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Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening autoimmune disorder caused by ADAMTS13 deficiency. Caplacizumab, an anti-VWF nanobody, is approved for iTTP treatment, reducing the need for therapeutic plasma exchange (TPE) and improving platelet count recovery and survival. We conducted a retrospective study on 42 acute iTTP cases in Austria and Germany, treated with a modified regimen aimed at avoiding TPE if platelet count increased after the first caplacizumab dose. Baseline characteristics and patient outcomes were compared with a control group of 59 patients with iTTP, receiving frontline treatment with TPE, caplacizumab, and immunosuppression. The main outcome was the time to platelet count normalization. Secondary outcomes included clinical response, exacerbation, refractory iTTP, iTTP-related deaths, and the time to platelet count doubling. The median time to platelet count normalization was similar between the two cohorts (3 and 4 days; P = 0.31). There were no significant differences in clinical response, exacerbations, refractoriness, iTTP-related deaths, or time to platelet count doubling reflecting the short-term treatment response. Four patients did not respond to the first caplacizumab dose and TPE was subsequently initiated. Cytomegalovirus infection, HIV/hepatitis B co-infection, an ovarian teratoma with associated anti-platelet antibodies, and multiple platelet transfusion before the correct diagnosis may have impeded immediate treatment response in these patients. In conclusion, caplacizumab and immunosuppression alone, without TPE, rapidly controlled thrombotic microangiopathy and achieved a sustained clinical response in iTTP. Our study provides a basis for TPE-free iTTP management in experienced centers via shared decision-making between patients and treating physicians.
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Mutant calreticulin (CALR) proteins resulting from a -1/+2 frameshifting mutation of the CALR exon 9 carry a novel C-terminal amino acid sequence and drive the development of myeloproliferative neoplasms (MPNs). Mutant CALRs were shown to interact with and activate the thrombopoietin receptor (TpoR/MPL) in the same cell. We report that mutant CALR proteins are secreted and can be found in patient plasma at levels up to 160 ng/mL, with a mean of 25.64 ng/mL. Plasma mutant CALR is found in complex with soluble transferrin receptor 1 (sTFR1) that acts as a carrier protein and increases mutant CALR half-life. Recombinant mutant CALR proteins bound and activated the TpoR in cell lines and primary megakaryocytic progenitors from patients with mutated CALR in which they drive thrombopoietin-independent colony formation. Importantly, the CALR-sTFR1 complex remains functional for TpoR activation. By bioluminescence resonance energy transfer assay, we show that mutant CALR proteins produced in 1 cell can specifically interact in trans with the TpoR on a target cell. In comparison with cells that only carry TpoR, cells that carry both TpoR and mutant CALR are hypersensitive to exogenous mutant CALR proteins and respond to levels of mutant CALR proteins similar to those in patient plasma. This is consistent with CALR-mutated cells that expose TpoR carrying immature N-linked sugars at the cell surface. Thus, secreted mutant CALR proteins will act more specifically on the MPN clone. In conclusion, a chaperone, CALR, can turn into a rogue cytokine through somatic mutation of its encoding gene.
