RESUMO
Ruxolitinib is beneficial in patients with myelofibrosis (MF) and polycythemia vera (PV). Information on ruxolitinib adherence is scant. The Ruxolitinib Adherence in Myelofibrosis and Polycythemia Vera (RAMP) prospective multicenter study (NCT06078319) included 189 ruxolitinib-treated patients. Patients completed the Adherence to Refills and Medications Scale (ARMS) and Distress Thermometer and Problem List (DTPL) at the earliest convenience, after registration in the study, and at later timepoints. At week-0, low adherence (ARMS > 14) and high distress (DT ≥ 4) were declared by 49.7% and 40.2% of patients, respectively. The main reason for low adherence was difficult ruxolitinib supply (49%), intentional (4.3%) and unintentional (46.7%) non-take. In multivariable regression analysis, low adherence was associated to male sex (p = 0.001), high distress (p < 0.001), and treatment duration ≥ 1 year (p = 0.03). Over time, rates of low adherence and high distress remained stable, but unintentional non-take decreased from 47.9% to 26.0% at week-48. MF patients with stable high adherence/low distress were more likely to obtain/maintain the spleen response at week-24. Low adherence to ruxolitinib represents an unmet clinical need that require a multifaceted approach, based on reason behind it (patients characteristics and treatment duration). Its recognition may help distinguishing patients who are truly refractory and those in need of therapy optimization.
Assuntos
Adesão à Medicação , Nitrilas , Policitemia Vera , Mielofibrose Primária , Pirazóis , Pirimidinas , Humanos , Mielofibrose Primária/tratamento farmacológico , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Masculino , Policitemia Vera/tratamento farmacológico , Feminino , Estudos Prospectivos , Idoso , Pessoa de Meia-Idade , Itália/epidemiologia , Adesão à Medicação/estatística & dados numéricos , Idoso de 80 Anos ou mais , AdultoRESUMO
BACKGROUND: Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). METHODS: We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. RESULTS: Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event. CONCLUSIONS: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).
Assuntos
Imidazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêutico , Trombose/induzido quimicamente , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas/efeitos adversos , Trombocitopenia/induzido quimicamente , Adulto JovemRESUMO
BACKGROUND: The incidence of chronic myeloid leukemia (CML) increases with age, but it is unclear how the characteristics of the disease vary with age. In children, where CML is very rare, it presents with more aggressive features, including huge splenomegaly, higher cell count and higher blast cell percentage. PATIENTS AND METHODS: To investigate if after childhood the disease maintains or loses these characteristics of aggressiveness, we analyzed 2784 adult patients, at least 18 years old, registered by GIMEMA CML WP over a 40-year period. RESULTS: Young adults (YAs: 18-29 years old) significantly differed from adults (30-59 years old) and elderly patients (at least 60 years old) particularly for the frequency of splenomegaly (71%, 63% and 55%, P < 0.001), and the greater spleen size (median value: 4.5, 3.0 and 1.0 cm, P < 0.001). According to the EUTOS score, that is age-independent, high-risk patients were more frequent among YAs, than among adult and elderly patients (18%, 9% and 6%, P < 0.001). In tyrosine kinase inhibitors-treated patients, the rates of complete cytogenetic and major molecular response were lower in YAs, and the probability of transformation was higher (16%, 5% and 7%, P = 0.011). CONCLUSIONS: The characteristics of CML or the host response to leukemia differ with age. The knowledge of these differences and of their causes may help to refine the treatment and to improve the outcome. CLINICAL TRIAL NUMBERS: NCT00510926, NCT00514488, NCT00769327, NCT00481052.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Esplenomegalia/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Tirosina Quinases/antagonistas & inibidores , Baço/patologia , Adulto JovemRESUMO
