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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10-3 and 36/67 (53%) and 53/67 (79%) at 10-4BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL.
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Proteínas de Fusión bcr-abl/genética , Cromosoma Filadelfia , Guías de Práctica Clínica como Asunto , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Consenso , Humanos , Neoplasia Residual , ARN Mensajero/análisisAsunto(s)
Antineoplásicos/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Ácidos Hidroxámicos/uso terapéutico , Indoles/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Adulto , Anciano , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Panobinostat , Adulto JovenRESUMEN
Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with <30% blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN+AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5% (95% CI, 14.6-43.9%)) vs AZA (14.3% (5.4-28.5%)). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60% (50-80%); AZA, 70% (50-80%)) or time to progression (PAN+AZA, 70% (40-90%); AZA, 70% (40-80%)). More grade 3/4 adverse events (97.4 vs 81.0%) and on-treatment deaths (13.2 vs 4.8%) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/patología , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/patología , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azacitidina/administración & dosificación , Médula Ósea/patología , Femenino , Humanos , Ácidos Hidroxámicos/administración & dosificación , Indoles/administración & dosificación , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidad , Leucemia Mielomonocítica Crónica/mortalidad , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Panobinostat , Resultado del TratamientoRESUMEN
BACKGROUND: Ertumaxomab (ertu) is a bispecific, trifunctional antibody targeting Her2/neu, CD3 and the Fcγ-receptors I, IIa, and III forming a tri-cell complex between tumor cell, T cell and accessory cells. METHODS: Patients (pts) with Her2/neu (1+/SISH positive, 2+ and 3+) expressing tumors progressing after standard therapy were treated to investigate safety, tolerability and preliminary efficacy. In this study, ertu was applied i.v. in 2 cycles following a predefined dose escalating scheme. Each cycle consisted of five ascending doses (10-500 µg) applied weekly within 28 days with a 21 day treatment-free interval. If 2 pts experienced a dose limiting toxicity (DLT) at a given dose level, the maximum tolerated dose (MTD) had been exceeded. RESULTS: Fourteen heavily pretreated pts (e.g. breast, rectal, gastric cancer) were enrolled in the four main cohorts. Three (21 %) pts had to be replaced. Two serious adverse events (SAE) with possible relation to the investigational drug were seen, both fully reversible. A DLT was not detected. Consequently, the MTD could not be determined. All adverse events (AE) were transient and completely reversible. Most frequent AEs were fatigue (14/14), pain (13/14), cephalgia (12/14), chills (11/14), nausea (8/14), fever (7/14), emesis (7/14) and diarrhea (5/14). Single doses up to 300 µg were well tolerated (total dose up to 800 µg per cycle). We observed one partial remission and two disease stabilizations after first treatment cycle. CONCLUSIONS: Single doses up to 300 µg could be safely administered in an escalating dose scheme. Immunological responses and clinical activity warrant further evaluation in patients with Her2 over expressing tumors. TRIAL REGISTRATION: EudraCT number: 2011-003201-14; ClinicalTrials.gov identifier: NCT01569412.
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Anticuerpos Monoclonales/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Administración Intravenosa , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Neoplasias de la Mama/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Neoplasias del Recto/metabolismo , Neoplasias Gástricas/metabolismo , Resultado del TratamientoRESUMEN
Targeting BCR/ABL with tyrosine kinase inhibitors (TKIs) is a proven concept for the treatment of Philadelphia chromosome-positive (Ph+) leukemias. Resistance attributable to either kinase mutations in BCR/ABL or nonmutational mechanisms remains the major clinical challenge. With the exception of ponatinib, all approved TKIs are unable to inhibit the 'gatekeeper' mutation T315I. However, a broad spectrum of kinase inhibition increases the off-target effects of TKIs and may be responsible for cardiovascular issues of ponatinib. Thus, there is a need for more selective options for the treatment of resistant Ph+ leukemias. PF-114 is a novel TKI developed with the specifications of (i) targeting T315I and other resistance mutations in BCR/ABL; (ii) achieving a high selectivity to improve safety; and (iii) overcoming nonmutational resistance in Ph+ leukemias. PF-114 inhibited BCR/ABL and clinically important mutants including T315I at nanomolar concentrations. It suppressed primary Ph+ acute lymphatic leukemia-derived long-term cultures that either displayed nonmutational resistance or harbor the T315I. In BCR/ABL- or BCR/ABL-T315I-driven murine leukemia as well as in xenograft models of primary Ph+ leukemia harboring the T315I, PF-114 significantly prolonged survival to a similar extent as ponatinib. Our work supports clinical evaluation of PF-114 for the treatment of resistant Ph+ leukemia.
