RESUMEN
Several studies reported that patients with acute myeloid leukemia (AML) who remain in long-term remission after allogeneic or autologous transplant have a shorter life expectancy, compared to the general population. However, little is known about the life expectancy of adult long-term survivors of AML who were treated with chemotherapy alone without a transplant and there have been no comparisons with survival among the general population. The current study indicates that the life expectancy of AML patients who achieved and maintained CR for at least 3 years is shorter than expected for age in the US population. This was observed also in patients who did not undergo a transplant including those who have not relapsed during the entire long follow-up period. Thus, late relapse does not explain why patients without transplants have a shortened life expectancy. Taken together, these data strongly suggest that prior chemotherapy for the underlying AML is at least a major contributing factor for the known shortened life expectancy post-transplant.
Asunto(s)
Leucemia Mieloide Aguda , Esperanza de Vida , Humanos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/tratamiento farmacológico , Persona de Mediana Edad , Masculino , Femenino , Adulto , Anciano , Trasplante de Células Madre Hematopoyéticas/métodos , AdolescenteRESUMEN
The introduction of the tyrosine kinase inhibitors (TKI) into the treatment of patients with Ph or BCR-ABL1-positive acute lymphoblastic leukemia has revolutionized the treatment of this poor prognosis acute leukemia. The combination of TKI with chemotherapy has improved response rates and allowed more patients to proceed to allogeneic hematopoietic cell transplant (alloHCT). Older patients have excellent responses to TKI and corticosteroids or in combination with minimal chemotherapy. This raises the question as to whether patients require full-intensity chemotherapy with TKI to achieve molecular remissions. The pediatricians have proposed that cure is achievable without alloHCT in children. These results have suggested that many patients may not require traditional chemotherapy in addition to TKI to achieve remission, and that patients who achieve a negative minimal residual disease state may not require alloHCT. The data in support of these questions is presented here and a suggested future clinical trial design based on these data is proposed.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Antineoplásicos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Neoplasia Residual , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto JovenAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células del Manto/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Estudios de Seguimiento , Humanos , Linfoma de Células del Manto/radioterapia , Prednisona/uso terapéutico , Radioinmunoterapia/métodos , Rituximab , Vincristina/uso terapéuticoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Resistencia a Antineoplásicos/genética , Perfilación de la Expresión Génica , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Adolescente , Adulto , Estudios de Cohortes , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/mortalidad , Estadificación de Neoplasias , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
PTPN11 encodes the Shp2 non-receptor protein-tyrosine phosphatase implicated in several signaling pathways. Activating mutations in Shp2 are commonly associated with juvenile myelomonocytic leukemia but are not as well defined in other neoplasms. Here we report that Shp2 mutations occur in human acute myeloid leukemia (AML) at a rate of 6.6% (6/91) in the ECOG E1900 data set. We examined the role of mutated Shp2 in leukemias harboring MLL translocations, which co-occur in human AML. The hyperactive Shp2E76K mutant, commonly observed in leukemia patients, significantly accelerated MLL-AF9-mediated leukemogenesis in vivo. Shp2E76K increased leukemic stem cell frequency and affords MLL-AF9 leukemic cells IL3 cytokine hypersensitivity. As Shp2 is reported to regulate anti-apoptotic genes, we investigated Bcl2, Bcl-xL and Mcl1 expression in MLL-AF9 leukemic cells with and without Shp2E76K. Although the Bcl2 family of genes was upregulated in Shp2E76K cells, Mcl1 showed the highest upregulation in MLL-AF9 cells in response to Shp2E76K. Indeed, expression of Mcl1 in MLL-AF9 cells phenocopies expression of Shp2E76K, suggesting Shp2 mutations cooperate through activation of anti-apoptotic genes. Finally, we show Shp2E76K mutations reduce sensitivity of AML cells to small-molecule-mediated Mcl1 inhibition, suggesting reduced efficacy of drugs targeting MCL1 in patients with hyperactive Shp2.
