Long-Term Outcome for De Novo Lymphoblastic Lymphoma (LL) After Frontline Therapy with Hyper-CVAD Regimen and Variants.
Authors: Thomas Deborah A. , Faderl Stefan , O'Brien Susan , Wierda William G. , Garcia-Manero Guillermo , Verstovsek Srdan , Konopleva Marina , Kadia Tapan , Kornblau Steven M. , Fayad Luis , Romaguera Jorge , Cortes Jorge E. , Kantarjian Hagop 
Published: October 2019

Abstract
Abstract 2831
The long-term outcome for newly diagnosed LL has improved with use of intensive chemotherapy regimens designed for acute lymphoblastic leukemia (ALL) when compared to the historical experience with modified NHL regimens. An early report established the hyper-CVAD regimen (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high dose methotrexate (MTX) and cytarabine) as an effective first line therapy for LL [Thomas D, Blood 104:1624, 2004]. From April 1992 to March 2009, 49 patients (pts) with de novo LL were treated with hyper-CVAD (n=20) or modified hyper-CVAD regimens (n=11 anthracycline intensification with liposomal daunorubicin-ara-C for course 2 [regimen detailed in Thomas D, Cancer, e-pub], n=18 without anthracycline intensification). CNS prophylaxis alternated intrathecal MTX and ara-C on days 2 and 7 of the first 4 courses in the absence of CNS disease. Bulky (> 7 cm) mediastinal disease at presentation was an indication for consolidative XRT (after consolidation prior to maintenance therapy). POMP (6-mercaptopurine, vincristine, MTX, prednisone) maintenance therapy was administered for 24 months with standard hyper-CVAD (MTX-L-asparaginase intensifications mos 7 & 11); and extended to 30 mos with the modified hyper-CVAD regimens (hyper-CVAD followed by MTX-L-asparaginase mos 6 & 7 and 18 & 19). Allogeneic stem cell transplant (SCT) was performed in first complete remission (CR) only if inadequate response to therapy. Median age was 31 yrs (range, 17–59); 77% were males. Mediastinal disease was noted in 74%; 30% were associated with pericardial and/or pleural effusions. Two pts had superior vena cava syndrome and five had CNS disease. T-lineage disease was present in majority (79%). Eight (17%) pts had bone marrow involvement. Overall CR rate was 96% in 46 evaluable patients (3 in CR at start), with remainder achieving partial response (PET scan negative residual mediastinal disease not qualifying for CR). Of the 23 pts with bulky mediastinal disease at presentation, 74% underwent XRT as planned. With a median follow-up of 80 months (range 30–187+ months), 31 (66%) pts remained alive without disease. Overall 5-yr rates for CR duration and survival were 72% and 68%, respectively. Fourteen pts relapsed or progressed within a median of 13 months (6 with standard, 8 with modified hyper-CVAD); five pts were successfully salvaged with chemotherapy and allogeneic SCT. The hyper-CVAD is a highly active regimen for de novo LL with long-term follow-up confirming the earlier report. Early anthracycline intensification was clearly not beneficial. The treatment paradigm for LL has recently changed owing to availability of new agents and data supporting superior efficacy of pediatric regimens compared with conventional adult regimens. For older adults with de novo LL, the deoxyguanosine analog nelarabine has now been incorporated into the hyper-CVAD regimen as a single agent during consolidation (cycles 9 & 10) and maintenance (in lieu of the early intensifications) [Vigil CE, ASCO 2010, abstract 6524], whereas adolescents and younger adults are treated according to the pediatric-inspired augmented Berlin-Frankfurt-Muenster regimen. An augmented hyper-CVAD regimen (dose intensifying VCR/dexamethasone components and incorporating pegylated asparaginase) has been successfully piloted in the salvage setting. The optimal first line chemotherapy of LL continues to be refined; the role of autologous or allogeneic SCT for LL in first CR remains unclear since majority of patients can be cured without use of these modalities.

Disclosures:
Off Label Use: Nelarabine for de novo T-lymphoblastic leukemia/lymphoma Nelarabine for de novo T-lymphoblastic leukemia/lymphoma.