RESUMO
In nature, organisms are exposed to variable environmental conditions that impact their performance and fitness. Despite the ubiquity of environmental variability, substantial knowledge gaps in our understanding of organismal responses to nonconstant thermal regimes remain. In the present study, using zebrafish (Danio rerio) as a model organism, we applied geometric morphometric methods to examine how challenging but ecologically realistic diel thermal fluctuations experienced during different life stages influence adult body shape, size, and condition. Zebrafish were exposed to either thermal fluctuations (22-32°C) or a static optimal temperature (27°C) sharing the same thermal mean during an early period spanning embryonic and larval ontogeny (days 0-30), a later period spanning juvenile and adult ontogeny (days 31-210), or a combination of both. We found that body shape, size, and condition were affected by thermal variability, but these plasticity-mediated changes were dependent on the timing of ontogenetic exposure. Notably, after experiencing fluctuating temperatures during early ontogeny, females displayed a deeper abdomen while males displayed an elongated caudal peduncle region. Moreover, males displayed beneficial acclimation of body condition under lifelong fluctuating temperature exposure, whereas females did not. The present study, using ecologically realistic thermal regimes, provides insight into the timing of environmental experiences that generate phenotypic variation in zebrafish.
RESUMO
Bone loss occurs frequently following allogeneic haematopoietic stem cell transplantation (alloSCT). The Australasian Leukaemia and Lymphoma Group conducted a prospective phase II study of pretransplant zoledronic acid (ZA) and individualised post-transplant ZA to prevent bone loss in alloSCT recipients. Patients received ZA 4 mg before conditioning. Administration of post-transplant ZA from days 100 to 365 post alloSCT was determined by a risk-adapted algorithm based on serial bone density assessments and glucocorticoid exposure. Of 82 patients enrolled, 70 were alive and without relapse at day 100. A single pretransplant dose of ZA prevented femoral neck bone loss at day 100 compared with baseline (mean change -2.6±4.6%). Using the risk-adapted protocol, 42 patients received ZA between days 100 and 365 post alloSCT, and this minimised bone loss at day 365 compared with pretransplant levels (mean change -2.9±5.3%). Femoral neck bone loss was significantly reduced in ZA-treated patients compared with historical untreated controls at days 100 and 365. This study demonstrates that a single dose of ZA pre-alloSCT prevents femoral neck bone loss at day 100 post alloSCT, and that a risk-adapted algorithm is able to guide ZA administration from days 100 to 365 post transplant and minimise further bone loss.
Assuntos
Densidade Óssea/fisiologia , Difosfonatos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imidazóis/uso terapêutico , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo/efeitos adversos , Difosfonatos/farmacologia , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imidazóis/farmacologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Ácido ZoledrônicoRESUMO
Tyrosine kinase inhibitor (TKI) therapy results in excellent responses in the majority of patients with chronic myeloid leukaemia. First-line imatinib treatment, with selective switching to nilotinib when patients fail to meet specific molecular targets or for imatinib intolerance, results in excellent overall molecular responses and survival. However, this strategy is less effective in cases of primary imatinib resistance; moreover, 25% of patients develop secondary resistance such that 20-35% of patients initially treated with imatinib will eventually experience treatment failure. Early identification of these patients is of high clinical relevance. Since the drug efflux transporter ABCB1 has previously been implicated in TKI resistance, we determined if early increases in ABCB1 mRNA expression (fold change from diagnosis to day 22 of imatinib therapy) predict for patient response. Indeed, patients exhibiting a high fold rise (⩾2.2, n=79) were significantly less likely to achieve early molecular response (BCR-ABL1IS ⩽10% at 3 months; P=0.001), major molecular response (P<0.0001) and MR4.5 (P<0.0001). Additionally, patients demonstrated increased levels of ABCB1 mRNA before the development of mutations and/or progression to blast crisis. Patients with high fold rise in ABCB1 mRNA were also less likely to achieve major molecular response when switched to nilotinib therapy (49% vs 82% of patients with low fold rise). We conclude that early evaluation of the fold change in ABCB1 mRNA expression may identify patients likely to be resistant to first- and second-generation TKIs and who may be candidates for alternative therapy.
