Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LL) after Frontline Therapy with Hyper-CVAD Regimens.

Abstract

AYAs aged 16–20 with de novo ALL or LL have superior outcomes when treated with intensive pediatric regimens; event-free survival (EFS) rates range from 60–70% compared to 30–40% after conventional adult chemotherapy [Stock W, Blood 2008, e-pub]. This is in part attributed to higher dose intensity (and cumulative dose) of the anthracycline, vincristine [VCR], corticosteroid and asparaginase components. Of note, the intensive hyper-CVAD regimen (cyclophosphamide, VCR, doxorubicin, dexamethasone alternating with methotrexate/cytarabine) was originally modeled after childhood therapy for Burkitt lymphoma. It has been applied as frontline adult ALL therapy without age restriction since 1992. In contrast to conventional adult or pediatric ALL regimens, asparaginase is not administered during the induction or consolidation phases. Modifications to the regimen have included the addition of rituximab for CD20 positive precursor B-cell ALL and LL owing to adverse influence of CD20 expression, particularly in the younger subgroup [Thomas D, Blood 2008, e-pub]. An adapted augmented Berlin-Frankfurt- Munster (BFM) regimen modeled after the CCG experience was developed specifically as frontline therapy for adolescents and adults up to age 30 in lieu of the hyper-CVAD regimen at our institution; accrual is ongoing. We reviewed the previous hyper-CVAD experience in the AYA subset. One hundred two pts aged 13 to 21 yrs (median 19 yrs) with de novo ALL (n=92) or LL (n=10) were treated with hyper-CVAD (15 with rituximab). Complete remission (CR) rate was 97%; 3-yr EFS and OS rates were 65% and 70%, respectively. Preliminary reports from other investigators suggest that an intensified pediatric approach may be feasible even up to age 60. The GRAALL-2003 study reported 42-mos EFS and OS rates of 55% and 58%, respectively, in 225 de novo ALL pts aged 15– 60 (median 31 yrs) [Huget F, ASCO 2008, abstr 7005]. Median follow-up was 37 mos. A similar cohort of pts treated with the hyper-CVAD regimens included 385 pts with a slightly older median age of 35 yrs. Median follow-up was 62 mos (range, 1–180 mos). EFS and OS rates for the entire cohort were 50% and 55%, respectively. For pts below the age of 35, these rates improved to 55% and 67%. Clearly age remains a prognostic factor even with intensive chemotherapy approaches. Outcomes with the hyper-CVAD regimens appear to more closely resemble those of the pediatric approaches than the conventional regimens. Continued monitoring of ongoing prospective clinical trials using pediatric regimens in adults is paramount to delineating the optimal approach.