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Toxicity and Efficacy of Defined Doses of CD4+ Donor
Lymphocytes for Treatment of Relapse After Allogeneic Bone Marrow
Transplant
Edwin P. Alyea,
Robert J. Soiffer,
Christine Canning,
Donna Neuberg,
Robert Schlossman,
Christopher Pickett,
Heather Collins,
Yulan Wang,
Kenneth C. Anderson, and
Jerome Ritz
From the Divisions of Hematologic Malignancies and Biostatistics,
Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical
School, Boston, MA.
Donor lymphocyte infusions (DLI) can induce remissions in patients
who have relapsed after allogeneic bone marrow transplantation (BMT).
However, DLI frequently also result in significant acute and/or
chronic graft-versus-host disease (GVHD). Several clinical and
experimental lines of evidence have suggested that CD8+ T
cells play a critical role in the pathogenesis of GVHD. To develop
methods to reduce the incidence of GVHD associated with DLI, we
administered defined numbers of CD4+ donor T cells after
ex vivo depletion of CD8+ lymphocytes to 40 patients with
relapsed hematologic malignancies after allogeneic BMT. Cohorts of
patients received 0.3, 1.0, or 1.5 × 108
CD4+ cells/kg. Overall, 12 of 38 patients (32%)
evaluable for toxicity developed acute or chronic GVHD. However, 6 of
27 patients (22%) receiving 0.3 × 108 CD4 cells/kg
developed GVHD compared with 6 of 11 patients (55%) who received
 1.0 × 108 CD4 cells/kg (P = .07).
Treatment-related mortality was low (3%), with 1 death related to
infection in the setting of immunosuppression for GVHD. Disease
responses after CD4+ DLI were documented in 15 of 19 patients (79%) with early-phase chronic myelogenous leukemia (CML)
relapse, 5 of 6 patients (83%) with relapsed multiple myeloma, and 1 patient with myelodysplasia. For patients with early-phase CML relapse,
the Kaplan-Meier probability of achieving complete cytogenetic
remission was 87% and the probability of complete molecular response
was 78% at 1 year after DLI. The median time to complete cytogenetic
response and molecular response in patients with CML was 13 weeks
(range, 9 to 30 weeks) and 34 weeks (range, 10 to 56 weeks),
respectively. The median time to response in patients with multiple
myeloma was 26 weeks (range, 15 to 62 weeks). All patients in this
trial who developed GVHD demonstrated tumor regression, but the
presence of GVHD was not required for patients to achieve a response,
because 48% of responding patients never developed evidence of GVHD.
Two patients with CML who did not respond at dose level 1 subsequently
achieved complete cytogenetic remission after a second infusion of
CD8-depleted cells at dose level 2. In patients with evidence of mixed
hematopoietic chimerism who achieved a complete remission after DLI,
cytogenetic analysis of marrow cells also demonstrated conversion to
complete donor hematopoiesis in all evaluable patients. These studies
suggest that relatively low numbers of CD8-depleted donor lymphocytes are effective in inducing complete remissions in patients with stable-phase CML and multiple myeloma who have relapsed after allogeneic BMT. Because of the relatively low risk of toxicity associated with the infusion of defined numbers of CD4+
donor cells, further studies can be undertaken in the setting of
persistent minimal residual disease to prevent relapse after allogeneic
BMT.
Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3671-3680
© 1998 by The American Society of Hematology.
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