RESUMEN
Twenty-two patients with hairy cell leukemia were treated with low-dose interferon alfa-2b (0.2 X 10(6) U/m2 given three times weekly) for 6-12 months. The overall response rate was 54%, with only 18% complete plus partial responses. The therapy had to be terminated early in five of these patients because their progressive disease led to severe cytopenia. Although the toxic effects with this regimen were minimal, the significantly lower response rate and the poorer quality of the responses prohibit its use as initial therapy in hairy cell leukemia.
Asunto(s)
Interferón Tipo I/administración & dosificación , Interferón-alfa/administración & dosificación , Leucemia de Células Pilosas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Médula Ósea/patología , Esquema de Medicación , Evaluación de Medicamentos , Femenino , Estudios de Seguimiento , Hemoglobinas/análisis , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Leucemia de Células Pilosas/sangre , Recuento de Leucocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas/efectos de los fármacos , Proteínas Recombinantes , Inducción de RemisiónRESUMEN
The FLT3 gene is mutated by an internal tandem duplication (ITD) in 20-25% of adults with acute myeloid leukemia (AML). We studied 82 adults <60 years of age with primary AML and normal cytogenetics, who received uniform high-dose therapy and found FLT3 ITD in 23 (28%) patients. When the 23 FLT3 ITD+ cases were compared with the 59 cases with wild-type (WT) FLT3, disease-free survival (DFS) was inferior (P = 0.03), yet overall survival (OS) was not different (P = 0.14). However, 8 (35%) of 23 FLT3 ITD/+ cases also lacked a FLT3 WT allele (FLT3(ITD-R)) as determined by PCR and loss of heterozygosity. Thus, three genotypic groups were identified: normal FLT3(WT/WT), heterozygous FLT3(ITD/WT), and hemizygous FLT3(ITD/-). DFS and OS were significantly inferior for patients with FLT3(ITD/-) (P = 0.0017 and P = 0.0014, respectively). Although DFS and OS for FLT3(WT/WT) and FLT3(ITD/WT) groups did not differ (P = 0.32 and P = 0.98, respectively), OS of the FLT3(ITD/-) group was worse than the FLT3(WT/WT) (P = 0.0005) and FLT3(ITD/WT) (P = 0.008) groups. We propose a model in which FLT3(ITD/-) represents a dominant positive, gain-of-function mutation providing AML cells with a greater growth advantage compared with cells having the FLT3(WT/WT) or FLT3(ITD/WT) genotypes. In conclusion, we have identified the FLT3(ITD/-) genotype as an adverse prognostic factor in de novo AML with normal cytogenetics. A poor prognosis of the relatively young FLT3(ITD/-) adults (median age, 37 years), despite treatment with current dose-intensive regimens, suggests that new treatment modalities, such as therapy with a FLT3 tyrosine kinase inhibitor, are clearly needed for this group of patients.
Asunto(s)
Duplicación de Gen , Leucemia Mieloide/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Enfermedad Aguda , Adulto , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Supervivencia sin Enfermedad , Femenino , Humanos , Cariotipificación , Leucemia Mieloide/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Mutación , Secuencias Repetidas en Tándem , Resultado del Tratamiento , Tirosina Quinasa 3 Similar a fmsRESUMEN
Sixty-nine patients with hairy-cell leukemia (HCL) were treated with interferon alfa-2b (IFN) in a single-institution study. The dose used was 2 x 10(6) U/m2 self-administered subcutaneously three times weekly, for a planned treatment duration of 12 to 18 months. Of the 68 evaluable patients, the major response rate was 75%, with 13% complete responses (CRs) and 62% partial responses (PRs). An additional eleven patients (16%) had minor responses (MRs). Duration of response was denoted as failure-free survival (FFS), defined as the time from the end of IFN therapy to a need for further antileukemic therapy. Of the 60 responding patients followed after discontinuation of IFN, 27 have relapsed, requiring further therapy. The median actuarial FFS for these 60 patients is 25.4 months. All but five patients are alive, and the actuarial overall survival for the 69 patients is 91% +/- 4% at 4 years from the start of IFN. The best indicators of relapse were the neutrophil alkaline phosphatase (NAP) score and degree of residual bone marrow hairy cells (%HCL) at the completion of therapy. Patients with NAP less than 30 (n = 21) had the best prognosis (median FFS, 30.4 months), while those with NAP greater than or equal to 30 and %HCL less than or equal to 30 (n = 21) or %HCL greater than 30 (n = 16) had intermediate and poor prognoses, respectively (median FFS, 23.5 and 12.4 months) (P = .0005). Fourteen of the relapsing patients are evaluable for response to a second course of IFN, with seven PRs and four MRs. Stratified randomized trials are indicated to determine the role of maintenance therapy for responding patients.