Assuntos
Transtornos Mieloproliferativos , Neoplasias , Humanos , Citocinas/metabolismo , Calreticulina/genética , Transtornos Mieloproliferativos/genética , Mutação , Fatores Imunológicos , Janus Quinase 2/genéticaRESUMO
BACKGROUND AIMS: Cyclosporin A (CsA) remains a major component of immunosuppressive regimens applied in allogeneic hematopoietic stem cell transplantation (HSCT). The impact of CsA trough levels during the first weeks after HSCT has not yet been investigated specifically in anti-T-lymphocyte globulin (ATLG)-based HSCT from matched related and unrelated donors. METHODS: To address this issue, we have retrospectively examined 307 consecutive matched related (n = 145) and unrelated (n = 162) HSCTs, using peripheral blood stem cells or bone marrow. HSCTs for active, uncontrolled malignancies were excluded. The initial three weeks' average mean CsA trough levels were analyzed in landmark and multi-state models, using a cut-off of 200 ng/mL. RESULTS: CsA levels >200 ng/mL were associated with a reduced risk of acute graft-versus-host disease (GVHD) grade 3-4 at the first-week landmark (subdistribution hazard ratio [SHR] 0.59, P = 0.03) and the second-week landmark (SHR 0.48, P = 0.004), whereas there was no impact at the third-week landmark (HR 0.87, P = 0.69). This was supported by a multi-state model, in which week 1 (hazard ratio [HR] 0.53, P = 0.006) and week 2 (HR 0.48, P = 0.003), but not week 3 (HR 0.80, P = 0.44) CsA levels >200 ng/mL were associated with a reduced acute GVHD 3-4 risk. Relapse incidence was not significantly affected by week 1 through 3 CsA levels. Despite ATLG's inherent GVHD-preventive properties, week 1 CsA trough levels >200 ng/mL following ATLG-based HSCT (n = 220) were associated with a significantly reduced risk of non-relapse mortality (SHR 0.52, P = 0.02) and improved overall survival (HR 0.61, P = 0.02). CONCLUSIONS: Our findings emphasize the continuing importance of ensuring CsA levels ≥200 ng/mL immediately post-transplant in the setting of ATLG-based HSCT.
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Ciclosporina , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante Homólogo , Humanos , Ciclosporina/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Transplante Homólogo/métodos , Estudos Retrospectivos , Depleção Linfocítica/métodos , Linfócitos T/imunologia , Imunossupressores/uso terapêutico , Adolescente , Idoso , Doença Aguda , Adulto JovemRESUMO
Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.
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Interferon alfa-2 , Interferon-alfa , Polietilenoglicóis , Proteínas Recombinantes , Trombocitemia Essencial , Humanos , Trombocitemia Essencial/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Interferon alfa-2/uso terapêutico , Interferon alfa-2/efeitos adversos , Interferon-alfa/uso terapêutico , Interferon-alfa/efeitos adversos , Estudos Prospectivos , Masculino , Feminino , Resultado do Tratamento , Adulto , Pessoa de Meia-Idade , IdosoRESUMO
Myelofibrosis (MF) is a clonal myeloproliferative neoplasm, typically associated with disease-related symptoms, splenomegaly, cytopenias and bone marrow fibrosis. Patients experience a significant symptom burden and a reduced life expectancy. Patients with MF receive ruxolitinib as the current standard of care, but the depth and durability of responses and the percentage of patients achieving clinical outcome measures are limited; thus, a significant unmet medical need exists. Pelabresib is an investigational small-molecule bromodomain and extraterminal domain inhibitor currently in clinical development for MF. The aim of this article is to describe the design of the ongoing, global, phase III, double-blind, placebo-controlled MANIFEST-2 study evaluating the efficacy and safety of pelabresib and ruxolitinib versus placebo and ruxolitinib in patients with JAKi treatment-naive MF. Clinical Trial Registration: NCT04603495 (ClinicalTrials.gov).
Myelofibrosis (MF) is a rare type of blood cancer that interferes with the process of blood cell production by the bone marrow. In patients with MF, the bone marrow becomes overactive, leading to scarring and subsequently a lack of healthy blood cells being produced. The main symptoms of MF include anemia, fatigue, weakness and pain or discomfort in the abdomen. MF is associated with a shortened life expectancy. The current go-to treatment for MF is ruxolitinib. However, ruxolitinib has shown limited efficacy in improving clinical symptoms long term; so, new safe and effective treatments are needed. Pelabresib is a novel drug currently in clinical development for treating MF. The aim of this article is to describe the design of the ongoing, global phase III MANIFEST-2 study. MANIFEST-2 is evaluating the efficacy and safety of pelabresib and ruxolitinib versus placebo and ruxolitinib in patients with MF.
