EBV-driven lymphoid neoplasms associated with pediatric ALL maintenance therapy

Sarah Elitzur*, Ajay Vora, Birgit Burkhardt, Hiroto Inaba, Andishe Attarbaschi, Andre Baruchel, Gabriele Escherich, Brenda Gibson, Hsi Che Liu, Mignon Loh, Anthony V. Moorman, Anja Möricke, Rob Pieters, Anne Uyttebroeck, Susan Baird, Jack Bartram, Shlomit Barzilai-Birenboim, Sandeep Batra, Miriam Ben-Harosh, Yves BertrandTrudy Buitenkamp, Kenneth Caldwell, Ricardo Drut, Ashley V. Geerlinks, Gil Gilad, John Grainger, Stephanie Haouy, Nicholas Heaney, Mary Huang, Danielle Ingham, Zdenka Krenova, Michaela Kuhlen, Thomas Lehrnbecher, Atsushi Manabe, Felix Niggli, Claudia Paris, Shoshana Revel-Vilk, Pierre Rohrlich, Mohamad G. Sinno, Tomasz Szczepanski, Melanie Tamesberger, Rajasekharan Warrier, Matthias Wolfl, Ronit Nirel, Shai Izraeli, Arndt Borkhardt, Kjeld Schmiegelow

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


The development of a second malignancy after the 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 (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus–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, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval [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 (hazard ratio, 7.32; 95% CI, 1.62-32.98; P = .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.

Original languageAmerican English
Pages (from-to)743-755
Number of pages13
Issue number7
StatePublished - 16 Feb 2023

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© 2023 The American Society of Hematology


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