[show abstract][hide abstract] ABSTRACT: We analyze the impact of cyclosporine (CsA) levels in the development of acute graft-versus-host disease (aGVHD) after reduced intensity conditioning allogeneic hematopoietic transplantation (allo-RIC). We retrospectively evaluated 156 consecutive patients who underwent HLA-identical sibling allo-RIC at our institution. CsA median blood levels in the 1st, 2nd, 3rd and 4th weeks after allo-RIC were 134 (range: 10-444), 219 (54-656), 253 (53-910) and 224 (30-699) ng/mL; 60%, 16%, 11% and 17% of the patients had median CsA blood levels below 150 ng/mL during these weeks. 53 patients developed grade 2-4 aGVHD for a cumulative incidence of 45% (95% CI 34-50%) at a median of 42 days. Low CsA levels on the 3rd week and sex-mismatch were associated with the development of GVHD. Risk factors for 1-year NRM and OS were advanced disease status (HR: 2.2, P = 0.02) and development of grade 2-4 aGVHD (HR: 2.5, P < 0.01), while there was a trend for higher NRM in patients with a low median CsA concentration on the 3rd week (P = 0.06). These results emphasize the relevance of sustaining adequate levels of blood CsA by close monitoring and dose adjustments, particularly when engraftment becomes evident. CsA adequate management will impact on long-term outcomes in the allo-RIC setting.
Mediators of Inflammation 01/2014; 2014:620682. · 3.88 Impact Factor
[show abstract][hide abstract] ABSTRACT: Introduction: Busulfan (Bu) represents a backbone as conditioning prior to hematopoietic stem cell transplantation (HSCT). The intravenous (IV) form of Busulfan allows 100% bioavaibility and a limited inter- and intra-patient (pt) variability compared to the oral form. In Europe, IV Bu (Busilvex® fixed dose of 0.8 mg/kg x 16 doses) in combination with Cyclophosphamide (60 mg/kg/d x 2 ) is indicated prior to conventional HSCT in adults when the combination is the best available option. IV BuCy2 allows a precise delivery with 80% of adult pts within the defined therapeutic window [900 μmol/L x min-100 μmol/L x min] without dose-adjustments. Despite major advances in the risk-stratification and management of acute myelogenous leukaemia (AML) based on cytogenetics and molecular biology, the relapse rate remains high. Several published experiences suggested that Bu exposure may have an impact on the clinical outcomes after allogeneic HSCT.
Study objective:The study was implemented to explore the use of a narrow range and high values of Bu exposure [4400 µmol/Lx min to 6000 µmol/Lx min] with a PK-guided dose adjustments and once-daily administration x 4 days.
Methods:The study was a prospective non-randomized multicentric phase II. The eligible pts were required to have AML in first complete (CR1, cytological remission) and to be eligible allogeneic HSCT following a myeloablative regimen. On the first day of the conditioning regimen IV Bu was administered as a single dose of 3.2 mg/kg; further daily dose of IV Bu were determined based on the previous Bu AUC exposure. The graft-versus-host disease (GVHD) prophylaxis consisted of calcineurin inhibitor, IV methotrexate post-transplant. The addition of antithymoglobulin (ATG) for unrelated donors was decided by each center based on their institutional guidelines. Pts could either receive related or unrelated bone marrow or peripheral blood stem cells. Nine centres with laboratory facilities for the pharmacokinetics analysis entered the study.
Patient and transplant characteristics: Thirty AML pts in CR1 (21 males, 70%) were treated between may 2010 and may 2012, 87% of pts had de novoAML. Twenty pts (67%) had matched sibling donor, the remaining pts received allograft from an unrelated donor. The median age of the cohort was 43.5 years [19.3-55.5]. The performance status score was comprised between 90 and 100. The majority of the cohort (83%) had an intermediate or unfavorable cytogenetic risk-factors. In 3 cases (10%) the karyotyping analyses could not be performed; 1 pt (3%) did not have cytogenetic test performed.
