RESUMEN
Karyotype complexity has major prognostic value in many malignancies. There is no consensus on the definition of a complex karyotype, and the prognostic impact of karyotype complexity differs from one disease to another. Due to the importance of the complex karyotype in the prognosis and treatment of several hematological diseases, the Francophone Group of Hematological Cytogenetics (Groupe Francophone de Cytogénétique Hématologique, GFCH) has developed an up-to-date, practical document for helping cytogeneticists to assess complex karyotypes in these hematological disorders. The evaluation of karyotype complexity is challenging, and it would be useful to have a consensus method for counting the number of chromosomal abnormalities (CAs). Although it is not possible to establish a single prognostic threshold for the number of CAs in all malignancies, a specific consensus prognostic cut-off must be defined for each individual disease. In order to standardize current cytogenetic practices and apply a single denomination, we suggest defining a low complex karyotype as having 3 CAs, an intermediate complex karyotype as having 4 CAs, and a highly complex karyotype as having 5 or more CAs.
Asunto(s)
Neoplasias Hematológicas , Hematología , Aberraciones Cromosómicas , Análisis Citogenético/métodos , Citogenética , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Humanos , Cariotipo , Pronóstico , Sociedades MédicasRESUMEN
Symptomatic nervous system leukemic infiltration is rarely observed in CLL. Various clinical manifestations including headache, confusion, cranial nerve palsies, focal central deficits and peripheral neuropathies have been seldom reported, occurring in less than 1% of patients. We report herein 2 CLL patients with unusual clinical presentations of nervous system invasion. They presented multiple progressive peripheral deficits due to meningoradiculitis. In both, CSF immunophenotyping analysis identified a majority of T cells (>90%), and less than 10% of B-CLL cells expressing CD5, CD19 and CD20. Our analyses revealed the transformation of CLL into an aggressive B-cell lymphoma in one case (Richter's syndrome). A post mortem study showed massive infiltration of cranial nerves and spinal roots by large B lymphomatous cells. In the other case, CNS oriented chemotherapy led to remission and total neurological recovery. In practice, the etiological diagnosis of neurological deficits in CLL patients is difficult. CSF analysis may be useful, requiring viral PCR, repeated cytological studies and immunophenotyping analysis. Although rare, leptomeningeal leukemic localization has to be discussed, even in the absence of overt Richter syndrome, and may require an early therapeutic test.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/patología , Meningitis/etiología , Meningitis/patología , Radiculopatía/etiología , Radiculopatía/patología , Anciano , Anciano de 80 o más Años , Nervios Craneales/patología , Resultado Fatal , Humanos , Infiltración Leucémica/patología , Masculino , Raíces Nerviosas Espinales/patologíaRESUMEN
The NUP98 gene is fused with 19 different partner genes in various human hematopoietic malignancies. In order to gain additional clinico-hematological data and to identify new partners of NUP98, the Groupe Francophone de Cytogénétique Hématologique (GFCH) collected cases of hematological malignancies where a 11p15 rearrangement was detected. Fluorescence in situ hybridization (FISH) analysis showed that 35% of these patients (23/66) carried a rearrangement of the NUP98 locus. Genes of the HOXA cluster and the nuclear-receptor set domain (NSD) genes were frequently fused to NUP98, mainly in de novo myeloid malignancies whereas the DDX10 and TOP1 genes were equally rearranged in de novo and in therapy-related myeloid proliferations. Involvement of ADD3 and C6ORF80 genes were detected, respectively, in myeloid disorders and in T-cell acute lymphoblastic leukemia (T-ALL), whereas the RAP1GDS1 gene was fused to NUP98 in T-ALL. Three new chromosomal breakpoints: 3q22.1, 7p15 (in a localization distinct from the HOXA locus) and Xq28 were detected in rearrangements with the NUP98 gene locus. The present study as well as a review of the 73 cases previously reported in the literature allowed us to delineate some chromosomal, clinical and molecular features of patients carrying a NUP98 gene rearrangements.
