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Summary: Involvement of the alternative complement pathway (AP) in microvascular endothelial cell (MVEC) injury characteristic of a thrombotic microangiopathy (TMA) is well documented. However, the role of the lectin pathway (LP) of complement has not been explored. We examined mannose‐binding lectin associated serine protease (MASP2), the effector enzyme of the LP, in thrombotic thrombocytopenic purpura, atypical hemolytic uremic syndrome and post‐allogeneic hematopoietic stem cell transplantation (alloHSCT) TMAs. Plasma MASP2 and terminal complement component sC5b‐9 levels were assessed by enzyme‐linked immunosorbent assay (ELISA). Human MVEC were exposed to patient plasmas, and the effect of the anti‐MASP2 human monoclonal antibody narsoplimab on plasma‐induced MVEC activation was assessed by caspase 8 activity. MASP2 levels were highly elevated in all TMA patients versus controls. The relatively lower MASP2 levels in alloHSCT patients with TMAs compared to levels in alloHSCT patients who did not develop a TMA, and a significant decrease in variance of MASP2 levels in the former, may reflect MASP2 consumption at sites of disease activity. Plasmas from 14 of the 22 TMA patients tested (64%) induced significant MVEC caspase 8 activation. This was suppressed by clinically relevant levels of narsoplimab (1·2 μg/ml) for all 14 patients, with a mean 65·7% inhibition (36.8–99.4%; P < 0·0001). In conclusion, the LP of complement is activated in TMAs of diverse etiology. Inhibition of MASP2 reduces TMA plasma‐mediated MVEC injury in vitro. LP inhibition therefore may be of therapeutic benefit in these disorders. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (HSCT) is one of curative treatment options for patients with hematologic malignancies. Although GVHD mediated by the donor's T lymphocytes remains the most challenging toxicity of allo-HSCT, graft-versus-leukemia (GVL) effect targeting leukemic cells, has an important role in affecting the overall outcome of patients with AML. Here we comprehensively characterized the TCR repertoire in patients who underwent matched donor or haplo-cord HSCT using next-generation sequencing approach. Our study defines the functional kinetics of each TCRA and TCRB clone, and changes in T-cell diversity (with identification of CDR3 sequences) and the extent of clonal expansion of certain T-cells. Using this approach, our study demonstrates that higher percentage of cord-blood cells at 30 days after transplant was correlated with higher diversity of TCR repertoire, implicating the role of cord-chimerism in enhancing immune recovery. Importantly, we found that GVHD and relapse, exclusive of each other, were correlated with lower TCR repertoire diversity and expansion of certain T-cell clones. Our results highlight novel insights into the balance between GVHD and GVL effect, suggesting that higher diversity early after transplant possibly implies lower risks of both GVHD and relapse following the HSCT transplantation. [ABSTRACT FROM AUTHOR]

Patients with relapsed/refractory leukemias or advanced myelodysplastic syndrome (MDS) fare poorly following allogeneic hematopoietic cell transplant (HCT). We report prospective phase II study results of 29 patients given clofarabine 30 mg/m2/day i.v. × 5 days followed immediately by HCT conditioning while at the cytopenic nadir. A total of 15/29 patients (52%) were cytoreduced according to pre-defined criteria (cellularity <20% and blasts <10%). Marrow cellularity (P<0.0001) and blast% (P=0.03) were reduced. Toxicities were acceptable, with transient hyperbilirubinemia (48%) and gr3-4 infections (10%). In all, 28/29 proceeded to transplant; 27 received ATG or alemtuzumab. Post HCT, 180 day non-relapse mortality (NRM) was 7% (95% confidence interval (CI): 1-21), relapse was 29% (95% CI: 13-46) and OS was 71% (95% CI: 51-85), comparing favorably to published data for high-risk patients. Two-year graft vs host disease incidence was 40% (95% CI: 21-58) and 2 year OS was 31% (95% CI: 14-48). Disease at the nadir correlated with inferior OS after HCT (HR=1.22 for each 10% marrow blasts, 95% CI: 1.02-1.46). For AML/MDS patients, there was a suggestion that successful cytoreduction increased PFS (330 vs 171 days, P=0.3) and OS (375 vs 195 days, P=0.31). Clofarabine used as a bridge to HCT reduces disease burden, is well tolerated, and permits high-risk patients to undergo HCT with acceptable NRM. Late relapses are common; thus, additional strategies should be pursued. NCT-00724009. [ABSTRACT FROM AUTHOR]

Desmoplastic small round cell tumor of the peritoneum (DSRCTP) is a rare, frequently fatal tumor. This retrospective study, based on CIBMTR registry data, describes the largest reported cohort of DSRCTP patients who have undergone Auto-SCT. The probabilities of disease-free survival (DFS) at 1 year for patients in CR and not in CR were 75% (95% confidence interval: 48-94%) and 35% (15-59%), respectively. The probability of OS at 3 years was 57% (29-83%) and 28% (9-51%) for patients in CR and not in CR, respectively. Median survival for the entire cohort was 31 months (36 months and 21 months for those in CR and not in CR, respectively). Engraftment at 42 days was 97% (88-100%). Treatment-related mortality was low, with only one death in the first 100 days. Auto-SCT is a tolerable approach in patients with DSRCTP, with the greatest benefit seen in those patients who obtain CR. For those not in CR, the median OS in this series is greater than previously reported (21 months vs 17 months), suggesting Auto-SCT is useful in prolonging DFS and OS, even in patients with residual or persistent disease pre-transplant. [ABSTRACT FROM AUTHOR]

