RESUMO
Advances in therapeutic approaches for melanoma urge the need for biomarkers that can identify patients at risk for recurrence and to guide treatment. The potential use of liquid biopsies in identifying biomarkers is increasingly being recognized. Here, we present a head-to-head comparison of several techniques to analyze circulating tumor cells (CTCs) and cell-free DNA (cfDNA) in 20 patients with metastatic melanoma. In this study, we investigated whether diagnostic leukapheresis (DLA) combined with multimarker flow cytometry (FCM) increased the detection of CTCs in blood compared to the CellSearch platform. Additionally, we characterized cfDNA at the level of somatic mutations, extent of aneuploidy and genome-wide DNA methylation. Both CTCs and cfDNA measures were compared to tumor markers and extracranial tumor burden on radiological imaging. Compared to the CellSearch method applied on peripheral blood, DLA combined with FCM increased the proportion of patients with detectable CTCs from 35% to 70% (P = 0.06). However, the median percentage of cells that could be recovered by the DLA procedure was 29%. Alternatively, cfDNA mutation and methylation analysis detected tumor load in the majority of patients (90% and 93% of samples successfully analyzed, respectively). The aneuploidy score was positive in 35% of all patients. From all tumor measurements in blood, lactate dehydrogenase (LDH) levels were significantly correlated to variant allele frequency (P = 0.004). Furthermore, the presence of CTCs in DLA was associated with tumor burden (P < 0.001), whereas the presence of CTCs in peripheral blood was associated with number of lesions on radiological imaging (P < 0.001). In conclusion, DLA tended to increase the proportion of patients with detectable CTCs but was also associated with low recovery. Both cfDNA and CTCs were correlated with clinical parameters such as LDH levels and extracranial tumor burden.
RESUMO
ABSTRACT: Autoimmune hemolytic anemia (AIHA) is a rare autoantibody-mediated disease. For steroid and/or rituximab-refractory AIHA, there is no consensus on optimal treatment. Daratumumab, a monoclonal antibody targeting CD38, could be beneficial by suppression of CD38+ plasma cells and thus autoantibody secretion. In addition, because CD38 is also expressed by activated T cells, daratumumab may also act via immunomodulatory effects. We evaluated the efficacy and safety of daratumumab monotherapy in an international retrospective study including 19 adult patients with heavily pretreated refractory AIHA. In warm AIHA (wAIHA, n = 12), overall response was 50% with a median response duration of 5.5 months (range, 2-12), including ongoing response in 2 patients after 6 and 12 months. Of 6 nonresponders, 4 had Evans syndrome. In cold AIHA (cAIHA, n = 7) overall hemoglobin (Hb) response was 57%, with ongoing response in 3 of 7 patients. One additional patient with nonanemic cAIHA was treated for severe acrocyanosis and reached a clinical acrocyanosis response as well as a Hb increase. Of 6 patients with cAIHA with acrocyanosis, 4 had improved symptoms after daratumumab treatment. In 2 patients with wAIHA treated with daratumumab, in whom we prospectively collected blood samples, we found complete CD38+ T-cell depletion after daratumumab, as well as altered T-cell subset differentiation and a severely diminished capacity for cell activation and proliferation. Reappearance of CD38+ T cells coincided with disease relapse in 1 patient. In conclusion, our data show that daratumumab therapy may be a treatment option for refractory AIHA. The observed immunomodulatory effects that may contribute to the clinical response deserve further exploration.
Assuntos
Anemia Hemolítica Autoimune , Anticorpos Monoclonais , Humanos , Anemia Hemolítica Autoimune/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Idoso , Estudos Retrospectivos , Resultado do Tratamento , ADP-Ribosil Ciclase 1/antagonistas & inibidoresAssuntos
Nitrilas , Mielofibrose Primária , Pirazóis , Pirimidinas , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Método Duplo-Cego , Nitrilas/uso terapêutico , Mielofibrose Primária/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Hydroxyurea (HU) is a commonly used first-line treatment in patients with polycythemia vera (PV). However, approximately 15%-24% of PV patients report intolerance and resistance to HU. METHODS: This phase IV, European, real-world, observational study assessed the efficacy and safety of ruxolitinib in PV patients who were resistant and/or intolerant to HU, with a 24-month follow-up. The primary objective was to describe the profile and disease burden of PV patients. RESULTS: In the 350 enrolled patients, 70% were >60 years old. Most patients (59.4%) had received ≥1 phlebotomy in the 12 months prior to the first dose of ruxolitinib. Overall, 68.2% of patients achieved hematocrit control with 92.3% patients having hematocrit <45% and 35.4% achieved hematologic remission at month 24. 85.1% of patients had no phlebotomies during the study. Treatment-related adverse events were reported in 54.3% of patients and the most common event was anemia (22.6%). Of the 10 reported deaths, two were suspected to be study drug-related. CONCLUSION: This study demonstrates that ruxolitinib treatment in PV maintains durable hematocrit control with a decrease in the number of phlebotomies in the majority of patients and was generally well tolerated.
