[Show abstract][Hide abstract] ABSTRACT: Although new agents have been approved for the treatment of MDS, the only curative approach is allogeneic hematopoietic stem cell transplantation (HSCT) and thus, in particular circumstances this procedure has been proposed as a treatment option for low risk patients. We have retrospectively analyzed the results of HSCT in 291 patients from the Spanish MDS registry with special attention to low risk MDS (LR-MDS) in order to define the variables that could impact their clinical evolution after transplantation. At 2 years OS was 51% and EFS was 50% (95% CI 0.7-4.5 years for OS and 95% CI 0.1-3.9 years for EFS). Among 43 LR-MDS, transplant-related mortality was 28%. At 3 years, OS was 67% (95% CI 264.7-8927.2 days for OS) and EFS was 64% (95% CI 0-9697.2 days for EFS). In the multivariate analysis only cytogenetics retained statistical significant effect on both OS (p=.047) and EFS (p=.046). Conditioning regimen could improve outcome among this subset of patients (OS 86% and RFS 100% for patients receiving RIC regimen). The present study confirms that specific disease characteristic as well as transplant characteristics have a significant impact on transplant outcome. Regarding low risk patients a non-myeloablative conditioning would be preferable especially in cases without high-risk cytogenetics.
[Show abstract][Hide abstract] ABSTRACT: We evaluated the impact of detection of minimal residual disease by flow cytometry (FCMRD) and CD3 chimerism in relapse in a cohort of 87 patients with acute myeloid leukemia or myelodysplastic syndrome undergoing stem cell transplantation. Patients with a positive FCMRD at day +100 after transplantation showed higher relapse rates and worse overall survival. In multivariate analysis, a positive FCMRD after transplantation was a significant predictor of relapse. Mixed chimerism showed a trend to statistical signification. We conclude that FCMRD at day 100 after SCT is the best predictor of relapse after SCT in patients with aggressive myeloid malignancies.
[Show abstract][Hide abstract] ABSTRACT: Although the survival rates of hematological patients admitted to the ICU are improving, little is known about the long-term outcome. Our objective was to identify factors related to long-term outcome in hematological patients after ICU discharge.
A prospective, observational study was carried out in seven centers in Spain. From an initial sample of 161 hematological patients admitted to one of the participating ICUs during the study period, 62 were discharged alive and followed for a median time of 23 (1 to 54) months. Univariate and multivariate analysis were performed to identify the factors related to long term-survival. Finally, variables that influence the continuation of the scheduled therapy for the hematological disease were studied.
Mortality after ICU discharge was 61%, with a median survival of 18 (1 to 54) months. In the multivariate analysis, an Eastern Cooperative Oncology Group score (ECOG) >2 at ICU discharge (Hazard ratio 11.15 (4.626 to 26.872)), relapse of the hematological disease (Hazard ratio 9.738 (3.804 to 24.93)) and discontinuation of the planned treatment for the hematological disease (Hazard ratio 4.349 (1.286 to 14.705)) were independently related to mortality. Absence of stem cell transplantation, high ECOG and high Acute Physiology and Chronic Health Evaluation II (APACHE II) scores decreased the probability of receiving the planned therapy for the hematological malignancy.
Both ICU care and post-ICU management determine the long-term outcome of hematological patients who are discharged alive from the ICU.
Critical care (London, England) 12/2013; 17(6):R302. · 5.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the rituximab era, lymphoma patients with persistent disease receiving autologous transplantation have a very poor outcome. The addition of radioimmunotherapy to the conditioning regimen may improve outcome for these patients. We have evaluated, in a prospective phase 2 study, the safety and efficacy of the addition of 90Y-Ibritumomab tiuxetan to the conditioning chemotherapy in refractory diffuse large B cell lymphoma patients. Thirty patients with induction failure (primary refractory; n=18) or refractory to salvage immunochemotherapy at relapse (n=12) were included in the study. Patients with a median age of 53 years (range, 25-67) received 90Y-Ibritumomab tiuxetan at a fixed dose of 0.4mCi/kg (maximum dose 32mCi) 14 days prior to the preparative chemotherapy regimen. Histology included de novo diffuse large B cell lymphoma (22) and transformed diffuse large B cell lymphoma (8). All patients had persistent disease at the time of transplantation, with 25 patients considered to be chemorefractory. Median time to neutrophil recovery (>500/ml) was 11 days (9-21), and to platelet recovery (>20.000/ml) was 13 days (11-35). Overall response at day +100 was 70% (95% CI, 53.6-86.4) with 60% (95% CI, 42.5-77.5) complete responses. After a median follow-up of 31 months for alive patients (range, 16-54), estimated 3-year overall and progression-free survival is 63% (95% CI, 48-82) and 61% (95% CI, 45-80), respectively. We conclude that autologous transplantation with conditioning including 90Y-Ibritumomab tiuxetan is safe, and results in a very high response rate with promising survival in this very poor prognosis group of refractory diffuse large B cell lymphoma patients. Study registered at European Union Drug Regulating Authorities Clinical Trials (EudraCT) No. 2007-003198-22.
