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1.
N Engl J Med ; 369(19): 1783-96, 2013 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-24180494

RESUMO

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 Jovem
2.
Leukemia ; 20(11): 2025-33, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16990779

RESUMO

Wilms tumor protein 1 (WT1) is a transcription factor overexpressed in several types of leukemia and solid tumors. For this reason, WT1 is an attractive target for immunotherapy. Four peptide nonamers from WT1 have been identified by others to generate a WT1-specific cytotoxic response in the context of human leukocyte antigen (HLA)-A0201 and A2402. However, as WT1 is a self-antigen, breaking tolerance is a potential obstacle to vaccination. Here, we use a strategy to circumvent tolerance by designing synthetic immunogenic analog peptides that could crossreact to the native peptides (a heteroclitic response). A number of synthetic peptides derived from nonamer sequences of the WT1 protein were designed in which single amino-acid substitutions were introduced at HLA-A0201 major histocompatibility complex (MHC)-binding positions. Several of new peptides could stabilize MHC class I A0201 molecules better than native sequences. Some analogs were also able to elicit WT1-specific T-cell recognition and cytotoxic T-cell lymphocytes more effectively than native sequences. Importantly, T cells stimulated with the new analogs crossreacted with the native WT1 peptide sequence and were able to kill HLA-matched chronic myeloid leukemia cell lines. In conclusion, analog heteroclitic WT1 peptides with increased immunogenicity can be synthesized and are potential cancer vaccine candidates.


Assuntos
Vacinas Anticâncer/imunologia , Antígenos HLA-A/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Fragmentos de Peptídeos/imunologia , Linfócitos T/imunologia , Proteínas WT1/genética , Sequência de Aminoácidos , Antígenos CD8/imunologia , Linhagem Celular Tumoral , Epitopos/imunologia , Antígenos HLA-A/metabolismo , Antígeno HLA-A2 , Humanos , Tolerância Imunológica/imunologia , Interferon gama/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/metabolismo , Ligação Proteica/imunologia , Linfócitos T/citologia , Linfócitos T/metabolismo , Proteínas WT1/metabolismo
3.
Mol Oncol ; 9(7): 1447-1457, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25957812

RESUMO

The median survival for metastatic melanoma is in the realm of 8-16 months and there are few therapies that offer significant improvement in overall survival. One of the recent advances in cancer treatment focuses on epigenetic modifiers to alter the survivability and immunogenicity of cancer cells. Our group and others have previously demonstrated that pan-HDAC inhibitors induce apoptosis, cell cycle arrest and changes in the immunogenicity of melanoma cells. Here we interrogated specific HDACs which may be responsible for this effect. We found that both genetic abrogation and pharmacologic inhibition of HDAC6 decreases in vitro proliferation and induces G1 arrest of melanoma cell lines without inducing apoptosis. Moreover, targeting this molecule led to an important upregulation in the expression of tumor associated antigens and MHC class I, suggesting a potential improvement in the immunogenicity of these cells. Of note, this anti-melanoma activity was operative regardless of mutational status of the cells. These effects translated into a pronounced delay of in vivo melanoma tumor growth which was, at least in part, dependent on intact immunity as evidenced by the restoration of tumor growth after CD4+ and CD8+ depletion. Given our findings, we provide the initial rationale for the further development of selective HDAC6 inhibitors as potential therapeutic anti-melanoma agents.


Assuntos
Proliferação de Células/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/efeitos dos fármacos , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Animais , Linhagem Celular Tumoral , Fase G1/efeitos dos fármacos , Desacetilase 6 de Histona , Humanos , Melanoma Experimental/enzimologia , Camundongos , Camundongos Endogâmicos C57BL
4.
Blood Rev ; 14(2): 111-20, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11012250

RESUMO

T cells are implicated in the effective control of chronic myeloid leukemia (CML). Recently, several clinical observations supported by laboratory data, indicate the presence of CML-specific T cells. Many proteins potentially act as leukemia-specific antigens for MHC-restricted cytotoxicity in CML. These include the bcr-abl fusion protein, myeloid-specific differentiation antigens and minor histocompatibility antigens. There is recent evidence to suggest that bcr-abl junctional peptides are capable of eliciting both CD4 and CD8 responses in normal healthy donors and in patients with CML. Moreover, T cell lines can be generated that react with autologous or HLA-matched fresh CML cells, suggesting that the bcr-abl fusion protein can be processed and expressed in the MHC cell surface molecules. Clinical trials exploiting the new understanding of the immunology of CML are underway.