Asunto(s)
Resistencia a Antineoplásicos/genética , Interleucina-3/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Mutación/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Células Madre Neoplásicas/patología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Animales , Apoptosis , Proteínas Reguladoras de la Apoptosis , Western Blotting , Proliferación Celular , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos C57BL , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales CultivadasRESUMEN
Loss of function mutations and deletions encompassing the plant homeodomain finger 6 (PHF6) gene are present in about 20% of T-cell acute lymphoblastic leukemias (ALLs). Here, we report the identification of recurrent mutations in PHF6 in 10/353 adult acute myeloid leukemias (AMLs). Genetic lesions in PHF6 found in AMLs are frameshift and nonsense mutations distributed through the gene or point mutations involving the second plant homeodomain (PHD)-like domain of the protein. As in the case of T-ALL, where PHF6 alterations are found almost exclusively in males, mutations in PHF6 were seven times more prevalent in males than in females with AML. Overall, these results identify PHF6 as a tumor suppressor gene mutated in AML and extend the role of this X-linked tumor suppressor gene in the pathogenesis of hematologic tumors.
Asunto(s)
Proteínas Portadoras/genética , Leucemia Mieloide Aguda/genética , Mutación , Adulto , Anciano , Animales , Femenino , Genes Supresores de Tumor , Células Madre Hematopoyéticas/metabolismo , Humanos , Leucemia Mieloide Aguda/etiología , Masculino , Ratones , Persona de Mediana Edad , Células Mieloides/metabolismo , Proteínas Represoras , Caracteres SexualesRESUMEN
The Eastern Cooperative Oncology Group (ECOG) performed a phase 2 study in B-cell chronic lymphocytic leukemia (CLL) of oral theophylline, a methylxanthine that inhibits cyclic nucleotide phosphodiesterases, thereby inducing the intracellular accumulation of cyclic adenosine monophosphate (cAMP). In 25 patients with Rai stages 0-I, theophylline, 200 mg given orally every 12 h was well tolerated. There was one complete response after 22.5 months of treatment, which continues at 27+ months, and 18 other patients had stable disease. In vitro exposure of patients' lymphocytes to aminophylline (75-250 microg/ml), the soluble form of theophylline, resulted in dose- and time-dependent induction of apoptosis in 9/20 patients studied. Apoptosis was documented flow-cytometrically by monitoring the expression of bcl-2 and bax, forward light scatter, fluorescence intensity of binding of CD45 antibody, and the binding of annexin. Patients whose leukemic lymphocytes were susceptible to apoptosis induction by aminophylline in vitro experienced a significantly longer progression-free survival than patients whose cells were resistant to the drug in culture (P=0.025). This suggests that in a CLL population treated with theophylline, induction of an apoptotic response to the drug in vitro is prognostic for absence of clinical progression.
Asunto(s)
Apoptosis/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Teofilina/uso terapéutico , Vasodilatadores/uso terapéutico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , AMP Cíclico/metabolismo , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Tasa de Supervivencia , Proteína X Asociada a bcl-2RESUMEN
We studied the pathogenesis of the bleeding disorder in acute promyelocytic leukemia by measuring procoagulant, profibrinolytic, and proinflammatory mediators in peripheral blood and bone marrow cells from 25 previously untreated patients. Patients were induced with either all-trans retinoic acid (ATRA) or chemotherapy. Plasma levels of fibrinopeptide A (FPA), fibrin d-dimer, thrombin antithrombin (TAT) complex, prothrombin fragment 1.2 (F1.2), urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (t-PA) and plasminogen activator-inhibitor 1 (PAI-1) were measured before and after therapy, as was the cellular expression of the genes for tissue factor (TF) and interleukin-1 beta (IL-1 beta). The mean plasma levels of fibrin d-dimer, F1.2, TAT and FPA were markedly elevated prior to therapy and declined during the first 30 days of treatment with either ATRA or chemotherapy, but more rapidly and to a greater extent in patients treated with ATRA. ATRA treatment was associated with a significant decrease in TF gene expression in bone marrow cells during the first 30 days of treatment, whereas IL-1 beta gene expression, which decreased in the cells of six patients treated with either chemotherapy or ATRA, actually increased in the remaining six patients treated with either chemotherapy or ATRA. In patients with APL, treatment with either chemotherapy or ATRA rapidly ameliorates the coagulopathy, as indicated by an abrupt decline in markers of clotting activation. An increase in cytokine gene expression (e.g. IL-1 beta) may provide an explanation for the persistent hypercoagulability observed in some patients with APL, regardless of therapeutic approach. Our data confirms and extends earlier observations by others that ATRA is more effective than chemotherapy alone in rapidly reducing the procoagulant burden of APL tumor cells. However, our data also suggests that cytokine expression in some patients may be accelerated by either chemotherapy or ATRA. The implications of this observation for understanding the retinoic acid syndrome will require further studies.
