RESUMO
Tyrosine kinase inhibitors (TKIs) are very effective in treating chronic myelogenous leukemia (CML), but primitive, quiescent leukemia stem cells persist as a barrier to the cure. We performed a comprehensive evaluation of metabolic adaptation to TKI treatment and its role in CML hematopoietic stem and progenitor cell persistence. Using a CML mouse model, we found that glycolysis, glutaminolysis, the tricarboxylic acid cycle, and oxidative phosphorylation (OXPHOS) were initially inhibited by TKI treatment in CML-committed progenitors but were restored with continued treatment, reflecting both selection and metabolic reprogramming of specific subpopulations. TKI treatment selectively enriched primitive CML stem cells with reduced metabolic gene expression. Persistent CML stem cells also showed metabolic adaptation to TKI treatment through altered substrate use and mitochondrial respiration maintenance. Evaluation of transcription factors underlying these changes helped detect increased HIF-1 protein levels and activity in TKI-treated stem cells. Treatment with an HIF-1 inhibitor in combination with TKI treatment depleted murine and human CML stem cells. HIF-1 inhibition increased mitochondrial activity and reactive oxygen species (ROS) levels, reduced quiescence, increased cycling, and reduced the self-renewal and regenerating potential of dormant CML stem cells. We, therefore, identified the HIF-1-mediated inhibition of OXPHOS and ROS and maintenance of CML stem cell dormancy and repopulating potential as a key mechanism of CML stem cell adaptation to TKI treatment. Our results identify a key metabolic dependency in CML stem cells persisting after TKI treatment that can be targeted to enhance their elimination.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Proteínas Tirosina Quinases , Camundongos , Humanos , Animais , Proteínas Tirosina Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Células-Tronco Neoplásicas/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Resistencia a Medicamentos AntineoplásicosRESUMO
MicroRNAs and heterogeneous ribonucleoproteins (hnRNPs) are posttranscriptional gene regulators that bind mRNA in a sequence-specific manner. Here, we report that loss of miR-328 occurs in blast crisis chronic myelogenous leukemia (CML-BC) in a BCR/ABL dose- and kinase-dependent manner through the MAPK-hnRNP E2 pathway. Restoration of miR-328 expression rescues differentiation and impairs survival of leukemic blasts by simultaneously interacting with the translational regulator poly(rC)-binding protein hnRNP E2 and with the mRNA encoding the survival factor PIM1, respectively. The interaction with hnRNP E2 is independent of the microRNA's seed sequence and it leads to release of CEBPA mRNA from hnRNP E2-mediated translational inhibition. Altogether, these data reveal the dual ability of a microRNA to control cell fate both through base pairing with mRNA targets and through a decoy activity that interferes with the function of regulatory proteins.
Assuntos
Ribonucleoproteínas Nucleares Heterogêneas/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , MicroRNAs/metabolismo , Animais , Crise Blástica , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Linhagem Celular Tumoral , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Complexo de Inativação Induzido por RNA/metabolismoRESUMO
BACKGROUND: Blood or marrow transplantation (BMT) survivors carry a high burden of morbidity, yet health care utilization by this vulnerable population remains understudied. Patterns and predictors of various domains of health care utilization in long-term BMT survivors were evaluated. METHODS: Study participants were drawn from the Bone Marrow Transplant Survivor Study (BMTSS). Patients transplanted between 1974 and 2014 at one of three transplant centers who had survived ≥2 years after BMT and were aged ≥18 years at the time of the study were included. A BMTSS survey served as the source of data for health care utilization, sociodemographics, and chronic health conditions. Domains of health care utilization in the 2 years preceding study participation included routine checkups, BMT-related visits, transplant/cancer center visits, emergency room (ER) visits, hospitalizations, and high health care utilization (≥7 physician visits during the 2 years before the study). Clinical characteristics and therapeutic exposures were abstracted from medical records. RESULTS: In this cohort of 3342 BMT survivors (52% allogeneic), the prevalence of health care utilization declined over time since BMT for both allogeneic and autologous BMT survivors, such that among those who had survived ≥20 years, only 49%-53% had undergone routine checkups, 37%-38% reported BMT-related visits, and 28%-29% reported transplant/cancer center visits. The presence of severe/life-threatening conditions and chronic graft-vs-host disease increased the odds of health care utilization across all domains. Lower education, lack of insurance, and Hispanic ethnicity were associated with a lower prevalence of routine checkups and/or transplant/cancer center visits. Lower income increased the odds of ER visits but reduced the odds of hospitalizations or high health care utilization. CONCLUSIONS: This study identified vulnerable populations of long-term BMT survivors who would benefit from specialized risk-based anticipatory care to reduce high health care utilization, ER visits, and hospitalizations.
