Doris M. Ponce, MD
Memorial Sloan Kettering Cancer Center

More than 30,000 attendees recently gathered, virtually and in person, in Atlanta, Georgia, for the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition to discuss the latest research, insights, and innovations in the diagnosis and treatment of hematologic diseases. This year’s conference included more than 3000 abstracts that were accepted for oral and poster presentations representing important novel research in the field.
Doris M. Ponce, MD, a hematologic oncologist from Memorial Sloan Kettering Cancer Center (MSKCC) in New York, provided insight into and key takeaways from research on graft-vs-host disease (GVHD) presented at the meeting. Dr Ponce is a board-certified hematologist and oncologist with expertise in using hematopoietic stem cell transplantation (HCT) to treat adults with hematologic malignancies.

Among the studies presented on GVHD at this year’s meeting, which abstracts did you find most interesting or clinically impactful?

Several notable studies were presented. The first I found interesting was a study reporting negative findings on the use of extracorporeal photopheresis (ECP) for the prevention of GVHD in patients treated with allogeneic HCT ( Identifier: NCT03204721).1 The study was the first randomized controlled trial on the use of ECP in this manner. The investigators found no significant differences in the number, type, extent of organ involvement, or severity of GVHD between the intervention group, which received ECP, and the control group. The findings suggest that ECP is not a strategy we should pick for the prevention of GVHD.
The open-label pilot study of itacitinib with haploidentical peripheral blood allogeneic HCT for prevention of GVHD and cytokine release syndrome was also important ( Identifier: NCT03755414).2 As we increase the use of post-transplant cyclophosphamide and conduct more haploidentical transplants, itacitinib may be promising in this particular context. The data showed that itacitinib with peripheral blood allogeneic HCT was safe with prompt engraftment and no engraftment failure. Rates of acute and chronic GVHD were low, and no episodes of severe cytokine release syndrome were observed. The findings were an important addition for the prevention of GVHD in general.
Also, a pilot study was presented on the use of ruxolitinib for primary or secondary myelofibrosis ( Identifier: NCT03427866).3 This was interesting because there was some signal that ruxolitinib had a role in preventing GVHD. Among 26 patients with myelofibrosis who were treated with ruxolitinib therapy before, during, and after allogeneic HCT, no grade 4 acute GVHD was reported; only 1 case of grade 3 acute GVHD, no severe chronic GVHD, and only 1 case of moderate chronic GVHD occurred.
One of the novel approaches that I liked was the joint Center for International Blood and Marrow Transplant Research/European Society for Blood and Marrow Transplantation (CIBMTR/EBMT) study of haploidentical vs matched unrelated donor transplant using post-transplant cyclophosphamide (PTCy) for the treatment of lymphoma.4 The study showed that patients with lymphoma receiving PTCy following HCT from a matched unrelated donor had better outcomes than patients with haploidentical donors overall, and there was no increased signal of relapse, which was also important. This suggests that in the future, we might be changing our practice and making PTCy the standard of care. Although this study did not establish practice changes, leaving the standard of care as calcineurin inhibitors and methotrexate, it does bring PTCy up to the plate, especially in cases in which the traditional combination may not be suitable for the patient. This was an important contribution.
Four more studies were particularly noteworthy: a study on mesenchymal stromal cells plus anti-CD25 antibody and calcineurin inhibitors for steroid-refractory GVHD5; a fecal microbiota transplant study of MaaT0136; a phase 1/2 trial of axatilimab in patients with chronic GVHD who were heavily pretreated, which was an early study that demonstrated that axatilimab is safe and that there is a signal for efficacy, so expanding this novel agent to phase 3 clinical trials makes sense7; and the phase 2 trial of abatacept in steroid-refractory chronic GVHD.8 Abatacept recently received approval from the US Food and Drug Administration (FDA) as the first drug for prevention of acute GVHD, making the presentation of this phase 2 study exploring the use of abatacept in chronic GVHD very timely.

It is a very exciting time in chronic GVHD with the recent approval of medications; we now have ibrutinib, ruxolitinib, and belumosudil for chronic GVHD. Going forward, I anticipate more customization of treatments.

One of the studies you and your colleagues conducted and presented at ASH 2021 focused on the role of the microbiome and its interaction with T cells in GVHD.9 Can you comment on the findings of this study and other notable studies on the microbiome in GVHD?

