Incidence of Secondary Malignancies Following Allogeneic Hematopoietic Cell Transplantation: A Single Center Experience
Authors: Michelis Fotios V. , Kotchetkov Rouslan , Grunwald Rebecca M. , Azeem Aamir , Uhm Jieun , Alam Naheed , McGillis Laura , Lambie Anna , Loach David , Gupta Vikas , Kuruvilla John , Lipton Jeffrey H. , Kim Dennis D. , Seftel Matthew D. , Messner Hans A. 
Published: October 2019

Abstract
Late effects occurring post allogeneic hematopoietic cell transplantation (HCT) include the development of secondary malignancies (SM). The purpose of this single-center study was to retrospectively assess the incidence of SM in 2200 patients that consecutively underwent HCT for a variety of hematological conditions between 1970 and 2013, and to investigate parameters associated with occurrence of SM and survival post diagnosis.
Median patient age at transplant was 42 years (range 17-71). Graft was bone marrow in 1310 patients (60%), peripheral blood stem cells (PBSC) in 890 patients (40%). Related donors were used in 1624 patients (74%), unrelated in 576 patients (26%). Transplants were performed for acute myeloid leukemia (AML, n=756, 34%), chronic myeloid leukemia (CML, n=486, 22%), acute lymphoblastic leukemia (ALL, n=275, 13%), non-Hodgkin lymphoma (n=174, 8%), myelodysplastic syndrome (n=159, 7%), aplastic anemia (n=128, 6%) and other conditions (n=222, 10%). Conditioning regimen was myeloablative in 1903 patients (87%) and reduced intensity in 297 patients (13%). Concerning total body irradiation (TBI) dose, 556 patients (25%) did not receive TBI, 1060 patients (48%) received 200-500 cGy and 584 patients (27%) received >500 cGy. Median follow-up of survivors was 120 months (range 1-398). SM was observed in 155 patients (7% of total). Of the patients that developed SM, 39 (25% of SM) were with skin malignancy (30 with non-metastatic squamous and basal cell carcinoma), 25 (16%) with gynecological malignancies, 18 (12%) with gastrointestinal, 19 (12%) with hematological, 20 (13%) with oral squamous carcinoma, 14 (9%) with prostate, 6 (4%) with lung, 4 (3%) with thyroid and 10 (6%) with other forms of SM.
Excluding patients with non-metastatic squamous and basal cell carcinoma of skin, the remaining 125 patients demonstrated a median time to SM of 99 months (range 1-393). Median time to development of SM was 4, 7 and 12 years for the age groups >55, 41-55 and <41 years of age respectively (p=0.0004). At 5 years post-HCT, 2.5% of patients had developed SM (95%CI 1.9-3.3), at 10 years 3.9% developed SM (95%CI 3.1-4.9) and at 15 years 6.0% of survivors had developed SM (95%CI 4.8-7.3). Analysis was performed for the effect of age at HCT, graft source, donor type, time period transplant was performed, conditioning intensity and TBI dose. In both the univariate and multivariable analysis, none of the aforementioned variables influenced cumulative incidence of SM.
Concerning the survival of the 125 patients following diagnosis of SM (excluding non-metastatic squamous and basal cell carcinoma of skin), median follow-up of survivors was 37 months (range 1-344 months), survival at 10 years post-SM was 49% (SE ±6.6%). 25% of patients died of causes related to SM. Univariate analysis demonstrated a significant influence of ECOG score at diagnosis of SM (p<0.0001), while age at SM, coexistence of GvHD at diagnosis, existence of other co-morbidities and time period from HCT to diagnosis of SM did not significantly influence survival. Multivariable analysis demonstrated ECOG score at diagnosis of SM as the only independent predictor of survival post diagnosis, with HR 2.8 for ECOG score 1 and HR 7.0 for ECOG score 2-4 compared to ECOG score 0 (p<0.0001).
In conclusion, incidence of SM post-HCT does not seem to be related to dose of TBI or conditioning intensity. Younger patients develop SM significantly later post-HCT, while a higher ECOG score at diagnosis of SM is independently prognostic of poor survival.

Disclosures
Messner: Otsuka Pharmaceuticals Inc: Research Funding.