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Protocolos de Quimioterapia Combinada Antineoplásica , Mielofibrose Primária , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Humanos , Inibidores de Janus Quinases/uso terapêutico , Nitrilas/uso terapêutico , Mielofibrose Primária/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
Active malignancy is an absolute contraindication to kidney transplantation. As for chronic myeloid leukemia (CML), a Philadelphia chromosome-positive myeloproliferative neoplasm, the introduction of tyrosine kinase inhibitors has transformed CML from a lethal into a manageable chronic disease with a close-to-normal life expectancy. To date it is unknown whether kidney transplantation can be safely performed in patients with pre-existing CML. We describe the clinical course of a 57-year-old male patient with chronic kidney disease caused by reflux nephropathy. This patient had undergone first kidney transplantation 20 years earlier and had again been on chronic hemodialysis for 6 years when CML was diagnosed. First-line therapy with 400 mg imatinib daily was well tolerated and induced an optimal cytogenetic and molecular response 3 months after initiation. One and a half years after CML diagnosis, a second kidney transplantation from a deceased donor was performed. Immunosuppression included basiliximab, tacrolimus, mycophenolate mofetil, and corticosteroids. Currently, 2 years posttransplant, renal allograft function is stable (serum creatinine 1.09 mg/dL, estimated glomerular filtration rate 75 mL/min per 1.73 m2 ), and CML remains in deep molecular remission with imatinib. Imatinib-treated CML in deep molecular remission could be regarded as inactive malignancy and may therefore not be viewed as an absolute contraindication to kidney transplantation.
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Antineoplásicos , Transplante de Rim , Leucemia Mielogênica Crônica BCR-ABL Positiva , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Doença Crônica , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêuticoRESUMO
OBJECTIVES: Cell counts have a significant impact on the complex mechanism of thrombosis in patients with essential thrombocythemia (ET). We recently demonstrated a considerable impact of white blood cell (WBC) counts on thrombotic risk in patients with optimized platelet counts by analysing a large anagrelide registry. In contrast, the current analysis of the registry aimed to estimate the influence of platelet counts on thrombotic risk in patients with optimized WBC counts. METHODS: Cox regression analysis and Kaplan-Meier plot were applied on all patients in the registry with optimized WBC counts. RESULTS: By using the calculated cut-off of 593 G/L for platelets, Cox regression analysis revealed a clear influence of elevated platelet counts on the occurrence of a major thrombotic event (P < .001). A Kaplan-Meier plot revealed a markedly shorter time to a major thrombotic event for patients with platelet counts above the cut-off (P < .001). CONCLUSIONS: The data show clear impact of platelet lowering on the thrombotic risk in ET patients with normal WBC counts. Therefore, selective platelet lowering with anagrelide appears sufficient for thrombotic risk reduction in WHO-diagnosed ET patients lacking leukocytosis.
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Plaquetas/metabolismo , Contagem de Leucócitos , Trombocitemia Essencial/sangue , Trombocitemia Essencial/complicações , Trombose/sangue , Trombose/etiologia , Idoso , Biomarcadores , Suscetibilidade a Doenças , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Prognóstico , Sistema de Registros , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/epidemiologia , Trombose/diagnóstico , Trombose/epidemiologiaRESUMO
The goal of current management of patients with chronic phase chronic myeloid leukemia (CML) is to reach treatment-free remission with sustained deep molecular remission (DMR) being the prerequisite therefor. Second-generation tyrosine kinase inhibitors can induce deeper and faster remission than imatinib, but are often associated with severe adverse events (AEs). The combination of pegylated interferon (IFN) with imatinib was shown to induce higher molecular remissions than imatinib alone in two studies. Treatment discontinuation rates due to IFN induced AEs were high in both studies. To investigate safety, tolerability (primary objective), and efficacy (secondary objective) of the combination of imatinib with ropeginterferon alpha-2b this phase I study was initiated. Twelve patients were planned to be enrolled. Nine patients completed the study according to protocol. Three patients terminated the study early, one due to occurrence of a dose-limiting toxicity (neutropenia grade 3), one due to an AE (panic attacks grade 2) and one due to the patient's decision. Tolerability was good, non-hematologic AEs were mainly grade 1/2, hematologic AEs were mainly neutropenias. No new AEs were reported for the combination of imatinib and ropeginterferon alpha-2b. In a nondose-dependent manner the addition of ropeginterferon alpha-2b led to the achievement of a DMR in four out of nine patients after a treatment duration of 18 months. The combination of imatinib and ropeginterferon alpha-2b is safe and showed in this phase I study the ability to deepen the molecular response in patients with chronic phase CML not achieving a DMR with imatinib alone.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Estudos de Viabilidade , Feminino , Humanos , Mesilato de Imatinib/administração & dosagem , Interferon alfa-2/administração & dosagem , Interferon-alfa/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Retratamento , Falha de Tratamento , Resultado do TratamentoRESUMO