Results: Thirty pts were treated and analyzed. The expected cumulative AUC over 4 days [17600 µmol/Lxmin -24000 µmol/Lxmin ] was reached in 90% of pts. The mean dose of IV Bu administered was 3.51 mg/kg/day. The mean total cumulative dose of IV Bu over 4 days was 13.25 mg/kg [8-21.3]. All pts engrafted. For the entire cohort, the neutrophil engraftment [absolute neutrophil count (ANC) > 0.5 x 10 9/L] occured at a median time of 17.5 d (11-35). Overall, 3 episodes (10%) of sinusoidal obstruction syndrome (S.O.S) occured (one mild, two severe, all resolved) in two patients. One pt developed 2 severe episodes of S.O.S and received defibrotide. Overall, 12 pts out of 30 (40%) developed acute GVHD between day 0 and day +100 after transplant (4 pts had grade III, 6 pts had grade II and 2 pts developed grade III, no patient developed grade IV). The median follow-up was 12 months [95% CI (11.9-12.2)] After day +100, 4 pts died of non-relapse causes ; one death from pulmonary fibrosis was related to the conditioning regimen. The cumulative incidence of TRM was 13.3% [95% CI (11.1%-15.6%)]. Five pts relapsed at a median time of 3.3 months [2-5.6] and 4 pts died of relapse. The cumulative incidence of one-year survival was 73.3% [95% CI (53.7%-85.7%)].
Conclusion: The AUC intensification with once-daily IV BuCy2 is effective and yields an acceptable one year TRM for pts with high-risk AML in CR1. However, longer follow-up is needed in order to assess the impact of AUC intensification on the relapse rate and survivals.
55th ASH Annual Meeting Exposition, New Orlean, LA; 12/2013
[show abstract][hide abstract] ABSTRACT: This study was conducted to determine whether the integration of the hematopoietic cell transplantation (HCT) Comorbidity Index (HCT-CI) and the European Group for Blood and Marrow Transplantation (EBMT) score would improve their individual capacity for stratification of high risk HCT candidates. A total of 442 consecutive patients receiving an allogeneic HCT after reduced toxicity conditioning were included. Final HCT-CI and EBMT scores were calculated and validated. Then, patients were grouped into a 6-category new combination model according to the HCT-CI (0, 1-2, ≥3) and EBMT scores (0-3, 4-7) and its predictive capacity was also evaluated. Median HCT-CI and EBMT scores were 3 and 4, respectively. Increased HCT-CI was associated with higher 4y-NRM and lower 4y-OS while a high EBMT score was associated with higher 4y-NRM. The HCT-CI showed a trend for a better predictive capacity than the EBMT score (c-statistic 0.6 vs 0.54, p=0.1). According to the new model, patients within HCT-CI= 0 and HCT-CI= 1-2 groups had similar risk of NRM independently of their EBMT score. Within the HCT-CI≥ 3 group, patients with low EBMT score showed lower NRM (25% vs 40%, p=0.04) and a trend to higher OS (52% vs 36%, p=0.06) than patients with high EBMT score. Moreover, these patients with HCT-CI ≥3 and EBMT score 0-3 had similar outcomes than those with HCT-CI= 1-2. In conclusion, the combination of HCT-CI and the EBMT score is feasible and might contribute to a better identification of high risk patients, improving selection of best allo-HCT candidates.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2013; · 3.15 Impact Factor
[show abstract][hide abstract] ABSTRACT: There are scarce disease-specific studies focusing on outcomes of umbilical cord blood transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. We report the outcome of 45 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia underwent myeloablative single unit cord blood transplantation from unrelated donors within the GETH/GITMO cooperative group. Conditioning regimens were based on combinations of thiotepa, busulfan, cyclophospamide or fludarabine, and antithymocyte globulin. At the time of transplantation, 35 patients (78%) were in first complete remission, 4 (8%) in second complete remision and 6 (14%) in second or subsequent response. The cumulative incidence of myeloid engraftment was 96% at a median time of 20 days and significantly better for patients receiving higher doses of CD34+ cells. The incidence of acute graft-versus-host disease grade II-IV and overall chronic graft-versus-host disease was 31% and 53%, respectively. Treatment-related mortality was 17% at day +100 and 31% at 5 years. The 5-year relapse, event-free survival and overall survival were 31%, 36% and 44%, respectively. Although patients without BCR/ABL transcripts detectable at time of transplant had a better event-free and overall survivals compared with those positive detection of BCR/ABL (46% vs 24% and 60% vs 30%, respectively) these differences were not statistically significant in the univariate analysis (p = 0.07, respectively). These results demonstrate that umbilical cord blood transplantation from unrelated donors can be a curative treatment for a substantial number of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.
