Roswell Park Transplant Specialists Explore New Strategies for Tackling GVHD

Philip McCarthy, MD

Director of Transplant and

Cellular Therapies

Professor of Oncology and

Internal Medicine

Roswell Park Comprehensive Cancer Center

Professor in the Department of Medicine

Jacobs School of Medicine

and Biomedical Sciences

University at Buffalo

Buffalo, New York

Although graft-versus-host disease (GVHD) remains a significant clinical challenge for transplant medicine specialists, recent research suggests new strategies for better predicting, addressing, and perhaps preventing this very serious adverse effect of treatment.

Presentation and Frequency

Investigators at Roswell Park Comprehensive Cancer Center in Buffalo, New York, are working on a variety of novel approaches, including developing prophylactic drug regimens, studying methods of rejuvenating the recipient’s immune system, and analyzing genetic characteristics to improve donor selection.GVHD is among the most common and significant toxicities that can occur after allogeneic hematopoietic cell therapy (allo-HCT), also known as allogeneic bone marrow transplant. Patients can develop GVHD shortly after transplant or long afterward, with symptoms ranging from mild to severe and life-threatening.

In allo-HCT, the transplantation of a suitable donor’s hematopoietic stem cells into a recipient results in the engraftment, or take, of the donor hematopoietic system. GVHD occurs for some transplant recipients after the donor cells recognize the recipient tissue as foreign, resulting in the activation of the donor’s immune system against the recipient and, in some cases, damage to normal tissue.

GVHD can occur in 30% to 60% of allo-HCT recipients; the likelihood that a patient will develop GVHD depends on several factors, including the type of donor, degree of tissue (human leukocyte antigen [HLA]) matching, and whether or not the patient is in remission. Acute GVHD usually arises within the first 100 days after transplant and typically affects the skin, gastrointestinal (GI) tract and/or liver. Chronic GVHD, meanwhile, usually occurs after day 100 post transplant.¹

Treating GVHD: Current Strategies

About 10% of allo-HCT recipients will experience severe GVHD.¹ A mild case can be a good sign that the transplant will be more successful over the long term, because patients with mild acute GVHD—especially milder chronic GVHD—are less likely to experience a cancer relapse.Several current treatment approaches aim to decrease the incidence and severity of GVHD. Corticosteroids and other immune-suppressing drugs help control the excessive immune response that can, in particular, attack the skin and GI tract during acute GVHD.

For chronic GVHD, steroids can be administered in topical creams for skin rashes, drops for eye symptoms, and mouth rinses for oral symptoms. However, high-dose corticosteroids may lead to additional adverse effects, such as muscle weakness, bone loss, and fractures, as well as increased risk of infection. Many patients with acute GVHD will receive medicines to prevent infections, and intravenous feeding can help those with severe GI GVHD regain strength. Patients using steroids long term may receive bone-strengthening medications.

Another treatment especially for chronic GVHD is photopheresis, a process in which a patient’s white blood cells are collected, exposed to a light-sensitizing drug, and treated with light therapy before being reinfused. This specialized treatment is part of standard therapy for patients with chronic GVHD at academic centers.

Table. Comparison of Conditioning Regimens for Chronic GVHD Prophylaxis²

Graft-Versus-Tumor Effect

To prevent acute GVHD during the early transplant process, investigators at Roswell Park have tested several regimens to determine whether they could improve the efficacy while reducing the toxicity of the standard approach of tacrolimus (TAC) and methotrexate (MTX) to prevent severe GVHD for patients who had received reduced-intensity conditioning before allo-HCT. They found that a regimen containing TAX, micro-dose MTX, and mycophenolate mofetil (MMF) was as effective as TAX/MTX and superior to TAC/MMF (Table).²Allo-HCT can also generate a graft-versus-tumor (GVT) effect against hematologic malignancies, whereby the donor’s immune system is activated to recognize and destroy the recipient’s cancer, primarily leukemias and lymphomas, and create a graft-versus-leukemia (GVL) effect.³ Donor T lymphocytes can cause GVHD and GVL. Removing all T lymphocytes will result in no GVHD but also no GVL—and, thus, a higher relapse rate. Decreasing the morbidity and mortality of GVHD while preserving the GVT/GVL effect is the holy grail of allo-HCT.

During the allo-HCT process, the recipient undergoes conditioning to encourage donor cell engraftment and prevent donor cell rejection by the recipient. Conditioning consists of immunosuppressive therapy to facilitate engraftment of the donor cells and some form of myeloablative or myelosuppressive therapy to eradicate or suppress recipient hematopoiesis (production of bone marrow and blood cells).

In the past, the donor and recipient needed very closely matched HLA within the major histocompatibility complex on chromosome 6, meaning that donors were usually suitably HLA-matched siblings or unrelated donors from the national Be The Match registry (bethematch.org).

Emerging Strategies

However, the development of an in vivo approach to deplete allo-reactive donor T lymphocytes using post—allo-HCT cyclophosphamide obviated the need for in vitro T-cell depletion and facilitated the widespread adoption of haploidentical, or half-matched, transplants.⁴ Thus, most patients can now find a suitable matched or half-matched donor among family members or through the Be The Match, dramatically expanding the field of potential suitable donors.Many Roswell Park investigators are assessing new treatment strategies and risk prediction models through current clinical trials.

