RESUMO
PURPOSE: Chronic myeloid leukemia (CP-CML) patients can achieve undetectable minimal residual disease (UMRD) and discontinue tyrosine kinase inhibitors (TKIs). Cellular immunity plays an important role in CML disease control. We conducted a randomized, non-blinded phase II trial of adjuvant immunotherapy with TKIs to facilitate TKI discontinuation. METHODS: TKI-treated patients with CP-CML were randomized to receive the K562/GM-CSF vaccine (vaccine) OR Interferon-α + Sargramostim (IFN). If UMRD was achieved, then all treatment was stopped. Patients who did not achieve UMRD within one year, had a molecular relapse, or discontinued therapy for toxicity could crossover. RESULTS: Thirty-four patients were randomized to IFN (n = 18) or vaccine (n = 16), and 21 patients crossed over (IFNâ¶vaccine: n = 9, vaccineâ¶IFN, n = 12). TKIs at enrollment included imatinib (n = 31), nilotinib (n = 2), and dasatinib (n = 1). No patients discontinued vaccine due to side effects, while 33 % of IFN-treated patients discontinued treatment. More patients randomized to IFN (47.4 %, 95 % CI: 16.7-66.7 %) versus vaccine (25.0 %, 95 % CI: 0.5-43.5 %) achieved UMRD within one year. Seven patients randomized to IFN discontinued treatment with 28.6 % (95 % CI: 8.9-92.2 %) sustaining treatment-free remission (TFR) at 1 year, while three patients randomized to vaccine discontinued treatment with none sustaining TFR. Including crossover, there was a cumulative discontinuation success rate of 36.4 % (95 % CI: 16.6 %-79.5 %) after adjuvant IFN. Patients who sustained TFR received a median of 29 months of imatinib prior to discontinuation. CONCLUSION: Adjuvant IFN led to durable TFRs with limited prior TKI exposure with comparable success to prior discontinuation trials, but many patients stopped IFN early.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/administração & dosagem , Imunoterapia/mortalidade , Leucemia Mieloide de Fase Crônica/mortalidade , Adulto , Idoso , Estudos Cross-Over , Dasatinibe/administração & dosagem , Feminino , Seguimentos , Humanos , Mesilato de Imatinib/administração & dosagem , Interferons/administração & dosagem , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/imunologia , Leucemia Mieloide de Fase Crônica/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Pirimidinas/administração & dosagem , Taxa de Sobrevida , Adulto JovemRESUMO
Accumulation in target cells is an essential pharmacokinetic step of targeted therapies. Tyrosine Kinase Inhibitors (TKI) against the BCR-ABL fusion protein in Chronic Phase-Chronic Myeloid Leukaemia (CP-CML) cells constitute a unique model in terms of efficacy, specificity, and in vivo demonstration of response heterogeneity by target cells. The overall therapeutic response to nilotinib is heterogeneous with no satisfactory explanation. To better understand the patients' response heterogeneity, we quantified nilotinib uptake by primary CP-CML cells in standardized conditions using flow cytometry, which allowed also distinguishing mature (polymorphonuclear cells) from immature (CD34+) cells. Nilotinib was undetectable in 13.3% of PMN and 40% of CD34+ cells. Moreover, in CD34+ cells, intracellular nilotinib did not completely abolish BCR-ABL activity (monitored by CrkL phosphorylation inhibition), although nilotinib accumulated well in most CD34+ cell samples. Intracellular nilotinib concentration was inversely correlated with disease burden parameters, Sokal score, and early haematologic response at day 6 ± 1 only in PMN, suggesting an intrinsic ability to limit nilotinib entry in the forms with higher tumor cell burdenat diagnosis. These findings suggest that nilotinib accumulation in CP-CML cells is influenced by individual characteristics and intra-clonal heterogeneity, and might be used for pharmacokinetic studies and to assess the therapeutic response.