I am interested in the gut microbiome in general. There are data demonstrating the importance of the microbiome from the early post-transplant setting and onward. These data show that many factors can influence the microbiome, and patients who have GVHD tend to have worse or more disrupted microbiomes.10 There appears to be a signal of protection if the microbiome is better preserved rather than disrupted. We define what we consider to be a “healthy” microbiome as one that is composed of a diverse array of predominantly anaerobic organisms coexisting with each other. When we see monodomination of an organism, particularly one that is predominantly aerobic in its metabolism, that microbiome is not considered healthy. The output from metabolic pathways of organisms making up the microbiome is important. For example, in a microbiome that we consider healthy, short-chain fatty acids are produced, and these short-chain fatty acids appear to interact with the gut epithelium to stimulate epithelial regeneration. They also increase local colonic regulatory T cells, which increases tolerance.11 This leads us to many hypotheses about how manipulation of the microbiome may improve patient outcomes.
In the study presented by Hana Andrlova, MD, of MSKCC, we found that after reconstitution of protective unconventional T-cell populations by allogeneic HCT, mucosal-associated invariant T cells (MAIT) and the Vδ2 subset of γδ T cells were dependent on a diverse microbiome and were associated with favorable allogeneic HCT outcomes.9 The MAIT and Vδ2 T cells showed cytotoxic/effector transcriptional profiles in post-transplant samples from patients with good outcomes compared with healthy donors. Additional studies are needed to determine the functional contributions of these cells; for example, whether these cells are controlling pathogenic bacteria or alloreactive T-cell subsets in the post-transplantation setting.
I found the HERACLES study ( Identifier: NCT03359980) of MaaT013 in steroid-refractory GVHD interesting because one of the major limitations when conducting microbiome or fecal transplant is using a “blind” donor.6 We typically do not know the content of the fecal sample until after the transplant has been done. This is because fecal transplant is a time-sensitive treatment, and the microbiome analyses take time to yield results. We usually try to recruit family members, friends, or other people who are close to the patient to be fecal donors. Thus, batch-to-batch variability across patients could partially explain why some patients respond after fecal transplant while others do not. The HERACLES trial evaluated the efficacy and safety of MaaT013 — a standardized, microbiome biotherapeutic developed from a pool of donors that is formulated to be delivered via enema — in 24 patients with grade 3 to 4 steroid-refractory gastrointestinal (GI)-acute GVHD. The trial also included an expanded access program in which 52 patients with steroid-dependent or steroid-refractory GI-acute GVHD were treated with MaaT013. All patients received this pooled-donor transplant (MaaT013), and batch-to-batch variability was decreased. The patients with GVHD could achieve response. At 28 days, the overall GI response rates were 38% and 60% in the HERACLES trial and the expanded access program, respectively, and the study reported that this clinical benefit appeared to positively affect 12-month overall survival (44% and 62%, respectively).

Are there other notable up-and-coming biotherapeutics for prevention of GVHD?

In MSKCC, we have an oral capsule that is in a multicenter study (at MSKCC and the University of Chicago; Identifier: NCT04995653). The biotherapeutic is not a fecal sample per se; it is a capsule compounded of bacteria that have been selected on the basis of their properties. Every patient will get exactly the same microbiome therapeutic capsule before HCT and after engraftment. An optional course will be provided if the patient is receiving a broad-spectrum antibiotic after transplant. The idea is to try to enhance recovery of the patient’s microbiome. This clinical trial is under way, and we hope to see promising results.

Were any notable advances in supportive care for patients with GVHD reported at ASH 2021?

Validation of a machine-learning grading system for acute GVHD was presented by the EBMT Working Party Committee.12 This grading system will streamline how we grade GVHD and will make our data more homogeneous. A study reported failure-free survival rates with belumosudil, which was recently approved by the FDA for use in chronic GVHD. Treatment with belumosudil resulted in high failure-free survival rates compared with historical benchmarks in patients with chronic GVHD refractory to prior therapy.13 Lastly, a study of human chorionic gonadotropin for life-threatening acute GVHD showed promising results ( Identifier: NCT02525029), with a median overall survival of 1.2 years for the entire cohort, and a 2-year survival of 67% for responders and 12% for nonresponders (P <.01).14

What are the future directions and goals for the field?

I think we are trying to establish prevention and treatment for both acute and chronic GVHD. For prevention of GVHD, a lot of work needs to be done. Even though we have preventive measures, many patients still develop GVHD. We are still learning how to optimize the use of methotrexate and cyclophosphamide along with other combinations, such as those that include ruxolitinib. We need better options for prevention and PTCy will likely play an important role in that.
We are going to be moving toward more customized treatment for acute GVHD either by clinical rating or by use of biomarkers for risk stratification. For patients with standard risk, we need to minimize steroid exposure because steroids can really affect patients’ quality of life and outcomes; clinical trials are now taking that into account. There will certainly be more studies of the microbiome and GVHD and of how we might manipulate the microbiome to prevent or treat GVHD.
It is a very exciting time in chronic GVHD with the recent approval of medications; we now have ibrutinib, ruxolitinib, and belumosudil for chronic GVHD. Going forward, I anticipate there will be more customization of treatments. For example, some drugs seem to be more promising for certain organs than others. I also anticipate seeing head-to-head comparisons of treatments soon.

