Personalized Approaches Are Emerging for GVHD in Hematologic Malignancies

The recent emergence of graft manipulation strategies such as Orca-T, improved prophylactic approaches, and novel therapies, including axatilimab-csfr (Niktimvo), underscores a shift toward more precise and personalized approaches for graft-vs-host disease (GVHD) in patients with hematologic malignancies who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT), according to a presentation given by Alexandra Gomez-Arteaga, MD, during the 2025 SOHO Annual Meeting.1

What Is Orca-T and How Is It Used to Combat Chronic GVHD?

Gomez-Arteaga began her presentation by underscoring that findings from the phase 3 BMT CTN 1301 trial (NCT02345850) support tacrolimus plus methotrexate as the standard of care (SOC) for the prophylactic treatment of chronic GVHD (cGVHD).2 She noted that data from the study showed that although treatment with CD34-selected peripheral blood stem cell grafts led to lower rates of cGVHD compared with bone marrow grafts followed by posttransplant cyclophosphamide (PTCy) or tacrolimus plus methotrexate, these patients experienced worse overall survival (OS) outcomes vs the PTCy and tacrolimus/methotrexate arms. The 2-year OS rates were 60.1%, 76.2%, and 76.1%, respectively.

“We all thought that CD34 selection was going to do so much better [than the other 2 approaches] because the cGVHD rate was so much lower,” Gomez-Arteaga said during the presentation. “But when the OS [data] came in, [we saw] that these patients did worse. The immune reconstitution of these patients was not good, so the incidence of grade 3 [or higher] infections was higher on CD34 selection.”

Gomez-Arteaga is an assistant professor of medicine in the Division of Hematology and Medical Oncology at Weill Cornell Medicine/NewYork-Presbyterian Hospital in New York, New York.

Orca-T is a precision-engineered immunotherapy made with donor cells that are collected as the patient is being prepared for treatment, Gomez-Arteaga explained.1 The donor cells are then sent to a manufacturing facility where they are divided into hematopoietic stem cells, regulatory T cells (Tregs), and conventional T cells (Tcons). The Tregs and the CD34 cells are then administered to the patient together at day 0, which allows the Tregs to infiltrate the lymph nodes and expand. Thus, when the Tcons are administered on day 2, the Tregs are already expanded, leading to better immune reconstitution and cGVHD control.

In the phase 3 Precision-T trial (NCT05316701), Orca-T was compared with SOC GVHD prophylaxis with tacrolimus plus methotrexate in patients with acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, or mixed-phenotype acute leukemia.3 Findings from the trial presented during SOHO revealed that patients who received Orca-T (n = 93) achieved a 12-month survival free of moderate-to-severe cGVHD rate of 78.0% (95% CI, 65.0%-86.6%) compared with 38.4% (95% CI, 26.2%-50.5%) among patients who received tacrolimus plus methotrexate (n = 94; HR, 0.26; 95% CI, 0.14-0.47; log-rank P < .00001). These findings met the primary end point of the study, Gomez-Arteaga emphasized.

Additional data from Precision-T demonstrated that Orca-T also improved the incidence of moderate-to-severe cGVHD compared with tacrolimus plus methotrexate, with incidence rates of 12.6% (95% CI, 5.3%-23.1%) and 44.0% (95% CI, 31.3%-56.1%), respectively (HR, 0.19; 95% CI, 0.08-0.43; Gray’s test P = .00002). The 12-month OS rates were 93.9% (95% CI, 85.8%-97.4%) and 83.1% (95% CI, 72.9%-89.8%), respectively (HR, 0.49; 95% CI, 0.20-1.22; log-rank P = .11823). The incidence rates of grade 3 infections at 12 months were 8.4% (95% CI, 3.6%-16%) and 16% (95% CI, 9.2%-25%), respectively.

“Based on [data from] this study, the company is submitting to the FDA this fall and hopefully [Orca-T] will be available soon,” Gomez-Arteaga commented.

How Can GVHD Prophylaxis Be Personalized?

Gomez-Arteaga then transitioned her presentation to discuss data from the phase 3 BMT CTN 1703/​1801 study (NCT03959241). BMT CTN 1703/​1801 evaluated tacrolimus plus methotrexate vs PTCy for the prevention of GVHD in patients with hematologic malignancies.4 The study compared the 2 approaches in the setting of reduced intensity conditioning allo-HSCT. The primary end point of the trial was GVHD-free relapse-free survival (RFS) at 1 year.

Findings from the 1703 portion of BMT CTN 1703/​1801 showed that patients who received PTCy (n = 214) achieved an adjusted 1-year GVHD-free RFS rate of 52.7% (95% CI, 45.8%-59.2%) compared with 34.9% (95% CI, 28.6%-41.3%) with standard prophylaxis (n = 217). The adjusted 1-year OS rates were 77.0% (95% CI, 70.8%-82.1%) and 72.2% (95% CI, 65.7%-77.6%), respectively.

