Acute graft-vs-host disease (GVHD) was the only identifiable risk factor for the development of chronic GVHD (cGVHD) in pediatric patients with hematologic malignancies who underwent allogeneic hematopoietic stem cell transplant (HSCT) from matched sibling donors, according to findings from a retrospective analysis presented at the 

“With increasing survival rates, focus on improving QOL [quality of life] becomes essential. Given that acute GVHD is a major risk factor for cGVHD, predicting occurrence of cGVHD and implementing timely interventions are critical,” Nermeen Alhawary, MD, lead study author and pediatric oncologist in the Department of Pediatric Oncology at the Children’s Cancer Hospital in Cairo, Egypt, and coauthors, wrote in the poster.

Why Study cGVHD Risk Factors and Predictors of Outcomes?

cGVHD remains the primary complication of HSCT and cause of posttransplant morbidity and mortality despite improvements in donor selection, conditioning regimens, graft manipulation, and supportive care. Within the past 10 years, 4 systemic therapies have been approved by the FDA for the treatment of patients with cGVHD, namely 

However, even with therapeutic intervention, cGVHD has a significant effect on patient QOL, which may be compounded by resulting adverse effects from therapy.

For example, in the pivotal phase 2 AGAVE-201 trial (NCT04710576) of axatilimab, grade 3 or 4 adverse reactions included viral infection (15%), infection (pathogen unspecified, 14%), bacterial infection (8%), diarrhea (5%), fatigue (4%), decreased appetite (4%), musculoskeletal pain (3%), nausea (3%), dyspnea (3%), drug hypersensitivity (3%), pyrexia (1%), edema (1%), headache (1%), and hemorrhage (1%).

Therefore, it is important to understand the associated risk factors and determinants of outcomes that can help tailor appropriate intervention and treatment.

How Was the Retrospective Study Designed to Evaluate This Unmet Need?

With this in mind, investigators conducted a retrospective analysis that included 304 patients aged 0.9 to 19.3 years who underwent allogeneic HSCT with either peripheral blood or bone marrow as a stem cell source between January 2007 and December 2020. All patients had received cyclosporine and methotrexate as GVHD prophylaxis.

National Institutes of Health 2014 Consensus Criteria were used to diagnosis and score cGVHD, and univariate and multivariate analyses were performed to ascertain the strength of potential risk factors.

Are There Certain Risk Factors for cGVHD That Can Help Me Predict Outcomes?

A total of 86 patients developed cGVHD; 217 did not, reflecting an incidence rate of 28.3%. Notably, there was no overall survival (OS) difference between the 2 populations (

Multivariate logistic regression analysis indicated that neither the source of stem cells (bone marrow vs peripheral blood; OR, 1.36; 95% CI, 0.76-2.41; 

 = .3) nor the presence of pretransplant fungal infections (21.67%; OR, 0.66; 95% CI, 0.38-1.14; 

 = .14) were significantly associated with the development of cGVHD. Notably, acute GVHD was significantly associated with the development of cGVHD (OR, 3.68; 95% CI, 2.09-6.51; 

With respect to predictors of outcome in the 55.8% (n = 48) of patients who experienced severe GVHD, none affected OS, event-free survival, or CIR. Proposed outcome predictors included multiple organ involvement (n = 61; 70.9%), liver involvement (n = 31; 36%), gastrointestinal involvement (n = 19; 22.1%), and lung cGVHD (n = 30; 28.3%). Most patients (n = 65; 75.6%) responded to steroids.

What Additional Research Is Needed to Push This Field Forward?

“Further studies are needed to identify key predictors of long-term outcomes,” the study authors concluded.

Alhawary N, Hafez H, Hammad M, et al. Risk factors and outcome predictors of chronic GVHD post allogenic HSCT in pediatric cancer patients: a single center experience from a LMIC setting. 

. 2025;25(suppl 1):S1014. doi:10.1016/S2152-2650(25)02777-6

Lee SJ, Zeiser R. FDA-approved therapies for chronic GVHD. 

. 2025;145(8):795-800. doi:10.1182/blood.2024026633

Niktimvo. Prescribing information. Incyte Corporation; 2024. Accessed September 26, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761411s000lbl.pdf

Articles

Acute graft-vs-host disease (GVHD) is identified as the sole risk factor for chronic GVHD (cGVHD) in pediatric patients undergoing allogeneic hematopoietic stem cell transplant (HSCT) from matched sibling donors. Despite advancements in donor selection and supportive care, cGVHD remains a significant post-transplant complication affecting quality of life. A retrospective study involving 304 patients revealed that acute GVHD significantly correlates with cGVHD development, while other factors like stem cell source and pretransplant fungal infections do not. Further research is needed to identify predictors of long-term outcomes.

