RESUMEN
BACKGROUND: A multistep pathogenesis of myeloid leukemia including mutations in epigenetic, spliceosome, and signaling genes has been recently demonstrated in a preclinical model but is poorly validated in patients. METHODS: Clinical, phenotypic, and biologic features were compared between three distinct molecularly defined CMML cohorts including TET2 monomutated patients (T, n = 10), TET2/SRSF2 bimutated patients (TS, n = 19), and patients who had NRAS mutations in addition to TET2/SRSF2 comutations (TSN, n = 14). RESULTS: Median survival was 90, 45, and 9 months, respectively (p = .001). Whereas no patient in the T and TS group transformed into acute myeloid leukemia (AML), 6/14 patients in the TSN group had AML at study entry or transformed during follow-up. Leukocyte counts, blast cell counts, and LDH levels were significantly higher in TSN vs. TS and T, respectively, whereas hemoglobin and platelet values were not significantly different. Increased growth factor-independent myeloid colony formation was restricted to TSN but not found in T and TS, respectively. The proportion of patients showing in vitro myelomonocytic skewing in T, TS, and TSN was 0%, 56%, and 100%, respectively (p = .010). CONCLUSION: Our results demonstrate that the model of multistep pathogenesis in CMML can be recapitulated in patients regarding clinical, phenotypic, and biologic features.
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Productos Biológicos , Leucemia Mieloide Aguda , Leucemia Mielomonocítica Crónica , Humanos , Leucemia Mielomonocítica Crónica/diagnóstico , Leucemia Mielomonocítica Crónica/genética , Mutación , PronósticoRESUMEN
BACKGROUND: Myelomonocytic skewing is considered as a key pathophysiologic phenomenon in chronic myelomonocytic leukemia (CMML), but its prevalence and potential correlation with phenotypic, genotypic, and clinical features are poorly defined. METHODS: Skewed differentiation toward the myelomonocytic over erythroid commitment as indicated by an inverse ratio of myelomonocytic/erythroid colonies was investigated in 146 patients with CMML by semisolid in vitro cultures. RESULTS: There was a high prevalence of myelomonocytic skewing in patients with CMML (120/146, 82%); whereas, this phenomenon was rare in normal individuals (1/98, 1%). Patients with CMML with myelomonocytic skewing had higher white blood cell and peripheral blast cell counts, and lower platelet values. The number of mutations in genes of the epigenetic and/or splicing category was higher in CMML patients with as compared with patients without skewing. Patients with myelomonocytic skewing had more frequently mutations in RASopathy genes and higher growth factor independent myeloid colony formation. Interestingly, the lack of myelomonocytic skewing discriminated patients with CMML with a particularly favorable prognosis (60 vs 19 months, P = .003) and a minimal risk of transformation. CONCLUSION: Myelomonocytic skewing as determined by semisolid cultures can discriminate subgroups of patients with CMML with a different phenotype, a different genotype, and a different prognosis.
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Leucemia Mielomonocítica Crónica/diagnóstico , Leucemia Mielomonocítica Crónica/mortalidad , Recuento de Leucocitos , Leucocitos Mononucleares/patología , Células Mieloides/patología , Biomarcadores , Biomarcadores de Tumor , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Leucemia Mielomonocítica Crónica/etiología , Leucocitos Mononucleares/metabolismo , Masculino , Mutación , Células Mieloides/metabolismo , Fenotipo , Pronóstico , Transducción de Señal , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
In older patients with chronic myelomonocytic leukaemia (CMML) and limited life expectancy due to age and or comorbidities, it is particularly important to consider the risk of transformation for individualised treatment decisions. There is limited information on potential differences between younger and older CMML patients regarding the cumulative risk of transformation as well as haematological, molecular and biologic characteristics. We analysed data from the Austrian Biodatabase for CMML (ABCMML) to compare these parameters in 518 CMML patients. Categorisation of patients into 3 age-related groups: <60 years, 60-79 years and ≥80 years, showed a significantly lower risk of transformation at higher age by competing risk analysis, with a 4-year risk of 39%, 23% and 13%, respectively (P < .0001). The lower probability of transformation was associated with a lower percentage of blast cells in the peripheral blood (PB) of older patients. Furthermore, we provide a simple score based on age, PB blasts and platelet counts that allowed us to define subgroups of CMML patients with a different cumulative transformation risk, including a low-risk group with a transformation risk of only 5%. Our findings may facilitate reasonable treatment decisions in elderly patients with CMML.