TKIs long-term treatment in CML may lead to persistent adverse events (AEs) that can promote relevant morbidity and mortality. Consequently, TKIs dose reduction is often used to prevent AEs. However, data on its impact on successful treatment-free remission (TFR) are quite scarce. We conducted a retrospective study on the outcome of CML subjects who discontinued low-dose TKIs from 54 Italian hematology centers participating in the Campus CML network. Overall, 1.785 of 5.108 (35.0%) regularly followed CML patients were treated with low-dose TKIs, more frequently due to relevant comorbidities or AEs (1.288, 72.2%). TFR was attempted in 248 (13.9%) subjects, all but three while in deep molecular response (DMR). After a median follow-up of 24.9 months, 172 (69.4%) patients were still in TFR. TFR outcome was not influenced by gender, Sokal/ELTS risk scores, prior interferon, number and last type of TKI used prior to treatment cessation, DMR degree, reason for dose reduction or median TKIs duration. Conversely, TFR probability was significantly better in the absence of resistance to any prior TKI. In addition, patients with a longer DMR duration before TKI discontinuation (i.e., >6.8 years) and those with an e14a2 BCR::ABL1 transcript type showed a trend towards prolonged TFR. It should also be emphasized that only 30.6% of our cases suffered from molecular relapse, less than reported during full-dose TKI treatment. The use of low-dose TKIs does not appear to affect the likelihood of achieving a DMR and thus trying a treatment withdrawal, but might even promote the TFR rate.
RESUMO
INTRODUCTION: Malignancies are a well-known complication of immunosuppressive therapy among renal transplant recipients, representing an important cause of long-term morbidity and mortality. Rapamycin has been shown to limit the proliferation of a number of malignant cell lines in vivo and in vitro. METHODS: Eight patients developed the following malignancies after kidney transplantation (mean 102.6 months; range 12 to 252): metastatic gastric cancer (n = 1), metastatic colon cancer (n = 1), bilateral nephrourothelioma (n = 1), skin cancer (n = 1), Kaposi's sarcoma (n = 2), posttransplant lymphoproliferative disorder (PTLD) (n = 2). After the diagnosis of malignancy, the patients were switched from calcineurin inhibitor-based immunosuppression to rapamycin (monotherapy, n = 2), associated with steroids (n = 4) or mycophenolate mofetil (n = 2). RESULTS: Both patients with metastatic cancer underwent chemotherapy and then succummbed after 6 and 13 months. After a mean follow-up of 20.3 months (range 2 to 47), the remaining six patients are free from cancer disease. Renal graft function was unchanged from diagnosis throughout the follow-up. CONCLUSION: Our observations suggested that rapamycin-based immunosuppression offered the possibility of regression of nonmetastatic tumors. Nevertheless, it is difficult to assess whether tumor regression was attributed to Rapamycin treatment or to the reduced immunosuppression.
Assuntos
Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Neoplasias/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Sirolimo/uso terapêutico , Humanos , Neoplasias/imunologia , Neoplasias/prevenção & controleRESUMO
BACKGROUND: Although imatinib is the standard treatment for chronic myeloid leukaemia, not all patients reach complete cytogenetic remission (CCR) and most maintain detectable disease at the molecular level. We investigated whether a vaccine targeting the BCR-ABL-derived p210 fusion protein was an active and specific immunotherapy. METHODS: We recruited 16 patients who had chronic myeloid leukaemia (with the b3a2 fusion point of p210), stable residual disease, a minimum treatment of 12 months of imatinib or 24 months of interferon alfa, and no further reduction of residual disease for at least 6 months preceding enrollment. They were given six vaccinations with a peptide vaccine derived from the sequence p210-b3a2 plus molgramostim and QS-21 as adjuvants (CMLVAX100) before assessment of immunological and disease response, which included detecting amounts of b3a2 transcripts by standardised quantitative real-time reverse-transcriptase PCR. RESULTS: Of ten patients on imatinib, nine started CMLVAX100 having had a median of 10 months' stable cytogenetic disease (median 10% Philadelphia-chromosome-positive metaphases), whereas one started in stable CCR. All patients' cytogenetic responses improved after six vaccinations, with five reaching CCR. Notably, three of these five patients also had undetectable amounts of b3a2 transcript (BCR-ABL:beta2 microglobulin ratio <0.00001). Six patients on interferon alfa treatment with a median of 17 months' stable residual disease (median 13% Philadelphia-chromosome-positive cells) were also vaccinated. All but one had improved cytogenetic responses, and two reached CCR. Overall, we recorded peptide-specific delayed-type hypersensitivity (in 11 of 16 patients), CD4 cell proliferation (13 of 14 assessed), and interferon gamma production (five of five assessed). INTERPRETATION: Addition of CMLVAX100 to conventional treatment in patients with chronic myeloid leukaemia might favour further reduction of residual disease and increase the number of patients reaching a molecular response.