Assuntos
Antígenos CD34/imunologia , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide de Fase Crônica , Pirimidinas/farmacologia , Humanos , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/imunologia , Leucemia Mieloide de Fase Crônica/patologia , Células Tumorais CultivadasRESUMO
CD8+ T-cell expansions are the primary manifestation of T-cell large granular lymphocytic leukemia (T-LGLL), which is frequently accompanied by neutropenia and rheumatoid arthritis, and also occur as a secondary phenomenon in leukemia patients treated with dasatinib, notably in association with various drug-induced side-effects. However, the mechanisms that underlie the genesis and maintenance of expanded CD8+ T-cell receptor (TCR)-Vß+ populations in these patient groups have yet to be fully defined. In this study, we performed a comprehensive phenotypic and clonotypic assessment of expanded (TCR-Vß+) and residual (TCR-Vß-) CD8+ T-cell populations in T-LGLL and dasatinib-treated chronic myelogenous leukemia (CML) patients. The dominant CD8+ TCR-Vß+ expansions in T-LGLL patients were largely monoclonal and highly differentiated, whereas the dominant CD8+ TCR-Vß+ expansions in dasatinib-treated CML patients were oligoclonal or polyclonal, and displayed a broad range of memory phenotypes. These contrasting features suggest divergent roles for antigenic drive in the immunopathogenesis of primary versus dasatinib-associated CD8+ TCR-Vß+ expansions.
Assuntos
Antineoplásicos/efeitos adversos , Linfócitos T CD8-Positivos/imunologia , Dasatinibe/efeitos adversos , Leucemia Linfocítica Granular Grande/tratamento farmacológico , Leucemia Linfocítica Granular Grande/imunologia , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Linfócitos T CD8-Positivos/citologia , Células Clonais , Dasatinibe/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
We describe here a simple model for the interaction between leukemic cells and the autologous immune response in chronic phase chronic myelogenous leukemia (CML). This model is a simplified version of the model we proposed in Clapp et al. (Cancer Res 75:4053-4062, 2015). Our simplification is based on the observation that certain key characteristics of the dynamics of CML can be captured with a three-compartment model: two for the leukemic cells (stem cells and mature cells) and one for the immune response. We characterize the existence of steady states and their stability for generic forms of immunosuppressive effects of leukemic cells. We provide a complete co-dimension one bifurcation analysis. Our results show how clinical response to tyrosine kinase inhibitors treatment is compatible with the existence of a stable low disease, treatment-free steady state.
Assuntos
Leucemia Mieloide de Fase Crônica/imunologia , Modelos Imunológicos , Antineoplásicos/uso terapêutico , Autoimunidade , Humanos , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Conceitos Matemáticos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidoresRESUMO
Tyrosine kinase inhibitors (TKIs) are highly effective for the treatment of chronic myeloid leukemia (CML), but very few patients are cured. The major drawbacks regarding TKIs are their low efficacy in eradicating the leukemic stem cells responsible for disease maintenance and relapse upon drug cessation. Herein, we performed ribonucleic acid sequencing of flow-sorted primitive (CD34+CD38low) and progenitor (CD34+ CD38+) chronic phase CML cells, and identified transcriptional upregulation of 32 cell surface molecules relative to corresponding normal bone marrow cells. Focusing on novel markers with increased expression on primitive CML cells, we confirmed upregulation of the scavenger receptor CD36 and the leptin receptor by flow cytometry. We also delineate a subpopulation of primitive CML cells expressing CD36 that is less sensitive to imatinib treatment. Using CD36 targeting antibodies, we show that the CD36 positive cells can be targeted and killed by antibody-dependent cellular cytotoxicity. In summary, CD36 defines a subpopulation of primitive CML cells with decreased imatinib sensitivity that can be effectively targeted and killed using an anti-CD36 antibody.