Whatman FTA® cards provide the most reliable method for DNA storage and extraction, however, the literature lacks reports on the epigenetic analysis of FTA card-derived tumor DNA. Therefore, this study aimed at demonstrating that punches from colonic adenoma samples preserved on FTA filter cards are suitable for methylation analysis by real-time methylation-specific PCR (MSP). Genomic DNA was isolated from a total of 40 sporadic colorectal adenoma samples stored on FTA cards for a median of 59.60 (range 48-72) months. After bisulfite treatment, deaminated DNA was analyzed by SYBR Green real-time MSP using primers specific for methylated and unmethylated promotor sequences of the secreted frizzled-related protein 1 (SFRP1) gene. Amplifiable DNA could be isolated from all FTA card punches while SFRP1 promotor methylation was present in 34/40 (85.0%) colorectal adenomas. Our results indicate that genomic DNA isolated from colonic tumor samples preserved on FTA cards is suitable for downstream methylation detection methodologies such as MSP even after prolonged storage periods.
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Pólipos do Colo/genética , DNA de Neoplasias/isolamento & purificação , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Manejo de Espécimes/métodos , Adenoma/genética , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Pólipos do Colo/patologia , Metilação de DNA/genética , Primers do DNA , DNA de Neoplasias/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Regiões Promotoras GenéticasRESUMO
Anagrelide is an established treatment option for essential thrombocythaemia (ET). A prolonged release formulation was developed with the aim of reducing dosing frequency and improving tolerability, without diminishing efficacy. This multicentre, randomized, double blind, active-controlled, non-inferiority trial investigated the efficacy, safety and tolerability of anagrelide prolonged release (A-PR) over a reference product in high-risk ET patients, either anagrelide-naïve or -experienced. In a 6 to 12-week titration period the individual dose for the consecutive 4-week maintenance period was identified. The primary endpoint was the mean platelet count during the maintenance period (3 consecutive measurements, day 0, 14, 28). Of 112 included patients 106 were randomized. The mean screening platelet counts were 822 × 109 /l (95% confidence interval (CI) 707-936 × 109 /l) and 797 × 109 /l (95% CI 708-883 × 109 /l) for A-PR and the reference product, respectively. Both treatments effectively reduced platelet counts, to mean 281 × 109 /l for A-PR (95% CI 254-311) and 305 × 109 /l (95% CI 276-337) for the reference product (P < 0·0001, for non-inferiority). Safety and tolerability were comparable between both drugs. The novel prolonged-release formulation was equally effective and well tolerated compared to the reference product. A-PR provides a more convenient dosing schedule and will offer an alternative to licensed immediate-release anagrelide formulations.
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Inibidores da Agregação Plaquetária/administração & dosagem , Quinazolinas/administração & dosagem , Trombocitemia Essencial/tratamento farmacológico , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Método Duplo-Cego , Composição de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/farmacocinética , Contagem de Plaquetas , Qualidade de Vida , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Resultado do TratamentoRESUMO
OBJECTIVES: Risk of thrombosis is significantly enhanced by both elevated platelet (PLT) and white blood cell (WBC) counts according to a retrospective analysis of a large anagrelide registry in thrombocythemic MPN patients. We were interested in the impact of elevated WBC counts on thrombosis risk in patients where PLT counts were reduced below the calculated cutoff of 574.5 G/L by treatment with anagrelide. METHODS: Cox regression analysis and Kaplan-Meier plot were applied on all patients in the registry with optimized PLT counts. RESULTS: Using the calculated cutoff of 9.66 G/L for WBC, Cox regression analysis revealed a clear influence of elevated WBC counts on the occurrence of a major thrombotic event (P = .012). A Kaplan-Meier plot revealed a markedly shorter time to a major thrombotic event for patients with WBC counts above the cutoff (P = .001). CONCLUSIONS: These data suggest that additional correction of elevated WBC counts is mandatory in patients with optimally managed PLT counts to reduce thrombotic risk. This study is the first investigation in a prospectively observed large patient cohort which was treated homogenously allowing for evaluation of single parameters for an effect on thrombophilia.
