ABSTRACT
With emerging new drugs in myelofibrosis (MF), a robust and harmonized framework for defining the severity of anemia and response to treatment will enhance clinical investigation and facilitate inter-study comparisons. Accordingly, the lead authors on the 2013 edition of the International Working Group-European LeukemiaNet (IWG-ELN) response criteria in MF were summoned to revise their document with the intent to i) account for gender-specific differences in determining hemoglobin levels for eligibility criteria, ii) revise definition of transfusion-dependent anemia (TDA) based on current restrictive transfusion practices, and iii) provide a structurally simple and easy to apply response criteria that are sensitive enough to detect efficacy signals (minor response) and also account for major responses. The initial draft of the 2024 IWG-ELN proposed criteria was subsequently circulated around a wider group of international experts and their feedback incorporated. The proposed articles include new definitions for TDA (≥3 units in the 12 weeks prior to study enrollment) and hemoglobin thresholds for eligibility criteria (<10 g/dL for women and <11 g/dL for men). The revised document also provides separate (TDA vs. non-TDA) and graded (major vs. minor response) response criteria while preserving the requirement for a 12-week period of screening and observation on treatment.
ABSTRACT
Essential thrombocythaemia (ET) is a myeloproliferative neoplasm characterized by an increased risk of vascular complications and a tendency to progress to myelofibrosis and acute leukaemia. ET patients have traditionally been stratified into two thrombosis risk categories based on age older than 60 years and a history of thrombosis. More recently, the revised IPSET-thrombosis scoring system, which accounts for the increased risk linked to the JAK2 mutation, has been incorporated into most expert recommendations. However, there is increasing evidence that the term ET encompasses different genomic entities, each with a distinct clinical course and prognosis. Moreover, the effectiveness and toxicity of cytoreductive and anti-platelet treatments differ depending on the molecular genotype. While anti-platelets and conventional cytoreductive agents, mainly hydroxycarbamide (hydroxyurea), anagrelide and pegylated interferon, remain the cornerstone of treatment, recent research has shed light on the effectiveness of novel therapies that may help improve outcomes. This comprehensive review focuses on the evolving landscape of treatment strategies in ET, with an emphasis on the role of molecular profiling in guiding therapeutic decisions. Besides evidence-based management according to revised IPSET-thrombosis stratification, we also provide specific observations for those patients with CALR-, MPL-mutated and triple-negative ET, as well as cases with high-risk mutations.
Subject(s)
Thrombocythemia, Essential , Humans , Thrombocythemia, Essential/drug therapy , Thrombocythemia, Essential/genetics , Janus Kinase 2/genetics , Janus Kinase 2/antagonists & inhibitors , Platelet Aggregation Inhibitors/therapeutic use , Platelet Aggregation Inhibitors/adverse effects , Mutation , Receptors, Thrombopoietin/agonists , Receptors, Thrombopoietin/genetics , CalreticulinABSTRACT
To elucidate the role of splanchnic vein thrombosis (SVT) and genomic characteristics in prognosis and survival, we compared patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting SVT at diagnosis (n = 69, median age 43 years) or during follow-up (n = 21, median age 46 years) to a sex- and age-matched control group of PV/ET without SVT (n = 165, median age 48 years). The majority of patients presenting with SVT at diagnosis were classified as myeloproliferative neoplasm with heterozygous JAK2 mutation (87% of cases vs. 69% in PV/ET control group, p < 0.05), characterized by low JAK2 allele burden and no high-risk mutations. Despite this lower molecular complexity, patients presenting with SVT showed a higher risk of death (HR 3.0, 95% CI 1.5-6.0, p = 0.003) and lower event-free survival (HR 3.0, 95% CI 1.9-4.8, p < 0.001) than age- and sex-matched PV/ET controls. In patients presenting with SVT, molecular high-risk was associated with increased risk of venous re-thrombosis (HR 5.8, 95% CI 1.4-24.0, p = 0.01). Patients developing SVT during follow-up were more frequently allocated in molecular high-risk than those with SVT at diagnosis (52% versus 13%, p < 0.05). In the whole cohort of patients, molecular classification identified PV/ET patients at higher risk of disease progression whereas DNMT3A/TET2/ASXL1 mutations were associated with higher risk of arterial thrombosis. In conclusion, clinical and molecular characteristics are different in PV/ET patients with SVT, depending on whether it occurs at diagnosis or at follow-up. Molecular characterization by NGS is useful for assessing the risk of thrombosis and disease progression in young patients with PV/ET.