Assuntos
Medula Óssea , Transplante de Células-Tronco Hematopoéticas , Humanos , Adolescente , Adulto , Transplante de Medula Óssea , Sobreviventes , Doença Crônica , Aceitação pelo Paciente de Cuidados de SaúdeRESUMO
Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase-CML. The primary goal of TKI therapy in patients with chronic phase-CML is to prevent disease progression to accelerated phase-CML or blast phase-CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase-CML.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide de Fase Crônica , Humanos , Crise Blástica/induzido quimicamente , Crise Blástica/tratamento farmacológico , Crise Blástica/genética , Inibidores de Proteínas Quinases/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Cromossomo Filadélfia , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Proteínas de Fusão bcr-abl/genéticaRESUMO
Melanin is a complex brown pigment, primarily responsible for the skin pigmentation. Therefore, cosmetic industries have always been in search of potent oxidative enzymes useful for melanin degradation, and to promise a fair complexion after using their products. In the present study, lignin peroxidase from Pseudomonas fluorescence LiP-RL5 isolate has been immobilized on super-paramagnetic nanoparticles to enhance its stability and reusability. The chitosan coated enzyme-nanomaterial complex (LiP@MFO-Chit) showed higher melanin decolorization (47.30 ± 2.3 %) compared to the graphene oxide coated nanoparticles (LiP@MFO-GO) (41.60 ± 1.6 %). Synthesized enzyme nanoparticle complexes showed microbicidal effect on skin infection causing pathogen, Pantoea agglomerans with an inhibitory zone of 6.0 ± 0.9 mm and 250 µg/100 µl minimum inhibitory concentration, and a 7.0 ± 1.5 mm zone and 170 µg/100 µl MIC for LiP@MFO-GO and LiP@MFO-Chit, respectively. Antioxidant potential of LiP@MFO-Chit and LiP@MFO-GO nano-conjugates showed a substantial DPPH scavenging activity of 75.7 % and 88.3 %, respectively. Therefore, LiP-nanoparticle hybrid complexes analyzed in this study are not only effective as skin whitening agents but they are potential molecules against various microbial skin infections as well as useful for different other biomedical applications like biorefinery, drug delivery, and dermatology, etc.
RESUMO
Blinatumomab, a bispecific antibody that directs CD3+ T cells to CD19+ tumor cells, shows variable efficacy in B-progenitor acute lymphoblastic leukemia (B-ALL). To determine tumor-intrinsic and -extrinsic determinants of response, we studied 44 adults with relapsed or refractory B-ALL (including 2 minimal residual disease positive) treated with blinatumomab using bulk tumor and single-cell sequencing. The overall response rate in patients with hematological disease was 55%, with a high response rate in those with CRLF2-rearranged Philadelphia chromosome-like ALL (12 [75%] of 16). Pretreatment samples of responders exhibited a tumor-intrinsic transcriptomic signature of heightened immune response. Multiple mechanisms resulted in loss of CD19 expression, including CD19 mutations, CD19-mutant allele-specific expression, low CD19 RNA expression, and mutations in CD19 signaling complex member CD81. Patients with low hypodiploid ALL were prone to CD19- relapse resulting from aneuploidy-mediated loss of the nonmutated CD19 allele. Increased expression of a CD19 isoform with intraexonic splicing of exon 2, CD19 ex2part, at baseline or during therapy was associated with treatment failure. These analyses demonstrate both tumor-intrinsic and -extrinsic factors influence blinatumomab response. We show that CD19 mutations are commonly detected in CD19- relapse during blinatumomab treatment. Identification of the CD19 ex2part splice variant represents a new biomarker predictive of blinatumomab therapy failure.
Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antígenos CD19/genética , Antígenos de Neoplasias/genética , Antineoplásicos Imunológicos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Terapia de Salvação , Subpopulações de Linfócitos T/efeitos dos fármacos , Adolescente , Adulto , Idoso , Sequência de Aminoácidos , Aneuploidia , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacologia , Antígenos CD19/biossíntese , Antígenos CD19/imunologia , Antígenos de Neoplasias/biossíntese , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/farmacologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Citotoxicidade Imunológica/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Recidiva , Estudos Retrospectivos , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Análise de Célula Única , Subpopulações de Linfócitos T/imunologia , Adulto JovemRESUMO
BACKGROUND: Therapy-related myeloid neoplasms (t-MN) are a leading cause of nonrelapse mortality after autologous peripheral blood stem cell transplantation (aPBSCT) in patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphomas (NHL). t-MN patients treated at an earlier stage of disease evolution have a better prognosis, and this presents a need to identify patients at risk for t-MN. METHODS: Using a prospective longitudinal study design, this study evaluated peripheral blood parameters pre-aPBSCT and on day 100, at 6 months, 1 year, 2 years, and 3 years in 304 patients treated with aPBSCT. The relation between peripheral blood parameters and subsequent development of t-MN was examined, and nomograms were developed to identify patients at risk for t-MN. RESULTS: Twenty-one patients developed t-MN at a median of 1.95 years post-aPBSCT. Hemoglobin, hematocrit, white blood cell, and platelet counts were lower among patients who developed t-MN compared to those who did not; these differences appeared soon after aPBSCT, persisted, and preceded development of t-MN. Older age at aPBSCT (hazard ratio [HR]per_year_increase = 1.08, P = .007), exposure to total body irradiation (TBI) (HR = 2.90, P = .04), and low 100-day platelet count (HRincrease_per_unit_decline_in_PLT = 1.01, P = .002) predicted subsequent t-MN. These parameters and primary diagnosis allowed identification of patients at high risk of t-MN (eg, an HL patient undergoing aPBSCT at the age of 70 years with TBI and with a day 100 PLT between 100,000 and 150,000 would have a 62% probability of developing t-MN at 6 years post-aPBSCT). CONCLUSIONS: Abnormalities in peripheral blood parameters can identify patients at high risk for t-MN after aPBSCT for HL or NHL, allowing opportunities to personalize close surveillance and possible disease-modifying interventions.
Assuntos
Linfoma , Transplante de Células-Tronco de Sangue Periférico , Idoso , Humanos , Estudos Longitudinais , Linfoma/etiologia , Linfoma/terapia , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Estudos Prospectivos , Transplante Autólogo/efeitos adversosRESUMO
Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive because of the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multiomics analysis of 74 CP and BC samples using whole-genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our data sets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called epigenetic switching, whereas PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. On the basis of these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP.
Assuntos
Crise Blástica/genética , Regulação Leucêmica da Expressão Gênica/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Complexo Repressor Polycomb 1/fisiologia , Complexo Repressor Polycomb 2/fisiologia , Diferenciação Celular , Imunoprecipitação da Cromatina , Metilação de DNA , Conjuntos de Dados como Assunto , Proteína Potenciadora do Homólogo 2 de Zeste/fisiologia , Dosagem de Genes , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 2/genética , Transcriptoma , Sequenciamento do Exoma , Sequenciamento Completo do GenomaRESUMO
The tenovins are a frequently studied class of compounds capable of inhibiting sirtuin activity, which is thought to result in increased acetylation and protection of the tumor suppressor p53 from degradation. However, as we and other laboratories have shown previously, certain tenovins are also capable of inhibiting autophagic flux, demonstrating the ability of these compounds to engage with more than one target. In this study, we present two additional mechanisms by which tenovins are able to activate p53 and kill tumor cells in culture. These mechanisms are the inhibition of a key enzyme of the de novo pyrimidine synthesis pathway, dihydroorotate dehydrogenase (DHODH), and the blockage of uridine transport into cells. These findings hold a 3-fold significance: first, we demonstrate that tenovins, and perhaps other compounds that activate p53, may activate p53 by more than one mechanism; second, that work previously conducted with certain tenovins as SirT1 inhibitors should additionally be viewed through the lens of DHODH inhibition as this is a major contributor to the mechanism of action of the most widely used tenovins; and finally, that small changes in the structure of a small molecule can lead to a dramatic change in the target profile of the molecule even when the phenotypic readout remains static.