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Evaluación del Impacto en la Salud , Leucemia Mielomonocítica Crónica/epidemiología , Leucemia Mielomonocítica Crónica/patología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Comorbilidad , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Leucemia Mielomonocítica Crónica/etiología , Leucemia Mielomonocítica Crónica/mortalidad , Masculino , Persona de Mediana Edad , Oportunidad Relativa , PronósticoRESUMEN
We have originally reported that colony-forming units granulocyte/macrophage (CFU-GM) formation is an in vitro feature of chronic myelomonocytic leukemia (CMML) and a strong predictor for short survival. Elucidation of the molecular basis underlying this in vitro phenomenon could be helpful to define molecular features that predict inferior outcome in patients. We studied the correlation between the mutational landscape and spontaneous colony formation in 164 samples from 125 CMML patients. As compared to wildtype samples, spontaneous in vitro CFU-GM formation was significantly increased in samples containing mutations in NRAS, CBL and EZH2 that were confirmed as independent stimulatory factors by multiple regression analysis. Inducible expression of mutated RAS but not JAK2 was able to induce growth factor independence of Ba/F3 cells. Whereas high colony CFU-GM growth was a strong unfavorable parameter for survival (p < 0.00001) and time to transformation (p = 0.01390), no single mutated gene had the power to significantly predict for both outcome parameters. A composite molecular parameter including NRAS/CBL/EZH2, however, was predictive for inferior survival (p = 0.00059) as well as for increased risk of transformation (p = 0.01429). In conclusion, we show that the composite molecular profile NRAS/CBL/EZH2 derived from its impact on spontaneous in vitro myeloid colony formation improves the predictive power over single molecular parameters in patients with CMML.
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Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/mortalidad , Leucemia Mielomonocítica Crónica/patología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Línea Celular Tumoral , Proteína Potenciadora del Homólogo Zeste 2/genética , Femenino , GTP Fosfohidrolasas/genética , Regulación Leucémica de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Janus Quinasa 2/genética , Masculino , Proteínas de la Membrana/genética , Ratones , Persona de Mediana Edad , Mutación , Pronóstico , Proteínas Proto-Oncogénicas c-cbl/genética , Ensayo de Tumor de Célula Madre , Proteínas ras/genéticaRESUMEN
Although the RAS-pathway has been implicated as an important driver in the pathogenesis of chronic myelomonocytic leukemia (CMML) a comprehensive study including molecular and functional analyses in patients with progression and transformation has not been performed. A close correlation between RASopathy gene mutations and spontaneous in vitro myeloid colony (CFU-GM) growth in CMML has been described. Molecular and/or functional analyses were performed in three cohorts of 337 CMML patients: in patients without (A, n = 236) and with (B, n = 61) progression/transformation during follow-up, and in patients already transformed at the time of sampling (C, n = 40 + 26 who were before in B). The frequencies of RAS-pathway mutations (variant allele frequency ≥ 20%) in cohorts A, B, and C were 30%, 47%, and 71% (p < 0.0001), and of high colony growth (≥20/105 peripheral blood mononuclear cells) 31%, 44%, and 80% (p < 0.0001), respectively. Increases in allele burden of RAS-pathway mutations and in numbers of spontaneously formed CFU-GM before and after transformation could be shown in individual patients. Finally, the presence of mutations in RASopathy genes as well as the presence of high colony growth prior to transformation was significantly associated with an increased risk of acute myeloid leukemia (AML) development. Together, RAS-pathway mutations in CMML correlate with an augmented autonomous expansion of neoplastic precursor cells and indicate an increased risk of AML development which may be relevant for targeted treatment strategies.
