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Fresh Strategies Aimed at Taming GVHD

Gina Battaglia, PhD
Published: Tuesday, Sep 20, 2016
Gary Schiller, MD

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.

“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.

Selective Targeting of T-Cell Activation

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.


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