Should ATG Be Added to Myeloablative Regimens for Hematopoietic Cell Transplantation?

Hematopoietic cell transplantation (HCT) is used to treat a wide range of hematologic malignancies. One anticipated complication is graft-versus-host disease (GVHD) – a condition experienced by 40 to 60 percent of patients that increases their risk for mortality and can negatively impact quality of life. Anti-thymocyte globulin (ATG) may ameliorate this complication, as previous studies have indicated that pre-treatment with ATG decreases the incidence of chronic GVHD at one year after transplantation, without adversely affecting rates of disease relapse, serious infection, or overall survival (OS).

Irwin Walker, MBBS, from McMaster University and Juravinski Hospital and Cancer Centre in Hamilton, Ontario, Canada, and colleagues conducted a phase III, multicenter, open-label, randomized, controlled trial to examine whether ATG reduces the need for long-term immunosuppressive treatment to prevent GVHD after transplantation.

Based on the study results, “ATG is effective in preventing chronic GVHD, the most serious long-term complication of HCT,” Dr. Walker told ASH Clinical News.

The study took place between June 9, 2010, and July 8, 2013, at 10 transplant centers in Canada and one center in Australia. Patients were eligible for study inclusion if they had a hematologic malignancy and were receiving either myeloablative or non-myeloablative conditioning preparative regimens before HCT from an unrelated donor.

A total of 203 patients were randomized to receive either:

  • Rabbit-derived ATG 4.5 mg/kg administered intravenously over 3 days prior to transplant plus standard GVHD prophylaxis (n=101)
  • Standard GVHD prophylaxis alone (n=102)

Standard GVHD prophylaxis treatment included either cyclosporine or tacrolimus with either methotrexate or mycophenolate.

The study’s primary endpoint was freedom from systemic immunosuppressive drugs without resumption up to 12 months after transplantation. Secondary endpoints included time to neutrophil and platelet engraftment; incidence of acute GVHD; incidence of and time to chronic GVHD; event-free survival; and times to non-relapse morality, all-cause mortality, and relapse of hematologic malignancy. Patient-reported quality-of-life measures were also analyzed.

Among the patients who were alive at 12 months, 37 percent in the ATG group (n=37) were free from immunosuppressive treatment, compared with 16 percent in the no-ATG group (n=16; odds ratio [OR] = 3.02; 95% CI 1.54-5.92; p=0.0010).

The proportion of patients with neutrophil engraftment at 100 days was similar in the ATG and no ATG cohorts: 97 percent (n=64/66) versus 98 percent (n=65/66). The median time to platelet engraftment was 20 days in the ATG group compared with 16.5 days in the no-ATG group (hazard ratio [HR] = 0.84; 95% CI 0.55-1.27; p=0.827).

“This is the third of three randomized trials of ATG in unrelated donor transplantation, all having had positive results in favor of ATG and all showing minimal likelihood of harm,” Dr. Walker told ASH Clinical News. “The optimal dose of ATG is unknown, but this may be critical, so clinicians should employ doses used in successful randomized trials.”

No differences were seen between the treatment groups in time to non-relapse mortality, time to disease relapse, or OS.

“Patients who received ATG reported significantly lower symptom burden attributable to chronic GVHD at 12 months than patients who did not receive ATG, as measured by the Lee scale [which measures the effect of GVHD symptoms on patients’ functioning and well-being],” Dr. Walker and co-authors wrote. Out of a possible 100 points (with higher scores reflecting higher symptom burden), patients who received ATG had Lee scale scores of 14.95, versus 20.93 in the no-ATG group (p=0.017).

At 12 months, 137 patients were alive without relapse and were given seven questionnaires to evaluate each treatments’ effects on quality of life. Overall happiness (measured by Atkinson Happiness Scale) was significantly higher in the ATG group, compared with the no-ATG group (with scores of 7.40 vs. 6.16; p=0.027).

Serious adverse events did not differ between the ATG and no ATG groups (34% vs. 42%), though Epstein-Barr virus reactivation was more common among patients receiving ATG (20 patients with one death [33%] vs. 2 patients with no deaths [3%]). No deaths were attributed directly to ATG, the researchers noted.

Limitations of the study included the non-blinded design and short follow-up period. “A longer follow-up might reveal additional symptom burden because organ damage and immunosuppressive side effects are expected to accumulate in patients affected by chronic GVHD,” noted Dr. Walker and co-authors.

The researchers noted that future clinical research should be conducted to find answers to several questions. “Although this study supports an important role for ATG in hematopoietic cell transplantation, several questions related to its use remain unanswered,” they wrote. “First, the optimum timing and dosing of ATG needs further investigation with respect to the potential harms of Epstein-Barr virus reactivation, post-transplantation lymphoproliferative disorder, and disease relapse after non-myeloablative and reduced intensity conditioning.”

Also, although an increase in disease relapse was not noted in this trial in patients receiving non-myeloablative conditioning, “a specifically designed trial with adequate numbers of patients is needed to resolve this controversial question.”

“ATG should be added to myeloablative and non-myeoablative preparative regimens for hematopoietic cell transplantation when using unrelated donors,” concluded Dr. Walker and colleagues. “The benefits of decreases in steroid use are clinically significant. Epstein-Barr virus reactivation is increased, but is manageable by prospective monitoring and the use of rituximab.”


Reference

Walker I, Panzarella T, Couban S, et al. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomized, controlled, open-label, phase 3, muticentre trial. Lancet Oncol. 2016;17:164-73.

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