, Mohamad Mohty, MD, PhD, discussed advancements in the management of graft-vs-host disease (GVHD) and highlighted unmet needs for patients with chronic (cGVHD) or acute GVHD (aGVHD), for whom standard-of-care therapies often fall short.

Mohty also expanded on ongoing research in GVHD reported at the 

3-year follow-up findings from the phase 2 ROCKstar trial

 (NCT03640481), which investigated belumosudil (Rezurock) in patients with cGVHD. The study showed that treatment with this agent yielded sustained responses, and no new safety signals were observed in eligible patients.

Although challenges remain, advancements showcased at the EBMT meeting continue to underscore a new era for the treatment of patients with GVHD, Mohty noted. He provided further insights and key takeaways from the EBMT Annual Meeting 

Mohty is a professor of hematology and the head of the Hematology and Cellular Therapy Department at Saint-Antoine Hospital and Sorbonne University in Paris, France. He is also head of the translational research team at the Saint-Antoine Research Center and the chairman of the Acute Leukemia Working Party of the EBMT.

: What data were seen in the aGVHD, steroid-refractory, and ruxolitinib-factory realm?

: GVHD remains a matter of concern after transplant. We’ve seen some major improvements over the past few years with the advent of posttransplant high-dose cyclophosphamide in particular. However, some patients are still [experiencing] aGVHD. Unfortunately, our first-line therapy remains focused on high-dose corticosteroids with deleterious adverse effects [AEs]; we also know that approximately 50% to 60% of patients are not going to respond to corticosteroids or are going to become corticosteroid dependent, which is not a good scenario.

We’ve been lucky over the past 3 to 4 years to have the 

approval of the JAK2 inhibitor ruxolitinib

, which proved to be a very good drug for patients who have steroid-refractory aGVHD. We are also struggling with a smaller group of patients who are becoming ruxolitinib refractory, resistant, or dependent. If you use ruxolitinib for salvage [therapy] after corticosteroids, a small group of patients may not be able to receive ruxolitinib, not everybody will respond, and some patients will lose their initial response to ruxolitinib. We then end up with a new group of patients who are ruxolitinib refractory. This is a new category of patients. We’re fortunate that we’re now seeing research in this subgroup of patients. During the EBMT meeting, I was very excited to see some novel data on modulation of the microbiota in these patients with advanced and refractory aGVHD.

Are there any follow-up data you’d like to expand on regarding the MaaT013 product?

An important piece of information regarding the use of MaaT013 as salvage treatment based on the early-access program is its excellent safety profile. We didn’t see severe AEs in the 140 patients who were treated. It is a single-shot treatment, which is important, instead of a treatment that is received and given to the patient on a chronic basis every day for several weeks or months.

Most importantly, the responses are very quick—within 1 week. Patients who are responding are [doing so] in an excellent manner and very rapidly. Now based on this early-access program, we have very important follow-up that gives us some confidence in these results, which I consider quite reliable.

Turning to cGVHD, how have you seen this landscape shift in recent years?

cGVHD incidence and severity have decreased over the past 10 years thanks to the efficacy of PTCy. However, we should bear in mind that we’re [performing transplant in] older patients. We are frequently using peripheral blood stem cells as well as donor lymphocyte infusion, including in the prophylaxis setting. At the end of the day, we still have a significant proportion of patients, at approximately 20%, who are continuing to experience moderate or severe cGVHD, which would require systemic immunosuppressive therapy.

Although cGVHD is not an immediate life-threatening condition, it dramatically alters the patient’s quality of life. Therefore, we still need to make progress in this arena. When it comes to the first-line therapy today, we don’t have options better than corticosteroids. That’s the bad news because we don’t like to use high-dose corticosteroids due to their deleterious AEs. We do have some good news about ruxolitinib because it was validated in the steroid-refractory cGVHD setting in the phase 3 REACH3 trial [NCT03112603].

But we have patients who may not be able to tolerate ruxolitinib; they may develop cytopenias over the long term or infections, or they may not respond to ruxolitinib. Therefore, novel options are needed, and this is where belumosudil, which was [granted regulatory] approved in 2021, is proving to be an excellent option. This drug has a new mechanism of action, as it’s a ROCK2 inhibitor. This mechanism of action is extremely interesting because when we look to the pathophysiology of cGVHD, we do have different phases. For instance, it is likely that ruxolitinib is acting well on the inflammatory component, which is an earlier phase, especially with the Th17 inflammatory response. But the use of a ROCK2 inhibitor such as belumosudil can also act not only on the inflammatory process but mainly on the fibrotic process. This is what makes it very attractive. This is what we saw in the ROCKstar trial, which allowed the approval of belumosudil in the United States and many other countries across the globe.

We can see more than a 70% response rate with belumosudil, and responses are in all organs usually involved with cGVHD, including the lung. [I stress] lung cGVHD because this is a terrible localization and [represents] a huge unmet need. Having a drug that [leads to] responses in the lung for cGVHD is most welcome. We are now getting closer to having better control of cGVHD. These drugs have been developed for the patient population with the most advanced, severe [disease]. The next step, and my wish, is to try to move these agents into earlier lines of use, even first-line treatment of cGVHD.

During the EBMT meeting we heard about the launch of a randomized trial with belumosudil in the first-line setting in combination with corticosteroids. The field is moving positively and, in my opinion, in the right direction.

Given the AE profile that comes with corticosteroids, will any work be devoted to understanding which patients respond to corticosteroids?

Biomarkers in the field of GVHD, whether acute or chronic, are highly desired. I don’t think anyone would question the need to have biomarkers to be able to predict the responses [and] also the failures, and maybe identify when to start treatment. Unfortunately, despite a lot of research and some very nice studies, I’m not aware of 100% reliable, robust biomarkers in acute or chronic GVHD.

There have been some great work and results, for instance, with the Mount Sinai Acute GVHD International Consortium criteria and biomarker [research], but I still don’t believe this is part of routine clinical practice. It’s also true that in cGVHD, we don’t have reliable biomarkers; maybe we will, but it will be difficult to find these biomarkers because cGVHD is a very heterogeneous condition. Clinically, cGVHD of the lungs or scleroderma may be different from dry eyes or dry mouth with cGVHD. In the ideal world, we would love to see these biomarkers. However, in the real world today, I don’t see them ready for primetime yet.

Cutler C, Lee SL, Pavletic S, et al. Belumosudil for chronic graft-versus-host disease after ≥2 prior lines of systemic therapy: 3-year follow-up of the ROCKstar study. Presented at: 50th Annual Meeting of the EBMT; April 14-17, 2024; Glasgow, Scotland. Abstract OS13-01.

Articles

Mohamad Mohty, MD, PhD, discusses unmet needs for patients with chronic or acute GVHD, for whom standard-of-care therapies often fall short.

Ongoing Research Aims to Expand Treatment Options, Address Unmet Needs in GVHD

, clinicians and researchers highlighted advancements in the blood and bone marrow transplant field, including significant advances centering on criteria for donor selection in allogeneic stem cell transplantation (ASCT) and ongoing efforts to refine outcomes and reduce complications in patients with graft-versus-host disease (GVHD), according to Mohamad Mohty, MD, PhD.

, Mohty highlighted key takeaways from the meeting, emphasizing the discussions that revolved around donor selection criteria, as well as the impact that haploidentical donors and other donor sources may have on patients' needs.