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Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/metabolismo , Mutación , Transducción de Señal , Proteínas ras/genética , Proteínas ras/metabolismo , Análisis Citogenético , Progresión de la Enfermedad , Regulación Leucémica de la Expresión Génica , Humanos , Leucemia Mielomonocítica Crónica/mortalidad , Leucemia Mielomonocítica Crónica/patología , Estadificación de Neoplasias , Células Madre Neoplásicas/metabolismo , Pronóstico , Estudios RetrospectivosRESUMEN
In chronic myelomonocytic leukemia (CMML), colony-forming units granulocyte/macrophage (CFU-GM), which grow in vitro in the absence of exogenous growth factors, arise from the abnormal clone that is responsible for the overproduction of granulomonocytic cells. Previous in vitro findings including ours suggest that divergent molecular aberrations in CMML seem to converge within the GM-CSF signaling pathway. As JAK2 is a sentinel kinase in this pathway, JAK2 inhibition may be an attractive treatment approach in CMML. We investigated the in vitro effects of the specific JAK2 inhibitor TG101209 on the autonomous CFU-GM formation from peripheral blood mononuclear cells of patients with CMML. TG101209 was found to either block or strongly inhibit spontaneous CFU-GM growth in all 10 patients tested. This inhibitory effect was dose dependent and significantly more pronounced as compared to the inhibitory effect on stimulated CFU-GM growth from normal individuals. In a CMML patient with splenomegaly, who was treated with the JAK1/2 inhibitor ruxolitinib off label, we can demonstrate a spleen response and the disappearance of constitutional symptoms which was associated with a decrease in autonomous CFU-GM formation ex vivo. Pharmacological JAK2 inhibition may be an interesting approach to be systematically studied in patients with CMML.
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Antineoplásicos/farmacología , Janus Quinasa 2/antagonistas & inhibidores , Leucemia Mielomonocítica Crónica/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Ensayo de Unidades Formadoras de Colonias , Relación Dosis-Respuesta a Droga , Femenino , Células Progenitoras de Granulocitos y Macrófagos/efectos de los fármacos , Humanos , Janus Quinasa 2/genética , Leucemia Mielomonocítica Crónica/diagnóstico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Mutación , Nitrilos , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Pirimidinas , Tomografía Computarizada por Rayos XRESUMEN
The spontaneous formation of colony-forming units granulocyte/macrophage (CFU-GM) in semisolid cultures has been shown to be due to the endogenous release of cytokines and/or to the hypersensitivity of cells against growth factors. We have reported that increased autonomous CFU-GM growth is an in vitro characteristic of myelofibrosis (MF) which may reflect aberrant hematopoiesis in vivo. Because of its cytokine synthesis-inhibiting action, we speculated that interleukin-10 (IL-10) may inhibit pathological overproduction of myeloid cells in MF by suppression of autonomous myelopoiesis. In this study, IL-10 significantly inhibited autonomous CFU-GM formation in vitro from peripheral blood mononuclear cells (PB MNC) in 10 of 11 patients with MF tested. In all patients, there was a mean inhibition of 69% ranging from 35% to 100%. Suppression of autonomous CFU-GM formation by IL-10 was dose dependent and reversible by the addition of anti-IL-10 antibodies. Our results indicate that IL-10 is a potentially useful molecule to affect aberrant myelopoiesis in patients with MF.
