Assessment of Secondary Malignancies after Allogeneic Hematopoietic Cell Transplant When Comparing Treatment with and without Post-Transplant Cyclophosphamide
Authors: Nurse Daniel P. , Wei Wei , Burns Amanda , Farinella Joseph , Jagadeesh Deepa , Dean Robert M. , Hanna Rabi , Rotz Seth J , Gerds Aaron T. , Brunstein Claudio , Kalaycio Matt , Sauter Craig S. , Hamilton Betty K. , Sobecks Ronald 
Published: December 2024

Introduction
Secondary malignancies (SM) may occur as a late toxicity after allogeneic hematopoietic cell transplant (alloHCT) and result in significant morbidity and mortality. It is currently unknown what effect the use of post-transplant cyclophosphamide (PTCy) may have on the development of SM. The primary objective of this study was to compare the incidence of SM after alloHCT between patients treated with and without PTCy.
Methods
We conducted a single-center retrospective cohort study of 1,124 patients who underwent alloHCT from 2011 to 2021. Time to the development of SM (ttSM) was calculated from the date of transplant until the first new malignancy was diagnosed, while death and subjects lost to follow-up were censored for the time-to-secondary malignancy analysis. Results were estimated by the Kaplan-Meier method and compared using the log rank test. Fisher's exact test and Wilcoxon rank sum test were used to associate PTCy with other patient and SCT characteristics.
Results
Out of 1,124 patients (which included 52 pediatric patients), 363 (32%) received PTCy and this cohort was older (median 64 vs. 53 years, p&lt;.0001), had higher HCT-comorbidity index scores (median 3 vs. 2, p=.0003), had less use of unrelated donors (48% vs. 59%, p&lt;.0001), more peripheral blood stem cell (PBSC) grafts (81% vs. 50%, p&lt;.0001), more TBI-based conditioning (52% vs. 34%, p&lt;.0001), less acute GvHD (35% vs. 49%, p&lt;.0001), less chronic GvHD (30% vs. 36%, p=.03) than those who did not receive PTCy. The majority of the PTCy and no PTCy subjects were White (86% vs. 89%) and male (60% vs. 56%). Median follow-up time was 49 months (range, 3-179). PTCy was not significantly associated with overall survival (OS), and the median OS of PTCy and no PTCy subjects were 36 and 42 months, respectively. Sixty-six developed a SM and the 5-year survival rate without developing a SM was 90%, 95% CI: 88-93%, with the majority (52%) being skin carcinomas (32 squamous or basal cell; 2 melanoma). The other SM included: 2 AML, 1 acute promyelocytic leukemia, 3 myeloid sarcomas, 5 PTLD, 1 high-grade glioma, 1 spindle cell sarcoma, 2 urothelial, 1 cervical, 1 breast, 5 lung, 1 colon, 1 appendiceal, 2 oral cavity, 2 thyroid, and 2 prostate carcinomas. Thirteen had multiple SM (8 with 2 SM, 4 with 3 SM and 1 with 4 SM) and 4 of them had received PTCy. Among those with SM 65% received PBSC, 29% bone marrow and 6% cord blood grafts; transplant conditioning included 7.5% myeloablative (MA) TBI-based, 56% MA chemotherapy-based, 29% reduced-intensity (RIC) TBI-based and 7.5% RIC chemotherapy-based. Twenty-nine (44%) of 66 patients who developed SM had acute GVHD and 35 (53%) had chronic GVHD. There was no difference in the 5-year survival rate without an SM between the PTCy and no PTCy cohorts 0.87 (0.80, 0.94) vs. 0.92 (0.89, 0.94) (p=0.27), nor when considering SM excluding skin malignancies 0.94 (0.89, 0.99) vs. 0.96 (0.94, 0.98) (p=.17). However, the 5-year survival rate without a SM was significantly worse for age ≥60 years 0.85 (0.79, 0.91; p&lt;.0001), Caucasian race 0.89 (0.86, 0.92; p=.012), non-myeloablative conditioning 0.76 (0.62, 0.93; p=.01), history of prior solid tumor 0.78 (0.66, 0.93; p=.048) and HCT-CI &gt;3 0.86 (0.82, 0.91; p=.008). Acute and chronic GvHD were not significantly associated with ttSM in this study population. Thirty-nine of those with SM remain alive at the time of analysis. The most common causes of death included 7 (11%) who died from the SM, 9 (14%) disease relapse, 2 (3%) GvHD, 2 (3%) infection, and 2 (3%) cardiac failure.
Conclusion
Our study found no significant difference in the rate of developing SM after alloHCT when comparing those treated with and without PTCy. It will be important to follow these patients to further elucidate the long-term risk of developing SM and whether certain types are more commonly associated with PTCy. Although chronic GvHD has been associated with the development of some SM, it may be anticipated that the lower incidence of GvHD with PTCy use may also reduce the long-term incidence of some SM. As further refinements in alloHCT evolve and more patients become long-term survivors, additional efforts for early detection of SM will be necessary to improve long-term outcomes.