Acute GVHD was shown to be a risk factor for chronic GVHD, but factors such as organ involvement showed no correlation with long-term outcomes. 

Predictors of cGVHD Outcomes Remain Elusive in Pediatric 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 

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).

 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.

 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.

 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 

 < .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 

 = .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 

 = .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.

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.

 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).

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.”

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.

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. 

. 2022;40(4):356-368. doi:10.1200/JCO.21.02293

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. 

. 2025;25(suppl 1):S1008-S1009. doi:10.1016/S2152-2650(25)02766-1

Bolaños-Meade J, Hamadani M, Wu J, et al; BMT CTN 1703 Investigators. Post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. 

. 2023;388(25):2338-2348. doi:10.1056/NEJMoa2215943

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. 

. 2025;31(suppl 2):S82-S83. doi:10.1016/j.jtct.2025.01.132

Recent advancements in graft manipulation strategies, such as Orca-T, and novel therapies like axatilimab-csfr, are paving the way for more personalized approaches to managing graft-vs-host disease (GVHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Orca-T, a precision-engineered immunotherapy, has shown promising results in improving survival rates and reducing moderate-to-severe chronic GVHD compared to standard prophylaxis. Additionally, axatilimab, in combination with other therapies, has demonstrated clinical responses in patients with refractory chronic GVHD, highlighting the potential for precision medicine in transplant care.

A panel of hematologic cancer experts discusses data on GVHD management from the 2025 SOHO Annual Meeting.

Personalized Approaches Are Emerging for GVHD in Hematologic Malignancies

Current data position Orca-T as a powerful platform for future advancements in allogeneic transplantation for patients with hematologic malignancies, given its superiority to conventional prophylaxis. However, David Miklos, MD, PhD, says questions remain regarding its long-term comparative standing against standard posttransplant cyclophosphamide (PTCy), according to David Miklos, MD, PhD.

Findings from the phase 3 component of the Precision-T trial (NCT05316701), presented at the 

, showed that moderate to severe chronic graft-vs-host-disease (cGVHD)–free survival (cGFS) was significantly higher at 1 year with Orca-T plus tacrolimus vs conventional allograft plus tacrolimus and methotrexate (HR, 0.26; 95% CI, 0.14-0.47; log-rank 

 < .00001), meeting the trial’s primary end point.

 Moreover, at 1 year, treatment with Orca-T plus tacrolimus reduced the incidence of moderate to severe cGVHD (HR, 0.19; 95% CI, 0.08-0.43; Gray’s test 

 = .00002), increased GVHD-free relapse-free survival (GRFS; HR, 0.37; 95% CI, 0.23-0.60; log-rank 

 = .00003), and showed a positive trend in overall survival (OS) vs tacrolimus and methotrexate (HR, 0.49; 95% CI, 0.20-1.22; log-rank 

“It seems a little early to be deciding what the preferred long-term regimen will be,” Miklos, a professor of medicine and chief of Stanford Medicine’s Blood and Marrow Transplantation and Cell Therapy Program, shared in an interview with 

®. “I think that graft engineering, and Orca-T, is going to be the superior long-term regimen [vs PTCy], but we’re all going to have to wait [for the data confirming it].”

In the interview, Miklos discussed efficacy outcomes with Orca-T from the Precision-T trial, the need for further comparative and long-term data to inform the roles of Orca-T vs PTCy in the current treatment paradigm, and the potential of graft engineering as a platform for future advancements in allogeneic transplantation.

: What did findings from the Precision-T trial indicate about Orca-T’s efficacy in preventing moderate to severe cGVHD and improving OS?

] and we are still waiting for the peer-review publication.

 What we do know is that the moderate to severe cGFS rate was 78% with Orca-T vs 38.4% with conventional tacrolimus-methotrexate prophylaxis. The other number to note is OS, which was 93.9% compared with 83.1%. Obviously, that represents a gold standard: a randomized, controlled trial publication with well-powered patient comparisons conducted at numerous sites. This is clear evidence that graft engineering with a T-regulatory component is superior to what has been done since the 1970s, which involved the use of methotrexate mixed with either tacrolimus or cyclosporine. There’s not much to discuss; it’s superior. Avoiding GVHD provides the quality of life [QOL] every patient hopes for. Avoiding cancer relapse is superior. OS is, obviously, the gold standard.

