In a French single-center retrospective cohort study reported in JACC: CardioOncology, Duléry et al found that posttransplantation cyclophosphamide was associated with a significantly increased risk of early cardiac events among patients receiving allogeneic hematopoietic stem cell transplantation (HSCT).

Study Details

The study included 331 consecutive patients aged ≥15 years who underwent allogeneic HSCT for hematologic malignancies at Saint-Antoine Hospital (Paris) between January 2013 and June 2018. Patients receiving unrelated cord blood were excluded.

Posttransplantation cyclophosphamide was given to all patients undergoing haploidentical HSCT. Those undergoing HSCT after March 2014 with a matched-unrelated or human leukocyte antigen (HLA) identical sibling donor also received posttransplantation cyclophosphamide in case of HLA-mismatch, renal insufficiency, or inclusion in a clinical trial.

The primary outcome measure was incidence of early cardiac events occurring within the first 100 days after HSCT. All patients underwent the same systematic cardiac monitoring.

Early Cardiac Events

Among donors, 89 (27%) were HLA identical siblings, 124 (37%) were unrelated, and 118 (36%) were haploidentical. A total of 136 patients received posttransplantation cyclophosphamide, and 195 did not. In the posttransplantation cyclophosphamide group, 33 patients received posttransplantation cyclophosphamide at 50 mg/kg/d for 1 day and 103 received posttransplantation cyclophosphamide at 50 mg/kg/d for 2 days. The posttransplantation cyclophosphamide group included 13 patients with unrelated donors and 6 with HLA-identical sibling donors.  

Early cardiac events occurred in 45 patients at a median of 17 days after transplantation (range = 1–90 days). The cumulative incidence of early cardiac events was 19% in the posttransplantation cyclophosphamide group vs 6% in the no posttransplantation cyclophosphamide group (P < 0.001). Left-ventricular systolic dysfunction occurred in 14.3% vs 2.1% (P = .001), acute pulmonary edema occurred in 6.7% vs 2.1% (P = .036), pericarditis occurred in 3.8% vs 0.5% (P = .09), arrhythmia occurred in 3.1% vs 3.1% (P = .95), and acute coronary syndrome occurred in 1.5% vs 0.5% (P = .36). The incidence of early cardiac events was 14% and 26% in patients receiving posttransplantation cyclophosphamide total doses of 50 mg/kg and 100 mg/kg, respectively.

Baseline cardiovascular risk factors were not associated with risk of early cardiac events. On multivariate analysis, use of posttransplantation cyclophosphamide was significantly associated with risk of early cardiac events (hazard ratio [HR] = 2.7, 95% confidence interval [CI] = 1.4–4.9, P = .002). Additional factors associated with increased risk of early cardiac events were cyclophosphamide exposure vs no exposure before HSCT (HR = 2.7, 95% CI = 1.5–5.0, P = .002), sequential conditioning regimen vs reduced-intensity and myeloablative regimens (HR = 2.6, 95% CI = 1.5–4.8, P = .001), and older age (HR = 1.4 per 10 years, 95% CI = 1.1–1.7, P = .007).

Graft-vs-Host Disease and Mortality Outcomes

At day 100, the cumulative incidence of grade II to IV and grade III to IV acute graft-vs-host disease (GVHD) was 22% and 7% in the posttransplantation cyclophosphamide group compared with 33% and 12% in the no posttransplantation cyclophosphamide group, respectively (P = .042 for grade II to IV GVHD and P = .140 for grade III to IV GVHD). At 2 years, the cumulative incidence of chronic GVHD was 25% vs 34% (P = .090). On multivariate analysis, the use of posttransplantation cyclophosphamide was associated with a significantly reduced risk of acute grade II to IV GVHD (HR = 0.60, 95% CI =0.40–0.97, P = .037), with no significant effect on chronic GVHD being observed.

After a median follow-up of 36.5 months, there were no significant differences between the two groups in cumulative incidence of nonrelapse mortality, relapse, overall survival, disease-free survival, or GVHD-free, relapse-free survival. Occurrence of early cardiac events was associated with significantly poorer overall survival (HR = 2.7, 95% CI = 1.8–4.2, P < .0001). Overall survival at 2 years was 31% in patients with early cardiac events vs 64% among those without them. Among patients surviving ≥ 100 days after HSCT, 2-year overall survival was 47% vs 72% (P = .046).

On multivariate analysis, use of posttransplantation cyclophosphamide was not associated with overall survival (HR = 1.19, 95% CI = 0.79–1.58, P = .52). Factors associated with poorer overall survival included history of a cardiac event before HSCT (HR = 1.83, 95% CI = 1.26–2.65, P = .002) and cyclophosphamide exposure before HSCT (HR = 2.04, 95% CI = 1.40–2.98, P < .001).

The investigators concluded, “Posttransplantation cyclophosphamide is associated with a higher incidence of early cardiac events occurring within the first 100 days after HSCT. Patients who have a cardiac event after HSCT have lower overall survival. These results may help to improve the selection of patients who are eligible to undergo HSCT with posttransplantation cyclophosphamide, especially older adult patients and patients with previous exposure to [the agent].”

Rémy Duléry, MD, of the Department of Clinical Hematology and Cellular Therapy, Saint-Antoine Hospital, Paris, is the corresponding author for the JACC: CardioOncology article.

Disclosure: The study was supported by the Association for Training, Education and Research in Hematology, Immunology, and Transplantation (ATERHIT). For full disclosures of the study authors, visit jacc.org.