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Interleucina-10/metabolismo , Mielopoyesis , Mielofibrosis Primaria/metabolismo , Anciano , Anciano de 80 o más Años , Ensayo de Unidades Formadoras de Colonias , Relación Dosis-Respuesta a Droga , Femenino , Células Progenitoras de Granulocitos y Macrófagos/efectos de los fármacos , Células Progenitoras de Granulocitos y Macrófagos/metabolismo , Humanos , Interleucina-10/farmacología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: CD33 is a well-known stem cell target in acute myeloid leukemia. So far, however, little is known about expression of CD33 on leukemic stem cells in chronic leukemias. DESIGN AND METHODS: We analyzed expression of CD33 in leukemic progenitors in chronic myeloid leukemia by multi-color flow cytometry and quantitative polymerase chain reaction. In addition, the effects of a CD33-targeting drug, gemtuzumab/ozogamicin, were examined. RESULTS: As assessed by flow cytometry, stem cell-enriched CD34(+)/CD38(-)/CD123(+) leukemic cells expressed significantly higher levels of CD33 compared to normal CD34(+)/CD38(-) stem cells. Moreover, highly enriched leukemic CD34(+)/CD38(-) cells (>98% purity) displayed higher levels of CD33 mRNA. In chronic phase patients, CD33 was found to be expressed invariably on most or all stem cells, whereas in accelerated or blast phase of the disease, the levels of CD33 on stem cells varied from donor to donor. The MDR1 antigen, supposedly involved in resistance against ozogamicin, was not detectable on leukemic CD34(+)/CD38(-) cells. Correspondingly, gemtuzumab/ozogamicin produced growth inhibition in leukemic progenitor cells in all patients tested. The effects of gemtuzumab/ozogamicin were dose-dependent, occurred at low concentrations, and were accompanied by apoptosis in suspension culture. Moreover, the drug was found to inhibit growth of leukemic cells in a colony assay and long-term culture-initiating cell assay. Finally, gemtuzumab/ozogamicin was found to synergize with nilotinib and bosutinib in inducing growth inhibition in leukemic cells. CONCLUSIONS: CD33 is expressed abundantly on immature CD34(+)/CD38(-) stem cells and may serve as a stem cell target in chronic myeloid leukemia.
Asunto(s)
ADP-Ribosil Ciclasa 1/metabolismo , Aminoglicósidos/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antígenos CD34/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Células Madre Neoplásicas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Proliferación Celular/efectos de los fármacos , Femenino , Gemtuzumab , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Lectina 3 Similar a Ig de Unión al Ácido Siálico , Células Tumorales Cultivadas , Adulto JovenAsunto(s)
Neoplasias Hematológicas , Trastornos Mieloproliferativos , Neoplasias , Humanos , Nitrilos , Pirazoles , PirimidinasRESUMEN
BACKGROUND: Patients with metastatic breast cancer (MBC) have a considerable symptom burden and may require extensive care for a long period of time. Palliative care (PC) has the potential to improve their quality of care and reduce their use of medical services. However, the role of specialised PC (SPC) in patients with MBC remains unclear. PATIENTS AND METHODS: We performed a retrospective analysis of the medical records of patients diagnosed with breast cancer (BC) from 2008 to 2018 at an university-based referral centre to examine the extent of early and late integration of SPC services for patients with MBC. A descriptive analysis of the patients was also established. RESULTS: In all, 932 patients were diagnosed with BC from 2008 to 2018; 225 of these patients had or developed metastases related to their BC. In addition, 132 patients received SPC (58.7%) and 93 patients did not receive SPC (41.3%). The median probability of overall survival (OS) for patients who did not receive SPC services was 3.6 years (95% CI 2.0 to 5.1) and 1.8 years (95% CI 1.3 to 2.3) (p<0.0001) for patients who did receive SPC. In multivariate analysis, referral to SPC services was independently associated with OS (HR 1.60, 95% CI 1.16 to 2.22, p=0.004). CONCLUSION: Patients who received SPC lived significantly shorter amounts of time than patients not referred for SPC services at our hospital. We concluded that the referral to SPC services was often too late and should be implemented earlier in the course of the disease. We suggest that patients with MBC should participate in a consultation by a SPC team ≤60 days after the start of systemic palliative anticancer therapy in addition to endocrine treatment. Larger prospective studies are needed to evaluate the benefit of the early integration of SPC services for patients with MBC.