Assuntos
Antineoplásicos/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Proteínas de Fusão bcr-abl/imunologia , Interferon-alfa/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Idoso , Benzamidas , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Humanos , Mesilato de Imatinib , Imunoterapia , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Saponinas/administração & dosagemRESUMO
For almost 10 years imatinib has been the therapeutic standard of chronic myeloid leukemia. The introduction of other tyrosine kinase inhibitors (TKIs) raised a debate on treatment optimization. The debate is still heated: some studies have protocol restrictions or limited follow-up; in other studies, some relevant data are missing. The aim of this report is to provide a comprehensive, long-term, intention-to-treat, analysis of 559 newly diagnosed, chronic-phase, patients treated frontline with imatinib. With a minimum follow-up of 66 months, 65% of patients were still on imatinib, 19% were on alternative treatment, 12% died and 4% were lost to follow-up. The prognostic value of BCR-ABL1 ratio at 3 months (⩽10% in 81% of patients) was confirmed. The prognostic value of complete cytogenetic response and major molecular response at 1 year was confirmed. The 6-year overall survival was 89%, but as 50% of deaths occurred in remission, the 6-year cumulative incidence of leukemia-related death was 5%. The long-term outcome of first-line imatinib was excellent, also because of second-line treatment with other TKIs, but all responses and outcomes were inferior in high-risk patients, suggesting that to optimize treatment results, a specific risk-adapted treatment is needed for such patients.
Assuntos
Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Retratamento , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
The aim of this study was to investigate the effects of a non-standard, intermittent imatinib treatment in elderly patients with Philadelphia-positive chronic myeloid leukaemia and to answer the question on which dose should be used once a stable optimal response has been achieved. Seventy-six patients aged ⩾65 years in optimal and stable response with ⩾2 years of standard imatinib treatment were enrolled in a study testing a regimen of intermittent imatinib (INTERIM; 1-month on and 1-month off). With a minimum follow-up of 6 years, 16/76 patients (21%) have lost complete cytogenetic response (CCyR) and major molecular response (MMR), and 16 patients (21%) have lost MMR only. All these patients were given imatinib again, the same dose, on the standard schedule and achieved again CCyR and MMR or an even deeper molecular response. The probability of remaining on INTERIM at 6 years was 48% (95% confidence interval 35-59%). Nine patients died in remission. No progressions were recorded. Side effects of continuous treatment were reduced by 50%. In optimal and stable responders, a policy of intermittent imatinib treatment is feasible, is successful in about 50% of patients and is safe, as all the patients who relapsed could be brought back to optimal response.
Assuntos
Antineoplásicos/administração & dosagem , Mesilato de Imatinib/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Feminino , Humanos , Mesilato de Imatinib/efeitos adversos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Projetos Piloto , Indução de Remissão/métodosRESUMO
Idiopathic myelofibrosis (IM), is a chronic myeloproliferative disorder (MPD) characterised by marrow fibrosis, extramedullary haematopoiesis and a leuco-erythroblastic picture of the peripheral blood. Cytogenetic data of IM is scarce: no specific karyotypic anomalies have been yet described. Trisomy 1q, del(13q), del(20q) and trisomy 8, appear in two-thirds of the cases with chromosome aberrations. We report on a 41-year-old patient diagnosed with IM associated with eosinophilia, bearing a novel translocation t(6;10)(q27;q11) as the sole chromosome anomaly. The patient, progressed to AML-M5a within 18 months from diagnosis. Recently new specific chromosomal translocations have been described in chronic MPD. These findings have allowed the classification of new syndromes with defined molecular abnormalities. The case we describe, because of the peculiar clinical features and the association with a previously unreported chromosomal translocation, might be a noteworthy addition.
