Fresh Strategies Aimed at Taming GVHD

Gary Schiller, MD

For the past 30 years, standard treatment for both acute and chronic graft-versushost disease (GVHD) has focused on corticosteroid regimens that are often ineffective and lead to disabling side effects or mortality.

“Therapies for graft-versus host-disease can induce a response but render the patient so immunocompromised that they die of opportunistic infection,” said Gary Schiller, MD, director of the Bone Marrow/Stem Cell Transplantation Program and professor of Hematology-Oncology at the UCLA David Geffen School of Medicine, and a spokesperson for the American Society of Hematology. Now, the FDA has granted breakthrough therapy designations for ruxolitinib (Jakafi) and ibrutinib (Imbruvica) for treatment of steroid-refractory acute and chronic GVHD, respectively, based on promising early data. If these targeted therapies continue to perform well in prospective clinical trials, they could introduce a new paradigm for less toxic, more effective therapies—a “huge area of need,” according to Steven Z. Pavletic, MD, MS, senior clinician, Experimental Transplantation and Immunology Branch and Head, Graft-versus-Host and Autoimmunity Section, Center for Cancer Research at the National Cancer Institute.

Pavletic said that an improved understanding of the pathophysiology and standardization of the disease description with consensus guidelines played an important role in the identification of ruxolitinib and ibrutinib and will likely help facilitate discovery of novel therapies, optimization of prophylactic regimens prior to hematopoietic stem cell transplantation, and identification of biomarkers that predict risk for GVHD and/or the likelihood of responding to therapy.

Selective Targeting of T-Cell Activation

“Overall, we are better positioned to further understand the biology and identify the role of new pharmacologic interventions and how they can intersect with the pathogenesis of chronic GVHD,” said Pavletic.Acute GVHD presents an inflammatory phenotype, usually within the first few months of allogeneic stem cell transplantation, on the skin, liver, and gastrointestinal tract.

Ferrara and colleagues described a 3-step pathogenic process¹ that begins with tissue damage initiated by the underlying disease and the pretransplantation conditioning regimen, which causes release of proinflammatory cytokines and other molecules.

Second, activation of donor T cells occurs after transplantation in response to recipient antigens on host antigen-presenting cells (APCs), which leads to proliferation and differentiation of various T-cell subtypes. The T cells travel to target organs, where they cause tissue destruction and recruit cytokines and other inflammatory cells to propagate GVHD.

However, allogeneic transplantation for malignant conditions also relies on activation of donor T cells in response to residual tumor antigens (known as a graft-versus-leukemia effect) to prevent recurrence of the malignancy. Therefore, preventing and treating GVHD while maintaining the intended graft-versus-tumor effect has been challenging, according to Kenneth R. Cooke, MD, director of the Kimmel Cancer Center’s Pediatric Bone Marrow Transplantation Program at Johns Hopkins School of Medicine in Baltimore.

“I’ve been doing this for 20 years, and we’re still trying to come up with new treatments and prevent GVHD but still maintain the graft-versustumor effects,” said Cooke. “That’s the Holy Grail.”

Conditioning regimens for patients undergoing stem cell transplantation for malignant disorders are used to achieve sufficient immunoablation to prevent graft rejection and to reduce tumor burden. Early research shows that broad T-cell depletion is commonly performed and is effective for preventing acute GVHD, but may increase the risk for delayed immune reconstitution, infection, graft failure, and relapse.² Calcinurin inhibitors (such as cyclosporine and tacrolimus), methotrexate, and/or mycophenolate mofetil are frequently used posttransplantation to attenuate T-cell activation.

Schiller noted that delineation of the donor T-cell activation process following transplantation has been instrumental for developing new prophylactic regimens that allow effective immune reconstitution and maintenance of graft-versus-tumor effects while selectively manipulating activated T cells that contribute to GVHD.

A 2015 study³ showed that a preconditioning regimen with total lymphoid irradiation and antithymocite globulin (ATG) yielded a low incidence of GVHD and durable remission from lymphoma, suggesting a benefit of ATG in combination with high-intensity conditioning regimens.

Cooke also described the use of cyclophosphamide posttransplantation, first introduced at Johns Hopkins, to selectively target proliferating, alloreactive T cells over nonproliferating, nonalloreactive T cells and preserve stem cells. In his experience, giving 2 doses of cyclophosphamide after transplantation has helped control rates of acute and chronic GVHD in his patients, even in those who receive a graft from a donor partially matched for human leukocyte antigen (HLA) type. However, one study showed an increased incidence of acute GVHD and worse overall survival with posttransplantation cyclophosphamide after reduced-intensity conditioning in patients with HLA-matched bone marrow transplantations than with historical controls who received tacrolimus-methotrexate prophylaxis. ⁴ Thus, further research may be needed to identify patient populations, graft types, and conditioning regimens that would benefit from inclusion of cyclophosphamide.

