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
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.
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
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
"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