Prospective, Randomized, Double-Blind, Phase III Clinical Trial of Anti-T-Lymphocyte Globulin to Assess Impact on Chronic Graft-Versus-Host Disease-Free Survival in Patients Undergoing HLA-Matched Unrelated Myeloablative Hematopoietic Cell Transplantation.

Abstract

Purpose Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graft-versus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days -3, -2, -1 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P = .004) and moderate-severe cGVHD (12% v 33%; P < .001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P = .47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% [ P = .04] and 59% v 74% [ P = .034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P = .026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P = .01). Conclusion In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.

• Authors: Robert J Soiffer, Haesook T Kim, Joseph McGuirk, Mitchell E Horwitz, Laura Johnston, Mrinal M Patnaik, Witold Rybka, Andrew Artz, David L Porter, Thomas C Shea, Michael W Boyer, Richard T Maziarz, Paul J Shaughnessy, Usama Gergis, Hana Safah, Ran Reshef, John F DiPersio, Patrick J Stiff, Madhuri Vusirikala, Jeff Szer, Jennifer Holter, James D Levine, Paul J Martin, Joseph A Pidala, Ian D Lewis, Vincent T Ho, Edwin P Alyea, Jerome Ritz, Frank Glavin, Peter Westervelt, Madan H Jagasia, Yi-Bin Chen
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 35 Issue 36 Pg. 4003-4011 (Dec 20 2017) ISSN: 1527-7755 [Electronic] United States
• PMID: 29040031 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Antilymphocyte Serum
• HLA Antigens
• Immunosuppressive Agents
• Tacrolimus
• Methotrexate

Topics

• Adolescent
• Adult
• Aged
• Antilymphocyte Serum (therapeutic use)
• Double-Blind Method
• Female
• Graft vs Host Disease (etiology, prevention & control)
• HLA Antigens (immunology)
• Hematopoietic Stem Cell Transplantation (adverse effects, methods)
• Humans
• Immunosuppressive Agents (therapeutic use)
• Leukemia, Myeloid, Acute (therapy)
• Male
• Methotrexate (therapeutic use)
• Middle Aged
• Myelodysplastic Syndromes (therapy)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (therapy)
• Prospective Studies
• Tacrolimus (therapeutic use)
• Young Adult