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In this prospective, open-label, multicenter phase 1/2 dose escalation study, we used a next-generation, mono-pegylated interferon (IFN) α-2b isoform, ropeginterferon alfa-2b. The unique feature of ropeginterferon alfa-2b is a longer elimination half-life, which allows administration every 2 weeks. We present data from 51 polycythemia vera patients. The main goal was to define the maximum tolerated dose and to assess safety and efficacy. A dose range of 50 to 540 µg was tested without the appearance of dose-limiting toxicities. All drug-related adverse events were known toxicities associated with IFN-α. The cumulative overall response rate was 90%, comprising complete response in 47% and partial response in 43% of patients; the best individual molecular response level was a complete response in 21% of patients and partial response in 47%. Notably, we did not observe any correlation between the dose level and the response rate or response duration, suggesting that already low levels of ropeginterferon alfa-2b are sufficient to induce significant hematologic and molecular responses. These data suggest promising efficacy and safety of ropeginterferon alfa-2b and support the development of the drug in a randomized phase 3 clinical trial. The study was disclosed at www.clinicaltrials.gov as #NCT01193699 before including the first patient.
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Interferon-alfa/uso terapêutico , Policitemia Vera/tratamento farmacológico , Polietilenoglicóis/química , Proteínas Recombinantes/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Meia-Vida , Humanos , Interferon alfa-2 , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Policitemia Vera/mortalidade , Policitemia Vera/patologia , Prognóstico , Indução de Remissão , Taxa de SobrevidaRESUMO
The aim of this study was to evaluate the efficacy and feasibility of intensified consolidation therapy employing fludarabine and ARA-C in cycle 1 and intermediate-dose ARA-C (IDAC) in cycles 2 through 4, in elderly acute myeloid leukemia (AML) patients and to analyze the effects of pegfilgrastim on the duration of neutropenia, overall toxicity, and hospitalization-time during consolidation in these patients. Thirty nine elderly patients with de novo AML (median age 69.9 years) who achieved complete remission (CR) after induction-chemotherapy were analyzed. To examine the effect of pegfilgrastim on neutropenia and hospitalization, we compared cycles 2 and 4 where pegfilgrastim was given routinely from day 6 (IDAC-P) with cycle 3 where pegfilgrastim was only administered in case of severe infections and/or prolonged neutropenia. All four planned cycles were administered in 23/39 patients (59.0%); 5/39 patients (12.8%) received 3 cycles, 3/39 (7.7%) 2 cycles, and 8/39 (20.5%) one consolidation-cycle. The median duration of severe neutropenia was 7 days in cycle 2 (IDAC-P), 11.5 days in cycle 3 (IDAC), and 7.5 days in cycle 4 (IDAC-P) (P < .05). Median overall survival was 1.1 years and differed significantly between patients aged <75 and ≥75 years (P < .05). The probability to be alive after 5 years was 32%. Together, intensified consolidation can be administered in AML patients ≥60, and those who are <75 may benefit from this therapy. Routine administration of pegfilgrastim during consolidation shortens the time of neutropenia and hospitalization in these patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia de Consolidação/métodos , Citarabina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Vidarabina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia de Consolidação/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Estudos de Viabilidade , Filgrastim , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Hospitalização/estatística & dados numéricos , Humanos , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Polietilenoglicóis , Prognóstico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/uso terapêuticoRESUMO
The 2016 revised WHO criteria for the diagnosis of pre-fibrotic/early primary myelofibrosis (pre-PMF) require at least one of the following four borderline expressed minor clinical criteria: anemia, leukocytosis, elevated lactate dehydrogenase and splenomegaly. In this study, we evaluated the relative frequency of these four criteria in a group of 170 pre-PMF patients and compared them to 225 ET cases. More than 91% of pre-PMF cases showed one or more of these features required for diagnosis, by contrast with only 48% of ET patients. According to clinical data the cumulative risk of progression to advanced/overt PMF in pre-PMF was 36.9% after 15 years. After fitting cox regression models to analyze the impact of the minor criteria on overall survival, only leukocytosis remained as a significant predictor of survival in both pre-PMF and ET. Molecular characterization showed differences in survival in pre-PMF but not ET, with CALR being a more favorable mutation than JAK2. The different outcome of pre-PMF versus ET and associated molecular genetic data supports the concept of two different entities, rather than a continuum of the same disease. Although slightly less than 50% of ET patients also show one or more minor clinical criteria, accurate distinction between ET and pre-PMF is possible by following an integrated approach including histomorphological diagnosis and presence of minor clinical criteria.
