Impact of positron emission tomography - computed tomography status on progression-free survival for relapsed follicular lymphoma patients undergoing autologous stem cell transplantation.

The optimum management approach for patients with relapsed or refractory follicular lymphoma remains uncertain. Autologous stem cell transplantation (autoSCT) is considered a standard option in suitable, younger patients with relapsed follicular lymphoma. AutoSCT is associated with very durable remissions in a minority of subjects, but also with significant, well-established toxicities. Although positron emission tomography (PET) status prior to autoSCT is an established prognostic factor in diffuse large B-cell lymphoma and Hodgkin lymphoma, no data exist in follicular lymphoma. We describe survival outcomes according to pre-transplant PET status, classified by the Lugano criteria into complete metabolic remission (CMR) versus non-CMR, in 172 patients with relapsed or refractory follicular lymphoma within a national, multicenter, retrospective British Society of Blood and Marrow Transplantation and Cellular Therapy registry study. The median number of lines of therapy prior to SCT was three (range, 1-6). The median follow-up after SCT was 27 months (range, 3-70). The median progression-free survival for all patients after autoSCT was 28 months (interquartile range, 23- 36). There was no interaction between age at transplantation, sex, number of months since last relapse, Karnofsky performance status or comorbidity index and achieving CMR prior to autoSCT. Superior progression-free survival was observed in 115 (67%) patients obtaining CMR versus 57 (33%) non-CMR patients (3-year progression-free survival 50% vs. 22%, P=0.011) and by pre-SCT Deauville score (continuous variable 1-5, hazard ratio [HR]=1.32, P=0.049). PET status was independently associated with progression-free status (non-CMR HR=2.02, P=0.003), overall survival (non-CMR HR=3.08, P=0.010) and risk of relapse (non-CMR HR=1.64, P=0.046) after autoSCT by multivariable analysis. Our data suggest that pre- SCT PET status is of clear prognostic value and may help to improve the selection of patients for autoSCT.

Autologous Stem Cell Transplantation Is an Effective Salvage Therapy for Primary Refractory Multiple Myeloma.

High-dose therapy and autologous stem cell transplantation (ASCT) have proven efficacy in patients with multiple myeloma responding well to induction therapy. For those who fail to achieve a stable partial response (PR), the effect of ASCT is unclear. We report on 126 patients identified from a national database, who underwent ASCT having achieved

Pediatric Adapted Risk index (PARI) to predict 2-year transplant related mortality post-HSCT in children.

Several attempts have been made to optimize pre-transplant risk assessment to improve hematopoietic stem cell transplantation (HSCT) decision-making and to predict outcome post- HSCT. However, its relevance to the pediatric population remains unclear. We report the results of revalidation of the HCT-CI in 874 children who received 944 HSCTs for malignant or non-malignant diseases at a single centre. After finding the HCT-CI invalid in our patient population; we proposed a modified pediatric adapted scoring system that captures risk factors (RF) and comorbidities (CoM) relevant to pediatrics. Each RF/CoM was assigned an integer weight based on its hazard ratio (HR) for TRM; 0 (HR <1.2), 1 (1.2 ≥HR <1.75), 2 (1.75 ≥HR <2.5), 3 (HR ≥2.5) .Using these weights, the pediatric adapted HSCT-RI (PARI) was devised, and patients were divided into 4 risk groups; group 1 without RF/CoM, group 2: scores 1-2, group 3: scores 3-4, group 4: scores ≥5. There was a linear increase in 2-year TRM from group 1 to 4 (TRM= 6.2% in group 1, 50.9% in group 4). PARI was successfully validated on an internal and external cohort of pediatric patients. Comparing models using c-statistics, PARI was found to be a better model than HCT-CI in predicting 2-year TRM in children with Akaike's and Schwarz's Bayesian information criteria (AIC and BIC) of 1069.245 and 1073.269; respectively using PARI vs 1223.158 and 1227.051; respectively using HCT-CI. We believe that PARI will be a valuable tool enabling better counselling and decision making for pediatric HSCT patients.

Outcome of donor lymphocyte infusion after T cell-depleted allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndromes.