Assuntos
Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/análise , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Células Cultivadas , Resistencia a Medicamentos Antineoplásicos , Expressão Gênica , Humanos , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Valor Preditivo dos Testes , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/análiseRESUMO
Background: The aim of this study was to evaluate patient preference and satisfaction for the subcutaneous (s.c.) versus intravenous (i.v.) formulation of rituximab given with chemotherapy in previously untreated patients with CD20+ diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Patients and methods: Patients received eight cycles of rituximab according to 2 schedules: Arm A received 1 cycle rituximab i.v. (375 mg/m2) and 3 cycles rituximab s.c. (1400 mg) then 4 cycles rituximab i.v.; Arm B received 4 cycles rituximab i.v. (375 mg/m2) then 4 cycles rituximab s.c. (1400 mg). Alongside rituximab, both arms received 6-8 cycles of chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP), cyclophosphamide, vincristine, prednisone (CVP), or bendamustine as per standard local practice). Preference for s.c. or i.v. administration was evaluated using the Patient Preference Questionnaire (PPQ) at cycles 6 and 8. Patient satisfaction and convenience were assessed using the Cancer Therapy Satisfaction Questionnaire (CTSQ), and Rituximab Administration Satisfaction Questionnaire (RASQ) at cycles 4 and 8. Results: At the primary data cut-off (19 January 2015), the intent-to-treat population comprised 743 patients. The majority had DLBCL (63%) and baseline characteristics were balanced between arms. At cycle 8, 81% of patients completing the PPQ preferred rituximab s.c. Preference was not impacted by treatment sequence or disease type. Patient satisfaction as measured by RASQ was higher for s.c. versus i.v. CTSQ scores were similar between arms. Adverse events were generally balanced between administration routes and no new safety signals were detected. Conclusion: Most previously untreated patients with CD20+ DLBCL or FL preferred s.c. to i.v. rituximab administration. Patient satisfaction with rituximab treatment was generally greater with s.c. administration. Registered clinical trial number: NCT01724021 (ClinicalTrials.gov).
Assuntos
Antineoplásicos/administração & dosagem , Linfoma Folicular/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Preferência do Paciente , Rituximab/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos Cross-Over , Feminino , Humanos , Infusões Intravenosas , Infusões Subcutâneas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Rituximab/efeitos adversosRESUMO
We retrospectively evaluated the use of computed tomography abdomen and pelvis (CTAP) in febrile neutropenic autologous stem cell transplant (ASCT) and acute myeloid leukaemia (AML) patients. CTAP was more common in ASCT patients (59%) compared with AML (31%; P < 0.001). Although abnormal findings were reported in 51%, only 10% resulted in therapy change (addition of anaerobic antibiotic/bowel rest), which would have otherwise been instituted based on clinical grounds. CTAP in these patients rarely provide useful information unsuspected clinically.
Assuntos
Abdome/diagnóstico por imagem , Neutropenia Febril/diagnóstico por imagem , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/terapia , Pelve/diagnóstico por imagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Austrália , Neutropenia Febril/tratamento farmacológico , Feminino , Febre/tratamento farmacológico , Hematologia , Humanos , Leucemia Mieloide Aguda/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
There is a paucity of evidence supporting the necessity or duration of Pneumocystis jirovecii and antiviral prophylaxis as well as revaccination following autologous stem cell transplant (ASCT). A survey aimed at evaluating these policies was distributed to 34 ASCT centres across Australasia. The 26 survey respondents demonstrated significant heterogeneity in their infection prophylaxis and revaccination strategy post-transplant despite the availability of consensual guidelines.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunização Secundária/normas , Micoses/prevenção & controle , Profilaxia Pós-Exposição/normas , Viroses/prevenção & controle , Austrália/epidemiologia , Humanos , Imunização Secundária/métodos , Micoses/etiologia , Nova Zelândia/epidemiologia , Profilaxia Pós-Exposição/métodos , Inquéritos e Questionários , Transplante Autólogo/efeitos adversos , Viroses/etiologiaRESUMO
Invasive fungal disease (IFD) causes significant morbidity and mortality in patients undergoing allogeneic haemopoietic stem cell transplantation or chemotherapy for haematological malignancy. Much of these adverse outcomes are due to the limited ability of traditional diagnostic tests (i.e. culture and histology) to make an early and accurate diagnosis. As persistent or recurrent fevers of unknown origin (PFUO) in neutropenic patients despite broad-spectrum antibiotics have been associated with the development of IFD, most centres have traditionally administered empiric antifungal therapy (EAFT) to patients with PFUO. However, use of an EAFT strategy has not been shown to have an overall survival benefit and is associated with excessive antifungal therapy use. As a result, the focus has shifted to developing more sensitive and specific diagnostic tests for early and more targeted antifungal treatment. These tests, including the galactomannan enzyme-linked immunosorbent assay and Aspergillus polymerase chain reaction (PCR), have enabled the development of diagnostic-driven antifungal treatment (DDAT) strategies, which have been shown to be safe and feasible, reducing antifungal usage. In addition, the development of effective antifungal prophylactic strategies has changed the landscape in terms of the incidence and types of IFD that clinicians have encountered. In this review, we examine the current role of EAFT and provide up-to-date data on the newer diagnostic tests and algorithms available for use in EAFT and DDAT strategies, within the context of patient risk and type of antifungal prophylaxis used.