Asunto(s)
Neoplasias Hematológicas/genética , Proteínas de Complejo Poro Nuclear/genética , Translocación Genética/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Análisis Citogenético , Femenino , Francia , Proteínas de Homeodominio/genética , Humanos , Hibridación Fluorescente in Situ , Lactante , Masculino , Persona de Mediana Edad , Receptores Citoplasmáticos y Nucleares/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sensibilidad y Especificidad , Sociedades MédicasRESUMEN
Acute lymphoblastic leukemia (ALL) in the elderly is characterized by its ominous prognosis. On the other hand, imatinib has demonstrated remarkable, although transient, activity in relapsed and refractory Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), which prompted us to assess the use of imatinib in previously untreated elderly patients. ALL patients aged 55 years or older were given steroids during 1 week. Ph+ve cases were then offered a chemotherapy-based induction followed by a consolidation phase with imatinib and steroids during 2 months. Patients in complete response (CR) after consolidation were given 10 maintenance blocks of alternating chemotherapy, including two additional 2-month blocks of imatinib. Thirty patients were included in this study and are compared with 21 historical controls. Out of 29 assessable patients, 21 (72%, confidence interval (CI): 53-87%) were in CR after induction chemotherapy vs 6/21 (29%, CI: 11-52%) in controls (P=0.003). Five additional CRs were obtained after salvage with imatinib and four after salvage with additional chemotherapy in the control group. Overall survival (OS) is 66% at 1 year vs 43% in the control group (P=0.005). The 1-year relapse-free survival is 58 vs 11% (P=0.0003). The use of imatinib in elderly patients with Ph+ ALL is very likely to improve outcome, including OS.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Metilprednisolona/uso terapéutico , Cromosoma Filadelfia , Piperazinas/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirugía , Pirimidinas/uso terapéutico , Resultado del Tratamiento , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzamidas , Supervivencia sin Enfermedad , Humanos , Mesilato de Imatinib , Metilprednisolona/administración & dosificación , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Trasplante de Células MadreRESUMEN
With combined antiretroviral therapy (cART), the risk for HIV-infected individuals to develop a non-Hodgkin lymphoma is diminished. However, the incidence of Burkitt lymphoma (BL) remains strikingly elevated. Most BL present a t(8;14) chromosomal translocation which must take place at a time of spatial proximity between the translocation partners. The two partner genes, MYC and IGH, were found colocalized only very rarely in the nuclei of normal peripheral blood B-cells examined using 3D-FISH while circulating B-cells from HIV-infected individuals whose exhibited consistently elevated levels of MYC-IGH colocalization. In vitro, incubating normal B-cells from healthy donors with a transcriptionally active form of the HIV-encoded Tat protein rapidly activated transcription of the nuclease-encoding RAG1 gene. This created DNA damage, including in the MYC gene locus which then moved towards the center of the nucleus where it sustainably colocalized with IGH up to 10-fold more frequently than in controls. In vivo, this could be sufficient to account for the elevated risk of BL-specific chromosomal translocations which would occur following DNA double strand breaks triggered by AID in secondary lymph nodes at the final stage of immunoglobulin gene maturation. New therapeutic attitudes can be envisioned to prevent BL in this high risk group.
Asunto(s)
Linfocitos B/metabolismo , Linfoma de Burkitt/genética , Productos del Gen tat/fisiología , Genes myc , Cadenas Pesadas de Inmunoglobulina/genética , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We analyzed the impact of cytogenetics on 193 children enrolled in two successive French trials (LAME89/91 and ELAM02), who received hematopoietic stem cell transplantation during CR1. Detailed karyotype was available for 66/74 (89%) in LAME89/91 and 118/119 (99%) in ELAM02. Several karyotype and transplant characteristics differed according to therapeutic protocol: unfavorable karyotypes were more frequent in ELAM02 (36% vs 18%), pretransplant chemotherapy included high-dose cytarabine in ELAM02 and not in LAME89/91, IV replaced oral busulfan in the conditioning regimen, methotrexate was removed from post-transplant immunosuppression, and matched unrelated donor and cord blood transplantation were introduced. Five-year overall survival (OS) was 78.2% in LAME89 and 81.4% in ELAM02. OS was significantly lower for the unfavorable cytogenetic risk group in LAME89/91 when compared with intermediate and favorable groups (50% vs 90.6 and 86.4%, P=0.001). This difference was no longer apparent in ELAM02 (80.9% vs 71.3% and 5/5, respectively). Survival improvement for children with unfavorable karyotype was statistically significant (P=0.026) and was due to decrease in relapse risk. Five-year transplantation-related mortality was 6.75% in LAME89/91. In ELAM02, it was 3.2% for patients with a sibling donor and 10.9% with an unrelated donor or cord blood. We conclude that the outcome of children with unfavorable karyotype transplanted in CR1 has improved.
