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1.
Blood ; 121(23): 4749-52, 2013 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-23603912

RESUMEN

Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) is a high-risk subgroup of T-lineage ALL characterized by specific stem cell and myeloid features. In adult ETP-ALL, no comprehensive studies on the genetic background have been performed to elucidate molecular lesions of this distinct subgroup. We performed whole-exome sequencing of 5 paired ETP-ALL samples. In addition to mutations in genes known to be involved in leukemogenesis (ETV6, NOTCH1, JAK1, and NF1), we identified novel recurrent mutations in FAT1 (25%), FAT3 (20%), DNM2 (35%), and genes associated with epigenetic regulation (MLL2, BMI1, and DNMT3A). Importantly, we verified the high rate of DNMT3A mutations (16%) in a larger cohort of adult patients with ETP-ALL (10/68). Mutations in epigenetic regulators support clinical trials, including epigenetic-orientated therapies, for this high-risk subgroup. Interestingly, more than 60% of adult patients with ETP-ALL harbor at least a single genetic lesion in DNMT3A, FLT3, or NOTCH1 that may allow use of targeted therapies.


Asunto(s)
Biomarcadores de Tumor/genética , ADN (Citosina-5-)-Metiltransferasas/genética , Exoma/genética , Mutación/genética , Células Precursoras de Linfocitos T/patología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adolescente , Adulto , Anciano , ADN Metiltransferasa 3A , Epigénesis Genética , Femenino , Estudios de Seguimiento , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Receptor Notch1/genética , Adulto Joven , Tirosina Quinasa 3 Similar a fms/genética
2.
Blood ; 120(23): 4470-81, 2012 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-23033265

RESUMEN

Significant improvements have been made in the treatment of acute lymphoblastic leukemia (ALL) during the past 2 decades, and measurement of submicroscopic (minimal) levels of residual disease (MRD) is increasingly used to monitor treatment efficacy. For a better comparability of MRD data, there are ongoing efforts to standardize MRD quantification using real-time quantitative PCR of clonal immunoglobulin and T-cell receptor gene rearrangements, real-time quantitative-based detection of fusion gene transcripts or breakpoints, and multiparameter flow cytometric immunophenotyping. Several studies have demonstrated that MRD assessment in childhood and adult ALL significantly correlates with clinical outcome. MRD detection is particularly useful for evaluation of treatment response, but also for early assessment of an impending relapse. Therefore, MRD has gained a prominent position in many ALL treatment studies as a tool for tailoring therapy with growing evidence that MRD supersedes most conventional stratification criteria at least for Ph-negative ALL. Most study protocols on adult ALL follow a 2-step approach with a first classic pretherapeutic and a second MRD-based risk stratification. Here we discuss whether and how MRD is ready to be used as main decisive marker and whether pretherapeutic factors and MRD are really competing or complementary tools to individualize treatment.


Asunto(s)
Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Citometría de Flujo , Proteínas de Fusión bcr-abl/genética , Reordenamiento Génico , Predisposición Genética a la Enfermedad/genética , Humanos , Inmunoglobulinas/genética , Mutación , Neoplasia Residual/genética , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pronóstico , Receptores de Antígenos de Linfocitos T/genética , Resultado del Tratamiento
3.
Blood ; 120(9): 1868-76, 2012 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-22442346

RESUMEN

Quantification of minimal residual disease (MRD) by real-time PCR directed to TCR and Ig gene rearrangements allows a refined evaluation of response in acute lymphoblastic leukemia (ALL). The German Multicenter Study Group for Adult ALL prospectively evaluated molecular response after induction/consolidation chemotherapy according to standardized methods and terminology in patients with Philadelphia chromosome-negative ALL. The cytologic complete response (CR) rate was 89% after induction phases 1 and 2. At this time point the molecular CR rate was 70% in 580 patients with cytologic CR and evaluable MRD. Patients with molecular CR after consolidation had a significantly higher probability of continuous complete remission (CCR; 74% vs 35%; P < .0001) and of overall survival (80% vs 42%; P = .0001) compared with patients with molecular failure. Patients with molecular failure without stem cell transplantation (SCT) in first CR relapsed after a median time of 7.6 months; CCR and survival at 5 years only reached 12% and 33%, respectively. Quantitative MRD assessment identified patients with molecular failure as a new high-risk group. These patients display resistance to conventional drugs and are candidates for treatment with targeted, experimental drugs and allogeneic SCT. Molecular response was shown to be highly predictive for outcome and therefore constitutes a relevant study end point. The studies are registered at www.clinicaltrials.gov as NCT00199056 and NCT00198991.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Quimioterapia de Inducción/métodos , Neoplasia Residual/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Terapia Combinada , Humanos , Persona de Mediana Edad , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pronóstico , Estudios Prospectivos , Inducción de Remisión , Análisis de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Adulto Joven
4.
Blood ; 120(26): 5185-7, 2012 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-23024237

