RESUMEN
BACKGROUND: Repeat elements constitute a large proportion of the human genome and recent evidence indicates that repeat element expression has functional roles in both physiological and pathological states. Specifically for cancer, transcription of endogenous retrotransposons is often suppressed to attenuate an anti-tumor immune response, whereas aberrant expression of heterochromatin-derived satellite RNA has been identified as a tumor driver. These insights demonstrate separate functions for the dysregulation of distinct repeat subclasses in either the attenuation or progression of human solid tumors. For hematopoietic malignancies, such as Acute Myeloid Leukemia (AML), only very few studies on the expression/dysregulation of repeat elements were done. METHODS: To study the expression of repeat elements in AML, we performed total-RNA sequencing of healthy CD34 + cells and of leukemic blast cells from primary AML patient material. We also developed an integrative bioinformatic approach that can quantify the expression of repeat transcripts from all repeat subclasses (SINE/ALU, LINE, ERV and satellites) in relation to the expression of gene and other non-repeat transcripts (i.e. R/G ratio). This novel approach can be used as an instructive signature for repeat element expression and has been extended to the analysis of poly(A)-RNA sequencing datasets from Blueprint and TCGA consortia that together comprise 120 AML patient samples. RESULTS: We identified that repeat element expression is generally down-regulated during hematopoietic differentiation and that relative changes in repeat to gene expression can stratify risk prediction of AML patients and correlate with overall survival probabilities. A high R/G ratio identifies AML patient subgroups with a favorable prognosis, whereas a low R/G ratio is prevalent in AML patient subgroups with a poor prognosis. CONCLUSIONS: We developed an integrative bioinformatic approach that defines a general model for the analysis of repeat element dysregulation in physiological and pathological development. We find that changes in repeat to gene expression (i.e. R/G ratios) correlate with hematopoietic differentiation and can sub-stratify AML patients into low-risk and high-risk subgroups. Thus, the definition of a R/G ratio can serve as a valuable biomarker for AML and could also provide insights into differential patient response to epigenetic drug treatment.
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Leucemia Mieloide AgudaRESUMEN
In the current World Health Organization (WHO)-classification, therapy-related myelodysplastic syndromes (t-MDS) are categorized together with therapy-related acute myeloid leukemia (AML) and t-myelodysplastic/myeloproliferative neoplasms into one subgroup independent of morphologic or prognostic features. Analyzing data of 2087 t-MDS patients from different international MDS groups to evaluate classification and prognostication tools we found that applying the WHO classification for p-MDS successfully predicts time to transformation and survival (both p < 0.001). The results regarding carefully reviewed cytogenetic data, classifications, and prognostic scores confirmed that t-MDS are similarly heterogeneous as p-MDS and therefore deserve the same careful differentiation regarding risk. As reference, these results were compared with 4593 primary MDS (p-MDS) patients represented in the International Working Group for Prognosis in MDS database (IWG-PM). Although a less favorable clinical outcome occurred in each t-MDS subset compared with p-MDS subgroups, FAB and WHO-classification, IPSS-R, and WPSS-R separated t-MDS patients into differing risk groups effectively, indicating that all established risk factors for p-MDS maintained relevance in t-MDS, with cytogenetic features having enhanced predictive power. These data strongly argue to classify t-MDS as a separate entity distinct from other WHO-classified t-myeloid neoplasms, which would enhance treatment decisions and facilitate the inclusion of t-MDS patients into clinical studies.