Assuntos
Eosinofilia/genética , Mielofibrose Primária/genética , Translocação Genética , Adulto , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 6/genética , Progressão da Doença , Eosinofilia/complicações , Humanos , Leucemia Monocítica Aguda/etiologia , Leucemia Monocítica Aguda/genética , Masculino , Transtornos Mieloproliferativos/etiologia , Transtornos Mieloproliferativos/genética , Mielofibrose Primária/etiologiaRESUMO
The lineage involvement in myelodysplastic syndromes (MDS) is still unclear. To determine the clonality and the evolution of the disorder, a retrospective study on bone marrow smears from seven MDS patients with trisomy 8 was performed using fluorescence in situ hybridization (FISH). We observed that the trisomy of chromosome 8 was selectively expressed in the myeloid-derived cells. No mature lymphocytes or plasma cells expressed three signals. Our studies demonstrate here the value of FISH for identifying the affected cell lineage. Furthermore, the easy quantification of the abnormal cells can help in assessing the progression of the disease.
Assuntos
Medula Óssea/patologia , Cromossomos Humanos Par 8 , Síndromes Mielodisplásicas/genética , Trissomia , Idoso , Linhagem Celular , Mapeamento Cromossômico , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Estudos Retrospectivos , Manejo de Espécimes , Células Tumorais Cultivadas , Cromossomo XRESUMO
Preclinical studies and retrospective evaluations of clinical trials of a number of cytotoxic drugs have provided a rationale for the use of high doses of chemotherapy in adults with acute myeloid leukemia (AML). To maximize cure and remission rates at an acceptable cost in toxicity, many schedules and combinations of dose-intensive chemotherapy have been tested in recent years in patients with de novo disease, cytosine arabinoside (Ara-C) being the most extensively evaluated drug. In this article we review the principal results of both randomized and non-controlled studies. Our analysis indicates that high-dose Ara-C (HIDAC) used during induction results is no substantial benefit relative to conventional doses of drug. On the other hand, consolidation with HIDAC is a major advance in the treatment of this disease. In fact, in individuals less than 60 years of age and a favorable or intermediate-risk karyotype, HIDAC-based regimens have resulted in survival estimates comparable to those of autologous or allogeneic bone marrow transplantation. Yet, the role of HIDAC is irrelevant in younger individuals with an unfavorable cytogenetic pattern and detrimental in patients greater than 60 years of age. Since recently new cytotoxic agents have expanded the armamentarium of antileukemic drugs, well conducted randomized trials of dose intensive chemotherapy still need to be performed to optimize schedules and combinations of drugs in patients with AML.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Doença Aguda , Adulto , Idoso , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ensaios Clínicos como Assunto , Citarabina/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de RemissãoRESUMO
Complex chromosome rearrangements (CCR) are rare structural rearrangements. Currently six cases of prenatally diagnosed balanced de novo CCR have been described. We present two new cases of prenatally ascertained balanced de novo CCR. In the first case, an amniocentesis revealed a balanced de novo three-way CCR involving chromosomes 5, 6, and 11 with a pericentric inversion of chromosome 5 [four breaks]. In the second case, a balanced de novo rearrangement was identified by amniocentesis which involved a reciprocal translocation between chromosomes 3 and 8 and a CCR involving chromosomes 6, 7, and 18 [six breaks]. The use of whole chromosome painting helped elucidate the nature of these rearrangements. A review of the postnatally ascertained cases suggests that most patients have congenital anomalies, minor anomalies, and/or developmental delay/mental retardation. In addition, there appears to be a relationship between the number of chromosome breaks and the extent of phenotypic effects. The paucity of information regarding prenatally diagnosed CCR and the bias of ascertainment of postnatal CCR cases poses a problem in counseling families.
