Similar Cardiac Toxicity Following Allogeneic Hematopoietic Cell Transplant (alloHCT) with Post-Transplant Cyclophosphamide Versus Calcineurin Inhibitor-Based Graft-Versus-Host Disease Prophylaxis

Background:

Post-transplant cyclophosphamide (PTCy) was developed as a graft-versus-host disease (GVHD) prophylactic regimen that allows for the use of haploidentical related donors and has more recently been adopted as a standard regimen for matched donor and mismatched unrelated donor (MMUD) transplant. Though effective in preventing GVHD, cyclophosphamide can be associated with an increased risk of cardiac toxicity. We evaluated cardiac toxicity in alloHCT with PTCy versus calcineurin inhibitor (CNI) based GVHD prophylactic regimens.

Methods:

We retrospectively compared cardiac toxicity between PTCy and CNI in all consecutive patients who received an alloHCT for hematologic malignancy at the Moffitt Cancer Center from 2018-2021. The primary outcome was incidence of cardiac toxicity within 3 months of transplant, where cardiac toxicity was defined as decrease in left ventricular ejection fraction (LVEF) >10% from baseline, cardiogenic pulmonary edema requiring treatment, pericarditis, arrhythmia, or acute coronary syndrome/elevated troponin. Secondary outcomes included overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM). Outcomes were also studied in the subgroup of patients with baseline cardiac comorbidities and in the subgroup of patients receiving PTCy. Cardiac comorbidities were defined as a history of coronary artery disease (CAD), myocardial infarction (MI), arrhythmias, LVEF <50%, valve disease, or pericardial effusion.

Results:

A total of 653 patients were included: 48% (n=314) received a PTCy regimen and 51% (n=339) received a CNI regimen. At the time of alloHCT, 69 (10.5%) patients had baseline cardiac comorbidities: 27 (9.0%) in the PTCy group and 44 (13%) in the CNI group (p<0.01). In the PTCy group, cardiac comorbidities included 15 CAD/MI, 8 arrhythmias, 1 LVEF < 50%, 1 valve disease, and 2 pericardial effusions. In the CNI group, cardiac comorbidities included 20 CAD/MI, 15 arrhythmia, 5 LVEF <50%, 2 valvular disease, and 2 pericardial effusions.

The incidence of cardiac toxicity at 3 months was 28% for the PTCy group and 23% for the CNI group (p=0.15). In multivariate analysis for the entire cohort, there was no difference in cardiac toxicity between the two groups (p=0.10). Acute lymphocytic leukemia (ALL) was associated with a higher risk of cardiac toxicity than acute myeloid leukemia (AML; HR=2.21; CI: 1.25-3.90; p< 0.01), while lymphoma was associated with lower risk of cardiac toxicity compared to AML (HR=0.19; CI: 0.04-0.87; p=0.03). Myeloablative fludarabine/busulfan was associated with a lower incidence of cardiac toxicity compared to fludarabine/melphalan (HR=0.38; CI: 0.24-0.60; p<0.01). There was no significant difference in OS or NRM at day 100 in patients who received PTCY versus CNI.

In subgroup analysis of patients with baseline cardiac comorbidities, the cumulative incidence of cardiac toxicity at 3 months was 23% in the PTCy group and 23% in the CNI group (p=0.95). OS and NRM in this subgroup were also similar between the PTCy and CNI groups.

In the PTCy subgroup, multivariable analysis showed a higher incidence of cardiac toxicity within 3 months of HCT in patients with ALL compared to AML (HR=2.65; CI 1.38-5.10; p< 0.01). Additionally, the risk of cardiac toxicity was lower with myeloablative fludarabine/busulfan compared to fludarabine/melphalan (HR=0.37; 0.19-0.71; p<0.01).

Conclusion:

Our study suggests that PTCy does not significantly increase the risk of cardiac toxicity compared to CNI. Among patients with baseline cardiac comorbidities, cardiac toxicity was also similar between the groups. For patients receiving PTCy, cardiac toxicity was instead associated with ALL and the use of melphalan-based conditioning regimens. These results suggest that PTCy remains a suitable option for GVHD prophylaxis even in patients with underlying cardiac disease.

Mishra:Novartis: Research Funding. Lazaryan:Sanofi: Consultancy, Honoraria, Other: Scientific advisory board. Nishihori:Novartis: Research Funding; ImmunoGen: Consultancy; Karyopharm: Other: drug only supply to the institution; Medexus: Membership on an entity's Board of Directors or advisory committees. Mirza:BMS: Speakers Bureau. Faramand:Sanofi: Consultancy, Honoraria; Autolus: Membership on an entity's Board of Directors or advisory committees; Orca Bio: Research Funding; Novartis: Research Funding; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees. Pidala:CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support; Regeneron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support; Abbvie: Other: Research Support; Takeda: Other: Research Support; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support; BMS: Other: Research Support; Janssen: Other: Research Support; Johnson and Johnson: Other: Research Support; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Research Support. Bejanyan:Anthem Bone Marrow/Stem Cell/Cellular Therapy NTQRC: Consultancy; Pfizer: Consultancy; AlloVir: Consultancy; ORCA Biosystem: Consultancy; CRISPR: Research Funding; CareDx: Consultancy. Elmariah:Shoreline Biosciences: Consultancy; BMS: Research Funding.