Assuntos
Citotoxicidade Celular Dependente de Anticorpos , Antígenos CD36/genética , Mesilato de Imatinib/farmacologia , Leucemia Mieloide de Fase Crônica/imunologia , Anticorpos Antineoplásicos/uso terapêutico , Antígenos de Neoplasias/imunologia , Antígenos CD36/imunologia , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/patologia , Análise de Sequência de RNA , Células Tumorais Cultivadas , Regulação para CimaRESUMO
Dasatinib is one of the key treatment options for chronic myeloid leukemia (CML) patients. Increase in lymphocyte counts has been known to be predictive of a good treatment response under dasatinib treatment as a second line therapy. However, clinical significance of lymphocyte dynamics in the upfront setting has yet to be clarified. To investigate the significance of lymphocyte dynamics in newly diagnosed chronic phase (CP)-CML, patient data of D-First study (ClinicalTrials.gov NCT01464411) were analyzed. Fifty-two CML-CP patients enrolled to this study were treated with dasatinib (100 mg day(-1) ) and all were followed-up for 18 months. The incidence of lymphocyosis was observed in 14 (27%), but it was not associated with deep molecular response achievement. However, natural killer (NK) cell or cytotoxic T lymphocyte (CTL) counts at 1 month were significantly higher in patients with deep molecular response (DMR) by 18 months compared to those without DMR. When the patients were divided into two groups according to those calculated thresholds by receiver operating characteristic curve (407/µL for NK cells and 347/µL for CTLs), the cumulative DMR rates by 18 months were significantly better in higher value group compared to lower value group. In contrast, regulatory T cell counts were significantly lower at 12 and 15 months in patients achieved DMR. These results suggest the presence of dual effects of dasatinib on immune system through the cytotoxic lymphocytes activation and Treg deregulation in different periods in newly diagnosed CML-CP.
Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Tiazóis/uso terapêutico , Antígenos CD/genética , Antígenos CD/imunologia , Dasatinibe , Proteínas de Fusão bcr-abl/imunologia , Expressão Gênica , Humanos , Imunofenotipagem , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Leucemia Mieloide de Fase Crônica/genética , Leucemia Mieloide de Fase Crônica/imunologia , Leucemia Mieloide de Fase Crônica/patologia , Contagem de Linfócitos , Linfocitose/induzido quimicamente , Linfocitose/genética , Linfocitose/imunologia , Linfocitose/patologia , Estudos Prospectivos , Curva ROC , Indução de Remissão , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologiaRESUMO
BACKGROUND: Flow cytometry (FC) is a commonly requested test in the workup of leukocytosis in community practices. The role of FC in chronic-phase chronic myeloid leukemia (CP-CML) is unknown. We hypothesized that finding aberrant cells with FC in CP-CML may predict early blast-phase (BP) transformation. METHODS: Results for FC performed at the time of diagnosis for adult and pediatric patients with CP-CML who were referred to our institution were reviewed, and they were correlated with outcomes. RESULTS: FC was performed at the time of diagnosis for 110 of 233 patients (47%) with CP-CML. Aberrant populations, representing a median of 2% (range, 0.3%-15%), were detected with FC in 30% of patients (33 of 110): 2 of these 33 patients expressed lymphoid markers, and 31 expressed aberrant myeloid markers. Patients received imatinib (85%), dasatinib (12%), or nilotinib (3%) as their first-line treatment. With a median follow-up of 43 months (range, 2-113 months), chronic myeloid leukemia transformed to BP in 5 of the 33 patients. The 2 patients with lymphoid markers and the 3 of 31 patients with aberrant myeloid markers experienced a transformation to lymphoid BP at a median of 11 months (range, 4-72 months) after the initiation of tyrosine kinase inhibitor therapy. Although both cases with detectable lymphoid markers rapidly progressed to lymphoid BP, the positive predictive value of BP transformation by the detection of myeloid aberrant cells with FC was only 10% (3 of 31). CONCLUSIONS: In contrast to aberrant myeloid markers, the detection of lymphoid markers by FC at the time of the diagnosis of CP-CML appears to be associated with early progression to lymphoid BP.