Assuntos
Vacinas Anticâncer/uso terapêutico , Imunoterapia Adotiva , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Proteínas de Fusão bcr-abl/imunologia , Proteínas de Fusão bcr-abl/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Linfócitos T Citotóxicos/imunologia
5.
Leukemia ; 27(1): 107-12, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22763385

RESUMO

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.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Terapia de Salvação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Feminino , Seguimentos , Humanos , Mesilato de Imatinib , Agências Internacionais , Leucemia Mieloide de Fase Crônica/mortalidade , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Adulto Jovem
6.
Leukemia ; 27(4): 907-13, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23174881

RESUMO

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.


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Adulto Jovem
7.
Mediterr J Hematol Infect Dis ; 2(1): e2010002, 2010 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21415944

RESUMO

We encountered a 60-year-old woman with a medical history of diabetes mellitus, osteoporosis, peripheral vascular disease, and hypertension who had earlier presented at an outside facility with knee pain, which led to a finding of elevated neutrophil count of 35×10(9)/L. Because she was otherwise asymptomatic but continued showing elevated neutrophil levels, she sought a second opinion at our facility. Serum protein immunoelectrophoresis with immunofixation revealed an immunoglobulin A (IgA)-κ monoclonal gammopathy concentration of 1305 mg/dL (normal 80-350 mg/dL) but relatively normal concentrations of IgG of 840 mg/dL (620-1400 mg/dL) and IgM of 36 mg/dL (45-250 mg/dL). Using clonal analysis, we found a polyclonal expression pattern in all cell types analyzed. Comprehensive work-up for multiple myeloma and infectious etiology of neutrophilia was negative. We concluded that our patient's neutrophilia may have been due to the underlying monoclonal gammopathy. This is the first case in the literature of a patient with monoclonal gammopathy of undetermined significance presenting with chronic neutrophilia, mimicking chronic neutrophilic leukemia (CNL). Patients with CNL have a poor prognosis; therefore, it is important to distinguish diagnostically between CNL and reactive neutrophilia.

9.
Leukemia ; 23(8): 1398-405, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19295545

RESUMO

Dasatinib, a broad-spectrum tyrosine kinase inhibitor (TKI), predominantly targets BCR-ABL and SRC oncoproteins and also inhibits off-target kinases, which may result in unexpected drug responses. We identified 22 patients with marked lymphoproliferation in blood while on dasatinib therapy. Clonality and immunophenotype were analyzed and related clinical information was collected. An abrupt lymphocytosis (peak count range 4-20 x 10(9)/l) with large granular lymphocyte (LGL) morphology was observed after a median of 3 months from the start of therapy and it persisted throughout the therapy. Fifteen patients had a cytotoxic T-cell and seven patients had an NK-cell phenotype. All T-cell expansions were clonal. Adverse effects, such as colitis and pleuritis, were common (18 of 22 patients) and were preceded by LGL lymphocytosis. Accumulation of identical cytotoxic T cells was also detected in pleural effusion and colon biopsy samples. Responses to dasatinib were good and included complete, unexpectedly long-lasting remissions in patients with advanced leukemia. In a phase II clinical study on 46 Philadelphia chromosome-positive acute lymphoblastic leukemia, patients with lymphocytosis had superior survival compared with patients without lymphocytosis. By inhibiting immunoregulatory kinases, dasatinib may induce a reversible state of aberrant immune reactivity associated with good clinical responses and a distinct adverse effect profile.


