New Approaches Combat GVHD and Improve Transplantation Outcomes in Hematologic Malignancies

Hematologic malignancies|

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Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents a potentially curative treatment option for patients with certain hematologic malignancies, the development of graft-vs-host disease (GVHD) remains a significant risk. During the 51st Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), expert investigators from around the world gathered to share their findings from studies examining approaches to optimizing allo-HSCT and preventing GVHD, including posttransplant cyclophosphamide (PTCy) and Orca-T.

“It seems that transplantation is becoming more tolerable as the years go on,” Arpita Gandhi, MD, MS, said. “There’s more work to be done, but it’s time to share this wealth of knowledge with our referring colleagues. Transplantation is tolerable, and it’s becoming more tolerable with novel approaches. I believe it’s time to take on the challenges of the difficult, refractory, and active diseases.”

In an OncLive Peer Exchange filmed during EBMT, a panel of expert hematologists and transplantation specialists gathered to discuss the present landscape of allo-HSCT in patients with hematologic malignancies, current and emerging approaches for GVHD prophylaxis, and the potential effects of notable data presented during the meeting.

Determining the Right Patients for Allo-HSCT and GVHD Prophylaxis Strategies

The panelists opened their conversation by briefly outlining their approach to selecting patients for allo-HSCT, including in patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and acute lymphoblastic leukemia (ALL).

“[In patients with] AML, we look into genetic risk factors and focus on the intermediate- and adverse-risk groups per European LeukemiaNet [ELN] classification,” Nelli Bejanyan, MD, said. “The updated version has more molecular features that were added, [which] define the adverse-risk patients. In patients with favorable-risk disease, we consider allo-HSCT if they are positive for minimal residual disease [MRD] post first consolidation or in their second complete remission [CR]; otherwise they do not have curative potential with allo-HSCT. In patients with intermediate-risk disease, allo-HSCT [had] a long-term survival benefit of [approximately] 50% and curative [potential]. In [patients with] adverserisk disease, the [survival benefit] is approximately 40% based on Center for International Blood and Marrow Transplant Research [CIBMTR] data.”

According to the 2024 ELN genetic risk classifications, adult patients with AML with favorable-risk disease harbor mutations in NPM1, IDH2, IDH1, and/or DDX41 or have disease with other cytogenetic and/or molecular abnormalities. Those in the intermediate-risk group have disease that is positive for internal tandem duplications of the FLT3 gene, NRAS mutations, and/or KRAS mutations. Those with TP53 mutations are classified as having adverse-risk disease.1 In patients with MDS, the Revised International Prognostic Scoring System can help hematologists with risk stratification by incorporating molecular and cytogenetic characteristics, noted Everett Meyer, MD, PhD. “We [consider] the risk stratification [factors], focusing on [patients with] intermediate- to high-risk [disease] to move to transplantation. There are also many clinically based factors to consider, [such as] how much their cytopenia is affecting them, fatigue, recurrent infections, bleeding risk, and transfusion requirements. By and large, [patients with] MDS are very underserved. It’s estimated that only [approximately] 20% of patients who could be eligible for transplant and benefit from it eventually get to transplant, so it’s an area where we need improvement.”

Caspian Oliai, MD, MS, explained that allo-HSCT in patients with ALL is an evolving field and questions remain in terms of which patients will benefit the most. Notably, data from the phase 3 ECOG-E1910 trial (NCT02003222) showed that patients with newly diagnosed MRD-negative, Philadelphia chromosome (Ph)–negative, B-cell–lineage ALL who underwent allo-HSCT and received blinatumomab (Blincyto) plus chemotherapy (n = 22) experienced a 3-year overall survival (OS) rate of 82% vs 71% in patients who received chemotherapy alone (n = 22; HR, 0.59; 95% CI, 0.12-2.11).2

“In patients [with] Ph–negative ALL without high-risk features, incorporating blinatumomab long term without allo-HSCT appears to be a curative strategy,” Oliai said. “In patients with Ph-like B-cell ALL, especially those with a CRLF2 rearrangement, the history of this subtype is not good; the [approximate] long-term survival rate is 25%. In my practice, I would try to give allo-HSCT in all these patients.

“In my practice, I don’t tend to give allo-HSCT in patients with Ph-positive B-cell ALL, unless there is an IKZF1 mutation with another mutation that puts them at high risk for relapse,” he continued. “There are many good ways to monitor these patients, and if there’s a reemergence of residual disease, that is the time to take them to allo-HSCT. A counterargument to this approach [would say] that it’s best to take a patient to allo-HSCT as early as possible. [For example], if you’re achieving nice responses with a chemotherapy-free tyrosine kinase inhibitor– [based] regimen and you see reemergence later, you have delayed transplant for a substantial amount of time, which could potentially affect its curative potential. It’s an interesting and controversial academic aspect of the field.”

GVHD remains a significant complication of allo- HSCT, underscoring the importance of effective GVHD prophylaxis strategies. The panelists noted that graft source as well as prophylaxis approach can be associated with varying risks of GVHD, especially chronic GVHD.