Assuntos
Crise Blástica/imunologia , Crise Blástica/patologia , Imunofenotipagem/métodos , Leucemia Mieloide de Fase Crônica/imunologia , Leucemia Mieloide de Fase Crônica/patologia , Adulto , Criança , Feminino , Citometria de Fluxo/métodos , Humanos , Masculino , Valor Preditivo dos TestesRESUMO
Although it is generally acknowledged that cytokines regulate normal hematopoiesis in an autocrine/paracrine fashion, their possible role in chronic myelogenous leukemia (CML) and resistance to imatinib mesylate treatment remain poorly investigated. Here, we report that CD34(+) progenitors from patients with CML at diagnosis are selectively targeted by the cytokine/alarmin interleukin (IL)-33. Indeed, CML CD34(+) progenitors upregulate their cell surface expression of the IL-33-specific receptor chain ST2, proliferate and produce cytokines in response to IL-33, conversely to CD34(+) cells from healthy individuals. Moreover, ST2 overexpression is normalized following imatinib mesylate therapy, whereas IL-33 counteracts in vitro imatinib mesylate-induced growth arrest in CML CD34(+) progenitors via reactivation of the STAT5 pathway, thus supporting the notion that IL-33 may impede the antiproliferative effects of imatinib mesylate on CD34(+) progenitors in CML. Clinically, the levels of circulating soluble ST2, commonly considered a functional signature of IL-33 signaling in vivo, correlate with disease burden. Indeed, these elevated peripheral concentrations associated with a high Sokal score predictive of therapeutic outcome are normalized in patients in molecular remission. Finally, we evidenced a facilitating effect of IL-33 on in vivo maintenance of CD34(+) progenitors from patients with CML by using xenotransplant experiments in immunodeficient NOG mice, and we showed that engraftment of mouse BCR-ABL-transfected bone marrow progenitors was less efficient in IL-33-deficient mice compared with wild-type recipients. Taken together, our results provide evidence that IL-33/ST2 signaling may represent a novel cytokine-mediated mechanism contributing to CML progenitor growth and support a role for this pathway in CML maintenance and imatinib mesylate resistance.
Assuntos
Antígenos CD34/biossíntese , Proteínas de Fusão bcr-abl/metabolismo , Interleucinas/metabolismo , Leucemia Mieloide de Fase Crônica/metabolismo , Células-Tronco Neoplásicas/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Antígenos CD34/imunologia , Benzamidas/farmacologia , Citocinas/biossíntese , Interações Medicamentosas , Feminino , Proteínas de Fusão bcr-abl/imunologia , Humanos , Mesilato de Imatinib , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Interleucinas/imunologia , Interleucinas/farmacologia , Janus Quinase 2/metabolismo , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/imunologia , Leucemia Mieloide de Fase Crônica/patologia , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Receptores de Superfície Celular/biossíntese , Receptores de Superfície Celular/imunologia , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para CimaRESUMO
It was recently recognized that some chronic myeloid leukemia patients with a complete molecular response could sustain that response after discontinuation of imatinib. To characterize the clinical outcomes and profiles of chronic phase chronic myeloid leukemia patients who could discontinue imatinib, we conducted a nationwide survey in Japan. Among 3,242 imatinib-treated chronic myeloid leukemia patients, we identified 50 who had discontinued imatinib for at least six months; of these we analyzed 43. Molecular recurrence was detected in 19 patients, and a complete molecular response rate was estimated to be 47% following imatinib discontinuation. Based on multivariate regression analysis, imatinib dose intensity and prior interferon-α administration were independently predictive of molecular recurrence within 12 months. The depth of the molecular response should be a factor influencing long-term sustained complete molecular response after discontinuation of imatinib. Additionally, an immunological mechanism modified by interferon-α might control chronic myeloid leukemia stem cells.