The identification of important amino acid substitutions associated with low survival in hematopoietic cell transplantation (HCT) is hampered by the large number of observed substitutions compared with the small number of patients available for analysis. Random forest analysis is designed to address these limitations. We studied 2107 HCT recipients with good or intermediate risk hematological malignancies to identify HLA class I amino acid substitutions associated with reduced survival at day 100 post transplant. Random forest analysis and traditional univariate and multivariate analyses were used. Random forest analysis identified amino acid substitutions in 33 positions that were associated with reduced 100 day survival, including HLA-A 9, 43, 62, 63, 76, 77, 95, 97, 114, 116, 152, 156, 166 and 167; HLA-B 97, 109, 116 and 156; and HLA-C 6, 9, 11, 14, 21, 66, 77, 80, 95, 97, 99, 116, 156, 163 and 173. In all 13 had been previously reported by other investigators using classical biostatistical approaches. Using the same data set, traditional multivariate logistic regression identified only five amino acid substitutions associated with lower day 100 survival. Random forest analysis is a novel statistical methodology for analysis of HLA mismatching and outcome studies, capable of identifying important amino acid substitutions missed by other methods. [ABSTRACT FROM AUTHOR]

To control disease before allogeneic hematopoietic cell transplantation (HCT) for relapsed/refractory AML, we used clofarabine cytoreduction. Seventeen patients received clofarabine 30-40 mg/m2 i.v. daily for 5 days with plans to initiate conditioning during the nadir, 14 days later. Bone marrow biopsy 12 days after clofarabine showed effective cytoreduction (that is,<20% cellularity with <10% blasts) in 10 of 17 patients (59%). Ineffective cytoreduction correlated with lower PFS (3.8 vs 6.4 months; HR=2.7, 95% CI=1.10-14.29, P=0.035) and OS (5.1 vs 16.6 months; HR=2.5, 95% CI=0.98-12.17, P=0.053). Significant toxicities before HCT, attributable to clofarabine, were grade 1-2 hyperbilirubinemia (18%); grade 1-2 (59%) or grade 3-4 (18%) transaminitis; and grade 1-2 (18%) creatinine elevation. Sixteen patients proceeded to HCT infusion 22 days (median) after initiation of clofarabine. Day 100 and 2-year transplant-related mortality were 6 and 36%. Nine patients relapsed. One year PFS and OS were 25 and 38%, respectively. Two patients are alive in remission at 18 and 52 months. Clofarabine cytoreduction followed by immediate HCT is feasible with acceptable toxicity and TRM. Outcomes for this cohort of patients with refractory AML remain poor and we are studying this approach in a prospective manner. [ABSTRACT FROM AUTHOR]

GVHD is partly mediated by host APCs that activate donor T cells. Extracorporeal photopheresis (ECP) can modulate APC function and benefit some patients with GVHD. We report the results of a study using ECP administered before a standard myeloablative preparative regimen intended to prevent GVHD. Grades II–IV acute GVHD developed in 9 (30%) of 30 recipients of HLA-matched related transplants and 13 (41%) of 32 recipients of HLA-matched unrelated or HLA-mismatched related donor transplants. Actuarial estimates of overall survival (OS) at day 100 and 1-year post transplant were 89% (95% CI, 78–94%) and 77% (95% CI, 64–86%), respectively. There were no unexpected adverse effects of ECP. Historical controls receiving similar conditioning and GVHD prophylaxis regimens but no ECP were identified from the database of the Center for International Blood and Marrow Transplant Research and multivariate analysis indicated a lower risk of grades II–IV acute GVHD in patients receiving ECP (P=0.04). Adjusted OS at 1 year was 83% in the ECP study group and 67% in the historical control group (relative risk 0.44; 95% CI, 0.24–0.80) (P=0.007). These preliminary data may indicate a potential survival advantage with ECP for transplant recipients undergoing standard myeloablative hematopoietic cell transplantation. [ABSTRACT FROM AUTHOR]

The absence of a graft-versus-malignancy (GVM) effect may be responsible for the higher relapse rate seen after autologous hematopoietic cell transplantation (auto-HCT) compared with allogeneic hematopoietic cell transplantation (allo-HCT). Acute GVHD developing after allo-HCT, however, is associated with significant morbidity and mortality. An autoimmune syndrome similar to acute GVHD has been reported to occur after auto-HCT and has been termed the ‘auto-aggression’ syndrome or autologous GVHD (auto-GVHD). Auto-GVHD tends to be milder than classical GVHD, most commonly involves the skin (rarely the gastrointestinal tract, liver or both) and often is self-limited. Auto-GVHD has been reported to occur both spontaneously and in subjects receiving post transplant immune modulation with CsA, IFN-γ or the combination. The development of auto-GVHD depends upon the derangement of self tolerance either through administration of post transplant CsA, depletion of regulatory T cells following the preparative chemoradiotherapy or both. Self-reactive CD8+ T cells paradoxically are able to recognize a self peptide antigen presented by MHC class II molecules and appear to mediate the syndrome. Many clinical trials have been performed using CsA with or without IFN-γ in an attempt to induce auto-GVHD. While many patients do indeed develop the syndrome, any associated anti-tumor effect remains questionable to date. New strategies to exploit auto-GVHD and enhance a GVM effect such as through the depletion of regulatory T cells or through use of newer immunomodulatory agents may improve the efficacy of auto-HCT.Bone Marrow Transplantation (2008) 41, 505–513; doi:10.1038/sj.bmt.1705931; published online 19 November 2007 [ABSTRACT FROM AUTHOR]