Asunto(s)
Coagulación Sanguínea , Fibrinólisis , Leucemia Promielocítica Aguda/tratamiento farmacológico , Tretinoina/farmacología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Antitrombinas/metabolismo , Células de la Médula Ósea/metabolismo , Línea Celular Tumoral , Niño , Preescolar , Citocinas/biosíntesis , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/biosíntesis , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Fibrinopéptido A/química , Humanos , Lactante , Interleucina-1/sangre , Masculino , Persona de Mediana Edad , Inhibidor 1 de Activador Plasminogénico/sangre , Ribonucleasas/metabolismo , Trombina/biosíntesis , Tromboplastina/biosíntesis , Factores de Tiempo , Activador de Tejido Plasminógeno/sangre , Activador de Plasminógeno de Tipo Uroquinasa/sangreRESUMEN
BACKGROUND: The availability of genotype-specific therapy for PML/RAR alpha(pos) acute promyelocytic leukemia (APL) requires that this disease be precisely diagnosed. Immunophenotypic characteristics heretofore proclaimed as reliably characterizing APL (HLA-DR(low), CD34(low), P-glycoprotein(low) myeloid phenotype) do not differentiate from APL-like immune profiles unassociated with the PML/RAR alpha fusion transcript. METHODS: To establish a surrogate marker profile for APL, we explored 19 potentially predictive markers compared with differentiated acute myeloid leukemia using the classification tree approach with recursive partitioning. RESULTS: In a test group of 58 APL patients, the most predictive immune profile was HLA-DR(low), CD11a(low) (alpha(L) subunit of the leukocyte integrin LFA-1), CD18(low) (beta(2) subunit of LFA-1). APL cells always expressed CD117 (c-kit) but lacked the progenitor antigen CD133 and the more mature myeloid antigen, CD11b (alpha(M) leukocyte integrin). This antigen pattern was validated in 90 additional APL patients. M3v APLs (n = 30) had more leukemic promyelocytes expressing the T-cell antigen, CD2 (P < 0.0001) or the stem cell marker, CD34 (P = 0.0003) and demonstrated higher fluorescence intensity for the binding of antibody to the common leukocyte antigen, CD45 (P = 0.0008) than M3 (n = 102). S-form APL (n = 45) had a higher percent of cells expressing CD2 or CD34 (P < 0.0001 for both) or the neural cell adhesion molecule CD56 (P = 0.001) than L-form APL (n = 66). CONCLUSIONS: PML/RAR alpha(pos) APL cells typically lack leukocyte integrins. HLA-DR(low), CD11a(low), CD18(low) is a reliable surrogate antigen expression profile for PML/RAR alpha(pos) APL, irrespective of morphology and transcript isoform.
Asunto(s)
Biomarcadores de Tumor/análisis , Leucemia Promielocítica Aguda/inmunología , Leucemia Promielocítica Aguda/patología , Antígenos de Neoplasias/análisis , Antígenos de Neoplasias/inmunología , Antígenos de Superficie/análisis , Antígenos de Superficie/inmunología , Biomarcadores de Tumor/inmunología , Aberraciones Cromosómicas , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Masculino , Proteínas de Neoplasias/análisis , Proteínas de Neoplasias/inmunología , Proteínas Nucleares/análisis , Proteínas Nucleares/inmunología , Proteínas de Fusión Oncogénica/análisis , Proteínas de Fusión Oncogénica/inmunología , Valor Predictivo de las Pruebas , Proteína de la Leucemia Promielocítica , Receptores de Ácido Retinoico/análisis , Receptores de Ácido Retinoico/inmunología , Receptor alfa de Ácido Retinoico , Factores de Transcripción/análisis , Factores de Transcripción/inmunología , Proteínas Supresoras de TumorRESUMEN
AP-1060 is a newly established acute promyelocytic leukemia (APL) cell line from a multiple-relapse patient clinically resistant to both all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). The line was initially derived as a granulocyte colony-stimulating factor-dependent strain that underwent replicative senescence and, following ethylnitrosourea treatment, as a phenotypically similar immortalized line. Immortalization was associated with broadened cytokine sensitivity but not growth autonomy, in contrast to three previously derived APL lines. Both the AP-1060 strain and line had shortened telomeres and low telomerase activity, while the line had higher expression of many genes associated with macromolecular synthesis. The karyotype was 46,XY,t(3;14)(p21.1;q11.2),t(15;17)(q22;q11)[100%]; the unique t(3;14) was observed in 4/9 t(15;17)-positive metaphase cells at previous relapse on ATRA therapy. The PML-RARalpha mRNA harbored a missense mutation in the RARalpha-region ligand-binding domain (Pro900Ser). This was associated with a right-shift and sharpening of the ATRA-induced maturation response compared to ATRA-sensitive NB4 cells, which corresponded to the transcriptional activation by PML-RARalphaPro900Ser of a cotransfected ATRA-targeted reporter vector in COS-1 cells. AP-1060 also manifested relative resistance to ATO-induced apoptosis at >/=1 microM, while 0.25 microM ATO stimulated limited atypical maturation. These findings suggest that AP-1060 will be useful for further assessing molecular elements involved in APL progression and drug response/resistance.
