Dr. Mary Flowers

Hematopoietic Stem Cell Transplant (HST) represents the only curative approach for many incurable diseases resulting in thousands of long-term disease-free survivors world wide. The new host immune system derived from the HST donor is responsible for eradicating the malignant disease but, unfortunately, can also attack the recipient causing graft-versus-host disease (GVHD). My clinical and research interest has been in the long-term follow-up (LTFU) of patients transplanted at FHCRC with focus on studiesof chronic GVHD and relapse of malignancy after HST.

CHRONIC GVHD
Chronic GVHD is the major transplant-related morbidity and mortality after three months following an allogeneic HST. Chronic GVHD occurs in approximately 50% of patients and, when severe, requires long-term systemic immunosuppressive treatment. Clinical management of patients with extensive chronic GVHD is difficult because of the wide variability of disease manifestation, clinical course, infectious complications, and treatment related toxicity [1]. In a cohort of 316 allogeneic transplant recipients, risk factors associated with the development of extensive chronic GVHD was analyzed using the results of screening tests performed 100 days after allogeneic matched sibling bone marrow transplant (BMT). In a multivariate analysis, significant risk factors for extensive chronic GVHD were prior history of acute GVHD and prednisone use [2]. Results of this study help to identify patients at risk for development of extensive chronic GVHD forenrollment in early clinical trials aimed to improve morbidity and mortality associated with chronic GVHD. In a randomized, phase III study, the use of G-CSF¡Vmobilized peripheral blood stem cell transplant (PBSCT) was associated with an improved survival compared to bone marrow transplant (BMT) [3]. Acute and chronic GVHD were similar in the two arms of that study. Because the PBSCT contained one log more T lymphocytes than BMT (a factor associated with risk of cGVHD), we investigated whether the clinical characteristics of cGVHD after PBSCT might be distinct from those that occur after BMT in patients with a longer follow-up enrolled in this trial at FHCRC. We evaluated the distribution of organ involvement by cGVHD, the incidence of clinical manifestations associated with high morbidity, the time and the type of onset of cGVHD, the duration of treatment and the numbers of immunosuppressive therapies needed to control the disease [4].

RECURRENCE OF PRIMARY MALIGNANCY AFTER HST
Relapse of malignancy represents one of the major causes of death after transplantation in patients transplanted for hematological malignancies. One approach to treat relapses after transplantation is to manipulate graft-versus-leukemia /tumor (GVL) effect by stopping immunosuppression and by transfusion of donor lymphocytes. The major complication of donor lymphocyte infusions (DLI) is graft-versus-host-disease (GVHD) and aplasia. In an attempt to prevent or ameliorate aplasia after DLI, we conducted two sequential studies of DLI in 26 patients with CML who relapsed after HSC transplantation. In the first study, cells for DLI were collected from 13 donors who were not treated with G-CSF (Group 1). In the second study, cells were collected from 13 donors who received G-CSF before apheresis (Group 2) containing 550-fold more CD34 + donor progenitor cells than those in Group 1. We found no significant difference in the incidence, onset time, or duration of aplasia after DLI in the two groups. Our findings support the hypothesis that the pathogenesis of aplasia after DLI is not restricted to the destruction of recipient hematopoietic cells but also involves failure of donor hematopoiesis by undefined mechanisms. Response rates, occurrence of GVHD, and survival were similar in the two groups. This study showed that G-CSF mobilized product did not prevent aplasia given as adoptive immunotherapy for recurrent CML after HST [5].

OTHER STUDIES UNDER INVESTIGATION
Two phase I-II clinical trials to decrease GVHD toxicity seen with DLI using a suicide gene transfected in donor T cells (protocol 1135 and 1276) are currently under investigation;
A phaseI-II clinical trial for patients with recurrent acute leukemia after allogeneic SCT using DLI plus IL-2 (protocol 1380) is being conducted in hopes of improving the GVL effect of DLI;
A study to decrease conditioning regimen toxicity in patients with Fanconi anemia undergoing HLA identical sibling SCT (protocol 1288) is being conducted in collaborations with others centers.