CMV and BK Virus Reactivation in Post Transplant Cyclophosphamide (PTCY) after Allogeneic MUD, MRD and Haploidentical Transplant

Abstract

Introduction: We previously reported that reduced intensity conditioning (RIC) regimens are safe for patients with XIAP deficiency. XIAP is ubiquitously expressed, and emerging evidence suggests that XIAP is a critical regulator of inflammasome activity and necroptotic cell death downstream of TNFR signaling. It is unknown if there may be an increased risk of death due to inflammatory problems following allogeneic hematopoietic cell transplantation (HCT) such as acute GVHD. Methods: We conducted a retrospective analysis of transplant outcomes of 15 XIAP deficient patients who underwent RIC HCT with alemtuzumab (proximal, distal, or intermediate schedule), fludarabine (150 mg/M2), and melphalan (140 mg/M2) at our center. Twelve patients received bone marrow grafts from either matched related (n = 3) or unrelated (n = 9) donors, and 3 patients received bone marrow grafts from mismatched unrelated donors. Acute GVHD prophylaxis consisted of methylprednisolone and a calcineurin inhibitor. Kaplan Meier survival curves were generated and the outcomes of patients with and without acute GVHD were compared using the log rank test. Results: Fifteen patients with XIAP deficiency underwent allogenic RIC HCT. All patients engrafted. There were no occurrences of severe toxicities such as hepatic veno-occlusive disease, and all patients survived beyond 100 days. All three patients who received mismatched donor grafts died with acute or chronic GVHD and associated infections or PTLD. Two additional patients who received grafts from matched sibling donors developed acute GVHD following donor lymphocyte infusion (intervention for mixed chimerism) and died with acute GVHD and multiple organ failure or chronic GVHD and infection. Only one patient who developed upfront acute GVHD survived, and acute GVHD in this patient developed in the setting of mixed chimerism. Overall long term survival probability of patients who did not develop acute GVHD was 100% versus 17% for patients who developed acute GVHD (all grades) (P = .004). Discussion: We observed very high late mortality in patients with XIAP deficiency treated with RIC HCT who received mismatched grafts and/or developed GVHD. It is possible that host XIAP-deficient tissues, which likely remain susceptible to abnormal inflammatory responses following transplant, may alter the natural history of acute and chronic GVHD in patients with XIAP deficiency. A multi-center survey is indicated to better determine if there is an increased risk of death due to acute GVHD following HCT in patients with XIAP deficiency, as this would alter decisions to pursue mismatched HCT or perform donor lymphocyte infusions.

The Presence of a CMV Immunodominant Allele in the Recipient Is Associated With Increased Survival in CMV Positive Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation

“…After haploidentical HSCT (HI HSCT), CMV reactivation rates are higher than typically seen following HLA matched HSCT (10–13), in part due to immune suppression of donor effector cells necessary to safely cross the major histocompatibility complex (MHC) barrier (14). However, HI HSCT also represents a situation where CMV epitope presentation to responder cells occurs in the context of MHC mismatch, which may further decrease the efficacy of the immune response to CMV (15).…”