RESUMEN

Persistence or recurrence of minimal residual disease (MRD) after chemotherapy results in clinical relapse in patients with acute lymphoblastic leukemia (ALL). In a phase 2 trial of B-lineage ALL patients with persistent or relapsed MRD, a T cell-engaging bispecific Ab construct induced an 80% MRD response rate. In the present study, we show that after a median follow-up of 33 months, the hematologic relapse-free survival of the entire evaluable study cohort of 20 patients was 61% (Kaplan-Meier estimate). The hema-tologic relapse-free survival rate of a subgroup of 9 patients who received allogeneic hematopoietic stem cell transplantation after blinatumomab treatment was 65% (Kaplan-Meier estimate). Of the subgroup of 6 Philadelphia chromosome-negative MRD responders with no further therapy after blinatumomab, 4 are in ongoing hematologic and molecular remission. We conclude that blinatumomab can induce long-lasting complete remission in B-lineage ALL patients with persistent or recurrent MRD. The original study and this follow-up study are registered at www.clinicaltrials.gov as NCT00198991 and NCT00198978, respectively.


Asunto(s)
Anticuerpos Biespecíficos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Adulto , Antineoplásicos/uso terapéutico , Terapia Combinada , Supervivencia sin Enfermedad , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Humanos , Estimación de Kaplan-Meier , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Recurrencia , Análisis de Supervivencia , Trasplante Homólogo
5.
Leukemia ; 38(6): 1315-1322, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38744919

RESUMEN

Minimal/measurable residual disease (MRD) diagnostics using real-time quantitative PCR analysis of rearranged immunoglobulin and T-cell receptor gene rearrangements are nowadays implemented in most treatment protocols for patients with acute lymphoblastic leukemia (ALL). Within the EuroMRD Consortium, we aim to provide comparable, high-quality MRD diagnostics, allowing appropriate risk-group classification for patients and inter-protocol comparisons. To this end, we set up a quality assessment scheme, that was gradually optimized and updated over the last 20 years, and that now includes participants from around 70 laboratories worldwide. We here describe the design and analysis of our quality assessment scheme. In addition, we here report revised data interpretation guidelines, based on our newly generated data and extensive discussions between experts. The main novelty is the partial re-definition of the "positive below quantitative range" category by two new categories, "MRD low positive, below quantitative range" and "MRD of uncertain significance". The quality assessment program and revised guidelines will ensure reproducible and accurate MRD data for ALL patients. Within the Consortium, similar programs and guidelines have been introduced for other lymphoid diseases (e.g., B-cell lymphoma), for new technological platforms (e.g., digital droplet PCR or Next-Generation Sequencing), and for other patient-specific MRD PCR-based targets (e.g., fusion genes).


Asunto(s)
Neoplasia Residual , Humanos , Neoplasia Residual/genética , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Reordenamiento Génico , Garantía de la Calidad de Atención de Salud , Guías de Práctica Clínica como Asunto/normas , Genes de Inmunoglobulinas , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Reacción en Cadena en Tiempo Real de la Polimerasa/normas
6.
Biol Blood Marrow Transplant ; 19(11): 1632-7, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23850653