[show abstract][hide abstract] ABSTRACT: Bacteremia is the most frequent infectious complication during neutropenia in patients receiving autologous hematopoietic stem cell transplantation (ASCT). The objective of this study was to analyze the incidence, characteristics, risk factors, and outcome of bacteremia during the early period after ASCT. A total of 720 patients undergoing ASCT in two observational prospective consecutive multicenter studies of the Programa Español para el Tratamiento de las Hemopatías group were analyzed. Bacteremia occurred in 20 % of patients. Coagulase-negative Staphylococcus was the most frequent (66 %) among the gram-positive agents and Escherichia coli (49 %) among the gram-negative agents. Multivariate analysis showed that the length of neutropenia <1 × 10(9)/L (more than 9 days) [relative risk (RR) of 2.6, p < 0.001] was the sole risk factor for overall bacteremia. We identified the length of neutropenia <1 × 10(9)/L (more than 9 days) (RR 4.98, p < 0.001) and the use of prophylactic fluoroquinolones (RR 0.46, p < 0.01) as specific risk factors for gram-negative bacteremia. Risk factors for gram-positive bacteremia were the use of total parenteral nutrition (RR 1.92, p < 0.01) and deep neutropenia (<0.1 × 10(9)/L), with duration over 5 days (RR 1.67, p < 0.027). Bacteremia showed an increased morbidity with no impact on neither overall nor infectious related mortality. The identification of such risk factors may be helpful to implement prophylactic and therapeutic risk-adapted strategies to reduce the incidence of bacteremia in ASCT.
Annals of Hematology 09/2013; · 2.87 Impact Factor
[show abstract][hide abstract] ABSTRACT: The current study was designed to assess the safety and efficacy of bortezomib in combination with fludarabine and melphalan as reduced intensity conditioning before allogeneic stem cell transplantation in patients with high risk multiple myeloma. Sixteen patients were evaluable. The median number of previous line of treatment was 3; all patients had relapsed following a prior autograft and 13 had previously received bortezomib. Fifteen of them either remained stable or improved disease status at day +100 post-transplant, including 11 patients with active disease. More specifically, nine patients (56%) and five patients (31%) reached complete remission and partial response, respectively. 25% developed grade III acute graft-versus-host disease. The cumulative incidence of non-relapse mortality, relapse and overall survival were 25%, 54% and 41%, respectively, at 3 years. Regarding the non-haematological toxicity (grade>2), two patients developed peripheral neuropathy, two patients liver toxicity and 1 pulmonary toxicity early post-transplant. The haematological toxicity was only observed during the first three cycles mostly related to low haemoglobin and platelet levels. The current trial is the first one evaluating the safety and efficacy of bortezomib as part of a reduced intensity conditioning regimen among patients with high risk multiple myeloma.
British Journal of Haematology 06/2013; · 4.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: The survival of relapsed acute myeloid leukemia (AML) after autologous hematopoietic stem cell transplantation (Autologous HCT) is very poor. We studied the outcomes of 302 patients who underwent secondary allogeneic hematopoietic cell transplantation (Allo-HCT) from an unrelated donor (URD) using either myeloablative (n=242) or reduced-intensity conditioning regimens (RIC, n=60) reported to CIBMTR. After a median follow-up of 58 months (range 2-160), the probability of treatment-related mortality (TRM) was 44% (95%CI 38-50) at 1-year. The 5-year incidence of relapse and overall survival (OS) was 32% (95%CI 27-38) and 22% (95%CI 18-27), respectively. In multivariate analysis significantly better OS was observed with RIC regimens (Hazard Ratio (HR) 0.51, 95%CI 0.35-0.75, p<0.001), with Karnofsky performance status (KPS) ≥90% (HR 0.62, 95%CI 0.47-0.82, p=0.001) and in CMV-negative recipients (HR 0.64, 95%CI 0.44-0.94, p=0.022). Longer interval (>18 months) from Autologous HCT to URD Allo-HCT was associated with significantly lower Relapse risk (HR 0.19, 95%CI 0.09-0.38, p<0.001) and improved LFS (HR 0.53, 95%CI 0.34-0.84, p=0.006). URD Allo-HCT after Autologous HCT relapse results in 20% long-term leukemia-free survival, with best results with longer interval to secondary URD transplantation, KPS ≥90%, in complete remission, and using RIC regimens. Further efforts to reduce TRM and relapse are still needed.