New Donor Leukocyte Approaches May Improve Outcomes in Relapsed CML Post-transplant

September 1, 1996

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.

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 especiallydifficult, because cytotoxic drugs and interferon-alfa (IntronA, Roferon-A) seldom cure the disease, and a second bone marrowtransplant is associated with high mortality.

However, among patients with relapsed chronic phase CML afterBMT who receive an infusion of allogeneic donor leukocytes, 70%to 80% can achieve a complete, durable remission, said RichardO'Reilly, md, and Jerome Ritz, md, said at a scientific subcommitteesession of the American Society of Hematology meeting.

This so-called adoptive immunotherapy induces not only a graft-vs-leukemiaeffect but also a high incidence of graft-vs-host disease (GVHD)and marrow aplasia; reported mortality in past studies has approached20%, Dr. O'Reilly said. Now, new techniques have been developedto lower toxicity by using fewer donor T-cells or by depletingthe 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 havesought to determine whether giving fewer donor leukocytes andtreating patients in early relapse would allow for a sufficientgraft-vs-leukemia response to induce remission, while resultingin lower treatment-related toxicity.

The results, presented at ASH (abstract 2251), have been verypromising. Ten patients in early CML relapse were given a singledose of between 3 × 106 and 1 × 107 T cells/kg, a fullorder of magnitude fewer cells than the standard donor leukocytedose.

Nine of these patients have achieved complete remission (molecularor cytogenetic); it was still too early to evaluate the responseof the 10th patient at the time of the meeting.

None of the nine responders developed acute GVHD, none developedcytopenia, 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 Institutehave taken a different approach to reducing GVHD toxicity in patientsreceiving donor leukocyte infusions. Although the precise lymphoidsubsets that mediate graft-vs-leukemia activity and GVHD haveyet to be identified, studies have suggested an important rolefor CD8+ T-cells in the pathogenesis of GVHD.

Thus, the Dana-Farber researchers conducted a clinical study todetermine whether donor leukocytes that have been depleted ofCD8+ T-cells could be effective at standard dosage levels, withoutinducing GVHD.

Prior to infusion, the donor leukocytes were depleted of CD8+T cells with monoclonal antibody and complement, which left primarilyCD4+ T-cells. The Dana-Farber team has evaluated three differentdose levels of CD4+ T-cells (0.3, 1.0, and 1.5 × 108 cells/kg),with five patients at each dose level. Patients included thosewith chronic and acute leukemia and three multiple myeloma patients.

The results, presented at ASH (abstract 1158) showed seven ofseven patients with stable-phase CML (relapsed after BMT) to bein hematologic remission, Dr. Ritz said. Five have achieved cytogeneticremission, and for two patients, it is still too early after infusionto predict the course of the remission.

In addition, only 5 of the 15 patients have developed GVHD. Allfive patients were treated at the two highest dose levels, andall responded to corticosteroids. Cytopenia was also a problemin some patients, but resolved spontaneously in all but one case.In this instance, a second infusion of donor stem cells resultedin recovery.

"It appears that we can begin to selectively modulate thedonor lymphocyte product, so that we can achieve a graft-vs-leukemiaeffect 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 identificationof unique populations of T-cells via analysis of T-cell receptorbeta genes.