RESUMEN

Patients with relapsed or refractory advanced T cell non-Hodgkin lymphoma have a dismal prognosis and may not even reach allogeneic hematopoietic stem cell transplantation (HSCT) in adequate condition. We present the outcome of 24 consecutive patients (age range 11 to 65 years) treated at a single institution in Kiel within a recent 5.5-year time frame with allogeneic HSCT in a rather uniform approach. Relapsed and refractory T and natural killer cell lymphomas of various subtypes were included. All patients except 1 were in progression or relapse before start of pretransplantation salvage therapy. Five patients had relapsed after autologous HSCT. With intensive remission induction therapy, usually the CLAEG (cladribine, cytosine arabinoside, and etoposide with granulocyte colony-stimulating factor support) protocol, attempts were made to improve disease control and proceed immediately to conditioning with carmustine, etoposide, cytosine arabinoside, melphalan (BEAM), and medium-dose alemtuzumab. Twenty of 21 patients who received CLAEG induction therapy benefited from this protocol and 1 patient appeared to be therapy-resistant. At the time of allogeneic HSCT, 9 patients were in complete remission (CR) (2 in CR1, 5 in CR2, and 2 in CR >2), whereas 50% had never achieved CR. Nineteen transplants were obtained from matched or partially matched unrelated donors and only 5 from siblings. With a median follow-up of 321 days (1252 days for surviving patients), 20 of 22 assessable patients reached CR. Five of these patients had hematologic or molecular relapse. With donor lymphocyte infusions, 1 patient became minimal residual disease MRD negative again and has maintained CR for more than 4 years. The frequency of grades II to IV acute graft-versus-host disease was 25% and chronic graft-versus-host disease, 30%. Intense reinduction therapy followed by reduced-intensity BEAM-alemtuzumab conditioning and allogeneic HSCT is effective and offers curative potential for patients with advanced T cell lymphomas, even for those not in remission.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Linfoma de Células T/terapia , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Alemtuzumab , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carmustina/administración & dosificación , Niño , Citarabina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/cirugía , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Inducción de Remisión , Quimera por Trasplante , Acondicionamiento Pretrasplante/efectos adversos , Trasplante Homólogo
7.
Mol Med ; 18: 138-45, 2012 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-21968789

RESUMEN

The frequent occurrence of stereotyped heavy complementarity-determining region 3 (VH CDR3) sequences among unrelated cases with chronic lymphocytic leukemia (CLL) is widely taken as evidence for antigen selection. Stereotyped VH CDR3 sequences are often defined by the selective association of certain immunoglobulin heavy diversity (IGHD) genes in specific reading frames with certain immunoglobulin heavy joining (IGHJ ) genes. To gain insight into the mechanisms underlying VH CDR3 restrictions and also determine the developmental stage when restrictions in VH CDR3 are imposed, we analyzed partial IGHD-IGHJ rearrangements (D-J) in 829 CLL cases and compared the productively rearranged D-J joints (that is, in-frame junctions without junctional stop codons) to (a) the productive immunoglobulin heavy variable (IGHV )-IGHD-IGHJ rearrangements (V-D-J) from the same cases and (b) 174 D-J rearrangements from 160 precursor B-cell acute lymphoblastic leukemia cases (pre-B acute lymphoblastic leukemia [ALL]). Partial D-J rearrangements were detected in 272/829 CLL cases (32.8%). Sequence analysis was feasible in 238 of 272 D-J rearrangements; 198 of 238 (83.2%) were productively rearranged. The D-J joints in CLL did not differ significantly from those in pre-B ALL, except for higher frequency of the IGHD7-27 and IGHJ6 genes in the latter. Among CLL carrying productively rearranged D-J, comparison of the IGHD gene repertoire in productive V-D-J versus D-J revealed the following: (a) overuse of IGHD reading frames encoding hydrophilic peptides among V-D-J and (b) selection of the IGHD3-3 and IGHD6-19 genes in V-D-J junctions. These results document that the IGHD and IGHJ gene biases in the CLL expressed VH CDR3 repertoire are not stochastic but are directed by selection operating at the immunoglobulin protein level.