Assuntos
Antineoplásicos/uso terapêutico , Interferon-alfa/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Benzamidas , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Mesilato de Imatinib , Imunidade Inata , Interferon-alfa/administração & dosagem , Japão , Leucemia Mieloide de Fase Crônica/imunologia , Leucemia Mieloide de Fase Crônica/mortalidade , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Células-Tronco Neoplásicas/imunologia , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Recidiva , Resultado do TratamentoRESUMO
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy for chronic myelogenous leukemia (CML). In this study, the long-term outcomes of HLA-matched sibling donor (MSD) with mismatched related donor (MRD) and unrelated donor (URD) transplantation for CML in the first chronic phase (CML-CP1) using different graft vs. host disease (GVHD) prophylaxis regimens according to donor source and the degree of HLA matching were compared. The data of 91 patients with CML-CP1 were analyzed with respect to GVHD, overall survival (OS), and transplant-related mortality (TRM). The incidence of grade II-IV acute GVHD was 25.5% in the MSD and 40.5% in the MRD/URD group (P = 0.133). The 1-year cumulative incidence of chronic GVHD was not different between the MSD and the MRD/URD groups, while extensive chronic GVHD was different between the two groups (31.9% vs. 10.8%, P = 0.023). The 5-year cumulative relapse rate was not different between the MSD and the MRD/URD groups, while TRM was different between the two groups (6.6% vs. 26.3%, P = 0.010). The 5-year cumulative OS was 90.9%, 71.5%, and 85.4% in the MSD, the MRD/URD, and the HLA allele-matched URD transplantation, respectively (MSD vs. MRD/URD, P = 0.013; MSD vs. HLA allele-matched URD, P = 0.437). In conclusion, survival in HLA allele-matched URD is equivalent to MSD, but in MRD and mismatched URD is inferior to MSD in patients with CML-CP1 undergoing allo-HSCT using different GVHD prophylaxis regimens according to donor source and degree of HLA matching. Patients undergoing MRD/URD transplantation have an equal quality of life as patients undergoing MSD transplantation.
Assuntos
Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide de Fase Crônica/terapia , Doadores de Tecidos , Adolescente , Adulto , China , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Teste de Histocompatibilidade , Humanos , Leucemia Mieloide de Fase Crônica/imunologia , Leucemia Mieloide de Fase Crônica/mortalidade , Leucemia Mieloide de Fase Crônica/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Irmãos , Análise de Sobrevida , Fatores de Tempo , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Early diagnosis and cure for patients with chronic myeloid leukemia (CML) exhibit significant clinical challenges because of the disease progression from chronic phase (CP) into a rapidly fatal blast crisis. Our earlier studies suggested an association of sperm associated antigen 9 (SPAG9) with various human malignancies. The present investigation revealed that SPAG9 mRNA and protein are expressed in CML patients (88%), in K562 and KCL-22 cells. Further, SPAG9 protein expression was also detected on cell surface suggesting that this molecule may be a suitable target for immunotherapy. Interestingly, 90% CML-CP patients showed humoral response against SPAG9, suggesting its important role in early diagnostic of CML-CP. Further investigation is warranted in establishing the potential of SPAG9 as a biomarker and immunotherapeutic target for early treatment of CML-CP patients.