Assuntos
Mielofibrose Primária/diagnóstico , Mielofibrose Primária/mortalidade , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/mortalidade , Idoso , Calreticulina/genética , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Mutação , Mielofibrose Primária/genética , Mielofibrose Primária/terapia , Fatores de Risco , Taxa de Sobrevida , Trombocitemia Essencial/genética , Trombocitemia Essencial/terapia , Organização Mundial da SaúdeRESUMO
Plerixafor in combination with granulocyte-colony stimulating factor (G-CSF) is approved for autologous stem cell mobilization in poor mobilizing patients with multiple myeloma or malignant lymphoma. The purpose of this study was to evaluate efficacy and safety of plerixafor in an immediate rescue approach, administrated subsequently to G-CSF alone or chemotherapy and G-CSF in patients at risk for mobilization failure. Eighty-five patients mobilized with G-CSF alone or chemotherapy were included. Primary endpoint was the efficacy of the immediate rescue approach of plerixafor to achieve ≥2.0 × 106 CD34+ cells/kg for a single or ≥5 × 106 CD34+ cells/kg for a double transplantation and potential differences between G-CSF and chemotherapy-based mobilization. Secondary objectives included comparison of stem cell graft composition including CD34+ cell and lymphocyte subsets with regard to the mobilization regimen applied. No significant adverse events were recorded. A median 3.9-fold increase in CD34+ cells following plerixafor was observed, resulting in 97% patients achieving at least ≥2 × 106 CD34+ cells/kg. Significantly more differentiated granulocyte and monocyte forming myeloid progenitors were collected after chemomobilization whereas more CD19+ and natural killer cells were collected after G-CSF. Fifty-two patients underwent transplantation showing rapid and durable engraftment, irrespectively of the stem cell mobilization regimen used. The addition of plerixafor in an immediate rescue model is efficient and safe after both, G-CSF and chemomobilization and results in extremely high success rates. Whether the differences in graft composition have a clinical impact on engraftment kinetics, immunologic recovery, and graft durability have to be analysed in larger prospective studies.
Assuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/uso terapêutico , Pré-Medicação/métodos , Adulto , Idoso , Autoenxertos/citologia , Benzilaminas , Ciclamos , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transplante Autólogo , Resultado do TratamentoRESUMO
Myeloid and lymphoid neoplasms with fibroblast growth factor receptor 1 (FGFR1) abnormalities, also known as 8p11 myeloproliferative syndrome (EMS), represent rare and aggressive disorders, associated with chromosomal aberrations that lead to the fusion of FGFR1 to different partner genes. We report on a third patient with a fusion of the translocated promoter region (TPR) gene, a component of the nuclear pore complex, to FGFR1 due to a novel ins(1;8)(q25;p11p23). The fact that this fusion is a rare but recurrent event in EMS prompted us to examine the localization and transforming potential of the chimeric protein. TPR-FGFR1 localizes in the cytoplasm, although the nuclear pore localization signal of TPR is retained in the fusion protein. Furthermore, TPR-FGFR1 enables cytokine-independent survival, proliferation, and granulocytic differentiation of the interleukin-3 dependent myeloid progenitor cell line 32Dcl3, reflecting the chronic phase of EMS characterized by myeloid hyperplasia. 32Dcl3 cells transformed with the TPR-FGFR1 fusion and treated with increasing concentrations of the tyrosine kinase inhibitors ponatinib (AP24534) and infigratinib (NVP-BGJ398) displayed reduced survival and proliferation with IC50 values of 49.8 and 7.7 nM, respectively. Ponatinib, a multitargeted tyrosine kinase inhibitor, is already shown to be effective against several FGFR1-fusion kinases. Infigratinib, tested only against FGFR1OP2-FGFR1 to date, is also efficient against TPR-FGFR1. Taking its high specificity for FGFRs into account, infigratinib could be beneficial for EMS patients and should be further investigated for the treatment of myeloproliferative neoplasms with FGFR1 abnormalities.
Assuntos
Cromossomos Humanos Par 8/genética , Imidazóis/farmacologia , Transtornos Mieloproliferativos/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas/genética , Piridazinas/farmacologia , Pirimidinas/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citoplasma/metabolismo , Humanos , Imidazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional , Transtornos Mieloproliferativos/tratamento farmacológico , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Compostos de Fenilureia/uso terapêutico , Proteínas Proto-Oncogênicas/metabolismo , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismoRESUMO
OBJECTIVES: Although guidelines recommend normalization of platelet counts as an appropriate endpoint for treatment in high-risk essential thrombocythemia (ET), retrospective studies could not prove a correlation of diagnostic platelet counts with an increased thrombotic rate. There is, however, an increasing evidence that leukocytosis is an important risk factor for arterial thrombosis in myeloproliferative neoplasms. METHODS: This study considers the Austrian cohort of a European registry regarding the platelet-lowering therapeutic anagrelide. Influence of platelet and white blood cell (WBC) counts on thrombotic risk was assessed. RESULTS: Using the calculated cutoffs of 574.5 G/L for platelets and 8.48 G/L for WBC counts, respectively, the Cox regression analysis revealed a clear influence of elevated platelets (P = 0.008) and WBC counts (P = 0.011) on the occurrence of major thrombotic events. The time to a major thrombotic event was shortest (P < 0.001) and the frequency related to 100 patient-years was highest (P = <0.001) when both platelet and WBC counts ranged above the calculated cutoffs. CONCLUSION: Our data add evidence to the impact of platelet and WBC counts on thrombosis in ET. We suspect a particular interaction between platelets and WBC which might be based on a biological interplay depending on particular cell counts.
Assuntos
Plaquetas , Contagem de Leucócitos , Trombocitemia Essencial/sangue , Trombocitemia Essencial/complicações , Trombose/sangue , Trombose/etiologia , Idoso , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Prognóstico , Modelos de Riscos Proporcionais , Quinazolinas/uso terapêutico , Sistema de Registros , Medição de Risco , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/epidemiologia , Trombose/tratamento farmacológico , Trombose/epidemiologiaRESUMO
Fifty-one polycythemia vera (PV) patients were enrolled in the phase I/II clinical study PEGINVERA to receive a new formulation of pegylated interferon alpha (peg-proline-IFNα-2b, AOP2014/P1101). Peg-proline-IFNα-2b treatment led to high response rates on both hematologic and molecular levels. Hematologic and molecular responses were achieved for 46 and 18 patients (90 and 35% of the whole cohort), respectively. Although interferon alpha (IFNα) is known to be an effective antineoplastic therapy for a long time, it is currently not well understood which genetic alterations influence therapeutic outcomes. Apart from somatic changes in specific genes, large chromosomal aberrations could impact responses to IFNα. Therefore, we evaluated the interplay of cytogenetic changes and IFNα responses in the PEGINVERA cohort. We performed high-resolution SNP microarrays to analyze chromosomal aberrations prior and during peg-proline-IFNα-2b therapy. Similar numbers and types of chromosomal aberrations in responding and non-responding patients were observed, suggesting that peg-proline-IFNα-2b responses are achieved independently of chromosomal aberrations. Furthermore, complete cytogenetic remissions were accomplished in three patients, of which two showed more than one chromosomal aberration. These results imply that peg-proline-IFNα-2b therapy is an effective drug for PV patients, possibly including patients with complex cytogenetic changes.