We describe treatment, outcomes and prognostic factors for patients who relapse following transplantation with a reduced intensity conditioning regimen. Seventy consecutive patients with high-risk myeloid malignancies underwent transplant and 25 (36%) relapsed, a median of 120 days later. The median percentage of bone marrow blasts at relapse was 24, the median donor chimerism was 73% and new karyotypic abnormalities occurred in 8 out of 20 (40%) evaluable patients. Twenty-one patients (84%) received aggressive treatment for relapse, including chemotherapy (60%), second hematopoietic cell transplantation (HCT; 52%) and/or donor lymphocyte infusion (DLI; 12%). Thirteen achieved a complete response (CR) and four remain in CR. Median overall survival (OS) after relapse was 6 months (95% confidence interval=2.7–9.9 months), and actuarial 1 year OS was 24%. Most deaths were due to disease progression (17/20, 85%). We did not observe an advantage for cellular therapy (DLI or second transplant) compared to chemotherapy. Salvage therapy for relapse after reduced intensity HCT is feasible, associated with low treatment-related mortality, and may result in prolonged survival in select patients. Studies exploring the optimal treatment for relapse following reduced intensity HCT are warranted.Bone Marrow Transplantation (2007) 40, 1027–1032; doi:10.1038/sj.bmt.1705852; published online 10 September 2007 [ABSTRACT FROM AUTHOR]

Alemtuzumab (Campath-1H)-based conditioning regimens are effective in preventing GVHD, but are associated with very high rates of cytomegalovirus (CMV) infection, a major limitation to their use. We evaluated 85 patients receiving conditioning with fludarabine 30 mg/m2/day (day −7 to day −3), alemtuzumab 20 mg/day (day −7 to day −3), and melphalan 140 mg/m2 on day −2. The initial patients received post transplant CMV prophylaxis with high-dose acyclovir. A very high incidence of CMV viremia was observed as has been commonly reported after alemtuzumab-based conditioning. Sixty-seven subsequent patients received pre-transplant ganciclovir and high-dose valacyclovir after engraftment. The cumulative incidence of CMV infection in the valacyclovir cohort was 29%. This compared favorably to the cumulative incidence of 53% in patients receiving only acyclovir (P=0.004) and to literature data. CMV prophylaxis with pre-transplant ganciclovir and high-dose valacyclovir after engraftment appears effective in preventing the excessive incidence of CMV infection after alemtuzumab-based conditioning regimens.Bone Marrow Transplantation (2006) 37, 307–310. doi:10.1038/sj.bmt.1705249; published online 9 January 2006 [ABSTRACT FROM AUTHOR]

Summary:The impact of disease burden on the outcome of patients with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplantation (SCT) has not been well defined. Data from several retrospective series suggest that overt leukemia at the time of transplant increases the risk of relapse. We reviewed the outcomes of 68 consecutive adults with AML (n=60) or myelodysplastic syndromes (MDS) (n=8) who received an allogeneic SCT at the University of Chicago between May 1986 and October 2002 to confirm the importance of currently recognized risk factors for overall survival (OS) and progression-free survival (PFS). In addition, we wanted to determine whether quantification of residual disease by blast percentage or cytogenetic abnormalities at the time of SCT was correlated with outcome. AML subtypes based on the FAB classification were as follows: M0=9, M1=9, M2=16, M3=2, M4=16, M5=3, M6=5. Cytogenetic analysis was available from 52 patients. Using standard morphologic criteria, 34 patients were in complete remission (CR) and 34 had visible leukemia present. The majority of donors were HLA-identical siblings (n=55). In all, 56 patients received myeloablative conditioning regimens and 12 received a reduced-intensity, fludarabine-based conditioning regimen. OS and PFS times were 7.1 months (95%CI, 4.8-10.4) and 5.1 months (95%CI, 3.2-7.8), respectively. Median follow-up from SCT was 4.6 years (range, 0.6-17.0) for survivors. In multivariate analysis, the following factors were found to be associated with worse survival: (1) increased percentage of blasts in the bone marrow at the time of SCT, (2) presence of acute graft-versus-host disease, (3) mismatched donor, (4) Zubrod performance score of?2, and (5) age?45 years. We also found a trend towards improved outcome among patients in cytogenetic remission as compared to those who had residual cytogenetic abnormalities and those in overt relapse. These data support an association between pre-transplant disease burden and poor outcome after SCT.Bone Marrow Transplantation (2005) 35, 965-970. doi:10.1038/sj.bmt.1704938 Published online 4 April 2005 [ABSTRACT FROM AUTHOR]

Summary:Nonmyeloablative allogeneic stem cell transplantation (NST) has considerable activity in patients with metastatic renal cell carcinoma (RCC), although there are limited long-term follow-up data. Between February 1999 and May 2003, 18 patients with metastatic RCC underwent 19 matched-sibling NSTs after conditioning with fludarabine and cyclophosphamide with tacrolimus and mycophenolate mofetil as post-transplant immunosuppression. Among the four objective responses, all were partial and have relapsed with a median response duration of 609 days (range, 107-926). All responders are alive at a median of 41 months. Median overall survival for the entire cohort was 14 months. There were four early treatment-related deaths and one late treatment-related death. Eight patients died from progressive disease and five (28%) from treatment-related mortality. Stratifying transplant outcome as early death, intermediate (no response, no early death), or response, the combination of pre-treatment anemia and decreased performance status, was associated with adverse outcome (P=0.015) and reduced survival (HR 5.4, 95%confidence interval of 1.4 to 21, P=0.007). Responders demonstrated prolonged survival compared to nonresponders (P=0.002). NST leads to durable responses in a minority of metastatic RCC patients. Appropriate patient selection is paramount. Anemia and decreased performance status may enable risk stratification.Bone Marrow Transplantation (2005) 35, 253-260. doi:10.1038/sj.bmt.1704760 Published online 15 November 2004 [ABSTRACT FROM AUTHOR]