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Biomarcadores de Tumor/análisis , Síndromes Mielodisplásicos/clasificación , Síndromes Mielodisplásicos/diagnóstico , Neoplasias Primarias Secundarias/clasificación , Neoplasias Primarias Secundarias/diagnóstico , Medición de Riesgo/métodos , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/terapia , Neoplasias Primarias Secundarias/terapia , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
We describe genetic and clinical characteristics of acute myeloid leukemia (AML) patients according to age from an academic population-based registry. Adult patients with newly diagnosed AML at 63 centers in Germany and Austria were followed within the AMLSG BiO registry (NCT01252485). Between January 1, 2012, and December 31, 2014, data of 3525 patients with AML (45% women) were collected. The median age was 65 years (range 18-94). The comparison of age-specific AML incidence rates with epidemiological cancer registries revealed excellent coverage in patients < 70 years old and good coverage up to the age of 80. The distribution according to the European LeukemiaNet (ELN) risk categorization from 2010 was 20% favorable, 31% intermediate-1, 28% intermediate-2, and 21% adverse. With increasing age, the relative but not the absolute prevalence of patients with ELN favorable and intermediate-1 risk (p < 0.001), with activating FLT3 mutations (p < 0.001), with ECOG performance status < 2 (p < 0.001), and with HCT-CI comorbidity index < 3 (p < 0.001) decreased. Regarding treatment, obesity and favorable risk were associated with an intensive treatment, whereas adverse risk, higher age, and comorbidity index > 0 were associated with non-intensive treatment or best supportive care. The AMLSG BiO registry provides reliable population-based distributions of genetic, clinical, and treatment characteristics according to age.
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Leucemia Mieloide Aguda , Mutación , Sistema de Registros , Tirosina Quinasa 3 Similar a fms , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Austria , Femenino , Alemania , Humanos , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
BACKGROUND: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT) has a dismal prognosis with limited therapeutic options. FLT3-ITD kinase inhibition is a reasonable but palliative experimental treatment alternative in this situation. Information on long-term outcome is not available. METHODS: We performed a long-term follow-up analysis of a previously reported cohort of 29 FLT3-ITD-positive AML patients, which were treated in relapse after allo-SCT with sorafenib monotherapy. FINDINGS: With a median follow-up of 7.5 years, 6 of 29 patients (21%) are still alive. Excluding one patient who received a second allo-SCT, five patients (17%) achieved sustained complete remissions with sorafenib. Four of these patients are in treatment-free remission for a median of 4.4 years. INTERPRETATION: Sorafenib may enable cure of a proportion of very poor risk FLT3-ITD-positive AML relapsing after allo-SCT.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Leucemia Mieloide Aguda/terapia , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Trasplante de Células Madre/efectos adversos , Secuencias Repetidas en Tándem , Tirosina Quinasa 3 Similar a fms/genética , Adolescente , Adulto , Anciano , Antineoplásicos/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Alemania , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Factores de Riesgo , Sorafenib , Factores de Tiempo , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
The aim of this cohort study was to compare a condensed schedule of consolidation therapy with high-dose cytarabine on days 1, 2 and 3 (HDAC-123) with the HDAC schedule given on days 1, 3 and 5 (HDAC-135) as well as to evaluate the prophylactic use of pegfilgrastim after chemotherapy in younger patients with acute myeloid leukemia in first complete remission. One hundred and seventy-six patients were treated with HDAC-135 and 392 patients with HDAC-123 with prophylactic pegfilgrastim at days 10 and 8, respectively, in the AMLSG 07-04 and the German AML Intergroup protocol. Time from start to chemotherapy until hematologic recovery with white blood cells >1.0 G/l and neutrophils >0.5 G/l was in median 4 days shorter in patients receiving HDAC-123 compared with HDAC-135 (P<0.0001, each), and further reduced by 2 days (P<0.0001) by pegfilgrastim. Rates of infections were reduced by HDAC-123 (P<0.0001) and pegfilgrastim (P=0.002). Days in hospital and platelet transfusions were significantly reduced by HDAC-123 compared with HDAC-135. Survival was neither affected by HDAC-123 versus HDAC-135 nor by pegfilgrastim. In conclusion, consolidation therapy with HDAC-123 leads to faster hematologic recovery and less infections, platelet transfusions as well as days in hospital without affecting survival.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Quimioterapia de Consolidación/métodos , Citarabina/administración & dosificación , Filgrastim/administración & dosificación , Leucemia Mieloide Aguda , Transfusión de Plaquetas , Polietilenglicoles/administración & dosificación , Adolescente , Adulto , Daunorrubicina/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Tiempo de Internación , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