Asunto(s)
Citogenética , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Niño , Femenino , Francia , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Cariotipificación , Leucemia Mieloide Aguda/mortalidad , Masculino , Inducción de Remisión , Análisis de Supervivencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
The inv(16) and related t(16;16) are found in 10% of all cases with de novo acute myeloid leukemia. In these rearrangements the core binding factor beta (CBFB) gene on 16q22 is fused to the smooth muscle myosin heavy chain gene (MYH11) on 16p13. To gain insight into the mechanisms causing the inv(16) we have analysed 24 genomic CBFB-MYH11 breakpoints. All breakpoints in CBFB are located in a 15-Kb intron. More than 50% of the sequenced 6.2 Kb of this intron consists of human repetitive elements. Twenty-one of the 24 breakpoints in MYH11 are located in a 370-bp intron. The remaining three breakpoints in MYH11 are located more upstream. The localization of three breakpoints adjacent to a V(D)J recombinase signal sequence in MYH11 suggests a V(D)J recombinase-mediated rearrangement in these cases. V(D)J recombinase-associated characteristics (small nucleotide deletions and insertions of random nucleotides) were detected in six other cases. CBFB and MYH11 duplications were detected in four of six cases tested.
Asunto(s)
Inversión Cromosómica , Cromosomas Humanos Par 16 , Leucemia Mieloide/genética , Enfermedad Aguda , Secuencia de Bases , Clonación Molecular , Subunidad beta del Factor de Unión al Sitio Principal , ADN Complementario , Proteínas de Unión al ADN/genética , Humanos , Intrones , Datos de Secuencia Molecular , Homología de Secuencia de Ácido Nucleico , Factor de Transcripción AP-2 , Factores de Transcripción/genéticaRESUMEN
PURPOSE: A small proportion of patients with chronic myeloid leukemia (CML) achieve a complete cytogenetic response (CCR), defined as the disappearance of Philadelphia (Ph) chromosome-positive metaphases, after treatment with interferon alfa (IFN). In this population of patients, the question of whether treatment should then be withdrawn is not yet resolved. PATIENTS AND METHODS: In the present study, we followed 15 patients who stopped IFN after achieving CCR. In nine patients IFN was stopped in view of adverse reactions (n = 8) or patient's choice (n = 1). For the remaining six patients, the treatment was stopped because no BCR/ABL rearrangement could be detected by reverse transcriptase polymerase chain reaction (RT-PCR) in four successive analyses using peripheral-blood samples. RESULTS: Loss of CCR and survival were not statistically different (P =.48; P =.7) for the 15 patients who stopped IFN compared with 41 other CCR patients who continued IFN therapy in our institution. The median follow-up after discontinuation of IFN treatment was 36 months (range, 6 to 108 months). Seven patients (47%) (females, or CCR > 24 months and RT-PCR negative before IFN cessation; P <.0001) did not relapse. Eight other patients (53%) relapsed (lost CCR) within 3 to 33 months of treatment discontinuation. One of them relapsed in major cytogenetic remission (MCR) and was still in MCR 87 months after stopping therapy without any treatment. CONCLUSION: It is possible to stop IFN treatment at least in some patients with CML who achieve a prolonged period of CCR. This study also illustrates the hypothesis that persistence of low numbers of Ph-positive cells does not necessarily imply hematologic relapse.
Asunto(s)
Antineoplásicos/administración & dosificación , Interferón-alfa/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Proteínas de Fusión bcr-abl/sangre , Proteínas de Fusión bcr-abl/genética , Humanos , Interferón-alfa/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia , Inducción de Remisión , Factores de Riesgo , Estadísticas no Paramétricas , Tasa de Supervivencia , Factores de TiempoRESUMEN
Fifteen chronic myelocytic leukemia patients in durable complete cytogenetic conversion (CCC) under interferon therapy, were monitored every three to six months by bone marrow (BM) karyotypes and/or reverse-transcription polymerase chain reaction (RT-PCR) on peripheral blood (PB) leukocytes (by a nested primer approach using two rounds of amplification, 30 cycles each). Special care was taken to minimize the risk of contamination. The median time of follow-up after first CCC was 12 months (range, 6-30). Thirty five BM karyotypes were performed. Only three patients demonstrated the transient reappearance of a few Philadelphia-positive metaphases, while other patients remained in CCC. Forty five PB samples were studied by RT-PCR. In two patients, no BCR/ABL transcript could be detected in three consecutive samples. In the 13 other cases, RT-PCR was intermittently negative, indicating a level of residual leukemic cells close to the threshold of sensitivity of the technique.
