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Transplantation: Improved Method for Safer T-Cell Depletion in AML, New Drug Shown to Prevent Veno-occlusive Disease

Carlson, Robert H.

doi: 10.1097/
Manifestations of GvHD include interstitial and perivascular lymphocytic infiltrates

Manifestations of GvHD include interstitial and perivascular lymphocytic infiltrates

NEW ORLEANS—Among the stem cell transplant-related research reported here at the ASH Annual Meeting were studies discussed at a news conference related to defibrotide, a new drug to prevent veno-occlusive disease after transplant; and a method of safer T-cell depleted transplantation in acute myelogenous leukemia (AML).

Graft-versus-host disease (GvHD) is most effectively prevented by removing T cells from the donor's stem cells before transplantation, but it is not used frequently because of the risk of transplant rejection, infections, and leukemia relapse, along with the lack of an FDA-approved method.



Now researchers from the Blood and Marrow Transplant Clinical Trials Network, reporting on “Protocol 0303,” showed that T cell depletion and hematopoietic stem cell transplant following myeloablative chemoradiotherapy can be performed in a multicenter setting using a single extensive T cell depletion method.

The trial included 44 patients with AML in first or second remission and with a high risk of relapse; all had matched sibling donors.

Patients first received myeloablative conditioning with total body irradiation and chemotherapy, followed by the HLA-identical sibling-matched CD34+ selected T cell depleted peripheral blood stem cells for transplant.

Lead author Steven Devine, MD, Director of the Blood and Marrow Transplant Program and Associate Professor of Internal Medicine at Ohio State University Comprehensive Cancer Center, reported that the rate of GvHD was very low among the patients engrafted—20% moderate GvHD and less than 10% severe GvHD. And the risk of relapse was less than 10% in the patients in first remission.

Treatment-related mortality was less than 10% at 100 days, and less than 20% at two years’ follow-up.

The disease-free survival rate was 81% at six months, and the overall survival rate was 74% at one year.

The eight-institution trial was co-sponsored by the National Heart, Lung and Blood Institute and the National Cancer Institute.

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Goal of T Cell Depletion

The object of T cell depletion, Dr. Devine explained, is to reduce the risk of GvHD while maintaining a low risk of relapse for the transplant. The procedure in this study was done without additional post-transplant prophylaxis, with excellent disease-free survival and overall survival, consistent engraftment, low tumor-related mortality, and a low incidence of relapse even in patients with unfavorable-risk AML in first complete response

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“The low incidences of acute and chronic GvHD in the absence of post-transplant prophylaxis were particularly encouraging,” Dr. Devine said.

Importantly, he added, the results show that T cell depletion can reduce the incidence of acute GvHD without the need for immune suppression, which makes the procedure less toxic. The results also suggest that the incidence of chronic graft-versus-host disease, a quality-of-life issue, is also reduced, he said.

“So that's all rather encouraging, but obviously we need longer follow-up.”

A concern was that if the T cells were removed completely and there were no GvHD, that might increase the risk of relapse. But that might not always be the case in AML.

“Plus, we're giving the patients relatively stringent doses of total body radiation and chemotherapy, which may help prevent relapse, as well as natural killer cells that emerge after T cell-depleted transplants,” Dr. Devine said. “Those may also be responsible for keeping these patients in remission.”

Dr. Devine speculated that T cells might not even be needed if the regimen given to patients is strong enough and if these other effector cells, such as natural killer cells, are able to reduce the risk of relapse.

“We think that we can apply this approach to patients who have a sibling donor. Hopefully this will lead to an improvement in their quality of life, because none of them are on any kind of drugs that are needed to prevent graft-versus-host disease.

“And since they have a low risk of the late type of graft-versus-host disease—i.e., chronic GVHD—they may also have a better quality of life.”

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Comments from News Conference Moderator

The moderator of the news conference, Armand Keating, MD, Chairman and Director of the Cell Therapy Program at Princess Margaret Hospital in Toronto, said in an OT Broadcast News “Live from ASH” podcast interview that he considered this an important study.