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 04/2013; · 3.15 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: Busilvex® (Bu) followed by Cyclophosphamide (Cy) is a standard conditioning therapy used prior to Allogeneic HSCT. Moreover, relapse rate in AML CR1 patients remains a matter of concern, being as high as 25%. Therefore, we hypothesized that Area Under the Curve (AUC) intensification may reduce the relapse incidence for high-risk patients. Primary objective: To target the upper range of the Bu therapeutic window (i.e.: AUC = 4400 - 6000 µmol/L.min) from a once daily BuCy2 regimen. Methods and patients: This prospective phase II study included 30 (9 females, 21 males) CR1 AML patients (26 de novo AML, 4 secondary AML). All patients received a once-daily 3.2 mg/kg dose of Busilvex® on day 1 of conditioning, with dose adjustment from day 2 to day 4 in order to target the middle of the defined therapeutic area (AUC = 5200 µmol/L.min). The total dose of Cy was 120 mg/kg. GVHD prophylaxis included ciclosporine, methotrexate, and ATG in case of unrelated donors. Median age: 43.5 years (19.3-55.5). Median time interval from the diagnosis to HSCT: 5.6 months (2.5-9); 20 patients were transplanted with a matched sibling donor and 10 with MUD; 13 patients received BM and 17 PBSC. Results: The median observed AUC was 4837 µmol/L.min at day 1 and 5297, 5709, 5395 µmol/L.min for the following adjusted doses. The inter-individual coefficient of variation of AUCs decreased from 29% at day 1 to 16%, 18% and 21% at days 2, 3 and 4, respectively. Based on the cumulated AUC over the 4 days, 27 out of 30 patients (90%) achieved the targeted therapeutic window. The median follow-up was 7.65 months (3.4-12.05). All patients engrafted: the median time to reach neutrophil and platelet engraftment was 17.5 (11-35) and 14 (8-49) days, respectively. The median duration of hospitalization post-HSCT was 25.5 days (14-75). At day +100, 2 cases of VOD occurred, one mild, one severe, both resolved. No death from organ toxicities occurred at 3 months. Overall, 25 patients were alive at last follow up. Two patients died of relapse and 3 of non-relapse. The cumulative incidence of relapse at one year was 16.9% [95% CI 14-20]. Conclusions: This study confirms that once-daily IV BuCy2 with AUC intensification is feasible, without major safety concerns, and is potentially an effective regimen in high risk AML.
39th Annual Meeting of the European Group for Blood and Marrow transplantation, London, UK; 04/2013
[show abstract][hide abstract] ABSTRACT: Patients with acute myeloid leukemia (AML) traditionally classified as having an intermediate cytogenetic risk [mostly cytogenetically normal AML (CN-AML)] really include a significant proportion of cases with a poor outcome. This is based on the molecular findings at diagnosis, mainly the presence of internal tandem duplication in the FMS-like tyrosine kinase 3 gene(s) (FLT3/ITD). Optimal postremission therapy for these high-risk molecular cases is not well established; as the prognosis is adverse hematopoietic cell transplantation (HCT), mainly allogeneic HCT (allo-HCT), is the most widely accepted strategy.
As a rule, patients with FLT3/ITD have a poor outcome with conventional chemotherapy alone. Only patients with an associated nucleophosmin 1 (NPM1) mutation and those with a low mutated-to-wild-type allelic ratio of FLT3/ITD have less unfavorable outcome. Most studies show an advantage of allo-HCT in first complete remission (CR1), with higher 3-5 year disease-free survival and lower relapse risk than with chemotherapy or autologous transplantation (auto-HCT). Regarding allo-HCT proceeding early after reaching CR1 seems to improve survival, rather than after several courses of consolidation chemotherapy.
Patients with intermediate-risk cytogenetics AML and FLT3/ITD, especially NPM1-wild cases and those NPM1 mutated with a high allelic ratio, should proceed to allo-HCT if possible early after achieving CR1.