Asunto(s)
Interferón Tipo I/uso terapéutico , Interferón-alfa/uso terapéutico , Leucemia de Células Pilosas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Ensayos Clínicos como Asunto , Esquema de Medicación , Evaluación de Medicamentos , Femenino , Estudios de Seguimiento , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Leucemia de Células Pilosas/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Pronóstico , Proteínas Recombinantes , Inducción de RemisiónRESUMEN
Clinical, histologic, and cytogenetic features in 63 patients with a therapy-related myelodysplastic syndrome (t-MDS) or acute nonlymphocytic leukemia (t-ANLL) following cytotoxic chemotherapy or radiotherapy for a previous disease were analyzed. Eleven patients had received only radiotherapy for the primary disorder. In most cases, high doses had been administered to treatment ports that included the pelvic or spinal bone marrow. Twenty-one patients had received only chemotherapy for their primary disease, all for more than 1 year and all but one with an alkylating agent, either alone or in combination with other drugs. Thirty-one patients had received both radiotherapy and chemotherapy, either concurrently or sequentially. A clonal chromosomal abnormality was observed in marrow or blood cells from 61 of the 63 patients (97%). Fifty-five patients (87%) had a clonal abnormality of chromosomes no. 5 and/or 7 consisting of loss of all or part of the long arm of the chromosome. The critical chromosome region that was consistently deleted in all 17 patients with del(5q) comprised bands q23 to q32. In addition to nos. 5 and 7, five other chromosomes (no. 1, 4, 12, 14, and 18) were found to be nonrandomly involved. Both t-MDS and t-ANLL are late complications of cytotoxic therapies that have distinctive clinical and histologic features and are associated with characteristic aberrations of chromosomes no. 5 and 7. It seems likely that these two chromosomes contain genes involved in the pathogenesis of these hematopoietic neoplasms.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos 4-5 , Cromosomas Humanos 6-12 y X , Leucemia/genética , Síndromes Mielodisplásicos/genética , Enfermedad Aguda , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Deleción Cromosómica , Femenino , Humanos , Leucemia/etiología , Leucemia Inducida por Radiación/genética , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/etiología , Neoplasias/terapia , Neoplasias Primarias Múltiples/etiología , Neoplasias Primarias Múltiples/genética , Traumatismos por Radiación/genética , Translocación GenéticaRESUMEN
PURPOSE: To prospectively compare cytogenetics and reverse transcriptase-polymerase chain reaction (RT-PCR) for detection of t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13;q22), aberrations characteristic of core-binding factor (CBF) acute myeloid leukemia (AML), in 284 adults newly diagnosed with primary AML. PATIENTS AND METHODS: Cytogenetic analyses were performed at local laboratories, with results reviewed centrally. RT-PCR for AML1/ETO and CBFbeta/MYH11 was performed centrally. RESULTS: CBF AML was ultimately identified in 48 patients: 21 had t(8;21) or its variant and AML1/ETO, and 27 had inv(16)/t(16;16), CBFbeta/MYH11, or both. Initial cytogenetic and RT-PCR analyses correctly classified 95.7% and 96.1% of patients, respectively (P =.83). Initial cytogenetic results were considered to be false-negative in three AML1/ETO-positive patients with unique variants of t(8;21), and in three CBFbeta/MYH11-positive patients with, respectively, an isolated +22; del(16)(q22),+22; and a normal karyotype. The latter three patients were later confirmed to have inv(16)/t(16;16) cytogenetically. Only one of 124 patients reported initially as cytogenetically normal was ultimately RT-PCR-positive. There was no false-positive cytogenetic result. Initial RT-PCR was falsely negative in two patients with inv(16) and falsely positive for AML1/ETO in two and for CBFbeta/MYH11 in another two patients. Two patients with del(16)(q22) were found to be CBFbeta/MYH11-negative. M4Eo marrow morphology was a good predictor of the presence of inv(16)/t(16;16). CONCLUSION: Patients with t(8;21) or inv(16) can be successfully identified in prospective multi-institutional clinical trials. Both cytogenetics and RT-PCR detect most such patients, although each method has limitations. RT-PCR is required when the cytogenetic study fails; it is also required to determine whether patients with suspected variants of t(8;21), del(16)(q22), or +22 represent CBF AML. RT-PCR should not replace cytogenetics and should not be used as the only diagnostic test for detection of CBF AML because of the possibility of obtaining false-positive or false-negative results.