Asunto(s)
Reordenamiento Génico de Cadena Pesada de Linfocito B/genética , Genes de las Cadenas Pesadas de las Inmunoglobulinas/genética , Leucemia Linfocítica Crónica de Células B/genética , Receptores de Antígenos de Linfocitos B/genética , Regiones Determinantes de Complementariedad/genética , Humanos , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN
8.
Blood ; 113(17): 4011-5, 2009 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-19144982

RESUMEN

MLL translocations in adult B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) are largely restricted to the immature CD10(-) immunophenotypes. MLL-AF4 is known to be the most frequent fusion transcript, but the exact frequencies of MLL aberrations in CD10(-) adult BCP-ALL are unknown. We present a genetic characterization of 184 BCR-ABL(-) CD10(-) adult ALL cases (156 cyIg(-), 28 cyIg(+)) diagnosed between 2001 and 2007 at the central diagnostic laboratory of the GMALL study group. Patient samples were investigated by RT-PCR for MLL-AF4, MLL-ENL, and MLL-AF9 and by long-distance inverse polymerase chain reaction, thus also allowing the identification of unknown MLL fusion partners at the genomic level. MLL-AF4 was detected in 101 (54.9%) and MLL-ENL in 11 (6.0%) cases. In addition, rare MLL fusion genes were found: 2 MLL-TET1 cases, not previously reported in ALL, 1 MLL-AF9, 1 MLL-PTD, a novel MLL-ACTN4, and an MLL-11q23 fusion. Chromosomal breakpoints were determined in all 118 positive cases, revealing 2 major breakpoint cluster regions in the MLL gene. Characteristic features of MLL(+) patients were significantly lower CD10 expression, expression of the NG2 antigen, a higher white blood count at diagnosis, and female sex. Proposals are made for diagnostic assessment.


Asunto(s)
Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cromosomas Humanos/genética , Femenino , N-Metiltransferasa de Histona-Lisina , Humanos , Masculino , Persona de Mediana Edad , Proteína de la Leucemia Mieloide-Linfoide/genética , Neprilisina/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Recombinantes de Fusión/genética , Sociedades Médicas
10.
J Immunol Methods ; 306(1-2): 128-36, 2005 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-16181633

RESUMEN

A single nucleotide polymorphism (SNP) of the FCGR3A gene results in two allotypes of Fcgamma receptor IIIA (FcgammaRIIIA) with valine (V) or phenylalanine (F) at amino acid 158. Since the FcgammaRIIIA-158 V/F polymorphism is associated with the efficacy of monoclonal antibody (mAb) treatment and a risk factor for autoimmune disease, widely applicable methods to assess the SNP are needed. We developed a novel flow cytometric test for this polymorphism using a mAb that recognized only the FcgammaRIIIA-158 V allele (MEM-154) together with a mAb that detected both FcgammaRIIIA-158 alleles (3G8). The expression of both FcgammaRIIIA epitopes on natural killer (NK) cells from 37 healthy donors were measured and compared to the FCGR3A genotype determined by a 5' nuclease assay. FcgammaRIIIA expression levels in individuals with identical FCGR3A genotypes varied considerably, resulting in overlapping immunofluorescences by both 3G8 and MEM-154 between FcgammaRIIIA-158 V/F allotypes. However, the ratio between fluorescences measured using those mAbs in a single individual predicted the FCGR3A genotype with 100% sensitivity and specificity. The novel flow cytometric assay for the FcgammaRIIIA-158 V/F polymorphism that is based on the MEM-154/3G8 fluorescence ratio requires commercially available reagents and a three-color flow cytometer only.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Citometría de Flujo/métodos , Células Asesinas Naturales/inmunología , Polimorfismo de Nucleótido Simple , Receptores de IgG/análisis , Receptores de IgG/genética , Alelos , Epítopos/análisis , Epítopos/genética , Epítopos/inmunología , Técnica del Anticuerpo Fluorescente , Genotipo , Humanos , Fenilalanina/genética , Receptores de IgG/inmunología , Valina/genética
11.
Best Pract Res Clin Haematol ; 15(4): 639-52, 2002 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-12617868