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Anticorpos Antineoplásicos/sangue , Leucemia Mieloide de Fase Crônica/metabolismo , Proteínas de Neoplasias/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Anticorpos Antineoplásicos/imunologia , Especificidade de Anticorpos , Antígenos de Neoplasias/biossíntese , Antígenos de Neoplasias/imunologia , Antígenos de Superfície/biossíntese , Antígenos de Superfície/imunologia , Biomarcadores Tumorais , Crise Blástica/patologia , Linhagem Celular Tumoral/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Imunoterapia , Células K562/metabolismo , Leucemia Mieloide de Fase Crônica/genética , Leucemia Mieloide de Fase Crônica/imunologia , Leucemia Mieloide de Fase Crônica/patologia , Leucemia Mieloide de Fase Crônica/terapia , Masculino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Expression of CD7, ELA-2, PR-3, and the polycomb group gene BMI-1 reflects the intrinsic heterogeneity and predicts prognosis of patients with chronic myeloid leukemia (CML) who were not treated with allogeneic stem cell transplantation (allo-SCT). This study investigated whether expression of these genes determined outcome following allo-SCT in a cohort of 84 patients with chronic-phase (CP) CML. We found that patients expressing BMI-1 at a "high" level before allo-SCT had an improved overall survival (P = .005) related to a reduced transplantation-related mortality. In multivariate analysis, when adjusted for the European Group for Blood and Marrow Transplantation (EBMT)-Gratwohl score and other prog-nostic factors, there was an independent association between BMI-1 expression and grades 2 to 4 acute graft-versus-host disease (relative risk [RR] = 2.85; 95% confidence interval [CI], 1.3-6.4; P = .011), suggesting that BMI-1 measured prior to allo-SCT can serve as a biomarker for predicting outcome in patients with CP-CML receiving allo-SCT, and may thus contribute to better therapeutic decisions.
Assuntos
Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/genética , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Transplante de Células-Tronco/efeitos adversos , Doença Aguda , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Expressão Gênica , Doença Enxerto-Hospedeiro/imunologia , Antígenos HLA , Humanos , Leucemia Mieloide de Fase Crônica/genética , Leucemia Mieloide de Fase Crônica/imunologia , Leucemia Mieloide de Fase Crônica/terapia , Masculino , Pessoa de Meia-Idade , Complexo Repressor Polycomb 1 , Prognóstico , IrmãosAssuntos
Crise Blástica/líquido cefalorraquidiano , Sistema Nervoso Central/imunologia , Leucemia Mieloide de Fase Crônica/líquido cefalorraquidiano , Linfócitos T/imunologia , Idoso , Antineoplásicos/uso terapêutico , Benzamidas , Crise Blástica/tratamento farmacológico , Crise Blástica/imunologia , Dasatinibe , Humanos , Mesilato de Imatinib , Imunofenotipagem , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/imunologia , Masculino , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Indução de Remissão , Tiazóis/uso terapêuticoRESUMO
Although donor lymphocyte infusion (DLI) induces complete remissions in 70% of patients with relapsed chronic myeloid leukemia (CML) after allogeneic stem-cell transplantation (SCT), some patients are refractory to DLI by showing disease persistence. In a patient who received DLI for relapsed CML, we observed persisting molecular disease despite a hematological and cytogenetic remission in the absence of graft-versus-host disease (GVHD). To determine the nature of this immune response, we isolated leukemia-reactive donor T-cell clones from the bone marrow (BM) of the patient at the time of clinical response. Four different types of CD8+ HLA class I restricted T-cell clones were obtained that were cytotoxic against Ebstein-Barr virus-transformed B-cell lines (EBV-LCL) of the patient, but not the donor, indicating recognition of minor histocompatibility antigens (mHags). By using survival studies with CFSE labelled BM cells populations, a hematopoietic progenitor cell inhibition assay and direct morphological examination we showed that the T-cell clones recognized mature monocytic and myeloid cells, whereas immature BM progenitor cells were insufficiently lysed. This patient's refractoriness for DLI appears to be caused by inadequate lysis of progenitor cells by these cytotoxic T cells. These findings support the hypothesis that for eradication of CML a cytotoxic T-cell response against leukemic progenitor cells is essential.