Current opinion in oncology 03/2013; 25(2):195-204. · 4.09 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hyperferritinemia has been associated with adverse outcome after allogeneic hematopoietic cell transplantation (allo-HCT) with myeloablative conditioning. However, its characteristics and impact on the outcome in the reduced-intensity conditioning (RIC) and in the lymphoid malignancies settings are far from clear. The study includes 201 adult patients undergoing allo-HCT with RIC (allo-RIC) for lymphoid malignancies with a median follow-up for survivors of 52 months (range 3-123). Median serum ferritin level at allo-RIC was 379 ng/ml (range 4-10790). In the multivariate analysis, patients with hyperferritinemia at transplant (>399ng/ml) showed lower 4-year overall survival (HR 1.8 [95%CI 1.2-2.8], p=0.008), higher NRM (HR 1.8 [95%CI 1.1-3.2], p=0.03) and higher infection related mortality (HR 2.3 [95%CI 1.1- 4.8], p=0.02) than patients without hyperferritinemia. Neutrophil and platelet engraftment and 100-days NRM were similar between both groups. The adverse outcome associated with hyperferritinemia seemed higher in patients without major comorbidities and it was not influenced by the elevation of acute phase reactants. Our results indicate that high ferritin levels at HCT are associated with an adverse outcome after allo-RIC in patients with lymphoid malignancies.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2013; · 3.15 Impact Factor
[show abstract][hide abstract] ABSTRACT: Strongyloides stercoralis is an intestinal nematode that causes strongyloidiasis, which affects 30 to 100 million people worldwide. Risk factors for hyperinfection and disseminated disease include immunosuppressive drug therapy, human T-lymphotropic virus-1 (HTLV-1) infection, solid organ and bone marrow transplantation, hematologic malignant diseases, hypogammaglobulinemia, and severe malnutrition and associated conditions. The diagnosis can be difficult because a single stool examination fails to detect larvae in up to 70% of the cases, and the symptoms are nonspecific. Although eosinophilia is a common finding in patients with chronic Strongyloides infection, it is an unreliable predictor of hyperinfection. Furthermore, the lack of eosinophilia while receiving immunosuppressive therapy cannot reliably exclude the underlying chronic Strongyloides infection. We report here a fatal Strongyloides hyperinfection in a patient receiving allogeneic stem cell transplantation; risk factors and outcome in this clinical setting are discussed.
[show abstract][hide abstract] ABSTRACT: This study was conducted to determine whether the integration of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and the European Group for Blood and Marrow Transplantation (EBMT) score would improve individual capacity for stratification of high-risk HCT candidates. A total of 442 consecutive patients receiving an allogeneic HCT after reduced-toxicity conditioning was included. Final HCT-CI and EBMT scores were calculated and validated. Then, patients were grouped into a 6-category new combination model according to the HCT-CI (0, 1 to 2, ≥3) and EBMT scores (0 to 3, 4 to 7), and the model's predictive capacity was also evaluated. Median HCT-CI and EBMT scores were 3 and 4, respectively. Increased HCT-CI was associated with higher 4-year nonrelapse mortality (NRM) and lower 4-year overall survival (OS), whereas a high EBMT score was associated with higher 4-year NRM. The HCT-CI showed a trend for a better predictive capacity than the EBMT score (c-statistic .6 versus .54, P = .1). According to the new model, patients within HCT-CI of 0 and HCT-CI of 1 to 2 groups had similar risk of NRM independently of their EBMT score. Within the HCT-CI ≥ 3 group, patients with low EBMT score showed lower NRM (25% versus 40%, P = .04) and a trend to higher OS (52% versus 36%, P = .06) than patients with a high EBMT score. Moreover, patients with HCT-CI ≥ 3 and EBMT score 0 to 3 had similar outcomes than those with HCT-CI of 1 to 2. In conclusion, the combination of HCT-CI and the EBMT score is feasible and might contribute to a better identification of high-risk patients, improving selection of best allogeneic HCT candidates.