RESUMEN

The evaluation of minimal residual disease (MRD) is a new diagnostic method which is applicable in various malignant disorders. Acute lymphoblastic leukaemia (ALL) is a somewhat ideal disease in this respect because >90% of the patients show individual clonal markers and because several methods for MRD evaluation are already established. Futhermore, it was demonstrated that level and course of MRD are significantly correlated with relapse risk in childhood and in adult ALL. In clinical practice MRD evaluation may serve for several purposes such as follow-up of individual course of disease, identification of new prognostic factors or evaluation of single treatment elements. We discuss these options as well as general considerations for MRD-based risk stratification and treatment options for risk groups. Practical applications are analysed because prospective MRD-based clinical trials have been recently started. Finally, future options for application of MRD evaluation and also limitations and pitfalls of this method are reviewed.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Factores de Edad , Protocolos Antineoplásicos , Ensayos Clínicos como Asunto/métodos , Humanos , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Recurrencia , Inducción de Remisión , Medición de Riesgo/métodos
12.
Eur J Obstet Gynecol Reprod Biol ; 107(1): 78-80, 2003 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-12593900

RESUMEN

OBJECTIVE: To analyze the lifetime incidence of benign gynecological tumors. STUDY DESIGN: The German Cohort Study on Women's Health was launched in 1998 as historic cohort study with prospective follow up. The study ascertained self-reported information on tumors by calendar time. The incidence of benign gynecological tumors was calculated from the data of the first cohort period. RESULTS: The cohort comprised 396000 women-years of observation and 1676 benign tumors were observed. This lead to incidence estimates of 27.0, 18.6, and 23.3 per 100000 women-years of observation for all benign tumors of the uterus, ovary, and breast respectively. CONCLUSION: In absence of other data, it is reasonable to use incidence rates generated by a large cohort of German women as a best estimate for the population up to 65 years of age.


Asunto(s)
Neoplasias de los Genitales Femeninos/epidemiología , Salud de la Mujer , Adolescente , Adulto , Anciano , Neoplasias de la Mama/epidemiología , Estudios de Cohortes , Femenino , Enfermedad Fibroquística de la Mama/epidemiología , Alemania , Humanos , Leiomioma/epidemiología , Persona de Mediana Edad , Quistes Ováricos/epidemiología , Neoplasias Ováricas/epidemiología , Neoplasias Uterinas/epidemiología
13.
J Clin Oncol ; 29(18): 2493-8, 2011 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-21576633

RESUMEN

PURPOSE: Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL. PATIENTS AND METHODS: Patients with MRD persistence or relapse after induction and consolidation therapy were included. MRD was assessed by quantitative reverse transcriptase polymerase chain reaction for either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dose of 15 µg/m2/24 hours. RESULTS: Twenty-one patients were treated, of whom 16 patients became MRD negative. One patient was not evaluable due to a grade 3 adverse event leading to treatment discontinuation. Among the 16 responders, 12 patients had been molecularly refractory to previous chemotherapy. Probability for relapse-free survival is 78% at a median follow-up of 405 days. The most frequent grade 3 and 4 adverse event was lymphopenia, which was completely reversible like most other adverse events. CONCLUSION: Blinatumomab is an efficacious and well-tolerated treatment in patients with MRD-positive B-lineage ALL after intensive chemotherapy. T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse.


Asunto(s)
Anticuerpos Biespecíficos/uso terapéutico , Sistemas de Liberación de Medicamentos , Inmunoterapia/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Linfocitos T Citotóxicos/efectos de los fármacos , Adulto , Agammaglobulinemia/inducido químicamente , Anciano , Anciano de 80 o más Años , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/farmacocinética , Especificidad de Anticuerpos , Antígenos CD19/inmunología , Antígenos de Neoplasias/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , Médula Ósea/patología , Complejo CD3/inmunología , Linaje de la Célula , Terapia Combinada , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Estimación de Kaplan-Meier , Activación de Linfocitos , Linfopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Inducción de Remisión , Especificidad del Receptor de Antígeno de Linfocitos T/efectos de los fármacos , Especificidad del Receptor de Antígeno de Linfocitos T/inmunología , Linfocitos T Citotóxicos/inmunología , Adulto Joven
14.
Blood ; 109(3): 910-5, 2007 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-17023577