Asunto(s)
Inversión Cromosómica , Cromosomas Humanos Par 16 , Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Proteínas Proto-Oncogénicas , Translocación Genética , Adulto , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Proteínas de Unión al ADN/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteína 1 Compañera de Translocación de RUNX1 , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/genéticaRESUMEN
The 8;21 chromosomal translocation involves the AML1 gene on chromosome 21 and the ETO gene on chromosome 8 and results in the transcription of a chimeric message. This translocation is most often associated with acute myelogenous leukemia with maturation (AML-M2). The leukemic cells of patients carrying t(8;21) often exhibit several characteristic morphologic features. We identified four cases in which the morphology led us to suspect a t(8;21), but in which this translocation was not observed by cytogenetic analysis. In two of the four cases, an AML1/ETO chimeric fragment was detected by reverse transcription and polymerase chain reaction (RT-PCR), and its sequence was found to be identical to that from patients with a cytogenetically proved t(8;21). Marrow specimens of the four patients lacking the t(8;21) cytogenetically were reviewed retrospectively with regard to seven morphologic features commonly reported to be associated with this translocation, and the results were compared to 13 morphologic controls with the t(8;21). Although none of the 13 controls had all of the characteristic morphologic features, all had at least six, as did the two t(8;21)-negative but RT-PCR-positive patients. The two patients who lacked the t(8;21) and who were RT-PCR-negative showed only three and four of these morphologic features, respectively. Both of the RT-PCR-positive patients had deletions of the long arm of chromosome 9, a common change associated with a t(8;21), supporting our assessment of these patients as having a cytogenetically undetected t(8;21).
Asunto(s)
Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Leucemia Mieloide Aguda/genética , Proteínas de Fusión Oncogénica/genética , Translocación Genética , Secuencia de Bases , Southern Blotting , Femenino , Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Masculino , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , ARN Mensajero/análisis , ADN Polimerasa Dirigida por ARN , Estudios RetrospectivosRESUMEN
Cytogenetic analysis was successfully performed on 31 of 40 patients with chronic B cell leukemia. Clonal abnormalities were seen in 16 patients using various culture methods. Fourteen of these had unstimulated cultures established of which 13 had the clonal abnormality. Trisomy 12 was observed in seven patients while a 14q32 translocation was present in four. Race, age, hemoglobin, WBC, percentage of lymphocytes and prolymphocytes in BM and PB, platelets, Smig, lymph node, spleen, liver, pattern of bone marrow infiltration, therapy free interval, and overall survival were all compared. Significant correlations between the presence of clonal abnormalities and prior therapy (p less than 0.005) and an increase in prolymphocytes in bone marrow (p = 0.05) and/or peripheral blood (p = 0.0014) were observed.
