[Show abstract][Hide abstract] ABSTRACT: The efficacy of erythropoietic stimulating agents (ESA) in chronic myelomonocytic leukemia (CMML) is unknown. Our objective was to analyze erythroid response (ER) and overall survival (OS) in a series of 94 patients with CMML treated with ESA.
We analyzed a series of 94 patients with CMML treated with ESA included in the Spanish and Düsseldorf-MDS registries.
ER was observed in 64% of patients and red blood cell (RBC) transfusion independence in 31%. The median duration of ER was 7 months (range, 0 - 88). CPSS and EPO level were significantly associated with ER in multivariate analysis (p=.003). Considering only patients with CPSS low or intermediate-1 risk-group, the absence of RBC transfusion dependence and erythropoietin (EPO) level predicted ER (p=.003 and p=.008, respectively). In multivariate analysis only the EPO level retained its prognostic value (p=.029). Achievement of ER correlated with a better survival since ER evaluation (p=.016).
The CPSS and EPO levels are adequate tools to select CMML patients with symptomatic anemia who may benefit from treatment with ESA. A significant ER to ESA is expected in anemic patients with low/intermediate-1 CMML risk by the CPSS and a low endogenous serum EPO level. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
European Journal Of Haematology 09/2015; DOI:10.1111/ejh.12679 · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The benefit of azacitidine treatment in survival of high risk myelodysplastic syndromes (MDS) patients compared to conventional care treatment (CCT) has not been established outside clinical trials. To assess its effectiveness, we compared overall survival between azacitidine and conventional treatment (CCT) in high-risk MDS patients, excluding those undergoing stem cell transplantation, submitted to the Spanish MDS registry from 2000 to 2013. Several Cox regression and competing risk models, considering azacitidine as a time-dependent covariate, were used to assess survival and AML progression. Among 821 patients included, 251 received azacitidine. Median survival was 13.4 (11.8-16) months for azacitidine-treated patients and 12.2 (11-14.1) for patients under CCT (P=0.41). In a multivariate model, age, IPSS and LDH were predictors of OS whereas azacitidine was not (adjusted odds ratio 1.08, 95% confidence interval 0.86-1.35, P=0.49). However, in patients with chromosome 7 abnormalities, a trend towards a better survival was observed in azacitidine-treated patients (median survival 13.3 [11-18] months) compared to CCT (median survival 8.6 [5-10.4] months, P=0.08). In conclusion, our data show that, in spite of a widespread use of azacitidine, there is a lack of improvement in survival over the years. Identification of predicting factors of response and survival is mandatory.Leukemia accepted article preview online, 06 May 2015. doi:10.1038/leu.2015.115.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2015; 29(9). DOI:10.1038/leu.2015.115 · 10.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute lymphoblastic leukemia (ALL) following solid organ or hematologic malignancy (secondary ALL, s-ALL) is not well characterized. We analyzed the characteristics and outcome of patients with s-ALL and compared with those of patients with de novo- ALL. Of 448 patients, 24 (5%) had previous neoplasia. Sixteen patients received previous cytotoxic therapy (therapy-associated ALL, t-ALL), and 8 did not (antecedent-malignancy ALL, am-ALL) . Except for more advanced age in patients with s-ALL, no statistically significant differences were observed in WBC count, CNS involvement, immunophenotype or cytogenetics between the groups, nor in complete remission (t-ALL: 94%; am-ALL: 75%; de novo-ALL: 85%), 3-yrear remission duration ( 58%; 50%; 72% ), overall survival (71%; 38%; 60%) or event-free survival (53%, 38%; 53%). Our study did not show poor clinical or cytogenetic features or inferior outcome in ALL patients with antecedent neoplastic disease, irrespective of the type of treatment received for the neoplasia.
[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.
Leukemia Research 08/2014; 38(10). DOI:10.1016/j.leukres.2014.07.009 · 2.35 Impact Factor
[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.
Leukemia research 05/2014; 38(5). DOI:10.1016/j.leukres.2014.02.001 · 2.35 Impact Factor
[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.
[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: Background:
The use of rituximab together with intensive chemotherapy in Burkitt's lymphoma or leukemia (BL) has been scarcely explored. This study prospectively evaluated and compared the outcome and toxicity of human immunodeficiency virus (HIV)-positive and HIV-negative patients with BL who were treated in an intensive immunochemotherapy-based and age-adapted trial.
A total of 118 adult patients (80 HIV-negative and 38 HIV-positive) aged 15 to 83 years were treated with 4 (nonbulky stages I-II) or 6 (stages II bulky, III-IV) cycles of intensive chemotherapy combined with rituximab. Reduction in chemotherapy doses and modification of the cycle schedules was performed in patients older than 55 years.
The clinical characteristics of HIV-positive patients were comparable with those who were HIV-negative. Complete remission rates were 82% and 87%, respectively, and 9 patients died in induction, 9 died in remission, and 7 relapsed. After a median follow-up of 2.5 years, nonsignificant differences were observed in the 4-year disease-free survival and overall survival (OS) probabilities (77% and 63% for HIV-positive and 80% and 78% for HIV-negative patients, respectively). Young HIV-infected patients presented higher incidences of grade 3 or 4 mucositis and severe infectious episodes. Poor general status and bone marrow involvement, but not advanced age, were associated with a shorter OS, allowing the definition of 3 prognostic groups, with the OS ranging from 50% to 92%.
Age-adapted intensive immunochemotherapy is highly effective in both HIV-negative and HIV-positive patients, with a higher toxicity in the latter group. Poor general status and bone marrow involvement had a negative impact on survival.
Cancer 05/2013; 119(9). DOI:10.1002/cncr.27918 · 4.89 Impact Factor
[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.
Cancer Research 10/2012; 73(1). DOI:10.1158/0008-5472.CAN-12-0806 · 9.33 Impact Factor
[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.
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.
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.
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.
[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. DOI:10.1016/j.leukres.2011.10.025 · 2.35 Impact Factor