Does the Addition of ATLG Improve Outcomes After Allogeneic Transplantation?

Previous studies have suggested that adding anti-T lymphocyte globulin (ATLG) to the treatment regimen for patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) could reduce the incidence of acute and chronic graft-versus-host disease (aGVHD; cGVHD), but a randomized, double-blind, phase III trial presented at the 2016 ASH Annual Meeting showed mixed results.

After two years of follow-up, the addition of ATLG to a standard prophylactic regimen of tacrolimus and methotrexate was found to lower the risk of grade 2-4 aGVHD and moderate-to-severe cGVHD in patients with acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL). However, ATLG-treated patients also had lower rates of overall survival (OS) and progression-free survival (PFS), compared with patients who received placebo.

Robert J. Soiffer, MD, from the Department of Medical Oncology at the Dana Farber Cancer Institute in Boston, Massachusetts, and authors analyzed the incidence of GVHD in 254 patients (median age = 48 years; range = 18-65 years) who had AML (64%), ALL (21%), or myelodysplastic syndromes (MDS; 15%) with <10 percent marrow blasts. Patients with AML and ALL were in first or subsequent complete remission at the time of enrollment.

All patients received human leukocyte antigen–matched unrelated products (mobilized peripheral blood [PB] = 80%; bone marrow [BM] = 20%) and received myeloablative conditioning with one of three possible regimens:

  • cyclophosphamide and total body irradiation (Cy/TBI): 27%
  • busulfan and cyclophosphamide: 33%
  • busulfan and fludarabine: 40%

Standard treatment included tacrolimus one day before alloHCT and methotrexate prophylaxis on days one, three, six, and 11 post-alloHCT. Patients were randomized to receive either placebo (n=128) or ATLG 20 mg/kg daily for the three days prior to alloHCT (n=126).

“Treatment arms were balanced with respect to age, diagnosis, remission status, cytogenetics, graft source (PB or BM), cytomegalovirus serostatus, and conditioning regimen,” Dr. Soiffer and authors noted.

After a median follow-up of 745 days (range = 61-1,425 days), investigators found no significant difference in rates of moderate-to-severe cGVHD-free survival between ATLG- and placebo-treated patients (48% vs. 44%, respectively; p=0.57) or the combined endpoint of GVHD- and relapse-free survival (38% vs. 40%, respectively; p=0.85).

Patients who received ATLG also appeared to have significantly worse survival than those who received placebo:

  • 2-year OS: 58% vs. 76% (p=0.016)
  • 2-year PFS: 47% vs. 67% (p=.024)

However, patients who received ATLG had a lower incidence of grade 2-4 acute GVHD at 6 months than patients who received placebo (23% vs. 40%; p=0.003); this trend continued at the two-year follow-up time point(12% vs. 33%; p=0.068).

“This discrepancy was due in part to a higher incidence of relapse among ATLG-treated patients (32% vs. 19%, p=0.068),” the authors noted. “Multivariable models confirmed that ATLG was associated with inferior OS (hazard ratio [HR] = 1.85; 95% CI 1.1-2.9; p=0.0075) and PFS (HR=1.63; 95% CI 1.1-2.41; p=0.015).”

Given these varying results, “further analyses are needed to understand the proper role for ATLG in alloHCT,” the authors concluded.

The study’s findings were limited by the variation in myeloablative condition regimens. According to a post-hoc analysis, there was “a dramatic difference” in survival outcomes in patients who received Cy/TBI conditioning (OS = 88% vs. 48% [p=0.006] and PFS = 75% vs. 29% [p=0.007] in placebo and ATLG arms, respectively). This effect was not observed among patients treated with the other conditioning regimens.


Reference

Soiffer RJ, Haesook TK, McGuirk J, et al. A prospective randomized double blind phase 3 clinical trial of anti-T lymphocyte globulin (ATLG) to assess impact on chronic graft-versus-host disease (cGVHD) free survival in patients undergoing HLA matched unrelated myeloablative hematopoietic cell transplantation (HCT). Abstract #505. Presented at the 2016 ASH Annual Meeting, December 4, 2016; San Diego, California.

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