“The 2024 EBMT Meeting was a very exciting meeting; we celebrated the 50th anniversary of the European Society for Blood and Marrow Transplantation [EBMT], which was originally founded in 1974,” Mohty said. “This EBMT Annual Meeting proved to be very successful, and we [saw] the greatest advances in this field.”

In the interview, Mohty discussed the implementation of post-transplant cyclophosphamide for GVHD prophylaxis, highlighted efforts to optimize cyclophosphamide dosing to minimize complications when treating this disease, and noted future directions for this research.

Mohty is a professor of hematology, as well as the head of the Hematology and Cellular Therapy Department at the Saint-Antoine Hospital and Sorbonne University in Paris, France. He is also a member and lead of the translational research team at the Saint-Antoine Research Center and is the chairman of the Acute Leukemia Working Party for the EBMT.

: What were the main themes of the recent EBMT meeting?

: What was striking for me were the criteria for choosing donors [and] the implementation and [expansion] of the use of posttransplant cyclophosphamide [PTCy] for GVHD prophylaxis. There are also novelties in the management of acute, especially steroid-refractory, but also ruxolitinib-refractory, GVHD. We’ve seen some great advances when it comes to cGVHD, and overall, this was a memorable EBMT meeting where milestone data were presented.

What data were presented on the criteria for choosing donors, and how have they helped further inform practice?

When it comes to choosing a suitable stem cell donor [for] ASCT, there is a lot of excitement about the use of haploidentical donors. When combining matched sibling donors, fully matched unrelated donors, mismatched unrelated donors, and now haploidentical donors, you’re able to find a suitable donor for approximately 95% of patients who need an ASCT. Although the use of cord blood cells has decreased over the past few years in the adult population, if you use cord blood cells [with] the new technologies and platforms for cord blood expansion, you would be able to cover approximately 100% of [patient] needs.

Interestingly, when it comes to living donors, the age of the donor remains an important parameter. Favoring a young donor, whether in the setting of haploidentical or unrelated donors, is likely to be an important parameter. Also, having a female donor to a male recipient remains an important risk factor for alloreactivity, especially in cGVHD. What remains controversial is how to choose between a young haploidentical donor, if available, and a young, fully matched, unrelated donor. Here we don’t have a final response to this question.

There are teams who now rely almost exclusively on family donors, and this would include matched sibling donors and haploidentical donors. There are still teams who prefer to have fully matched 10 out of 10 unrelated donors. This is proving to be very exciting, and despite the debates, the good news is [there is a possibility of] finding a donor for almost everybody who needs an ASCT.

When you say that younger patients are favorable donors, does this refer to chronological age or biological age?

Age of the donor is important when selecting a given donor—on the other hand, you must take into account the age of the recipient [too]. When it comes to the recipient’s age, it is very important to consider the comorbidities, which will play an important role in the final outcome. We know from daily clinical experience that a patient who is 60 years old—but has comorbidities such as hypertension, diabetes, a heavy smoking history, and cardiovascular complications—[will be affected by] these comorbidities. [They will] negatively impact the incidence of nonrelapse mortality.

However, a patient who’s 70 years old but also fit and without any comorbidities [will] have a lower likelihood of developing toxicities. We can see an important separation between biological age vs physiological age, which is correlated with comorbidities. The development of comorbidity indexes and trying to use new electronic artificial intelligence tools to try to predict outcomes are going to be major [focuses] of future research.

What data supported the entrance and now increased use of PTCy over more historical paradigms?

The use of posttransplant high-dose cyclophosphamide has, in the past 15 years, proved to be a major breakthrough in ASCT because it has allowed safe haploidentical stem cell transplantation [to be performed for the first time, thus] allowing for engraftment while reducing the risk of severe aGVHD and cGVHD.

The use of PTCy has rapidly spread because it is a relatively cheap drug and physicians are quite familiar with the use of cyclophosphamide, as it is a very common drug in hematology and oncology. It has great efficacy in depleting the alloreactive T cells. Now there is an accumulating body of evidence explaining the mechanism of action that allows PTCy to effectively prevent GVHD.

[Although] the initial experience started in the haploidentical setting, use of PTCy is spreading beyond haploidentical transplant and is being used increasingly in the mismatched unrelated setting. Some teams are also using it in the unrelated matched sibling setting. These are the positives with use. We also know with some long-term follow-up and greater experience that high-dose PTCymay not be suitable or safe for everybody because there is a risk of cardiac complications, which were described especially in patients with cardiovascular risk factors. We also know [there is] the high risk of hemorrhagic cystitis related to the BK virus.

At the EBMT meeting, we saw very nice translational work showing that PTCy can impact the immune repertoire and immune anti-infectious control—that can explain the higher incidence of infectious and opportunistic infections after PTCy. With this background, efforts are aiming to test lower doses of PTCy, and our team presented data on reducing the dose by 20% or even 30%.

For instance, [we used] 35 mg/kg per day for 2 days on day 3 and day 4 or day 3 and day 5. You can achieve similar GVHD prevention while reducing the risk of complications, especially cardiac [and] infectious complications, but also shortening the duration of neutropenia and thrombocytopenia. This needs to be validated in prospective future randomized trials, but the use of PTCywill continue to grow. This is something that will make the ASCT procedure safer and more feasible, especially in older and frail patients.

Mohamad Mohty, MD, PhD, highlights key takeaways from the 50th Annual EBMT Meeting, focusing on ongoing efforts within the GVHD treatment arena.

Mohty Shares Key Takeaways From the 50th Annual EBMT Meeting, Highlighting Advances in GVHD

Ongoing research with Orca-T cell therapy continues to indicate that the regulatory T-cell enriched donor cell therapy is safe and offers favorable outcomes without significantly increasing non–relapse mortality (NRM) rates vs unmanipulated graft in patients with hematologic malignancies undergoing allogeneic transplant and myeloablative conditioning; this is particularly promising for elderly patients, for whom myeloablative conditioning was traditionally considered too risky, according to Amandeep Salhotra, MD.

 Meeting of the European Society for Blood and Marrow Transplantation

revealed superior 1-year relapse-free survival (RFS) rates, NRM rates, and overall survival rates with Orca-T vs post-transplant cyclophosphamide (PTCy)–based myeloablative conditioning and allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute leukemia or myelodysplastic syndrome (MDS; 

(NCT05088356) reported at the same meeting showed a 12-month relapse-free survival rate of 77% (95% CI, 49%-91%) with Orca-T plus reduced-intensity conditioning and tacrolimus (n = 20), indicating that it is a viable alternative to conventional transplant for patients with advanced hematologic malignancies.

“This is important because we normally do not offer a myeloablative conditioning regimen to older patients,” Salhotra, who is an associate professor in the Division of Leukemia, Department of Hematology and Hematopoietic Cell Transplantation, at City of Hope in Duarte, California, said in an interview with 

Further research is needed to compare Orca-T with other transplant approaches and optimize post-transplant therapies to prevent complications like chronic graft-vs-host disease (cGVHD), Salhotra added in the interview. Meanwhile, research exploring novel or standard therapies and investigating T-cell repertoire dynamics post-transplant with PTCy could help inform strategies to prevent post-transplant complications, especially cGVHD, he noted.

In the interview, Salhotra discussed the early-phase data showing the efficacy and safety of Orca-T in patients undergoing reduced-intensity allogeneic transplant, expanded on retrospective data comparing outcomes with Orca-T and PTCy-based approaches, and highlighted continued efforts to optimize transplant outcomes by leveraging other agents and enhancing oncologists’ understanding of GVHD mechanisms.

