Following unmodified allogeneic bone marrow transplantation (BMT), up to 60% of patients with chronic myelogenous leukemia (CML) will relapse. The management of relapsed CML has proven especially difficult, because cytotoxic drugs and interferon-alfa (Intron A, Roferon-A) seldom cure the disease, and a second bone marrow transplant is associated with high mortality.
However, among patients with relapsed chronic phase CML after BMT who receive an infusion of allogeneic donor leukocytes, 70% to 80% can achieve a complete, durable remission, said Richard O'Reilly, md, and Jerome Ritz, md, said at a scientific subcommittee session of the American Society of Hematology meeting.
This so-called adoptive immunotherapy induces not only a graft-vs-leukemia effect but also a high incidence of graft-vs-host disease (GVHD) and marrow aplasia; reported mortality in past studies has approached 20%, Dr. O'Reilly said. Now, new techniques have been developed to lower toxicity by using fewer donor T-cells or by depleting the donor cells of specific cells thought to play a role in GVHD.
Memorial Sloan-Kettering Study
Dr. O'Reilly and his colleagues at Memorial Sloan-Kettering have sought to determine whether giving fewer donor leukocytes and treating patients in early relapse would allow for a sufficient graft-vs-leukemia response to induce remission, while resulting in lower treatment-related toxicity.
The results, presented at ASH (abstract 2251), have been very promising. Ten patients in early CML relapse were given a single dose of between 3 × 106 and 1 × 107 T cells/kg, a full order of magnitude fewer cells than the standard donor leukocyte dose.
Nine of these patients have achieved complete remission (molecular or cytogenetic); it was still too early to evaluate the response of the 10th patient at the time of the meeting.
None of the nine responders developed acute GVHD, none developed cytopenia, and there were no treatment-related mortalities, Dr. O'Reilly said. Two of the nine did develop mild chronic GVHD.
Dana-Farber Research
Dr. Ritz and his colleagues at the Dana-Farber Cancer Institute have taken a different approach to reducing GVHD toxicity in patients receiving donor leukocyte infusions. Although the precise lymphoid subsets that mediate graft-vs-leukemia activity and GVHD have yet to be identified, studies have suggested an important role for CD8+ T-cells in the pathogenesis of GVHD.
Thus, the Dana-Farber researchers conducted a clinical study to determine whether donor leukocytes that have been depleted of CD8+ T-cells could be effective at standard dosage levels, without inducing GVHD.
Prior to infusion, the donor leukocytes were depleted of CD8+ T cells with monoclonal antibody and complement, which left primarily CD4+ T-cells. The Dana-Farber team has evaluated three different dose levels of CD4+ T-cells (0.3, 1.0, and 1.5 × 108 cells/kg), with five patients at each dose level. Patients included those with chronic and acute leukemia and three multiple myeloma patients.
The results, presented at ASH (abstract 1158) showed seven of seven patients with stable-phase CML (relapsed after BMT) to be in hematologic remission, Dr. Ritz said. Five have achieved cytogenetic remission, and for two patients, it is still too early after infusion to predict the course of the remission.
In addition, only 5 of the 15 patients have developed GVHD. All five patients were treated at the two highest dose levels, and all responded to corticosteroids. Cytopenia was also a problem in some patients, but resolved spontaneously in all but one case. In this instance, a second infusion of donor stem cells resulted in recovery.
"It appears that we can begin to selectively modulate the donor lymphocyte product, so that we can achieve a graft-vs-leukemia effect without graft-vs-host disease," Dr. Ritz summed up. "Now the interesting question is, what is happening immunologically, and how can we begin to sort this out?"
Dr. Ritz said that his group is focusing on the identification of unique populations of T-cells via analysis of T-cell receptor beta genes.
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