In 2 separate clinical trials, Sophia Balderman,MD, and Christine Ho, MD, are examining the use of mobilized peripheral blood cells and tocilizumab (Actemra) with posttransplant cyclophosphamide for GVHD prophylaxis in haploidentical transplant recipients and the use of posttransplant cyclophosphamide for GVHD prophylaxis following sibling and unrelated-donor allo-HCT (NCT03333486, NCT03192397).

Our team also has developed a systematic approach to studying preclinical and clinical GVHD during allo-HCT. George Chen, MD, has a particular interest in the understanding and control of acute and chronic GVHD.^5,6 His current work includes developing both preclinical models of GVHD and strategies to enhance immune reconstitution after allo-HCT.

Our collaborator, Elizabeth Repasky, PhD, studies the role of ß-adrenergic signaling in the development and control of GVHD.^7,8 Our goals with this work are translational clinical research protocol development to investigate addressing GVHD during allo-HCT and enhancing the GVL effect.

Clinical and Research Priorities

Theresa Hahn, PhD, coleads a genome‑wide association study (GWAS) in more than 3500 patients who received an HLA-matched unrelated donor allo-HCT. Several publications have been generated from this GWAS that may lead to better donor selection, which may result in less morbidity and mortality for the recipient and improved outcomes.^9-11 This data set has also been used to validate previous genetic associations with chronic GVHD.12 Further analyses are ongoing.Four major clinical priorities that need to be addressed after allo-HCT: infection, overall toxicity, GVHD infection, and relapse. If we can minimize immunosuppression, decrease the severity of GVHD, and preserve GVT/GVL, we will decrease the complications of allo-HCT and improve the cure rate.

We are very excited to embrace these challenges with the tools and strategies that have emerged in the past several years. Although we’ve been highly encouraged to see survival following allo-HCT improving, our work is not done until we can cure every case of GVHD.

References

1. Arora M, Cutler CS, Jagasia MH, et al. Late acute and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22(3):449-455. doi: 10.1016/j.bbmt.2015.10.018.
2. Chen GL, Zhang Y, Hahn T, et al. Acute GVHD prophylaxis with standard-dose, micro-dose or no MTX after fludarabine/melphalan conditioning. Bone Marrow Transplant. 2014;49(2):248-253. doi: 10.1038/bmt.2013.167.
3. Chen GL, Liu H, Zhang Y, et al. Early versus late preemptive allogeneic hematopoietic cell transplantation for relapsed or refractory acute myeloid leukemia. Biol Blood Marrow Transplant. 2014;20(9):1369-74. doi: 10.1016/j. bbmt.2014.05.013.
4. Luznik L, O’Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14(6):641-50. doi: 10.1016/j.bbmt.2008.03.005.
5. Aurora M, Hemmer MT, Ahn KW, et al. Center for International Blood and Marrow Transplant Research chronic graft-versus-host disease risk score predicts mortality in an independent validation cohort. Biol Blood Marrow Transplant. 2015;21(4):640-645. doi: 10.1016/j.bbmt.2014.10.022.
6. Chen GL, Carpenter PA, Broady R, et al. Anti-platelet-derived growth factor receptor alpha chain antibodies predict for response to nilotinib in steroid-refractory or -dependent chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2018;24(2):373-380. doi: 10.1016/j.bbmt.2017.10.021.
7. Leigh ND, Kokolus, KM, O’Neill RE, et al. Housing temperature-induced stress is suppressing murine graft-versus-host disease through ß2-adrenergic receptor signaling. J Immunol. 2015;195(10):5045-5054. doi: 10.4049/jimmunol.1500700.
8. Mohammadpour H, O’Neil R, Qiu J, McCarthy PL, Repasky EA, Cao X. Blockade of host ß2-adrenergic receptor enhances graft-versus-tumor effect through modulating APCs. J Immunol. 2018;200(7):2479-2488. doi: 10.4049/jimmunol.1701752.
9. Hahn T, Sucheston-Campbell LE, Preus L, et al. Establishment of definitions and review process for consistent adjudication of cause-specific mortality after allogeneic unrelated-donor hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2015;21(9):1679-1686. doi: 10.1016/j.bbmt.2015.05.019.
10. Karaesmen E, Rizvi AA, Preus LM, et al. Replication and validation of genetic polymorphisms associated with survival after allogeneic blood or marrow transplant. Blood. 2017;130(13):1585-1596. doi: 10.1182/blood-2017-05-784637.
11. Zhu Q, Yan L, Liu Q, et al. Exomechip analyses identify genes affecting mortality after HLAmatched unrelated donor blood and marrow transplantation. Blood. 2018; 131(22):2490- 2499; doi: 10.1182/blood-2017-11-817973.
12. Martin PJ, Fan W, Storer BE, et al. Replication of associations between genetic polymorphisms and chronic graft-versus-host disease. Blood. 2016;128(20):2450-2456. doi: 10.1182/blood-2016-07-728063.