Abhyankar Sh

Long term disease-free survival in acute leukemia patients recovering with increased γδ T cells after partially mismatched related donor bone marrow transplantation

Allogeneic stem cell transplantation (ASCT) has improved leukemia-free survival (LFS) in many but not all patients with acute leukemia. This is an eight-year follow-up to our previous study showing a survival advantage to patients with an increased γδ T cells following ASCT. γδ T cell levels were collected prospectively in 153 patients (acute lymphoblastic leukemia (ALL) n=77; acute myelogenous leukemia (AML) n=76) undergoing partially mismatched related donor ASCT. Median age was 22 years (1–59), and 62% of the patients were in relapse at transplant. Patient–donor human leukocyte antigen (HLA) disparity of three antigens was 37% in the graft-versus-host disease (GvHD) and 29% in the rejection directions. All patients received a partially T cell-depleted graft using T10B9 (n=46) or OKT3 (n=107). Five years LFS and overall survival (OS) of patients with increased γδ compared to those with normal/decreased numbers were 54.4 vs 19.1%; P<0.0003, and 70.8 vs 19.6% P<0.0001, respectively, with no difference in GvHD (P=0.96). In a Cox multivariate analysis, normal/decreased γδ (hazard ratio (HR) 4.26, P=0.0002) and sex mismatch (HR 1.45 P=0.049) were associated with inferior LFS. In conclusion, γδ T cells may facilitate a graft-versus-leukemia (GvL) effect, without causing GvHD. Further evaluations of this effect may lead to specific immunotherapy for patients with refractory leukemia.

Recombinant human tumor necrosis factor receptor fusion protein as complementary treatment for chronic graft-versus-host disease.

BACKGROUND Chronic graft-versus-host disease (cGVHD) remains one of the major late complications in allogeneic bone marrow transplantation (BMT). Prolonged immunosuppression often results in significant morbidity and mortality. Cytokine dysregulation is implicated in the pathophysiology of cGVHD, and tumor necrosis factor-alpha (TNF-alpha) plays a central role. METHODS Recombinant soluble TNF receptor (Enbrel) was explored for the use of steroid-dependent cGVHD in 10 patients. Enbrel was given as a subcutaneous injection twice weekly for 4 weeks followed by once weekly for 4 more weeks. Progression or regression of cGVHD was monitored closely by regular clinical follow-up. RESULTS Eight patients finished the 8-week treatment course without adverse side effect. Seven of them showed improvement (subjectively and/or objectively) in cGVHD. Steroid taper was initiated as early as 1 month. CONCLUSIONS This preliminary encouraging result merits additional studies to optimize Enbrel as a potential complementary therapy for resolution of steroid-dependent cGVHD.

De novo chronic graft-versus-host disease presenting as hemolytic anemia following partially mismatched related donor bone marrow transplant

Chronic graft-versus-host disease (cGVHD) is a disease of immune dysregulation that resembles an autoimmune disease. It usually involves the skin, mucosal and serosal surfaces and, less commonly, the hematopoietic system. We report hemolytic anemia (HA) as the primary manifestation of de novo cGVHD in recipients of partially mismatched related donor transplants. Five of 40 eligible patients developed HA at a median of 168 days post-transplant. Recipients were mismatched for one to three major HLA antigens. Conditioning therapy consisted of total body irradiation, etoposide, Ara-C, cyclophosphamide and steroids. GVHD prophylaxis included partial T cell depletion, using anti α/β CD3 antibody (T10B9) and complement, in addition to post-transplant immunosuppression. At presentation, all patients were receiving cyclosporine with or without low-dose steroids. Along with a mean Hb of 7.1g%, patients had an increased reticulocyte count, a mild raised lactic dehydrogenase and a positive Coombs’ test (in 2/5 patients). Four patients had also demonstrated a decrease in platelet count. Treatment was initiated with high-dose steroids and intravenous gamma globulin and response was observed within 1 week. Awareness of this presentation of cGVHD and early therapeutic intervention can result in successful reversal of presumed immune-mediated red cell and platelet destruction.

Late onset Epstein-Barr virus-associated lymphoproliferative disease after allogeneic bone marrow transplant presenting as breast masses.

We report a patient who developed breast masses 17 months after a T cell-depleted partially mismatched related donor (PMRD) bone marrow transplant (BMT) for chronic myeloid leukemia. The patient had severe chronic graft-versus-host disease (GVHD) and the masses were due to Epstein–Barr virus (EBV) lymphoproliferative disease (LPD). The patient expired from fungal pneumonia after chemotherapy for the EBV-LPD.

Donor leukocyte infusion for treatment of graft rejection post partially mismatched related donor bone marrow transplant

Graft rejection following bone marrow transplantation is more common in patients who receive their grafts from alternative donors and whose marrow is T cell depleted. Rejection in these patients is mediated by persistent host cells that interfere with successful establishment of donor-derived hematopoietic recovery. We describe a patient with chronic myelogenous leukemia in accelerated phase who rejected a T cell-depleted bone marrow graft, 2 months following partially mismatched related donor bone marrow transplant. Unmanipulated peripheral blood donor leukocyte infusion, without additional chemotherapy or immunosuppressive therapy resulted in complete hematopoietic recovery. Cytogenetics and RFLP demonstrated hematopoietic donor chimerism. The patient did not develop graft-versus-host disease.

Evaluation of the Half-Life of Intravenous Human Cytomegalovirus Immune Globulin in Patients Receiving Partially Mismatched Related Donor Bone Marrow Transplantation

Study Objective. To evaluate the pharmacokinetics and use of intravenous human cytomegalovirus immune globulin (CytoGam) in allogeneic bone marrow transplantation (BMT).