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Antineoplásicos/farmacología , Proteínas de Fusión bcr-abl/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación , Piridinas/farmacología , Triazoles/farmacología , Animales , Antígenos Ly/metabolismo , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Análisis Mutacional de ADN , Femenino , Humanos , Imidazoles/farmacología , Concentración 50 Inhibidora , Células K562 , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Mutagénesis , Mutación Puntual , Proteínas Proto-Oncogénicas c-kit/metabolismo , Piridazinas/farmacología , Translocación Genética , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa 3 Similar a fms/metabolismoAsunto(s)
Transfusión Sanguínea , Eritropoyetina/uso terapéutico , Ácidos Hidroxámicos/uso terapéutico , Indoles/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Administración Oral , Eritropoyetina/administración & dosificación , Humanos , Ácidos Hidroxámicos/administración & dosificación , Indoles/administración & dosificación , PanobinostatRESUMEN
Panobinostat is a potent oral pandeacetylase inhibitor that leads to acetylation of intracellular proteins, inhibits cellular proliferation and induces apoptosis in leukemic cell lines. A phase Ia/II study was designed to determine the maximum-tolerated dose (MTD) of daily panobinostat, administered on two schedules: three times a week every week or every other week on a 28-day treatment cycle in patients with advanced hematologic malignancies. The criteria for hematologic dose-limiting toxicities differed between patients with indications associated with severe cytopenias at baseline (leukemia and myeloid disorders) and those less commonly associated with baseline cytopenias (lymphoma and myeloma). In patients with leukemia and myeloid disorders, 60 mg was the MTD for weekly as well as biweekly panobinostat. In patients with lymphoma and myeloma, 40 mg was the recommended dose for phase II evaluation (formal MTD not determined) of weekly panobinostat, and 60 mg was the MTD for biweekly panobinostat. Overall, panobinostat-related grade 3-4 adverse events included thrombocytopenia (41.5%), fatigue (21%) and neutropenia (21%). Single-agent activity was observed in several indications, including Hodgkin lymphoma and myelofibrosis. This phase Ia/II study provided a broad analysis of the safety profile and efficacy of single-agent panobinostat in patients with hematologic malignancies.
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Antineoplásicos/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/uso terapéutico , Ácidos Hidroxámicos/uso terapéutico , Indoles/uso terapéutico , Acetilación , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Esquema de Medicación , Femenino , Neoplasias Hematológicas/diagnóstico , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Histonas/metabolismo , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/efectos adversos , Indoles/administración & dosificación , Indoles/efectos adversos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Panobinostat , Resultado del Tratamiento , Adulto JovenRESUMEN
Minimal residual disease (MRD) after allogeneic stem cell transplantation (SCT) for Ph+ acute lymphoblastic leukemia (ALL) is predictive of relapse. Imatinib administration subsequent to SCT may prevent relapse, but the role of scheduling and its impact on outcome are not known. In a prospective, randomized multicenter trial, we compared the tolerability and efficacy of post-transplant imatinib administered either prophylactically (arm A; n=26) or following detection of MRD (arm B; n=29). Prophylactic imatinib significantly reduced the incidence of molecular recurrence after SCT compared with MRD-triggered imatinib (40% vs 69%; P=0.046). Median duration of PCR negativity was 26.5 and 6.8 months, respectively (P=0.065). Five-year survival in both interventional groups was high (80 and 74.5%), despite premature discontinuation of imatinib in the majority of patients because of poor tolerability. Relapse probability was significantly higher in patients who became MRD positive (P=0.017). In conclusion, post-transplant imatinib results in a low relapse rate, durable remissions and excellent long-term outcome in patients with BCR-ABL1-positive ALL irrespective of whether it is given prophylactically or MRD-triggered. Reappearance of BCR-ABL1 transcripts early after SCT or at higher levels identifies a small subset of patients who do not benefit sufficiently from imatinib, and in whom alternative approaches should be explored.
