Prophylactic treatment with low-dose corticosteroids accelerated platelet recovery and significantly decreased the prevalence of acute graft-versus-host disease among high-risk patients undergoing haploidentical hematopoietic stem cell transplantation, according to the results of an open-label, randomized control trial.
Prophylaxis further appeared to reduce the rate of adverse events without increasing the rate of infections, results showed.
“Allogeneic HSCT is limited by the major lethal complication of graft-versus-host disease [GVHD],” Xiao-Jun Huang, MD, PhD, director and chief physician in the department of hematology at Peking University People’s Hospital, told HemOnc Today. “Corticosteroids are a nonspecific immunosuppressive agent, which may contribute to high rates of infection, although prophylaxis with corticosteroids can reduce the risk for acute GVHD. Therefore, novel strategies are needed that reduce the incidence of acute GVHD without increasing infection rates.”
Huang and colleagues evaluated data from 228 patients undergoing haploidentical allogeneic HSCT. Researchers used bone marrow allogeneic graft CD4–CD8 ratios to categorize patients at low risk (Group A; n = 83; median age, 33 years) or high risk (n = 145) for GVHD.
The researchers assigned high-risk patients to a course of low-dose glucocorticoid prophylaxis (Group B; n = 72; median age, 26.5 years) or no prophylactic treatment (Group C; n = 73; median age, 30 years).
Patients in Group B received low-dose IV methylprednisolone (0.5 mg/kg) on days 5 and 12 after transplantation. After day 12, the dose was reduced to 0.25 mg/kg per day for 10 days, then further reduced to 0.125 mg/kg per day.
The incidence of grade 2 to grade 4 acute GVHD served as the primary endpoint.
Cumulative rates of acute grade 2 to grade 4 GVHD at 100 days after transplantation appeared comparable in Group A (26%; 95% CI, 16-36) and Group B (21%; 95% CI, 11-31). However, rates were significantly higher in Group C (48%; 95% CI, 32-60; P < .001).
The median interval for developing acute GVHD was 25 days (range, 16-50) in Group B, compared with 15 days (range, 9-57) in Group C and 21 days (range, 10-58) in Group A (P < .05).
Low-dose corticosteroid prophylaxis significantly lowered risk for acute grade 2 to grade 4 GVHD (HR = 0.66; 95% CI, 0.49-0.89) and with rapid platelet recovery (HR = 3.3; 95% CI, 2.1-4.37).
Patients in Group B had the lowest cumulative incidence of moderate-to-severe chronic GVHD (21%), whereas incidence rates were 50% (P = .025) in Group A and 36% in Group C.
Group B had a total corticosteroid dose amount of 205.41 ± 111.38 mg in the first 100 days after HSCT. This was comparable to that used in Group A (229.3 ± 148.91 mg), but significantly lower than Group C (286.54 ± 259.67 mg; P = .016).
Fourteen percent of patients in Group B developed corticosteroid-refractory acute GVHD, compared with 23% of patients in Group A and 18% in Group C.
The three groups had similar incidence rates of common adverse events, including cytomegalovirus or Epstein-Barr virus reactivation, post-transplantation lymphoproliferative disorder, hemorrhagic cystitis, bacteremia and invasive fungal infection.
However, a significantly smaller proportion of patients in Group B experienced osteonecrosis of the femoral head (P = .034) and secondary hypertension (P = .015) than Group A or Group C.
Thirty-two patients died of nonrelapse causes, the most common of which was infection (Group A, n = 7; Group B, n = 8; Group C, n = 7). Infection rates were comparable across groups.
The researchers acknowledged study limitations, including the lack of placebo, the open-label design and the exclusive investigation of patients undergoing haploidentical transplants.
“If our innovative trial design could be further confirmed by researchers in other transplant modalities, such as HLA–matched unrelated-donor transplant, we may achieve individual-based GVHD prevention,” Huang said.
The study was not adequately powered to detect other potentially important endpoints, such as OS or treatment-related mortality, Edwin P. Alyea III, MD, associate professor of medicine at Harvard Medical School and associate director of stem cell transplantation and director of oncology hospital medicine at Dana-Farber Cancer Institute, wrote in an accompanying editorial.
“How would this optimized regimen and the excellent outcomes reported compare with other regimens being used in haploidentical transplantation?” Alyea wrote. “The rate of acute GVHD would not be an appropriate endpoint for comparison. For example, the incidence of acute GVHD in both the low-risk group and the corticosteroid-treated high-risk group in this trial seems to be higher than the rates given in recently published data that used post-transplant cyclophosphamide.”
Comparative trials are needed to validate the routine use of corticosteroid prophylaxis.
“The endpoint of these comparative studies must be OS, treatment-related mortality and relapse rates,” Alyea wrote. – by Cameron Kelsall
For more information:
Xiao-Jun Huang, MD, PhD, can be reached at firstname.lastname@example.org.
The researchers and Alyea report no relevant financial disclosures.