Asunto(s)
Línea Celular Tumoral , Resistencia a Antineoplásicos , Leucemia Promielocítica Aguda/patología , Trióxido de Arsénico , Arsenicales/farmacología , Técnicas de Cultivo de Célula/métodos , Citocinas/farmacología , Humanos , Cariotipificación , Mutación Missense , Óxidos/farmacología , Receptores de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico , Telomerasa/metabolismo , Telómero/ultraestructura , Tretinoina/farmacologíaRESUMEN
CD65s appears when the progenitor antigen CD34 disappears, suggesting that this sialylated carbohydrate antigen marks a turning point in normal myeloid differentiation. We characterized acute myeloid leukemia (AML) with low CD65s expression (CD65s(low) AML) in 711 patients entered on seven Eastern Cooperative Oncology Group AML treatment trials (1986-1999). Of those, 198 (28%) qualified as having CD65s(low) AML. Morphologically, CD65s(low) AML was more common in FAB subgroups with minimal differentiation, M0/M1 (P=<0.0001). Early precursor antigens CD34, CD117 and terminal transferase were more frequent in CD65s(low) than CD65s(high) AML (P=<0.0001). Myeloperoxidase was present in fewer CD65s(low) myeloblasts, and the more mature myeloid antigens, CD15 and CD11b, were rarely detected (P=<0.0001). Yet, the two diagnoses did not differ in the distribution of cytogenetic prognostic groups or the occurrence of the multidrug-resistance mediator, P-glycoprotein. CD65s(low) AML patients were significantly older than CD65s(high) cases (P<0.0001). Furthermore, the incidence of CD65s(low) cases increased with age, from 20% in patients under the age of 50 years to 67% in patients older than 80 years (P<0.0001). Overall, complete remission (CR) rate and overall survival were comparable in CD65s(low) and CD65s(high) AML. However, among patients >55 years of age, CD65s(low) AML had a decreased CR rate of 33 vs 44% in CD65s(high) AML (P=0.055). Thus, CD65s(low) AML represents immunophenotypically undifferentiated disease and occurs predominantly in older adults. Although not statistically significant, the observed association between low CD65s expression and decreased CR rate only in patients over the age of 55 is intriguing.
Asunto(s)
Antígenos de Diferenciación Mielomonocítica/análisis , Leucemia Mieloide/patología , Células Mieloides/patología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/análisis , Enfermedad Aguda , Anciano , Anciano de 80 o más Años , Antígenos CD/análisis , Biomarcadores/análisis , Diferenciación Celular , Humanos , Inmunofenotipificación , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/mortalidad , Persona de Mediana Edad , Células Mieloides/metabolismo , Peroxidasa/análisis , Pronóstico , Inducción de Remisión , Tasa de SupervivenciaRESUMEN
The term minimal residual disease (MRD) in its currently accepted application refers to low-level disease detected in a whole variety of clinical situations. It is used to describe residual disease after suboptimal induction chemotherapy, but at the same time refers to the lowest levels of disease potentially compatible with cure or to molecularly defined relapse after long-term remission. This discussion intends to redefine MRD into some biologically relevant subcategories which may warrant their own independent terminology.
