T-Cell Depletion Improves Transplant Outcomes in Adults With Acute Myeloid Leukemia

Roxanne Nelson

December 10, 2009

December 10, 2009 (New Orleans, Louisiana) — T-cell depletion appears to be an effective strategy for reducing the incidence of graft-versus-host disease (GvHD) in patients with acute myeloid leukemia (AML) who undergo allogeneic hematopoietic cell transplantation. The data, which were presented here at the American Society of Hematology 51st Annual Meeting, show that disease-free survival was similar to that of other transplant procedures, but with a low incidence of GvHD.

Our results are preliminary but quite encouraging.

"Our results are preliminary but quite encouraging," said lead author Steven M. Devine, MD, associate professor at the Ohio State University Comprehensive Cancer Center in Columbus. "We had high rates of engraftment, low mortality rates, and a low risk of acute and chronic graft-versus-host disease, which can affect survival and quality of life."

GvHD is a major complication of transplantation, "but traditionally, conservative T-cell depletion has increased the risk of relapse and the risk of infection," said Karen Ballen, MD, director of the Center for Leukemia, Massachusetts General Hospital, and associate professor of medicine at Harvard Medical School in Boston. Dr. Ballen was not involved in the study.

"I think, in recent years, the pendulum has swung to not doing T-cell depletion, although there are still several centers in the United States that do it preferentially," said Dr. Ballen. "We're also looking at pharmacological strategies to reduce the risk of graft-versus-host disease."

This study is interesting in that it suggests that T-cell depletion might have a role, she noted, adding that the risk for relapse was low even among patients who were at high risk.

These data could have applications outside of leukemia, Dr. Ballen suggested. "Even though this study was conducted in leukemia patients, I think the role of T-cell depletion may extend to other nonmalignant diseases, such as autoimmune disorders and genetic diseases, where we are not so concerned about relapse," she said.

T-cell depletion might also have a role in select transplant patients who are at very high risk for GvHD. "They may be getting an unrelated transplant that's mismatched, where the risk of graft-versus-host disease is prohibitively high," she said. "Undergoing T-cell depletion reduces that risk, and that may allow specific subgroups of patients to transplant more safely."

"Overall, I think this study suggests that we shouldn't close the book on T-cell depletion, as it may have a role in certain select patients," she added.

Procedure Fraught With Complications

AML is a potentially devastating disease and the majority of patients diagnosed with this disease are destined to relapse and die, especially when treated with conventional approaches, explained Dr. Devine. "For years, we've known that allogeneic transplantation has been the most effective means of preventing relapse in acute myeloid leukemia, but it can be fraught with complications."

Acute and chronic GvHD are common complications of allogeneic transplantation that affect quality of life and survival. The most effective method of preventing GvHD is with ex vivo T-cell depletion of the allograft, explained Dr. Devine, but this strategy has been limited in its use by logistical difficulties, lack of a standard method approved by the US Food and Drug Administration, and concern about the potential risk for graft rejection, posttransplant infection, and relapse.

Although T-cell depletion is not a new concept — many centers have studied it over the years — most of the studies have been single-center reports. The studies have also included different types of diseases and T-cell depletion processing methods, which can all affect outcomes, according to Dr. Devine.

The single-center reports have shown it to be an effective approach, but this could not be reproduced at a multicenter level. "We felt that one way to improve outcomes in patients with AML undergoing transplantation was to perform a multicenter trial using a uniform approach, and to remove the issue of patient selection by performing it at multiple centers," he said.

Low Incidence of GvHD and Relapse

The study was designed by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), and was cosponsored by the National Institutes of Health's National Heart, Lung, and Blood Institute and the National Cancer Institute. The result was the BMT CTN 0303 trial, which used a single processing method to provide extensive T-cell depletion that did not require posttransplant GvHD prophylaxis and included only adults with AML in first or second complete remission.

Dr. Devine and colleagues hypothesized that the undesired adverse effects of T-cell depletion in patients undergoing transplantation would be reduced if it was combined with a conditioning regimen that was highly immunosuppressive and antileukemic. The primary objective was to achieve a disease-free survival rate at 6 months posttransplant that exceeded 75%; secondary objectives included assessments of engraftment, transplant-related mortality, GvHD, relapse, and performance of a single T-cell depletion method, which was CD34+ cell selection using the Miltenyi CliniMACS device.

A total of 47 patients with AML in first or second remission were enrolled from October 2005 to December 2008. Of this group, 44 underwent transplantation at 8 different centers. Most of the cohort was in first remission (n = 37); within this subgroup, 49% had an unfavorable cytogenetic or molecular risk profile.

The conditioning regimen consisted of total body irradiation (1375 cGy in 11 fractions) with partial lung shielding, thiotepa (10 mg/kg), cyclophosphamide (120 mg/kg), and rabbit antithymocyte globulin (1.5 mg/kg). All stem cell donors were human-leukocyte-antigen-identical siblings and all received granulocyte colony-stimulating factor to ensure a graft with a high CD34+ cell content.

The majority of patients (81%) received the targeted CD34+ cell dose, and none received more than 1.0 × 105 CD3+ T-cells/kg. Dr. Devine pointed out that patients did not receive any pharmacologic GvHD prophylaxis post transplant.

"All of the patients engrafted and there were no primary graft failures," said Dr. Devine. "The risks of graft-versus-host disease were minimal. In addition, the relapse rates were quite low."

Summary of Study Results

Outcome 100 Days (95% CI) 6 Months (95% CI) 12 Months (95% CI)
GvHD      
-Acute, grades 2–4 20.5% (8.7 -23.3)    
-Acute, grades 3–4 4.5% (0.0 – 10.6)    
-Chronic     17.7% (5.8 - 29.6)
-Extensive chronic     7.6% (0 - 15.7)
Survival      
-Disease-free   81.3% (66.1 - 90.2) 64.0% (46.5 - 77.1)
-Overall     74.3% (57.3 - 85.4)
Relapse      
-First complete remission     9.6% (0.0 - 19.8)
-Second complete remission     64.3% (27.5 - 100.0)

"The trial did meet its primary end point, which was to have at least 75% of the patients alive and disease-free 6 months posttransplant," said Dr. Devine. "Even though the trial is preliminary, the results are encouraging."

Dr. Devine added that a follow-up study is being planned by the BMT CTN in which unrelated donor allografts will be used.

The authors have disclosed no relevant financial relationships.

American Society of Hematology (ASH) 51st Annual Meeting. Abstract 655. Presented December 7, 2009.

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