Assuntos
Hidroxiureia , Policitemia Vera , Pirazóis , Humanos , Pessoa de Meia-Idade , Hidroxiureia/efeitos adversos , Policitemia Vera/diagnóstico , Policitemia Vera/tratamento farmacológico , Nitrilas , Pirimidinas/uso terapêuticoRESUMO
In light of the associated risks, the question has been raised whether the decision to give a blood transfusion should solely be based on the hemoglobin level. As mitochondria are the final destination of oxygen transport, mitochondrial parameters are suggested to be of added value. The aims of this pilot study were to investigate the effect of a red blood cell transfusion on mitochondrial oxygenation as measured by the COMET device in chronic anemia patients and to explore the clinical usability of the COMET monitor in blood transfusion treatments, especially the feasibility of performing measurements in an outpatient setting. To correct the effect of volume load on mitochondrial oxygenation, a red blood cell transfusion and a saline infusion were given in random order. In total, 21 patients were included, and this resulted in 31 observations. If patients participated twice, the order of infusion was reversed. In both the measurements wherein a blood transfusion was given first and wherein 500 mL of 0.9% saline was given first, the median mitochondrial oxygen tension decreased after red blood cell transfusion. The results of this study have strengthened the need for further research into the effect of blood transfusion tissue oxygenation and the potential role of mitochondrial parameters herein.
RESUMO
BACKGROUND: The aim of this randomized, controlled trial is to determine whether antisevere acute respiratory syndrome coronavirus 2 hyperimmune globulin (COVIG) protects against severe coronavirus disease 2019 (COVID-19) in severely immunocompromised, hospitalized, COVID-19 patients. METHODS: Patients were randomly assigned to receive COVIG or intravenous immunoglobulin (IVIG) without SARS-CoV-2 antibodies. RESULTS: Severe COVID-19 was observed in 2 of 10 (20%) patients treated with COVIG compared to 7 of 8 (88%) in the IVIG control group (P = .015, Fisher's exact test). CONCLUSIONS: Antisevere acute respiratory syndrome coronavirus 2 hyperimmune globulin may be a valuable treatment in severely immunocompromised, hospitalized, COVID-19 patients and should be considered when no monoclonal antibody therapies are available.
Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Imunoglobulinas Intravenosas/uso terapêutico , Resultado do Tratamento , Soroterapia para COVID-19 , Imunização Passiva/efeitos adversosAssuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Pirazóis/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Niacinamida/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Background: Thrombocytopenia is a common feature of myelofibrosis (MF), a myeloproliferative neoplasm driven by dysregulated JAK/STAT signaling; however, pivotal trials assessing the efficacy of ruxolitinib (a JAK1/2 inhibitor) excluded MF patients with low platelet counts (<100 × 109/L). Objectives: Determination of the maximum safe starting dose (MSSD) of ruxolitinib was the primary endpoint, with long-term safety and efficacy as secondary and exploratory endpoints, respectively. Design: EXPAND (NCT01317875) was a phase 1b, open-label, ruxolitinib dose-finding study in patients with MF and low platelet counts (50 to <100 × 109/L). Methods: Patients were stratified according to baseline platelet count into stratum 1 (S1, 75 to <100 × 109/L) or stratum 2 (S2, 50 to <75 × 109/L). Previous analyses established the MSSD at 10 mg twice daily (bid); long-term results are reported here. Results: Of 69 enrolled patients, 38 received ruxolitinib at the MSSD (S1, n = 20; S2, n = 18) and are the focus of this analysis. The incidence of adverse events was consistent with the known safety profile of ruxolitinib, with thrombocytopenia (S1, 50%; S2, 78%) and anemia (S1, 55%; S2, 44%) the most frequently reported adverse events and no new or unexpected safety signals. Substantial clinical benefits were observed for patients in both strata: 50% (10/20) and 67% (12/18) of patients in S1 and S2, respectively, achieved a spleen response (defined as ⩾50% reduction in spleen length from baseline) at any time during the study. Conclusion: The final safety and efficacy results from EXPAND support the use of a 10 mg bid starting dose of ruxolitinib in patients with MF and platelet counts 50 to <100 × 109/L. Registration: ClinicalTrials.gov NCT01317875.