Summary:Follicular non-Hodgkin's lymphomas usually present in advanced stage and although frequently are chemotherapy-sensitive remain incurable using conventional approaches. Treatment options are evolving rapidly and now include targeted therapies such as monoclonal antibodies. Recent studies, including the EBMTR-sponsored‘CUP Trial’(conventional Chemotherapy, Unpurged autograft, Purged autograft), demonstrate that for patients under age 60 years with recurrent chemotherapy-sensitive disease, autologous stem cell transplantation (ASCT) provides a survival benefit over conventional therapy. Allogeneic stem cell transplantation (alloSCT) has become a more effective option. Although incorporation of TBI into the preparative regimen may increase treatment-related mortality (TRM), relapses appear to be reduced compared to a chemotherapy-alone regimen. Reduced-intensity alloSCT procedures are now being performed at an increasing rate, in part due to a lower risk for TRM. Until more data are available, however, reduced-intensity alloSCT should be considered only in cases where myeloablative conditioning is contra-indicated. There are no clear means for choosing ASCT vs alloSCT, a decision influenced by the amount of residual tumor, disease-responsiveness, degree of marrow involvement and extent of prior chemotherapy. ASCT or alloSCT in first remission remains an investigational procedure. Future considerations include incorporation of novel preparative regimens, in vitro purging techniques, antilymphoma vaccines, post transplant immunotherapy and ex vivo-manipulated donor lymphocyte infusions.Bone Marrow Transplantation (2004) 34, 929-938. doi:10.1038/sj.bmt.1704654 Published online 18 October 2004 [ABSTRACT FROM AUTHOR]

Our purpose was to study the risk factors associated with disease progression after high-dose chemotherapy followed by autologous stem cell transplantation in patients with recurrent or refractory Hodgkin's lymphoma (HL). We analyzed the tong-term outcome of 184 patients with recurrent or refractory HL who underwent autologous hematopoietic stem cell transplantation. At the time of transplantation, 82 patients were in first relapse or second remission, 46 patients were refractory to the primary induction chemotherapy, and 56 patients were beyond first relapse or second remission. In 64 patients, the disease had proved refractory to the chemotherapy regimen administered immediately prior to transplantation. The median follow-up of patients who were alive and free of disease at the time of this report was 8.9 years (range, 0.1-19.0 years). At 10 years, the overall and disease-free survival rates were 34% (95% CI 27-42) and 29% (95% CI 22- 36) respectively. The major cause of treatment failure was disease relapse. Chemotherapy resistance prior to trans- plantation, advanced stage, and higher number of chemotherapy regimens administered prior to transplantation were adverse prognostic factors for disease progression. We conclude that autologous transplantation is an effective salvage treatment for recurrent HL. [ABSTRACT FROM AUTHOR]

Summary:A total of 31 consecutive patients with hematologic malignancies who were considered poor candidates for TBI underwent allogeneic stem cell transplantation after conditioning with fludarabine and melphalan. A total of 25 matched sibling recipients received fludarabine 25?mg/m2 × 5 days and melphalan 70?mg/m2 × 2 days. For unrelated and haploidentical donor recipients, fludarabine was increased to 30?mg/m2 and ATG 30?mg/kg × 4 days was added. Graft-versus-host disease prophylaxis consisted of tacrolimus and mini methotrexate. All patients engrafted. Regimen-related toxicity was considerable and included mainly renal, hepatic and mucosal toxicity. There were seven regimen-related-deaths including two VOD, two pulmonary, one renal, one cardiac and one mucosal toxicity. One case of fatal pulmonary toxicity death could be attributed to pre-existing pulmonary damage. Progression-free survival at 12 months was 44% (90% CI: 30-58%) for recipients of HLA-identical sibling transplants and 33% (90% CI: 21-45%) for all patients. In conclusion, the fludarabine-melphalan regimen leads to consistent engraftment. The regimen-related toxicity is considerable and cannot be explained solely by patient selection. Cardiac toxicity is emerging as a unique toxicity of this regimen. Despite toxicity, fludarabine-melphalan has considerable activity and leads to durable remission in a proportion of patients.Bone Marrow Transplantation (2003) 32, 471-476. doi:10.1038/sj.bmt.1704166 [ABSTRACT FROM AUTHOR]

Summary:Fludarabine, thiotepa and total body irradiation (TBI) has been used as conditioning in haplo-identical transplantation. We studied this conditioning regimen in adults undergoing matched sibling transplantation and alternative donor transplantation. A total of 30 consecutive patients underwent matched related, haplo-identical related or matched unrelated donor transplantation with fludarabine, thiotepa and TBI conditioning. All but four had advanced hematologic malignancies. For haplo-identical transplant, ATG was added to the regimen. All patients received peripheral blood stem cells; these were T-cell depleted for 2-antigen or 3-antigen mismatched related transplantation. Additional graft-versus-host disease prophylaxis consisted of tacrolimus and mini-methotrexate. One recipient of haplo-identical transplant failed to engraft; all other evaluable patients had prompt engraftment. Four patients died of regimen-related toxicity. In all, 14 additional patients died of regimen-related causes including four from failure to thrive with persistent thrombocytopenia and four from delayed pulmonary toxicity. Six patients relapsed. Progression-free survival at 12 months was 47% (90% CI: 25-69%) for recipients of HLA-identical sibling transplants and 30% (90% CI: 14-46%) for all patients. Five of six long-term survivors have extensive chronic GVHD. As a result of the delayed complications and a relatively high recurrence rate, we abandoned this regimen.Bone Marrow Transplantation (2003) 32, 9-13. doi:10.1038/sj.bmt.1704088 [ABSTRACT FROM AUTHOR]