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Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Neoplasia Residual , Piperazinas/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pirimidinas/uso terapéutico , Trasplante de Células Madre , Adolescente , Adulto , Antineoplásicos/efectos adversos , Benzamidas/efectos adversos , Terapia Combinada , Femenino , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Piperazinas/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pirimidinas/efectos adversos , Análisis de Supervivencia , Adulto JovenRESUMEN
The purpose was to assess predictive factors for outcome in patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP) treated with nilotinib after imatinib failure. Imatinib-resistant and -intolerant patients with CML-CP (n=321) were treated with nilotinib 400 mg twice daily. Of 19 baseline patient and disease characteristics and two response end points analyzed, 10 independent prognostic factors were associated with progression-free survival (PFS). In the multivariate analysis, major cytogenetic response (MCyR) within 12 months, baseline hemoglobin ≥ 120 g/l, baseline basophils <4%, and absence of baseline mutations with low sensitivity to nilotinib were associated with PFS. A prognostic score was created to stratify patients into five groups (best group: 0 of 3 unfavorable risk factors and MCyR by 12 months; worst group: 3 of 3 unfavorable risk factors and no MCyR by 12 months). Estimated 24-month PFS rates were 90%, 79%, 67% and 37% for patients with prognostic scores of 0, 1, 2 and 3, respectively, (no patients with score of 4). Even in the presence of poor disease characteristics, nilotinib provided significant clinical benefit in patients with imatinib-resistant or -intolerant CML. This system may yield insight on the prognosis of patients.
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Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Resistencia a Antineoplásicos , Femenino , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/fisiopatología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Adulto JovenRESUMEN
Nilotinib (Tasigna) is a BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (CML-CP) who are newly diagnosed or intolerant of or resistant to imatinib. The 48-month follow-up data for patients with CML-CP treated with nilotinib after imatinib resistance or intolerance on an international phase II study were analyzed. Overall, 59% of patients achieved major cytogenetic response; 45% achieved complete cytogenetic response while on study. The estimated rate of overall survival (OS) and progression-free survival (PFS) at 48 months was 78% and 57%, respectively. Deeper levels of molecular responses at 3 and 6 months were highly positively correlated with long-term outcomes, including PFS and OS at 48 months. Of the 321 patients initially enrolled in the study, 98 (31%) were treated for at least 48 months. Discontinuations were primarily due to disease progression (30%) or adverse events (21%). Nilotinib is safe and effective for long-term use in responding patients with CML-CP who are intolerant of or resistant to imatinib. Further significant improvements in therapy are required for patients who are resistant or intolerant to imatinib.
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Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Terapia Recuperativa , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Benzamidas , Femenino , Estudios de Seguimiento , Humanos , Mesilato de Imatinib , Agencias Internacionales , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
MK-0457, an Aurora kinase and BCR-ABL inhibitor, was studied on a Phase I/II study in 77 patients with refractory hematologic malignancies. The average number of cycles per patient was 3 (range 1-21). Maximum tolerated doses for a 5-day short infusion and continuous infusion regimens were 40 mg/m(2)/h and 144 mg/m(2)/h, respectively. Drug-related adverse events (AEs) included transient mucositis and alopecia. Eight of 18 patients with BCR-ABL T315I-mutated chronic myelogenous leukemia (44%) had hematologic responses and one of three patients (33%) with Philadelphia chromosome-positive acute lymphoblastic leukemia obtained complete remission. MK-0457 has important activity in patients with leukemias expressing the highly resistant T315I BCR-ABL mutation.