Assuntos
Amniocentese , Aberrações Cromossômicas , Aberrações Cromossômicas/diagnóstico , Transtornos Cromossômicos , Adulto , Aberrações Cromossômicas/genética , Bandeamento Cromossômico , Feminino , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Masculino , GravidezRESUMO
Solitary loss of the X chromosome is associated with Turner syndrome and not hematological disorders. We describe five patients with non-constitutional loss of the X chromosome as the sole cytogenetic abnormality in their bone marrow. Three of the five patients had myelodysplastic syndrome (MDS), one case had AML M-6 with evidence suggestive of an evolving MDS, and the last patient had a dysplastic marrow. A review of the literature identified sporadic reports of an association of monosomy X and several hematologic disorders, as well as a few solid tumors. In this series of patients, monosomy X as a sole non-constitutional cytogenetic abnormality in bone marrow is associated with myelodysplastic diseases. In addition, fluorescence in situ hybridization analysis with an X centromere probe indicated that monosomy X was present in erythroid precursors, myeloblasts, promyelocytes, myelocytes, metamyelocytes, granulocytes, and monocytes, while mature lymphocytes presented with two copies of the X chromosome. The molecular cytogenetic evidence supports the diagnosis of a myelodysplastic disorder in these cases and documents the potential role of FISH in hematological disease.
Assuntos
Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Crônica/genética , Monossomia/genética , Síndromes Mielodisplásicas/genética , Cromossomo X/genética , Adulto , Idoso , Feminino , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-IdadeRESUMO
We present two cases with hidden Philadelphia translocations that resulted from an insertion and a complex translocation. These cases were unusual in having the BCR/ABL fusion localized to chromosome 9q34. A review of cases with these uncommon presentations of BCR/ABL and prognostic presentation is presented.
Assuntos
Cromossomos Humanos Par 9 , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Adolescente , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Pessoa de Meia-Idade , Cromossomo FiladélfiaAssuntos
Imunidade Celular/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Linfócitos T/imunologia , Adolescente , Adulto , Benzamidas , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Criança , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Mesilato de Imatinib , Imunização , Interferon-alfa/uso terapêutico , Linfócitos T/efeitos dos fármacosAssuntos
Análise Mutacional de DNA/métodos , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adulto , Idoso , Antineoplásicos/uso terapêutico , Feminino , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/genética , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêuticoAssuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Neoplasias Cutâneas/diagnóstico , Idoso , Benzamidas , Neoplasias Encefálicas/tratamento farmacológico , Aberrações Cromossômicas , Análise Citogenética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/análise , Doenças Hematológicas , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
Nilotinib is a highly selective Bcr-Abl inhibitor approved for imatinib-resistant chronic myeloid leukemia (CML). Nilotinib and dasatinib, a multi-targeted kinase inhibitor also approved for second-line therapy in CML, have different patterns of kinase selectivity, pharmacokinetics, and cell uptake and efflux properties, and thus patients may respond to one following failure of the other. An international phase II study of nilotinib was conducted in CML patients (39 chronic phase (CP), 21 accelerated phase (AP)) after failure of both imatinib and dasatinib. Median times from diagnosis of CP or AP to nilotinib therapy were 89 and 83 months, respectively. Complete hematological response and major cytogenetic response (MCyR) rates in CP were 79% and 43%, respectively. Of 17 evaluable patients with CML-AP, 5 (29%) had a confirmed hematological response and 2 (12%) a MCyR. The median time to progression has not yet been reached in CP patients. At 18 months 59% of patients were progression-free. Median overall survival for both populations has not been reached, and the estimated 18-month survival rate in CML-CP was 86% and that at 12 months for CML-AP was 80%. Nilotinib is an effective therapy in CML-CP and -AP following failure of both imatinib and dasatinib therapy.