: What early clinical data have demonstrated the efficacy and safety of Orca-T in patients with hematologic malignancies undergoing reduced-intensity allogeneic transplant?

Orca-T is a manipulated product where patients receive fixed doses of CD34 stem cells in combination with regulatory T cells on day 0 followed by conventional T cells a couple of days later. [Pooled] data from phase 1b [NCT04013685] and phase 2 [NCT01660607] 

 This is a large data set of 375 patients who got unmanipulated graft compared with 151 patients [who received] Orca-T graft. Investigators looked at outcomes like 1-year GVHD RFS [GRFS] and OS, and the GRFS rate favored Orca-T. The 1-year GRFS rate in patients who received the Orca-T graft was 70% compared with 21% in the patients who got the unmanipulated graft. The benefit of this superior GRFS is that patients have a better quality of life, they do not have GVHD, and they have a superior RFS. That translates into better outcomes and OS in this subgroup of patients.

Some subset analyses were performed in this large subset of 151 patients who got the Orca-T graft [in the phase 2 and phase 1b trials]. These subsets [included] patients who [underwent] BFT conditioning, which is a combination of [intravenous] busulfan, fludarabine, and thiotepa. Patients who [received] this conditioning along with the Orca-T graft had a superior 1-year RFS rate of 81% and a 1-year OS rate of 94%.

What unmet needs still exist for elderly patients with hematologic malignancies undergoing allogeneic transplantation, and how might the use of Orca-T address them?

Based on recent data from the Center for International Blood and Marrow Transplant Research [CIBMTR], we know that most patients who develop acute myeloid leukemia [AML] tend to be above the age of 60 to 65. The median age [of patients diagnosed with AML] is 67, and AML remains the number 1 indication for allogeneic stem cell transplantation. [The question is whether] there is a way we can improve the outcomes of patients who undergo an allogeneic transplant in this subset of patients. Since these are older patients, are we able to give them a myeloablative conditioning regimen? That was what we wanted to study in this [older] subset.

These data were [previously] presented by my colleague Caspian Oliai, MD, MS, of UCLA Health, at the 2023 ASH Annual Meeting and Exposition. [The phase 1b study (NCT04013685)) included] approximately 25 patients above the age of 55 who got an Orca-T graft. The median age [in this patient population] was approximately 60 years old. Importantly, patients who were older did not display any NRM at the 1-year mark, and their OS was comparable with patients who were under the age of 55. The 1-year OS rate was approximately [96%] in patients who were older.

The benefit of a myeloablative conditioning regimen, as shown in phase 3 studies, is that it reduces the relapse rate. [However], NRM [rates often] prevent our older patients from benefitting from them. We can potentially improve the outcomes of these AML patients by using a backbone of myeloablative conditioning with the manipulated Orca-T graft.

What prior research informed your retrospective analysis of survival outcomes with Orca-T vs PTCy–based allo-HSCT following myeloablative conditioning in patients with acute leukemia or MDS?

[One of] the 2 major platforms that are emerging for the prevention of GVHD is PTCy. This was first developed at Johns Hopkins, where patients who underwent the haploidentical transplant received cyclophosphamide on days 3 and 4 at 50 mg/kg in addition to tacrolimus and mycophenolate mofetil. [PTCy was] initially evaluated in the haploidentical setting, but as the results came out it has been increasingly adopted for matched unrelated donors and mismatched unrelated donors. It has been very successful in terms of reducing the incidence of cGVHD compared with our current standard, which is tacrolimus and methotrexate.

There was also the subsequent [phase 2] PROGRESS I study [(NCT02208037) conducted by the] Blood and Marrow Transplant [BMT] Clinical Trials Network [BMT CTN] of patients who received myeloablative conditioning and got PTCy. In that study, PTCy did not seem to have a superior cGVHD [rate] and RFS compared with the current standard of care [SOC].

What did findings from this retrospective analysis indicate about the feasibility and safety of using Orca-T plus tacrolimus vs the PTCy-based approach for patients with matched unrelated donors? What were the study’s main limitations?

In the BMT field, there is great interest in seeing how the data for Orca-T compare with [that of] PTCy. That was [what I] presented in the retrospective review. [The retrospective study included] approximately 85 patients who were propensity matched compared with the Orca-T patients from the CIBMTR dataset. Most of these patients were unrelated donors. In the Orca-T [arm], there were approximately 111 patients with a mix of match-related and matched-unrelated donors. Almost all the patients received busulfan-based conditioning across both groups.

RFS was superior in the Orca-T [arm, at] approximately 77% vs 62% in the PTCy arm. We also noticed that in patients older than age of 55 who received PTCy, the NRM goes up. There was a survival benefit in patients who received the Orca-T graft vs those who received PTCy.

The drawback was that this is a retrospective study. We did not have minimal residual disease data from most of the patients, and the median age of the patients who received the Orca-T graft was a little bit lower than in the PTCy arm, at 49 as opposed to 52. We need a head-to-head trial, where we can compare the outcomes in a similar patient population between PTCy and the Orca-T graft.

Could you expand on research exploring the use of novel or standard therapies to ensure safe transplantation? How can these studies improve oncologists’ understanding and ability to prevent post-transplant complications when treating patients with cGVHD?

[Performing] transplant safely is very important, and preventing post-transplant complications is another important goal of transplant physicians. [There was the] randomized phase 1/2 [AGAVE-201 (NCT04710576)] study presented at the meeting [evaluating] axatilimab [SNDX-6352]. Three 3 doses were studied: 0.3 mg/kg every 2 weeks, 1 mg/kg every 2 weeks, and 3 mg/kg every 4 weeks. The 0.3 mg [dose] every 2 weeks was the most efficacious in patients with established cGVHD. The overall response rate [ORR] was approximately 74%, and patients with fibrotic organ involvement had good responses to treatment. This is one of the newer approaches [leveraging] axatilimab antibodies, [which] target the monocyte macrophage pathway. It’s a pathway that is different from the conventional [ones] that we target when managing GVHD, which [involve] T cells or B cells. That’s another important [approach] for us to [potentially use when] treating patients with cGVHD.

Another study that I thought was important was [the phase 3 BMT CTN 1703 and 1801 study (NCT03959241)] documenting how PTCy works in patients. This [featured] retrospective biospecimen collection data in patients [receiving] reduced intensity [conditioning allogeneic transplantation] and compared PTCy with tacrolimus and methotrexate. Leslie S. Kean, MD, PhD, of Dana-Farber Cancer Institute and Boston Children’s Hospital presented these data. She had blood samples of patients collected posttransplant at different time points. She wanted to see how the T-cell repertoire develops in patients following transplant. She showed that there is rapid decline in the T-cell repertoire after patients get PTCy, which leads to a very significant reduction in the T-cell clones by day 30. These clones subsequently expand and repopulate the immune system or reconstitute the immune system 6 months and 1 year later. Using sophisticated T-cell receptor clonotypes by adaptive biotechnology, [researchers] showed that the repertoire of T cells is limited in patients who get PTCy. That might to some extent explain why patients had more infectious complications in the BMT CTN 1703 study, as the grade 2 to 4 infection rates were a bit higher compared with patients who received tacrolimus and methotrexate in the comparator arm.

What do results from BMT CTN 1703 suggest about the use of PTCy? Is any other research underway to further elucidate the viability of this strategy?

[That study] gives us a mechanism to understand why patients have infectious complications after PTCy. It’s a very important strategy for us to reduce the incidence of cGVHD, and it’s certainly better than what we’ve been using traditionally, which is tacrolimus and methotrexate. Further refinement of how we use PTCy is important.