Assuntos
Antineoplásicos/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Linfocitose/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Linfócitos T Citotóxicos/efeitos dos fármacos , Tiazóis/farmacologia , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Estudos de Coortes , Colite/induzido quimicamente , Dasatinibe , Feminino , Humanos , Imunofenotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Proteínas de Neoplasias/antagonistas & inibidores , Pleurisia/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Tiazóis/efeitos adversos , Tiazóis/uso terapêutico
10.
Curr Opin Hematol ; 7(4): 247-54, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10882181

RESUMO

Monoclonal antibodies have become an important modality for cancer therapy. Genetically engineered chimeric and humanized antibodies have demonstrated activity against overt lymphoma and leukemia, as well as minimal residual disease. Radioimmunotherapy in both nonmyeloablative and myeloablative regimens has produced significant responses and also minimized radiation exposure to normal tissues. Targeted alpha-particle therapy offers the possibility of selective tumor cell kill. Antibody-drug conjugates have produced remissions in acute leukemia. Many proteins potentially act as leukemia or lymphoma-specific antigens for major histocompatibility complex-restricted T cell cytotoxicity. These include the idiotype proteins, breakpoint cluster region (bcr)-abl and other fusion oncoproteins, myeloid-specific differentiation antigens and minor histocompatibility antigens. Clinical trials exploiting the new understanding of the T cell immunology are underway.


Assuntos
Neoplasias Hematológicas/terapia , Imunoterapia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Formação de Anticorpos , Apresentação de Antígeno , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Ensaios Clínicos como Assunto , Células Dendríticas/imunologia , Células Dendríticas/transplante , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/radioterapia , Humanos , Imunidade Celular , Imunoconjugados/uso terapêutico , Idiótipos de Imunoglobulinas/imunologia , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/radioterapia , Linfoma não Hodgkin/terapia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Radioimunoterapia , Terapia de Salvação
11.
Blood ; 95(5): 1781-7, 2000 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-10688838

RESUMO

Chronic myelogenous leukemia (CML) presents a unique opportunity to develop therapeutic strategies using vaccination against a truly tumor-specific antigen that is also the oncogenic protein required for neoplasia. CML is characterized by the t(9;22) that results in the bcr-abl fusion oncogene and in the expression of a chimeric protein product p210. Previously we have shown that peptides derived from amino acid sequences crossing the b3a2 fusion breakpoint in p210 elicit class I restricted cytotoxic T lymphocytes and class II responses, respectively, in vitro. Such sequences may thus comprise absolutely tumor-specific antigens in a peptide-based vaccine. We evaluated the safety and immunogenicity of a multidose, bcr-abl breakpoint peptide vaccine in 12 adults with chronic-phase CML. Cohorts of 3 patients each received either 50 microg, 150 microg, 500 microg, or 1500 microg total peptide mixed with 100 microg QS-21 as an immunological adjuvant. Delayed-type hypersensitivity (DTH), humoral responses, and unprimed ex vivo autologous proliferation ((3)H-thymidine incorporation) and cytotoxicity (chromium-51 release) responses were measured. All 68 vaccinations were well tolerated without significant adverse effects. In 3 of the 6 patients treated at the 2 highest dose levels of vaccine, peptide-specific, T-cell proliferative responses (n = 3) and/or DTH responses (n = 2) were generated that lasted up to 5 months after vaccination. Cytotoxic T lymphocytes have not been identified. In conclusion, a tumor-specific, bcr-abl derived peptide vaccine can be safely administered to patients with chronic-phase CML and can elicit a bcr-abl peptide-specific immune response despite the presence of active disease in these patients and approximately 10(12) leukemia cells. (Blood. 2000;95:1781-1787)


Assuntos
Vacinas Anticâncer/imunologia , Proteínas de Fusão bcr-abl/imunologia , Imunização Passiva , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Fragmentos de Peptídeos/imunologia , Vacinação , Adjuvantes Imunológicos , Adulto , Idoso , Sequência de Aminoácidos , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Anergia Clonal , Relação Dose-Resposta Imunológica , Ensaio de Imunoadsorção Enzimática , Feminino , Proteínas de Fusão bcr-abl/administração & dosagem , Humanos , Hipersensibilidade Tardia/imunologia , Imunização Passiva/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fragmentos de Peptídeos/administração & dosagem , Segurança , Alinhamento de Sequência , Linfócitos T Citotóxicos/imunologia , Resultado do Tratamento
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