Significance of Minimal Residual Disease (MRD) by Multiparameter Flow Cytometry (MFC) In Adults with De Novo Acute Lymphoblastic Leukemia (ALL) After Therapy with the Modified Hyper-CVAD Regimen
Authors: Thomas Deborah A. , O'Brien Susan , Jorgensen Jeffrey , Wang Sa A. , Faderl Stefan , Wierda William G. , Garris Rebecca , Andreeff Michael , Cortes Jorge E. , Kantarjian Hagop 
Published: October 2019

Abstract
Abstract 2145
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 with early and late intensifications. The regimen was modified in 1999 in order to improve on the results. Induction chemotherapy was administered in a laminar air flow room for pts aged 60 years or older owing to high induction mortality rate (17%). Rituximab 375 mg/m2 (days 1 & 11 of hyper-CVAD, days 1 & 8 of MTX-cytarabine for 8 total doses) was given if CD20 expression was > 20% owing to association with increased propensity for relapse [Thomas D, Blood 113:6330, 2009]. 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). The maintenance phase was extended from 24 to 30 mos with modifications of the early and late intensifications (hyper-CVAD followed by MTX-L-asparaginase mos 6 & 7 and 18 & 19) in order to reduce incidence of late relapses. Newly diagnosed or primary refractory (1 course only) pts with Philadelphia chromosome negative B-lymphoblastic leukemia (n=126) were treated with this modified hyper-CVAD regimen without anthracycline intensification (pts age 30 years or less have been allocated to treatment with the pediatric-inspired augmented Berlin-Frankfurt-Muenster regimen since 2006). Median age was 43 yrs (range, 15–83). CD20 expression was noted in 49%. Overall CR rate of the group was 93%; the rate of MRD negativity by 4- or 6-color MFC (sensitivity of 0.01%) 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% versus 21%, p=.01) and lower 3-yr CR duration rates (45% versus 78%, p=.01). The CD20 positive pts (n=57) who were treated with rituximab had a higher rate of MRD negativity by MFC at CR than their CD20 negative counterparts (81% versus 58%, p=.02). MRD positivity by MFC after hyper-CVAD and rituximab was associated with a significantly lower 3-yr CR duration rate (24% versus 82%, p=.002), but survival rates were not statistically different (27% versus 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 was not associated a with lower 3-yr CR duration rate (58% versus 63%). Dectectable MRD by MFC at the time of CR, despite subsequent eradication with consolidation chemotherapy in the majority of patients, predicts for increased risk of disease recurrence. Strategies to improve the MRD negativity rate at the time of CR (e.g., addition of monoclonal antibodies directed at other lymphoblast antigens such as CD22 for the CD20 negative subset and use of the newer anti-CD20 monoclonal antibodies for the CD20 positive subset) may further improve outcome after frontline therapy with the modified hyper-CVAD regimens.

Disclosures:
Thomas: Novartis: Honoraria; Bristol-Meyer-Squibb: Honoraria; Pfizer:; Amgen: Research Funding. Off Label Use: Imatinib for de novo Philadelphia positive ALL. Dasatinib for de novo Philadelphia positive ALL. Rituximab for CD20 positive ALL and Burkitt leukemia/lymphoma. Nelarabine for de novo T-lymphoblastic leukemia/lymphoma.