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Summary:The role of T-cell depletion (TCD) to prevent graft-versus-host disease (GVHD) after matched unrelated donor allogeneic bone marrow transplant (MUD BMT) remains undefined. Most studies employ total body irradiation and pan TCD. Between March 1993 and June 2002, we treated 33 relapsed acute myelogenous leukemia (AML) patients with busulfan-based preparative regimens and selective TCD. The preparative regimen consisted of busulfan 14?mg/kg, cyclophosphamide 120?mg/kg and VP-16 50?mg/kg in all but one patient who only received busulfan and cyclophosphamide. Donor marrow was depleted of CD8+T cells by immunomagnetic bead separation. The patients were also treated with cyclosporine and methylprednisolone or FK-506 and mini-dose methotrexate. Four (15%) of 33 patients developed graft failure or rejection. However, three of these patients were serologically mismatched at HLA-Cw. Although 67%of evaluable patients developed acute GVHD, severe grade III-IV acute GVHD only developed in 19%. The severity of acute GVHD correlated with the degree of CD8+TCD. Median relapse-free survival was 5 months among 20 patients treated with active AML, and 28 months among 13 patients treated in complete remission. Our results confirm that MUD BMT with CD8+TCD for AML is a potentially curative treatment option.Bone Marrow Transplantation (2005) 35, 247-252. doi:10.1038/sj.bmt.1704736 Published online 6 December 2004 [ABSTRACT FROM AUTHOR]

Presents a study that examined clinical parameters associated with the development of mucositis, a common complication of autologous progenitor cell transplantation. Background on high-dose chemotherapy with autologous peripheral blood progenitor cell transplantation; Details on the tool used for monitoring mucositis after radiation therapy or chemotherapy; Analysis of variables that contribute to worsening mucositis during autologous transplantation.

Nonmyeloablative peripheral blood stem cell transplantation (PBSCT) is a novel therapeutic strategy for patients with malignant and non-malignant hematologic diseases. Infectious complications of this procedure have not been previously well described. Data on 12 patients transplanted at a tertiary care center were collected prospectively and verified retrospectively. Neutropenia developed in a third of patients, lasting for a median of 5 days. All patients developed some degree of graft-versus-host disease, as intended. Most patients achieved full chimerism by week 5. Bacterial infections occurred in two patients (17%). Cytomegalovirus (CMV) viremia occurred in five patients (42%) at a median of 80 days; none had received CMV prophylaxis. Viremia was associated with fever and fatigue in three patients, possible gastrointestinal involvement in one patient and was asymptomatic in one patient. All viremic patients responded to intravenous ganciclovir therapy. No fungal infections were documented. No patients died as a result of infection. The incidence of CMV viremia in our patients was high, but the incidence of invasive disease due to CMV was low. The best strategy to prevent CMV in patients undergoing nonmyeloablative PBSCT remains to be determined, but strategies employed in traditional allogeneic bone marrow transplantation should be considered in these patients. Bone Marrow Transplantation (2001) 28, 491–495. [ABSTRACT FROM AUTHOR]

Cytogenetic aberrations identified by metaphase cytogenetics (MC) have important diagnostic, prognostic and therapeutic roles in myelodysplastic syndromes (MDS). Fluorescence in situ hybridization (FISH) complements MC by the ability to evaluate large numbers of both interphase and metaphase nuclei. However, clinically practical FISH strategies are limited to detection of known lesions. Single nucleotide polymorphism array (SNP-A)-based karyotyping can reveal unbalanced defects with superior resolution over MC and FISH and identify segmental uniparental disomy (UPD) undetectable by either method. Using a standardized approach, we focused our investigation on detection of -5/del(5q), -7/del(7q), trisomy 8 and del(20q) in patients with MDS (N=52), MDS/myeloproliferative overlap syndromes (N=7) and acute myeloid leukemia (N=15) using MC, FISH and SNP-A karyotyping. The detection rate for del(5q) was 30, 32 and 32% by MC, FISH, and SNP-A, respectively. No single method detected all defects, and detection rates improved when all methods were used. The rate for detection of del(5q) increased incrementally to 35% (MC+FISH), 38% (MC+SNP-A), 38% (FISH+SNP-A) and 39% (all three methods). Similar findings were observed for -7/del(7q), trisomy 8 and -20/del(20q). We conclude that MC, FISH and SNP-A are complementary techniques that, when applied and interpreted together, can improve the diagnostic yield for identifying genetic lesions in MDS and contribute to the better description of abnormal karyotypes., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

The development of laboratory tests for the diagnosis and monitoring of graft-vs-host disease (GVHD) is hampered by a lack of knowledge of minor histocompatibility Ags triggering alloresponses. We hypothesized that the unique molecular structure of the TCR could be used as a marker for the unidentified Ags and exploited for molecular monitoring of GVHD posttransplant. To identify alloreactive T cell clones, we performed in vitro allostimulation cultures for a cohort of patients undergoing hemopoietic stem cell transplantation and determined the sequence of the CDR3 of immunodominant alloreactive clones; 10 corresponding clonotypes restricted to activated T cells were identified. As an alternative method for the identification of alloreactive clones, molecular TCR analysis was applied to biopsies of GVHD-affected tissues. Culture- and biopsy-derived clonotypes were used to design sequence-specific quantitative PCR assays to monitor the levels of putative allospecific clonotypes in posttransplant blood samples and subsequent biopsies. Because of the rational design of the methods used to identify immunodominant clonotypes, we were able to follow the behavior of potentially GVHD-specific T cells during the transplant course. Based on our results, we conclude that molecular T cell diagnostics can be a powerful tool for monitoring immune responses posttransplantation.