Assuntos
Aspergilose/prevenção & controle , Candidíase/prevenção & controle , Febre de Causa Desconhecida/microbiologia , Neoplasias Hematológicas/imunologia , Transplante de Células-Tronco Hematopoéticas , Profilaxia Pré-Exposição , Algoritmos , Antifúngicos/uso terapêutico , Consenso , Estado Terminal , Esquema de Medicação , Medicina Baseada em Evidências , Febre de Causa Desconhecida/tratamento farmacológico , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Humanos , Hospedeiro Imunocomprometido , Reação em Cadeia da Polimerase , Guias de Prática Clínica como AssuntoRESUMO
There is a strong argument for the use of antifungal prophylaxis in high-risk patients given the significant mortality associated with invasive fungal disease, the late identification of these infections, and the availability of safe and well-tolerated prophylactic medications. Clinical decisions about which patients should receive prophylaxis and choice of antifungal agent should be guided by risk stratification, knowledge of local fungal epidemiology, the efficacy and tolerability profile of available agents, and estimates such as number needed to treat and number needed to harm. There have been substantial changes in practice since the 2008 guidelines were published. These include the availability of new medications and/or formulations, and a focus on refining and simplifying patient risk stratification. Used in context, these guidelines aim to assist clinicians in providing optimal preventive care to this vulnerable patient demographic.
Assuntos
Antifúngicos/uso terapêutico , Neoplasias Hematológicas/imunologia , Transplante de Células-Tronco Hematopoéticas , Infecções Oportunistas/microbiologia , Infecções Oportunistas/prevenção & controle , Profilaxia Pré-Exposição , Aspergilose/prevenção & controle , Candidíase/prevenção & controle , Consenso , Análise Custo-Benefício , Fidelidade a Diretrizes , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Testes de Sensibilidade Microbiana , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Profilaxia Pré-Exposição/economia , Medição de RiscoRESUMO
Vanishing bile duct syndrome (VBDS) in association with Hodgkin lymphoma (HL) is well described but not well understood. We report an unusual case of a 75-year-old patient presenting with biopsy-proven VBDS and immunodeficiency, without identifiable cause, which showed a waxing and waning course, culminating in the development of HL 18 months later. To our knowledge, this is the first adult case in which VBDS preceded the diagnosis of HL by such a long period.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ductos Biliares Intra-Hepáticos/patologia , Colagogos e Coleréticos/administração & dosagem , Colestase/diagnóstico , Doença de Hodgkin/diagnóstico , Ácido Ursodesoxicólico/administração & dosagem , Idoso , Bleomicina/administração & dosagem , Colestase/tratamento farmacológico , Colestase/imunologia , Doxorrubicina/administração & dosagem , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/imunologia , Humanos , Hospedeiro Imunocomprometido , Masculino , Neutropenia , Síndrome , Resultado do TratamentoRESUMO
The effectiveness of ethanol locks for prevention of central venous catheter (CVC)-associated bloodstream infection (CLABSI) in adult haematology patients has not been thoroughly evaluated. This study aimed to compare prospectively heparinized saline with 70% ethanol locks using 2 h dwell time in patients with tunnelled CVCs. In saline (N = 43) and ethanol (N = 42) groups, CLABSI rates were 6.0 [95% confidence interval (CI): 3.4-9.8] and 4.1 (95% CI: 1.9-7.7) per 1000 CVC days, respectively (P = 0.42). In the ethanol group, two exit-site infections and one tunnel/pocket infection were observed. Reduction in device-associated infection was not achieved with prophylactic 70% ethanol locks in patients with haematological malignancy and tunnelled CVCs.