Asunto(s)
Aberraciones Cromosómicas , Leucemia Linfocítica Crónica de Células B/genética , Adulto , Anciano , Mapeo Cromosómico , Cromosomas Humanos Par 12 , Femenino , Humanos , Cariotipificación , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana EdadRESUMEN
The results of polymerase chain reaction (PCR) analysis after transplantation for chronic myelogenous leukemia (CML) are difficult to interpret clinically. Positive findings for BCR/ABL can be seen not only in patients who go on to relapse but also in patients who, after years of follow-up, remain in complete remission. The cause for the lack of concordance between PCR findings and relapse is not clear. We identified two patients with CML who had rare pseudo-Gaucher cells in their bone marrow aspirate specimens prior to, and at 1, and 6 or 12 months following syngeneic or allogeneic hematopoietic transplantation. After the transplant, the patients obtained clinical remission and were shown to be cytogenetically normal and to have germline MBCR in blood or bone marrow by Southern analysis. One patient was PCR-positive for BCR/ABL in the marrow at 12 months. In order to determine whether the pseudo-Gaucher histiocytes were BCR/ABL-positive, we used fluorescence in situ hybridization and probes for MBCR and ABL and analyzed Wright-stained smears to correlate molecular cytogenetic findings with cell type. On three aspirate smears from each patient (at 6 or 12 months post-transplant), all of the pseudo-Gaucher cells studied (10/10 in one patient and 12/12 in the other) showed the fusion for BCR/ABL. Other cells analyzed randomly (erythroid precursors, granulocytes and rare monocytes, lymphocytes and plasma cells) did not. Our cases provide the first proof that pseudo-Gaucher cells carry the BCR/ABL fusion. Furthermore, they illustrate that these cells can be found in the marrow for up to 12 months following transplantation. Our results permit speculation that pseudo-Gaucher cells or other long-lived histocytes may be one cause of persistent PCR positivity after transplantation that is not predictive of disease relapse.
Asunto(s)
Trasplante de Médula Ósea , Proteínas de Fusión bcr-abl/análisis , Trasplante de Células Madre Hematopoyéticas , Histiocitos/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Adulto , Médula Ósea/patología , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , MasculinoRESUMEN
A patient is described with neutropenia associated with large granular lymphocyte proliferation, whose peripheral blood cells were analyzed with the beta chain gene probe of the T cell receptor (TCR). The pattern of rearrangement of the TCR was unusually complex, and apparently involved rearrangement of both J beta 1 loci with upstream V beta segments and of both J beta 2 loci with a downstream V beta by inversion. This case represents a unique pattern of rearrangement of the beta-chain of TCR. These results suggest caution in estimating the number of clones present in apparent oligoclonal proliferations.
Asunto(s)
Reordenamiento Génico de la Cadena beta de los Receptores de Antígenos de los Linfocitos T , Linfocitosis/genética , Neutropenia/genética , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T/fisiología , Adolescente , Southern Blotting , División Celular , ADN/aislamiento & purificación , Femenino , Humanos , Linfocitosis/complicaciones , Neutropenia/complicaciones , Linfocitos T/ultraestructuraRESUMEN
We studied changes in peripheral blood and bone marrow biopsy specimens obtained before, during, and after recombinant alpha 2b-interferon (IFN-alpha 2b) therapy in 25 patients with hairy cell leukemia. During therapy, only 1 patient showed no improvement in at least one of the parameters monitored. Granulocytopenia, thrombocytopenia, and monocytopenia resolved in 19/20, 14/15, and 17/18 patients, respectively. In 18/21 patients with Hb less than 12g/dl before treatment, the anemia became less severe. Hairy cells disappeared or decreased in numbers in the peripheral blood in all patients. In the bone marrow, numbers of hairy cells decreased and numbers of granulocytic, erythroid, and megakaryocytic cells increased usually within 3-6 months after the start of therapy. In no patient were hairy cells ever completely absent from the bone marrow. After cessation of IFN-alpha, the median Hb value, WBC, and platelet counts changed little for up to 12 months, but the absolute neutrophil count and absolute monocyte count decreased. Hairy cells reappeared in the peripheral blood of three patients. In the bone marrow the percentage of hairy cells increased, whereas the percentage of granulocytic and erythroid cells decreased. Neutrophil alkaline phosphatase (NAP) scores were abnormally high in 18/18 patients studied prior to IFN-alpha, but became normal in 17 of these during therapy and were normal in seven first studied during therapy. The median NAP score doubled by 3 months after cessation of therapy and was abnormal in 17/19 patients followed for 6 months. NAP score may be useful in predicting changes in the bone marrow in patients treated with IFN-alpha. We did not find any parameter in the pretherapy specimens that would have allowed us to predict individual response.