[show abstract][hide abstract] ABSTRACT: Allogeneic stem cell transplantation (ASCT) from related or unrelated donors may cure patients with myelodysplastic syndromes (MDS), a heterogeneous group of clonal stem cell disorders. We analysed 384 elderly patients (55-69 years) with advanced MDS who received either ASCT (n=247) and were reported to The European Group for Blood and Marrow Transplantation (EBMT) or a non -transplant approach (n=137) reported to the Düsseldorf registry. Besides an attempt to answer the question of "comparison", the purpose of this work is to explain the difficulties in comparing a non-transplant with a transplant cohort, when death before transplant is likely but unknown and the selection of patients for transplant is based on assumptions. It shows which methods are almost always biased and that even the most sophisticated approaches crucially rely on clinical assumptions. Using the most appropriate model for our data, we derive an overall univariate non-significant survival disadvantage for the transplant cohort (HR: 1.29, p = 0.11). We show that such an "average" hazard ratio is however misleading due to non-proportionality of the hazards reflecting early treatment related mortality, the occurring of which is logically correlated with the interval between diagnosis and transplant creating a disproportional drop in the (reconstructed) survival curve of the transplanted patients. Also in multivariate analysis (correcting for age > 60 (HR: 1.4, p = 0.02) and abnormal cytogenetics (HR: 1.46, p = 0.01)), transplantation seems to be worse (HR: 1.39, p = 0.05) but only in the (incorrect but commonly applied) model without time varying covariates. The long term (time depending) hazard ratio is shown to be virtually 1 and overall survival is virtually identical in both groups. Nonetheless no conclusion can be reached from a clinical point of view without assumptions which are by their very nature untestable unless all patients would be followed from diagnosis.
PLoS ONE 01/2013; 8(10):e74368. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background. Different graft-versus-host disease prophylaxis have been proposed in the setting of reduced intensity and non-myeloablative allogeneic stem cell transplantation. An alternative combination with Sirolimus and Tacrolimus has recently been tested although comparative studies in front of the classical combination with a Calcineurin-inhibitor and Mycophenolate Mofetil or Methotrexate, are lacking. Design and Methods. We describe the results of a prospective multicenter trial using Sirolimus-Tacrolimus as immunoprophylaxis, and compare this approach with our previous experience using Cyclosporine-Mycophenolate in the unrelated donor transplant setting after reduced-intensity conditioning. Results. Forty-five patients received Cyclosporine-Mycophenolate between 2002 and mid-2007, while the subsequent 50 patients receiving transplants from late-2007 received Sirolimus-Tacrolimus. No significant differences were observed either in terms of hematopoietic recovery or acute graft versus host disease, although gastrointestinal aute graft versus host disease ≥2 was more common in the Cyclosporine-Mycophenolate group (55 vs. 21%, respectively, p=0.003). The 1-year cumulative incidence of chronic graft versus host disease was 50% versus 90% for Sirolimus versus Cyclosporine- based regimen, respectively (p<0.001), while the incidence of the extensive chronic disease was 27% versus 49%, respectively (p=0.043). Two-year non-relapse mortality was 18% versus 38% for patients receiving Sirolimus versus Cyclosporine- based regimen, respectively (p=0.02). The event-free survival and overall survival at 2 years were 53% versus 29% (p=0.028) and 70% versus 45% (p=0.018) among patients receiving Sirolimus versus Cyclosporine- based regimen, respectively. Conclusions. In the setting of reduced intensity transplantation from unrelated donor, promising results can be achieved with the combination of Sirolimus-Tacrolimus, due to a lower risk of chronic Graft versus host disease and non-relapse mortality, which translates into better event-free and overall survival, in comparison with Cyclosporine-Mycophenolate. This trial was registered at www.clinicaltrials.gov as 2007-006416-32 by GEL-TAMO/GETH.
[show abstract][hide abstract] ABSTRACT: Community-acquired respiratory virus (CARV) infections have been recognized as a significant cause of morbidity and mortality in patients with leukemia and those undergoing hematopoietic stem cell transplantation (HSCT). Progression to lower respiratory tract infection (LRTI) with clinical and radiological signs of pneumonia and respiratory failure appears to depend on the intrinsic virulence of the specific CARV as well as factors specific to the patient, the underlying disease and its treatment. To better define the current state of knowledge of CARVs in leukemia and HSCT patients, and to improve CARV diagnosis and management, a working group of the 4(th) European Conference on Infections in Leukaemia (ECIL-4) 2011 reviewed the literature on CARVs, graded the available quality of evidence and made recommendations according to the IDSA grading system. Due to differences in screening, clinical presentation and therapy for influenza and adenovirus, ECIL-4 recommendations are summarized for CARVs other than influenza and adenovirus.