Assuntos
Anticoagulantes/farmacologia , Infecções Relacionadas a Cateter/prevenção & controle , Cateteres Venosos Centrais/microbiologia , Desinfetantes/farmacologia , Etanol/farmacologia , Heparina/farmacologia , Sepse/prevenção & controle , Adolescente , Adulto , Idoso , Feminino , Neoplasias Hematológicas/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemAssuntos
Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/uso terapêutico , Receptores Fc/uso terapêutico , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/uso terapêutico , Trombopoetina/uso terapêutico , Idoso , Avaliação de Medicamentos , Quimioterapia Combinada , Feminino , Infecções por HIV/complicações , Hepatite C/complicações , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Prednisolona/uso terapêutico , Púrpura Trombocitopênica Idiopática/etiologia , Fatores de TempoRESUMO
Therapeutic options are limited for elderly patients with acute myeloid leukemia (AML). A phase Ib/II study was undertaken to evaluate the maximum-tolerated dose (MTD) and preliminary efficacy of the pan-histone deacetylase inhibitor panobinostat (LBH589) in combination with azacitidine in patients with AML or high-risk myelodysplastic syndrome (MDS) naïve to intensive chemotherapy. Thirty-nine patients (AML=29, MDS=10) received azacitidine 75 mg/m(2) subcutaneously (days 1-5) and oral panobinostat (starting on day 5, thrice weekly for seven doses) in 28-day cycles until toxicity or disease progression. Dose-limiting toxicities during the phase Ib stage were observed in 0/4 patients receiving 10 mg panobinostat, in 1/7 patients (fatigue) receiving 20 mg, in 1/6 patients (fatigue) receiving 30 mg and in 4/5 patients (fatigue, syncope, hyponatremia and somnolence) receiving 40 mg. In phase II, an additional 17 patients received panobinostat at a MTD of 30 mg. The overall response rate (ORR=CR+CRi+PR) in patients with AML was 31% (9/29) and that in patients with MDS was 50% (5/10). After a median follow-up of 13 months, the median overall survival was 8 and 16 months in patients with AML and MDS, respectively. Increased histone H3 and H4 acetylation was a useful early biomarker of clinical response. Combining panobinostat with azacitidine was tolerable and clinically active in high-risk MDS/AML patients, warranting further exploration.
RESUMO
Anti-thymocyte globulin (ATG) is polyclonal, containing Ab specificities capable of binding to various immune-cell subsets implicated in the pathogenesis of GVHD, including T cells, B cells, natural killer cells, monocytes/macrophages, neutrophils and DC. We wished to determine which ATG specificities are important for GVHD prevention. We measured day 7 serum levels of 23 ATG specificities in 120 hematopoietic cell transplant recipients whose myeloablative conditioning included 4.5 mg/kg ATG (thymoglobulin). High levels of ATG specificities capable of binding to T- and B-cell subsets were associated with a low likelihood of acute GVHD (aGVHD). High levels of these ATG specificities were associated with increased rates of viral but not bacterial or fungal infections. They were not associated with an increased risk of malignancy relapse; on the contrary, high levels of ATG specificities capable of binding to regulatory T cells and invariant NKT cells were associated with a low risk of relapse. In conclusion, high levels of ATG antibodies to Ag(s) expressed on T and B cells are associated with a low risk of aGVHD and a high risk of viral but not bacterial or fungal infections. These antibodies have neutral or beneficial effects on relapse.