There are some important studies underway where we can potentially reduce the dose of cyclophosphamide. There’s the phase 2 OPTIMIZE study [NCT06001385], where the primary end point is to look at safety and whether we can safely reduce the dose of cyclophosphamide without affecting the incidence of cGVHD. In that trial patients will get a reduced dose of cyclophosphamide at 37.5 mg/kg in 2 days and that can go down to 25 mg/kg, to find the lowest dose of cyclophosphamide that would still be effective. Hopefully this would reduce the T-cell repertoire at day 30, allowing for the expansion or repopulation of the immune system with a much more diverse clone of cells, and [ensuring that] the graft-vs-leukemia and the graft-vs-infection immunity is preserved in patients.

Would you like to spotlight any additional research within the GVHD space?

I [also] presented a retrospective review on cGVHD. We repurposed an old drug called leflunomide [Arava] which is approved in rheumatoid arthritis. It’s a pyrimidine biosynthesis inhibitor [and functions] similarly to other drugs like methotrexate. This is an investigator-initiated, single-center study. The goal of the study was to use leflunomide at the approved oral dose of 20 mg daily in patients with moderate to severe cGVHD. We treated approximately 18 patients in this study, and we looked at the safety, efficacy, and adverse effect profile of the patients with cGVHD. The primary end point was ORR at the 6-month mark. Approximately 50% of patients experienced a response with the drug. It was safe, well tolerated, and most patients were able to complete the 6-month study duration period. Also, few patients elected to go on study beyond that.

[Leflunomide is] an important adjunct that can be added [to treatment approaches] for patients who are not responding to standard treatments or who have plateaued on currently approved drugs [such as] ruxolitinib [Jakafi]. This can be used as an add-on therapy. [Notably,] we found high response rates [with leflunomide] in patients with mucosal involvement; those patients tend to respond well. It’s available for physicians to use at the 20 mg dose per day, and we should be sharing our data and outcomes in a manuscript that will be published soon.

Salhotra A, Arteaga AG, Oliai C, et al. A retrospective analysis comparing Orca-T to post-transplant cyclophosphamide based allogeneic hematopoietic stem cell transplant in patients with matched unrelated donors receiving myeloablative conditioning. Presented at: EBMT 50th Annual Meeting; April 14-17, 2024. Glasgow, Scotland. Abstract A107.

Villar-Prados A, Sutherland K, Negrin R, et al. Phase 1 trial results for patients with advanced hematological malignancies treated with Orca-T cell therapy with reduced intensity conditioning and single agent tacrolimus. Presented at: EBMT 50th Annual Meeting; April 14-17, 2024. Glasgow, Scotland. Abstract A121.

Oliai C, Pavlova A, Muffly L, et al. Precision-engineered cell therapy Orca-T demonstrates high relapse-free survival at 1 year while reducing graft-versus-host disease and toxicity. Presented at: 2023 Transplantation & Cellular Therapy Meetings of ASCT and CIBMTR; February 15-19, 2023; Orlando, FL. Abstract 54.

Amandeep Salhotra, MD, discusses the feasibility and safety of Orca-T graft in patients undergoing allogeneic transplant for hematologic malignancies.

Orca-T Offers Favorable Post-Transplant Outcomes in Advanced Hematologic Malignancies

Belumosudil (Rezurock) elicited sustained responses and generated no new safety signals in patients with chronic graft-vs-host disease (cGVHD), according to 3-year follow-up findings from the phase 2 ROCKstar trial (NCT03640481) that were presented at the 

At a median follow-up of 30 months and a data cutoff of September 1, 2022, the 3-year overall response rates (ORRs) in the populations of patients who received belumosudil at 200 mg once daily (n = 77) and twice daily (n = 75) were 74% (95% CI, 63%-83%; 

“Response rates remained extremely stable, without a marked change by the addition of 20 additional patients,” according to lead study author Corey S. Cutler, MD, MPH, FRCPC, of Dana-Farber Cancer Institute in Boston, Massachusetts.

Previous results from ROCKstar, reported in 2021 after a median follow-up of 14 months, showed ORRs of 74% (95% CI, 62%-84%) and 77% (95% CI, 65%-87%) in patients who received the agent once daily and twice daily, respectively.

In the initial data report, belumosudil was well tolerated, and the observed adverse effects (AEs) were consistent with those expected in patients with cGVHD receiving immunosuppressive therapies, such as corticosteroids.

In 2021, based on preliminary results from ROCKstar, the oral, selective ROCK-2 inhibitor belumosudil 

 for the treatment of patients with cGVHD who had received prior allogeneic hematopoietic cell transplant.

The open-label, multicenter ROCKstar trial randomly assigned 132 patients at least 12 years of age with persistent cGVHD who had received 2 to 5 prior lines of systemic therapy and were indicated to receive additional systemic therapy to receive belumosudil at either 200 mg once daily (n = 77) or 200 mg twice daily (n = 75). Patients received continuous treatment in 28-day cycles until clinically significant cGVHD progression or unacceptable toxicity. Patients were stratified by prior ibrutinib (Imbruvica) exposure (yes vs no) and severe cGVHD status (yes vs no).

ORR served as the primary end point, and key secondary end points included duration of response (DOR), change in Lee Symptom Scale (LSS) summary score, time to next treatment (TTNT), time to response, change in corticosteroid or calcineurin inhibitor dose, failure-free survival (FFS), and overall survival.

The 3-year follow-up analysis of ROCKstar included data from an additional 20 patients who were enrolled in a biomarker cohort after the ROCKstar publication data cutoff of August 19, 2020. The trial’s modified intent-to-treat (mITT) population (n = 152) included all randomly assigned patients who had received at least 1 dose of belumosudil.

In the overall trial population, patients had a median age of 54.5 years (range, 18-77), a median of 28.1 months (range, 1.6-162.4) from cGVHD diagnosis to trial enrollment, and had received a median of 0.19 mg/kg per day (range, 0.02-1.07) of prednisone-equivalent doses of corticosteroids. In total, 69.7% of patients had severe cGVHD at screening, and 52.0% of patients had at least 4 organs involved. Overall, 48.7% of patients had received more than 3 prior lines of therapy, including ibrutinib (34.2%) and ruxolitinib (Jakafi; 36.2%). Seventy-three percent of patients were refractory to their last line of therapy.

At 1 and 3 years of follow-up, the median DORs among responders who received once-daily belumosudil were 50.4 weeks and 69.9 weeks, respectively. These respective values were 74.3 weeks and 85.0 weeks among responders who received twice-daily treatment, and 54.1 weeks and 77.1 weeks in the overall population of responders.

Among the overall mITT population, 61% of patients each at 1 and 3 years of follow-up exhibited a 7-point reduction in LSS score. At 1 and 3 years of follow-up, in the arm of the mITT population that received once-daily dosing, 59% and 58% of patients, respectively, exhibited a 7-point reduction in LSS score. These respective values were 62% and 64% in the arm of the mITT population that received twice-daily dosing.

Among all responders in both arms, 70% and 69% of patients at 1 (n = 100) and 3 (n = 108) years of follow-up, respectively, exhibited a 7-point reduction in LSS score. These respective values were 69% and 68% in responders who received once-daily dosing and 71% each in the responders who received twice-daily dosing.