Assuntos
Acetanilidas/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias/tratamento farmacológico , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Polifarmacologia , Sirtuína 1/antagonistas & inibidores , Tioureia/análogos & derivados , Proteína Supressora de Tumor p53/metabolismo , Autofagia , Proliferação de Células , Di-Hidro-Orotato Desidrogenase , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Tioureia/farmacologia , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genéticaRESUMO
Autologous blood or marrow transplantation (BMT) is a curative option for several types of childhood cancer. However, there is little information regarding the risk of late mortality. We examined all-cause mortality, relapse-related mortality (RRM), and nonrelapse-related mortality (NRM) in 2-year survivors of autologous BMT performed before age 22 between 1980 and 2010 at 1 of 2 US transplant centers. Vital status information was collected using medical records, National Death Index, and Accurint databases. Overall survival was calculated using Kaplan-Meier techniques. Cumulative incidence of mortality used competing risk methods. Standardized mortality ratio (SMR) was calculated using age-, sex-, and calendar-specific mortality rates from Centers for Disease Control and Prevention. Cox regression analysis was used to determine predictors of all-cause late mortality. Among the 345 2-year survivors, 103 deaths were observed, yielding an overall survival of 70.3% 15 years post-BMT. The leading causes of death included primary disease (50.0%), subsequent neoplasm (21.4%), and infection (18.2%). Overall, the cohort was at a 22-fold increased risk of late mortality (SMR, 21.8; 95% CI, 17.9-26.3), compared with the general population. Mortality rates remained elevated among the 10-year survivors (SMR, 20.6; 95% CI, 9.9-37.2) but approached those of the general population ≥15 years post-BMT. The 10-year cumulative incidence of RRM (14.3%) exceeded that of NRM (10.4%). The 10-year cumulative mortality rate declined over time (<1990, 35.1%; 1990-1999, 25.6%; 2000-2010, 21.8%; P = .05). In conclusion, childhood autologous BMT recipients have an increased risk of late mortality, compared with the general population. The late mortality rates have declined over the past 3 decades.
Assuntos
Transplante de Medula Óssea/mortalidade , Adolescente , Adulto , Causas de Morte , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Incidência , Lactente , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Linfoma/mortalidade , Linfoma/terapia , Masculino , Neuroblastoma/mortalidade , Neuroblastoma/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Fatores Sexuais , Fatores de Tempo , Transplante Autólogo/mortalidade , Adulto JovemRESUMO
Chronic myeloid leukemia (CML) stem/progenitor cells (SPCs) express a transcriptional program characteristic of proliferation, yet can achieve and maintain quiescence. Understanding the mechanisms by which leukemic SPCs maintain quiescence will help to clarify how they persist during long-term targeted treatment. We have identified a novel BCR-ABL1 protein kinase-dependent pathway mediated by the upregulation of hsa-mir183, the downregulation of its direct target early growth response 1 (EGR1), and, as a consequence, upregulation of E2F1. We show here that inhibition of hsa-mir183 reduced proliferation and impaired colony formation of CML SPCs. Downstream of this, inhibition of E2F1 also reduced proliferation of CML SPCs, leading to p53-mediated apoptosis. In addition, we demonstrate that E2F1 plays a pivotal role in regulating CML SPC proliferation status. Thus, for the first time, we highlight the mechanism of hsa-mir183/EGR1-mediated E2F1 regulation and demonstrate this axis as a novel, critical factor for CML SPC survival, offering new insights into leukemic stem cell eradication.