Summary:To establish the incidence of CMV viremia after allogeneic blood stem cell transplantation, we studied 51 consecutive allogeneic peripheral blood stem cell (PBSC) transplant recipients. A total of 12 recipients were at moderate risk for CMV disease and 39 were at high risk. Conditioning regimens varied, but GvHD prophylaxis consisted of tacrolimus and mini-methotrexate in all patients. All patients received prophylactic ganciclovir from admission until day -2 and prophylactic acyclovir from day -1 until day 180 after transplantation. CMV viremia was treated with ganciclovir. Using a PCR-based technique, the cumulative incidence of CMV viremia was 31±14% by day 100 and 35±14% by day 150. Donor type, CMV risk group, underlying disorder, conditioning regimen, GvHD, and steroid use were not associated with the risk for CMV viremia. No cases of CMV disease occurred. We hypothesize that the low rate of CMV viremia and the absence of CMV disease in this cohort of PBSCT transplant recipients, which contrasts with other reports, may be related to the prophylactic use of high-dose acyclovir and possibly to pretransplant use of ganciclovir.Bone Marrow Transplantation (2003) 31, 813-816. doi:10.1038/sj.bmt.1703916 [ABSTRACT FROM AUTHOR]

Background: Intermediate- and high-grade NHL are generally chemosensitive diseases with high initial response rates to combination chemotherapy. Dose intensification via autologous and allogeneic transplantation provides viable treatment options in specific clinical settings. Currently, autologous transplantation is the standard of care for relapsed but chemosensitive aggressive B-cell NHL. However, tools such as the International Prognostic Index allow risk-adapted analyses, and show that the magnitude of benefit from autologous transplantation differs in lymphoma subsets. Methods: Low-risk patients appear to do well regardless of salvage approaches, whereas high-risk patients have suboptimal outcomes with autologous transplantation. In high-risk patients, high-dose chemotherapy with autologous stem-cell transplantation has been examined as part of initial therapy, with long-term data promising but still evolving. Discussion: A significant concern with autologous transplantation in aggressive and high-grade NHL is the risk of graft contamination with tumor cells. Several investigators have demonstrated the presence of malignant cells in both BM and PBSC, although the clonagenic potential of such cells is unclear. Allogeneic stem-cell transplantation has several potential advantages over autologous transplantation for NHL,including procurement of an uncontaminated stem-cell graft, GvL effects, and the elimination of hematopoietic stem-cell damage and consequent secondary leukemia. Results: The ideal application of allogeneic transplantation in aggressive and high-grade lymphomas is still unclear; but the lower relapse rates demonstrated in several comparisons of the two approaches make this an exciting area to pursue. Finally, non-myeloablative stem-cell transplantation may broaden the use of allogeneic transplantation by lowering regimen-related mortality while capitalizing on GvL. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplantation is increasingly considered as a curative though risky treatment option for adults with sickle cell disease. Little is known about attitudes of adult patients and their health care providers regarding the risks and benefits of transplantation. A survey of 100 patients and their health care providers was undertaken. Assessment of risk was by a reference gamble paradigm. Comparison was made of the characteristics of those accepting substantial risk vs those not accepting risk, as well as assessment of agreement on risks recommended by health care providers and accepted by patients. Sixty-three of 100 patients were willing to accept some short-term risk of mortality in exchange for the certainty of cure. Fifteen patients were willing to accept more than 35% mortality risk. No differences in patient or disease-related variables were identified between those accepting risk and those not accepting risk. There was no agreement between the recommendations of health care providers and the risk accepted by patients. A substantial proportion of adults with sickle cell disease are interested in curative treatment, at the expense of considerable risk. The decision to accept risk is influenced by individual patient values that cannot be easily quantified and that do not correlate with the assessment of the health care provider. Given the substantial interest in curative therapy, education about and consultation for allogeneic stem cell transplantation in sickle cell patients should be encouraged. Bone Marrow Transplantation (2001) 28, 545–549. [ABSTRACT FROM AUTHOR]

Severe regimen-related toxicity often complicates second transplant procedures performed in patients with hematological malignancies that have relapsed after an initial hematopoietic stem cell (HSC) transplant. Therefore, we studied the safety and efficacy of a reduced-intensity fludarabine and melphalan based conditioning regimen in 11 patients who had relapsed following an autologous (n = 7) or allogeneic (n = 4) HSC transplant. All patients received allogeneic peripheral blood HSC from either an HLA-identical (n = 7) or an HLA-mismatched (n = 4) relative. Diagnoses included AML (n = 9), ALL (n = 1), or Hodgkin’s disease (n = 1). Only one patient was in complete remission at the time of second transplant. The median interval between first transplant and relapse was 163 days (range 58–1885). Recipients of HLA-mismatched transplants received antithymocyte globulin in addition to fludarabine and melphalan as part of the conditioning regimen. All 11 patients received acute GVHD prophylaxis consisting of tacrolimus and methotrexate. Ten of 11 patients achieved hematopoietic engraftment with a median time to absolute neutrophil count >0.5 × 109/l and to platelet count of >20 × 109/l of 14 and 19 days, respectively. All engrafting patients achieved 100% donor chimerism on initial analysis, except for one with persistent leukemia at day +19. Two patients experienced grade 3 regimen-related toxicity, manifesting as acute renal failure. Acute GVHD grades 2–4 occurred in two recipients and chronic GVHD in four. The 100-day mortality from all causes was 36%. Ten of 11 patients (91%) died a median of 140 days (range 9–996) after the second transplant. The causes of death included relapse (n = 5), sepsis (n = 4), and idiopathic pneumonia syndrome (n = 1). One patient with AML survives in remission at 880 days post-transplant. We conclude that fludarabine- and melphalan-based conditioning promotes full donor... [ABSTRACT FROM AUTHOR]