Asunto(s)
Interferón Tipo I/uso terapéutico , Leucemia de Células Pilosas/terapia , Fosfatasa Alcalina/sangre , Médula Ósea/patología , Humanos , Leucemia de Células Pilosas/patología , Recuento de Leucocitos , Neutrófilos/enzimología , Recuento de Plaquetas , Proteínas Recombinantes/uso terapéutico , Factores de TiempoRESUMEN
Chronic myelogenous leukemia (CML) is a stem cell disorder which progresses from a chronic phase (CP) to an accelerated phase (AP), and/or a blast phase (BP) of myeloid (M) or lymphoid (L) phenotype. This progression is frequently preceded or accompanied by recurring secondary chromosomal abnormalities which are believed to play a role in the transformation. In order to investigate the relationship between the secondary change and the development of BP, we undertook a study using fluorescence in situ hybridization to determine in which cells the secondary abnormalities were present. We observed that in one case of L-BP, the secondary change (trisomy 8) appeared to be in a subclone that was different from the blast cells, as it was absent from the lymphoblasts but present in differentiating erythroid, monocytic and granulocytic cells. In two cases, the secondary change (trisomy 8, extra Ph) probably occurred prior to an acute transforming event as it was present in CP or AP predominantly in differentiated granulocytic or monocytic cells. In one case of M-BP, the secondary change (trisomy 8) probably occurred after the acute transformation, as it appeared in only a subset of the blasts. Lastly, in four cases of L-BP, the secondary change (monosomy 7, extra Ph or hyperdiploidy) was closely associated with the BP as it was present in all of the blasts. The findings indicate that some secondary abnormalities may be directly related to the development of BP and may provide clues to the identity of genes responsible for the acute phase transition. Other abnormalities occurring before, or after the acute transformation or in a different subclone from the acute phase blasts, may be more important for denoting genomic instability than for helping to understand the mechanism of blast transformation.
Asunto(s)
Aberraciones Cromosómicas/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mieloide de Fase Acelerada/patología , Adolescente , Adulto , Niño , Trastornos de los Cromosomas , Progresión de la Enfermedad , Femenino , Humanos , Hibridación Fluorescente in Situ , Leucemia Mieloide de Fase Acelerada/genética , Masculino , Persona de Mediana EdadRESUMEN
Cladribine has been reported to have little activity in fludarabine- refractory chronic lymphocytic leukemia (CLL). We sought to determine whether resistance to therapy with cladribine in fludarabine-refractory CLL patients represented primary drug resistance or the inability to tolerate the myelosuppression associated with this therapy. Patients with fludarabine refractory CLL patients without severe thrombocytopenia (platelets >/=50 x 10(9)/l) or granulocytopenia (neutrophils >1.5 x 10(9)/l) were enrolled. All patients received cladribine (0.14 mg/kg) as a 2-h intravenous infusion daily for 5 days, repeated every 4 weeks. Patients received up to six cycles of therapy. Twenty-eight patients enrolled; 13 had intermediate (Rai stage I or II) and 15 high (Rai stage III and IV) risk stages. No patient had a complete remission, but nine (32%; 95% confidence interval, 15-49%) attained a partial remission when assessed using the modified NCI criteria (1996). The median time to relapse for responders was 12 months, while median progression-free survival for the entire group was 9 months (95% confidence interval, 4-14 months). The median overall survival was 2.2 years (95% confidence interval, 0.8-3.1 years). Response was predicted by pre-treatment Rai status with seven of 13 (54%) intermediate risk vs two of 15 (13%) high-risk patients responding (P = 0.04). Toxicity was myelosuppression and infections (grade 3-5: neutropenia 75%, thrombocytopenia 68%, and infections 43%). Cladribine has modest clinical activity and considerable toxicity in a very selected group of patients with fludarabine-refractory CLL lacking pre-treatment neutropenia and thrombocytopenia.