RESUMEN

Although levels of minimal residual disease (MRD) decrease below the detection limit in most adult patients with standard-risk acute lymphoblastic leukemia (ALL) after consolidation treatment, about 30% of these patients will ultimately relapse. To evaluate the power of MRD monitoring as an indicator of impending relapse, we prospectively analyzed postconsolidation samples of 105 patients enrolled in the German Multicenter ALL (GMALL) trial by real-time quantitative polymerase chain reaction (PCR) of clonal immune gene rearrangements. All patients were in hematologic remission, had completed first-year polychemotherapy, and tested MRD negative prior to study entry. Twenty-eight of 105 patients (27%) converted to MRD positivity thereafter, and 17 of 28 (61%) relapsed so far. Median time from molecular (MRD-positive) to clinical relapse was 9.5 months. In 15 of these patients, MRD within the quantitative range of PCR was measured in hematologic remission, and 13 of these patients (89%) relapsed after a median interval of 4.1 months. Of the 77 continuously MRD-negative patients, only 5 (6%) have relapsed. We conclude that conversion to MRD positivity during the early postconsolidation phase in adult standard-risk ALL patients is highly predictive of subsequent hematologic relapse. As a result of the study, as of spring 2006, salvage treatment in the ongoing GMALL trial is intended to be started at the time of recurrence of quantifiable MRD.


Asunto(s)
Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos como Asunto , Femenino , Estudios de Seguimiento , Reordenamiento Génico , Humanos , Masculino , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular , Neoplasia Residual/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Valor Predictivo de las Pruebas , Estudios Prospectivos , Recurrencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Terapia Recuperativa
15.
Blood ; 107(6): 2271-8, 2006 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-16332971

RESUMEN

To evaluate the prognostic impact of minimal residual disease (MRD), quantitative real-time polymerase chain reaction (RQ-PCR) of clonal IGH rearrangements was performed in 29 patients with mantle cell lymphoma (MCL) treated with high-dose radiochemotherapy and autologous stem cell transplantation (ASCT). Fourteen of 27 patients evaluable for MRD after ASCT achieved complete clinical and molecular remission, whereas 13 patients had detectable MRD within the first year after ASCT. Molecular remission after ASCT was strongly predictive for improved outcome, with a median progression-free survival (PFS) of 92 months in the MRD-negative group compared with 21 months in the MRD-positive group (P < .001). Median overall survival (OS) was 44 months in the MRD-positive group and has not been reached in the MRD-negative group (P < .003). In multivariate analysis, molecular remission and bulky disease were independent prognostic factors for PFS (P = .001 and P = .021, respectively). While cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP)-like cytoreduction had only modest influence, ara-C-containing mobilization and myeloablative radiochemotherapy significantly reduced MRD. Quantitative MRD measured in the stem cell products of 27 patients was not predictive for molecular remission. We conclude that sequential quantitative monitoring of residual disease after ASCT is a powerful indicator for treatment outcome in MCL and defines subgroups of patients with a significantly different prognosis.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Trasplante de Células Madre Hematopoyéticas , Linfoma de Células del Manto/diagnóstico , Neoplasia Residual/diagnóstico , Valor Predictivo de las Pruebas , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Linfoma de Células del Manto/mortalidad , Masculino , Métodos , Persona de Mediana Edad , Pronóstico , Inducción de Remisión , Análisis de Supervivencia , Trasplante Autólogo , Resultado del Tratamiento
16.
Blood ; 107(3): 1116-23, 2006 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-16195338