Asunto(s)
Interferón-alfa/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Adulto , Femenino , Estudios de Seguimiento , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Persona de Mediana Edad , Cromosoma Filadelfia , Reacción en Cadena de la Polimerasa , ARN Mensajero/análisis , Inducción de Remisión , Transcripción GenéticaRESUMEN
To improve the management of chronic myeloid leukemia (CML) in a single center, we used interferon alpha (IFN alpha) to treat newly diagnosed CML patients and investigated the factors predictive of a major cytogenetic response. Fifty-two patients (pts) with a median age of 51.5 years (16-68), were given interferon alpha (IFN alpha) (5 millions/m2/day, subcutaneously). The median interval between diagnosis and IFN alpha was 41.5 days (0-160). The doses of INF alpha were adjusted to maintain the white blood cell (WBC) count between 1.5 and 5 x 10(9)/l and the platelet count between 50 and 100 x 10(9)/l. At diagnosis, Sokal's criteria were used to classify patients into three groups: low (n = 24), intermediate (n = 19) and high risk (n = 9). A complete hematological response (CHR) was achieved in 42 cases (80.7%). A partial response was present in nine; only one patient did not respond. By multivariate logistic regression analysis, only the age at diagnosis was found to influence the CHR rate (P = 0.06). Cytogenetic response was evaluated in 46 responder patients. Twenty-three patients achieved a major cytogenetic response (MCR) which was either partial ( > or = 65% pH negative cells) (n = 3) or complete (CCR) (n = 20). By univariate analysis, two disease-related variables were found to influence the MCR rate in 40 evaluable CHR patients: spleen size at diagnosis and peripheral blood blast percentage. However, using either univariate or multivariate analysis, the most significant factor was the achievement of CHR within 3 months (P < 0.0004 and P < 0.0002, respectively). These results show that IFN alpha can induce high rates of hematological and cytogenetic responses when administered in doses leading to myelosuppression. The achievement of CHR within 3 months could be useful to identify early, those patients who will not respond to IFN alpha and who need alternative treatments such as allogeneic or autologous stem cell transplantation.
Asunto(s)
Interferón Tipo I/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Adolescente , Adulto , Anciano , Femenino , Humanos , Inyecciones Subcutáneas , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Masculino , Persona de Mediana Edad , Cromosoma Filadelfia , Valor Predictivo de las Pruebas , Proteínas Recombinantes , Análisis de Regresión , Análisis de SupervivenciaRESUMEN
We report minimal residual disease evaluation in 18 chronic myelocytic leukemia patients who achieved a durable complete cytogenetic conversion (CCC) under interferon alpha (IFN) therapy. Monitoring was performed every 3-6 months using bone marrow (BM) karyotypes and/or two-step reverse transcription polymerase chain reaction (RT-PCR) on peripheral blood samples. Median follow-up after first CCC was 47 months (range 15-69). All patients maintained complete hematological remission during follow-up. A median of five BM karyotypes were performed per patient (range: 3-11). The estimated chances of maintaining a major cytogenetic response (either CCC or less than 35% Ph positive metaphases were 93 +/- 13% (95% CI) at 36 months. One patient lost his cytogenetic response. A median of seven RT-PCR reactions were performed per patient (range: 1-11). A residual disease was detectable even in cases with long periods of CCC. However, in two patients, RT-PCRs were often negative; one, who had four successive negative RT-PCR was taken off IFN therapy and did not receive any other treatment; later in this case, RT-PCRs were again positive, but CCC was maintained for 39 months. Of the three who were taken off IFN and no longer treated, two maintained CCC (39+ and 33+ months); the third had a recurrence of 7% Ph-positive metaphases, and later returned to CCC. These results confirm that in most well-responding patients, the disease is not eradicated. However, it seems that the clonogenic potential of the residual leukemic clone is low. In patients taken off IFN therapy, IFN may have a particular remnant effect.