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Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Mutación/genética , Piperazinas/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Aurora Quinasas , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pronóstico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Inducción de Remisión , Adulto JovenAsunto(s)
Antineoplásicos/uso terapéutico , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Recurrencia , Adulto JovenRESUMEN
Imatinib is highly effective in newly diagnosed, but not in relapsed, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). BCR-ABL tyrosine kinase domain (TKD) mutations are associated with acquired imatinib resistance, but their role in primary resistance is uncertain. Using highly sensitive ligation-PCR and denaturing high-performance liquid chromatography (DHPLC), we identified baseline TKD mutations in 21% and 42% of imatinib-naïve patients with newly diagnosed (n=26) or recurrent (n=65) Ph+ ALL, respectively (P=ns). Within 4 weeks of starting the imatinib treatment, absolute levels of mutant bcr-abl transcripts increased significantly in patients with advanced, but not with de novo, Ph+ ALL. The net expansion of pre-existing mutant clones during imatinib treatment resulted in the rapid appearance of initially undetectable TKD mutations, which after 4 weeks were detectable in 70% of patients with advanced disease. There was a high degree of concordance between the type of mutations detected at relapse and during initial imatinib treatment. The profoundly different outgrowth dynamics of leukemic clones with bcr-abl mutations in imatinib-treated patients who differ in their disease history, provides clinical-translational evidence for a contributory role of non-mutational resistance mechanisms, possibly induced by prior chemotherapy. Moreover, the prevalence of pre-existing, clinically relevant TKD may have been underestimated in tyrosine kinase inhibitor-naïve patients with Ph+ ALL.
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Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/genética , Mutación/genética , Recurrencia Local de Neoplasia/genética , Piperazinas/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Benzamidas , Ensayos Clínicos Fase II como Asunto , Femenino , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/epidemiología , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Prevalencia , Pronóstico , Estudios Prospectivos , ARN Mensajero/genética , Ensayos Clínicos Controlados Aleatorios como Asunto , Reacción en Cadena en Tiempo Real de la Polimerasa , Inducción de Remisión , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto JovenRESUMEN
Tyrosine kinase inhibitors (TKIs) directed against the ABL kinase are now used routinely during frontline therapy for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) and result in hematologic remission rates exceeding 90%. Minimal residual disease levels are generally lower when TKIs are used in combination with chemotherapy rather than as monotherapy. Although outcome has improved substantially with TKI-based regimens compared with historic controls, allogeneic stem cell transplantation (SCT) in first remission provides the best chance of cure for the majority of patients eligible for SCT. Administration of imatinib after SCT further reduces molecular recurrence and is associated with greatly improved relapse-free and overall survival. The high relapse rate in non-transplanted patients is largely attributable to the emergence of leukemic clones with mutations in the tyrosine kinase domain of BCR-ABL. Ongoing studies with newer TKIs will determine whether these more potent agents are able to sustain remissions without SCT. Assessment of minimal residual disease has become an integral part of the management of Ph+ALL, as it has prognostic importance and is used to guide therapeutic intervention. Novel immunotherapeutic interventions and combinations of TKIs are currently being investigated in clinical trials and may further improve the prognosis of patients with Ph+ALL.
RESUMEN
Nilotinib is a selective inhibitor of BCR-ABL approved for use in newly diagnosed and imatinib-resistant or -intolerant patients with chronic myeloid leukemia (CML) in chronic phase. In this study, 400 mg of nilotinib was administered twice daily to the patients with myeloid (MBP, n=105) or lymphoid blastic phase (LBP, n=31) CML. After a minimum follow-up of 24 months, major hematologic responses were observed in 60% (MBP) and 59% (LBP) of patients. Major cytogenetic responses (MCyR) were attained in 38% (MBP) and 52% (LBP) of patients; and complete cytogenetic responses in 30% and 32%, respectively. Median duration of MCyR was 10.8 (MBP) and 3.2 months (LBP). Median overall survival was 10.1 (MBP) and 7.9 (LBP) months with 12- and 24-month survival of 42% (MBP 44%, LBP 35%) and 27% (MBP 32%, LBP 10%), respectively. Twelve MBP patients and two LBP patients received subsequent stem cell transplantation. Myelosuppression was frequent, with grade 3/4 neutropenia, thrombocytopenia, and anemia in 68%, 63% and 47% of patients, respectively. Grade 3/4 hypophosphatemia, hyperbilirubinemia and lipase elevation were observed in 15%, 11% and 11% of patients, respectively. Nilotinib has significant efficacy in patients with BP CML, but given the limited long-term survival of these patients, novel agents are needed.
