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Steroid-Resistant GvHD Responds to Novel Treatments

Carlson, Robert H.

doi: 10.1097/01.COT.0000316083.26441.8e

ATLANTA—There are no effective standard therapies yet for the 10% to 20% of allogeneic transplant patients who develop steroid-refractory graft-versus-host disease (GvHD), but data from two studies presented here at the ASH Annual Meeting describe novel approaches for effective therapy with tumor necrosis factor-alpha (TNF-alpha) plus interleukin-2 (IL-2), and pentostatin.

A third study, however, attempting to prevent GvHD with hydroxychloroquine, was negative.

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TNF-Alpha & IL-2 in Acute Disease



Researchers from the National Cancer Institute, the National Heart, Lung and Blood Institute, and the National Institute of Aging, reported an 88% response rate after patients with steroid-resistant GvHD received a regimen blocking two cytokines, TNF-alpha and IL-2.

Each is an important mediator of GvHD, but single-agent monoclonal antibody therapy against the IL-2 receptor alpha chain or TNF-alpha has had only modest activity against steroid-refractory GvHD.

Ramaprasad Srinivasan, MD, PhD, a senior investigator with NCI's Urologic Oncology Branch, described the regimen of the IL-2 blocker daclizumab and the TNF-alpha blocker infliximab.

This study began with 98 patients undergoing nonmyeloablative conditioning for peripheral blood stem cell transplant to treat a variety of hematologic diseases as well as hematologic and solid tumors.

Before transplant, patients received a reduced-intensity conditioning regimen of cyclophosphamide and fludarabine alone (80 patients) or with anti-thymocyte globulin (18 patients) to immunosuppress the host.

Cyclosporin, with either mofetil or methotrexate, was used as GvHD prophylaxis but in 16 patients the disease eventually became refractory to methylprednisolone, primarily in the lower gastrointestinal tract. The median onset was in 28 days following transplant.

“Between 30 and 50 percent of patients who develop GvHD won't respond to steroids,” Dr. Srinivasan said. “And upwards of 70 to 80 percent of the steroid-refractory GvHD patients end up dying.”

Infliximab and daclizumab in combination were given when it became evident the GvHD was not going to respond to steroids.

Patients also received a treatment unique to this regimen, aspergillus prophylaxis and empiric broad-spectrum antibiotics with a rapid reduction in the corticosteroids.

“We observed a remarkably high response rate following therapy, with 14 of the 16 patients having a complete response—88%,” Dr. Srinivasan said. “This is very different from what we see in the literature, response rates with other approaches are usually a dismal 30 to 50 percent.”

Three of the responding patients had recurrent GvHD in 30 to 45 days after treatment but all responded completely to re-treatment.

The median survival time was 230 days, versus the typical course of death within a few weeks after developing steroid refractory GvHD, Dr. Srinivasan said.

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Pentostatin in Refractory Chronic Disease

A group of patients with chronic steroid-refractory GvHD treated with pentostatin had a 50% response rate including a complete response rate of approximately 10%, reported Javier Bolaños Meade, MD, Assistant Professor of Oncology in the Division of Hematologic Malignancies at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University.

Pentostatin is a purine nucleoside analog extremely toxic to lymphocytes and has been used successfully to treat acute steroid-refractory GvHD.

“Because GvHD could be seen as a type of autoimmune disease, we believed a drug like this that creates a severe immune suppression may be useful for the treatment,” he said.

The Johns Hopkins team had published a report on treatment of steroid-refractory acute GvHD with pentostatin in April in the Journal of Clinical Oncology (2005;23:2661–2668). This new report is on a large pilot study of 52 patients with chronic GvHD who had not responded to at least two immunosuppressive regimens, including 30 days of prednisone.

The patients' median age was 40, with a range of five to 67. Treatment began with pentostatin at 4 mg/m2 every two weeks for six months. Patients with improving disease were allowed to continue pentostatin treatments at three- to four-week intervals.

Steroids were tapered early in this treatment and prophylactic antibiotics were given. At the end of three months, patients with stable or improving chronic GvHD were weaned off their medications but maintained on a calcineurin inhibitor.

Dr. Bolaños Meade said that the final results are not in yet, but among 42 patients assessable for response, 21 had some type of response—five had a complete resolution of chronic GvHD symptoms and 16 had partial responses

“In patients who are already steroid refractory this is very remarkable,” he said, adding that this was a heavily pretreated high-risk population, since some had donor lymphocyte infusion after which GvHD is usually more severe, and some had mismatched transplant.

“Even with this small group, a response rate of 50 percent is very encouraging,” he said.



Five other patients had mixed response (improvement in one organ with deterioration in another), and 16 had disease progression. Four patients died of infections.

The five complete responders were children or adolescents, and Dr. Bolaños Meade said that pentostatin may be especially beneficial to this group.

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No Benefit with Hydroxychloroquine

Hydroxychloroquine is an immunosuppressive lysosomotropic amine that interferes with antigen processing and decreases the cytokine production used to treat autoimmune disorders such as systemic lupus erythematosus or rheumatoid arthritis.

Hydroxychloroquine has previously shown activity against GvHD, but researchers conducting a randomized Phase III trial at Washington University School of Medicine in St. Louis found that adding the agent to single-agent cyclosporin A did not reduce either acute or chronic GvHD. It also did not appear to have a significant effect on relapses or survival.

Thomas Fong, MD, a hematology/oncology fellow, noted that the research team had previously conducted a positive Phase II study of hydroxychloroquine in graft-versus-host disease, which found low incidences of acute GvHD in unrelated donor transplant recipients who received prophylactic hydroxychloroquine in addition to standard GvHD prophylaxis of methotrexate and cyclosporin A (Biol Blood Marrow Transplant 2003;9:714–721).

But the data presented at the ASH meeting from a single-institution double-blind Phase III study showed no benefit for hydroxychloroquine in the prophylactic setting.

Dr. Fong reported on 95 recipients of matched sibling allogeneic peripheral blood stem cell transplantation with a fully myeloablative regimen with cyclosporin and total body irradiation who were randomized to receive hydroxychloroquine or placebo starting 21 days pre-transplant and continued for one year after transplant. Both groups of patients also received prophylactic cyclosporin A.

The new trial used a higher single-dose rate with lower total dose of total body irradiation, and did not include prophylactic methotrexate out of concern for excess toxicity.

Hydroxychloroquine was well tolerated and not associated with side effects, but the incidence of GvHD was similar or identical in both arms—acute GvHD occurred in 59% of patients in each group, and severe acute GvHD occurred in 11% of the hydroxychloroquine group and 14% of the placebo patients.

And 76% of patients developed chronic GvHD in the placebo arm, compared with 61% in the hydroxychloroquine arm.

Relapse-free overall survivals were comparable in both groups at 18 months median follow-up. “Unfortunately this was a negative study,” Dr. Fong said. “We saw no difference in relapse-free survival or overall survival. But it's important to have negative studies, too.”

© 2006 Lippincott Williams & Wilkins, Inc.
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