Asunto(s)
Leucemia/patología , Neoplasia Residual/patología , Citodiagnóstico , Humanos , Inmunofenotipificación , Leucemia/diagnóstico , Técnicas de Diagnóstico Molecular , Monitorización Inmunológica , Neoplasia Residual/diagnósticoRESUMEN
A Phase II study of GM-CSF with intermediate-dose cytarabine and mitoxantrone was conducted in patients with high-risk myelodysplastic syndrome. It was designed to evaluate if priming with growth factor could increase the efficiency of chemotherapy. In this older population only two of 10 patients achieved a bone marrow CR, including one patient whose leukemic blasts had an "S" phase increase of 2.55x at 48 hr. Unexpected hepatotoxicity was noted. This regimen cannot be recommended for this elderly population of patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Anciano , Anemia Refractaria con Exceso de Blastos/tratamiento farmacológico , Anemia Refractaria con Exceso de Blastos/mortalidad , Anemia Refractaria con Exceso de Blastos/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Médula Ósea/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Citarabina/administración & dosificación , Citarabina/efectos adversos , Replicación del ADN/efectos de los fármacos , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Humanos , Hiperbilirrubinemia/inducido químicamente , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/mortalidad , Leucemia Mielomonocítica Crónica/patología , Masculino , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Mitoxantrona/efectos adversos , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Pancitopenia/inducido químicamente , Pancitopenia/tratamiento farmacológico , Proyectos Piloto , Proteínas Recombinantes , Inducción de Remisión , Fase S/efectos de los fármacos , Insuficiencia del TratamientoRESUMEN
Anticipation, a phenomenon in which an inherited disease is diagnosed at an earlier age in each successive generation of a family, has been demonstrated in certain heritable neurological disorders and in multiple myeloma, non-Hodgkin's lymphoma and other haematological neoplasms. The present study was conducted to determine whether anticipation occurs in familial chronic lymphocytic leukaemia (CLL). Fourteen published reports of multigenerational familial CLL were analysed for anticipation, together with 10 previously unreported families with familial CLL, and the difference in disease-free survival between generations was determined. The difference between age at onset for each affected parent-child pair was tested against the null hypothesis that there was no difference in age at onset. The age at onset of the studied cases was also compared with that of the Surveillance Epidemiology and End Results (SEER) Program of the U.S. National Cancer Institute. The median ages at onset in the child and parent generations of all families (51.0 and 72.0 years respectively) were significantly different (P < 0.000001), and the null hypothesis was rejected (P < 0.000001). A significant difference was observed between the ages of onset of the child generation and the SEER population (P < 0.00001), but not between the parent generation and the SEER population. Anticipation characterizes familial CLL.
Asunto(s)
Anticipación Genética , Bases de Datos Factuales , Leucemia Linfocítica Crónica de Células B/genética , Programa de VERF , Edad de Inicio , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/mortalidad , Modelos Logísticos , Masculino , Persona de Mediana Edad , Linaje , Tasa de SupervivenciaRESUMEN
Expression of CD56, a marker of natural killer (NK) cells, in acute lymphocytic leukemia (ALL) is rare and, to date, has been described only in non-B lineage ALL. Among 194 patients with CD56 analysis on the ongoing Eastern Cooperative Oncology Group (ECOG) ALL trial, E2993, 6 cases of CD56+ ALL were found (3.1%) with a median of 95% of blast cells expressing CD56, compared with a median of 1% of blast cells in CD56- ALL (P = 0.0001). FAB-L2 characteristics dominated, without granulation. Blast cells from four CD56+ patients expressed T-cell antigens at variable levels of maturation. A clonal rearrangement of the T-cell receptor beta (TCRbeta) gene was detected only in one patient. TCRbeta variable gene usage studies in this and one other CD56+ ALL patient demonstrated a significantly perturbed usage pattern in both patients when compared with control lymphocytes. The two remaining cases typed as early pre-B ALL (CD19+, CD10+), with one case co-expressing CD7. Cytogenetically, 4 patients were normal, 1 complex abnormal, and 1 Philadelphia chromosome positive. Epstein-Barr virus (EBV) sequences were detected in one T- and both B-lymphoid cases. Our data suggest that CD56 is expressed at a precursor stage common to the T- and the B-cell lineage.
