By Mary Jo Lechowicz, MD
2009-12-07
In the world of allogeneic transplantation, there are many
challenges. Availability of a donor can be an obstacle, preventing many
patients from receiving a potentially life-saving treatment for a hematologic
malignancy or another disorder. Haploidentical transplantation has increased
the available donor pool, but overcoming HLA restrictions in haploidentical
transplants can be problematic. Similarly, escaping the ravages of
graft-versus-host disease (GVHD), relapse, infectious complications, and
treatment-related mortality is difficult.
In yesterday’s Plenary
Session, Dr. Massimo Martelli and colleagues presented the results of a phase
I/II study of the consequences of early infusion of purified donor CD4+/CD25+ regulatory T-cells (Tregs),
followed by donor-matched conventional T cells (Tcons) and immunoselected CD34+
cells, on immune recovery and GVHD following human haploidentical transplants,
based on successful animal models. Twenty-eight patients have been enrolled
since September 2008. The investigators studied the effects of escalating doses
of Tregs with omission GVHD prophylaxis.
In the trial, patients received total body irradiation
(8Gy single fraction) with thiotepa (4 mg/kg x 2), fludarabine (40 mg/m2 x 5),
and cyclophosphamide (35 mg/kg x 2) for their conditioning regimen. Patients
were then infused with escalating doses of Tregs, followed three days later by immune-selected CD34+
cells together with individual doses of
donor mature T-cells. Twenty-six of 28 patients achieved primary engraftment.
The authors found two of the 26 patients developed grade II or higher GVHD. The
patients showed marked improvement in their post-transplant immune recovery
compared with previous studies, and a significant reduction in the incidence of
CMV reactivation. The non-relapse
mortality rate, with a median follow-up of six months, was 37 percent.
Dr. Martelli discussed
future plans following this work, including improved understanding of the
effects of Tregs on the graft-versus-leukemia effect. The group has already
begun improving the purification process of Tregs. Identifying the optimal subset of Tregs for
reinfusion will be helpful in improving outcomes for this transplant approach.
Dr. Maurio Ianni of the University of Perugia
and first author of the abstract believes, “This is the first step forward in
what may well prove to be a winning strategy for immune reconstitution after
HLA haploidentical hematopoietic stem cell transplantation for patients with
high-risk hematologic malignancies who were otherwise prone to life-threatening
infections.” The group’s next steps will be to continue their work by enlarging
their series of patients and to continue monitoring patients for a longer
period of time. If successful, this approach can be extended to other
conditioning regimens.
Special mention was made to acknowledge the late Dr. A. Tabilio for his collaboration on this project.
Dr. Lechowicz indicated no relevant conflicts of
interest.
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