Two Decade Single Institution Experience Highlights Rare Survivors with Relapsed or Refractory Burkitt Lymphoma
Authors: Molla Rabeya , Berman Ellin , Caron Philip , Donnelly Gerard , Falchi Lorenzo , Hamlin Paul A. , Horwitz Steven , Intlekofer Andrew M. , Johnson William T. , Jurcic Joseph G , Kumar Anita , Lue Jennifer Kimberly , Moskowitz Alison , Owens Colette , Dahi Parastoo B , Palomba Maria Lia , Portlock Carol S. , Salles Gilles , Sauter Craig S , Vardhana Santosha A. , Shah Gunjan L. , Straus David J. , Younes Anas , Younes Anas , Zelenetz Andrew D. , Noy Ariela 
Published: December 2024

Burkitt lymphoma (BL) is a highly aggressive and curable disease, but associated with poor outcomes if relapsed/refractory (R/R). Those at highest risk of relapse were identified in a prospective trial as having central nervous system (CNS), marrow or peripheral blood BL (Roschewsi, JCO 2020) or in retrospective series as age ≥ 40, ECOG ≥ 2, LDH &gt; 3× ULN, and CNS as equally weighted independent factors (Olszewski JCO 2020). The outcome of R/R disease is dismal: 2/35 (Short, Am J Hematol. 2017) and 0/10 (Gamero, ASH, 2019), though one report had 11/74 survivors. (Manji, ASH, 2021) We retrospectively performed a database search at Memorial Sloan Kettering Cancer Center between 1/1/1988 to 12/21/2021, identifying 276 BL patients (pts) of whom 28 had R/R disease (1997-2021). Here we describe these 28 pts. High risk baseline features include stage IV disease (21), leptomeningeal disease (LMD) (7), bone marrow disease (7). Five had HIV. The vast majority received ‘intensive’ first line therapies, ie. CODOX/IVAC, DA-EPOCH; including 20 with rituximab on account of study time frame. Initial responses were complete response (CR) (8), partial response (PR) (10), and progression of disease (POD) (10). Among the 8 pts with complete response, the median time to relapse was 5 months. Salvage therapy was given in 13/28 with intention to achieve a CR, typically platinum based or high dose MTX +/-cytarabine; while others receiving a variety of palliative treatments. After 1st salvage therapy, CR was 0% and POD 74%. Four pts achieved CR after &gt;=1 salvage chemotherapy and 1 after radiation. Two pts received allogeneic stem cell transplant (BMT) but 1 died due to complications within a week of transplant and 1 had POD 5 months after BMT. Three pts were long term survivors: one with stage I and two with stage IV disease with bone marrow and leptomeningeal disease (LMD) at initial diagnosis. All received consolidative autologous BMT. Their unique trajectory of treatment was as follows.
The first pt had HIV (normal CD4 count and undetectable HIV viral load) associated BL stage I with a 10 cm axillary mass. He had 3 cycles of R-Hyper-CVAD x 3 cycles with biopsy proven PR, RICE x 1 with no response and 30 Gy radiation with pathologic CR followed by consolidative autologous BMT and remains in remission 12 years later.
The second pt had radiographic testicular involvement and LMD at diagnosis and was treated with CODOX-M/IVAC-R (including 4 doses of IT MTX+ ARA-C and 2 doses of HD-MTX) followed by orchiectomy without evidence of lymphoma. 5 months post therapy a liver biopsy showed only necrotic cells and only a lung nodule showed BL with no other sites of disease. Salvage therapies over 4 months consisted of gemcitabine-oxaliplatin (1 cycle) without response; R-EPOCH x 2 cycles with initial POD, but while undergoing transplant evaluation, repeat imaging revealed response, followed by R-EPOCH x2 with further response; and radiation (30 cGy hyper fractionated IFRT to residual hilar LN), leading to CR, followed by consolidative autologous BMT. He developed secondary AML 31 months later, underwent a 10/10 MUD transplant and has remained without evidence of disease for more than 10 years.
The third surviving pt completed 5 cycles of front-line DA-EPOCH-R achieving control of disease except progression in R level 2 node, surgically resected. For LMD at diagnosis, he received MTX/ARA-C via Ommaya twice weekly for 4 weeks with clearance, followed by maintenance weekly for 6 weeks and then monthly treatment (13 doses). Post resection he had 2 adjuvant cycles of HyperCVAD part B with methotrexate and high dose cytarabine followed by auto BMT and no evidence of disease for almost 10 years.
We identified 28 pts over two decades with R/R BL of whom only three were long term survivors. Our results are in keeping with other prior single institution reports. Notably, two pts had LMD at first diagnosis and all three had very limited systemic disease at relapse, possibly all stage I. All surviving pts underwent autologous BMT in second remission and remained BL free for 10 years. Overall, long term survival is possible for only a minority with R/R BL. Better front-line therapies for those with high-risk features are warranted to reduce the risk of R/R as current salvage therapies are of limited benefit including chimeric antigen T-cell receptor therapies recently reported as unsuccessful for 13 pts across multiple institutions (Samples, ASCO, 2023).