But the question remains: Is this the alternative treatment for the prevention of cGVHD, or has the world moved forward in the 5 years since the trial was conducted and analyzed? Of course, [using] PTCy instead of the antimetabolite methotrexate used in combination with mycophenolic acid and tacrolimus, is now the new standard. In fact, the National Marrow Donor Program tells us that everyone has a donor, and that mismatched and haploidentical transplants can be performed using this regimen, making allogeneic transplants available to the world.

Given the superiority of Orca-T vs tacrolimus-methotrexate in Precision-T, do these data position Orca-T as a viable alternative to PTCy as the new standard?

Now we are left in this perplexing situation. We know that PTCy comparison will be required in good faith…but what do we do with this information? We can look at retrospective data and perhaps the current publication of the phase 3 ALLG BM12 CAST trial (ACTRN12618000505202) from the Australian group. That study included 130 patients, it was much smaller than Precision-T, and we don’t have the data for a head-to-head propensity comparison. [However], it does provide a very good dataset for comparison. Visually, it looks very similar, with both GRFS and OS appearing similar. That would suggest that PTCy is still a contender, and perhaps it’s more accessible globally. Here’s the thing, though: How do we advance PTCy from here, and how can we begin to understand graft engineering as a platform to improve therapies? This would involve extending it to less intensive conditioning, older patient populations, and reducing relapse by utilizing antitumor benefits, which is another aspect of what Orca-T graft engineering offers.

The jury is [still] out and people have to decide for themselves. We don’t know anything about price, reimbursement, or long-term outcomes beyond 2 years. Similarly, for most PTCy treatments, we don’t know about outcomes beyond 1 year, specifically regarding non–relapse mortality [NRM], complications of infection, long-term effects, and whether there will be late relapses.

Beyond the initial transplant complications, what longer-term complications need to be monitored to assess Orca-T’s and PTCy’s true effect on survival outcomes?

OS is a process influenced by 3 things: toxicity from chemotherapy during the transplant, acute GVHD toxicity, and relapse or late toxicity. We’re past the initial window of concern for transplant GVHD complications, [which is typically] around day 30, day 90, or 1 year. Now we’re focused on immune reconstitution, protection from viruses, and drug protection from viruses. [We don’t know much] about concerns for bronchiolitis obliterans, organizing pneumonias, and other viral transformations not only for treatment with Orca-T graft engineering but also for PTCy. I’m a convert to the CAR [chimeric antigen receptor] T community. We track these patients for 5 and 15 years after these genetic modifications. Longer-term follow-up, as required, has shown us that the NRM in patients receiving these [CD19-directed CAR T-cell] therapies is [approximately] 16% at 5 years due to infectious complications. What will be the infectious complications after PTCy, where we have greatly reduced the numbers of surviving T cells, or in an Orca-T graft, where you’re putting in fewer T cells but providing a better environment with regulatory T cells where you’re not selecting against allogeneic cells to enable long-term antitumor benefit? We don’t know.

Given the need for FDA approval and the agency’s focus on response rates, having set this 1-year GRFS [rate], it seems that the [investigators] met the bar. I have great enthusiasm for the ability to engineer [this therapy]; however, OS [outcomes] will require longer follow-up.

How might Orca-T’s observed reductions in grade 3 or higher acute GVHD, serious infections, and rehospitalizations translate into improved patient QOL and a reduced health burden following transplant?

Readmission to a hospital due to ongoing GVHD, infectious complications, or recurrence of the cancer represents a cost that continually needs to be paid not only by an insurance company but also by the patient and their family, who are living through the burden of requiring additional management and medical care. What is that worth financially? We’re about to find out, because that type of QOL calculation is probably what agencies, insurance companies, and patients themselves will be trying to understand. It is worth a lot. CGVHD is the morbidity of allogeneic transplants. NRM due to recurrent infections is a common problem after these cell therapies. If graft engineering overcomes this, not only is it better today, but it also provides the platform and the path to future improvements.

Given that the Precision-T trial compared Orca-T plus tacrolimus to conventional tacrolimus-methotrexate rather than PTCy, how should these results be contextualized within the evolving GVHD prophylaxis paradigm?