During EBMT, investigators presented data from a retrospective study that aimed to characterize late events and long-term outcomes with PTCy following allo-HSCT in patients with AML. The study included adult patients with AML in the EBMT registry who received PTCy-based allo-HSCT in first remission from a haploidentical donor, matched sibling donor (MSD), or 10/10 matched unrelated donor (MUD) between 2010 and 2022 and were leukemia free at 2 years post transplant.3

Findings from the study demonstrated that patients in the overall population (N = 1289) experienced 2- and 5-year OS rates of 94% (95% CI, 92%-95%) and 84% (95% CI, 80%-88%), respectively. The leukemia-free survival rates at these respective time points were 90% (95% CI, 88%-92%) and 82% (95% CI, 79%-86%). The cumulative incidences of chronic GVHD at 2 and 5 years were 4% (95% CI, 2%-6%) and 7% (95% CI, 4%-10%), respectively. The rates of chronic GVHD– free relapse-free survival (GRFS) were 92% (95% CI, 88%-94%) and 87% (95% CI, 80%-92%), respectively.3 Using the MSD group (n = 175) as the reference, the HRs in terms of OS in the MUD (n = 208) and haploidentical (n = 906) groups were 1.86 (95% CI, 0.59-5.87; P = .29) and 1.73 (95% CI, 0.67-4.48; P = .26), respectively. The HRs for leukemia-free survival in the MUD and haploidentical groups were 1.74 (95% CI, 0.71-4.27; P = .22) and 1.28 (95% CI, 0.61-2.65; P = .51), respectively.3

“Thinking about how these data from this study taken together influence the field, they show that PTCy is associated with good OS, even in the myeloablative setting; 66% of patients in this study received myeloablative conditioning,” Oliai said. “If we can reproduce these long-term outcomes in prospective clinical trials, that would be fantastic.”

In another study presented during EBMT, investigators shared real-world data regarding the incidence of GVHD according to prophylaxis strategy in patients with hematologic malignancies who received allo-HSCT from MSDs and MUDs. The study included patients from 13 centers in Spain treated from 2018 to 2020.4

At a median follow-up of 47.3 months, the 3-year progression-free survival and OS rates in the overall population (N = 489) were 57% (95% CI, 54%-60%) and 66% (95% CI, 63%-69%). The 1-year nonrelapse mortality rate was 14% (95% CI, 12%-16%), and the 3-year GRFS rate was 39% (95% CI, 35%-44%).4

Additionally, data from a multivariate analysis revealed that patients in the MSD group who received GVHD prophylaxis with a calcineurin inhibitor plus methotrexate (HR, 1.34; 95% CI, 0.93-1.94; P = .117) or with antithymocyte globulin (ATG; HR, 1.05; 95% CI, 0.27-4.10; P = .950) were more likely to develop moderate or severe chronic GVHD vs those who received PTCy. In the MUD group, patients did not experience a benefit with any of these approaches vs PTCy in terms of preventing moderate or severe chronic GVHD.4

In univariate analysis, patients in the MSD group who received a calcineurin inhibitor plus methotrexate (HR, 2.69; 95% CI, 1.82-3.98; P < .001) and sirolimus-based (HR, 2.97; 95% CI, 1.85-4.76; P < .001) GVHD prophylaxis were significantly more likely to experience grade 2 to 4 acute GVHD vs those who received PTCy. Compared with PTCy, ATG- (HR, 2.07; 95% CI, 1.25-3.43; P = .005) and sirolimus-based (HR, 2.97; 95% CI, 1.80-4.90; P < .001) prophylaxis were significantly associated with worse acute GVHD rates in the MUD group, as was prophylaxis with a calcineurin inhibitor plus methotrexate (HR, 4.98; 95% CI, 3.21-7.70; P < .001).4

“[Data from] this retrospective study showed a benefit [with PTCy in terms of] reduction of both acute and chronic GVHD, which is what we have seen in multiple [other] retrospective and prospective studies, confirming what our clinical inclination has been,” Amandeep Salhotra, MD, commented.

Investigators Share Exciting Clinical Trial Data with Orca-T During EBMT

The panelists transitioned their conversation to discuss updated clinical trial data presented during EBMT about the investigational allogeneic T-cell immunotherapy Orca-T, which employs high-purity regulatory T cells for GVHD prophylaxis.5

“Orca-T is a high-precision immune therapy [that] is composed of stem and immune cells that are derived from an allogeneic donor, and it leverages a highly purified and polyclonal [regulatory T-cell] population that is capable of controlling alloreactive immune responses,” Oliai explained. “The standard allograft of hematopoietic cell transplantation is composed of a variety of cell types that are typically administered together in a single infusion. However, the full benefits of allo-HSCT could be achieved by cellular selection, in which you purify for certain cell types that provide a therapeutic benefit while reducing other cell types that pose a potential risk.”