In the overall population, the median TTNT at 3 years of follow-up was 27.3 months. This value was not available (NA) at 1 year of follow-up. In the arm that received once-daily dosing, the median TTNT was 16.6 months at 1 year of follow-up and 24.2 months at 3 years of follow-up. These respective values were NA and not yet reached among patients who received twice-daily dosing.

A total of 23.4% and 25.3% of patients in the once-daily and twice-daily arms, respectively, successfully stopped all corticosteroid therapy. Furthermore, at 3 years of follow-up, 69% and 29% of patients reduced or discontinued their corticosteroid use, respectively, vs 65% and 21% of patients at 1 year of follow-up.

In the mITT population, the FFS rates were 75%, 56%, and 44% at 6 months, 1 year, and 18 months/2 years/3 years, respectively. In the investigator-assessed responder population, the 3-year FFS rate was 51.8%.

“For over half of the subjects who were given belumosudil for their late-stage cGVHD, belumosudil was the last immunosuppressant drug that they required, telling us that this may induce long-term tolerance, and this in fact may be the end of the journey with prolonged immune suppression for patients with severe cGVHD,” Cutler emphasized in the presentation.

The most common any-grade AEs were fatigue (1 year of follow-up, 38%; 3 years of follow-up, 38%), diarrhea (33%; 39%), nausea (31%; 31%), cough (28%; 28%), upper respiratory tract infection (27%; 26%), dyspnea (25%; 28%), headache (24%; 29%), peripheral edema (23%; 26%), vomiting (21%; 23%), and muscle spasms (20%; 18%). The rates of grade 3 or higher neutropenia and anemia were 1.3% and 3.3%, respectively. No grade 3 or higher thrombocytopenia was observed.

In the mITT population, 8% and 7% of patients in the once-daily and twice-daily arms, respectively, remained on treatment for at least 36 months, and 13.2% of patients discontinued treatment because of AEs. An increase in discontinuation rates because of AEs was observed each year after follow-up. In total, 11.2%, 1.3%, and 0.7% of patients discontinued treatment due to AEs after being on treatment for 1 year or less, 1 to 2 years, and more than 2 years, respectively.

“Treatment with belumosudil is very well tolerated, with a decreasing incidence of AEs over time,” Cutler concluded.

Dr Cutler reports consultant roles with Incyte, Novartis, Rigel, Sanofi, and Syndax; as well as data safety monitoring board membership with Allovir and Angiocrine.

Cutler C, Lee SL, Pavletic S, et al. Belumosudil for chronic graft-versus-host disease after ≥2 prior lines of systemic therapy: 3-year follow-up of the ROCKstar study. Presented at: EBMT 50th Annual Meeting; April 14-17, 2024. Glasgow, Scotland. Abstract OS13-01.

Cutler C, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study [published correction appears in Blood. 2022 Mar 17;139(11):1772]. 

. 2021;138(22):2278-2289. doi:10.1182/blood.2021012021

FDA approves belumosudil for chronic graft-versus-host disease. FDA. July 16, 2021. Accessed April 17, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belumosudil-chronic-graft-versus-host-disease#:~:text=On%20July%2016%2C%202021%2C%20the,prior%20lines%20of%20systemic%20therapy.

Belumosudil elicited sustained responses and generated no new safety signals in patients with chronic graft-vs-host disease.

Belumosudil Produces Long-Term Responses Without New Safety Concerns in cGVHD

Prophylactic administration of a twice-daily, 200-mg dose of itacitinib was well tolerated and decreased the incidence and severity of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) in patients with lymphoma who received axicabtagene ciloleucel (Yescarta; axi-cel), according to data from a phase 2 trial (NCT04071366) presented during the 

Assessment of CRS incidence by day 14 showed a significantly lower rate of grade 2 or higher CRS in the itacitinib arm (n = 23) compared with the placebo arm (n = 23), and the rates of grade 2 CRS were 17.4% and 56.5%, respectively (95% CI, 0.14-0.65; 

= .003). The overall incidence of CRS was 65.2% in the itacitinib arm vs 87.0% with placebo. Tocilizumab (Actemra) was administered for CRS in 65.2% of patients in the placebo arm vs 17.4% of patients in the itacitinib arm, and an additional 13.0% of patients in the placebo arm also received dexamethasone. In the itacitinib arm, the time to CRS onset was 2 days (range, 0-8), and the median duration of grade 2 or higher CRS was 2 days (range, 1-8). In the placebo arm, these respective ranges were 3 days (range, 0-9) and 2 days (range, 1-5).

At day 28, the estimated CRS-free survival was 70% (95% CI, 47%-84%) in patients treated with itacitinib and 26% (95% CI, 11%-45%) in those who received placebo. The incidence of grade 2 or higher CRS was 17.4% with itacitinib and 47.8% with placebo. Moreover, the rate of patients who received tocilizumab for CRS was higher in the itacitinib arm (8.7%) vs the placebo arm (26.1%). No patients required corticosteroids for CRS in either arm, and 1 patient died prior to day 28 in the itacitinib arm.

“Prophylactic itacitinib does appear to have promising activity for reducing the incidence of CRS, but also [shows] a signal [for] reducing ICANS in patients receiving axi-cel,” presenting author Richard Maziarz, MD, medical director of the Blood & Marrow Transplant & Cellular Therapy Program at Oregon Health and Science University in Portland, stated in an oral presentation of the data. “Biomarker analyses also demonstrate [itacitinib’s] potential benefit in not inhibiting CAR T-cell expansion.”

Further evaluation of ICANS events revealed that 3 patients developed ICANS by day 28 following itacitinib treatment vs 8 patients who received placebo. The overall incidence of ICANS was 13.0% (95% CI, 2.8%-33.6%) in the itacitinib arm vs 34.8% (95% CI, 16.4%-57.3%) with placebo. Grade 1, 2, and 3 ICANS events were experienced by 4.3% of patients each in the itacitinib arm; these rates were 13.0%, 8.7%, and 13.0% in the placebo arm.

Dexamethasone treatment for ICANS was administered in 4.3% of patients in the placebo arm vs 30.4% of patients in the itacitinib arm, with another 4.3% of patients in the placebo arm being treated with siltuximab (Sylvant). In the itacitinib arm, the time to ICANS onset was 5 days (range, 4-9), and the median duration of any-grade ICANS was 2 days (range, 2-11). In the placebo arm, these respective ranges were 6.5 days (range, 2-11) and 3.5 days (range, 2-13).

However, there was a higher incidence of grade 3/4 neutropenia and thrombocytopenia that was not resolved at day 28 with itacitinib vs placebo, and the rates of severe infection were similar between the 2 arms.

CRS and ICANs events are frequently observed after treatment with immune effector cell therapy. These adverse effects (AEs) are characterized by the release of inflammatory cytokines, which are activated through the downstream JAK signaling pathway.

Itacitinib, a potent and selective JAK1 inhibitor known for its extensive anti-inflammatory effects in various preclinical disease models, has also shown promise in reducing cytokine expression induced by CAR T-cell therapy.

“We all know that we can manage CRS and ICANs, but it is a real demand on health resource utilization,” Maziarz explained during the presentation. “If we can control these [toxicities], it could positively impact the further delivery of CAR T-cell therapy.

Accordingly, a randomized, double-blind, placebo-controlled phase 2 study was conducted to evaluate whether a twice-daily, 200-mg dose of itacitinib could mitigate CRS in patients with lymphoma who received axi-cel. The study consisted of 2 parts respectively assessing a daily and twice-daily 200-mg dose of itacitinib. Previously reported data from part 1 of this phase 2 study also showed that administering 200 mg of prophylactic itacitinib per day was tolerable and associated with signals of activity for CRS prevention in patients treated with commercial immune effector cell therapy.

