Low-Dose ATLG Prevents GVHD in Pediatric Hematologic Malignancies

July 28, 2017

A lower dose of rabbit anti–T-lymphocyte globulin was superior to a higher dose in children with hematologic malignancies undergoing transplant from an unrelated donor.

Use of a lower dose of rabbit anti–T-lymphocyte globulin (ATLG) was superior to a higher dose in children with hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation (HSCT) from an unrelated donor, according to the results of a study published in Lancet Oncology.

“Our results show that, in an era in which high-resolution molecular typing for class I and class II HLA [human leukocyte antigen] loci has significantly improved the clinical outcome of unrelated donor HSCT by decreasing the risk of immunological complications, lowering the ATLG dose to 15 mg/kg did not affect the time to engraftment and, more importantly, the incidence of acute or chronic GVHD [graft-vs-host disease], and was associated with an improved probability of event-free survival, mainly due to a reduced risk of nonrelapse mortality,” wrote Franco Locatelli, MD, of the department of oncoematologia pediatrica, IRCCS Ospedale “Bambino Gesù” in Rome, and colleagues.

According to the study, ATLG is widely used to prevent acute and chronic GVHD in patients who underwent allogeneic HSCT. However, some research has shown that the use of ATLG may increase risk for relapse and infections. In this study, Locatelli and colleagues examined the optimal dose of ATLG for children with hematologic malignancies.

The randomized phase III study included 180 patients aged 0 to 18 years with hematologic malignancies who underwent transplant from an unrelated donor selected using high-resolution typing for HLA-class I/II loci. All patients received a myeloablative regimen and cyclosporine-A plus short-term methotrexate as post-transplantation GVHD prophylaxis. The patients were randomly assigned to 30-mg/kg ATLG or 15-mg/kg ATLG.

After a median follow-up of 3.4 years, the 100-day cumulative incidence rate of grade II to IV acute GVHD was 36% for the 15-mg/kg group compared with 29% for the 30-mg/kg group (hazard ratio [HR], 0.74; 95% CI, 0.44–1.25; P = .26).

“Post-hoc analyses showed that patients transplanted from a donor who was not fully HLA-compatible had a greater risk of developing grade II–IV acute GVHD,” the researchers wrote. No difference in chronic GVHD was seen between the two groups.

The cumulative incidence rate of nonrelapse mortality was 9% for patients assigned to the 15-mg/kg dose compared with 19% in the 30-mg/kg group (HR, 2.08; 95% CI, 0.89–4.96; P = .092). There were similar rates of disease recurrence between the two groups, with a cumulative incidence rate of 14% in the 15-mg/kg group and 20% in the 30-mg/kg group (HR, 1.54; 95% CI, 0.74–3.21; P = .25).

Among the whole study population, the 5-year overall survival probability rate was 70%; it was 78% for the 15-mg/kg group compared with 62% in the 30-mg/kg group (P = .045). Patients in the 15-mg/kg group had a significantly improved 5-year event-free survival rate (77% vs 61%; P = .028).

“Remarkably, the advantage of 15-mg/kg ATLG over the 30-mg/kg dose was evident in patients transplanted from donors with one or more HLA disparities, who represented almost half of the study population,” the researchers wrote. “The use of 15-mg/kg ATLG was associated with statistically improved event-free survival in the subgroups of children with acute leukemia or with acute lymphoblastic leukemia, which represents the more frequent indication for an allograft in hematologic malignancies of childhood.”

Based on these results, they concluded that the 15-mg/kg ATLG dose should be the standard serotherapy regimen in unrelated-donor transplantation in this patient population.