Advanced Age at Transplant Increases the Risk of Second Solid Malignancy (SSM) after Haematopoetic Stem Cell Transplantation (HSCT)
Authors: Murray John , Chadwick John , Bloor Adrian , Cavet Jim , Dennis Mike , Somervaille Tim , Sommerfeld Sven Armin , Eliott John , Muthia Siobhan , Leather Angie , Angelica Rita , Brown Rachel , Tomlins Jo , Kulkarni Samar 
Published: October 2019

Abstract
Introduction: It is increasingly important to understand the long term risk associated with transplantation because the number of long term survivors is steadily growing. In comparison to other long term risks following transplantation like infertility, cataracts, endocrine dysfunction, etc. the risk of second malignancy is likely to be associated with increased risk of mortality and hence significant impact on survival outcomes. This retrospective, single centre analysis was undertaken to evaluate the risk of second solid malignancy in patients undergoing HSCT.
Methods: From February 1973 to November 2013, 1983 patients (median age: 45yr., range: 14-76 yr.; M: 1259, F: 724) received stem cell transplants for haematological malignancies (Ac. Leuk: 507, Chr. Leuk: 97, lymphoma:645, myeloma:621, solid tumours:113). Donor was allogeneic (n=528) or autologous (n=1455) and conditioning was with (n=556) or without TBI (n=1427). Donor was sibling (n=302), matched unrelated (n=220) or cord blood (n=6). Source of stem cell was marrow (n=322), PBSC (n=1627), both (n=28) or cord blood (n=6). GVH prophylaxis included Campath in 203 cases. Of all the patients 1774 received single transplant but 209 received more than one transplant. Data was analysed as of 01/12/2013 using competing risk models with death as the competing event. Patients who developed second haematological malignacy were not included in this analysis.
Results: Patient follow-up was more than 10 years in 382 cases (19%), between 5 to 10 years in 328 (17%), 1 to 5 years in 667 (34%) and less than 1 year in 606 cases (31%). Second solid malignancy developed in 70 patients with the incidence of 1% at 5yr (95% CI: 0.5-1.6), 2.2% at 10 yr (95% CI: 1.6-3.3), 4.8% at 15yr (95% CI: 3.6-6.8) and 8% (95% CI: 5.9-10.5) at 20 years. Site of second malignancy was brain (n=2), breast (n=15), cervix (n=3), GIT (n=11), genitourinary (n=9), lung (n=3), skin (n=17), head & neck (n=7), thyroid (n=3) and non EBV related lymphoma (n=3). In univariate analysis 10 yr. probability of developing SSM was not influenced by gender, stage of disease, primary diagnosis, type of HSCT, use of TBI, cranial top-up radiation, type of donor or year of transplant. It was significantly higher with use of PBSC (1.4% vs. 2.6%, p=0.02) and age above 65yr. (1.5% vs. 11%, p=0.001). In multi-variate analysis age above 65yr. (RR: 1.8, 95% CI: 1.1-2.9, p=0.02) and PBSC (RR: 9.4, 95% CI: 1-99, p=0.05) were independently associated with increased risk of SMN. 19 patients have died due to SSM (27%) and survival was significantly shorter with gastrointestinal, genitourinary and lung cancers.
Conclusion: This single centre analysis shows that the risk of developing SSM increases with advancing age, longer follow-up and the survival is poor. Long term survivors of stem cell transplants need follow-up probably for life in speciality clinics. Continued vigilance, avoidance of known carcinogens and life style changes are strongly recommended.

Disclosures
Bloor: GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavet:Novartis: Research Funding; BMS: Research Funding.