Assuntos
Soro Antilinfocitário/uso terapêutico , Linfócitos B/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/uso terapêutico , Linfócitos T/imunologia , Adulto , Idoso , Alberta/epidemiologia , Anemia Aplástica/terapia , Soro Antilinfocitário/efeitos adversos , Soro Antilinfocitário/sangue , Soro Antilinfocitário/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Estudos de Coortes , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/fisiopatologia , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/sangue , Imunossupressores/metabolismo , Incidência , Leucemia/prevenção & controle , Leucemia/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/prevenção & controle , Síndromes Mielodisplásicas/terapia , Infecções Oportunistas/epidemiologia , Infecções Oportunistas/etiologia , Infecções Oportunistas/virologia , Prevenção Secundária , Índice de Gravidade de Doença , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Viroses/epidemiologia , Viroses/etiologia , Viroses/virologia , Adulto JovemRESUMO
Chronic GVHD (cGVHD) is an important complication of allogeneic hematopoietic cell transplantation (HCT). As preemptive therapy might be efficacious if administered early post transplant, we set out to determine whether cGVHD can be predicted from the serum level of a biomarker on day 7 or 28. In a discovery cohort of 153 HCT recipients conditioned with BU, fludarabine and rabbit antithymocyte globulin (ATG), we determined serum levels of B-cell-activating factor, vascular endothelial growth factor, soluble TNF-α receptor 1, soluble IL2 receptor α, IL5, IL6, IL7, IL15, γ-glutamyl transpeptidase, cholinesterase, total protein, urea and ATG. Patients with low levels of IL15 (<30.6 ng/L) on day 7 had 2.7-fold higher likelihood of developing significant cGVHD (needing systemic immunosuppressive therapy) than patients with higher IL15 levels (P<0.001). This was validated in a validation cohort of 105 similarly-treated patients; those with low IL15 levels had 3.7-fold higher likelihood of developing significant cGVHD (P=0.001). Low IL15 was not associated with relapse; it trended to be associated with acute GVHD and was associated with low infection rates. In conclusion, low IL15 levels on day 7 are predictive of cGVHD, and thus could be useful in guiding preemptive therapy.
Assuntos
Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Interleucina-15/sangue , Leucemia/sangue , Adulto , Idoso , Doença Crônica , Estudos de Coortes , Feminino , Doença Enxerto-Hospedeiro/imunologia , Humanos , Interleucina-15/imunologia , Leucemia/cirurgia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Adulto JovemRESUMO
The relationship between CsA levels and area under the curve (AUC) in allo-SCT recipients, and the effect of age, concomitant use of steroid and MDR-1 polymorphism on this relationship remain largely unexplored. Steady-state CsA blood concentrations at time 0 (C0), 1 (C1), 1.5 (C1.5), 2 (C2), 3 (C3), 4 (C4), 6 (C6), 8 (C8) and 12 (C12) h post oral CsA dose were taken from 27 consenting allo-SCT recipients (receiving myeloablative or non-myeloablative conditioning) at D(15)-D(25) (all participants) and D(40)-D(80) (participants with myeloablative conditioning). The CsA AUC(0-4h), AUC(0-8h) and AUC(0-12h) were determined using trapezoidal rule, and the relationships between AUCs and CsA concentrations at various time points were examined. Poor correlation was observed between C0 and AUC(0-4h) (r(2)=0.15), AUC(0-8h) (r(2)=0.21) and AUC(0-12h) (r(2)=0.53). C2 was better correlated with AUC(0-4h) (r(2)=0.88), AUC(0-8h) (r(2)=0.76) and AUC(0-12h) (r(2)=0.83). The aforementioned factors did not influence the observed relationship. CsA levels taken at 2 h post oral CsA administration may represent the optimal time point for monitoring the biological effects of calcineurin inhibitors in allo-SCT recipients.
Assuntos
Ciclosporina/administração & dosagem , Ciclosporina/farmacocinética , Doença Enxerto-Hospedeiro/prevenção & controle , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Área Sob a Curva , Relação Dose-Resposta a Droga , Feminino , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Transplante HomólogoAssuntos
Dor Abdominal/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Hemoglobinúria Paroxística/tratamento farmacológico , Intestino Delgado/irrigação sanguínea , Isquemia/tratamento farmacológico , Microvasos , Dor Abdominal/diagnóstico , Dor Abdominal/etiologia , Adulto , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/diagnóstico , Humanos , Intestino Delgado/efeitos dos fármacos , Isquemia/complicações , Isquemia/diagnóstico , Masculino , Microvasos/efeitos dos fármacos , Microvasos/patologia , Prevenção SecundáriaRESUMO
Around 40-50% of patients with chronic myeloid leukemia (CML) who achieve a stable complete molecular response (CMR; undetectable breakpoint cluster region-Abelson leukemia gene human homolog 1 (BCR-ABL1) mRNA) on imatinib can stop therapy and remain in CMR, at least for several years. This raises the possibility that imatinib therapy may not need to be continued indefinitely in some CML patients. Two possible explanations for this observation are (1) CML has been eradicated or (2) residual leukemic cells fail to proliferate despite the absence of ongoing kinase inhibition. We used a highly sensitive patient-specific nested quantitative PCR to look for evidence of genomic BCR-ABL1 DNA in patients who sustained CMR after stopping imatinib therapy. Seven of eight patients who sustained CMR off therapy had BCR-ABL1 DNA detected at least once after stopping imatinib, but none has relapsed (follow-up 12-41 months). BCR-ABL1 DNA levels increased in all of the 10 patients who lost CMR soon after imatinib cessation, whereas serial testing of patients in sustained CMR showed a stable level of BCR-ABL1 DNA. This more sensitive assay for BCR-ABL1 provides evidence that even patients who maintain a CMR after stopping imatinib may harbor residual leukemia. A search for intrinsic or extrinsic (for example, immunological) causes for this drug-free leukemic suppression is now indicated.