[Show abstract][Hide abstract] ABSTRACT: Abstract The tolerability of azacitidine (AZA) allows its administration in elderly patients. The objective of this study was to analyze the clinical and biological characteristics, transfusion independence (TI), overall survival (OS) and toxicity of a series of 107 patients ≥75 years of age from the Spanish Registry of myelodysplastic syndromes (MDS) treated with AZA. The median age (range) was 78 (75-90) years. According to the WHO classification 86/102 (84%) were MDS, 10/102 (10%) mixed myeloproferative/myelodysplastic, and 6/102 (6%) were acute myeloblastic leukemia. Regarding MDS by the International Prognostic System score on initiation of AZA 38/84 (45%) were low-intermediate-1 risk and 46/84 (55%) were intermediate-2-high risk. Ninety-five patients (89%) were red blood cell or platelet transfusion dependent. The AZA schedule was 5-0-0 in 39/106 (37%) patients, 5-2-2 in 36/106 (34%) patients, and 7 consecutive days in 31/106 (29%) patients. The median number of cycles administered was 8 (range, 1-30). Thirty eight out of 94 (40%) patients achieved TI. Median OS (95%CI) was significantly better in patients achieving TI (n=38) compared to patients that did not (n=56) (22 [20.1, 23.9] months vs. 11.1 [4.8, 17.5] months, p=.001). No significant differences were observed in TI rate and OS among the three different schedules. With a median follow-up of 14 [min-max, 1-50] months, the median OS (95%CI) of the 107 patients was 18 (12-23) months and the probability of OS (95%CI) at 2 years was 34% (22%-46%). Cycles were delayed in 31/106 (29%) patients and 47/101 patients (47%) were hospitalized for infection. These results show that treatment with AZA was feasible and effective in this elderly population, with 40% achieving TI, having a better OS than patients not achieving it. The schedule of AZA administration did not affect efficacy and toxicity.
[Show abstract][Hide abstract] ABSTRACT: Granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF2) is a cytokine produced in the hematological compartment that may enhance anti-tumor immune responses, mainly by activation of dendritic cells. Here we show that more than a third of human colorectal tumors exhibit aberrant DNA demethylation of the GM-CSF promoter and overexpress the cytokine. Mouse engraftment experiments with autologous and homologous colon tumors engineered to repress the ectopic secretion of GM-CSF revealed the tumor-secreted GM-CSF to have an immune-associated antitumor effect. Unexpectedly, an immune-independent anti-tumor effect was observed that depended on the ectopic expression of GM-CSF receptor subunits by tumors. Cancer cells expressing GM-CSF and its receptor did not develop into tumors when autografted into immunocompetent mice. Similarly, 100% of the patients with human colon tumors that overexpressed GM-CSF and its receptor subunits survived at least 5 years after diagnosis. These data suggest that expression of GM-CSF and its receptor subunits by colon tumors may be a useful marker for prognosis as well as for patient stratification in cancer immunotherapy.
[Show abstract][Hide abstract] ABSTRACT: Matrix metalloprotease-9 (MMP-9) plays a critical role in acute myeloid leukemia (AML) by increasing the invasive properties of malignant myeloblasts. The role of this enzyme in high-risk myelodysplastic diseases (MDS) and the effect of azacitidine on its expression in MDS and AML have not been studied in detail. In this work, we have analyzed the effect of different concentrations of azacitidine in two well-established MDS-derived acute myeloid leukemic cell lines: MOLM-13 and SKM-1. We have demonstrated that 1 μM azacitidine decreases MMP9 DNA methylation levels and that this is correlated with a significant increase in mRNA expression in both cell lines. Surprisingly, changes in protein levels were minor. This paradoxical effect is explained by the drug dependent induction of apoptosis that reduces the amount of active secreting cells. A balance between induced expression and apoptosis was established at an azacitidine concentration of 0.2 μM in MOLM-13 cells. This dose significantly increased the invasive capacity of viable cells, as measured in the Matrigel assay. To evaluate the clinical relevance of this observation, we have examined the effect of azacitidine on MMP-9 expression in bone marrow from 5 patients with MDS, with the finding that this drug significantly increased MMP-9 protein levels in all analyzed patients after 6 cycles of treatment. Based on these results, we conclude that azacitidine increases MMP9 expression and may enhance invasiveness in vitro. As all of these patients relapsed, these findings might explain, at least partially, the clinical failure of the drug and the progression to a more aggressive disease.