The non-relapse mortality of autologous stem cell transplant is low enough that the procedure has been extended to older patients with non-Hodgkin's lymphoma. We treated 537 non-Hodgkin's lymphoma patients with high-dose chemotherapy consisting of busulfan, cyclophosphamide, and etoposide followed by autologous stem cell transplant. Sixteen patients were identified who died of pulmonary complications at a five-year incidence of 3.6%. Risk factors for pulmonary mortality included older age and lower baseline D(CO) and FEV1. We conclude that high-dose busulfan is associated with pulmonary mortality after autologous transplant, particularly in older patients.

Purpose: The risk factors for treatment-related myelodysplastic syndrome (t-MDS) and acute myelogenous leukemia (AML) after autologous stem-cell transplantation (ASCT) are similar to those that increase the risk of difficult stem-cell harvests. We reviewed our experience in 526 patients with lymphoma treated by ASCT to determine whether difficult stem-cell harvests predict for an increased risk of t-MDS/AML., Patients and Methods: Autologous peripheral stem cells were initially mobilized with granulocyte colony-stimulating factor (G-CSF; or granulocyte-macrophage colony-stimulating factor) alone (n = 334), etoposide and G-CSF (n = 166), or cyclophosphamide and G-CSF with or without etoposide (n = 26). Difficult harvests were those that required more than 5 days to collect enough stem cells and those that required additional attempts with etoposide and/or cyclophosphamide plus G-CSF (n = 52). All patients were then treated with high-dose chemotherapy alone and observed for outcome., Results: With a median follow-up time for surviving patients of 69 months, 20 patients developed t-MDS/AML, for an actuarial incidence of 6.8% at 10 years. Pretransplantation characteristics, including age, diagnosis of non-Hodgkin's lymphoma or Hodgkin's disease, bone marrow involvement, prior radiation therapy, prior exposure to chemotherapy, lactate dehydrogenase at the time of ASCT, disease status, and method of stem-cell mobilization, were then analyzed with respect to the subsequent development of t-MDS/AML. By multivariable analysis, prior exposure to radiation therapy, four or more chemotherapy regimens, and more than 5 days of apheresis needed to harvest enough stem cells were identified as independent risk factors for t-MDS/AML. Bootstrap analysis confirmed these results., Conclusion: These results suggest that identifiable pretransplantation factors predict for t-MDS/AML after ASCT.

Objective: In allogeneic hematopoietic stem cell (HSCT) transplantation, recovery of the T cell receptor (TCR) repertoire depends upon the composition of the graft and is modulated by peri-transplant immunosuppression, viral infections, and graft-vs-host disease (GVHD). We hypothesized that after allogeneic HSCT, molecular analysis of the TCR repertoire can be used to identify and quantitate immunodominant T cell clones that may play a role in GVHD or other clinical events., Methods: We utilized a rational strategy for the analysis of the expanded CTL clones. First, we studied the VB spectrum in a cohort of patients who had received either matched sibling or unrelated donor grafts. The CDR3 sequences of immunodominant clones were identified and clonotypic PCR and sequencing was applied to determine the level of clonotype sharing., Results: Significant expansions of VB families were observed following transplantations; 61% were oligo/monoclonal. Immunodeficiency was reflected by depletion of multiple VB families from both the CD8 and CD4 repertoires. The level of sharing varied between clonotypes, suggesting that some antigens have a more "public" spectrum while others are restricted to specific patients. Immunodominant CDR3 sequences common to allogeneic HSCT, healthy controls, and other conditions were identified., Conclusion: The clonotypes of expanded CTL clones may reflect responses to alloantigens (e.g., in correlation with clinical GVHD) or pathogens. In the future, molecular T cell diagnostics may become a powerful clinical tool in transplantation to monitor disease and to direct treatment.

The outcome of patients with transformed diffuse large-cell lymphoma is poor. High-dose chemotherapy and autologous peripheral blood progenitor cell (PBPC) transplantation is the treatment of choice for patients with relapsed nontransformed diffuse large-cell lymphoma. The role of transplantation for transformed lymphoma is poorly studied. We retrospectively reviewed 118 consecutive diffuse large-cell lymphoma patients undergoing autologous PBPC transplantation from 1994 through 1999 and compared 18 transformed diffuse large-cell lymphoma patients with 100 nontransformed patients. The transformed patients were more likely to be older (median age, 52 years vs. 45 years, P = 0.03), had a longer time from diagnosis to transplant (median, 35 months vs. 10 months; P < 0.0001), were more likely to have bone marrow involvement at diagnosis (61% vs. 15%, P = 0.0001), and were more likely to have had 2 or more courses of prior chemotherapy (94% vs. 71%, P = 0.04) than were nontransformed patients. Ninety-nine percent of patients received high-dose busulfan/cyclophosphamide/etoposide as the transplant preparative regimen. Event-free survival and overall survival were similar in the two treatment groups. Four-year overall survival was 53% in the nontransformed group versus 61% in the transformed group; 4-year event-free survival was 37% in the nontransformed group versus 38% in the transformed group. We concluded that autologous PBPC transplantation is a viable and potentially effective treatment option for patients who have transformed diffuse large-cell lymphoma.