Relapse occurs in 30%-50% of recipients of T cell-depleted (TCD) reduced-intensity conditioned (RIC) hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). Despite limited published supportive data, donor lymphocyte infusion (DLI) is used preemptively (pDLI) to improve donor chimerism and prevent relapse, and therapeutically (tDLI) after disease recurrence. We evaluated the efficacy and toxicity of pDLI and tDLI in 113 patients after TCD (alemtuzumab, n = 99; antithymocyte globulin, n = 14) RIC HSCT for AML or MDS. Recipients of pDLI (n = 62) had an estimated 5-year overall survival (OS) of 80% and an event-free survival of 65%. More than one-half (52%; n = 32) of the patients received pDLI within 6 months post-HSCT; despite this, the 5-year incidence of graft-versus-host disease was only 31% (95% confidence interval [CI], 19%-43%). Recipients of tDLI (n = 51) had an estimated 5-year OS of 40% and a 5-year relapse/progression rate of 69% (95% CI, 54%-81%). Recipients of tDLI at >6 months post-HSCT had a significantly superior 5-year OS after tDLI compared with those treated earlier (P = .008). The cumulative incidence of graft-versus-host disease at 5 years after tDLI was 45% (95% CI, 23%-65%). We demonstrate that pDLI safely promotes durable remission after TCD RIC HSCT for AML or MDS, and that tDLI salvages patients after late relapse with greater efficacy.

Haematopoietic stem cell transplantation (HSCT) in severe autoimmune diseases: analysis of UK outcomes from the British Society of Blood and Marrow Transplantation (BSBMT) data registry 1997-2009.

The British Society of Blood and Marrow Transplantation Data Registry was used to analyse outcomes of haematopoietic stem cell transplantation (HSCT) in severe autoimmune diseases (SADs) from 1997 to 2009. 55 autologous and 15 allogeneic HSCT were registered (0·22% of overall UK HSCT activity). Sustained responses were observed following HSCT, although toxicity was significant. This is the first reported national analysis of long-term outcomes of HSCT in SADs, and should be viewed in the context of translational and developmental phases of HSCT in poor prognosis and refractory SADs. Treatment of poor-risk but reversible SADs with adequate fitness for HSCT in accordance with current guidelines is warranted.

Unrelated donor peripheral blood stem cell transplants incorporating pre-transplant in-vivo alemtuzumab are not associated with any increased risk of significant acute or chronic graft-versus-host disease.

There is little information published comparing peripheral blood stem cells (PBSC) with bone marrow (BM) as the stem cell source in the long-term outcome in recipients of T-cell depleted (TCD) unrelated donor (UD) transplants. We present retrospective outcome data on 306 recipients of myeloablative, human leucocyte antigen-matched UD allografts using pre-transplant in-vivo Alemtuzumab. Transplants were performed between 2000 and 2007 for chronic myeloid leukaemia in first chronic phase and acute leukaemia in first or second complete remission; 184 patients received BM and 122 PBSC. The median age was 28·9 years (<1-58) and the median follow-up was 48 months. Overall survival at 8 years was 53%. The incidence of acute graft-versus-host disease (GvHD) was significantly higher in PBSC (65%) than BM recipients (49%; P=0·012). This represented only grade 1 GvHD with no difference in grade II-IV aGvHD (BM 23% PBSC 24%). The incidence of chronic GvHD, either overall (BM 47%, PBSC 49%) or extensive (BM 15%, PBSC 13%) was not increased with PBSC. The incidence of relapse, non-relapse mortality and survival were not significantly different. Whilst accepting the limitations of retrospective analyses, we suggest the increased risk of GvHD in recipients of PBSC in T-replete transplants is offset by in-vivo Alemtuzumab, and that either stem cell source can be used with good outcomes in this setting.

Presence of donor-encoded centromeric KIR B content increases the risk of infectious mortality in recipients of myeloablative, T-cell deplete, HLA-matched HCT to treat AML.

The reported influence of donor Killer-cell Immunoglobulin-like Receptor (KIR) genes on the outcomes of haematopoietic cell transplantation (HCT) are contradictory, in part due to diversity of disease, donor sources, era and conditioning regimens within and between different studies. Here, we describe the results of a retrospective clinical analysis establishing the effect of donor KIR motifs on the outcomes of 119 HLA-matched, unrelated donor HCT for adult acute myeloid leukaemia (AML) using myeloablative conditioning (MAC) in a predominantly T-cell deplete (TCD) cohort. We observed that HCT involving donors with at least one KIR B haplotype were more likely to result in non-relapse mortality (NRM) than HCT involving donors with two KIR A haplotypes (p = 0.019). Upon separation of KIR haplotypes into their centromeric (Cen) and telomeric (Tel) motif structures, we demonstrated that the Cen-B motif was largely responsible for this effect (p = 0.001). When the cause of NRM was investigated further, infection was the dominant cause of death (p = 0.006). No evidence correlating donor KIR B haplotype with relapse risk was observed. The results from this analysis confirm previous findings in the unrelated, TCD, MAC transplant setting and imply a protective role for donor-encoded Cen-A motifs against infection in allogeneic HCT recipients.