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: Hematology patients admitted to the ICU frequently experience respiratory failure and require mechanical ventilation. Noninvasive mechanical ventilation (NIMV) may decrease the risk of intubation, but NIMV failure poses its own risks. METHODS: To establish the impact of ventilatory management and NIMV failure on outcome, data from a prospective, multicenter, observational study were analyzed. All hematology patients admitted to one of the 34 participating ICUs in a 17-month period were followed up. Data on demographics, diagnosis, severity, organ failure, and supportive therapies were recorded. A logistic regression analysis was done to evaluate the risk factors associated with death and NIVM failure. RESULTS: Of 450 patients, 300 required ventilatory support. A diagnosis of congestive heart failure and the initial use of NIMV significantly improved survival, whereas APACHE II score, allogeneic transplantation, and NIMV failure increased the risk of death. The risk factors associated with NIMV success were age, congestive heart failure, and bacteremia. Patients with NIMV failure experienced a more severe respiratory impairment than did those electively intubated. CONCLUSIONS: NIMV improves the outcome of hematology patients with respiratory insufficiency, but NIMV failure may have the opposite effect. A careful selection of patients with rapidly reversible causes of respiratory failure may increase NIMV success.
Critical care (London, England) 07/2012; 16(4):R133. · 5.04 Impact Factor
This article is viewable in ResearchGate's enriched format
RG Format enables you to read in context with side-by-side figures, citations, and feedback from experts in your field.
[Show abstract][Hide abstract] ABSTRACT: The severity of neutropenia in myelodysplastic syndrome (MDS) has not been completely studied. We analyzed the prognostic significance of severe neutropenia (neutrophils count <0.5×10(9)/L) at diagnosis in 1109 patients with de novo MDS and low/intermediate-1 IPSS included in the Spanish MDS Registry. Severe neutropenia was present at diagnosis in 48 of 1109 (4%). Patients with severe neutropenia were most strongly represented within the groups of refractory cytopenia with multilineage dysplasia (40%) and refractory anemia with excess of blast type 1 (29%). Severe neutropenia had negative effects on the low/intermediate-1 risk group. A significant difference in overall survival was observed between patients with severe neutropenia (28 months) and patients with a neutrophil count higher than 0.5×10(9)/L (66 months) (p<0.0001). Also, severe neutropenia predicted a significantly reduced on leukemia-free survival (p<0.0001). In the multivariate analysis, severe neutropenia retained its independent prognostic influence on overall survival [HR: 2.19, 95% CI (1.41-3.10), p<0.0001] and leukemia free survival [HR: 3.51, 95% CI (1.97-6.26), p<0.0001]. The degree of neutropenia should be considered as additional prognostic factor in low/intermediate-1 IPSS MDS.
Leukemia research 11/2011; 36(3):287-92. · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The prognostic value of cytogenetic findings in chronic myelomonocytic leukemia is unclear. Our purpose was to evaluate the independent prognostic impact of cytogenetic abnormalities in a large series of patients with chronic myelomonocytic leukemia included in the database of the Spanish Registry of Myelodysplastic Syndromes.
We studied 414 patients with chronic myelomonocytic leukemia according to WHO criteria and with a successful conventional cytogenetic analysis at diagnosis. Different patient and disease characteristics were examined by univariate and multivariate methods to establish their relationship with overall survival and evolution to acute myeloid leukemia.
Patients with abnormal karyotype (110 patients, 27%) had poorer overall survival (P=0.001) and higher risk of acute myeloid leukemia evolution (P=0.010). Based on outcome analysis, three cytogenetic risk categories were identified: low risk (normal karyotype or loss of Y chromosome as a single anomaly), high risk (presence of trisomy 8 or abnormalities of chromosome 7, or complex karyotype), and intermediate risk (all other abnormalities). Overall survival at five years for patients in the low, intermediate, and high risk cytogenetic categories was 35%, 26%, and 4%, respectively (P<0.001). Multivariate analysis confirmed that this new CMML-specific cytogenetic risk stratification was an independent prognostic variable for overall survival (P=0.001). Additionally, patients belonging to the high-risk cytogenetic category also had a higher risk of acute myeloid leukemia evolution on univariate (P=0.001) but not multivariate analysis.
Cytogenetic findings have a strong prognostic impact in patients with chronic myelomonocytic leukemia.
[Show abstract][Hide abstract] ABSTRACT: Internal tandem duplications of the FLT3 gene (FLT3-ITDs) are frequent in patients with acute promyelocytic leukemia (APL), however its clinical impact remains controversial.
