Factors associated with the development of second primary malignancies after allogeneic stem cell hematopoietic transplantation. no association with In Vivo T-cell depletion

Abstract

Abstract Introduction: Second primary malignancies (SPMs) are a well-known complication following allogeneic stem cell hematopoietic transplantation (Allo-HSCT). Factors such as age and the use of unfractionated total body irradiation (TBI) at high doses have been related to its occurrence (Baker. Blood. 2019; 27;133(26):2790-2799); more recently, the combination of PTCy and ATG as graft-versus-host Disease (GVHD) prophylaxis has been associated with a reduced risk (Desai. Br J Haematol. 2025; 00:1–8.). However, there is no data on the impact of single-agent use of ATG or PTCy as GVHD prophylaxis on the development of SPMs. Moreover, few studies have systematically explored the combined influence of conditioning regimens and GVHD prophylaxis strategies on the development of SPMs. Material and methods: We retrospectively analyzed the incidence of SPM, associated factors and survival of 517 consecutive patients (pts) who underwent Allo-HSCT at our institution between 2010 and 2020 and had at least one year of follow-up. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Cumulative incidence (CI) was calculated using the Fine-Gray method. Variables with p<0.05 in univariate analysis were included in multivariate Cox regression. All patients gave their informed consent in accordance with the Declaration of Helsinki, allowing their personal data to be used for research. Results: The median follow-up was 88 months. Median age at transplant was 46 years (IQR 18–74), and 45% were female. Most patients (74%) received myeloablative conditioning; 11% received 12 Gy fractionated TBI. The stem cell source was bone marrow (65%), peripheral blood (34%), or cord blood (1%). The primary indication for Allo-HSCT was acute myeloid leukemia (34%) followed by acute lymphoid leukemia (14%) and myelodysplastic syndromes (13%). Most patients (82%) had a matched related or unrelated donor, others included haploidentical (15%) and mismatched unrelated donors (3%). GVHD prophylaxis consisted in the combination of a calcineurin inhibitor (CsA or FK) plus a short course of methotrexate (MTX) or mycophenolate of mofetil (MMF) in 294 (57%) pts, ATG containing schemes in 138 (27%) and PTCy containing schemes in 85 (16%) pts. Seventy (14%) pts underwent a second Allo-HST; these were censored at the time of the second transplant. Fifty-one pts (9.9%) developed a single SPM. The 5 and 10-year CI of SMPs were 6% (95% CI 4–9) and 11% (95% CI 9–16), respectively. The median time to SPM diagnosis was 60 months (IQR 39–102). The most frequent SPMs were skin (n=16), gastrointestinal (n=13), and lung cancer (n=11). Other cases included hematological malignancies (AML/MDS, n=4; lymphoma, n=2), bladder (n=2), central nervous system (n=1), muscle (n=1), and genital neoplasms (n=1). OS of patients who developed SPM at 1 and 2 years from SPM diagnosis were 45% (95% CI 31-58) and 31% (95% CI 19-44) respectively. All patients who developed a skin SPM were alive and of the 35 remaining patients, 16 (44%) died to SPM-related causes. The 10y-OS from Allo-HSCT for patients without SPMs was 68% (95% CI 63-72) and for those patients with a no-skin SPMs was 33% (95% CI 17-50) p<0.01. Univariate analysis identified increasing age at transplant (>50y) (HR 3.6; 95% CI, 2–6.5; p<0.01), use of fludarabine (HR 3.0; 95% CI, 1.4–6.8; p<0.01) and treosulfan (HR 2.7; 95% CI, 1.2–6.5; p=0.02) as significant risk factors. The use of ATG (HR 1.4; 95% CI, 0.7–2.5; p=0.3) or PTCy (HR 1.0; 95% CI, 0.7–2.5; p=0.9) was not associated with an increased SPM risk. Sex, a second Allo-HSCT, donor type, graft source, TBI, busulfan, melphalan, thiotepa, and any grade of cGVHD or moderate-severe cGVHD were not significantly associated with SPMs. In multivariate analysis, only age at transplant>50y (HR 3; 95% CI, 1.7–5.3; p<0.01) remained independently associated with SPM development. Fludarabine (HR 1.9; 95% CI, 0.9–4.4; p=0.1) and treosulfan (HR 1.8; 95% CI, 0.8–4.4; p=0.2) lost statistically significance. Conclusion: SPMs remain a significant late complication after Allo-HSCT. GVHD prophylaxis with ATG or PTCy was not associated with increased SPM risk. Age at transplant >50y was the only independent risk factor identified. These findings support the safety of ATG and PTCy-based prophylaxis from an oncologic standpoint and highlight the need for long-term surveillance in older patients.