Asunto(s)
Cladribina/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Vidarabina/análogos & derivados , Vidarabina/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Cladribina/administración & dosificación , Cladribina/efectos adversos , Intervalos de Confianza , Supervivencia sin Enfermedad , Esquema de Medicación , Resistencia a Antineoplásicos , Humanos , Infusiones Intravenosas , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Selección de Paciente , Tasa de Supervivencia , Factores de TiempoRESUMEN
Myelodysplastic syndromes (MDS) characterized by multilineage cytopenias and dysplasia but lacking an increase in blasts, with no Auer rods or monocytosis, do not exactly fit any of the categories of the French-American-British (FAB) classification of MDS and are often diagnosed as refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), or 'unclassifiable' MDS. It has been suggested that these 'unclassifiable' cases form a distinct subset with a clinical behavior more like that of refractory anemia with excess of blasts (RAEB) than that of RA or RARS, but few studies have been undertaken that characterize this group. We compared the clinical, hematologic, morphologic and cytogenetic features of 18 such patients - for whose disease we propose the designation 'refractory cytopenia with multilineage dysplasia' (RCMD) - to those of 42 patients meeting the FAB criteria for RA or RARS (14 patients) and RAEB (28 patients). Our results show that cytopenias in RCMD are more severe than those in RA or RARS, but are similar to those in RAEB. Erythroid hyperplasia and dyserythropoiesis are the main findings in bone marrow specimens of RA or RARS, but the major features in RCMD are multilineage proliferation and dysplasia, which, except for the lack of increased blasts resemble the findings in RAEB. Only 1/14 patients (7%) with RA or RARS had an abnormal karyotype, whereas RCMD resembled RAEB in terms of the frequency (41 vs 50%, respectively) and type of karyotypic lesions. Abnormalities of chromosomes 5 and 7 (excluding del(5q) as an isolated finding) or complex aberrations were seen only in RCMD and RAEB. in RCMD, the median survival was 24 months, with a 4-year survival rate of48 +/- 13%, intermediate between the findings in RA/RARS (107 months and 77 +/- 12%, respectively) and RAEB (18 months and 27 +/- 9%, respectively). Our data indicate that RCMD is a distinct subset of MDS, with an unfavorable clinical outcome. The designation 'refractory cytopenia with multilineage dysplasia' emphasizes the differences between such cases and the primarily dyserythropoietic, indolent subgroups of MDS, such as RA or RARS.
Asunto(s)
Médula Ósea/patología , Síndromes Mielodisplásicos/patología , Adulto , Anciano , Anciano de 80 o más Años , Anemia Refractaria/sangre , Anemia Refractaria/genética , Anemia Refractaria/patología , Anemia Refractaria con Exceso de Blastos/sangre , Anemia Refractaria con Exceso de Blastos/genética , Anemia Refractaria con Exceso de Blastos/patología , Anemia Sideroblástica/sangre , Anemia Sideroblástica/genética , Anemia Sideroblástica/patología , Linaje de la Célula , Aberraciones Cromosómicas , Eritropoyesis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/genética , PronósticoRESUMEN
Chronic myelogenous leukemia (CML) can sometimes present in lymphoid blast phase (L-BP), and can be difficult to distinguish from Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Some have suggested that the determination of cell lineages involved by the Ph chromosome may be used for distinguishing CML presenting in L-BP (presumably multilineage disease) from Ph+ ALL (presumably lymphoid-restricted), although others have suggested the term 'stem cell ALL' for the multilineage process. Because it has been difficult to perform lineage studies of the Ph chromosome, we investigated the use of fluorescence in situ hybridization (FISH) with probes for BCR (on chromosome 22) and ABL (on chromosome 9) to study lineage involvement in Ph+ lymphoblastic malignancies. We analyzed routine blood and marrow specimens from eight patients who presented with Ph+ lymphoblastic leukemia and found that FISH recognized the 9;22 translocation, distinguished between the two common molecular variants, and readily identified multilineage vs lymphoblast-restricted disease. In our series, four patients had multilineage and four had lymphoblast-restricted disease. Multilineage disease was associated with morphologic features of CML at diagnosis and/or reversion to chronic phase CML after treatment leading us to consider it as CML presenting in L-BP. Patients with lymphoid-restricted disease lacked such findings. The survival of three of our four patients with multilineage disease was prolonged, at 25, 28+, and 126+ months, and when data from our entire series are added to those of 18 previously reported cases that were studied for lineage involvement (reviewed in Leukemia 1993; 7: 147), the difference in overall survival between patients with multilineage and lymphoblast-restricted disease is significant (median overall survival of 47 months vs 8 months, respectively; P=0.013, log rank). Our findings illustrate that FISH analysis can be used to recognize lineage involvement in patients presenting with Ph+ lymphoblastic malignancies, and they provide further support to the notion that multilineage and lymphoblast-restricted disease are distinct clinically as well as biologically.