We evaluated the impact of salvage regimens and allogeneic hematopoietic cell transplantation (allo-HCT) in acute myeloid leukemia (AML) with induction failure. Between 1993 and 2009, 3324 patients with newly diagnosed AML were enrolled in 5 prospective treatment trials of the German-Austrian AML Study Group. After first induction therapy with idarubicin, cytarabine and etoposide (ICE), 845 patients had refractory disease. In addition, 180 patients, although responding to first induction, relapsed after second induction therapy. Of the 1025 patients with induction failure, 875 (median age 55 years) received intensive salvage therapy: 7+3-based (n=59), high-dose cytarabine combined with mitoxantrone (HAM; n=150), with all-trans retinoic acid (A; A-HAM) (n=247), with gemtuzumab ozogamicin and A (GO; GO-A-HAM) (n=140), other intensive regimens (n=165), experimental treatment (n=27) and direct allo-HCT (n=87). In patients receiving intensive salvage chemotherapy (n=761), response (complete remission/complete remission with incomplete hematological recovery (CR/CRi)) was associated with GO-A-HAM treatment (odds ratio (OR), 1.93; P=0.002), high-risk cytogenetics (OR, 0.62; P=0.006) and age (OR for a 10-year difference, 0.75; P<0.0001). Better survival probabilities were seen in an extended Cox regression model with time-dependent covariables in patients responding to salvage therapy (P<0.0001) and having the possibility to perform an allo-HCT (P<0.0001). FLT3 internal tandem duplication, mutated IDH1 and adverse cytogenetics were unfavorable factors for survival.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/mortalidad , Leucemia Mieloide Aguda/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Terapia Recuperativa , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Inducción de Remisión , Tasa de Supervivencia , Trasplante Homólogo , Adulto JovenAsunto(s)
Cromosomas Humanos Par 21/genética , Leucemia Mieloide Aguda/genética , Mutación/genética , Proteínas Represoras/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Austria , Femenino , Alemania , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Pronóstico , Translocación Genética/genética , Adulto JovenAsunto(s)
Leucemia Mieloide Aguda/terapia , Terapia Recuperativa , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Recurrencia , Resultado del Tratamiento , Adulto JovenRESUMEN
We studied acute myeloid leukemia (AML) patients with lympho-myeloid clonal hematopoiesis (LM-CH), defined by the presence of DNA methyltransferase 3A (DNMT3A) mutations in both the myeloid and lymphoid T-cell compartment. Diagnostic, complete remission (CR) and relapse samples were sequenced for 34 leukemia-related genes in 171 DNMT3A mutated adult AML patients. AML with LM-CH was found in 40 patients (23%) and was associated with clonal hematopoiesis of indeterminate potential years before AML, older age, secondary AML and more frequent MDS-type co-mutations (TET2, RUNX1 and EZH2). In 82% of AML patients with LM-CH, the preleukemic clone was refractory to chemotherapy and was the founding clone for relapse. Both LM-CH and non-LM-CH MRD-positive AML patients who achieved CR had a high risk of relapse after 10 years (75% and 75%, respectively) compared with patients without clonal hematopoiesis in CR with negative MRD (27% relapse rate). Long-term survival of patients with LM-CH was only seen after allogeneic hematopoietic stem cell transplantation (HSCT). We define AML patients with LM-CH as a distinct high-risk group of AML patients that can be identified at diagnosis through mutation analysis in T cells and should be considered for HSCT.
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Células Clonales , Hematopoyesis , Leucemia Mieloide Aguda/patología , Células Progenitoras Linfoides/patología , Células Progenitoras Mieloides/patología , Recurrencia Local de Neoplasia/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Terapia Combinada , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Células Progenitoras Linfoides/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Células Progenitoras Mieloides/metabolismo , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias , Pronóstico , Tasa de Supervivencia , Adulto JovenAsunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicos/terapia , Acondicionamiento Pretrasplante , Anciano , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Recurrencia , Análisis de Supervivencia , Trasplante Homólogo , Resultado del TratamientoAsunto(s)
Factores Inmunológicos/uso terapéutico , Mutación , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Talidomida/análogos & derivados , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Anciano de 80 o más Años , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Femenino , Humanos , Lenalidomida , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Prospectivos , Talidomida/uso terapéuticoRESUMEN
Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.