Subject(s)
Polycythemia Vera , Thrombocythemia, Essential , Thrombosis , Venous Thrombosis , Humans , Adult , Middle Aged , Polycythemia Vera/complications , Polycythemia Vera/genetics , Polycythemia Vera/diagnosis , Thrombocythemia, Essential/complications , Thrombocythemia, Essential/genetics , Thrombocythemia, Essential/diagnosis , Venous Thrombosis/genetics , Thrombosis/etiology , Thrombosis/genetics , Genomics , Disease Progression , Janus Kinase 2/geneticsABSTRACT
Investigating the evaluation of eligibility for transplant in myelofibrosis (MF): The role of HCT-CI and BMI. HCT-CI emerges as a key prognostic factor, while BMI shows limited impact. This study expands insights for better clinical decision-making in MF allo-HCT.
Subject(s)
Hematopoietic Stem Cell Transplantation , Neoplasms , Primary Myelofibrosis , Humans , Body Mass Index , Primary Myelofibrosis/therapy , Retrospective Studies , Transplantation ConditioningABSTRACT
Prognostic impact of non-MPN driver gene mutations in primary myelofibrosis. MIPSS70: Mutation-Enhanced International Prognostic Score System.
Subject(s)
Primary Myelofibrosis , Humans , Prognosis , Primary Myelofibrosis/diagnosis , Primary Myelofibrosis/genetics , Mutation , Janus Kinase 2/genetics , Gene FrequencyABSTRACT
BACKGROUND: This retrospective study focused on analyzing community-acquired respiratory virus (CARV) infections, in particular human parainfluenza virus (hPIV) after allogeneic stem cell transplant (allo-SCT) in adults recipients. It aimed to assess the impact of ribavirin treatment, clinical characteristics, and risk factors associated with lower respiratory tract disease (LRTD) progression and all-cause mortality. PATIENTS AND METHODS: The study included 230 allo-SCT recipients diagnosed with hPIV between December 2013 and June 2023. Risk factors for the development of LRTD, disease severity, and mortality were analyzed. Ribavirin treatment was administered at physician discretion in 61 out of 230 cases (27%). RESULTS: Risk factors for LRTD progression in multivariate analysis were corticosteroids > 30 mg/day (Odds ratio (OR) 3.5, 95% Confidence Interval (C.I.) 1.3-9.4, p = 0.013), fever at the time of hPIV detection (OR 3.89, 95% C.I. 1.84-8.2, p < 0.001), and absolute lymphocyte count (ALC) < 0.2 × 109/L (OR 4.1, 95% C.I. 1.42-11.9, p = 0.009). In addition, the study found that ribavirin therapy significantly reduced progression to LRTD [OR 0.19, 95% C.I. 0.05-0.75, p = 0.018]. Co-infections (OR 5.7, 95% C.I. 1.4-23.5, p = 0.015) and ALC < 0.2 × 109/L (OR 17.7, 95% C.I. 3.6-87.1, p < 0.001) were independently associated with higher day + 100 after hPIV detection all-cause mortality. There were no significant differences in all-cause mortality and infectious mortality at day + 100 between the treated and untreated groups. CONCLUSION: ALC, corticosteroids, and fever increased the risk for progression to LRTD while ribavirin decreased the risk. However, mortality was associated with ALC and co-infections. This study supports further research of ribavirin therapy for hPIV in the allo-HSCT setting.
ABSTRACT
It is unknown whether Torque Teno virus (TTV) DNA load monitoring could anticipate the development of infectious events in hematological patients undergoing treatment with small molecular targeting agents. We characterized the kinetics of plasma TTV DNA in patients treated with ibrutinib or ruxolitinib and assessed whether TTV DNA load monitoring could predict the occurrence of Cytomegalovirus (CMV) DNAemia or the magnitude of CMV-specific T-cell responses. Multicenter, retrospective, observational study, recruiting 20 patients treated with ibrutinib and 21 with ruxolitinib. Plasma TTV and CMV DNA loads were quantified by real-time PCR at baseline and days +15, +30, +45, +60, +75, +90, +120, +150, and +180 after treatment inception. Enumeration of CMV-specific interferon-γ (IFN-γ)-producing CD8+ and CD4+ T-cells in whole blood was performed by flow cytometry. Median TTV DNA load in ibrutinib-treated patients increased significantly (p = 0.025) from baseline (median: 5.76 log10 copies/mL) to day +120 (median: 7.83 log10 copies/mL). A moderate inverse correlation (Rho = -0.46; p < 0.001) was found between TTV DNA load and absolute lymphocyte count. In ruxolitinib-treated patients, TTV DNA load quantified at baseline was not significantly different from that measured after treatment inception (p ≥ 0.12). TTV DNA load was not predictive of the subsequent occurrence of CMV DNAemia in either patient group. No correlation was observed between TTV DNA loads and CMV-specific IFN-γ-producing CD8+ and CD4+ T-cell counts in either patient group. The data did not support the hypothesis that TTV DNA load monitoring in hematological patients treated with ibrutinib or ruxolitinib could be useful to predict either the occurrence of CMV DNAemia or the level of CMV-specific T-cell reconstitution; nevertheless, due to the small sample size, further studies involving larger cohorts are warranted to elucidate this issue.