Asunto(s)
Interferón Tipo I/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Cariotipificación , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Proteínas RecombinantesRESUMEN
The pericentric inversion on chromosome 16 [inv(16)(p13q22)] and related t(16;16)(p13;q22) are recurrent aberrations associated with acute myeloid leukemia (AML) M4 Eo. Both abberations result in a fusion of the core binding factor beta (CBFB) and smooth muscle myosin heavy chain gene (MYH11). A selected genomic 6.9-kb BamHl probe detects MYH11 DNA rearrangements in 18 of 19 inv(16)/t(16;16) patients tested using HindIII digested DNA. The rearranged fragments were not detectable after remission in two cases tested, while they were present after relapse in one of these two cases tested.
Asunto(s)
Inversión Cromosómica , Cromosomas Humanos Par 16 , ADN de Neoplasias/genética , Reordenamiento Génico , Leucemia Mielomonocítica Aguda/genética , Cadenas Pesadas de Miosina/genética , Humanos , Cadenas Pesadas de Miosina/biosíntesis , Proteínas de Fusión Oncogénica/biosíntesis , Proteínas de Fusión Oncogénica/genética , Translocación GenéticaRESUMEN
To accurately estimate the incidence of HOX11L2 expression, and determine the associated cytogenetic features, in T-cell acute lymphoblastic leukemia (T-ALL), the Groupe Français de Cytogénétique Hématologique (GFCH) carried out a retrospective study of both childhood and adult patients. In total, 364 patients were included (211 children =15 years and 153 adults), and 67 (18.5%) [47 children (22.4%) and 20 adults (13.1%)] were shown to either harbor the t(5;14)q35;q32) translocation or express the HOX11L2 gene or both. Most of the common hematological parameters did not show significant differences within positive and negative populations, whereas the incidence of CD1a+/CD10+ and cytoplasmic CD3+ patients was significantly higher in positive than in negative children. Out of the 63 positive patients investigated by conventional cytogenetics, 32 exhibited normal karyotype, whereas the others 31 showed clonal chromosome abnormalities, which did not include classical T-ALL specific translocations. Involvement of the RANBP17/HOX11L2 locus was ascertained by fluorescence in situ hybridization in six variant or alternative (three-way translocation or cytogenetic partner other than 14q32) translocations out of the 223 patients. Our results also show that HOX11L2 expression essentially occurs as a result of a 5q35 rearrangement, but is not associated with another identified T-ALL specific recurrent genetic abnormality, such as SIL-TAL fusion or HOX11 expression.
Asunto(s)
Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 5/genética , Proteínas de Homeodominio/genética , Leucemia-Linfoma de Células T del Adulto/genética , Proteínas Oncogénicas/genética , Translocación Genética , Adolescente , Adulto , Niño , Preescolar , Aberraciones Cromosómicas , Células Clonales , Femenino , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Ploidias , Proteínas Proto-Oncogénicas , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de SupervivenciaRESUMEN
Poor anticoagulant response to APC is conveniently screened by a commercially available functional test (Coatest APC Resistance) allowing identification of APC-resistant patients. These patients may then be genotyped with respect to factor V, the Arg -> Gln mutation being the principle cause of APC resistance. However, determination of phenotype generally precedes that of genotype, and the need for an "abnormality threshold" prompted a study of inter-batch variations and the clinical conditions associated with an altered APC response. The response to APC was assessed twice in plasma from 111 patients using two of four successive kit batches. A modest but significant inter-batch variability was observed. At the same time, we also tested 130 patients with retinal venous occlusion (RVO), 28 patients with glaucoma and 24 normal volunteers. The APCaPTT/aPTT ratio was found to be lower in the presence of elevated thrombin-antithrombin complexes (r = 0.167, p < 0.02) and low blood viscosity (at high shear rate: r = 0.305, p < 0.0001) independently of any alteration in genotype.