RESUMO
Immune thrombocytopenia (ITP) is an acquired autoimmune disorder that is characterized by low platelet count and increased bleeding risk. COVID-19 vaccination has been described as a risk factor for de novo ITP, but the effects of COVID-19 vaccination in patients with ITP are unknown. We aimed to investigate the effects of COVID-19 vaccination in patients with ITP on platelet count, bleeding complications, and ITP exacerbation (≥50% decline in platelet count, or nadir platelet count < 30 × 109/L with a >20% decrease from baseline, or use of rescue therapy). Platelet counts in patients with ITP and healthy controls were collected immediately before and 1 and 4 weeks after the first and second vaccinations. Linear mixed-effects modeling was applied to analyze platelet counts over time. We included 218 patients with ITP (50.9% female; mean age, 55 years; and median platelet count, 106 × 109/L) and 200 healthy controls (60.0% female; mean age, 58 years; median platelet count, 256 × 109/L). Platelet counts decreased by 6.3% after vaccination. We did not observe any difference in decrease between the groups. Thirty patients with ITP (13.8%; 95% confidence interval [CI], 9.5-19.1) had an exacerbation and 5 (2.2%; 95% CI, 0.7-5.3) suffered from a bleeding event. Risk factors for ITP exacerbation were platelet count < 50 × 109/L (odds ratio [OR], 5.3; 95% CI, 2.1-13.7), ITP treatment at time of vaccination (OR, 3.4; 95% CI, 1.5-8.0), and age (OR, 0.96 per year; 95% CI, 0.94-0.99). Our study highlights the safety of COVID-19 vaccination in patients with ITP and the importance of the close monitoring of platelet counts in a subgroup of patients with ITP. Patients with ITP with exacerbation responded well on therapy.
Assuntos
COVID-19 , Púrpura Trombocitopênica Idiopática , Trombocitopenia , COVID-19/complicações , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/complicações , Púrpura Trombocitopênica Idiopática/epidemiologia , Trombocitopenia/complicações , Trombocitopenia/etiologia , Vacinação/efeitos adversosAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias/tratamento farmacológico , Trombocitemia Essencial/mortalidade , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Países Baixos/epidemiologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Trombocitemia Essencial/induzido quimicamente , Trombocitemia Essencial/epidemiologia , Trombocitemia Essencial/patologia , Fatores de Tempo , Adulto JovemRESUMO
Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by clinical findings including thrombosis and/or obstetric complication and laboratory findings, e.g. ≥1 positive antiphospholipid antibodies (aPL) (lupus anticoagulant, anticardiolipin IgG/IgM and/or anti-ß2-glycoprotein IgG/IgM). A rare APS clinical entity is severe necrosis which is difficult to treat and often does not respond to anticoagulant therapy. Three consecutive patients with primary or secondary APS who presented with necrotic skin lesions secondary to APS were treated with therapeutic plasma exchange (TPE), glucocorticoids and low-molecular-weight heparin. All patients had a rapid-onset, either full or significant recovery of their APS-related necrotic lesions. Upon treatment, one patients showed resolution of lupus anticoagulant. Two patients had a decrease of at least 88 % in aPL titers after the initial treatment, and were kept on TPE maintenance every 5-6 weeks. None of the patients experienced significant side effects of the TPE. This is the first case series showing the clinical benefits of TPE in patients with ischemic and necrotic skin lesions due to severe anticoagulant-refractory vascular APS.
Assuntos
Anticoagulantes/química , Síndrome Antifosfolipídica/imunologia , Isquemia/terapia , Troca Plasmática/métodos , Dermatopatias/terapia , Idoso , Anticorpos Anticardiolipina/sangue , Síndrome Antifosfolipídica/patologia , Síndrome Antifosfolipídica/terapia , Feminino , Glucocorticoides/uso terapêutico , Heparina de Baixo Peso Molecular , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Isquemia/patologia , Inibidor de Coagulação do Lúpus/imunologia , Masculino , Pessoa de Meia-Idade , Necrose/patologia , Necrose/terapia , Dermatopatias/patologia , Trombose/imunologia , beta 2-Glicoproteína I/imunologiaRESUMO
BACKGROUND: Circulating tumour cell (CTC)-derived organoids have the potential to provide a powerful tool for personalised cancer therapy but are restrained by low CTC numbers provided by blood samples. Here, we used diagnostic leukapheresis (DLA) to enrich CTCs from patients with metastatic prostate cancer (mPCa) and explored whether organoids provide a platform for ex vivo treatment modelling. METHODS: We prospectively screened 102 patients with mPCa and performed DLA in 40 patients with ≥5 CTCs/7.5 mL blood. We enriched CTCs from DLA using white blood cell (WBC) depletion alone or combined with EpCAM selection. The enriched CTC samples were cultured in 3D to obtain organoids and used for downstream analyses. RESULTS: The DLA procedure resulted in a median yield of 5312 CTCs as compared with 22 CTCs in 7.5 mL of blood. Using WBC depletion, we recovered 46% of the CTCs, which reduced to 12% with subsequent EpCAM selection. From the isolated and enriched CTC samples, organoid expansion succeeded in 35%. Successful organoid cultures contained significantly higher CTC numbers at initiation. Moreover, we performed treatment modelling in one organoid cell line and identified substantial tumour heterogeneity in CTCs using single cell DNA sequencing. CONCLUSIONS: DLA is an efficient method to enrich CTCs, although the modest success rate of culturing CTCs precludes large scale clinical application. Our data do suggest that DLA and subsequent processing provides a rich source of viable tumour cells. Therefore, DLA offers a promising alternative to biopsy procedures to obtain sufficient number of tumour cells to study sequential samples in patients with mPCa. TRIAL REGISTRATION NUMBER: NL6019.