Subject(s)
Cytomegalovirus Infections , Hematologic Neoplasms , Torque teno virus , Humans , Cytomegalovirus/genetics , Retrospective Studies , Torque teno virus/genetics , DNA, Viral , Interferon-gamma , Viral LoadABSTRACT
Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-targeted chimeric antigen receptor (CAR) T cells approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We performed a retrospective study to evaluate safety and efficacy of axi-cel and tisa-cel outside the setting of a clinical trial. Data from consecutive patients with R/R LBCL who underwent apheresis for axi-cel or tisa-cel were retrospectively collected from 12 Spanish centers. A total of 307 patients underwent apheresis for axi-cel (n=152) and tisa-cel (n=155) from November 2018 to August 2021, of which 261 (85%) received a CAR T infusion (88% and 82%, respectively). Median time from apheresis to infusion was 41 days for axi-cel and 52 days for tisa-cel (P=0.006). None of the baseline characteristics were significantly different between both cohorts. Both cytokine release syndrome and neurologic events (NE) were more frequent in the axi-cel group (88% vs. 73%, P=0.003, and 42% vs. 16%, P<0.001, respectively). Infections in the first 6 months post-infusion were also more common in patients treated with axi-cel (38% vs. 25%, P=0.033). Non-relapse mortality was not significantly different between the axi-cel and tisa-cel groups (7% and 4%, respectively, P=0.298). With a median follow-up of 9.2 months, median PFS and OS were 5.9 and 3 months, and 13.9 and 11.2 months for axi-cel and tisa-cel, respectively. The 12-month PFS and OS for axi-cel and tisa-cel were 41% and 33% (P=0.195), 51% and 47% (P=0.191), respectively. Factors associated with lower OS in the multivariate analysis were increased lactate dehydrogenase, ECOG ≥2 and progressive disease before lymphodepletion. Safety and efficacy results in our real-world experience were comparable with those reported in the pivotal trials. Patients treated with axi-cel experienced more toxicity but similar non-relapse mortality compared with those receiving tisa-cel. Efficacy was not significantly different between both products.
Subject(s)
Immunotherapy, Adoptive , Lymphoma, Large B-Cell, Diffuse , Humans , Adaptor Proteins, Signal Transducing , Antigens, CD19 , Immunotherapy, Adoptive/adverse effects , Lymphoma, Large B-Cell, Diffuse/therapy , Retrospective StudiesABSTRACT
The SARS-CoV-2 pandemic has favored the expansion of telemedicine. Philadelphia-negative chronic myeloproliferative neoplasms (Ph-MPN) might be good candidates for virtual follow-up. In this study, we aimed to analyze the follow-up of patients with Ph-MPN in Spain during COVID-19, its effectiveness, and acceptance among patients. We present a multicenter retrospective study from 30 centers. Five hundred forty-one patients were included with a median age of 67 years (yr). With a median follow-up of 19 months, 4410 appointments were recorded. The median of visits per patient was 7 and median periodicity was 2.7 months; significantly more visits and a higher frequency of them were registered in myelofibrosis (MF) patients. 60.1% of visits were in-person, 39.5% were by telephone, and 0.3% were videocall visits, with a predominance of telephone visits for essential thrombocythemia (ET) and polycythemia vera (PV) patients over MF, as well as for younger patients (< 50 yr). The proportion of phone visits significantly decreased after the first semester of the pandemic. Pharmacological modifications were performed only in 25.7% of the visits, and, considering overall management, ET patients needed fewer global treatment changes. Telephone contact effectiveness reached 90% and only 5.4% required a complementary in-person appointment. Although 56.2% of the cohort preferred in-person visits, 90.5% of our patients claimed to be satisfied with follow-up during the pandemic, with an 83% of positive comments. In view of our results, telemedicine has proven effective and efficient, and might continue to play a complementary role in Ph-MPN patients' follow-up.