Asunto(s)
Pruebas de Coagulación Sanguínea , Proteína C/farmacología , Anciano , Envejecimiento/sangre , Resistencia a Medicamentos/genética , Estudios de Evaluación como Asunto , Femenino , Hemostasis/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Reología , Estadística como AsuntoRESUMEN
Serial marrow karyotyping was performed in 31 chronic myeloid leukemia (CML) patients treated with allogeneic bone marrow transplantation (BMT). Of 11 hematological relapses, seven were heralded for up to 20 months by a cytogenetic relapse (characterized by increasing percentages of Philadelphia (Ph)-positive metaphases, seen on serial karyotypes). Chromosomal abnormalities additional to the Ph, seen before BMT, were not found again at relapse. Relapses were characterized by clonal evolutions of the Ph-positive cells, likely corresponding to cytogenetic patterns of treatment-induced leukemia [del(5q), del(7q), complex karyotypes] and were different from those generally found in CML evolution. Involvement of chromosome 1 was also frequent. Sporadic Ph-positive metaphases (not seen in repeated karyotypes) were seen only during the first 8 months after BMT.
Asunto(s)
Trasplante de Médula Ósea , Leucemia Mielógena Crónica BCR-ABL Positiva/cirugía , Adolescente , Adulto , Aberraciones Cromosómicas , Citogenética , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/cirugía , Masculino , Persona de Mediana Edad , Cromosoma Filadelfia , Factores de TiempoRESUMEN
Two different molecular techniques were used to monitor chimerism following 17 non-T cell-depleted BMTs from female donors to male recipients: pHY10, a Y chromosome-specific probe (Southern or slot blots), and a set of primers for Y chromosome sequence-specific amplification by the polymerase chain reaction (PCR). On Southern blots, male DNA was detectable at a level less than 1% of 10 micrograms DNA while cross-reactivity with autosomal sequences was avoided. On slot blots, male DNA was reliably detectable at levels less than 0.5%, even in small sample (0.5 microgram DNA). With the PCR technique, male DNA was detectable at levels of 1:10(6) to 1:10(7) of 0.5 microgram DNA. Slot blot and PCR results were concordant in 19 of 23 samples. Both techniques demonstrated a constant small mixed chimerism during the first year after BMT and in four of nine patients, this chimerism persisted even longer (up to 29 months after BMT).
Asunto(s)
Trasplante de Médula Ósea/patología , Quimera/genética , Cromosoma Y , Adolescente , Adulto , Southern Blotting , Niño , Preescolar , Estudios de Evaluación como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Técnicas de Sonda Molecular/estadística & datos numéricos , Reacción en Cadena de la Polimerasa/métodos , Reacción en Cadena de la Polimerasa/estadística & datos numéricos , Sensibilidad y Especificidad , Sexo , Donantes de TejidosRESUMEN
To improve the management of chronic myeloid leukemia (CML) in a single center, we have used interferon-alpha (IFN-alpha) to treat newly diagnosed Ph-positive CML patients and investigated the factors predictive of a major cytogenetic response. Eighty-one patients with a median age of 50.5 y (17-70) were given IFN-alpha (5 x 10(6)/sqm/day, s.c.). The median interval between diagnosis and IFN-alpha was 45 days (0-160). IFN-alpha doses were adjusted to maintain the white blood cell (WBC) count between 1.5 and 5 x 10(9)/l and the platelet count between 50 and 100 x 10(9)/l. At diagnosis, Sokal's criteria were used to classify patients into three groups: low (n = 39), intermediate (n = 32) and high risk (n = 10). A complete hematological response (CHR) was achieved in 66 cases (81.5%). Cytogenetic response was evaluated in these 66 responders. Thirty-six patients (44.4%) achieved a major cytogenetic response (MCR) (> or = 65% Ph-negative cells), 31 of them having a complete cytogenetic response. The 5-y transformation-free survival (TFS) of the 81 patients was 77 +/- 14% (95% CI) and was statistically influenced by the CHR rate at three months (p = 0.008) and the achievement of MCR or CCR (p < 0.0009 and p < 0.0005, respectively). Moreover, we found that the MCR or CCR were significantly influenced by the obtaining of CHR at three months (p < 0.001 and p < 0.0001, respectively). These results show that IFN-alpha can induce high rates of hematological and cytogenetic responses when administered in doses leading to myelosuppression. The achievement of CHR within three months could be useful to identify early those patients who will not respond to IFN-alpha and who need alternative treatments such as allogeneic or autologous stem cell transplantation.