[show abstract][hide abstract] ABSTRACT: Chronic graft-versus-host disease (cGVHD) is a major complication after allogeneic stem cell transplantation with an adverse effect on both mortality and morbidity. In 2005, the National Institute of Health proposed new criteria for diagnosis and classification of chronic graft-versus-host disease for clinical trials. New sub-categories were recognized such as late onset acute graft-versus-host disease and overlap syndrome.
We evaluated the prognostic impact of the new sub-categories as well as the clinical scoring system proposed by the National Institute of Health in a retrospective, multicenter study of 820 patients undergoing allogeneic stem cell transplantation between 2000 and 2006 at 3 different institutions. Patients were retrospectively categorized according to the National Institute of Health criteria from patients' medical histories.
As far as the new sub-categories are concerned, in univariate analysis diagnosis of overlap syndrome adversely affected the outcome. Also, the number of organs involved for a cut-off value of 4 significantly influenced both cGVHD related mortality and survival. In multivariate analysis, in addition to NIH score, platelet count and performance score at the time of cGVHD diagnosis, plus gut involvement, significantly influenced outcome. These 3 variables allowed us to develop a simple score system which identifies 4 subgroups of patients with 84%, 64%, 43% and 0% overall survival at five years after cGVHD diagnosis (score 0: HR=15.96 (95% CI: 6.85-37.17), P<0.001; score 1: HR=5.47 (95% CI: 2.6-11.5), P<0.001; score 2: HR=2.8 (95% CI: 1.32-5.93), P=0.007).
In summary, we have identified a powerful and simple tool to discriminate different subgroups of patients in terms of chronic graft-versus-host disease related mortality and survival.
[show abstract][hide abstract] ABSTRACT: Although Hodgkin's lymphoma is a highly curable disease with modern chemotherapy protocols, some patients are primary refractory or relapse after first-line chemotherapy or even after high-dose therapy and autologous stem cell transplantation. We investigated the potential role of allogeneic stem cell transplantation in this setting.
In this phase II study 92 patients with relapsed Hodgkin's lymphoma and an HLA-identical sibling, a matched unrelated donor or a one antigen mismatched, unrelated donor were treated with salvage chemotherapy followed by reduced intensity allogeneic transplantation. Fourteen patients showed refractory disease and died from progressive lymphoma with a median overall survival after trial entry of 10 months (range, 6-17). Seventy-eight patients proceeded to allograft (unrelated donors, n=23). Fifty were allografted in complete or partial remission and 28 in stable disease. Fludarabine (150 mg/m(2) iv) and melphalan (140 mg/m(2) iv) were used as the conditioning regimen. Anti-thymocyte globulin was additionally used as graft-versus-host-disease prophylaxis for recipients of grafts from unrelated donors.
The non-relapse mortality rate was 8% at 100 days and 15% at 1 year. Relapse was the major cause of failure. The progression-free survival rate was 47% at 1 year and 18% at 4 years from trial entry. For the allografted population, the progression-free survival rate was 48% at 1 year and 24% at 4 years. Chronic graft-versus-host disease was associated with a lower incidence of relapse. Patients allografted in complete remission had a significantly better outcome. The overall survival rate was 71% at 1 year and 43% at 4 years.
Allogeneic stem cell transplantation can result in long-term progression-free survival in heavily pre-treated patients with Hodgkin's lymphoma. The reduced intensity conditioning approach significantly reduced non-relapse mortality; the high relapse rate represents the major remaining challenge in this setting. The HDR-Allo trial was registered in the European Clinical Trials Database (EUDRACT, https://eudract.ema.europa.eu/) with number 02-0036.
[show abstract][hide abstract] ABSTRACT: Whether the intensity of the conditioning regimen affects febrile neutropenia (FN) and severe bacterial infections (SBIs) is not well established. We analyzed the risk factors (RFs) for the development of FN and SBI in the first 100d post-transplant in 195 consecutive adult recipients of a reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC-allo).
The RIC regimens consisted of fludarabine plus melphalan (62%) or busulphan (38%) (FluMel or FluBu). SBIs include pneumonia, urinary tract infections, and bacteremia.