We analyzed the prognostic significance of FLT3-ITD mutant level and size, as well as FLT3-D835 point mutations, PML-RARalpha expression and other predictive factors in 129 APL patients at diagnosis enrolled on the Spanish LPA96 (n=43) or LPA99 (n=86) PETHEMA trials.
FLT3-ITDs and D835 mutations were detected in 21% and 9% of patients, respectively. Patients with increased ITD mutant/wild-type ratio or longer ITD size displayed shorter 5-year relapse-free survival (RFS) (P=0.048 and P<0.0001, respectively). However, patients with D835 mutations did not show differences in RFS or overall survival (OS). Moreover, patients with initial normalized copy number (NCN) of PML-RARalpha transcripts less than the 25(th) percentile had adverse clinical features and shorter 5-year RFS (P<0.0001) and OS (P=0.004) compared to patients with higher NCN. Patients with low NCN showed increased incidence of ITDs (P=0.001), with higher ratios (P<0.0001) and/or longer sizes (P=0.007). Multivariate analysis showed that long FLT3-ITD (P=0.001), low PML-RARalpha levels (P=0.004) and elevated WBC counts (>10x10(9)/L) (P=0.018) were independent predictors for shorter RFS. We identified a subgroup of patients with high WBC, long FLT3-ITD and low NCN of transcripts that showed an extremely bad prognosis (5-year RFS 23.4%, P<0.0001).
In conclusion, FLT3-ITD size and PML-RARalpha transcript levels at diagnosis could contribute to improve the risk stratification in APL.
[Show abstract][Hide abstract] ABSTRACT: About one half of adults with acute lymphoblastic leukemia are not cured of the disease and ultimately die. The objective of this study was to explore the factors influencing the outcome of adult patients with relapsed acute lymphoblastic leukemia.
We analyzed the characteristics, the outcome and the prognostic factors for survival after first relapse in a series of 263 adult patients with acute lymphoblastic leukemia (excluding those with mature B-cell acute lymphoblastic leukemia) prospectively enrolled in four consecutive risk-adapted PETHEMA trials.
The median overall survival after relapse was 4.5 months (95% CI, 4-5 months) with a 5-year overall survival of 10% (95% CI, 8%-12%); 45% of patients receiving intensive second-line treatment achieved a second complete remission and 22% (95% CI, 14%-30%) of them remained disease free at 5 years. Factors predicting a good outcome after rescue therapy were age less than 30 years (2-year overall survival of 21% versus 10% for those over 30 years old; P<0.022) and a first remission lasting more than 2 years (2-year overall survival of 36% versus 17% among those with a shorter first remission; P<0.001). Patients under 30 years old whose first complete remission lasted longer than 2 years had a 5-year overall survival of 38% (95% CI, 23%-53%) and a 5-year disease-free survival of 53% (95% CI, 34%-72%).
The prognosis of adult patients with acute lymphoblastic leukemia who relapse is poor. Those aged less than 30 years with a first complete remission lasting longer than 2 years have reasonable possibilities of becoming long-term survivors while patients over this age or those who relapse early cannot be successfully rescued using the therapies currently available.
[Show abstract][Hide abstract] ABSTRACT: We have analyzed brain and acute leukemia, cytoplasmic (BAALC) gene expression and other genetic markers (ERG, EVI1, MN1, PRAME, WT1, FLT3, and NPM1 mutations) in 127 intermediate-risk acute myeloid leukemia (AML) patients: 98 cytogenetically normal and 29 with intermediate-risk cytogenetic alterations. High versus low BAALC expressers showed a higher refractoriness to induction treatment (31% vs 10%; p = .005), lower complete remission rate after salvage therapy (82% vs 97%; p = .010), and lower 3-year overall (23% vs 58%, p < .001) and relapse-free survival (26% vs 52%, p = .006). Similar results were found when cytogenetic subgroups were analyzed separately. Multivariate models confirmed the unfavorable prognosis of this marker. In conclusion, BAALC is a relevant prognostic marker in intermediate-risk AML.
Annals of Hematology 11/2009; 89(5):453-8. · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The PI3/AKT pathway is up-regulated in acute myeloid leukemia (AML), but its prognostic relevance in cytogenetically normal AML (CN-AML) is unclear. We evaluated RNA levels of AKT and two downstream substrates (FOXO3a-p27) in 110 de novo CN-AML, included in the Spanish PETHEMA therapeutic protocols. Patients with high FOXO3a gene expression displayed shorter OS (p=0.015) and RFS (p=0.048) than low FOXO3a expressers. Features selected in the multivariate analysis as having an independent prognostic value for a shorter survival were WBC>50x10(9)/L, age >65 years and high FOXO3a expression. We concluded that FOXO3a assessment could contribute to improve the molecular-based risk stratification in CN-AML.
Leukemia research 06/2009; 33(12):1706-9. · 2.36 Impact Factor