Asunto(s)
Antineoplásicos/uso terapéutico , Interferón Tipo I/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Leucemia Mieloide de Fase Crónica/terapia , Adolescente , Adulto , Anciano , Antineoplásicos/efectos adversos , Terapia Combinada , Tolerancia a Medicamentos , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Interferón Tipo I/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , Tasa de SupervivenciaRESUMEN
Between 1980 and 1996, we transplanted 72 patients with CML using blood stem cells collected at diagnosis before treatment and without any mobilization. The median age of patients at diagnosis was 47.5 years (range 20.5-59.5). The median numbers of nucleated cells and CFU-GM transplanted were 10 x 10(8)/kg and 97 x 10(4)/kg, respectively. The median duration to reach more than 0.5 x 10(9)/l neutrophils and 50 x 10(9)/l platelets was 12 (range 5-19) and 11 days (range 0-79), respectively. Twenty patients (group I) were transplanted in chronic phase either for resistance to IFN (14 patients) (group IA) or because the Sokal index was more than 1.2 (six patients) (group IB). All those patients had preparative regimen with busulfan (4 mg/kg/day x 4) and melphalan (140 mg/m2). They were treated with recombinant alpha-interferon (IFN) after transplant. The cumulative incidence of major cytogenetic response (MCR) at 12 months was 25 +/- 21% (95% CI), the 5-year survival was 75 +/- 42% (95% CI). These results (observed in patients with bad prognosis factors) are similar to those usually observed in CML patients treated by IFN, whatever the Sokal risk. Thus autologous transplantation is able to reproduce for poor prognosis patients the results observed in standard risk patients treated with IFN. This suggests that it could prolong survival. Fifty-two other patients (group II) were transplanted for CML in transformation (accelerated phase = 32; blast crisis = 20) after a preparative regimen containing either total body irradiation (TBI) or busulfan. The median survival was short (10.4 months) and only 21 patients survived more than 1 year. The survival was longer for patients transplanted in accelerated phase (vs blast crisis), those who were due to receive a double transplant (vs single) (34 patients), those who were treated with IFN after transplant (vs hydroxyurea) and for the patients who obtained a complete hematologic response.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Adulto , Femenino , Hematopoyesis , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Masculino , Persona de Mediana Edad , Trasplante AutólogoRESUMEN
Autologous blood stem cell transplantation (ASCT) was performed in 32 patients with high risk chronic myelogenous leukemia (CML). Prior to ASCT, the patients were given Busulfan and high-dose Melphalan. Peripheral blood stem cells collected at diagnosis were used to rescue hematopoiesis. Recombinant Interferon was administered after ASCT. In 24 patients transplanted in transformation, 23 achieved a complete hematological response and nine are still alive 9 to 73 months after ASCT. Eight other patients were transplanted in chronic phase for either the presence of bad prognostic factors (Sokal's classification) or no response to IFN. Seven are alive without transformation 16 to 48 months after ASCT. Although few patients presented a cytogenetical response (10/28), the survival observed in this series of patients compares favorably with that of patients treated conventionally. Thus, the place of ASCT in CML could now be tested prospectively.
Asunto(s)
Crisis Blástica/terapia , Transfusión de Componentes Sanguíneos , Transfusión de Sangre Autóloga , Factores Inmunológicos/uso terapéutico , Interferón Tipo I/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mieloide de Fase Acelerada/terapia , Adulto , Crisis Blástica/mortalidad , Purgación de la Médula Ósea , Busulfano , Terapia Combinada , Francia/epidemiología , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Melfalán , Persona de Mediana Edad , Pronóstico , Proteínas Recombinantes , Riesgo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
We present the case of a two-year-old child with an atypical presentation of chronic myeloid leukemia. At diagnosis, he showed clinical and biological features of juvenile chronic myeloid leukemia (CML). However, eosinophilia was observed in blood and bone marrow. The bone marrow karyotype did not demonstrate the Philadelphia chromosome but BCR-ABL rearrangement was shown to be present by reverse transcriptase polymerase chain reaction (RT-PCR) analysis and confirmed by fluorescent in situ hybridization (FISH) analysis. Discussion centres on the differentiation between juvenile CML and childhood chronic myelogenous Leukemia and the importance of carrying out RT PCR for all juvenile CML cases.