Assuntos
Fator de Transcrição E2F1/biossíntese , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Regulação Leucêmica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , RNA Neoplásico/metabolismo , Regulação para Cima , Animais , Proliferação de Células , Sobrevivência Celular , Fator de Transcrição E2F1/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Camundongos Knockout , MicroRNAs/genética , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/patologia , RNA Neoplásico/genética , Transdução de SinaisRESUMO
Aberrantly expressed cytokines in the bone marrow (BM) niche are increasingly recognized as critical mediators of survival and expansion of leukemic stem cells. To identify regulators of primitive chronic myeloid leukemia (CML) cells, we performed a high-content cytokine screen using primary CD34+ CD38low chronic phase CML cells. Out of the 313 unique human cytokines evaluated, 11 were found to expand cell numbers ≥2-fold in a 7-day culture. Focusing on novel positive regulators of primitive CML cells, the myostatin antagonist myostatin propeptide gave the largest increase in cell expansion and was chosen for further studies. Herein, we demonstrate that myostatin propeptide expands primitive CML and normal BM cells, as shown by increased colony-forming capacity. For primary CML samples, retention of CD34-expression was also seen after culture. Furthermore, we show expression of MSTN by CML mesenchymal stromal cells, and that myostatin propeptide has a direct and instant effect on CML cells, independent of myostatin, by demonstrating binding of myostatin propeptide to the cell surface and increased phosphorylation of STAT5 and SMAD2/3. In summary, we identify myostatin propeptide as a novel positive regulator of primitive CML cells and corresponding normal hematopoietic cells.
Assuntos
Células-Tronco Hematopoéticas , Leucemia Mielogênica Crônica BCR-ABL Positiva , Antígenos CD34 , Medula Óssea , Células Cultivadas , Citocinas , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Miostatina/genéticaRESUMO
Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide de Fase Crônica , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Oncologia , Cromossomo Filadélfia , Translocação GenéticaRESUMO
Tyrosine kinase inhibitors (TKIs) of the BCR-ABL fusion protein have dramatically changed the mortality of chronic myeloid leukemia (CML) but they carry a risk of serious vascular morbidity. While TKIs do not cure CML, daily oral administration of a TKI can control CML and TKIs are chronic medications. Interestingly, vascular complications can occur at any time a patient is on a TKI. Therefore, it is imperative that all care team members and patients are aware of and watching for possible vascular complications. In the following review, a case of arterial thrombosis secondary to the TKI ponatinib is presented as well as a discussion of thrombotic and vascular adverse events reported with TKIs. TKIs are metabolized through the cytochrome P450 system and important drug interactions to consider are reviewed. Finally, we present a multidisciplinary approach to the management of patients with CML on TKIs.