Asunto(s)
Antígeno CD56/análisis , Genotipo , Fenotipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Adulto , Antígenos CD19/análisis , Antígenos CD7/análisis , ADN Viral/análisis , Supervivencia sin Enfermedad , Femenino , Reordenamiento Génico de la Cadena beta de los Receptores de Antígenos de los Linfocitos T , Herpesvirus Humano 4/genética , Humanos , Inmunofenotipificación , Cariotipificación , Células Asesinas Naturales/inmunología , Masculino , Persona de Mediana Edad , Neprilisina/análisis , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Inducción de RemisiónRESUMEN
The associations of cytogenetics with complete remission (CR) rates, overall survival (OS), and outcomes after CR were studied in 609 previously untreated AML patients younger than 56 years old in a clinical trial comparing 3 intensive postremission therapies: intensive chemotherapy, autologous transplantation (ABMT), or allogeneic bone marrow transplantation (alloBMT) from matched related donors. Patients were categorized into favorable, intermediate, unfavorable, and unknown cytogenetic risk groups based on pretreatment karyotypes. CR rates varied significantly (P <.0001) among the 4 groups: favorable, 84% (95% confidence interval [CI], 77%-90%); intermediate, 76% (CI, 71%-81%); unfavorable, 55% (CI, 48%-63%); and unknown, 54% (CI, 33%-74%). There was similar significant heterogeneity of OS (P <.0001), with the estimated relative risk of death from any cause being 1.50 (CI, 1.10-2.05), 3. 33 (CI, 2.43-4.55), and 2.66 (CI, 1.59-4.45) for the intermediate, unfavorable, and unknown risk groups, respectively, compared with the favorable group. In multivariate analyses, the effects of cytogenetic risk status on CR rate and OS could not be explained by other patient or disease characteristics. Among postremission patients, survival from CR varied significantly among favorable, intermediate, and unfavorable groups (P =.0003), with significant evidence of interaction (P =.017) between the effects of treatment and cytogenetic risk status on survival. Patients with favorable cytogenetics did significantly better following ABMT and alloBMT than with chemotherapy alone, whereas patients with unfavorable cytogenetics did better with alloBMT. Cytogenetic risk status is a significant factor in predicting response of AML patients to therapy; however, to tighten treatment correlates within genetically defined AML subsets, a significantly larger leukemia cytogenetic database is warranted.
Asunto(s)
Aneuploidia , Aberraciones Cromosómicas , Cariotipificación , Leucemia Mieloide/genética , Enfermedad Aguda , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea , Cromosomas Humanos/ultraestructura , Terapia Combinada , Citarabina/administración & dosificación , Femenino , Humanos , Idarrubicina/administración & dosificación , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/mortalidad , Leucemia Mieloide/terapia , Tablas de Vida , Masculino , Persona de Mediana Edad , Inducción de Remisión , Riesgo , Análisis de Supervivencia , Translocación Genética , Trasplante Autólogo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Acute megakaryocytic leukemia (AMegL) is a rare subtype of acute myeloid leukemia (AML) evolving from primitive megakaryoblasts. Because of its rarity and the lack of precise diagnostic criteria in the past, few series of adults treated with contemporary therapy have been reported. Twenty among 1649 (1.2%) patients with newly diagnosed AML entered on Eastern Cooperative Oncology Group (ECOG) trials between 1984 and 1997 were found to have AMegL. The median age was 42.5 years (range 18-70). Marrow fibrosis, usually extensive, was present in the bone marrow. Of the 8 patients who had cytogenetic studies performed, abnormalities of chromosome 3 were the most frequent. The most consistent immunophenotypic finding was absence of myeloperoxidase in blast cells from 5 patients. In the most typical 3 cases, the leukemic cells were positive for one to 2 platelet-specific antigens in addition to lacking myeloperoxidase or an antigen consistent with a lymphoid leukemia. Myeloid antigens other than myeloperoxidase and selected T-cell antigens (CD7 and/or CD2) were frequently expressed. Induction therapy included an anthracycline and cytarabine in all cases. Complete remission (CR) was achieved in 10 of 20 patients (50%). Two patients remain alive, one in CR at 160+ months. Resistant disease was the cause of induction failure in all but 3 patients. The median CR duration was 10.6 months (range 1-160+ months). The median survival for all patients was 10.4 months (range 1-160+ months). Although half of the patients achieved CR, the long-term outcome is extremely poor, primarily attributable to resistant disease. New therapeutic strategies are needed.