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Neoplasias de la Mama , Cuidados Paliativos , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/terapia , Femenino , Humanos , Prevalencia , Derivación y Consulta , Estudios RetrospectivosRESUMEN
Normal hematopoietic function is maintained by a well-controlled balance of myelomonocytic, megaerythroid and lymphoid progenitor cell populations which may be skewed during pathologic conditions. Using semisolid in vitro cultures supporting the growth of myelomonocytic (CFU-GM) and erythroid (BFU-E) colonies, we investigated skewed differentiation towards the myelomonocytic over erythroid commitment in 81 patients with myelofibrosis (MF). MF patients had significantly increased numbers of circulating CFU-GM and BFU-E. Myelomonocytic skewing as indicated by a CFU-GM/BFU-E ratio ≥ 1 was found in 26/81 (32%) MF patients as compared to 1/98 (1%) in normal individuals. Patients with myelomonocytic skewing as compared to patients without skewing had higher white blood cell and blast cell counts, more frequent leukoerythroblastic features, but lower hemoglobin levels and platelet counts. The presence of myelomonocytic skewing was associated with a higher frequency of additional mutations, particularly in genes of the epigenetic and/or splicing machinery, and a significantly shorter survival (46 vs. 138 mo, p < 0.001). The results of this study show that the in vitro detection of myelomonocytic skewing can discriminate subgroups of patients with MF with a different phenotype, a different mutational profile and a different prognosis. Our findings may be important for the understanding and management of MF.
RESUMEN
Patients with a myeloproliferative neoplasm (MPN) sometimes show a chronic myelomonocytic leukemia (CMML)-like phenotype but, according to the 2016 WHO classification, a documented history of an MPN excludes the diagnosis of CMML. Forty-one patients with an MPN (35 polycythemia vera (PV), 5 primary myelofibrosis, 1 essential thrombocythemia) and a CMML-like phenotype (MPN/CMML) were comprehensively characterized regarding clinical, hematologic, biologic and molecular features. The white blood cell counts in MPN/CMML patients were not different from CMML patients and PV patients. The hemoglobin values and platelet counts of these patients were higher than in CMML but lower than in PV, respectively. MPN/CMML patients showed myelomonocytic skewing, a typical in vitro feature of CMML but not of PV. The mutational landscape of MPN/CMML was not different from JAK2-mutated CMML. In two MPN/CMML patients, development of a CMML-like phenotype was associated with a decrease in the JAK2 V617F allelic burden. Finally, the prognosis of MPN/CMML (median overall survival (OS) 27 months) was more similar to CMML (JAK2-mutated, 28 months; JAK2-nonmutated 29 months) than to PV (186 months). In conclusion, we show that patients with MPN and a CMML-like phenotype share more characteristics with CMML than with PV, which may be relevant for their classification and clinical management.
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Interleucina-10/uso terapéutico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Antígeno B7-2/biosíntesis , Regulación hacia Abajo , Evaluación de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Interleucina-10/genética , Interleucina-10/farmacología , Leucemia Mielomonocítica Crónica/patología , Masculino , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Muramidasa/sangre , Proteínas de Neoplasias/sangre , Proyectos Piloto , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Piel/patología , Células Tumorales CultivadasAsunto(s)
Células Precursoras Eritroides/patología , Células Progenitoras de Granulocitos y Macrófagos/patología , Mielofibrosis Primaria/patología , Trombocitemia Esencial/patología , Médula Ósea/patología , Recuento de Células , Proliferación Celular , Humanos , Mielofibrosis Primaria/diagnóstico , Trombocitemia Esencial/diagnósticoRESUMEN
The correlation of molecular and phenotypic evolution in individual patients with chronic myelomonocytic leukemia (CMML) is poorly investigated. The longitudinal follow up of a CMML patient for more than 10 years illustrates that the emergence of clones harboring mutations in TET2, SRSF2, RUNX1, MPL, NRAS, and finally in multiple genes, respectively, was mirrored by thrombocytopenia, thrombocytosis, myeloproliferation and transformation into acute myeloid leukemia. Moreover, molecular aberrations of the RAS genes were associated with markedly increased spontaneous in vitro myeloid colony formation which has been shown to be a functional indicator of RAS pathway hyperactivation.