“It is important to recognize that patients [in part 1] were not receiving any intervention for grade 1 CRS,” Maziarz added. “We saw a positive signal, and it was decided that we would proceed to the second part of the study.”

Part 2 of the study included patients who were at least 18 years of age and were eligible for treatment with axi-cel. Patients were also required to have an ECOG performance status of 0 or 1. Patients were randomly assigned 1:1 to receive either the previously specified dose of itacitinib or twice-daily placebo on days –3 to 26 of treatment with axi-cel. Notably, tocilizumab could be administered for grade 1 CRS if no improvements were observed within 72 hours. Hematologic disease assessments were conducted at day 90. Maziarz noted that patients underwent continuous temperature monitoring to avoid missing fevers at home.

The study’s primary end point was the incidence of grade 2 or higher CRS by day 14 per ASTCT consensus grading. Secondary end points included the incidence of ICANS by day 28, CRS and ICANS duration, safety, pharmacokinetics, biomarkers, and overall response rate achieved with immune effector cell therapy.

Forty-two of the 47 patients enrolled onto part 2 of the trial completed treatment, comprising 21 patients in each arm. Reasons for treatment discontinuation included AEs (4.3% in the itacitinib arm; 8.3% in the placebo arm), disease progression (4.3%; 0.0%), and physician’s choice to withdraw (0.0%; 4.2%).

Baseline characteristics were similar across treatment groups. All patients had diffuse large B-cell lymphoma (LBCL) with the exception of 1 patient with transformed follicular lymphoma in the itacitinib arm.

The median age of patients was 66 years (range, 29-80) in the itacitinib arm and 64 years (range, 31-79) in the placebo arm. Over half of patients (56.5%) in the itacitinib arm were at least 65 years old vs 41.7% of those in the placebo arm. Most patients across both arms were men (itacitinib, 65.2%; placebo, 70.8%), White (91.3%; 87.5%), had an international prognostic index score of 3 or higher (56.5%; 58.3%), and had Ann Arbor stage III/IV disease (56.5%; 50.0%). Germinal center B-cell subtype was present in 52.2% and 37.5% of patients in the itacitinib and placebo arms, respectively. The median number of prior regimens received in the itacitinib arm was 2 (range, 1-6) vs 1.5 (range, 1-4) in the placebo arm. Prior hematopoietic stem cell transplant had been administered to 21.7% and 16.7% of patients in the itacitinib and placebo arms, respectively. No patients in the itacitinib arm had a history of primary refractory disease vs 16.7% of those in the placebo arm. Lastly, the median lactate dehydrogenase level in the itacitinib arm was 200.0 U/L (range, 117-863) vs 208.5 U/L (range, 136-905) in the placebo arm.

Regarding safety, 8.7% of patients in the itacitinib arm experienced grade 3 or higher infections vs 12.5% of those who received placebo. Observed grade 3 or higher infections included pneumonia (itacitinib, 0.0%; placebo, 4.2%), sepsis (0.0%; 8.3%), urinary tract infection (8.7%; 4.2%), and bacterial infection (0.0%; 4.2%)

At day 28, persistent grade 4 neutropenia and grade 4 thrombocytopenia were respectively reported in 13.6% and 18.2% of patients treated with itacitinib. No patients experienced either grade 4 AE with placebo. Other grade 3 cytopenias observed at day 28 included neutropenia (itacitinib, 18.2%; placebo, 13.6%), thrombocytopenia (18.2%; 18.2%), and anemia (9.1%; 4.5%). One platelet transfusion was administered to 2 patients in the itacitinib arm and 1 patient in the placebo arm after day 28. No fatal AEs were observed.

Subsequent evaluation of responses with axi-cel showed that the best overall response rate (ORR) was 78.3% (95% CI, 56.3%-92.5%) in the itacitinib arm and 73.9% (95% CI, 51.6%-89.8%) in the placebo arm. In the itacitinib arm, the 3- and 6-month ORRs were 60.9% (95% CI, 38.5%-80.3%) and 39.1% (95% CI, 19.7%-61.5%), respectively; corresponding rates in the placebo arm were 47.8% (95% CI, 26.8%- 69.4%) and 26.1% (95% CI, 10.2%-48.4%), respectively.

“The best ORR at 3 and 6 months was actually, [although] these are small numbers, numerically higher in the itacitinib arm,” Maziarz expanded. “This signals [that itacitinib treatment] does not impair the function of the CAR T-cell therapy.”

Additionally, CAR T-cell infusion was found to produce a transient increase in the systemic cytokines tumor necrosis factor 

 < .001) and interleukin-6 (IL-6; adjusted 

Maziarz explained that “one of the questions that we also raised was: ‘Can we examine the actual impact [of itacitinib] sequentially on cytokines?’ In part 2, characteristic cytokines of 

 and IL-6 were higher in the patients who received placebo vs itacitinib, meeting what we would have anticipated.”

Analysis of CAR T-cell expansion over time also showed that expansion reached its peak 7 to 14 days after axi-cel infusion. Notably, no significant difference in CAR T-cell expansion was observed in patients with LBCL who received axi-cel infusion followed by itacitinib vs placebo.

Maziarz concludes by stating that further investigations of itacitinib’s effect on CAR T-cell expansion and function are ongoing.

Dr Maziarz reports serving as an advisor or consultant for Artiva, CRISPR Therapeutics, Incyte Corporation, Allovir, and Novartis; providing research support for Bristol-Myers Squibb, Orca Biotech, and Novartis; and participating in data and safety monitoring boards for Novartis, Athersys, Vor Pharmaceuticals, and Century Therapeutics.

Frigault M, Maziarz R, Park J, et al. Itacitinib for the prevention of immune effector cell therapy-associated cytokine release syndrome: results from the phase 2 Incb 39110-211 placebo-controlled randomized cohort. Presented at: EBMT 50th Annual Meeting; April 14-17, 2024. Glasgow, Scotland. Abstract OS6-04.

Prophylactic itacitinib, a JAK1 inhibitor, was well tolerated and significantly reduced the incidence and severity of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) in lymphoma patients treated with axicabtagene ciloleucel (axi-cel). The phase 2 trial demonstrated lower rates of grade 2 or higher CRS and ICANS in the itacitinib arm compared to placebo. Despite higher incidences of grade 3/4 neutropenia and thrombocytopenia with itacitinib, the overall response rates were comparable between the two groups, indicating no impairment of CAR T-cell therapy efficacy.

Itacitinib prophylaxis showed signals for reducing CRS and ICANS following treatment with axicabtagene ciloleucel in patients with B-cell lymphoma. 

Prophylactic Itacitinib May Safely Mitigate CRS Following Axi-Cel Administration in Lymphoma

The regulatory T cell enriched donor cell therapy Orca-T proved to be a safe and feasible alternative to conventional transplant for patients with advanced hematologic malignancies in the reduced intensity conditioning setting, according to findings from a phase 1 study (NCT05088356) presented during the 

At the December 1, 2023, data cutoff, at a median follow-up of 9.65 months (range, 1.0-22.6), interim results from the study demonstrated that patients who received Orca-T cell therapy in combination with reduced intensity conditioning and tacrolimus (n = 20) achieved a 12-month relapse-free survival rate of 77% (95% CI, 49%-91%); notably no surviving patients experienced disease relapse and 4 patients died. Four patients developed acute or late acute onset grade II to IV graft-versus-host disease (GVHD), no patients developed acute or late acute onset grade III to IV GVHD, and 1 patient developed moderate to severe chronic GVHD.