A Role for Dysregulated B-Cell Signaling Unlike acute GVHD, chronic GVHD often develops several months after transplantation and demonstrates a fibrotic, autoimmune syndrome that can affect multiple organs, including the skin, liver, GI tract, lung, eyes, joints, and genitourinary tract in women. Describing the pathophysiology of chronic GVHD has been difficult due in part to the complexity of the condition and inadequacy of animal models.

Chronic GVHD has been shown to involve dysregulation of alloreactive antibodies, B cells, conventional T cells, and T-regulatory cells, but the relationships between these and other cells and subsets (such as APCs, autologous and allogeneic antigens, and inflammatory mediators) need to be clarified to further target prophylaxis and treatment of chronic GVHD.

Recent recognition of dysregulated B-cell signaling in pathogenesis of chronic GVHD has been particularly instrumental for identifying targets for prophylaxis and treatment. In a 2005 study, David Miklos, MD, PhD, clinical director of Cancer Cell Therapy and medical director of Stanford Cellular Therapeutics and Transplantation Laboratory at Stanford University, and his colleagues showed that the incidence of chronic GVHD was higher with female-to-male transplantation due to female donor B cells creating antibodies against Y-chromosome-encoded proteins.⁵

This study was among the first to introduce the role of B cells in the pathogenesis of chronic GVHD and led to a follow-up study that showed rituximab, a monoclonal antibody against the CD20 protein on B cells, led to a 70% clinical response rate and decreased the required dose of corticosteroids in patients with steroid-refractory chronic GVHD.⁶ Although a retrospective analysis⁷ showed a lower incidence of acute GVHD (a key risk factor for chronic GVHD) in patients who received rituximab pre- or posttransplantation, prospective studies investigating rituximab for prevention of acute GVHD have not been performed.

Two prospective phase II trials suggest rituximab prophylaxis may decrease chronic GVHD incidence, and Corey S. Cutler, MD, MPH, of the Dana-Farber Cancer Institute, is currently leading an NCI-sponsored, multisite, randomized, placebo-controlled clinical trial testing whether the anti-CD20 drug obinutuzumab (Gazyva) will prevent or decrease GVHD.

Pavletic also noted that guidelines from the National Institutes of Health (NIH) consensus conference, which published its first set of recommendations in 2005 and an updated version in 2014, have improved description, standardization, and taxonomy of acute and chronic GVHD. Along with the development of improved animal models that better represent the human condition, these guidelines have helped clarify the pathophysiology of chronic GVHD that starts with acute inflammation and injury of multiple tissues (notably the thymus) that occurs with conditioning and transplantation, followed by a state of chronic inflammation and disordered reconstitution of the immune system that often leads to fibrosis in multiple tissues.

Foundation for Targeted Therapies

Ruxolitinib

“On the clinical level, we are able to recognize the inflammatory, fibrotic, or autoimmune presentations,” said Pavletic. “Right now, studies need to be done to answer the question of whether different clinical types have distinct immunologic pathways or whether all have an initial triggering factor.”Although the understanding of the pathophysiology has improved dramatically over the past several years, FDA-approved treatment for GVHD is limited to corticosteroids. Patients who become steroid-refractory have limited treatment options that are often ineffective, according to Schiller. Additionally, long-term steroid use can cause severe immunosuppression that leads to life-threatening opportunistic infections. “Most of my patients don’t die of GVHD. They may even get a response [to corticosteroid therapy], but they die of secondary infections later on,” said Schiller. Pavletic noted that development of the NIH consensus conference has helped facilitate initiation of clinical trials by developing clinical guidelines for diagnosis and staging, pathology, biomarkers, therapeutic response, supportive care, and clinical trial design. “The recommendations…allowed testing of the proliferating and expanding knowledge of the biology and technology, as well as the ability to generate new molecules that intersect with the pathophysiology,” he said.Early retrospective data suggest that ruxolitinib could be an effective therapy for both acute and chronic GVHD. Ruxolitinib selectively inhibit Janus kinase (JAK) 1 and 2, which are central signaling molecules in cytokine receptor cascades and mediate naïve T-cell homing. The drug is currently approved in myelofibrosis and polycythemia vera. A retrospective analysis⁸ showed that 44 of 54 (81.9%) patients with severe (grades 3 or 4) acute steroid-refractory GVHD and 35 of 41 (85.3%) patients with moderate to severe chronic steroidrefractory GVHD responded to ruxolitinib.

Another analysis9 of ruxolitinib for second- to fifth-line salvage therapy for chronic GVHD showed complete resolution of clinical manifestations in the lungs, mouth, skin, liver, musculoskeletal system, and gastrointestinal tract, as well as subjective improvement in sclerodermatous and ocular chronic GVHD.