Autologous and allogeneic transplantation are increasingly used in the management of patients with chronic lymphocytic leukemia. Many questions regarding patient selection, efficacy and outcome are unresolved, hence a review of the literature through Medline search. Autologous transplantation for CLL has been used mainly in selected patients under the age of 60. Conditioning typically involves total body irradiation (TBI). Bone marrow and more recently peripheral blood stem cells are used. Treatment-related mortality in most series is less than 10%. Molecular remissions after autologous transplantation are common, and clinical remissions can be prolonged in some patients. Randomized studies are needed to establish whether autologous transplantation confers a survival benefit over standard chemotherapy approaches. Allogeneic transplantation has a considerable treatment-related mortality, but durable remissions sometimes occur in patients with advanced disease. The use of non-myeloablative 'mini-transplants' has been investigated as a method to reduce treatment-related mortality, but prolonged follow-up will be required to establish the cure rate obtained with this procedure. Autologous and allogeneic transplantation are promising treatment modalities. Further refinements of transplant techniques and properly designed prospective studies are necessary to establish the role of stem cell transplantation in the overall management of CLL. [ABSTRACT FROM AUTHOR]

The purpose of the study was to evaluate in patients with recurrent intermediate-grade NHL, the tolerance to and efficacy of an intensive salvage regimen consisting of high doses of ifosfamide, etoposide and mitoxantrone with G-CSF support, followed by autologous stem cell transplantation and to identify prognostic factors for survival in patients with recurrent aggressive lymphoma. Patients with recurrent intermediate-grade NHL under the age of 60 years were eligible. Induction consisted of ifosfamide 10 g/m2 and etoposide 900 mg/m2 with G-CSF 5 μg/kg twice a day. Upon recovery, patients underwent stem cell apheresis. Patients achieving complete remission (CR) underwent autologous stem cell transplantation using BEAM conditioning. Those with partial remission (PR) received treatment with ifosfamide 10 g/m2, mitoxantrone 20 mg/m2 and G-CSF 5 μg/kg. Those with CR received BEAM, those with PR received cyclophosphamide 4.5 g/m2, etoposide 1200 mg/m2 and cisplatin 135 mg/m2 with stem cell rescue followed by BEAM. Antibiotic prophylaxis was given with all treatment cycles. The results were compared with those obtained in a prior study that used MINE-ESHAP salvage. Forty-four patients with recurrent intermediate-grade NHL were enrolled between March 1994 and September 1996. Median age was 50 years (24–61). Eleven patients had transformed lymphoma and seven had a T cell phenotype. Response rate to the high-dose ifosfamide regimen was 77% ± 12% after two cycles and the complete response rate was 41% ± 14%. Myelosuppression was profound but short. Median nadir ANC was 0 and the median duration of ANC <0.5 × 109/l was 6 days (range 3–12). No severe infections occurred; 55% of the patients required blood transfusion and 42% required platelet transfusions. Myelosuppression and transfusion requirements were similar after the first and second cycles.... [ABSTRACT FROM AUTHOR]

Although allogeneic transplantation can be curative for patients with sickle cell disease, the toxicity of conditioning regimens has precluded its use in adults with significant end-organ damage. Newer conditioning regimens have been developed that are less toxic and that may broaden the applicability of allogeneic transplantation in this disorder. We report two adults with end-stage sickle cell disease, who underwent allogeneic transplantation from an HLA-identical sibling donor after conditioning with fludarabine/melphalan and ATG. Both patients had been extensively transfused and one had multiple RBC antibodies. One of the patients also had end-stage renal disease, and was dialysis dependent. Engraftment occurred promptly in both patients. Both achieved 100% donor chimerism and both were free of pain crises after transplant. The first patient died of a respiratory failure related to chronic graft-versus-host disease (GVHD) on day 335 after transplantation. The second patient developed severe gastro-intestinal GVHD and TTP and died on day 147 after transplantation. Conditioning with fludarabine/melphalan and ATG followed by allogeneic stem cell transplantation resulted in prompt and reliable engraftment in adults with end-stage sickle cell disease. The incidence of severe GVHD was unacceptably high and may be related to the ethnicity of the patients or to the inflammatory state associated with pre-existing sickle cell disease. Bone Marrow Transplantation (2000) 26, 445–449. [ABSTRACT FROM AUTHOR]

Patients with acute leukemias relapsing within 1 year of an allogeneic BMT have a poor prognosis. We studied the use of melphalan 180 mg/m2 followed by allogeneic peripheral blood stem cells (PBSC) as salvage treatment for patients relapsing after related (n = 7) or matched unrelated transplants (n = 3). Diagnoses were AML (n = 4), ALL (n = 3), biphenotypic acute leukemia (n = 2) and CML in blast crisis (n = 1). Eight patients were beyond first relapse and none were in remission. The median time from previous transplant to relapse was 146 days (range 66–206). The melphalan dose was 90 mg/m2 intravenously on days -4 and -3 with pbsc infusion on day 0. gvhd prophylaxis consisted of cyclosporine and methylprednisolone. the median time to an absolute neutrophil count >0.5 × 109/l and to a platelet count >20 × 109/l was 11 and 13 days, respectively. All engrafting patients (n = 8) had 100% donor cells. Two patients died before day 30, but no other grade 3 or 4 toxicity occurred. Acute GVHD grades II–III occurred in two subjects, and chronic GVHD in four. Seven patients achieved CR, but relapsed at a median of 116 days (range 56–614). Leukemia was the cause of death in eight patients. Median survival was 149 days (range 6–614). This treatment produced responses in the majority of this poor prognosis group. However, durable remissions were not observed, and new treatments to consolidate the responses achieved in this setting are needed. This regimen could be considered for short-term disease control to facilitate donor lymphocyte infusion-based immunotherapy or other measures to prevent disease recurrence. Bone Marrow Transplantation (2000) 26, 333–338. [ABSTRACT FROM AUTHOR]