“Reduced intensity conditioning allogenic bone marrow transplant remains the only curative option for older/unfit patients with hematological malignancies,” Alejandro Villar-Prados, MD, PhD, a hematology and oncology fellow at Stanford University School of Medicine in Palo Alto, California, and coauthors wrote in a poster presentation of the trial. “Orca-T cell therapy is a viable approach in the reduced intensity conditioning setting for patients with hematological malignancies, with robust engraftment and no new safety signals identified.”

The single-center, open-label feasibility and safety study enrolled patients who were 18 to 75 years old with histopathologically-confirmed acute myeloid, lymphoid, or mixed phenotype leukemia in complete remission (CR) or CR with incomplete hematologic recovery (CRi) or beyond first complete remission without the presence of minimal residual disease (MRD). Patients could not have disease in morphologic CR with bone marrow infiltration by leukemic blasts of 10% or less, or in morphologic CR with evidence of MRD positivity. Patients with primary refractory acute myeloid, lymphoid, or mixed phenotype leukemia, chronic myelogenous leukemia, myelodysplastic syndromes, or myeloproliferative syndromes were also eligible.

The study was divided into arms A1 (n = 11), A2 (n = 7), and C (n = 2). All patients received fludarabine 40 mg/m

 on days -7 to -4, total body irradiation of 2 Gy on days -3 to-2, andtacrolimus 5 to 10 ng/mL following day 3. Patients in arm A1 also received melphalan 50 mg/m

 on day -7, patients in arm A2 received thiotepa 10 mg/kg on day -7 to -6, and patients in arm C received thiotepa 10mg/kg on day -7 to -6 as well as mycophenolate 1000 mg after day 4. On day 0, all patients were treated with a hematopoietic stem and progenitor cell infusion of 1.5 to 5.8 x 10

 cells/kg and Treg infusion of 2 to 3 x 10

 cells/kg followed by Tcon infusion of 2 to 3 x 10

The coprimary end points were GVHD-free RFS following hematopoietic cell transplantation, overall survival (OS) post-HCT, incidence of grade III to IV acute GVHD, incidence and timing of primary graft failure, and donor CD3 chimerism at day 60-plus post-HCT. Secondary end points included OS, GVHD-free RFS, secondary graft failure, treatment-emergent adverse effects, any-grade acute GVHD, and disease-free survival, among others.

At baseline, the median age in the overall population was 68 years (range, 65-72) and the median Karnofsky performance score was 90% (range, 70%-100%). Most patients were male (70%) and the medianhematopoietic cell transplantation comorbidity index was 3.0 (range, 0-5). The study included patients with acute myelogenous (n = 11), acute lymphoblastic (n = 2), and mixed phenotype acute (n = 1) leukemias, as well as patients with myeloproliferative neoplasms (n = 3) and myelodysplastic syndrome (n = 3). All patients with acute leukemia were in CR or CRi.

Additional findings from the trial revealed that the median CD15 donor chimerism was 100% (range, 99%-100%) at day 30 and 100% (range, 98%-100%) at day 90. The median CD3 chimerism was 98% (range, 40%-100%) and 99% (range, 78%-100%), respectively. The median day of neutrophil and platelet engraftment was 14.5 (range, 9-35) and 19 (range, 14-70), respectively; 2 patients required a CD34-plus boost as well.

Further, safety data showed that 6 patients developed grade 3 or higher infections in the first 90 days following transplant, including bacteremia (n = 3), viremia (n = 1), and fungal pneumonia (n = 2). Two patients died from severe infections and there were also 2 cases of hepatic sinusoidal obstruction.

Villar-Prados A, Sutherland K, Negrin R, et al. Phase I trial results for patients with advanced hematological malignancies treated with ORCA-T cell therapy with reduced intensity conditioning and single agent tacrolimus

Presented at: EBMT 50th Annual Meeting; April 14-17, 2024. Abstract A121.

Reduced intensity allogeneic HCT in advanced hematologic malignancies w/​T-Cell depleted graft. ClinicalTrials.gov. Updated February 20, 2024. Accessed April 15, 2024. https://clinicaltrials.gov/study/NCT05088356

The regulatory T cell enriched donor cell agent Orca-T was safe and displayed activity in the reduced intensity conditioning setting for patients with advanced hematologic malignancies. 

Orca-T Proves Safe and Effective in Advanced Hematologic Malignancies

Simulation-based education can improve health care professionals’ understanding of the treatment of patients with CAR T-cell therapy and elevate confidence and preparedness levels regarding patient care across health care disciplines, according to a presentation given at the 

A simulation-based education initiative that aimed to improve the confidence and competence of undergraduate and postgraduate health care professionals at St George’s who treat patients receiving CAR T-cell therapy at the St George’s Advanced Patient Simulation and Skills Centre in London, United Kingdom, significantly improved health care professionals’ understanding of the pathway of patients who receive CAR T-cell therapy. The results showed Likert survey responses of 1.60 before participation in the course vs 3.76 after course participation (

“As a simulation and skills center, we have extensive experience over the past 20 to 25 years of both developing new courses to help multidisciplinary team members and health care professionals improve their skills, as well as delivering well-established courses like advanced trauma life support,” Jack Gallagher, anesthetics trainee and simulation fellow at St George’s University Hospitals NHS Foundation Trust in London, said in the presentation.

CAR T-cell therapy is associated with risks and life-threatening toxicities, such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). According to the 2021 Best Practice Recommendations of the EBMT, JACIE, and EHA, early recognition of these adverse effects, as well as comprehensive multidisciplinary team involvement that includes intensive care unit (ICU) and neurology specialists, are crucial for delivering safe and effective care and improving outcomes of patients receiving CAR T-cell therapy.

Accordingly, Gallagher and colleagues conducted a multistage educational platform consisting of a learning needs analysis, intervention design and delivery, and evaluation of the intervention.

 The learning needs analysis first comprised semistructured focus group interviews with key stakeholders at St George’s, from which the investigators identified the learning needs of multidisciplinary team members at the center. Those needs were compiled in a formal thematic analysis that was used to design a 1-day simulation-based course that was designed to follow a patient through the CAR T-cell therapy process, from CAR T-cell center admission and receipt of therapy to discharge from the center. Course participants consisted of a range of multidisciplinary team members, including doctors, nurses, allied health professionals, and pharmacists. Participants were given a 1-hour lecture consisting of an overview of CAR T-cell therapy, its associated toxicities, and general care of patients receiving this therapy.

After the lecture, participants gained hands-on experience through 4 simulation-based sessions that used trained actors and high-fidelity mannequins to simulate communication situations and CAR T-cell therapy–associated toxicities. In simulation 1, participants followed a patient through CAR T-cell center admission and shared information with the patient. In simulation 2, participants cared for a deteriorating patient experiencing grade 1/2 CRS or ICANS. In simulation 3, participants cared for a critically unwell patient in the ICU experiencing severe CRS or ICANS that required collaboration with neurology and ICU colleagues. In simulation 4, participants communicated with the patient regarding discharge from the CAR T-cell center and addressed some of the patient’s psychosocial and holistic needs.

“Some of the unique advantages of this are that participants come from different backgrounds and can learn from each other in a safe and supportive environment,” Gallagher emphasized in the presentation.