RESUMEN
In the Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML) clinicolaboratory real-life data have been captured from 606 CMML patients from 14 different hospitals over the last 30 years. It is the only large biodatabase worldwide in which functional methods such as semisolid in vitro cultures complement modern molecular methods such as next generation sequencing. This provides the possibility to comprehensively study the biology of CMML. The aim of this study was to compare patient characteristics with published CMML cohorts and to validate established prognostic parameters in order to examine if this real-life database can serve as a representative and useful data source for further research. After exclusion of patients in transformation characteristics of 531 patients were compared with published CMML cohorts. Median values for age, leukocytes, hemoglobin, platelets, lactate dehydrogenase (LDH) and circulating blasts were within the ranges of reported CMML series. Established prognostic parameters including leukocytes, hemoglobin, blasts and adverse cytogenetics were able to discriminate patients with different outcome. Myeloproliferative (MP) as compared to myelodysplastic (MD)-CMML patients had higher values for circulating blasts, LDH, RAS-pathway mutations and for spontaneous myelomonocytic colony growth in vitro as well as more often splenomegaly. This study demonstrates that the patient cohort of the ABCMML shares clinicolaboratory characteristics with reported CMML cohorts from other countries and confirms phenotypic and genotypic differences between MP-CMML and MD-CMML. Therefore, results obtained from molecular and biological analyses using material from the national cohort will also be applicable to other CMML series and thus may have a more general significance.
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Investigación Biomédica , Leucemia Mielomonocítica Crónica , Adulto , Anciano , Anciano de 80 o más Años , Austria , Femenino , Humanos , Almacenamiento y Recuperación de la Información , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
Patients with aplastic anemia or hypoplastic myelodysplastic syndrome (MDS) may respond to immunosuppressive therapy, including the anti-CD52 antibody alemtuzumab. We analyzed treatment responses to alemtuzumab in 5 patients with MDS or aplastic anemia (AA) evolving to MDS. Two patients with hypoplastic MDS (hMDS) showed a partial response (PR) to alemtuzumab. In both responding patients, a concomitant paroxysmal nocturnal hemoglobinuria (PNH) clone was detected before therapy. One responder relapsed after 15 months and underwent successful allogeneic stem cell transplantation. Both patients are still alive and in remission after 40 and 20 months, respectively. The other patients showed no response to alemtuzumab. One patient died from pneumonia 4 months after treatment. In summary, our data confirm that alemtuzumab is an effective treatment option for a subset of patients with MDS, even in the presence of a PNH clone.
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Alemtuzumab/administración & dosificación , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/patología , Antineoplásicos/administración & dosificación , Enfermedades Mielodisplásicas-Mieloproliferativas/tratamiento farmacológico , Enfermedades Mielodisplásicas-Mieloproliferativas/patología , Adulto , Anciano , Anemia Aplásica/complicaciones , Antineoplásicos Inmunológicos/administración & dosificación , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Enfermedades Mielodisplásicas-Mieloproliferativas/complicaciones , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVES: The levels of circulating hematopoietic progenitor cells are often increased in myelofibrosis with myeloid metaplasia (MMM). The prognostic relevance of this phenomenon is largely unknown. DESIGN AND METHODS: We determined the number of circulating myeloid (CFU-GM), erythroid (BFU-E), and pluripotent (CFU-GEMM) progenitors, in 110 patients with MMM at diagnosis using a semi-solid colony assay. Overall survival was investigated by plots of the Kaplan-Meier estimator; known risk factors and the number of circulating progenitor cells were tested by univariate and multiple Cox regression analysis. RESULTS: Univariate analysis showed that hemoglobin concentration (p=0.019), CFU-GM (p< 0.0001), BFU-E (p=0.002), and age (p=0.002) predicted survival. Numbers of circulating CFU-GM above the 75th percentile were associated with a significantly shorter survival than were CFU-GM levels at or below the 75th percentile (27 vs. 74 months, p=0.0007). Similarly, high numbers of BFU-E in peripheral blood (> 75th percentile) predicted a shorter survival (33 vs. 74 months; p=0.007). When myeloid and erythroid progenitor cells were calculated separately in the multiple Cox regression analysis, both CFU-GM (hazard ratio 2.8, 95% CI, 1.35 to 5.93) and BFU-E (hazard ratio 2.57, 95% CI, 1.26 to 5.21) numbers above the 75th percentile were independent adverse prognostic factors in our patients. INTERPRETATION AND CONCLUSIONS: High levels of circulating myeloid and erythroid progenitor cells are novel risks factors in patients with MMM. The assessment of hematopoietic progenitor cells may be useful to determine risk-adjusted treatment strategies.