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Análisis Mutacional de ADN/métodos , Leucemia Promielocítica Aguda/genética , Diferenciación Celular , Proteínas de Unión al ADN/genética , Exoma/genética , Perfilación de la Expresión Génica , Humanos , Proteínas Nucleares/genética , Recurrencia , Factores de Transcripción/genéticaAsunto(s)
Factores Inmunológicos/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Talidomida/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Femenino , Humanos , Estimación de Kaplan-Meier , Lenalidomida , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Talidomida/uso terapéutico , Resultado del TratamientoRESUMEN
Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.
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Corticoesteroides/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Neoplasias Hematológicas/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Pirazoles/uso terapéutico , Terapia Recuperativa , Adulto , Anciano , Animales , Modelos Animales de Enfermedad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Neoplasias Hematológicas/terapia , Humanos , Quinasas Janus/antagonistas & inhibidores , Masculino , Ratones , Persona de Mediana Edad , Estadificación de Neoplasias , Nitrilos , Pronóstico , Pirimidinas , Recurrencia , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante Homólogo , Adulto JovenRESUMEN
Higher-risk myelodysplastic syndromes (MDS) are rarely curable and have a poor prognosis. We investigated the accuracy of physicians' perception of patients' health status and the patients' preferences for involvement in treatment decisions. We examined 280 newly diagnosed higher-risk elderly MDS patients paired with their physicians. Survey tools included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and the Control Preference Scale. Overall concordance was 49% for physician perception of patient preferences for involvement in treatment decisions. In 36.4% of comparisons there were minor differences and in 14.6% there were major differences. In 44.7% of the patients preferring a passive role, physicians perceived them as preferring an active or collaborative role. Absence of the patient's request for prognostic information (P=0.001) and judging the patient as having a poor health status (P=0.036) were factors independently associated with the physicians' attitude toward a lower degree of patient involvement in clinical decisions. Agreement on health status was found in 27.5% of cases. Physicians most frequently tended to overestimate health status of patients who reported low-level health status. The value of decision aid-tools in the challenging setting of higher-risk MDS should be investigated to further promote patient-centered care.
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Estado de Salud , Síndromes Mielodisplásicos/terapia , Prioridad del Paciente , Relaciones Médico-Paciente , Médicos , Adulto , Anciano , Anciano de 80 o más Años , Toma de Decisiones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/psicología , Participación del Paciente/psicología , Participación del Paciente/estadística & datos numéricos , Prioridad del Paciente/estadística & datos numéricos , Percepción , Médicos/psicología , Médicos/estadística & datos numéricos , Calidad de Vida , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
UNLABELLED: DNA-hypomethylating agents are a viable treatment option for AML/myelodysplastic syndrome (MDS) relapse after allograft by upregulating Ags on blasts before DLI. Seventy-two patients with relapsed AML (n=62), MDS (n=8) and other myeloid neoplasms (n=2) after allograft were treated with low-dose 5-azacytidine and, if feasible, DLI. PATIENT CHARACTERISTICS: median age 62 years (range 20-75), 42% with adverse cytogenetics, 82% not in remission at transplant and 83% received fludarabine-based reduced-toxicity conditioning. Median duration from transplant to 5-azacytidine was 289 days (range 59-2133). Response criteria: CR, temporary disease control or treatment failure. A median of 2.7 courses (range 1-10) were administered; 65 out of 72 patients also received DLI (41 already before 5-azacytidine). Ten patients developed acute GVHD and two succumbed to treatment-related sepsis. CR rate was 9.7% (in two patients lasting >5 years), 44% had temporary disease control (median duration 71 days, range 31-380). Median survival from 5-azacytidine was 108 days, 21 patients proceeded to subsequent transplant. In multivariate analysis, peripheral blood blasts <1% were predictive of longer OS (P=0.03). Taken together, long-term remissions can be induced by this well-tolerated outpatient treatment, particularly in patients without peripheral blood blasts.