The phase 3 Precision-T trial (NCT05316701) compared Orca-T with standard-of-care allo- HSCT in patients aged 18 to 65 years with AML, MDS, ALL, or mixed-phenotype acute leukemia who otherwise would have undergone standard allo-HSCT and were in CR or CR with incomplete count recovery. The primary end point was moderate to severe chronic GVHD–free survival (cGFS). Secondary end points included OS, GRFS, and the incidence of moderate to severe chronic GVHD.5

Data from the Precision-T trial demonstrated that patients who received Orca-T with tacrolimus (n = 93) achieved a 1-year cGFS rate of 78.0% (95% CI, 65.0%-86.6%) vs 38.4% (95% CI, 26.2%-50.5%) among patients treated with allo-HSCT and tacrolimus plus methotrexate (n = 94; HR, 0.26; 95% CI, 0.14-0.47; log-rank P < .00001). The rates of moderate to severe chronic GVHD were 12.6% (95% CI, 5.3%-23.1%) compared with 44.0% (95% CI, 31.3%-56.1%), respectively (HR, 0.19; 95% CI, 0.08-0.43; Gray test P = .00002). The 1-year OS rates were 93.9% (95% CI, 85.8%-97.4%) vs 83.1% (95% CI, 72.9%-89.8%), respectively (HR, 0.49; 95% CI, 0.20-1.22; log-rank P = .11823; Table).5

“This is the first time that a high-precision immunotherapy derived from a donor graft has been delivered across the country from variable apheresis centers to a centralized manufacturing facility and then to the 19 participating centers with no graft failures,” Meyer, who presented the findings during the meeting, commented. “[This is] remarkable. It’s something that would be very difficult for each of our individual centers to do. That’s an achievement because it opens up a new era of the potential to deliver this and other future graft-engineered products to our patients.”

Additionally, data from a retrospective study that included long-term follow-up from a subset of patients treated with Orca-T in a phase 1b study (NCT04013685) showed that patients treated with Orca-T achieved a higher OS rate vs those who received PTCy. The study compared outcomes for patients treated in the study with those of patients from the CIBMTR registry who received PTCy.6

“This was not randomized clinical trial data; it is a comparison of a phase 1 trial of Orca-T [with] real-world outcomes of PTCy,” Gandhi noted. “When we selected patients for this comparison, they were chosen in terms of eligibility similar to what would be [required] on [Precision-T]. In both groups, patients underwent transplantation in 2018 or after, and the age group was similar compared with the phase 3 study, which is 18 to 65 years [old] using myeloablative conditioning.”

Patients who received Orca-T (n = 77) achieved 1-, 2-, and 3-year OS rates of 96% (95% CI, 88%-99%), 88% (95% CI, 78%-94%), and 86% (95% CI, 73%-92%), respectively. Comparatively, these respective rates were 82% (95% CI, 78%-87%), 73% (95% CI, 68%-79%), and 67% (95% CI, 61%-74%) among patients from the CIBMTR registry who received PTCy (n = 293).6

“[In the future], I want to see analyses [comparing] all of the approaches we have [available],” Gandhi said in conclusion. “[This should include] not just 1 randomized study, but an [analysis] of all of our GVHD prophylaxis and transplant platforms.”

References

1. Döhner H, DiNardo CD, Appelbaum FR, et al. Genetic risk classification for adults with AML receiving less-intensive therapies: the 2024 ELN recommendations. Blood. 2024;144(21):2169-2173. doi:10.1182/blood.2024025409

2. Liedtke M, Sun Z, Litzow MR, et al. Assessment of outcomes of allogeneic stem cell transplantation by treatment arm in newly diagnosed measurable residual disease negative patients with B-lineage acute lymphoblastic leukemia randomized to conventional chemotherapy +/- blinatumomab in the ECOG-ACRIN E1910 phase III National Clinical Trials Network trial. Blood. 2024;144(suppl 1):779. doi:10.1182/ blood-2024-207557

3. Rodríguez-Arbolí E, Ferhat Berland AT, Angelucci E, et al. Late events and long-term outcomes after post-transplant cyclophosphamide-based haploidentical allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia: an ALWP-EBMT study. Presented at: 51st Annual EBMT Meeting; March 30-April 2, 2025; Florence, Italy. Abstract OS13-08.

4. Bento L, Jurado M, Salas MQ, et al. Incidence of graft versus host disease according to prophylaxis strategy in matched related and unrelated donor allogeneic hematopoietic stem cell transplantation: real-world experience of GETH-TC. Presented at: 51st Annual EBMT Meeting; March 30-April 2, 2025; Florence, Italy. Abstract OS11-07.

5. 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.

6. Gandhi AP, Srour SA, Oliai C, et al. Observational comparison of overall survival between phase 1B Orca-T and registry-based post-transplant cyclophosphamide patients. Presented at: 51st Annual EBMT Meeting; March 30-April 2, 2025; Florence, Italy. Abstract OS3-04.