Assuntos
Antineoplásicos/uso terapêutico , DNA de Neoplasias/genética , Proteínas de Fusão bcr-abl/genética , Doença Enxerto-Hospedeiro/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Reação em Cadeia da Polimerase/métodos , Pirimidinas/uso terapêutico , Adulto , Idoso , Benzamidas , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Sensibilidade e Especificidade , Taxa de Sobrevida , Resultado do TratamentoAssuntos
Fluordesoxiglucose F18 , Leucemia Mieloide Aguda/diagnóstico por imagem , Leucemia Mieloide Aguda/cirurgia , Tomografia por Emissão de Pósitrons/métodos , Complicações Pós-Operatórias/diagnóstico por imagem , Transplante de Células-Tronco , Adulto , Gerenciamento Clínico , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Prevenção Secundária , Transplante de Células-Tronco/efeitos adversos , Transplante Homólogo , Resultado do TratamentoRESUMO
Fractionated TBI and etoposide (FTBI-VP16) conditioning is effective therapy for patients receiving allogeneic stem cell transplants for ALL. One of the major dose-limiting toxicities with this regimen is mucositis although its effect on patients and hospital resources is not well described. To determine the severity of mucositis (WHO grade 3-4) experienced and assess resource utilisation, we compared the non-haematological toxicities of 38 patients receiving FTBI-VP16 with 104 patients receiving CY and TBI (CYTBI). FTBI-VP16 patients were more likely to develop severe mucositis (odds ratio (OR) 6.0 (95% confidence interval (CI) 1.36, 54.42), P<0.01) and its duration was longer (11.5 vs 8 days, P<0.01). Resource utilisation was considerably higher especially in the use and duration of i.v. narcotics and parenteral nutrition, nursing care requirements and plt-transfusion support. Patients receiving FTBI-VP16 conditioning are ideal candidates for new therapies to prevent or reduce the severity of mucositis.
Assuntos
Ciclosporina/administração & dosagem , Etoposídeo/efeitos adversos , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Mucosite/induzido quimicamente , Condicionamento Pré-Transplante/efeitos adversos , Adolescente , Adulto , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Quimioterapia Combinada , Etoposídeo/administração & dosagem , Feminino , Humanos , Imunossupressores/administração & dosagem , Leucemia/terapia , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Irradiação Corporal Total/efeitos adversos , Adulto JovemRESUMO
GVHD is partly mediated by host APCs that activate donor T cells. Extracorporeal photopheresis (ECP) can modulate APC function and benefit some patients with GVHD. We report the results of a study using ECP administered before a standard myeloablative preparative regimen intended to prevent GVHD. Grades II-IV acute GVHD developed in 9 (30%) of 30 recipients of HLA-matched related transplants and 13 (41%) of 32 recipients of HLA-matched unrelated or HLA-mismatched related donor transplants. Actuarial estimates of overall survival (OS) at day 100 and 1-year post transplant were 89% (95% CI, 78-94%) and 77% (95% CI, 64-86%), respectively. There were no unexpected adverse effects of ECP. Historical controls receiving similar conditioning and GVHD prophylaxis regimens but no ECP were identified from the database of the Center for International Blood and Marrow Transplant Research and multivariate analysis indicated a lower risk of grades II-IV acute GVHD in patients receiving ECP (P=0.04). Adjusted OS at 1 year was 83% in the ECP study group and 67% in the historical control group (relative risk 0.44; 95% CI, 0.24-0.80) (P=0.007). These preliminary data may indicate a potential survival advantage with ECP for transplant recipients undergoing standard myeloablative hematopoietic cell transplantation.