outcomes for Adult Lymphoblastic Leukemia (ALL) Are Mainly Influenced by Age and Status of Minimal Residual Disease (MRD) by Multiparameter Flow Cytometry (MFC) After Therapy with the Modified Hyper-CVAD (with or without Rituximab) Regimen
Authors: Thomas Deborah A. , Kantarjian Hagop M , Jorgensen Jeffrey L. , Faderl Stefan , Jabbour Elias , Wierda William G. , Ravandi Farhad , Verstovsek Srdan , Garcia-Manero Guillermo , Koller Charles Asa , Burger Jan A. , Ferrajoli Alessandra , Konopleva Marina , Kadia Tapan , Borthakur Gautam , Kornblau Steven M. , Andreeff Michael , Garris Rebecca , Cortes Jorge E. , O'Brien Susan 
Published: October 2019

Abstract
Abstract 1524
The hyper-CVAD regimen is an effective frontline program for de novo adult ALL [Kantarjian, JCO 18: 547, 2000; Kantarjian, Cancer 101: 2788, 2004]. Intensive cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternate 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 pts aged 60 years or older. Rituximab 375 mg/m2 (Days 1 & 11 of hyper-CVAD, Days 1 & 8 of MTX-cytarabine for 8 total doses) was administered for CD20 expression > 20% to counteract increased propensity for relapse [Thomas D, Blood 113: 6330, 2009]. Early anthracycline intensification with liposomal daunorubicin and cytarabine was incorporated from 1999–2000 then omitted from the regimen [Thomas D, Cancer 116: 4580, 2010]. CNS prophylaxis alternated intrathecal MTX day 2 with cytarabine day 7 of the first 3 courses for low CNS risk and first 4 courses for high CNS risk (in the absence of CNS disease). Maintenance therapy was extended from 24 to 30 months inclusive of early and late intensifications (hyper-CVAD followed by weekly MTX and L-asparaginase mos 6 & 7 then mos 18 & 19) to reduce incidence of late relapses. Results in the CD20 positive B-lymphoblastic subset treated with hyper-CVAD and rituximab were encouraging; 3-yr rates of CR duration (CRD) and survival (OS) were 60% and 50% overall, respectively. In younger (age < 60 years) CD20-positive subset, rates of CRD and OS were superior compared with standard hyper-CVAD (70% v 38%; P <.001% and 75% v 47%, P =.003) [Thomas D, JCO 28: 3830, 2010]. Historical experience in the adolescent and young adult (AYA) subset aged 15 – 30 yrs with CD20 positive B-lymphoblastic leukemia (now treated with pediatric augmented BFM regimen) showed that the addition of rituximab improved the 3-yr CRD rates from 26% to 65% (P =.001) and 3-yr OS rates from 47% to 75% (P =.05) compared with standard hyper-CVAD. There were no significant differences in outcome for the AYA subset by regimen (standard or modified) for the CD20 negative groups (all 3-yr rates > 70%). In contrast to the Burkitt leukemia experience, elderly pts with CD20 positive B-lymphoblastic leukemia treated with hyper-CVAD and rituximab did not benefit (rates of CRD 45% v 50%, P = NS and OS 28% v 32%, P = NS, respectively), related in part to deaths in CR. For the modified hyper-CVAD regimen (no anthracycline intensification), the rate of MRD negativity by 4- or 6-color MFC (sensitivity 0.01%, assay now 8-color MFC) at the time of CR in 95 evaluable pts was 72%. Overall, MRD positivity by MFC at the time of CR was associated with a higher relapse rate (52% v 21%, P =.01) and lower 3-yr CR duration rates (45% v 78%, P =.01). CD20 positive pts treated with rituximab had a higher rate of MRD negativity by MFC at CR than their CD20 negative counterparts (81% v 58%, P =.02). MRD positivity by MFC after hyper-CVAD and rituximab was associated with a significantly lower 3-yr CR duration rate (24% v 82%, P =.002), but survival rates were not statistically different (27% v 70%) likely due in part to deaths in CR in the older subset of the MRD-negative group. In contrast, for the CD20 negative subset, presence of detectable MRD by MFC at the time of CR did not influence 3-yr CR duration rate (58% v 63%). Additional doses of rituximab have been added to the consolidation cycles (Day 1 of cycles 5 – 8) and during the maintenance phase. Upfront dose reductions have been implemented for the induction-consolidation phase according to age and performance status in order to reduce deaths in CR. MTX-cytarabine cycles now include vincristine. All pts receive 8 IT treatments in the absence of CNS disease. Younger pts age 40 – 50 yrs receive pegylated asparginase (2000 Units/m2 with capping) during the induction-consolidation phase and early/late intensifications (augmented hyper-CVAD). Elderly pts or younger pts with B-lymphoblastic leukemia with contraindications to asparaginase are now treated with the hyper-CVAD and ofatumumab regimen regardless of CD20 expression. The cumulative experience of the serial modifications to the hyper-CVAD regimen stratified by age/MRD status and the preliminary experience with the frontline version of the augmented hyper-CVAD regimen will be presented.

Disclosures:
Off Label Use: Rituximab in Lymphoblastic Leukemia.