Subject(s)
COVID-19 , Myeloproliferative Disorders , Polycythemia Vera , Primary Myelofibrosis , Thrombocythemia, Essential , Humans , Aged , Pandemics , Retrospective Studies , Patient Satisfaction , Spain/epidemiology , SARS-CoV-2 , Myeloproliferative Disorders/epidemiology , Myeloproliferative Disorders/therapy , Polycythemia Vera/epidemiology , Primary Myelofibrosis/epidemiology , Thrombocythemia, Essential/epidemiologyABSTRACT
Allogeneic hematopoietic cell transplant (allo-HCT) provides the only potential route to long-term remission in patients diagnosed with blast phase transformation of myeloproliferative neoplasm (BP-MPN). We report on a large, retrospective European Society for Blood and Marrow Transplantation registry-based study of BP-MPN patients undergoing allo-HCT. BP-MPN patients undergoing first allo-HCT between 2005 and 2019 were included. A total of 663 patients were included. With a median follow-up of 62 months, the estimated 3-year overall survival (OS) was 36% (95% confidence interval [CI], 32-36). Factors associated with lower OS were Karnofsky Performance Score (KPS) <90 (hazard ratio [HR] 1.65, p < .001) and active disease at allo-HCT (HR 1.45, p < .001), whereas patients undergoing allo-HCT more recently associated with a higher OS (HR 0.96, p = .008). In a selected patient's population, the 3-year OS of patients undergoing allo-HCT in complete response (CR) and with a KPS ≥90 was 60%. KPS < 90 (HR 1.4, p = .001) and active disease (HR 1.44, p = .0004) were associated with a lower progression-free survival (PFS). Conversely, most recent allo-HCT associated with a higher PFS (HR 0.96, p = .008). Active disease at allo-HCT (HR 1.34, p = .03) was associated with a higher cumulative incidence of relapse (RI) and allo-HCT in earlier calendar years (HR 0.96, p = .02) associated with a lower RI. Last, KPS < 90 (HR 1.91, p < .001), active disease (HR 1.74, p = .003) and allo-HCT from mismatched related donors were associated with a higher non-relapse mortality (HR 2.66, p = .003). In this large series of BP-MPN patients, about one third were alive at 3 years after transplantation. Patients undergoing allo-HCT in the more recent era, with a KPS ≥90 and in CR at transplant had a better prognosis.
Subject(s)
Hematopoietic Stem Cell Transplantation , Myeloproliferative Disorders , Humans , Retrospective Studies , Hematopoietic Stem Cell Transplantation/adverse effects , Transplantation, Homologous/adverse effects , Blast Crisis/therapy , Bone Marrow , Neoplasm Recurrence, Local/etiology , Myeloproliferative Disorders/therapy , Myeloproliferative Disorders/etiology , Transplantation ConditioningABSTRACT
BACKGROUND: There is scarce information on the natural kinetics of cytomegalovirus (CMV) DNAemia and dynamics of CMV-specific T-cell reconstitution in allogeneic hematopoietic transplant recipients (allo-HSCT) undergoing letermovir (LMV) prophylaxis. METHODS: Twelve adult CMV-seropositive high-risk recipients (median age, 53 years; 9 males/3 females) undergoing LMV prophylaxis and 13 non-LMV allo-HSCT controls (median age, 58 years; 7 males/6 females) were included. CMV DNAemia in plasma was monitored by real-time polymerase chain reaction. Preemptive antiviral therapy (PET) was administered upon detection of ≥1500 IU/ml. CMV-specific interferon-gamma (IFN-γ)-producing CD8+ and CD4+ T cells were enumerated by flow cytometry around days +30, +60, and +90 after allo-HSCT. Ex vivo experiments assessing of the potential effect of LMV on CMV-specific T-cell expansion in a single CMV-seropositive donor were also conducted. RESULTS: Five LMV patients (41.6%) developed CMV DNAemia that cleared spontaneously. Four patients (33.3%) developed CMV DNAemia after LMV cessation, of which two required PET. Nine non-LMV patients (69.2%) developed CMV DNAemia (five required PET). The percentage of LMV and non-LMV patients exhibiting detectable CMV-specific T-cell responses was comparable (7/10 vs. 10/13; p = .71). Nevertheless, median CMV-specific CD4+ and CD8+ T-cell counts were lower in LMV patients by days +60 (p = .006 and .02, respectively) and +90 (p = .08 and .02). Ex vivo, CMV-specific CD8+ T cells expanded to the same level either in the presence (19.8%) or in the absence of LMV (20.6%). CONCLUSIONS: In our series, episodes of CMV DNAemia in LMV patients cleared spontaneously. A diminished degree of CMV-specific T-cell reconstitution in LMV patients compared to non-LMV patients was observed.