The randomized, controlled Precision-T trial did not include PTCy. In the current environment, we see PTCy being compared with tacrolimus-methotrexate with the exact same intention of randomization. Neither of these [studies is] blinded. The end points of cGVHD are not entirely objective, so there are arguments that there is a subtle interpretation of what is going on with the patients. OS is a hard end point that is beneficial to patients, but OS without any type of moderate or severe cGVHD is also critical for QOL. We are going to have to conduct an analysis of side-by-side comparisons, because no randomized trial that can match PTCy is going to be conducted in the next 2 years. We’re going to have to move forward with the data we have.

[Outcomes with Orca-T vs PTy] are close, but there’s an obvious long-term benefit when you haven’t greatly reduced the repertoire of T cells surviving PTCy. Instead, an enriched immune system can be fostered with a T-regulatory environment. One is a very negative selection, and one is a positive growth going forward.

What insights can be gained from concurrent retrospective data with PTCy and clinical trial data with Orca-T? What do these preliminary comparisons suggest regarding Orca-T’s benefit and readiness for widespread adoption?

[We have] a bit of insight from a concurrent retrospective data collection on PTCy and the treatment arm of the Orca-T trial. There’s only the treatment arm of the Orca-T trial and some in-house Stanford data [available] for comparison due to the limited number of patients treated, whereas PTCy is being used by many centers across the country and can be extensively analyzed through [the Center for International Blood and Marrow Transplant Research] and other registries. The OS [outcomes with PTCy in a historical cohort] were inferior [to that of Orca-T per long-term follow-up data]. This [result] is a major concern for survival, and would indicate that the use of graft engineering is superior. However, there’s going to be a lot of arguing about trials that were never meant to be compared head-to-head: about the quality of a clinical trial vs retrospective studies done in a nontrial situation, and about the selection of patients onto a trial vs those receiving the standard of care at institutions. That probably will just lead to more discussion and no clear solution.

Despite these challenges, what significant advances in allogeneic transplantation have been achieved in the last 5 years and where do you see the field heading?

We are left with advances in allogeneic transplantation from the past 5 years, which we’ve all waited for. We shouldn’t be disappointed by these results. These are 2 fantastic ways to move forward: achieving OS in excess of 80% at 1 year in an acute myeloid leukemia population, and greatly reducing the risk of severe cGVHD or improving the combined GRFS/OS. NRM risk is less than 5% after a couple of years when using Orca-T. Those are end points we only dreamed of. This is not a problem; this is [providing] 2 opportunities to move forward. Science, fortunately, has a way of figuring things out. It may take a couple more trials, but I’m sure that we will make incremental improvements in the field of allogeneic transplantation, so that by the time I turn 80, a therapy will be able to provide me with new, healthy stem cells in a bone marrow failure situation, which will give me higher survival [benefit]. Isn’t that what we’re after?

What strategies are being explored to improve antitumor benefits and avoid relapse with both PTCy and Orca-T?

Instead of adding more intensity to chemotherapy, which [a patient] won’t be able to tolerate at 80 years of age, [we’re asking ourselves]: How about we use targeted therapies against early hematopoietic blasts or leukemic cells themselves? What if we were able to target CD33, CD117, or early tumor antigen surface proteins with either a monoclonal antibody added to a toxin such as gemtuzumab ozogamicin [Mylotarg] or a CAR T-cell product that could identify the target tumor antigens? This would allow for less intensification during treatment and lead to less relapse.

[With] Orca-T, we have a hematopoietic stem cell bag, a conventional T-cell bag, and a T-regulatory cell bag. What about a fourth bag that—in this case, a CD19/CD22 CAR T-cell product—that targets B cells within the host? The loss of CAR, with the recurrence of B-cell disease after autologous CAR T-cell treatment, is associated with disease relapse.

At Stanford, we’ve done this in the field of B-cell acute lymphoblastic leukemia. [Data from a phase 1 study (NCT05507827)] leveraging the Orca-T platform [presented during the 

2024 ASH [American Society of Hematology] Annual Meeting

2025 Transplant and Cellular Therapy Meetings

 showed] incredible tolerance to the [allogeneic CD19/CD20] CAR itself, [as it] is being inserted at the time of an allogeneic transplant. [Moreover], the persistence of the CAR made from the donor cells allowed for the extension of benefit beyond a year. Although the study is aging, the lead patients are out 3.5 years. In the analysis at ASH, the 10 patients beyond 1 year had B-cell aplasia, measurable CAR T cells, full donor engraftment, no cGVHD, and ongoing disease-free survival. In fact, all 17 patients treated on study are alive and are proceeding without those problems. [These results may show] that the combination of stem cells and nontargeted T cells can be greatly improved by adding a targeting agent, like a CAR T cell, into the graft made from donor cells. This is something we call an "allo-CAR transplant." This is a concept that you can build as a platform, not only off Orca-T but potentially off PTCy.

