Second Solid Cancers after Allogeneic Stem Cell Transplantation: The Vancouver Experience.
Authors: Gallagher Genevieve , Hogge Donna E. , Nevill Thomas J. , Nantel Stephen H. , Barnett Michael J. , Shepherd John D. , Sutherland Heather J. , Toze Cynthia L. , Smith Clayton A. , Lavoie Julye C. , Song Kevin W. , Forrest Donna L. 
Published: April 2020

Abstract
The development of second solid cancers in recipients of hematopoietic stem cell transplants (SCT) represents a serious complication among long term survivors. To assess the incidence and associated risk factors for second solid cancers following allogeneic SCT we performed a retrospective analysis of 926 consecutive patients (pts) who underwent an allogeneic (n=918) or syngeneic (n=8) SCT between January 1985 and December 2003. Primary diagnoses were AML (235), ALL (103), CML (216), lymphoproliferative disorders (150), MDS (96), MM (80) or other (46). Median age at SCT was 39 years (range 12–65) and median time from diagnosis to SCT was 5.1 months (range 0.2–345). 640 pts had a sibling donor (602 matched/38 mismatched) and 286 had an unrelated donor (225 matched/61 mismatched). Stem cell source was bone marrow (810), peripheral blood (109) or both (7). Conditioning regimens were: TBI-based (488), BuCy +/− other (414), other (24). The graft was unmanipulated in 883 pts and T-cell depleted in 43 pts. GvHD prophylaxis consisted of CSA and MTX in 84%. With a median follow-up of 22.2 months post SCT (range 0.07–230.5) for all 926 pts and 84.2 months (range 8.4–230.5) for surviving pts, 30 solid malignancies have occurred in 28 pts at a median of 81.4 months post SCT (range 1.4–207.5). These second tumors involved skin (8 basal cell carcinoma, 4 invasive squamous cell carcinoma), lung (5), oral cavity (4), colon (2), bladder (2) breast (1), kidney (1), parotid gland (1), vulva-in situ (1) and primary unknown (1). 6 of the 28 pts died from the second cancer at a median of 6.1 months (range 0.9–36) following the diagnosis. The cumulative incidence of all second solid cancers at 10 and 15 years was 3.1% (95% CI 2–5%) and 5.7% (95% CI 3–9%), respectively. Excluding basal cell carcinoma and carcinoma in situ, the 10 and 15-year cumulative incidence rates were 2.3% (95% CI 1–4%) and 4.0% (95% CI 2–6%), respectively. Compared to age and gender adjusted cancer rates in the general population of BC, the relative risk (RR) of developing a second solid cancer after allografting excluding basal cell carcinoma and squamous cell carcinoma of the skin was 1.85 (95% CI 1.04–3.06), p =0.019. Risk factors evaluated included initial diagnosis, gender, age at SCT, donor gender, donor age, interval from diagnosis to SCT, year of SCT, source of stem cells, HLA disparity, conditioning regimen, T cell depletion, prior history of radiation therapy, incidence of aGvHD, incidence of cGvHD and aGvHD therapy. In multivariate analysis, significant risk factors were recipient age at SCT &gt;40 years (RR 4.8), p=0.01 and donor gender [female donor/male recipient (RR 5.4), female donor/female recipient (RR 2.3)] p=0.002. We conclude that allogeneic SCT recipients are at an increased risk of developing a second solid cancer as compared to the general population, particularly if the recipient is &gt;40 years at the time of allografting. It is also apparent that male recipients of a female graft have a high risk of second solid cancers. Since we did not find an association between second cancers and aGvHD or cGvHD in our analysis, is it interesting to speculate whether this is somehow related to subclinical GvHD. Regardless, longer follow-up is needed to more fully assess the incidence and risk factors for second solid tumors post-transplant due to their long latency period.