Long Term Follow-Up Of De Novo Or Minimally Treated Burkitt Lymphoma/Leukemia (BL/B-ALL) After Frontline Therapy Per The Hyper-CVAD Regimen With Or Without Rituximab: 20-Year Cumulative Experience
Authors: Jain Preetesh , Kantarjian Hagop M , Cortes Jorge E. , Jabbour Elias J. , Faderl Stefan H. , Wierda William G. , Garcia-Manero Guillermo , Ferrajoli Alessandra , Verstovsek Srdan , Burger Jan A. , Fayad Luis , Romaguera Jorge , Garris Rebecca , Ravandi Farhad , O'Brien Susan , Thomas Deborah 
Published: October 2019

Abstract

Background
Incorporation of the anti-CD20 monoclonal antibody rituximab into intensive, multi-agent chemotherapy regimens has been widely applied as frontline therapy of BL/B-ALL. We previously reported significant improvements in disease-free (DFS) and overall survival (OS) rates with the addition of rituximab to hyper-CVAD compared with the historical experience. We now report a cumulative update of the findings over a 20-year period.

Methods
52 patients (pts) with newly diagnosed non-HIV BL (n=12) or B-ALL (n=40) were treated with hyper-CVAD and rituximab from February 2000 to June 2013. Chemoimmunotherapy was administered as previously described (Thomas DA et al, Cancer 2006:106; 1569-80). A separate cohort (n=9) with bcl-2 expression was excluded since they represented the category of B-cell lymphoma, unclassifiable, with intermediate features between diffuse large B-cell lymphoma and BL as per the 2008 revision of the WHO classification. Median age was 41 yrs (range, 17–77); 11 (21%) were aged 60 yrs or older. Six of the 52 pts were inevaluable for response: 3 were enrolled in complete remission (CR) after pretreatment with one cycle of chemotherapy and 3 had surgical resection of the tumor mass without evidence of residual disease. Seven (13%) had CNS involvement at presentation. Lactate dehydrogenase (LDH) level (ULN > 618 U/L) was elevated in 40 (77%). Outcome of the chemoimmunotherapy group was compared to historical experience with 44 pts treated with hyper-CVAD without rituximab from August 1992 to January 2000.

Results
All evaluable pts responded; 42 of 44 (95%) achieved CR and 2 achieved partial response. All 11 pts aged 60 yrs or older achieved CR. After a median follow up of 90 months, 10 (19%) pts relapsed with only one survivor (late relapse after 7 yrs successfully salvaged with DA-EPOCH-R). Twelve (29%) pts died in CR from infections (n=4), other malignancies (n=4), other preexisting comorbid medical conditions (n=2), or unknown causes (n=2). Overall 5-yr DFS and OS rates were 70% and 70% respectively, improved compared with corresponding historical cohort rates of 60% and 51%. Six pts developed secondary dyscrasias (1 with acute myelogenous leukemia [AML] at 7 yrs, 1 with t(8;21) AML at 3 yrs, 1 with monosomy 7 AML at 3 yrs, 3 with myelodysplastic syndrome (range 1-8 yrs). Toxicity profile was similar to hyper-CVAD alone. In the cohort (n=9) of bcl-2 positive dual hit lymphoma/leukemia (DHL) typically associated with poor prognosis, the 5-yr DFS and OS rates were 71% and 56% respectively; 4 were long-term survivors beyond 5 years without disease recurrence.

Conclusions
The incorporation of rituximab into the hyper-CVAD regimen has improved outcomes for de novo BL/B-ALL, with achievement of respectable cure rates. Bortezomib has been incorporated for the DHL subset in an effort to improve the results. Later generation anti-CD20 monoclonal antibodies such as ofatumumab have supplanted rituximab. Investigation of other novel monoclonal antibodies such as blinatumomab or inotuzumab for BL/B-ALL is clearly warranted.

Disclosures:
No relevant conflicts of interest to declare.