Favorable outcomes with alemtuzumab-conditioned unrelated donor stem cell transplantation in adults with high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in first complete remission.

BACKGROUND: Approximately 40% of adults with Philadelphia chromosome-negative acute lymphoblastic leukemia achieve long-term survival following unrelated donor hematopoietic stem cell transplantation in first complete remission but severe graft-versus-host disease remains a problem affecting survival. Although T-cell depletion abrogates graft-versus-host disease, the impact on disease-free survival in acute lymphoblastic leukemia is not known. DESIGN AND METHODS: We analyzed the outcome of 48 adults (median age 26 years) with high-risk, Philadelphia-chromosome-negative acute lymphoblastic leukemia undergoing T-cell depleted unrelated donor-hematopoietic stem cell transplantation (67% 10 of 10 loci matched) in first complete remission reported to the British Society of Blood and Marrow Transplantation Registry from 1993 to 2005. RESULTS: T-cell depletion was carried out by in vivo alemtuzumab administration. Additional, ex vivo T-cell depletion was performed in 21% of patients. Overall survival, disease-free survival and non-relapse mortality rates at 5 years were 61% (95% CI 46-75), 59% (95% CI 45-74) and 13% (95% CI 3-25), respectively. The incidences of grades II-IV and III-IV acute graft-versus-host disease were 27% (95% CI 16-44) and 10% (95% CI 4-25), respectively. The actuarial estimate of extensive chronic graft-versus-host disease at 5 years was 22% (95%CI 13-38). High-risk cytogenetics at diagnosis was associated with a lower 5-year overall survival (47% (95% CI 27-71) vs. 68% (95% CI 44-84), p=0.045). CONCLUSIONS: T-cell depleted hematopoietic stem cell transplantation from unrelated donors can result in good overall survival and low non-relapse mortality for adults with high-risk acute lymphoblastic leukemia in first complete remission and merits prospective evaluation.

Cell membrane trans-fatty acids and the risk of primary cardiac arrest.

BACKGROUND: The relation of trans-fatty acid intake to life-threatening arrhythmias and primary cardiac arrest is unknown. METHODS AND RESULTS: We investigated the association of trans-fatty acid intake, assessed through a biomarker, with the risk of primary cardiac arrest in a population-based case-control study. Cases, aged 25 to 74 years, were out-of-hospital cardiac arrest patients attended by paramedics in Seattle, Washington from 1988 to 1999 (n=179). Controls, matched to cases by age and sex, were randomly identified from the community (n=285). Participants were free of previous clinically diagnosed heart disease. Blood was obtained at the time of cardiac arrest (cases) or at the time of an interview (controls) to assess trans-fatty acid intake. Higher total trans-fatty acids in red blood cell membranes was associated with a modest increase in the risk of primary cardiac arrest after adjustment for medical and lifestyle risk factors (odds ratio for interquintile range, 1.5; 95% CI, 1.0 to 2.1). However, trans isomers of oleic acid were not associated with risk (odds ratio for interquintile range, 0.8; 95% CI, 0.5 to 1.2), whereas higher levels of trans isomers of linoleic acid were associated with 3-fold increase in risk (odds ratio for interquintile range, 3.1; 95% CI, 1.7 to 5.4). CONCLUSIONS: These findings suggest that dietary intake of total trans-fatty acids is associated with modest increase and trans isomers of linoleic acid with a larger increase in the risk of primary cardiac arrest. These associations need to be confirmed in future studies that distinguish between trans isomers of linoleic acid and trans isomers of oleic acid.

Inhaled beta-2 adrenergic receptor agonists and primary cardiac arrest.

