EBV-driven lymphoid neoplasms associated with pediatric ALL maintenance therapy

• Published in: Blood Vol. 141; no. 7; pp. 743 - 755
• Main Authors: Elitzur, Sarah, Vora, Ajay, Burkhardt, Birgit, Inaba, Hiroto, Attarbaschi, Andishe, Baruchel, Andre, Escherich, Gabriele, Gibson, Brenda, Liu, Hsi-Che, Loh, Mignon, Moorman, Anthony V., Möricke, Anja, Pieters, Rob, Uyttebroeck, Anne, Baird, Susan, Bartram, Jack, Barzilai-Birenboim, Shlomit, Batra, Sandeep, Ben-Harosh, Miriam, Bertrand, Yves, Buitenkamp, Trudy, Caldwell, Kenneth, Drut, Ricardo, Geerlinks, Ashley V., Gilad, Gil, Grainger, John, Haouy, Stephanie, Heaney, Nicholas, Huang, Mary, Ingham, Danielle, Krenova, Zdenka, Kuhlen, Michaela, Lehrnbecher, Thomas, Manabe, Atsushi, Niggli, Felix, Paris, Claudia, Revel-Vilk, Shoshana, Rohrlich, Pierre, Sinno, Mohamad G., Szczepanski, Tomasz, Tamesberger, Melanie, Warrier, Rajasekharan, Wolfl, Matthias, Nirel, Ronit, Izraeli, Shai, Borkhardt, Arndt, Schmiegelow, Kjeld
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.02.2023
• Subjects: Child; Epstein-Barr Virus Infections - complications; Epstein-Barr Virus Infections - diagnosis; Herpesvirus 4, Human; Humans; Lymphoma - complications; Lymphoma, Non-Hodgkin - pathology; Neoplasms, Second Primary; Precursor Cell Lymphoblastic Leukemia-Lymphoma - complications; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2022016975

•A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state precipitated by ALL maintenance therapy.•Treatment strategies for these lymphoid neoplasms are distinct from sporadic NHL because they may respond to reduction of immunosuppression. [Display omitted] 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. Second malignancies after childhood acute lymphoblastic leukemia (ALL) are rare. Elitzur and colleagues present a retrospective survey of 85 patients who developed non-Hodgkin lymphoma (NHL) following chemotherapy for pediatric ALL. Over 80% occurred during or within 6 months of maintenance therapy. The majority had features characteristic of immunodeficiency-associated NHL, and 65% were associated with Epstein-Barr virus (EBV). This previously unheralded association has implications for posttreatment monitoring and therapy of secondary NHL.