Thirty adults with leukemia or lymphoma transplanted with marrow or blood stem cells from 1-antigen mismatched related donors received tacrolimus and minidose methotrexate to prevent acute graft-versus-host disease (GVHD). The group had a median age of 42 years (range 18–56 years). Twenty-seven patients had advanced disease, and 13 were resistant to conventional therapy. Tacrolimus was administered at 0.03 mg/kg/day i.v. by continuous infusion from day -2, converted to oral at four times the i.v. dose following engraftment, and continued to day 180 post-transplant. Methotrexate 5 mg/m2 was given i.v. on days 1, 3, 6 and 11. Mild nephrotoxicity was common before day 100; 69% of patients had a doubling of creatinine, 56% had a peak creatinine greater than 2 mg/dl, and two patients were dialyzed. Other toxicities prior to day 100 thought to be related to tacrolimus included hypertension (45%), hyperkalemia (17%), hyperglycemia (14%), seizures (13%), headache (3%) and hemolytic uremic syndrome (3%). Grades 2–4 GVHD occurred in 59% (95% CI, 38–70%), and grades 3–4 GVHD in 17% (95% CI, 1–32%). Overall survival at 1 year was 29% (95% CI, 12–45%). We conclude that tacrolimus and minidose methotrexate is active post-transplant immunosuppression for patients with 1-antigen mismatched donors. [ABSTRACT FROM AUTHOR]

To determine the safety of single daily dose (SDD) gentamicin in recipients of stem cell transplantation (SCT), we evaluated all adult patients at MD Anderson Cancer Center who received SDD gentamicin for treatment of febrile neutropenia. Thirty-three patients received gentamicin 5 mg/kg i.v. every 24 h. Mean duration of therapy was 7 days (range 3–32 days). All patients received vancomycin and 17 received cisplatinum. All patients had normal renal function prior to therapy. Serum gentamicin levels were monitored only when renal function deteriorated. The incidence of nephrotoxicity and clinically significant ototoxicity was 3% and 12%, respectively. All four patients who developed ototoxicity had normal renal function before and during therapy. The mean duration of gentamicin therapy was significantly longer in patients who developed ototoxicity, 20 days vs 9 days (P = 0.001). Patients treated with SDD gentamicin for >10 days were more likely to develop ototoxicity (P = 0.045). Single daily dosing of gentamicin was associated with clinically significant ototoxicity in 12% of our patients. A larger randomized EORTC trial evaluating SDD vsMDD amikacin failed to detect a difference in ototoxicity. However, the median duration of therapy was only 8 days. The increased incidence of ototoxicity in our study may be due to prolonged therapy, type of aminoglycoside used, concomitant ototoxic agents, small sample size, or a combination of the above. [ABSTRACT FROM AUTHOR]

Thirty-six adults with chronic myelogenous leukemia (CML) in second or greater chronic phase, accelerated phase, or blast crisis underwent marrow or blood stem cell transplantation from an HLA-matched sibling using high-dose thiotepa, busulfan and cyclophosphamide (TBC) as the preparative regimen. All evaluable patients engrafted and had complete donor chimerism. One patient failed to clear meningeal leukemia, and one patient had one of 30 metaphases positive for the Philadelphia chromosome at 2 months post transplant. The remainder of the patients studied had eradication of CML documented by cytogenetics and/or Southern blot for BCR gene rearrangement, and 13 of 15 patients studied became negative for the BCR gene rearrangement by polymerase chain reaction. Three-year relapse rate is 42% (95% CI, 19–64%). The relapse rate was significantly lower for patients transplanted without blast crisis (9% vs 100%, P < 0.001). eight (22%, 95% ci, 10–39%) patients had severe or fatal veno-occlusive disease (vod). elevated liver enzymes within 1 month prior to transplantation and transplantation using marrow were significantly associated with the occurrence of vod. three-year survival is 28% (95% ci, 13–43%). survival was significantly higher for patients transplanted without blast crisis (45% vs 0%, P = 0.01). TBC is an effective preparative regimen for CML in accelerated phase but not refractory blast crisis, and it should be used with caution in patients with prior hepatopathy who have an increased risk of severe VOD. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) disease can be prevented by administration of ganciclovir prophylactically post-transplant. However, up to 30% of patients discontinue use of ganciclovir as a result of profound neutropenia and may subsequently develop CMV infections while unprotected. To prevent reactivation of CMV, we administered foscarnet to 39 adults unable to receive ganciclovir due to delayed engraftment or ganciclovir-induced neutropenia. Twenty-four (62%) of the patients had received T cell-depleted marrow transplants. Foscarnet sodium 60 mg/kg i.v. daily was continued until the neutropenia resolved, at which time ganciclovir was resumed. CMV prophylaxis commenced at a median of 28 days following transplantation. Median time to initiation of foscarnet was day 60 post-transplant, and the median duration of treatment was 22 days. Foscarnet was well-tolerated. Six (15%) patients had CMV detected while receiving prophylaxis, and CMV-related mortality was 5%. Foscarnet is a safe and effective agent for prevention of CMV disease in allogeneic transplant recipients unable to receive ganciclovir. [ABSTRACT FROM AUTHOR]

Donor lymphocyte infusions, by virtue of a graft-versus-tumor effect, have been shown to induce remissions in leukemia that recurs after allogeneic bone marrow transplantation. Similar effects have been postulated to contribute to the decreased recurrence rate observed after allogeneic transplantation in non-Hodgkin’s lymphoma. This lower recurrence rate may be due to a variety of other mechanisms. We aimed to evaluate the role of graft-versus-lymphoma effects in patients in whom lymphomas recur after allogeneic transplantation. At the time of recurrence, immunosuppressive therapy was withheld. Patients with non-responding disease received an infusion of donor lymphocytes. Patients were observed for response and graft-versus-host disease. Disease in four of nine patients responded to withdrawal of immunosuppressive therapy. A minor response was observed in one of three recipients of donor lymphocyte infusions. Responses were observed among two patients with follicular lymphoma, one with large cell lymphoma and one with lymphoblastic lymphoma. A minor response was observed in a patient with prolymphocytic leukemia/lymphoma. We conclude that withdrawal of immunosuppressive therapy and donor lymphocyte infusion can induce durable remissions in patients with recurrent lymphoma after allogeneic transplantation. [ABSTRACT FROM AUTHOR]