Asunto(s)
Biomarcadores de Tumor/análisis , Crisis Blástica/patología , Proteínas de Fusión bcr-abl/análisis , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Proteínas de Neoplasias/análisis , Células Madre Neoplásicas/patología , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Adolescente , Adulto , Crisis Blástica/genética , Linaje de la Célula , Niño , Preescolar , Femenino , Humanos , Hibridación Fluorescente in Situ , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Células Madre Neoplásicas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMEN
In lymphoid neoplasms, nonrandom cytogenetic abnormalities correlate with clinical, morphologic and immunophenotypic features. A subtype of non-Hodgkin's lymphoma, which expresses the Ki-1 antigen (CD30) and has distinct morphologic and clinical features, has recently been described. We now report the association of a reciprocal translocation involving the short arm of chromosome 2 (band p23) and the long arm of chromosome 5 (band q35), t(2;5)(p23;q35), with Ki-1 positive anaplastic large cell lymphoma. Rearrangement of the genes that are located at the breakpoints on chromosomes 2 and 5 may be a critical step in the pathogenesis of this lymphoma.
Asunto(s)
Cromosomas Humanos Par 2 , Cromosomas Humanos Par 5 , Linfoma no Hodgkin/genética , Translocación Genética , Adolescente , Adulto , Antígenos de Diferenciación , Antígenos de Neoplasias , Femenino , Reordenamiento Génico , Humanos , Antígeno Ki-1 , Linfoma no Hodgkin/inmunología , Linfoma no Hodgkin/patología , MasculinoRESUMEN
Specific chromosomal abnormalities are independent predictors of response to therapy in acute nonlymphocytic leukemia (ANLL) de novo. In a series of 149 patients with ANLL, we sought to determine whether the t(8;21), t(15;17), t(9;11) or other abnormalities of the long arm of chromosome 11, inv(16) or t(16;16), inv(3) or t(3;3), trisomy 8, and abnormalities of chromosome 5 (-5/5q-) or of chromosome 7 (-7/7q-) identify differences in susceptibility to chemotherapy drugs in vivo. The immediate outcome of the first cycle of remission induction chemotherapy was analyzed for patients in each cytogenetic subgroup as an index of the drug susceptibility of the leukemia cells in vivo. Patients with t(8;21), inv(16), t(16;16), or 11q abnormalities had high rates of complete remission after initial therapy (60-100%), whereas patients with -7/7q- or -5/5q- had low initial response rates (0-36%), suggestive of drug resistance in vivo. In general, cytogenetic groups with high initial complete remission rates ("drug sensitive") also had long disease-free survivals; those groups with low initial remission rates ("drug resistant") had short remission durations even if these patients eventually achieved complete remission with further therapy. Patients with acute promyelocytic leukemia (APL), all of whom had the t(15;17), were the exception; despite low initial remission rates, they had long disease-free survivals, possibly due to a more rapid cytotoxic effect of chemotherapy on the clonogenic APL cells than on the more numerous malignant promyelocytes. We conclude that the prognostic importance of specific chromosomal abnormalities in ANLL resides in part in differing susceptibilities to chemotherapy.