RESUMEN

Adult patients with acute lymphoblastic leukemia (ALL) who are stratified into the standard-risk (SR) group due to the absence of adverse prognostic factors relapse in 40% to 55% of the cases. To identify complementary markers suitable for further treatment stratification in SR ALL, we evaluated the predictive value of minimal residual disease (MRD) and prospectively monitored MRD in 196 strictly defined SR ALL patients at up to 9 time points in the first year of treatment by quantitative polymerase chain reaction (PCR). Frequency of MRD positivity decreased from 88% during early induction to 13% at week 52. MRD was predictive for relapse at various follow-up time points. Combined MRD information from different time points allowed definition of 3 risk groups (P < .001): 10% of patients with a rapid MRD decline to lower than 10(-4) or below detection limit at day 11 and day 24 were classified as low risk and had a 3-year relapse rate (RR) of 0%. A subset of 23% with an MRD of 10(-4) or higher until week 16 formed the high-risk group, with a 3-year RR of 94% (95% confidence interval [CI] 83%-100%). The remaining patients whose RR was 47% (31%-63%) represented the intermediate-risk group. Thus, MRD quantification during treatment identified prognostic subgroups within the otherwise homogeneous SR ALL population who may benefit from individualized treatment.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Adolescente , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasia Residual , Proyectos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento
17.
Eur J Haematol ; 74(4): 353-8, 2005 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15777349

RESUMEN

OBJECTIVES: Classical mantle cell lymphoma (MCL) and its blastoid variant (MCL-BV) are characterized by an extremely poor prognosis. Long-time survivors are rare, only very few patients with an overall survival over 10 years have been reported. We present a case of a 41-year-old male with a 12 yr history of MCL stage I to show, that very late relapses in MCL are possible and may present as a transformation into an aggressive blastoid variant and to illustrate the value of quantitative minimal residual disease (MRD) monitoring for treatment guidance. METHODS: Diagnostic lymph node and bone marrow samples were investigated by immunohistochemistry. Clonality analysis was performed by immunoglobulin heavy chain gene (IGVH) and t(11;14) PCR. The MRD assessment was done by real-time quantitative PCR (RQ-PCR) on available follow-up samples. RESULTS: By histologic review and sequencing of the clonal IGVH and t(11;14) PCR products we demonstrated a common clonal origin of the leucemic MCL-BV and the classical MCL diagnosed 12 yr earlier. Quantitative MRD assessment revealed significant MRD levels after intensive conventional chemotherapy including Rituximab. Therefore, treatment was early intensified by myeloablative radio-chemotherapy and allogeneic peripheral stem cell transplantation from an unrelated HLA-identical donor. This did not translate into a sustained remission as reflected by persisting MRD levels after transplantation and the patient died from rapid progressive disease 3.5 months after transplant. CONCLUSION: This report presents a rare case of long-term survivor of MCL with a progression of the original MCL cell clone to MCL-BV and demonstrates the clinical value of quantitative MRD assessment for optimized therapeutic management.


Asunto(s)
Linfoma de Células del Manto/patología , Adulto , Secuencia de Bases , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 14/genética , ADN de Neoplasias/genética , Resultado Fatal , Genes de Inmunoglobulinas , Humanos , Linfoma de Células del Manto/etiología , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/terapia , Masculino , Trasplante de Células Madre de Sangre Periférica , Factores de Tiempo , Translocación Genética
18.
Blood ; 104(8): 2600-2, 2004 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-15205268

RESUMEN

The aim of this study was to investigate if graft-versus-leukemia (GVL) activity conferred by allogeneic stem cell transplantation (allo-SCT) is effective in chronic lymphocytic leukemia (CLL) with unmutated V(H) gene status. The kinetics of residual disease (MRD) were measured by quantitative allele-specific immunoglobulin heavy chain (IgH) polymerase chain reaction (PCR) in 9 patients after nonmyeloablative allo-SCT for unmutated CLL. Despite an only modest decrease in the early posttransplantation phase, MRD became undetectable in 7 of 9 patients (78%) from day +100 onwards subsequent to chronic graft-versus-host disease or donor lymphocyte infusions. With a median follow-up of 25 months (range, 14-37 months), these 7 patients remain in continuous clinical and molecular remission. In contrast, PCR negativity was achieved in only 6 of 26 control patients (23%) after autologous SCT for unmutated CLL and it was not durable. Taken together, this study shows for the first time that GVL-mediated immunotherapy might be effective in CLL with unmutated V(H).


Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Inmunoterapia/métodos , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/terapia , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Adulto , Femenino , Humanos , Cinética , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Persona de Mediana Edad , Neoplasia Residual/inmunología , Reacción en Cadena de la Polimerasa , Trasplante de Células Madre , Inmunología del Trasplante , Trasplante Homólogo/inmunología
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