What are the logistical complexities involved in collecting donor cells for the Orca-T strategy?

Logistically, collecting donor T cells that are nonmobilized or non-GCSF mobilized, and then having that donor undergo GCSF and plerixafor mobilization to collect the stem cell product, is more complicated. Both products were necessary for this study. We’re still trying to understand if a separate collection for the cells used to make the CAR T cell was necessary; additional studies will be needed.

That trial stands on its own, especially when we compare the same CARs against CD19-targeted or CD19/CD22-targeted [CAR T-cell therapies] with the autologous studies that have been well done in this space and have shown an overall recurrence of [approximately] 50% by 6 months. These patients are out beyond a year and proceeding well. Long-term follow-up is always beneficial, but incremental studies are needed to see whether we do this after PTCy, if we need to use G-mobilization, or if we could have made the CAR from T cells that went through G-mobilization.

There are a lot of [unanswered] questions. One of the questions answered, though, was whether tacrolimus was necessary for the graft. Tacrolimus administration did not impede the expansion or benefits of the CAR T cell. Early concerns that tacrolimus or other immunosuppressive medicines would impede the benefit of a CAR T cell have been removed through this trial, as well as through studies where patients who have had prior CAR T cells are undergoing treatments.

Meyer EH, Salhotra A, Gandhi AP, et al. Orca-T demonstrates improved survival free of chronic GvHD compared to conventional allogeneic hematopoietic stem cell transplant: a randomized phase 3 trial in advanced hematologic malignancies. Presented at: 51st Annual EBMT Meeting; March 30-April 2, 2025; Florence, Italy. Abstract OS15-01.

Orca-T has emerged as a promising platform for allogeneic transplantation in hematologic malignancies, demonstrating superior outcomes compared to conventional prophylaxis. The Precision-T trial revealed significant improvements in chronic graft-vs-host disease-free survival and overall survival with Orca-T plus tacrolimus. However, its long-term efficacy compared to post-transplant cyclophosphamide (PTCy) remains uncertain. The trial's findings suggest Orca-T's potential as a new standard, but further comparative studies are needed. The evolving landscape of graft engineering and targeted therapies offers opportunities for advancing transplantation outcomes and reducing relapse rates.

David Miklos, MD, PhD, discusses the potential role for Orca-T vs standard PTCy after allogeneic transplant in hematologic malignancies. 

Orca-T Delivers Major Gains Beyond Conventional Prophylaxis in Hematologic Malignancies

Treatment with Orca-T plus tacrolimus significantly improved moderate to severe chronic graft-vs-host-disease (cGVHD)–free survival (cGFS), incidence of cGVHD, and GVHD-free relapse-free survival (GRFS) compared with conventional allograft plus tacrolimus and methotrexate, according to findings from the phase 3 component of the Precision-T trial (NCT05316701) presented at the 

Findings showed that the 1-year cGFS rate was 78% (95% CI, 65.0%-86.6%) with Orca-T vs 38.4% (95% CI, 26.2%-50.5%) with tacrolimus and methotrexate (HR, 0.26; 95% CI, 0.14-0.47; log-rank 

 < .00001). The 1-year incidence rate of moderate to severe cGVHD was 12.6% (95% CI, 5.3%-23.1%) and 44% (95% CI, 31.3%-56.1%), respectively (HR, 0.19; 95% CI, 0.08-0.43; Gray’s test 

“The trial met its primary end point, demonstrating higher cGFS with Orca-T, likely driven by reduced cGVHD [incidence], and a positive trend in overall survival [OS],” Rawan Faramand, MD, of Moffitt Cancer Center in Tampa, Florida, and study coauthors wrote in the poster presentation.

How Was Precision-T Designed and What Was the Focus?

GVHD remains a primary treatment-related complication after allogeneic hematopoietic stem cell transplant (allo-HSCT) despite multimodal prophylaxis. Orca-T is an investigational allogeneic T-cell immunotherapy that uses high-purity regulatory T cells to prevent GVHD.

The primary purpose of the study was to compare moderate to severe cGFS in patients who received either Orca-T or standard GVHD prophylaxis with tacrolimus/methotrexate. Secondary end points included cumulative incidence of cGVHD, GRFS, and OS.