Assuntos
Anticoagulantes/uso terapêutico , Antineoplásicos/efeitos adversos , Estenose das Carótidas/tratamento farmacológico , Imidazóis/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas/efeitos adversos , Acidente Vascular Cerebral/tratamento farmacológico , Trombose/tratamento farmacológico , Idoso , Estenose das Carótidas/induzido quimicamente , Estenose das Carótidas/diagnóstico por imagem , Interações Medicamentosas , Feminino , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Terapia de Alvo Molecular/efeitos adversos , Fatores de Risco , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/diagnóstico por imagem , Trombose/induzido quimicamente , Trombose/diagnóstico por imagem , Resultado do TratamentoRESUMO
BACKGROUND: The authors examined Medicare spending and patient spending in older patients with chronic myelogenous leukemia (CML) over the first 5 years from the time of CML diagnosis in the tyrosine kinase inhibitor (TKI) era. METHODS: Medicare beneficiaries with CML who were diagnosed between 2007 and 2012 at age >65 years were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (805 beneficiaries). A noncancer Medicare beneficiary sample was frequency-matched based on age, sex, and race/ethnicity (805 individuals). Patients were followed until 5 years from diagnosis, disenrollment, death, or December 31, 2014, whichever came first. Total Medicare spending, service-specific spending, and amount owed by patients was estimated monthly and then summed over 60 months and averaged to generate annual spending. RESULTS: The median age at the time of diagnosis of CML was 76 years (range, 66-102 years). Overall, 51.4% of patients received TKIs (27.8% received imatinib alone), 28% received non-TKI therapy, and 21% received no treatment. The 5-year survival rate for patients with ≥85% time receiving TKIs was 79% compared with 76% for noncancer controls versus 62% for those with <85% time receiving TKIs. Annual Medicare spending was found to be significantly higher for patients treated with TKIs ($143,053) compared with those treated without TKIs ($41,268 vs $10,498 for noncancer controls). Annual patient cost responsibility was $11,712 per patient receiving any TKIs versus $7330 for those receiving non-TKI outpatient chemotherapy versus $3561 for noncancer controls. CONCLUSIONS: Older patients with CML with adequate time receiving TKI therapy have 5-year survival rates that are comparable to those of their counterparts without cancer. However, TKI use is accompanied with significant Medicare and patient spending; patients receiving multiple TKIs (ie, dasatinib or nilotinib along with imatinib) constitute the group with the highest spending.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/economia , Medicare/normas , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Programa de SEER , Estados UnidosRESUMO
BACKGROUND: Late mortality was investigated in patients with chronic myelogenous leukemia (CML) who underwent blood or bone marrow transplant (BMT) with or without prior tyrosine kinase inhibitor (TKI) therapy. METHODS: By using data from the Blood or Marrow Transplant Survivor Study, the authors examined late mortality in 447 patients with CML who underwent BMT between 1974 and 2010, conditional on surviving ≥2 years post-BMT. For vital status information, the medical records, the National Death Index, and the Accurint database were used. Standardized mortality ratios (SMRs) were calculated using general population age-specific, sex-specific, and calendar-specific mortality rates. Kaplan-Meier techniques and Cox regression were used for all-cause mortality analyses. Cumulative incidence and proportional subdistribution hazards models for competing risks were used for cause-specific mortality analyses. RESULTS: The 10-year overall survival rate was 65.7% and 73% for those who underwent transplant with and without pre-BMT exposure to TKI therapy, respectively. Patients who underwent transplant with and without pre-BMT TKI experienced SMRs of 6.4 and 6.4, respectively (P = .8); and the SMRs were 11.6 and 8.1, respectively, for those with high-risk disease (P = .2). Independent predictors of non-CML-related mortality included chronic graft-versus-host disease (hazard ratio [HR], 2.8; 95% CI, 1.8-4.4) and busulfan/cyclophosphamide conditioning (HR, 0.5; 95% CI, 0.3-0.9; reference, total body irradiation/cyclophosphamide conditioning). The 20-year cumulative incidence of CML-related and non-CML-related mortality was 6% and 36%, respectively, for the entire cohort. Both CML-related mortality (HR, 1.0; 95% CI, 0.1-12.6) and non-CML-related mortality (HR, 1.3; 95% CI, 0.6-3.1) were comparable for those with and without pre-BMT TKI therapy. CONCLUSIONS: The similar late mortality experienced by patients with CML who undergo transplantation with or without pre-BMT TKIs suggests that allogeneic BMT can be considered in the context of TKI intolerance or nonadherence. The prevention of post-BMT non-CML-related mortality could favorably affect long-term survival.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Adolescente , Adulto , Idoso , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/métodos , Causas de Morte , Criança , Pré-Escolar , Terapia Combinada , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Tyrosine kinase inhibitor (TKI) treatment of chronic myeloid leukemia (CML) has limited efficacy against leukemia stem cells (LSC) responsible for disease propagation, and most CML patients require continued TKI treatment to maintain remission. LSC maintenance is related, at least in part, to signals from the bone marrow microenvironment (BMM). Our previous studies have shown that Wnt signaling from the BMM contributes to preservation of CML LSC following TKI treatment. Secretion of Wnt ligands requires their modification by the O-acyl transferase Porcupine (PORCN). Here we investigated the activity of a potent and selective PORCN inhibitor, WNT974, against CML stem and progenitor cells. WNT974 efficiently antagonized Wnt signaling in human CML CD34+ cells, and in combination with the TKI nilotinib (NIL) significantly enhanced inhibition of proliferation and colony-forming potential of CML stem and progenitor cells and reduced their growth in immunodeficient mice in vivo, in comparison with NIL alone. Treatment of transgenic CML mice in vivo with NIL in combination with WNT974 significantly reduced leukemic stem and progenitor cell numbers, reduced regeneration of leukemic long-term hematopoietic stem cells in secondary transplant recipients, and enhanced survival of mice after discontinuation of treatment, in comparison with NIL alone. CML progenitors demonstrated enhanced sensitivity to Wnt stimulation, associated with increased expression of the FZD4 receptor. FZD4 knockdown inhibited CML progenitor growth. These results support further investigation of PORCN targeting to inhibit Wnt secretion and signaling and enhance targeting of CML stem cells while sparing their normal counterparts.
