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NEW ORLEANS -- A three-drug regimen should be the standard for graft-versus-host disease (GvHD) prophylaxis in blood cancer patients undergoing reduced-intensity conditioning allogeneic hematopoietic cell transplantation (allo-HCT) from well-matched donors, findings from a randomized trial suggested.

For the study's primary endpoint, prophylaxis with the triplet -- which consists of post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil (MMF) -- significantly improved GvHD/relapse-free survival at 12 months compared with the doublet of tacrolimus and methotrexate (52.7% vs 34.9%), according to Shernan Holtan, MD, of the University of Minnesota in Minneapolis.

This benefit with the triplet was significant (HR 0.641, P<0.001) and driven by twofold reductions in both severe acute GvHD (grade III-IV) and chronic GvHD requiring systemic immune suppression:

• Severe acute: 6.3% vs 14.7% at 100 days post-transplant (P<0.001)
• Chronic: 12.5% vs 25% at 12 months post-transplant (P<0.001)

GvHD-free survival at 12 months post-transplant was 61.9% with the triplet and 44.9% with the doublet (P=0.0004), and the improved GvHD outcomes did not come at the expense of cancer relapse or progression (20.8% vs 20.2% at 12 months, respectively, P=0.906), Holtan reported here at the American Society of Hematology annual meeting.

There was slightly delayed hematopoietic recovery and more grade 2 infections with the three-drug regimen, but no differences in grade 3 infections, she said.

"Based upon these results, we believe that post-transplant cyclophosphamide, tacrolimus, and MMF should be the standard GvHD prophylaxis in well-matched reduced-intensity transplantation," Holtan concluded.

From June 2019 to June 2021, the phase III study enrolled 431 hematologic cancer patients with well-matched donors undergoing allo-HCT with reduced-intensity conditioning across 37 centers. Participants were randomized to either the triplet (post-transplant cyclophosphamide, tacrolimus, and MMF) or doublet (tacrolimus, methotrexate) GvHD prophylactic regimens. The study's primary endpoint (GvHD/relapse-free survival) is a time-to-event endpoint defined as grade III/IV acute GvHD, chronic GvHD requiring systemic immune suppression, disease relapse or progression, or death.

"I want to point out how far the transplant community has come," said Richard John Jones, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, speaking during a Q&A session following the late-breaking presentation. He noted that patients on study had a median age of 66, and that many were in their upper 70s.

"Not very long ago that would have been an exclusion to transplant," said Jones.

Baseline characteristics were well balanced, said Holtan, with a slight male predominance in both arms (about 60% overall), roughly half having a Karnofsky Performance Scale of 90-100, and approximately one-third in each arm categorized as high or very-high on the Disease Risk Index. The transplant comorbidity index was less than 4 for about three-fourths of participants.

Most had acute myeloid leukemia (46-50%) or myelodysplastic syndromes (29-30%), followed by lymphoma (8-11%), acute lymphoblastic leukemia (6-12%), chronic myeloid leukemia (2-3%), and biphenotypic leukemia (0.5% in each arm).

Donors were well matched, said Holtan: 8/8 matched unrelated donors in about two-thirds, 6/6 matched related donors in 28-30%, and 7/8 matched unrelated donors in 3-4%.

Ultimately, 208 and 212 patients in the triplet and doublet arms, respectively, received transplant.

Transplant-related mortality was similar at 1 year (12.3% in the triplet arm vs 17.2% in the doublet arm, P=0.167), as was overall survival rate (77% vs 72.2%, P=0.252). While there were no differences in deaths (48 in the triplet arm and 56 in the doublet arm), there were differences in the patterns of death, with more organ failure seen in patients who received the triplet (22.9% of deaths) and more deaths due to acute GvHD in those receiving the doublet (14.3%).

No differences were seen between the two regimens for disease-free survival at 12 months or cumulative incidence of grade II-IV acute GvHD at day 100 (54% in the triplet arm and 52% in the doublet arm), with 35% of patients in each arm experiencing upper gastrointestinal GvHD.

As noted, grade 2 infections at 12 months were significantly less frequent with the doublet (21% vs 34% with the triplet), but there were no differences in grade 3 infections (13% and 12%, respectively). And hematologic recovery was more frequent at day 28 with the doublet (93% vs 90% with the triplet regimen, both for neutrophils and platelets).

There were no significant differences in full chimerism (68-69%) or donor rejection rates (0.5-3.0%) between arms. Secondary graft failures occurred in 3% of patients on the triplet regimen and 1% of those on the doublet (P=0.172).

The most common conditioning regimens were fludarabine/melphalan (57%) or fludarabine/busulfan (27%), and one-fourth received post-transplant maintenance therapy.

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