Key Takeaways

  • A joint CIBMTR/EBMT study showed that patients with lymphoma receiving PTCy following HCT from matched unrelated donors had better outcomes than patients with haploidentical donors. Although more studies are needed, PTCy following HCT has the potential to be practice changing.
  • Studies continue to reaffirm the role of the microbiome in GVHD; biotherapeutics, such as MaaT013, are showing promising results.
  • Future studies of GVHD will likely include minimization of steroid exposure, customization of treatment for patients with GVHD, head-to-head comparisons of treatments, and development of biotherapeutics.

This Q&A was edited for clarity and length.


Doris M. Ponce, MD, reported affiliations with CareDx, Guidepoint Global LLC, Evive Biotech, Gerson Lehrman Group, Kadmon Holdings, Inc., and Slingshot Insights.


  1. Ali MM, Gedde-Dahl T, Veierød MB, Tjønnfjord GE, Iversen PO. Role of extracorporeal photopheresis in prevention of graft-versus-host disease in patients treated with allogeneic hematopoietic stem cell transplantation: a randomized controlled trial. Presented at American Society of Hematology Annual Meeting; December 11-14, 2021. Abstract 102. 
  2. Abboud R, Gao F, Rettig MP, et al. A single-arm, open-label, pilot study of the JAK1 selective inhibitor itacitinib for the prophylaxis of graft-versus-host disease and cytokine release syndrome in T-cell replete haploidentical peripheral blood hematopoietic cell transplantation. Presented at American Society of Hematology Annual Meeting; December 11-14, 2021. Abstract 100. 
  3. Hobbs G, Kim HT, Bottoms AJS, et al. A phase II study of ruxolitinib pre-, during- and post-hematopoietic cell transplantation for patients with primary or secondary myelofibrosis. Presented at American Society of Hematology Annual Meeting; December 11-14, 2021. Abstract 169. 
  4. Mussetti A, Kanate AS, Wang T, et al. Haploidentical vs. matched unrelated donor transplants using post-transplant cyclophosphamide for lymphoma: a joint CIBMTR/EBMT study. Presented at American Society of Hematology Annual Meeting; December 11-14, 2021. Abstract 174. 
  5. Zhao K, Lin R, Fan Z, et al. Mesenchymal stromal cells plus anti-CD25 antibody and calcineurin inhibitors for steroid-resistant acute graft-versus-host disease: a multicenter, randomized, phase 3 trial. Presented at American Society of Hematology Annual Meeting; December 11-14, 2021. Abstract 260. 
  6. Malard F, Loschi M, Cluzeau T, et al. Pooled allogenic fecal microbiotherapy MaaT013 for the treatment of steroid-refractory gastrointestinal acute graft-versus-host disease: results from the phase IIa Heracles study and expanded access program. Presented at American Society of Hematology Annual Meeting; December 11-14, 2021. Abstract 262. 
  7. Lee SJ, Arora M, Defilipp Z, et al. Safety, tolerability, and efficacy of axatilimab, a CSF-1R humanized antibody, for chronic graft-versus-host disease after 2 or more lines of systemic treatment. Presented at American Society of Hematology Annual Meeting; December 11-14, 2021. Abstract 263. 
  8. Koshy AG, Kim HT, Stroopinsky D, et al. Phase II clinical trial of abatacept for steroid-refractory chronic graft versus host disease. Presented at American Society of Hematology Annual Meeting; December 11-14, 2021. Abstract 264. 
  9. Andrlova H, Miltiadous O, Dai A, et al. MAIT and Vδ2 unconventional T cells predict favorable outcome after allogeneic HCT and are supported by a diverse intestinal microbiome. Presented at American Society of Hematology Annual Meeting; December 11-14, 2021. Abstract 331. 
  10. Ilett EE, Jørgensen M, Noguera-Julian M, et al. Associations of the gut microbiome and clinical factors with acute GVHD in allogeneic HSCT recipients. Blood Adv. 2020;4(22):5797-5809. doi:10.1182/bloodadvances.2020002677
  11. Smith PM, Howitt MR, Panikov N, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341(6145):569-573. doi:10.1126/science.1241165
  12. Turki AT, Peczynski C, Penack O, et al. Validating a machine learning grading system for acute GVHD. A study on behalf of the EBMT Transplant Complications Working Party. Presented at American Society of Hematology Annual Meeting; December 11-14, 2021. Abstract 1809. 
  13. Lazaryan A, Cutler C, Yang Z, et al. Belumosudil for patients with chronic graft-versus-host disease: combined analysis of failure-free survival (FFS) in the KD025-208 and pivotal Rockstar trials. Presented at American Society of Hematology Annual Meeting; December 11-14, 2021. Abstract 3898. 
  14. Holtan SG, Ustun C, Hoeschen A, et al. Phase 2 results of urinary-derived human chorionic gonadotropin/epidermal growth factor as treatment for life-threatening acute GVHD. Presented at American Society of Hematology Annual Meeting; December 11-14, 2021. Abstract 261. 

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Reviewed January 2022