A total of 48 health care professionals participated in this course over 3 days, 42 of whom completed Likert surveys before and after course participation. Likert scores ranged from 1, meaning not at all, to 5, meaning very, in response to questions regarding participants’ preparedness, understanding of resources, understanding of the patient pathway, and confidence.

In addition to the observed improvement in participant understanding of the CAR T-cell patient pathway, these survey results also demonstrated improved mean Likert scores regarding confidence when treating patients using CAR T-cell therapy (pre-course, 1.36 vs post-course, 3.38; 

< .001), self-assessed preparedness when treating patients (1.71 vs 3.76; 

< .0010), and understanding of the availability of relevant resources to help treat patients using CAR T-cell therapy, including nationally and internationally available guidance, as well as local protocols and resources (1.43 vs 3.76; 

An expanded version of the course is planned to take place regionally throughout London.

“The feedback we’ve had from participants and from colleagues working on the shop floor at our center has been really positive,” Gallagher concluded in the presentation. “This [course] is unique in terms of the opportunities it provides our colleagues at our center and in centers around London to develop their skills in a safe place and to translate some of the knowledge which they’ve already been obtaining from online materials and lectures they’ve attended and try to put them into practice.”

Gallagher J, Fernando A, Sureshkumar S, et al. Interprofessional simulation-based education at a new CAR T centre: the CARTELS approach. Presented at: EBMT 50th Annual Meeting; April 14-17, 2024. Glasgow, Scotland. Abstract OS02-05.

Hayden PJ, Roddie C, Bader P, et al. Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA). 

. 2022;33(3):259-275. doi:10.1016/j.annonc.2021.12.003

Simulation-based education can improve health care professionals’ understanding and confidence regarding the treatment of patients with CAR T-cell therapy.

Simulations Improve CAR T-Cell Therapy Understanding and Administration Confidence

The high-precision cell therapy Orca-T plus tacrolimus may improve outcomes compared with post-transplant cyclophosphamide (PTCy)-based myeloablative conditioning (MAC) peripheral blood stem cells (PBSC) hematopoietic stem cell transplantation (HSCT) in patients with acute leukemia or myelodysplastic syndrome (MDS), according to data from a retrospective analysis presented during the 

Data from the retrospective analysis showed that the 1-year relapse-free survival (RFS) rates were 77% for patients who received Orca-T vs 62% for those treated with PTCy (HR, 0.5; 95% CI, 0.3-0.9); 1-year non-relapse mortality (NRM) rates were 0% vs 17%, respectively. Additionally, patients who received Orca-T achieved a 1-year overall survival (OS) rate of 94% whereas patients who received PTCy experienced a 1-year OS rate of 77% (HR, 0.2; 95% CI, 0.1-0.6).

“The positive impact on RFS, NRM, and OS, in addition to reduced graft-versus-host disease [GVHD] seen with Orca-T highlight the importance of identifying treatment approaches that may be beneficial across all key transplant outcomes,” Amandeep Salhotra, MD, a hematologist-oncologist as well as an associate professor in the Division of Leukemia, Department of Hematology and Hematopoietic Cell Transplantation, at City of Hope in Duarte, California, and coauthors, wrote in a poster presentation of the data.

Additionally, patients in the acute myeloid leukemia (AML)/MDS cohort achieved a 1-year RFS rate of 86% in the Orca-T group vs 63% in the PTCy group (HR, 0.3; 95% CI, 0.1-0.8); the 1-year NRM rates were 0% vs 17%, respectively. The 1-year OS rates were 100% vs 76%, respectively. Further, an analysis of the myeloid subgroup revealed that age impacted NRM rates for patients treated with PTCy; the 1-year NRM rate was 8.5% for patients 55 years or less and 24.0% for those over 55 years. In the Orca-T group, 1-year NRM rates were 0% irrespective of age.

“Identifying an allogeneic HSCT modality that can reduce GVHD, lower NRM, and increase RFS is key to improving outcomes for patients with hematologic malignancies. Recently, the [use] of PTCy as prophylaxis against GVHD has increased; however, PTCy-based HSCTs after MAC may be associated with higher toxicities requiring prolonged hospitalization, NRM, and relapse at 1 year,” study authors explained.

The study included data obtained from the Center for International Blood and Marrow Transplant Research on patients who underwent transplantation from 2011 to 2018. Patients over the age of 18 who had GVHD prophylaxis with PTCy and calcineurin inhibitor/mycophenolate mofetil, and MDS or AML/acute lymphoblastic leukemia (ALL) in first or second complete response were included in the analysis. Additionally, matched unrelated donors who were treated with myeloablative conditioning and a GCSF-mobilized PBSC allograft between 2015 and 2018 were included.

Patients who comprised the Orca-T arm of the analysis were over 18 years of age with MDS, AML, ALL, or mixed-phenotype acute leukemia in CR/CRi; they received Orca-T between 2019 and 2022 as part of a multicenter phase 1b single-arm trial (NCT04013685) and had an 8/8 matched unrelated donor or matched related donor.

Orca-T treatment was comprised of MAC with single-agent prophylaxis using tacrolimus from day -10 to -2 followed by HSPC Tregs and Tcons and the post-transplant period. The HSPC Tregs infusion was administered on day 0 at a cell dose of 3e6 Treg/kg and vein to vein time was less than 72 hours; Tcons were given via infusion on day 2 at a cell dose of 3e6 Tcells/kg. Tacrolimus monotherapy was then administered on day 3 at a target dose of 5 to 10 ng/mL. Study authors noted that methotrexate, PTCy, or additional immunosuppressive therapies were not given with Orca-T.

Patients included in the study who received T-cell replete graft plus PTCy/CNI/MMD (n = 83) were a median age of 52 years (range, 18-71) compared with 49 years (range, 20-65) for those in the Orca-T and tacrolimus arm (n = 111). Most patients in both arms were male (51% vs 53%), all received MAC, and the median follow-up time was 12 months vs 17 months, respectively. Primary disease sites consisted of ALL (26.5% vs 33.3%), AML (49.4% vs 45.9%), MDS (24.1% vs 15.3%), chronic myeloid leukemia (0.0% vs 3.6%), and mixed-phenotype leukemia (0.0% vs 1.8%) in the PTCy vs Orca-T groups. Additionally, all patients in the PTCy arm had an unrelated donor compared with 49.5% in the Orca-T arm.

Furthermore, in the AML/MDS cohorts, the median age among patients who received T-cell replete graft plus PTCy/CNI/MMD (n = 61) was 57 years (range, 20-71) compared with 54 years (range, 20-64) for those in the Orca-T and tacrolimus arm (n = 48). Patients had AML (67.2% vs 77.1%) or MDS (32.8% vs 22.9%), most patients in both arms were male (51% vs 52%), and all received MAC, respectively. Additionally, all donors were unrelated in the PTCy arm vs 42% in the Orca-T arm.

Study authors noted that longer-term data will aid in determining the differences in clinical outcomes and a randomized phase 3 trial (NCT05316701) evaluating Orca-T vs. standard allogeneic HSCT is currently ongoing.

Salhotra A, Arteaga AG, Oliai C, et al. A retrospective analysis comparing ORCA-T to post-transplant cyclophosphamide based allogeneic hematopoietic stem cell transplant in patients with matched unrelated donors receiving myeloablative conditioning. Presented at: EBMT 50th Annual Meeting; April 14-17, 2024. Abstract A107.

Orca-T demonstrated positive impacts on relapse-free survival and overall survival vs PTCy-based HSCT in acute leukemias and myelodysplastic syndrome.

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