Ibrutinib

Even though the therapeutic responses from both studies appear promising, Pavletic noted that the drug is frequently prescribed off-label and reimbursed by insurance companies even though phase III clinical trials have not begun, which may interfere with the performing of timely, formal, and controlled clinical trials that provide an accurate assessment of the drug’s benefits and risks.Although the early research by Miklos and colleagues on rituximab suggested that specific anti-B cell therapy may benefit patients with chronic GVHD, rituximab was not able to fully treat or eliminate allogeneic B-cell responses with chronic GVHD, thus prompting his search for more potent and different schedules of anti-B cell therapies.

Ibrutinib, a novel inhibitor of Bruton tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK), was initially approved for mantle cell lymphoma in 2013 and subsequently for chronic lymphocytic leukemia and Waldenström macroglobulinemia. Miklos and colleagues investigated ibrutinib in patients with steroid-refractory, steroid-dependent GVHD.

Preliminary results of a phase I/II trial investigation, ¹⁰ presented at the 2016 European Bone Marrow Transplant meeting in Valencia, Spain, showed an overall response rate of 55% and a 35% reduction in steroid dose. Serum biomarker analysis also showed reductions in levels of B-cell activating factor (BAFF) and T-cell activation, supporting previous research in murine models that ibrutinib targets both B and T cells.

Minimizing Risk Factors for GVHD

“It creates a unique phenotype in the T-cell population where it protects cytotoxic T cells that are Th1 CD8-positive, but decreases the Th2-CD4 cells,” said Miklos. “Here is an example of a drug that has targeted these two pathways and is fairly well tolerated. That’s what the excitement is about.” Prospective clinical trials of its efficacy and safety are ongoing. Furthermore, the anticancer effects of ibrutinib could potentially reduce risk for recurrence of the underlying malignancy and introduce a treatment paradigm for testing certain anticancer agents for treatment of chronic GVHD, according to Pavletic. “With these new possibilities for pharmacologic interventions, maybe we can have a [therapy that produces a] double benefit,” he said.Much of the recent research focuses on therapeutic agents for GVHD, but most researchers agree that prevention of the disease would be ideal. A report from the Center for International Blood and Marrow Transplant Research (CIBMTR) showed an increase from 1995 to 2007 in the proportion of patients that developed chronic GVHD within 1 year of an allogeneic transplant for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or myelodysplastic syndrome (MDS).¹¹

Multivariate analysis also revealed that the risk for chronic GVHD was higher with a bone marrow graft from an unrelated donor or peripheral blood graft from related or unrelated donor than with a bone marrow graft from a HLA-identical sibling. Pavletic noted that the increased incidence of chronic GVHD during this time period corresponded to a substantial expansion in the utilization of allogeneic transplantation for cancer, as well as improvements in survival within the first 100 days of transplantation.

While data on current incidence of GVHD have not been published, he predicted that refinements in preconditioning regimens, expanding the donor pool to increase likelihood of finding an HLA match, and identifying biomarkers that predict risk for GVHD and response to therapy would help reduce incidence of GVHD.

Cooke emphasized that selecting a perfectly matched donor, while ideal in theory, may be impractical particularly for patients with ethnic backgrounds that have few donor matches or those with aggressive leukemia that requires urgent transplantation. Thus, expanding the availability of alternative stem cell sources, such as umbilical cord blood and partial HLA-matched donors, while refining conditioning regimens will allow a greater number of patients to undergo transplantation with a minimal increase in risk for GVHD.

Miklos also showed that his institution’s preconditioning regimen of total lymphoid irradiation and ATG has enabled low-risk transplantation in older patients and female-to-male transplantation—2 groups typically at high risk for GVHD. “That’s the preconditioning regimen we really believe is a strong platform on which patients up to age 78 [years] can undergo an allogeneic transplant and achieve a graft-versus-leukemia benefit,” said Miklos. He indicated that this regimen may even produce better outcomes for female-to-male transplants due to an enhanced graft-versus-leukemia response.

New Directions for Prevention and Therapy Cooke emphasized that the improved understanding of how adaptive- and innatemediated immunity contribute to GVHD has been a “major breakthrough” in finding targets for prevention and treatment, and that improved use and refinement of animal models will be a continued source of new ideas for targeted therapies in the near future.

Schiller was also optimistic about the potential role of ruxolitinib and ibrutinib, but cautioned that their efficacy and safety still need to be demonstrated in a prospective randomized trial through multiple endpoints, such as rapid tapering of steroids, resolution of signs and symptoms of GVHD, reduced incidence of infection and pancytopenia, and improvement in long-term survival.

In light of recent breakthroughs in understanding of the disease process, Pavletic stated that conducting more phase I and II trials will be important to test novel agents in patients with GVHD, and that collaboration of drug sponsors, academic researchers, and referring physicians will be essential for facilitating this process. “We have a very unique opportunity to make a difference,” he said.

References

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