Secondary malignancies after hematopoietic cell transplantation for sickle cell disease: A single-center experience

Abstract Introduction: Sickle cell disease (SCD) is a severe inherited hemoglobinopathy associated with significant morbidity and mortality. Hematopoietic cell transplantation (HCT) remains the only curative therapy for SCD, offering improved survival and quality of life. However, long-term complications of HCT, including the risk of secondary malignancies, remain a growing concern. Data on the incidence and outcomes of secondary malignancies in SCD patients post-HCT are limited. This study aims to describe our single-center experience and evaluate the occurrence and clinical characteristics of secondary malignancies following HCT in patients with SCD. Methods: We conducted a retrospective review of all patients with sickle cell disease (SCD) who underwent non-myeloablative conditioning with alemtuzumab and 300 cGy total body irradiation (TBI) for allogeneic hematopoietic cell transplantation (HCT) at our center. The study population included adolescent and adult patients aged ≥14 years who received a matched related donor (MRD) transplant. Patients who underwent myeloablative regimens or haploidentical transplants were excluded. The minimum duration of follow-up was one year. The primary objective was to assess and describe the occurrence of secondary malignancies in this cohort. Data were summarized using descriptive statistics, including counts, percentages, medians, and ranges. Result: A total of 391 patients with sickle cell disease underwent non-myeloablative allogeneic HCT. The median age at transplant was 25 years (range, 14–48), and 189 (48%) were male. The median follow-up was 1,242 days (range, 215–3,505), equivalent to approximately 3.4 years (range, 0.6–9.6 years). At last follow-up, 379 patients (97%) were alive, and 12 (3%) had died. Graft failure occurred in 24 patients (6.1%), and 14 underwent a second transplant. Among 391 patients who underwent non-myeloablative transplant for sickle cell disease, six (1.5%) developed secondary malignancies. The median age at diagnosis was 28.5 years (range: 21–43), and the median time to malignancy post-transplant was 2.4 years (range: 107 days–4.8 years). Diagnoses included MDS (n=2), MDS transformed to AML (n=1), CML (n=1), Philadelphia-positive ALL (n=1), and EBV-related PTLD with stage IV DLBCL (n=1). Summary of Patients with Secondary Malignancy Conclusion: Secondary malignancies following non-myeloablative hematopoietic stem cell transplantation in sickle cell disease patients are rare but clinically significant, with an observed incidence of 1.5% in our cohort. The rate of myeloid neoplasm in this large cohort with long follow up is 0.76%. The myeloid malignancy happen mainly in patients with GF and underlying leukemia predisposing condition. These findings highlight the importance of long-term surveillance and early molecular monitoring to detect clonal evolution and guide timely interventions. Further studies with larger cohorts are needed to better define risk factors and optimize prevention strategies. Patient Age Gender Time post-transplant Diagnosis Chimerism at Diagnosis Genetic Abnormalities Treatment Current Status Latest Chimerism HbS (%) 1 38 Male 4.8 years Graft failure MDS 0% del(7q31), del(13q14), ASXL1, PTPN11, RUNX1 2nd transplant (FluBu4), Azacitidine MDS recurrence post 2nd HCT 11% 4.1 2 29 Female 3.5 years Graft failurepost 2nd and 3rd HCTMDS 89.5% del(7q22), del(17p13) Azacitidine Active disease 63.3% 37 3 28 Female 2.4 years Ph+ ALL 46% t(9;22), del(9p21), TEL gene deletionBCR-ABL p190 Ponatinib + Blinatumomab ×4, HyperCVAD Part B MRD-negative remission 96.91% 26.2 4 24 Male 1.3 years CML 70% t(9;22), BCR-ABL p210 Dasatinib Remission 80% 38 5 21 Female 143 days EBV-related DLBCL (Stage IV) 56% None R-CHOP ×6 CR >1.5 yearsGraft failure 0% 43.8 (on transfusion) 6 43 Male 107 days MDS → AML (Li-Fraumeni) 35% Complex cytogenetics, TP53 mutation (homozygous) Induction chemo Died (fungal infection) – –