PURPOSE: We sought to investigate if short-acting, inhaled beta2-adrenergic receptor agonists were associated with higher risk of primary cardiac arrest in patients with asthma or chronic obstructive pulmonary disease (COPD). SUBJECTS AND METHODS: We conducted a population-based study involving 454 patients enrolled in a health maintenance organization, aged 40 to 79 years, who had asthma or COPD and who experienced primary cardiac arrest during 1980 to 1994. We randomly selected 586 controls from strata of enrollees, defined by age, sex, calendar year, and prior heart disease. Medication use was assessed from computerized pharmacy data, and risk factors from medical record review. RESULTS: Use of inhaled beta-agonists was associated with a twofold increased risk of primary cardiac arrest (odds ratio [OR] = 1.9; 95% confidence interval [CI]: 1.1 to 3.3) among patients with asthma, but not among those with COPD (OR = 1.3; 95% CI: 0.6 to 2.7), after adjustment for risk factors. This association was observed only with use of two or more canisters of metered-dose, inhaled beta-agonists for 3 months, and when inhaled steroids were not used. CONCLUSION: These results support current guidelines recommending inhaled steroids as first-line asthma therapy.

Incidence of out-of-hospital cardiac arrest.

Estimates of the incidence of out-of-hospital primary cardiac arrest (CA) have typically relied solely upon emergency medical service or death certificate records and have not investigated incidence in clinical subgroups. Overall and temporal patterns of CA incidence were investigated in clinically defined groups using systematic methods to ascertain CA. Estimates of incidence were derived from a population-based case-control study in a large health plan from 1986 to 1994. Subjects were enrollees aged 50 to 79 years who had had CA (n = 1,275). A stratified random sample of enrollees who had not had CA was used to estimate the population at risk with various clinical characteristics (n = 2,323). Poisson's regression was used to estimate incidence overall and for 3-year time periods (1986 to 1988, 1989 to 1991, and 1992 to 1994). The overall CA incidence was 1.89/1,000 subject-years and varied up to 30-fold across clinical subgroups. For example, incidence was 5.98/1,000 subject-years in subjects with any clinically recognized heart disease compared with 0.82/1,000 subject-years in subjects without heart disease. In subgroups with heart disease, incidence was 13.69/1,000 subject-years in subjects with prior myocardial infarction and 21.87/1,000 subject-years in subjects with heart failure. Risk decreased by 20% from the initial to the final time period, with a greater decrease observed in those with (25%) compared with those without (12%) clinical heart disease. Thus, CA incidence varied considerably across clinical groups. The results provide insights regarding absolute and population-attributable risk in clinically defined subgroups, information that may aid strategies aimed at reducing mortality from CA.

Digoxin therapy and the risk of primary cardiac arrest in patients with congestive heart failure: effect of mild-moderate renal impairment.

BACKGROUND AND OBJECTIVE: The cardiac safety of digoxin therapy for congestive heart failure (CHF) is a source of concern, especially among those with renal impairment. METHODS: Using a case-control design, we examined the risk of primary cardiac arrest (PCA) associated with digoxin therapy within three levels of renal function. RESULTS: After adjustment for other clinical characteristics, digoxin therapy for CHF was not associated with an increased risk of PCA [odds ratio (OR)=0.97, 95% confidence interval (CI) 0.59-1.62] among patients with normal renal function (serum creatinine

Long-term outcome of unrelated donor transplantation for AML using myeloablative conditioning incorporating pretransplant Alemtuzumab.

The outcome of 55 patients who underwent matched unrelated donor (MUD) transplantation for acute myelogenous leukemia (AML) following a conditioning regimen of cyclophosphamide and total-body irradiation (TBI) with the addition of Alemtuzumab 10 mg/kg/day on days -5 to -1 is described. All patients received graft-versus-host disease (GVHD) prophylaxis with cyclosporine as well as 3 doses of posttransplant methotrexate. Forty-one patients were transplanted in complete remission (CR) (20 in CR1, 20 in CR2, and 1 in CR3), and 14 were not in remission at the time of transplantation as they were refractory to chemotherapy either at induction or at relapse. The group consisted of adult patients with a median age of 37 years. Thirty-five patients were fully matched at HLA-A, -B, -C, and -DRB1. All patients engrafted and there were no cases of graft rejection. Grade II-IV acute GVHD occurred in only 2 patients. Chronic GVHD developed in 30% of patients but was extensive in only 3 cases. The predicted TRM was 11% at day 100 and 26% at 1 year. In multivariate analysis the receipt of an HLA mismatched transplant was associated with a higher transplant-related mortality (TRM) (55% versus 15%). Twelve of the 14 transplant-related deaths were due to infection. The 5-year cumulative incidence of relapse was 36% for the whole group and 28% for patients in CR at transplantation. The 5-year cumulative survival for the whole group was 38% and was 49% for those in remission at transplantation. Seven of the 12 patients transplanted in CR1 with adverse risk cytogenetics remain alive and in remission, and the predicted 5-year overall survival (OS) for this group is 50%. These results support the use of Alemtuzumab for unrelated donor hematopoietic stem cell transplant (HSCT) for poor risk AML in CR1 and for relapsed AML in CR2. The addition of Alemtuzumab is highly effective in preventing both rejection and severe acute and extensive chronic GVHD without an increased relapse risk.