Assuntos
Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proteínas de Membrana/antagonistas & inibidores , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteínas Tirosina Quinases/antagonistas & inibidores , Aciltransferases , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteínas de Membrana/metabolismo , Camundongos Transgênicos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Células Tumorais Cultivadas , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
A major limitation of current leukemia treatment is that most patients ultimately relapse. Leukemia cells show heterogeneous potential and response to treatment. We have shown that primitive leukemia stem cells (LSC) in chronic myelogenous leukemia resist elimination by treatment, and persist as a source of relapse. The bone marrow microenvironment (BMM) plays a critical role in of hematopoietic stem cell maintenance and regulation. There is increasing interest in the role of the BMM in promoting LSC maintenance, resistance to therapy, and ultimately disease relapse. Recent studies have shown that leukemia-induced changes in the BMM provide a competitive growth advantage to LSC, and support their preservation after treatment. We are studying mechanisms of niche regulation of LSC to guide development of novel approaches to target LSC and enhance cures.
Assuntos
Resistencia a Medicamentos Antineoplásicos/fisiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Células-Tronco Neoplásicas/fisiologia , Inibidores de Proteínas Quinases/uso terapêutico , Nicho de Células-Tronco/fisiologia , Microambiente Tumoral/fisiologia , Apoptose , Medula Óssea , Proliferação de Células , Citocinas/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Células-Tronco Hematopoéticas , Humanos , Recidiva Local de Neoplasia , Indução de Remissão , Nicho de Células-Tronco/imunologia , Microambiente Tumoral/imunologiaRESUMO
Treatment of chronic myelogenous leukemia (CML) with BCR-ABL tyrosine kinase inhibitors (TKI) fails to eliminate leukemia stem cells (LSC). Patients remain at risk for relapse, and additional approaches to deplete CML LSC are needed to enhance the possibility of discontinuing TKI treatment. We have previously reported that expression of the pivotal proinflammatory cytokine interleukin-1 (IL-1) is increased in CML bone marrow. We show here that CML LSC demonstrated increased expression of the IL-1 receptors, IL-1 receptor accessory protein and IL-1 receptor type 1 (IL-1R1), and enhanced sensitivity to IL-1-induced NF-κB signaling compared with normal stem cells. Treatment with recombinant IL-1 receptor antagonist (IL-1RA) inhibited IL-1 signaling in CML LSC and inhibited growth of CML LSC. Importantly, the combination of IL-1RA with TKI resulted in significantly greater inhibition of CML LSC compared with TKI alone. Our studies also suggest that IL-1 signaling contributes to overexpression of inflammatory mediators in CML LSC, suggesting that blocking IL-1 signaling could modulate the inflammatory milieu. We conclude that IL-1 signaling contributes to maintenance of CML LSC following TKI treatment and that IL-1 blockade with IL-1RA enhances elimination of TKI-treated CML LSC. These results provide a strong rationale for further exploration of anti-IL-1 strategies to enhance LSC elimination in CML.