By Binod Dhakal, MD, MS

“I just want to be a normal person, doctor,” Greg said, “but that’s not an option.” Greg, 58 years old, underwent hematopoietic stem cell transplantation (HSCT) for high-risk acute myeloid leukemia (AML) three years ago using cells from his brother. The transplant went well, and it seemed to have cured his cancer. But 10 months after HSCT, he started to develop tightness in his muscles that progressed to body stiffness, a condition called chronic graft-versus-host disease (GVHD). This poignant tale, shared by many others, depicts a debilitating and potentially life-threatening condition that results when donor cells forget their limits to attack cancer and wreak havoc on other organs in patients undergoing allogeneic (allo-)HSCT for life-threatening hematologic malignancies. Patients such as Greg might get cured of their primary disease but are left with a chronic illness with a profound impact on their quality of life — it’s like trading one disease for another. Effective prevention and management of this maddeningly mysterious condition have always been challenging, leaving physicians with the obvious question that is still considered to be the holy grail of the HSCT field: How can we preserve graft-versus-tumor (GVT) effect without causing GVHD? Another critical question, as Linda J. Burns, MD, noted during the abstract introduction, “What is the optimal GVHD prophylaxis to preserve the GVT in a reduced-intensity conditioning [RIC] setting?”

In the first Plenary abstract, Annoek E.C. Broers, MD, PhD, of Erasmus MC Cancer Institute in Rotterdam, presented the results of the HOVON-96 trial, a prospective randomized, multicenter, phase III tri- al comparing a post-transplant cyclophosphamide (PTCY) –based immunosuppressive regimen with conventional immunosuppression (CIS) in patients with matched-related (MR) and matched-unrelated (MU) donors after allo-HSCT. Based on the preclinical studies in the 1960s, the pioneering clinical studies of PTCY were initially performed in the haploidentical transplant (haplo-HSCT) platform by Leonido Luznik, MD, and colleagues from Johns Hopkins University in the early 2000s. This novel technology not only allowed HSCT across human leukocyte antigen (HLA) barriers but also allowed immune surveillance with preservation of GVT effects, enabling the use of PTCY-based HLA–haplo-HSCT to increase rapidly worldwide. Given the success in this platform, PTCY has subsequently been applied to other transplantation settings, but the data were mainly limited to retrospective studies, and thus came with all the caveats that attend such studies. A prospective randomized study comparing the PTCY approach versus conventional approaches in non–haplo-HSCT was an unmet need.

In the HOVON-96 trial, 160 patients with MR or MU donors were randomized in a 2:1 fashion between PTCY on day +3 and +4 with CIS containing cyclosporine (CSA) from day +5 until day +70, versus CIS only containing a GVHD prophylaxis regimen (CSA until day +120 followed by tapering until day +180 and mycophenolate mofetil until day 84 post-HSCT) in patients with hematologic malignancies. The two groups were comparable at baseline; 98 percent had RIC conditioning regimens, 97 percent received peripheral blood grafts, and approximately 70 percent were MU donors. The results showed a significant reduction in both acute and chronic GVHD in the PTCY arm versus the CIS arm (cumulative incidence [CI] at six months of grade II-IV acute GVHD was 32% vs. 48% [subdistribution HR, 0.52; 95% CI, 0.31-0.87; p=0.014]; grade III-IV GVHD was 6% vs. 12%; and 2-year CI of chronic extensive GVHD was 19% vs. 50% [subdistribution HR, 0.38; 95% CI, 0.21-0.67; p=0.001]), respectively. The three-year outcomes (progression-free survival, overall survival, and CI of relapse) were similar between the two groups, but, one-year GVHD-free/relapse-free survival (GRFS) was significantly longer in the PTCY-based arm (45% vs. 22%, respectively).The results clearly showed the superiority of the PTCY-based approach in reducing acute and chronic GVHD and prolonging GRFS. Consistent with these results, a phase II multicenter, three-arm randomized U.S. study (BMTCTN 1203) showed the superiority of the PTCY-based approach in improving GRFS and has formed the basis of a phase III study (BMTCTN 1703). While we wait for the long-term follow-up of the HOVON-96 trial and the results of CTN1703, it is not premature to state that PTCY may not only extend a transplant option to virtually everybody who stands to benefit from it, it may also replace standard GVHD prophylaxis. PTCY, based on these results, serves as the most promising and disruptive innovation to achieve our elusive goal of separating GVHD from GVT in the RICsetting.


Dr. Dhakal indicated no relevant conflicts of interest.

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