The study enrolled patients between aged 18 and 65 years with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute lymphocytic leukemia (ALL), or mixed-phenotype acute leukemia (MPAL) who would have been eligible to receive standard allo-HSCT and were in complete response (CR)/CR with incomplete hematologic recovery (CRi).

A total of 187 patients were enrolled and randomly assigned: 93 to Orca-T and 94 to tacrolimus/methotrexate, which comprised the intention-to-treat population. Ultimately, 89 patients received Orca-T, and 93 received tacrolimus/methotrexate. Eighty-eight and 85 patients completed trial follow-up in the Orca-T and tacrolimus/methotrexate arms, respectively, and 88 and 94 patients were included in the respective safety populations for each arm.

Regarding baseline characteristics, the mean patient age was 43.6 years, and 26.7% were 55 years or older. Most patients were male (55.1%), White (74.3%), and had a primary diagnosis of AML (53.5%). Most patients also had matched sibling donors (50.8%) and an intermediate Disease Risk Index score (81.3%). Baseline Hematopoietic Cell Transplantation–specific Comorbidity Index scores were 0 (24.1%), 1 (25.7%), 2 (22.5%), 3 (17.1%), 4 (10.2%), or 5 (0.5%).

What Additional Efficacy and Safety Measures Were Presented for Orca-T?

Additional findings from the trial demonstrated that the 1-year OS rate was 93.9% (95% CI, 85.8%-97.4%) with Orca-T vs 83.1% (95% CI, 72.9%-89.8%) with tacrolimus/methotrexate (HR, 0.49; 95% CI, 0.20-1.22; log-rank 

 = .11823). The 1-year rates of GRFS were 63.1% (95% CI, 50.1%-73.6%) and 30.9% (95% CI, 20.0%-42.5%) with Orca-T and tacrolimus/methotrexate, respectively (HR, 0.37; 95% CI, 0.23-0.60; log-rank 

Moreover, the cumulative incidence of grade 3 infections at 1 year was 8.4% (95% CI, 3.6%-16%) with Orca-T vs 16% (95% CI, 9.2%-25%) with tacrolimus/methotrexate. The primary causes of death in the Orca-T arm were relapse (n = 4), infection (n = 2), and GVHD (n = 1). In the tacrolimus/methotrexate arm, the primary causes of death were relapse (n = 3), infection (n = 3), GVHD (n = 5), and organ failure (n = 4).

With respect to survival outcomes, the 1-year non-relapse mortality rate was 3.4% in the Orca-T arm vs 13% in the tacrolimus/methotrexate arm. The 1-year RFS rates were 76% and 74%, respectively. A total of 39% and 56% of patients had a serious treatment-emergent adverse effect (AE) in the Orca-T and tacrolimus/methotrexate arms, respectively. The 1-year incidence of grade 2 or greater acute GVHD was 22% in the Orca-T arm vs 30% in the tacrolimus/methotrexate arm. The 1-year rates of grade 3 or greater acute GVHD were 6.2% and 16%, respectively. A total of 17% and 49% of patients in the respective arms had cGVHD.

In terms of engraftment and hospitalization, the median time to neutrophil engraftment was 13 days and 14 days in the Orca-T and tacrolimus/methotrexate arms, respectively. The median timing of platelet engraftment was 17 days and 18 days, respectively. A total of 27% and 46% of patients in the Orca-T and tacrolimus/methotrexate arms were rehospitalized because of an AE. There were no graft failures in either arm, and only 1 case of secondary graft failure occurred in the Orca-T arm.

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. Presented at: SOHO 2025 Annual Meeting; September 3-6, 2025; Houston, TX. Abstract CT-262.

Orca-T, an investigational allogeneic T-cell immunotherapy, significantly improved outcomes in patients with hematologic malignancies undergoing allogeneic hematopoietic stem cell transplant (allo-HSCT). The phase 3 Precision-T trial demonstrated that Orca-T, combined with tacrolimus, enhanced chronic graft-vs-host-disease (cGVHD)–free survival, reduced cGVHD incidence, and improved GVHD-free relapse-free survival compared to conventional allograft with tacrolimus and methotrexate. Orca-T also showed favorable overall survival, lower non-relapse mortality, and reduced serious adverse effects, highlighting its potential as a superior GVHD prophylaxis strategy.

Treatment with an investigational allogeneic T-cell immunotherapy improved outcomes vs conventional transplant in patients with hematologic malignancies

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