Assuntos
Separação Celular , Leucaférese , Células Neoplásicas Circulantes/patologia , Neoplasias da Próstata/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , DNA de Neoplasias/genética , Heterogeneidade Genética , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Células Neoplásicas Circulantes/efeitos dos fármacos , Células Neoplásicas Circulantes/metabolismo , Organoides , Estudos Prospectivos , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Resultado do Tratamento , Células Tumorais CultivadasRESUMO
In a randomized clinical trial of 86 hospitalized COVID-19 patients comparing standard care to treatment with 300mL convalescent plasma containing high titers of neutralizing SARS-CoV-2 antibodies, no overall clinical benefit was observed. Using a comprehensive translational approach, we unravel the virological and immunological responses following treatment to disentangle which COVID-19 patients may benefit and should be the focus of future studies. Convalescent plasma is safe, does not improve survival, has no effect on the disease course, nor does plasma enhance viral clearance in the respiratory tract, influence SARS-CoV-2 antibody development or serum proinflammatory cytokines levels. Here, we show that the vast majority of patients already had potent neutralizing SARS-CoV-2 antibodies at hospital admission and with comparable titers to carefully selected plasma donors. This resulted in the decision to terminate the trial prematurely. Treatment with convalescent plasma should be studied early in the disease course or at least preceding autologous humoral response development.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , COVID-19/terapia , Citocinas/sangue , SARS-CoV-2/imunologia , Idoso , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Doadores de Sangue , COVID-19/sangue , COVID-19/virologia , Progressão da Doença , Feminino , Hospitalização , Humanos , Imunização Passiva , Imunoglobulina G/sangue , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Glicoproteína da Espícula de Coronavírus/imunologia , Resultado do Tratamento , Soroterapia para COVID-19RESUMO
Patients with myeloproliferative neoplasms (MPNs), polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have an increased risk of thrombosis. Risk of recurrent thrombosis can be reduced with antithrombotic therapy and/or cytoreduction, but the optimal long-term management in patients with MPN with a history of venous thromboembolism (VTE) is unknown, and clinical practice is heterogeneous. We performed a systematic review and meta-analysis of randomized trials and observational studies evaluating anticoagulant and/or antiplatelet therapy, with or without cytoreduction, in MPN patients with a history of VTE. A total of 5675 unique citations were screened for eligibility. No randomized trials were identified. Ten observational studies involving 1295 patients with MPN were included in the analysis. Overall, 23% had an arterial or recurrent venous thrombotic event on follow-up. The recurrence risk was lowest for patients on oral anticoagulation plus cytoreduction (16%); 55 of 313 (18%) with vitamin K antagonists (VKA) and 5 of 63 (8%) with direct oral anticoagulants (DOACs). In 746 analyzed patients, the risk of recurrent VTE ranged up to 33% (median 13%) and was low in 63 DOAC plus cytoreduction-treated patients (3.2%). All types of antithrombotic treatments were associated with a lower risk of recurrent VTE when combined with cytoreduction. Most studies had a high risk of bias, whereas clinical and statistical heterogeneity led to inconsistent and imprecise findings. In summary, evidence on the optimal antithrombotic treatment of VTE in patients with MPN is based on observational studies only with low certainty for all strategies. Our data suggest that a combination of anticoagulation and cytoreduction may provide the lowest recurrence risk.