Assuntos
Antígenos de Diferenciação/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Células-Tronco Hematopoéticas/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Mieloide de Fase Crônica/imunologia , Neoplasia Residual/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto , Antígenos de Diferenciação/biossíntese , Linfócitos T CD8-Positivos/imunologia , Linhagem da Célula/imunologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Transfusão de Linfócitos/métodos , Masculino , Neoplasia Residual/genética , Linfócitos T Citotóxicos/transplante , Transplante HomólogoRESUMO
Graft-versus-host disease (GVHD) is a major source of morbidity in allogenic stem cell transplantation. We previously showed that recipient antigen-presenting cells (APCs) are required for CD8-dependent GVHD in a mouse model across only minor histocompatibility antigens (minor H antigens). However, these studies did not address the function of donor-derived APCs after GVHD is initiated. Here we show that GVHD develops in recipients of donor major histocompatibility complex class I-deficient (MHC I(-)) bone marrow. Thus, after initial priming, CD8 cells caused GVHD without a further requirement for hematopoietic APCs, indicating that host APCs are necessary and sufficient for GHVD. Nonetheless, GVHD was less severe in recipients of MHC I(-) bone marrow. Therefore, once initiated, GVHD is intensified by donor-derived cells, most probably donor APCs cross-priming alloreactive CD8 cells. Nevertheless, donor APCs were not required for CD8-mediated graft-versus-leukemia (GVL) against a mouse model of chronic-phase chronic myelogenous leukemia. These studies identify donor APCs as a new target for treating GVHD, which may preserve GVL.
Assuntos
Células Apresentadoras de Antígenos/imunologia , Transplante de Medula Óssea/efeitos adversos , Linfócitos T CD8-Positivos/imunologia , Doença Enxerto-Hospedeiro/etiologia , Efeito Enxerto vs Leucemia/imunologia , Animais , Células Apresentadoras de Antígenos/transplante , Linfócitos T CD8-Positivos/transplante , Células Dendríticas/imunologia , Imunofluorescência , Doença Enxerto-Hospedeiro/imunologia , Efeito Enxerto vs Leucemia/fisiologia , Técnicas Histológicas , Leucemia Mieloide de Fase Crônica/imunologia , Camundongos , Camundongos Endogâmicos C3H , Baço/patologiaRESUMO
BACKGROUND AND OBJECTIVES: CD4+ T helper cells are an integral part of effective immune responses against various malignancies; however in tumor-bearing patients they are frequently functionally unresponsive. T helper cells of patients with chronic myeloid leukemia (CML), analyzed as part of mononuclear cell fractions, show a loss of signaling molecules, a compromised Th1 cytokine production and a shift towards a non-productive Th2 state. The underlying mechanism is unknown and may involve intrinsic T cell defects as well as indirect effects mediated by leukemia or antigen-presenting cells. The purpose of the present study was to analyze the intrinsic cytokine-producing capacity of purified CML T helper cells in the absence of other cell types. DESIGN AND METHODS: Untouched CD4+ T cells with a purity of more than 90% were isolated from 10 patients with Ph+ chronic phase CML on maintenance treatment with hydroxyurea. The cells were isolated by density gradient centrifugation followed by immunomagnetic depletion of leukemia and accessory cells. The ex vivo cytokine-producing capacity of CML T helper cells in response to polyclonal stimulation with anti-CD3 and anti-CD28 was then compared to that of cells purified from matched healthy volunteers. RESULTS: T helper cells purified from CML patients produced comparable amounts of the Th1 cytokines interleukin (IL)-2 and interferon (IFN)-g as cells purified from healthy volunteers. Likewise, no difference between CML and control T helper cells was found with respect to the Th2 cytokines, IL-4 and IL-13, as well as the immunomodulatory cytokine, IL-10. INTERPRETATION AND CONCLUSIONS: In the absence of leukemia and accessory cells, the intrinsic cytokine-producing capacity of CML T helper cells is normal. A Th2 shift was not detected, and the predominant presence of an IL-10-producing, immunosuppressive T helper cell subset could be excluded.