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Recuento de Células Sanguíneas , Células Madre Hematopoyéticas , Mielofibrosis Primaria/sangre , Adulto , Anciano , Anciano de 80 o más Años , Ensayo de Unidades Formadoras de Colonias , Células Precursoras Eritroides , Femenino , Estudios de Seguimiento , Humanos , Tablas de Vida , Masculino , Persona de Mediana Edad , Células Mieloides , Recuento de Plaquetas , Células Madre Pluripotentes , Mielofibrosis Primaria/mortalidad , Pronóstico , Modelos de Riesgos Proporcionales , Recuento de Reticulocitos , Esplenomegalia/sangre , Análisis de SupervivenciaRESUMEN
We analyzed in vitro growth characteristics of bone marrow mononuclear cells (BMMCs) from 322 patients with acute myeloid leukemia (AML) in relation to cytogenetic abnormalities. Median colony growth was low in each of the cytogenetic changes associated with a favorable outcome. Most karyotypic abnormalities in the intermediate prognosis group were associated with low growth potential, but 11 q23 abnormalities exhibited 8 times higher in vitro growth. Cytogenetic changes that included abn(3q) seemed to display the highest colony growth in the unfavorable prognosis group, whereas isolated -7 may have been associated with limited growth potential. In vitro growth behavior was predictive of neither rate of complete remission (CR) nor survival of AML patients within the 3 cytogenetic risk groups. In contrast, colony growth differed significantly in the subgroup of patients with a normal karyotype who achieved remission with induction treatment and those who had no remission (10 versus 81.5/10(5) BMMCs; P = .015). Significantly more patients with normal cytogenetics and colony growth below the 50th percentile went into CR than did patients with colony growth above the 50th percentile (82.8% versus 71.2%). Only 4 (6.8%) of the patients in the low growth group had no remission, compared with 12 (23.1%) of the patients with higher in vitro growth (P = .031, chi-square test). In conclusion, colony growth may prove useful as a prognostic factor for early treatment failure in AML patients with a normal karyotype.
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Leucemia Mieloide/genética , Leucemia Mieloide/patología , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , División Celular , Ensayo de Unidades Formadoras de Colonias , Análisis Citogenético , Humanos , Leucemia Mieloide/mortalidad , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Inducción de Remisión , Análisis de Supervivencia , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
Unstimulated methylcellulose cultures in 25 myelofibrosis (MF) patients were performed to better understand the role of cytokines in the proliferation of MF cells. Compared to controls MF patients show a variable but highly increased spontaneous CFU-GM formation (66 vs 4.8/10(5) PBMNC). There was a marked reduction of autonomous CFU-GM growth by the cytokine-synthesis-inhibiting molecule IL-10 as well as by antibodies against GM-CSF whereas antibodies against IL-3, G-CSF, M-CSF and IL-1ß showed heterogeneous effects. Spontaneous CFU-GM growth >100/10(5) PBMNC predicted shorter survival. Constitutive release of GM-CSF seems to contribute to proliferation of MF cells in vitro and possibly in vivo.