Long-term outcomes of myeloablation and autologous transplantation of relapsed acute myeloid leukemia in second remission: a British Society of Blood and Marrow Transplantation registry study.

Relapsed acute myeloid leukemia (AML) in adults has a poor prognosis if treated with chemotherapy alone. Case series have previously supported the role of myeloablation and autologous transplantation as a potentially curative treatment. This study aimed to use the large numbers and extended follow-up data in the British Society of Blood and Marrow Transplantation (BSBMT) registry database to establish long-term outcomes and relate these to biological and procedural factors. The BSBMT registry database was used to retrospectively identify 152 adult patients (age, 16-69 years) with AML in second remission treated with autologous transplantation in 1982-2003. Cytogenetic data were available for 68% of the patients; of these, at diagnosis, 42% had good risk features, 57% had standard risk features, and 1% had poor risk features. Conditioning regimens varied; autologous rescue was provided with bone marrow (BM) (71%), peripheral blood stem cells (PBSCs) (18%), or both (11%), which were harvested during first complete remission (CR1) and/or second CR (CR2). Median follow-up was 84 months (range, 2-200 months). At 10 years, actuarial overall survival (OS) was 32%, progression-free survival (PFS) was 28%, and relapse rate (RR) was 57%. The 100-day nonrelapse mortality (NRM) was 7%, rising to 11% at 1 year and to 14% at 10 years. OS was significantly related to M3 subtype (5-year OS, 66%; P = .005), patient age at diagnosis (P = .005) and transplantation (P = .026), and length of CR1, with greatest significance if the patient was dichotomized at CR1 duration of < 8 months or > or = 8 months (P = .0001). There was no difference in OS between regimens containing total body irradiation (TBI) and chemotherapy alone (P = .7). In relation to the nature of autologous graft material, there was improved OS (P = .025) and PFS (P = .009) with the use of cells harvested entirely in CR1 compared with cells harvested in CR2 or in both CR1 and CR2. Engraftment times were significantly shortened with the use of PBSCs alone or in combination with BM compared with BM alone (P = .0001), but there was no significant long-term impact on OS, PFS, RR, or NRM. This study provides long-term follow-up data in one of the largest series of patients with standard-risk and good-risk AML in CR2 treated with autologous transplantation and supports earlier observations that long-term survival is achievable in about 1/3 of patients overall and in about 2/3 of patients with M3 with a relatively low NRM. Outcomes are better in patients with CR1 > or = 8 months by use of grafts obtained entirely in CR1 and use of PBSCs. TBI conditioning did not confer an advantage. Randomized studies against unrelated donor transplantation are warranted.

The outcome of sibling and unrelated donor allogeneic stem cell transplantation in adult patients with acute myeloid leukemia in first remission who were initially refractory to first induction chemotherapy.

The optimal management of patients with initially refractory acute myeloid leukemia is unknown. We analyzed the outcomes of 68 adult patients (median age, 37 years) with acute myeloid leukemia in first complete remission with initially refractory disease who were treated with matched sibling (n=44) or unrelated donor (n=22) stem cell transplantation or who received transplants from other donors (n=2). Thirty-one patients took 2 courses of chemotherapy to achieve first complete remission, a further 31 took 3 courses, and 6 patients took 4 or 5 courses. Ten patients (15%) had adverse cytogenetics. Patients were mainly conditioned with cyclophosphamide and total body irradiation (87%). Four patients (6%) did not engraft by day 28; 2 of these engrafted at 47 and 60 days. Grades II to IV and III/IV acute graft-versus-host disease (GVHD) were seen in 34% and 14% of patients, respectively. Chronic GVHD was seen in 50% of patients. The estimated actuarial disease-free and overall survivals were 34% and 37%, respectively, at 4 years. The performance status of survivors is good; 82% of patients have Karnofsky scores of 90 to 100. On multivariate analysis, overall and disease-free survival were associated with adverse cytogenetics (P=.055 and .023). Approximately one third of patients survived 4 years after allogeneic stem cell transplantation for initially refractory acute myeloid leukemia in first complete remission: relapse and treatment-related mortality were the major causes of treatment failure. Further studies are needed to determine the optimal conditioning regimens and GVHD prophylaxis.