“When we looked at the infection rates, there was a higher incidence of grade 2 or 3 infections for PTCy [vs tacrolimus plus methotrexate alone] at 40.0% [95% CI, 33.2%-46.7%] vs 30.4% [95% CI, 24.3%-36.7%], respectively,” Gomez-Arteaga said. “This means that immune reconstitution is still affected. We don’t know exactly what will happen to these patients in terms of immune reconstitution.”

Gomez-Arteaga noted that in the 1801 portion of the study, investigators prospectively collected samples from the donors and patients to assess immune reconstitution in the microbiome.1 This portion of the study evaluated more than 2300 samples using flow cytometry for T-cell phenotype, bulk T-cell receptor (TCR) sequencing for T-cell repertoire, and single-cell RNA/TCR sequencing for paired T-cell phenotype and clonotype.

Findings from the 1801 portion showed that the T cells of patients who received PTCy had reduced T-cell repertoire diversity compared with those who received standard GVHD prophylaxis, Gomez-Arteaga explained. The TCR diversity was also reduced for up to 2 years following transplant in the PTCy arm, she added. Virus-associated TCRs were also reduced in the investigational arm compared with the control arm.

“PTCy is an amazing way of doing transplants, but it’s still not the best way of getting them done,” Gomez-Arteaga said. “We have to do better with immune reconstitution.”

How Can Axatilimab Be Used to Combat cGVHD?

Gomez-Arteaga concluded her presentation by highlighting combination approaches for the treatment of patients with refractory cGVHD. She specifically highlighted data from a retrospective study of the CSF-1R inhibitor axatilimab in combination with ruxolitinib (Jakafi) and/or belumosudil (Rezurock).5

The study included 8 patients with mild (n = 4), moderate (n = 3), or severe (n = 1) cGVHD at diagnosis. Patients received axatilimab plus ruxolitinib (n = 1), axatilimab plus belumosudil (n = 3), or axatilimab in combination with belumosudil and ruxolitinib (n = 4). Gomez-Arteaga emphasized that at the time of axatilimab initiation, all 8 patients had severe cGVHD; 5 patients also had sclerodermatous skin involvement and 1 had bronchiolitis obliterans. The median time to initiation of axatilimab after cGVHD diagnosis was 21.1 months (range, 9.9-110.2).

Findings from the retrospective study showed that 2 patients achieved a partial response (PR) per National Institutes of Health (NIH) criteria and 6 had a PR per Clinically Significant Symptomatic Improvement (CSSI) criteria. Five patients had stable disease per NIH criteria, and 1 had stable disease per CSSI criteria. The median time to response per NIH and CSSI criteria was 71 days and 103 days, respectively, and the respective duration of response was 295 days and 219 days.

“What [has happened] in the transplant world [during] 2024 and 2025 is that we are changing a bit and we need to do more precision medicine,” Gomez-Arteaga said in her conclusion. “We need to figure out how to do transplants better by defining how to do GVHD prophylaxis, how we think about what we are doing, and how [to improve] immune reconstitution. When we do treatment studies, like this important trial for axatilimab, we need to figure out how to study these patients better because the reality is that these patients are not what the clinical trials show, and we still have so much more to do.”

References

1. Gomez-Arteaga A. What we learned in 2024 and 2025: best of stem cell transplant. Presented at: 2025 SOHO Annual Meeting; September 3-6, 2025; Houston, TX.
2. Luznik L, Pasquini MC, Logan B, et al. Randomized phase III BMT CTN trial of calcineurin inhibitor-free chronic graft-versus-host disease interventions in myeloablative hematopoietic cell transplantation for hematologic malignancies. J Clin Oncol. 2022;40(4):356-368. doi:10.1200/JCO.21.02293
3. Faramand R, Salhotra A, Gandhi A, et al. A randomized phase 3 trial in patients with hematologic malignancies demonstrates improved survival free of chronic GVHD with Orca-T compared to conventional allogeneic hematopoietic stem cell transplant. Clin Lymphoma Myeloma Leuk. 2025;25(suppl 1):S1008-S1009. doi:10.1016/S2152-2650(25)02766-1
4. Bolaños-Meade J, Hamadani M, Wu J, et al; BMT CTN 1703 Investigators. Post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. N Engl J Med. 2023;388(25):2338-2348. doi:10.1056/NEJMoa2215943
5. Caputo J, Peddireddi A, Wall SA, et al. Axatilimab combination therapies with ruxolitinib and/or belumosudil induces clinical responses in patients with severe, treatment-refractory chronic GVHD. Transplant Cell Ther. 2025;31(suppl 2):S82-S83. doi:10.1016/j.jtct.2025.01.132