Allogeneic bone marrow transplantation for advanced hematologic cancer is associated with a high risk of early treatment-related morbidity and mortality. To determine the short-term benefits of allogeneic blood stem cell transplants when compared to bone marrow transplants, we reviewed outcomes of 74 adults with advanced hematologic cancer transplanted from HLA-matched related donors after conditioning with thiotepa, busulfan and cyclophosphamide. There were three cohorts: group 1 received bone marrow transplants with cyclosporine (CsA) and methotrexate (MTX) for GVHD prophylaxis; group 2 received bone marrow transplants with CsA and methylprednisolone (MP); and group 3 received blood stem cells with CsA and MP. All patients received filgrastim post-transplant. Median times (range) to neutrophils 0.5 × 109/l were 17 (8–30), 9 (8–16) and 10 (8–13) days post-transplant, and to platelets 20 × 109/l were 28 (14–100+), 19 (13–100+) and 14 (9–86) days post-transplant for groups 1, 2 and 3, respectively (P < 0.05 only for group 1 vs group 3 for both outcomes). Blood stem cell recipients had the least regimen-related toxicity, fewest early deaths and earliest discharge. There was no significant difference in acute GVHD between the three groups. One hundred and eighty-day survivals (95% CI) were 53% (35–72%), 32% (10–53%), and 68% (49–87%) for groups 1, 2 and 3, respectively (P < 0.05 only for group 2 vs group 3). For allogeneic transplantation, use of blood stem cell grafts has substantial advantages over marrow grafts. [ABSTRACT FROM AUTHOR]

We evaluated the response to and toxicity of allogeneic or autologous bone marrow transplantation (BMT) for patients with non-Hodgkin’s lymphoma (NHL) who relapsed after autologous BMT. Since 1990, 172 patients have received autologous BMTs for NHL at the MD Anderson Cancer Center and 75 have relapsed. Twelve patients (median age, 42 years), with disease recurrence underwent either allogeneic BMT (eight patients) or a second autologous BMT (four patients). Ten patients received thiotepa, busulfan and cyclophosphamide as conditioning, one patient received cyclophosphamide and total body irradiation and one received BCNU, etoposide, Ara-c and melphalan. The median interval between the first and second transplants was 23.5 months (range 5–80 months). Three patients who underwent allogeneic BMT had refractory relapses, three had a responsive relapse and two were in complete response (CR) at the time of BMT. Five patients received peripheral blood stem cells and three patients, allogeneic bone marrow. Three patients are alive and disease-free at 25, 22 and 7 months after allogeneic BMT. Four patients died of treatment-related causes and one from disease recurrence. All four patients undergoing autologous BMT had responsive relapses. Three patients received peripheral blood stem cells and one patient bone marrow. Two patients are alive and disease-free at 12 and 30 months after autologous transplants. There were no treatment-related deaths; two patients died of disease recurrence. This retrospective study shows that in selected patients, allogeneic or autologous BMT is an effective salvage therapy for NHL which recurs after autologous BMT. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma" by C. Anasetti and colleagues.

Comments on a study finding which indicates that with reduced intensity conditioning, age over 55 no longer represents a contra-indication for unrelated donor transplantation. Occurrence of hematologic malignancies; Critical factors in transplantation technology; Advances in transplant technology; Varying methods of graft-versus-host diseases prophylaxis; MD Anderson's pioneering of the fludarabine melphalan regimen.

The aim was to determine the efficacy and safety of decitabine in the settings of relapse post-allogeneic progenitor cell transplantation or as part of the conditioning regimen. Three patients (two AML, one ALL) received single agent decitabine 1000 mg/m² total dose) for treatment of relapse post-transplant (group 1). Median age was 32 years. Median time to relapse was 7 months. In another study four patients (three CML in an accelerated phase, one AMML) received decitabine 400 mg/m², with busulfan 12 mg/kg and cyclophosphamide 100 mg/kg as conditioning for allogeneic stern cell transplantation (group 2). Median age was 42 years; median time to transplant was 5 months. All patients received at least 4 × 106 CD34+ cells from their HLA compatible donors. All patients in group 1 achieved complete remissions after decitabine therapy. The median time to neutrophil and platelet recovery were 24 and 23 days, respectively. Two patients required reinfusion of donor cells because of delayed engraftment. One patient remains alive and in remission 160 days post-decitabine therapy. Two patients in group 2 engrafted on days 23 and 25. Two patients required reinfusion of stem cells because of lack of neutrophil recovery by day 21. Two patients achieved complete cytogenetic and hematologic remission. Three patients are alive at 167, 129, and 109 days post-transplant. One patient died of progressive Pseudomonas cellulitis 54 days post-initial infusion. Decitabine therapy is well tolerated in the setting of allogeneic stem cell transplantation, initial results in patients relapsing after transplant are encouraging and warrant further studies. The causes of delayed engraftment after single agent or combination therapy need to be better explored. The existence of active metabolites of decitabine which may still be present in the blood at the time of stem cell infusions, and/or insufficient immuno-suppression of the preparative regimen are being explored as possible explanations for this phenomenon. [ABSTRACT FROM AUTHOR]

A letter to the editor that features a case report on severe intestinal graft-versus-host disease following autologous stem cell transplantation is presented.

Leukemia (2003) 17, 271–272. doi:10.1038/sj.leu.2402735 [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article about the combination of fludarabine, melphalan and alemtuzumab, which was published online on May 14, 2007.