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Antineoplásicos/uso terapéutico , Crisis Blástica , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Piperazinas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Antineoplásicos/efectos adversos , Benzamidas , Resistencia a Antineoplásicos , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Persona de Mediana Edad , Pirimidinas/efectos adversos , Análisis de Supervivencia , Adulto JovenRESUMEN
Assessment of minimal residual disease (MRD) has acquired a prominent position in European treatment protocols for patients with acute lymphoblastic leukemia (ALL), on the basis of its high prognostic value for predicting outcome and the possibilities for implementation of MRD diagnostics in treatment stratification. Therefore, there is an increasing need for standardization of methodologies and harmonization of terminology. For this purpose, a panel of representatives of all major European study groups on childhood and adult ALL and of international experts on PCR- and flow cytometry-based MRD assessment was built in the context of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008. The panel summarized the current state of MRD diagnostics in ALL and developed recommendations on the minimal technical requirements that should be fulfilled before implementation of MRD diagnostics into clinical trials. Finally, a common terminology for a standard description of MRD response and monitoring was established defining the terms 'complete MRD response', 'MRD persistence' and 'MRD reappearance'. The proposed MRD terminology may allow a refined and standardized assessment of response to treatment in adult and childhood ALL, and provides a sound basis for the comparison of MRD results between different treatment protocols.
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Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Citometría de Flujo , Proteínas de Fusión bcr-abl/genética , Reordenamiento Génico , Genes de Inmunoglobulinas , Humanos , Neoplasia Residual/diagnóstico , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaRESUMEN
This article describes studies that investigated the pharmacokinetics of nilotinib, a highly specific, oral, second-generation BCR-ABL tyrosine kinase inhibitor. After a once- or twice-daily regimen at doses ranging from 50 to 1,200 mg/day in 119 patients with chronic myeloid leukemia (CML), the area under the serum concentration-time curve (AUC) and peak serum concentration (C(max)) of nilotinib were found to be nearly dose proportional up to a dose of 400 mg once daily. Solubility-limited absorption at higher doses was observed, but this was partially overcome by dividing the daily dose into two. For instance, the administration of 400 mg nilotinib twice daily resulted in a 35% increase in AUC as compared to a once-daily dose of 800 mg. Exploratory pharmacodynamic assessment showed a general trend of greater reduction in white blood cell (WBC) levels with increase in nilotinib concentrations. This finding was consistent with the observation of an 82% reduction in WBC levels in patients after a regimen of 400 mg nilotinib twice daily for 15 days. The type and quantity of food intake variably affected nilotinib absorption. When administered after a high-fat meal, the AUC of nilotinib increased by 50% in CML patients (n = 10) and by 82% in healthy volunteers (n = 44).
Asunto(s)
Antineoplásicos/farmacocinética , Interacciones Alimento-Droga , Proteínas de Fusión bcr-abl/farmacocinética , Proteínas Tirosina Quinasas/farmacocinética , Pirimidinas/farmacocinética , Administración Oral , Adulto , Anciano , Antineoplásicos/administración & dosificación , Área Bajo la Curva , Grasas de la Dieta , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Proteínas de Fusión bcr-abl/administración & dosificación , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Proteínas Tirosina Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Solubilidad , Adulto JovenRESUMEN
The t(9;22) translocation leads to the formation of the chimeric bcr/abl fusion gene, which encodes the BCR/ABL fusion protein. In contrast to its physiological counterpart c-ABL, the BCR/ABL kinase is constitutively activated, inducing the leukemic phenotype. The N-terminus of c-ABL (Cap region) contributes to the regulation of its kinase function. It is myristoylated, and the myristate residue binds to a hydrophobic pocket in the kinase domain known as the myristoyl-binding pocket in a process called 'capping', which results in an auto-inhibited conformation. Because the cap region is replaced by the N-terminus of BCR, the BCR/ABL 'escapes' this auto-inhibition. Allosteric inhibition by myristate 'mimics', such as GNF-2, is able to inhibit unmutated BCR/ABL, but not the BCR/ABL that harbors the 'gatekeeper' mutation T315I. In this study, we analyzed the possibility of increasing the efficacy of allosteric inhibition by blocking BCR/ABL oligomerization. We showed that inhibition of oligomerization was able to not only increase the efficacy of GNF-2 on unmutated BCR/ABL, but also overcome the resistance of BCR/ABL-T315I to allosteric inhibition. These results strongly suggest that the response to allosteric inhibition by GNF-2 is inversely related to the degree of oligomerization of BCR/ABL. In summary, our observations establish a new approach for the molecular targeting of BCR/ABL and its resistant mutants represented by the combination of oligomerization and allosteric inhibitors.