Secondary Malignancies After Allogeneic Stem-Cell Transplantation in the Era of Reduced-Intensity Conditioning; The Incidence Is Not Reduced
Authors: Shimoni Avichai , Shem-Tov Noga , Volchek Yulia , Yerushalmi Ronit , Nagler Arnon 
Published: October 2019

Abstract
Abstract 655
Allogeneic stem-cell transplantation (SCT) is a potentially curative therapy for a variety of hematological malignancies and non-malignant diseases. Secondary malignancies are a known complication in long-term survivors. The incidence and kinetics of secondary malignancies have been reported mostly after myeloablative conditioning (MAC). Reduced-intensity conditioning (RIC) has been introduced over the last decade to allow SCT in patients not eligible for standard SCT. RIC has been shown to reduce the incidence of transplant-related complications, however due to the relative limited long-term follow-up of RIC recipients, the incidence and risk-factors for secondary malignancies in the RIC era have not been well defined. We retrospectively reviewed a single institution database of 931 allogeneic SCTs given over the last 12 years to identify patients with secondary malignancies. Conditioning regimens included standard MAC (n=261, TBI-based in 111 pts), fludarabine-based RIC (n=463) or fludarabine-based reduced-toxicity myeloablative conditioning (RTC, n=207). The incidence of secondary malignancies was calculated by cumulative incidence analysis with death due to other causes considered a competing risk. The incidence was correlated with patient and transplant characteristics. Three patients with PTLD and 2 with therapy-related leukemia and relapse of the prior malignancy after SCT were not considered secondary malignancies in this analysis. Twenty-four patients had secondary malignancies including squamous cell carcinoma of the skin (n=5), penis (n=1) vagina (n=1), tongue (n=1) and esophagus (n=2), colon cancer (n=3), breast cancer (n=2), pancreatic cancer (n=2), metastatic cancer of unknown primary (n=1), melanoma (n=1), metastatic sarcoma (n=1), Kaposi sarcoma (n=1) and donor-derived MDS/AML (n=3). In all, 5 patients had metastatic or locally advanced solid tumor at presentation. The median age at SCT was 56 years (29-70). Thirteen patients had acute leukemia (of 545 patients in this cohort), 9 had lympho- proliferative malignancy (of 285), 2 had CML or MPD (of 75) and none had non-malignant disease (of 26). Twenty-one patients were given fludarabine-based RIC/RTC and none had total-body irradiation. The median time from SCT to diagnosis of secondary malignancy was 39 months (7 months-11.5 years). Nineteen patients had prior chronic GVHD, 12 of them moderate-severe, and 16 were still on immunosuppressive therapy at the time of diagnosis of secondary malignancy. The cumulative incidence of secondary malignancy 10 years after SCT was 6.1% (95%CI, 3.8–9.7%). It was higher in older patients (>50 years) than in younger patients; 7.0% Vs 5.0% (p=0.01). Secondary malignancies were less common in patients with CML and nonmalignant diseases compared with patients with prior chemotherapy; 1.0% and 7.3%, respectively (p=0.06). Patients given MAC had a cumulative incidence of 1.8%, compared with 9.1% for patients given fludarbine-based RIC or RTC (p=0.01). Among patients surviving more than 1 year after SCT, a history of moderate-severe chronic GVHD was associated with a higher incidence of secondary malignancies, 13.3% Vs 9.1% (p=0.04). Multivariate analysis identified chronic GVHD (HR 1.7, p=0.001), and RIC/RTC (HR 1.6, p=0.03) as adverse prognostic factors, while a diagnosis of CML or non-malignant disorder was protective (HR 0.4, p=0.001). Patients were treated with surgery for localized tumors and with chemo-radiotherapy or palliative therapy for metastatic disease. Currently, seventeen patients are alive and 7 have died including 4 patients with advanced solid tumor and the 3 with donor MDS/AML. The cumulative incidence of death due to secondary malignancy was 2.8% at 10 years after SCT. In conclusion, secondary malignancies are rare but significant complication after allogeneic SCT. Curative approach is feasible in a subset of patients. Chronic GVHD and treatment for hematologic malignancy other than CML predict for higher incidence. The incidence is not reduced in the RIC era, possibly due to the inclusion of older and more heavily pretreated patients to these protocols. The possible adverse effect of fludarabine in the conditioning regimen can not be ruled out. Although single center analysis has the advantage of more complete follow-up and minimal reporting bias, larger registry studies with a larger number of events are needed to confirm these observations.

Disclosures:
No relevant conflicts of interest to declare.