Assuntos
Antineoplásicos/uso terapêutico , Aberrações Cromossômicas , Interferon-alfa/uso terapêutico , Janus Quinase 2/genética , Policitemia Vera/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Aberrações Cromossômicas/efeitos dos fármacos , Estudos de Coortes , DNA/genética , Feminino , Frequência do Gene/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Policitemia Vera/sangue , Policitemia Vera/genética , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Resultado do TratamentoRESUMO
Accurate prediction of thrombosis in essential thrombocythemia (ET) provides the platform for prospective studies exploring preventive measures. Current risk stratification for thrombosis in ET is 2-tiered and considers low- and high-risk categories based on the respective absence or presence of either age > 60 years or history of thrombosis. In an international study of 891 patients with World Health Organization (WHO)-defined ET, we identified additional independent risk factors including cardiovascular risk factors and JAK2V617F. Accordingly, we assigned risk scores based on multivariable analysis-derived hazard ratios (HRs) to age > 60 years (HR = 1.5; 1 point), thrombosis history (HR = 1.9; 2 points), cardiovascular risk factors (HR = 1.6; 1 point), and JAK2V617F (HR = 2.0; 2 points) and subsequently devised a 3-tiered prognostic model (low-risk = < 2 points; intermediate-risk = 2 points; and high-risk = > 2 points) using a training set of 535 patients and validated the results in the remaining cohort (n = 356; internal validation set) and in an external validation set (n = 329). Considering all 3 cohorts (n = 1220), the 3-tiered new prognostic model (low-risk n = 474 vs intermediate-risk n = 471 vs high-risk n = 275), with a respective thrombosis risk of 1.03% of patients/y versus 2.35% of patients/y versus 3.56% of patients/y, outperformed the 2-tiered (low-risk 0.95% of patients/y vs high-risk 2.86% of patients/y) conventional risk stratification in predicting future vascular events.
Assuntos
Índice de Gravidade de Doença , Trombocitemia Essencial/classificação , Trombocitemia Essencial/diagnóstico , Organização Mundial da Saúde , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Classificação Internacional de Doenças , Masculino , Pessoa de Meia-Idade , Prognóstico , Projetos de Pesquisa , Trombocitemia Essencial/patologia , Adulto JovemRESUMO
Studies by the International Working Group showed that the prognosis of myelofibrosis patients is predicted by the Dynamic International Prognostic Scoring System (DIPSS) risk categorization, which includes patient age, constitutional symptoms, hemoglobin, leukocyte count, and circulating blasts. We evaluated the prognostic usefulness of the DIPSS in 170 patients with myelofibrosis, 12 to 78 years of age (median, 51.5 years of age), who received hematopoietic cell transplantation (HCT) between 1990 and 2009 from related (n = 86) or unrelated donors (n = 84). By DIPSS, 21 patients had low-risk disease, 48 had intermediate-1, 50 had intermediate-2, and 51 had high-risk disease. Five-year incidence of relapse, relapse-free survival, overall survival, and nonrelapse mortality for all patients were 10%, 57%, 57%, and 34%, respectively. Among patients with DIPSS high-risk disease, the hazard ratio for post-HCT mortality was 4.11 (95% CI, 1.44-11.78; P = .008), and for nonrelapse mortality was 3.41 (95% CI, 1.15-10.09; P = .03) compared with low-risk patients. After a median follow-up of 5.9 years, the median survivals have not been reached for DIPSS risk groups low and intermediate-1, and were 7 and 2.5 years for intermediate-2 and high-risk patients, respectively. Thus, HCT was curative for a large proportion of patients with myelofibrosis, and post-HCT success was dependent on pre-HCT DIPSS classification.