FN occurred in 141 patients (72%), always in the first 30d post-allo-RIC. However, a SBI occurred in only 27 patients (14%) during this early post-transplant period (<day +30), while 29 evaluable patients (15%) developed a SBI in the intermediate post-transplant period (days +31 to +100). In multivariate analysis, RFs for the development of FN included onset of neutropenia before day +5 after allo-RIC (P<0.02) and NCI CTC grade III-IV mucosal damage in the first 10d post-transplantation (P=0.03). RFs identified to SBI by multivariate analysis included corticosteroid therapy before day +100 (P<0.01), mycophenolate mofetil-based graft-versus-host disease (GVHD) prophylaxis (P<0.01), and previous SBI before day +30 (P<0.01). The rate of SBI from day +30 to +100 varied according to the number of RFs; thus, the rate of SBI was 1% in patients without any RF, 17% in patients with one RF, 29% with one RFs, and 53% in those with all three RFs.
After an RIC-allo, FN and early SBI occurred mostly in patients with severe mucositis and early-onset neutropenia, while postengraftment high-dose steroid therapy for acute GVHD was the major RF.
European Journal Of Haematology 01/2012; 88(1):46-51. · 2.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Pretransplant pulmonary function tests (PFTs) have been checked mostly in myeloablative allogeneic stem cell transplantation (Allo-SCT). Their value in the setting of reduced intensity conditioning Allo-SCT (Allo-RIC) has been less explored. We retrospectively evaluated the predictive value of PFTs on posttransplant pulmonary complications (PPC) and outcomes in 195 consecutive Allo-RIC patients, based on fludarabine plus busulphan or melphalan. PFT parameters included forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC ratio, total lung capacity (TLC), residual volume, and diffusion capacity for carbon monoxide (DLCo) corrected for the hemoglobin levels. Pretransplant PFTs abnormalities were observed in 130 patients (66%). The most frequent abnormalities were abnormal DLCO (n = 83, 44%), followed by FEV1/FVC (n = 75, 38%) and FVC (n = 47, 24%). The abnormalities were severe in 25 (13%) patients, moderate in 65 (33%) and mild in 40 patients (21%). Multivariate analysis showed that TLC was significantly associated with PPC, nonrelapse mortality and overall survival (OS), (HR 4.2, 95% CI. 2-8.5; HR 3.8, 95% CI. 1.7-8.5; HR 2.3, 95% CI. 1.3-4.1, respectively, P = 0.01), while abnormal FVC had a negative impact on PPC and OS (HR 1.8, 95% CI. 0.98-3.6, P = 0.06 and HR 1.7, 95% CI. 1.1-2.6, P = 0.008). This study emphasizes the valuable role of PFTs in identifying patients at risk for PPC, NRM, and lower OS in the Allo-RIC setting.
American Journal of Hematology 01/2012; 87(1):9-14. · 4.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: We studied the outcome of allogeneic hematopoietic stem cell transplantation after lower-intensity conditioning regimens (reduced-intensity conditioning and nonmyeloablative) in patients with non-Hodgkin lymphoma who relapsed after autologous hematopoietic stem cell transplantation. Nonrelapse mortality, lymphoma progression/relapse, progression-free survival (PFS), and overall survival were analyzed in 263 patients with non-Hodgkin lymphoma. All 263 patients had relapsed after a previous autologous hematopoietic stem cell transplantation and then had undergone allogeneic hematopoietic stem cell transplantation from a related (n = 26) or unrelated (n = 237) donor after reduced-intensity conditioning (n = 128) or nonmyeloablative (n = 135) and were reported to the Center for International Blood and Marrow Transplant Research between 1996 and 2006. The median follow-up of survivors was 68 months (range, 3-111 months). Three-year nonrelapse mortality was 44% (95% confidence interval [CI], 37%-50%). Lymphoma progression/relapse at 3 years was 35% (95% CI, 29%-41%). Three-year probabilities of PFS and overall survival were 21% (95% CI, 16%-27%) and 32% (95% CI, 27%-38%), respectively. Superior Karnofsky Performance Score, longer interval between transplantations, total body irradiation-based conditioning regimen, and lymphoma remission at transplantation were correlated with improved PFS. Allogeneic hematopoietic stem cell transplantation after lower-intensity conditioning is associated with significant nonrelapse mortality but can result in long-term PFS. We describe a quantitative risk model based on pretransplantation risk factors to identify those patients likely to benefit from this approach.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2011; 18(8):1255-64. · 3.15 Impact Factor