Asunto(s)
Aberraciones Cromosómicas/genética , Leucemia/genética , Enfermedad Aguda , Adolescente , Adulto , Anciano , Aberraciones Cromosómicas/tratamiento farmacológico , Trastornos de los Cromosomas , Resistencia a Medicamentos , Humanos , Cariotipificación , Leucemia/tratamiento farmacológico , Persona de Mediana Edad , Pronóstico , Inducción de RemisiónRESUMEN
We report on the chromosomal pattern of 120 patients with childhood AML de novo. One hundred and fifteen patients (96%) had adequate samples for analysis; 98 (85%) of these showed clonal karyotypic abnormalities. They were classified into cytogenetic subgroups which were closely correlated with FAB subtypes: t(8;21) and M2 (n = 9); t(15;17) and M3 (n = 12); inv(16) and M4Eo (n = 9); t(9;11) and M5a (n = 10); t(11q23) other than t(9;11) and M4-M5 (n = 11); and t(1;22) and M7 (n = 4). In patients with -7/del(7q) (n = 6), leukemia was preceded by MDS in half of the cases, although they had diverse FAB subtypes. Thirty-seven patients had miscellaneous abnormalities. Despite a high CR rate, patients with t(8;21) had a very poor survival: only one child was event-free at 3 years from diagnosis. One third of patients with t(15;17) died during induction. Those eight who achieved CR fared well: only two relapsed, and six were event-free survivors. Patients with inv(16) had a high remission rate and a long survival: five children were in CR 20 to 136 months. Both groups with t(9;11) and t(11q23) had a high remission rate: however, outcome was superior for the t(9;11) group when compared to either the t(11q23) group (EFS at 3 years +/- SE, 56 +/- 17% vs. 11 +/- 10%, p = 0.07) or to the remaining patients (p = 0.06). Both -7/del(7q) and t(1;22) groups had low CR rates (50%) and poor survival. Cytogenetic analysis identifies clinically distinct subsets of childhood AML and is useful in tailoring treatment for these patients. Favorable cytogenetic groups (t(15;17), inv(16), and t(9;11)) may do well with current therapy protocols, whereas unfavorable groups (t(11q23), t(8;21), -7/del(7q), and t(1;22)) require more effective therapies.
Asunto(s)
Aberraciones Cromosómicas , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Niño , Inversión Cromosómica , Humanos , Monosomía , Pronóstico , Translocación GenéticaRESUMEN
Autopsy material from 22 patients with hairy cell leukemia was examined. All patients had the expected widespread involvement of the hematopoietic system. Peripheral lymphadenopathy was detected in only three cases, but significantly enlarged mediastinal, retroperitoneal, and abdominal lymph nodes were present in 15. Lymph nodes of two patients showed malignant lymphoma, large-cell type. Evidence of pulmonary infiltration by hairy cells was present in 15 cases; but in 14 of the 15, there was evidence of coexisting pneumonia, and in 13 of the 15 cases the presence of microorganisms was documented. Only one patient demonstrated clinical findings attributable solely to lung involvement by hairy cell leukemia. Liver involvement was present in every case, but the extent of the leukemic infiltration did not always correlate with serum biochemical abnormalities, and there was no correlation with the hairy cell count in the peripheral blood. M kansasii was found in the lymph nodes of three patients and in the lung and liver specimens of one of these. The tissue response in two of the patients with M kansasii consisted of the presence of poorly formed granuloma; the third patient had only focal areas of necrosis, with no polymorphonuclear or macrophage response.
Asunto(s)
Leucemia de Células Pilosas/patología , Adulto , Anciano , Autopsia , Médula Ósea/patología , Encéfalo/patología , Sistema Digestivo/patología , Femenino , Humanos , Riñón/patología , Hígado/patología , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Sistema Respiratorio/patología , Bazo/patologíaRESUMEN
In the preceding paragraphs, the features that define the various members of the CMPD have been reviewed. These features are summarized in Table 4. Knowledge of these guidelines will aid the clinician and pathologist in arriving at a proper classification; however, in most cases, it is the occasional patient whose clinical, laboratory, and morphologic findings lie across the different categories that unifies these CMPDs, and that provides the challenge which makes them interesting.
Asunto(s)
Trastornos Mieloproliferativos/sangre , Trastornos Mieloproliferativos/patología , Médula Ósea/patología , Enfermedad Crónica , Diagnóstico Diferencial , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/clasificación , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Trastornos Mieloproliferativos/clasificación , Trastornos Mieloproliferativos/genética , Policitemia Vera/sangre , Policitemia Vera/patología , Mielofibrosis Primaria/sangre , Mielofibrosis Primaria/patología , Trombocitosis/sangre , Trombocitosis/patologíaRESUMEN
The classification of malignant lymphoma has, for decades, provided a fertile area for controversy, discussion, and change. Such debate is necessary in order to appropriately assimilate new knowledge regarding this group of neoplasms. In this review, we provide a brief account of the evolution of classification schemes for lymphoma, and emphasize the recently proposed Revised European-American Lymphoma (REAL) classification as a synthesis of current knowledge of clinical, morphologic, immunologic, and molecular data. Specific entities that are recently described or for which there are current controversies are discussed. The necessity of communication between clinicians and pathologists in the workup of a patient with malignant lymphoma is emphasized.