Assuntos
Transtornos Mieloproliferativos , Neoplasias , Trombose , Tromboembolia Venosa , Anticoagulantes/uso terapêutico , Fibrinolíticos/uso terapêutico , Humanos , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/tratamento farmacológico , Neoplasias/tratamento farmacológico , Trombose/tratamento farmacológico , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controleAssuntos
Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Púrpura Trombocitopênica Idiopática/etiologia , Idoso , Betacoronavirus , COVID-19 , Infecções por Coronavirus/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/terapia , Púrpura Trombocitopênica Idiopática/terapia , SARS-CoV-2RESUMO
In daily haematological practice, predicting bleeding in thrombocytopenic patients is difficult, and clinicians adhere to transfusion triggers to guide patients through the aplastic phase of chemotherapy. Platelet count is not the only determinant of bleeding and additional mechanisms for impending haemostasis are likely. Beside clot formation, platelets are essential for the maintenance of integrity of vascular beds. We therefore prospectively investigated associations between biomarkers for endothelial damage (urine albumin excretion) and inflammation (C-reactive protein) and bleeding (WHO grading) in 88 patients with 116 on-protocol episodes. We found an increase in grade 2 bleeding with a higher urine albumin/creatinine ratio one day after the measurement [odds ratio (OR) 1·24 for every doubling of the ratio, 95% CI 1·05-1·46, P-value 0·01] and a 29% increase in the odds of grade 2 bleeding for every doubling of serum C-reactive protein (CRP) (95% CI 1·04-1·60, P-value 0·02) after correction for morning platelet count. The 24 h post-transfusion corrected count increment (CCI24 ) showed a significant association with these biomarkers: increasing urine albumin/creatinine ratio and CRP were associated with lower CCI24. We report two inexpensive and easy-to-apply biomarkers that could be useful in designing a prediction model for bleeding risk in thrombocytopenic patients.
Assuntos
Albuminúria , Proteína C-Reativa/metabolismo , Endotélio Vascular/metabolismo , Hemorragia , Trombocitopenia , Adulto , Idoso , Albuminúria/sangue , Albuminúria/terapia , Biomarcadores/sangue , Biomarcadores/urina , Feminino , Hemorragia/sangue , Hemorragia/urina , Humanos , Inflamação/sangue , Inflamação/urina , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Estudos Prospectivos , Trombocitopenia/sangue , Trombocitopenia/urinaRESUMO
Current treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKI) is effective in many patients, but is not curative and frequently limited by intolerance or resistance. Also, treatment free remission is a novel option for CML patients and requires reaching a deep molecular remission, which is not consistently achieved with TKI monotherapy. Together, multiple unmet clinical needs remain and therefore the continued need to explore novel treatment strategies. With increasing understanding of CML biology, many options have been explored and are under investigation. This includes the use asciminib as first in class inhibitor targeting the myristoyl pocket of BCR-ABL, combination treatments with established non-TKI drugs such as interferon and drugs with novel targets relevant to CML biology such as gliptins and thiazolidinediones. Together, an overview is provided of treatment strategies in development for CML beyond current TKI monotherapy.
RESUMO
BACKGROUND: Ruxolitinib is an approved treatment for myelofibrosis patients, but data regarding patients with baseline thrombocytopenia are limited. The EXPAND study recently suggested tolerability of ruxolitinib, with a maximum starting dose of 10 mg 2 times a day (BID). However, the small sample size and vigorous follow-up in this trial hamper direct translation of these results to routine practice. PATIENTS AND METHODS: We report retrospective data on Dutch ruxolitinib-treated myelofibrosis patients, focusing on those with baseline thrombocytopenia. Additionally, we reviewed current literature regarding ruxolitinib treatment in this subgroup. RESULTS: In our cohort, 12 of 119 patients had a baseline platelet count of < 100 × 109/L. Spleen responses at a mean treatment duration of 25 weeks were documented in 1 of 6 and 15 of 47 patients with and without baseline thrombocytopenia, respectively. Despite a high rate of grade 3 or higher thrombocytopenia in thrombocytopenic versus nonthrombocytopenic patients (42% vs. 15%), no grade 3 or higher hemorrhage was reported. Median doses in thrombocytopenic patients were 15 and 10 mg BID at the start and after 12 weeks of treatment, respectively. Additionally, 238 thrombocytopenic patients were identified in the available literature, of whom 59 were treated in routine practice. Incidences of severe thrombocytopenia reported separately for patients with baseline thrombocytopenia were 30% to 59% (grade 3 or higher) and 4% to 60% (grade 4). Severe bleeding, pooled across our data and evaluable studies, occurred in 2.4%. CONCLUSION: Ruxolitinib treatment appears to be safe for patients with platelet counts of 50 to 100 × 109/L in real-life practice. We did not find any reason to discourage a starting dose of 10 mg BID in this subgroup.