High Rate of Second Malignancies after Reduced Intensity Double Cord Blood Transplants in Adults.
Authors: Ballen Karen K , Cutler Corey , Yeap Beow Y , McAfee Steven L , Dey Bimalangshu R , Attar Eyal C , Haspel Richard L , Liney Deborah , Koreth John , Ho Vincent , Alyea Edwin P , Soiffer Robert J , Spitzer Thomas R , Antin Joseph H 
Published: April 2020

Abstract
Reduced intensity conditioning (RIC) double cord blood transplantation is an effective strategy in adults to provide allogeneic donors for patients with uncommon HLA types. However, the risk of second cancers has not been established. We treated 53 patients with hematologic malignancies using a RIC regimen of fludarabine 30 mg/m2/day Days −8 through −3 (total dose 180 mg/m2), melphalan 100 mg/m2 Day −2 and rabbit antithymocyte globulin 1.5 mg/kg Days −7, -5, -3, -1 (total dose 6 mg/kg). Cord blood units were a 4/6 or higher HLA A, B, DR allele match with the patient and each other and achieved a minimum precryopreservation cell dose of 3.7 x 107 NC/kg. Twenty-one patients received GVHD prophylaxis with cyclosporine and mycophenolate mofetil and 32 patients received tacrolimus and sirolimus. Median age was 49 (range 19–67) years and the majority of patients had acute leukemia or relapsed lymphoma. Median follow-up was 27 months among the 29 patients still alive. Nine patients developed a second malignancy. Seven patients had lymphoma and two had MDS/MPD. The second cancers occurred at a median of 141 days (range 39 days-26 months) after transplant. Five second cancers (both MDS/MPD and 3 of 7 lymphomas) were donor derived; the origin of the others was not determined. Patients with Epstein Barr Virus lymphoproliferative disorder (EBV-LPD) had a median EBV viral load of 445,000 copies/ml (range 3300–5.4 million). Six of seven patients with lymphoma had wide spread organ involvement; 6 patients were treated with Rituxan but only one of them had a sustained response; the rest died of EBV-LPD. Both cases of MDS/MPD were donor derived and fatal. One occurred in a patient transplanted for CLL; the other patient was transplanted for AML. The overall survival for the entire cohort of 53 patients was 55% at two years. The actuarial rate of second malignancy was 19% at 26 months post-transplant (2 year rate of 16%). The rate of donor-derived myeloid disease was 6%. Second malignancy was the leading cause of death, with relapse the second leading cause of death. Neither age, GVHD prophylaxis, HLA matching, nor total nucleated cell dose predicted for a higher rate of second malignancy. There was a trend to a higher risk of second cancer in patients who received an infused CD34+ cell dose of ≤ 1.9 x 105 cells/kg)—(30% vs. 7%, P=0.070). In summary, 1) Second malignancies occur at a high rate after RIC cord blood transplantation; 2) A low infused CD34+ cell dose/kg may be associated with a higher risk of second cancer; 3) Strategies to reduce thymoglobulin dose may be important to reduce the incidence of EBV-LPD; 4) It is important to assess the genetic origin of post-transplant myeloid diseases to establish the risk of donor-derived leukemia.
723: Recurrence, Secondary Neoplasia, and Late Complications