Assuntos
Leucemia Mieloide de Fase Crônica/imunologia , Células Th1/imunologia , Células Th2/imunologia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Benzamidas , Citocinas/biossíntese , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Hidroxiureia/uso terapêutico , Mesilato de Imatinib , Interferon-alfa/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Piperazinas/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêuticoRESUMO
In chronic myelogenous leukaemia (CML), clonal change occurs in all myeloid and B-cell lineages, but very rarely T-cell lineages. A detailed three-colour cytometric analysis of peripheral lymphocytes was performed in 22 patients with chronic-phase CML (CP-CML). CD45 gating analysis was used to discriminate between lymphocytes and basophils. The peripheral lymphocyte pool was comprised of a significant proportion of naive CD4 cells, defined by a CD4+45RA+ phenotype [47.0 +/- 19.6% (mean +/- SD) of the total CD4+ cells], and naive CD8 cells, defined by a CD8+CD45RA+CD28+ phenotype (35.1 +/- 19.7% of total CD8+ cells), even in patients with long disease duration. The percentage of CD8 naive T cells showed inverse correlation with age, whereas no correlation was observed with disease duration. Possible explanations for the preservation of naive lymphocytes include (1) that the naive T cells differentiated from co-existing normal stem cells or (2) that long-lived naive T cells persisted from the CML onset and expanded peripherally (thymus independent). Either mechanism or a combination of both mechanisms might contribute to maintaining the naive compartment size.
Assuntos
Leucemia Mieloide de Fase Crônica/imunologia , Subpopulações de Linfócitos T/patologia , Adulto , Fatores Etários , Idoso , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Separação Celular/métodos , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem/métodos , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
One-hundred and two patients with good risk myeloid leukemia (CML first chronic phase or AML first CR) were transplanted from HLA-related donors after conditioning with (n = 45) or without anti-thymocyte globulin (ATG) (n = 57). One graft failure was observed in the non-ATG and none in the ATG group. The median time to leukocyte engraftment (> 1 x 10(9)/l) was 16 (range 12-33) in the ATG group and 17 days (range 11-29) in the non-ATG group (NS) and for platelet engraftment (> 20 x 10(9)/l) 24 and 19 days (P = 0.002), respectively. Acute GVHD grade II-IV was observed in 47% of the non-ATG and in 20% of the ATG group (P = 0.004). Grade III/IV GVHD occurred in 7% of the ATG and in 32% of the non-ATG group (P = 0.002). Chronic GVHD was seen in 36% and 67% (P = 0.005), respectively. After a median follow-up of 48 months (range 2-128), the 5-year estimated OS is 66% (95% KI: 51-81%) for the ATG group and 59% (95% KI: 46-72%) for the non-ATG group (NS). The 5-year estimated DFS is 64% (95% KI: 50-78%) for ATG and 55% (95% KI: 43-67%) for the non-ATG regimen (NS). The 5-year probability of relapse was 5% in the ATG and 15% in the non-ATG group (NS). ATG as part of the conditioning regimen leads to a significant reduction in GVHD without increase of relapse in patients with myeloid leukemia after stem cell transplantation from HLA-related donors.
Assuntos
Soro Antilinfocitário/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide de Fase Crônica/terapia , Depleção Linfocítica/métodos , Linfócitos T/imunologia , Adolescente , Adulto , Criança , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide de Fase Crônica/imunologia , Masculino , Pessoa de Meia-Idade , Doadores de Tecidos , Transplante HomólogoRESUMO
A woman with Ph-positive chronic myeloid leukaemia (CML) with an atypical e1a3 BCR-ABL hybrid gene is described. To our knowledge, this is the first report of this transcript type as a unique naturally occurring BCR-ABL fusion in a CML patient. This case was characterized by a low leucocyte count and a very indolent course without treatment. Because the deletion of ABL exon 2 sequences results in deletion of an essential part of the ABL SH3 domain, our case suggests that this ABL SH3 domain is not absolutely necessary for efficient induction of a myeloproliferative disease in the context of BCR-ABL/p190.