Reply to R. Meisel

We appreciate Meisel's¹ recognition of the relevance of our study² on secondary neoplasms after hematopoietic cell transplant for sickle cell disease. Of particular interest is the occurrence of eight secondary neoplasms in children age ≤12 years at transplantation.² There were 634 children age ≤12 years with eight secondary neoplasms per 4,342 person-years that translates to 1.84 cases per 1,000 person-years. Five of eight were solid neoplasms. With the exception of one patient with sarcoma (not specified) who was lost to follow-up a month after diagnosis, the remaining four patients are alive at the following interval from diagnosis of neoplasm to the most recent follow-up: 21 months (embryonal rhabdomyosarcoma), 26 months (Kaposi sarcoma), 55 months (ependymoma grade II), and 145 months (medulloblastoma). Two patients, one with myelodysplastic syndrome and another with T-cell large granulocytic leukemia (donor-derived leukemia after unrelated donor transplantation) are alive 97 and 101 months, respectively, after diagnosis of neoplasm. The remaining patient with acute myeloid leukemia died within a month of diagnosis. In our study,² six of 22 neoplasms, predominantly solid neoplasms and after a relatively short latency period, were recorded after busulfan/cyclophosphamide conditioning regimen.^3,4 The author¹ recommended that an analysis of risk factors for neoplasm be undertaken in children and an examination of risk factors for neoplasm that included the French cohort. In our published analyses, the multivariable Fine-Gray regression model did not identify age at transplantation as a risk for secondary neoplasms.² Consequently, a subset analysis in children was not performed. With only eight events in our cohort and none reported to-date in the French cohort, it is unclear whether additional knowledge would be gained by examining patient, disease, and transplant characteristics that are typically considered in an analysis of risk factors for neoplasms. We hypothesize that the etiology of neoplasms in sickle cell disease is multifactorial. Our data support choosing transplantation regimens intended to establish donor chimerism without persistence of host cells.² In addition, we propose approaches for consideration in the context of hematopoietic cell transplantation and other curative treatments for sickle cell disease: (1) systematic examination of pretransplant biospecimens for myeloid mutations, mutations in DNA damage response genes (TP53, PPM1D, and CHEK2); (2) sequential sampling to study DNA damage response clones after allogeneic hematopoietic cell transplantation or gene therapy/gene editing; and (3) sequential examinations for proinflammatory markers and markers for hemolysis.^5-7 We acknowledge that these approaches require substantial investment from governmental agencies and/or industry partners. One such example is the Cure Sickle Cell Initiative by the National Heart Lung and Blood Institute in the United States.⁸ The Cure Sickle Cell Initiative supports a phase II trial of gene therapy in the United States that also addresses the incomplete understanding that mutations in certain genes may predict progression to malignancy (ClinicalTrials.gov identifier: NCT05353647). We would like to emphasize that our observations² provide a foundation to discuss neoplasms after hematopoietic cell transplant for sickle cell disease and highlight an urgent need for recommendations for screening and surveillance. Our data also offer an opportunity to design studies prospectively that are aimed at determining etiologies that increase the risk for neoplasms and longer term, risk-benefit ratio of hematopoietic cell transplant and gene therapy/gene editing for sickle cell disease.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Reply to R. Meisel

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No potential conflicts of interest were reported.