Incidence of Second Malignant Neoplasms (SMN) after Haematopoetic Stem Cell Transplant.
Authors: Kulkarni Samar , Potter Michael , Ethell Mark , Saso Radovan , Treleaven Jennifer , Brennan Joy , Kaczmarek Pawel , Hiwarkar Prashant , Kanagasabapathy Pamala , Alvares Caroline , Horton Clive , Powles Raymond , Saran Frank , Morgan Gareth 
Published: October 2019

Abstract
From August 1973 to December 2003, 1651 patients (median age: 28yr., range: 1–74 yr.; M: 982, F: 669) received stem cell transplants for haematological malignancies (Ac. Leuk: 1246, Chr. Leuk: 182, other: 223). Donor was allogeneic (n=1088), autologous (n=537) or syngeneic (n=26) and conditioning was with (n=1243) or without TBI (n=408). Primary disease was classed as high risk in 714 and low risk in 937 patients. Dose of TBI was ≤9.5 Gy (n=342), 10.5 Gy (n=613) or ≥ 10.5 Gy (n=282) delivered in single fraction (n=1015) or multiple fractions (n=222). Donor was sibling (n=900), matched unrelated (n=135) or mismatched family member (n=53). Cranial top-up radiation was used in 357 patients. Source of stem cell was marrow (n=1312), PBSC (n=320) or both (n=19). GVH prophylaxis was CyA alone (n=527), CyA with other agent (n=516) or other measures (n=45). Of all the patients 1515 received single transplant but 136 received more than one transplant. Data was analysed as of 01/07/2006. Of all the patients 897 (54.3%) survived for at least 1 yr. post transplant and the median follow-up in this group was 27yr. Second cancers developed in 50 cases with the incidence of 2.6% at 5yr (95% CI: 1.3–3.9), 7.5% at 10 yr (95% CI: 4.9–10.1) and 11.5% at 15yr (95%CI: 7.6–15.4). Site of second malignancy was brain (n=10), breast (n=6), cervix (n=3), GIT (n=2), lung (n=1), skin (n=9), sarcoma (n=3), thyroid (n=1), oral cavity (n=4), MDS (n=6), CML (n=1), ovary (n=1) and non EBV related lymphoma (n=3). In univariate analysis 10 yr. probability of developing SMN was significantly higher with chronic GVHD (5% vs. 10%, p=0.008, high risk disease (5% vs. 11%, p=0.0007), cranial RT (4% vs. 18%, p=0.015) and ALL as primary diagnosis (4% vs. 10%, p=0.06). In multi-variate analysis advanced stage disease (RR: 2.4, 95% CI: 1.3–4.2, p=0.004), Chr. GVHD (RR: 2.5, 95% CI: 1.4–4.4, p=0.003) and cranial RT (RR: 2.3, 95% CI: 1.2–4.4, p=0.01) were independently associated with increased risk of SMN. There was strong interdependence between cranial RT and ALL as primary diagnosis. It was noted that the multi-variate risk factors were different for site specific SMNs. For brain tumours cranial RT (RR: 12.8, 95% CI:2–75.5, p=0.006) and age <16 yr at the time of transplant (RR:15.7, 95% CI:1.9–130.6, p=0.011) were associated with increased risk. For epithelial malignancies Chr. GVHD (RR: 5.8, 95% CI: 2.2–15.5, p=0.0005), female sex (RR: 3.0, 95% CI:1.1–8.3, p=0.033) and advanced stage disease (RR: 3.6, 95% CI: 1.4–9.4, p=0.01) were associated with increased risk. No independent risk factors could be identified for development of skin or haematological malignancies. 25 patients have died due to SMN (49%) at a median of 31 months. Survival was significantly better in skin SMNs (85%) as compared to haematological SMNs (20%), brain tumours (30%) and epithelial SMNs (56%)(p=0.02). This single centre analysis shows that the risk of developing SMN does not relate to the type of conditioning and increases with longer follow-up. The risk factors vary for the different sites of SMNs. These patients need long term cancer screening.