Assuntos
Leucemia Mieloide de Fase Acelerada/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , Adulto , Idoso , Benzamidas , Dasatinibe , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Mesilato de Imatinib , Agências Internacionais , Leucemia Mieloide de Fase Acelerada/mortalidade , Leucemia Mieloide de Fase Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Piperazinas/uso terapêutico , Terapia de Salvação , Taxa de Sobrevida , Tiazóis/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The hematological and quality of life (QoL) changes associated with darbepoetin alfa (DA) therapy were assessed in anemic patients with previously untreated low- and intermediate-1-risk myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Fifty-three patients received DA administered subcutaneously once a week for 24 weeks. Treatment was initiated at 150 microg fixed dose and was doubled if after the first 12 weeks there was no or suboptimal erythroid response. RESULTS: The final response rate was 24/53 (45%), with 21 major and three minor responses. Most of the responses (21/24; 87.5%) were obtained at the dose of 150 microg. With a median follow-up of 9.4 months, 17 patients maintain their response. Treatment was well tolerated with no relevant side-effects. MDS progression was observed in one case. Increases in hemoglobin levels were positively correlated with improved QoL scores using both the linear analog scale assessment (energy level, r = 0.429, P = 0.036; daily activities, r = 0.653, P < 0.001; overall well-being, r = 0.457, P = 0.024) and the Functional Assessment of Cancer Therapy-Anemia questionnaire (r = 0.247, P = 0.025). In multivariate analysis, only low levels (<200 IU/l) of endogenous erythropoietin predicted response to DA therapy. CONCLUSIONS: DA is an active, safe and well tolerated treatment for anemia in a substantial proportion of patients with low- and intermediate-1-risk MDS, and has a positive impact on the patients' QoL.
Assuntos
Anemia/tratamento farmacológico , Eritropoetina/análogos & derivados , Síndromes Mielodisplásicas/complicações , Idoso , Idoso de 80 Anos ou mais , Anemia/sangue , Anemia/etiologia , Apoptose , Transfusão de Sangue , Darbepoetina alfa , Eritropoetina/administração & dosagem , Eritropoetina/uso terapêutico , Feminino , Seguimentos , Hemoglobinas/metabolismo , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Qualidade de Vida , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND: Once-weekly dosing of recombinant human erythropoietin (rhEPO) in patients with myelodysplastic syndromes (MDS) has not been investigated thoroughly. We performed a clinical trial to evaluate the effects of this new dosing regimen in patients with MDS who were unresponsive to the conventional three-times-weekly schedule. PATIENTS AND METHODS: Forty-eight patients with low- or intermediate-risk MDS were enrolled in a 12-week study. rhEPO alpha (rhEPOalpha) was administered once-weekly by subcutaneous injection with a starting dose of 40,000 U fixed dose. The drug dosage was increased to 60,000 U fixed dose if after 6 weeks there was no or suboptimal erythroid response. RESULTS: Clinically significant responses were seen in 13 (27%) patients, with 11 improving their response after dose escalation of rhEPOalpha. Only one patient (case 23) maintains a response after a follow-up period of 14 months. All other patients had responses lasting between 10 and 43 weeks, with a median time to relapse of 20 weeks. Treatment was well tolerated, with no relevant adverse events. Response to therapy was associated with significantly higher concentrations of circulating erythroid blast-forming units and a decrease of the bone marrow fraction of apoptic CD34+ cells. CONCLUSIONS: Once-weekly rhEPOalpha therapy results in an improvement of erythropoiesis in a subset of MDS patients who are unresponsive to conventional dosing, and may act by inhibiting apoptosis of erythroid precursors. These results warrant further investigation of this dosing regimen either alone or in combination with other agents.