A Balancing Act: Outcomes of Post-Transplant Cyclophosphamide in Older Patients

Background: Post-transplant cyclophosphamide (PTCy) has emerged as a definitive regimen for graft versus host disease (GvHD) prophylaxis in hematopoietic stem cell transplants (HCT). However, there are concerns that when combined with myeloablative or even reduced intensity conditioning (RIC) regimens, PTCy can lead to intolerable toxicities in some patients. In the haploidentical setting, Fludarabine and Melphalan (Flu-Mel) conditioning has been associated with high levels of transplant related mortality (TRM) and renal failure when combined with PTCy (Eastburg et al, 2022).

Methods: We performed a single-center, retrospective analysis of all patients receiving an allogeneic HCT in 2023 that received PTCy for GvHD prophylaxis for a wide array of hematologic malignancies. We used our prospectively collected database to collect demographic data, transplant characteristics, and treatment outcomes including toxicities within the first 100 days of transplant. We excluded second HCT and one patient with prior end stage kidney disease (ESKD).

Results: Fifty patients were included in the analysis. The majority (24; 48%) had acute myeloid leukemia (AML), followed by acute lymphoblastic leukemia (ALL) (9; 18%), and myelodysplastic syndrome (MDS) (6; 12%). The median age of patients was 61 (range 24-76). Eighteen patients (36%) had a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) score >3 and six (12%) had a HCTCI score >5. Twelve (24%) patients had a GFR <90 prior to starting their conditioning regimen. . Eight patients had a matched sibling donor; two had a haploidentical donor, thirty-one had a matched unrelated , and nine had a mismatched unrelated donor (eight with 7/8 and one with 6/8 HLA-matched). The most common regimen was a reduced intensity conditioning regimen involving Flu-Mel with or without 200-400 centigray (cGy) total body irradiation (TBI). Seven patients with ALL received a myeloablative conditioning regimen with Etoposide and TBI at 1200 cGy.

Eight patients died (16%) at a median of 73 days post-HCT (range 18 - 177 days). Seven patients relapsed after transplant, and two of these patients died from progression of disease. Disease free survival was 74% at day 100 and 66.6% at 1 year. Nineteen patients (38%) developed acute GvHD, with five patients (10%) developing grade 3 or 4 GvHD.

The most common grade 3or higher toxicities in the first 100 days post-transplant (excluding expected cytopenias) were neutropenic fever (28; 56%), bacteremia (19; 38%), and acute kidney injury (19; 38%). Of the nineteen patients with AKI, twelve were over the age of 60, and six had a GFR < 90 on day of admission (53-89 mL/min). Other common grade 3 or higher toxicities included mucositis (14; 28%), anorexia (10; 20%), diarrhea (6; 12%), and cardiomyopathy (3; 6%).

We further analyzed the six patients who died from transplant related complications. One younger patient with heavily pretreated NK/T-cell lymphoma of the nasopharynx died of diffuse alveolar hemorrhage from aspiration. The other five patients were over age 60, including three over age 70, and four patients were male. They received a total of fludarabine 90mg/m² and one dose of melphalan at 100 or 140mg/m², and two of them received TBI at 200 or 400cGy. Three of these patients had a GFR < 90 on day of admission, and all five eventually developed grade 4 nephrotoxicity requiring renal replacement therapy (RRT) prior to death.

Conclusions:

Overall, our patient outcomes were favorable when adding PTCy for GVHD prophylaxis to both RIC and myeloablative conditioning regimens. Older patients who had underlying renal dysfunction had significantly greater morbidity and mortality. For patients that required RRT, mortality was 100%. In older patients (>60 years of age), PTCy should be used with caution in combination with higher intensity conditioning regimens. This observational study provides a rationale for studying reduced dosing of PTCy in patients who have underlying renal insufficiency.

Yamshon:Bristol Myers Squibb: Consultancy; Kite Pharma: Consultancy.