“But the issue that concerns me in any T cell depletion protocol is: What is the increased probability of relapse as a result of this? Because if you deplete T cells, what you might be doing is reducing the graft-versus-leukemia effect as well as eliminating graft-versus-host disease.”

Dr. Keating said he was encouraged by the fact that this is a relatively complex manipulation that was done in the context of a multicenter clinical trial. “And the only way that could have been done was through the Blood and Marrow Transplant Clinical Trials Network,” he said.

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In another report highlighted in the transplantation news conference, a large study from Germany has shown that preemptive use of the drug defibrotide to prevent hepatic veno-occlusive disease after transplant in pediatric patients reduced the overall incidence by 40%, compared with a control group who received the drug prophylactically.

The incidence of renal failure was reduced with the treatment—1% with defibrotide vs 6% in controls, as was the overall incidence and severity of acute GvHD—32% with defibrotide vs 43% in controls.

SELIM CORBACIOGLU, MD: “Our study confirms that defibrotide is safe and effective for preventing veno-occlusive disease in this high-risk pediatric population

SELIM CORBACIOGLU, MD: “Our study confirms that defibrotide is safe and effective for preventing veno-occlusive disease in this high-risk pediatric population

Veno-occlusive disease is a life-threatening complication and one of the most common causes of death after allogeneic stem cell transplant, with a particularly high incidence in children. It is increasingly referred to as sinusoidal obstruction syndrome.

Defibrotide, an oligonucleotide, has demonstrated a protective effect on vascular endothelial cells in vitro, and small nonrandomized trials to assess defibrotide for the prophylaxis of veno-occlusive disease were promising but without significant anticoagulant effects.

In the prospective Phase II/III randomized multicenter study of defibrotide by researchers from the University of Ulm in Germany, defibrotide was assessed for safety and efficacy in the prevention of veno-occlusive disease. The study, which lead author Selim Corbacioglu, MD, said is the largest-ever international, multicenter study of high-risk pediatric patients undergoing stem cell transplants, was co-sponsored by the European Group for Blood and Marrow Transplantation.

A total of 360 high-risk patients with a median age of five were enrolled in the study (24% of whom were infants; 52%, children age 2 to 11; and 23%, adolescents age 12 to 18). All were at high risk for veno-occlusive disease because of one or more risk factors, including conditioning with busulfan and melphalan, preexisting liver disease, second myeloablative transplant, allogeneic stem cell transplantation for leukemia in second relapse, macrophage-activating syndromes, prior abdominal irradiation, prior treatment with gemtuzumab, osteopetrosis, and adrenoleukodystrophy.

Dr. Corbacioglu, Assistant Professor in the Department of Hematology/Oncology, Immunology, and Stem Cell Transplantation, said that 68% of the patients underwent allogeneic stem cell, and 31% received an autologous stem cell transplant. Patients were prospectively randomized prior to stem cell transplantation to receive either defibrotide or no preventive therapy for veno-occlusive disease.

Patients randomized to defibrotide received intravenous infusions from the start of conditioning until 30 days post-stem cell transplant or discharge from the hospital.

Patients in the control arm received no preventive therapy, but rather defibrotide at the time of a diagnosis of veno-occlusive. Preventive use of defibrotide reduced the overall incidence of veno-occlusive disease by 40% compared with the control group, Dr. Corbacioglu reported.

Both study arms had similar numbers of adverse events.

“Our study confirms that defibrotide is safe and effective for preventing veno-occlusive disease in this high-risk pediatric population,” Dr. Corbacioglu said. “Eventually this may be the new gold standard to prevent veno-occlusive disease.”

Dr. Keating said this approach, using the drug to prevent veno-occlusive disease rather than waiting to treat it when it occurs, is a substantial advance in stem cell transplantation.

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Hear More!

Steven Devine talks more about his study on T-cell depletion to avoid GVHD in AML in a “Live from ASH” OT Broadcast News podcast (Program #2) available at and on iTunes. Also commenting are George Canellos and Armand Keating.

© 2010 Lippincott Williams & Wilkins, Inc.
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