EBV-driven lymphoid neoplasms associated with pediatric ALL maintenance therapy

Abstract

The development of a second malignancy after diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHL) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients enrolled in 12 collaborative pediatric ALL trials between 1980-2018, who developed NHL following ALL diagnosis. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56/85). Forty-six of these 56 cases (82%) occurred during or within six months of maintenance therapy. The majority (65%) exhibited histopathological characteristics associated with immunodeficiency, predominantly evidence of Epstein-Barr virus (EBV)-driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, five-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% CI, 56-81). Five-year cumulative risks of lymphoid neoplasm- and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7- 22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (HR, 7.32; 95% CI, 1.62 to 32.98; p=0.01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.

Epstein–Barr virus‐associated lymphomas decoded

“…Patients were generally at an advanced stage. The 5‐year event‐free survival and OS from the lymphoid neoplasm diagnosis were 66.6% and 67.4% respectively 66 . By multivariable analysis, the presence of HLH was the only variable associated with an increased risk of mortality.…”

“…The 5-year event-free survival and OS from the lymphoid neoplasm diagnosis were 66.6% and 67.4% respectively. 66 By multivariable analysis, the presence of HLH was the only variable associated with an increased risk of mortality. Treatment varied and typically involved stopping maintenance therapy.…”

“…Involved field therapy in select. Older patients receive reduced-intensity chemotherapy 64 EBV-associated DLBCL-NOS R-CHOP (rituximab, cyclophosphamide, doxorubicin and prednisone) Polatuzumab with rituximab and cyclophosphamide, doxorubicin and prednisone 65 Immune-deficiency lymphoproliferative disorder associated with paediatric ALL maintenance therapy Ceasing maintenance therapy, rituximab monotherapy, rituximab with chemotherapy and chemotherapy alone 66 Burkitt lymphoma Intensive chemotherapy, including R-CODOX-M-IVAC (rituximab), DA-R-EPOCH (doseadjusted) and infusional chemotherapy of rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin 67 Chronic active EBV Immune suppression includes corticosteroids, ciclosporin and azathioprine. Chemotherapy (CHOP); allogenic stem cell transplant 68 Extra-nodal NK/T-cell lymphoma, nasal type Sequential sandwich therapy for advanced-stage disease.…”

“…Recently, Elitzur et al reported on the development of lymphoid neoplasms following paediatric acute lymphoblastic leukaemia (ALL) therapy. 66 The study included 12 international collaborative paediatric ALL trials between 1980 and 2018 and excluded stem cell transplantation. Most of the patients developed immune deficiency lymphoproliferative disorder (IA-LPD) within 6 months of maintenance therapy (typically prednisolone, vincristine, methotrexate and 6-mercaptopurine 'POMP') or shortly after its cessation.…”

“…Recently, Elitzur et al. reported on the development of lymphoid neoplasms following paediatric acute lymphoblastic leukaemia (ALL) therapy 66 . The study included 12 international collaborative paediatric ALL trials between 1980 and 2018 and excluded stem cell transplantation.…”