Subject(s)
Cytomegalovirus Infections , Hematopoietic Stem Cell Transplantation , Adult , Male , Female , Humans , Middle Aged , Cytomegalovirus , Cytomegalovirus Infections/drug therapy , CD8-Positive T-Lymphocytes , Transplant Recipients , Hematopoietic Stem Cell Transplantation/adverse effects , Transplantation, Homologous/adverse effects , Antiviral Agents/therapeutic useABSTRACT
BACKGROUND: We investigated whether donor-recipient mismatch involving one or more cytomegalovirus (CMV) immunodominant (ID) human leukocyte antigen (HLA)-I alleles may impact on the degree of CMV pp65/immediate-early 1 (IE-1) T-cell reconstitution and the incidence of CMV DNAemia in patients undergoing unmanipulated haploidentical hematopoietic stem cell transplantation with high-dose posttransplant cyclophosphamide (PT/Cy-haplo). METHODS: Multicenter observational study including 106 consecutive adult PT/Cy-haplo patients (34 CMV ID HLA-I matched and 72 mismatched). A real-time PCR was used for plasma CMV DNA load monitoring. Enumeration of CMV-specific (pp65/IE-1) interferon (IFN)-γ-producing T cells from several patients was performed by flow cytometry by days +30, +60, +90 and +180 after transplantation. RESULTS: The cumulative incidence of CMV DNAemia, clinically significant CMV DNAemia episodes (cs-CMVi), and recurrent CMV DNAemia was comparable across CMV ID HLA-I matched and mismatched patients (71.8% vs. 80.9%, p = .95; 40.7% vs. 44.2%, p = .85; 16.4% vs. 28.1%; p = .43, respectively). The percentage of patients exhibiting detectable CMV-specific IFN-γ-producing T-cell responses (either CD8+ or CD4+ ) was similar across groups; nevertheless, significantly higher CMV-specific CD8+ T-cell counts were enumerated in the CMV ID HLA-I matched compared to mismatched patients by day +60 (p = .04) and +180 (p = .016) after transplantation. CONCLUSION: CMV ID HLA-I matching may impact on the magnitude of CMV-pp65/IE-1-specific CD8+ T-cell reconstitution; yet, this effect seemed not to have an impact on the incidence of initial, recurrent CMV DNAemia, or cs-CMVi.
Subject(s)
Cytomegalovirus Infections , Hematopoietic Stem Cell Transplantation , Immune Reconstitution , Adult , Humans , Cytomegalovirus , Incidence , Transplantation, Homologous , Hematopoietic Stem Cell Transplantation/adverse effectsABSTRACT
BACKGROUND: Ruxolitinib is approved for patients with polycythemia vera (PV) who are resistant/intolerant to hydroxyurea, but its impact on preventing thrombosis or disease-progression is unknown. METHODS: A retrospective, real-world analysis was performed on the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to subsequent treatment with ruxolitinib (n = 105) or the best available therapy (BAT; n = 272). Survival probabilities and rates of thrombosis, hemorrhage, acute myeloid leukemia, myelofibrosis, and second primary cancers were calculated according to treatment. To minimize biases in treatment allocation, all results were adjusted by a propensity score for receiving ruxolitinib or BAT. RESULTS: Patients receiving ruxolitinib had a significantly lower rate of arterial thrombosis than those on BAT (0.4% vs 2.3% per year; P = .03), and this persisted as a trend after adjustment for the propensity to have received the drug (incidence rate ratio, 0.18; 95% confidence interval, 0.02-1.3; P = .09). There were no significant differences in the rates of venous thrombosis (0.8% and 1.1% for ruxolitinib and BAT, respectively; P = .7) and major bleeding (0.8% and 0.9%, respectively; P = .9). Ruxolitinib exposure was not associated with a higher rate of second primary cancers, including all types of neoplasia, noncutaneous cancers, and nonmelanoma skin cancers. After a median follow-up of 3.5 years, there were no differences in survival or progression to acute leukemia or myelofibrosis between the 2 groups. CONCLUSIONS: The results suggest that ruxolitinib treatment for PV patients with resistance/intolerance to hydroxyurea may reduce the incidence of arterial thrombosis. LAY SUMMARY: Ruxolitinib is better than other available therapies in achieving hematocrit control and symptom relief in patients with polycythemia vera who are resistant/intolerant to hydroxyurea, but we still do not know whether ruxolitinib provides an additional benefit in preventing thrombosis or disease progression. We retrospectively studied the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to whether they subsequently received ruxolitinib (n = 105) or the best available therapy (n = 272). Our findings suggest that ruxolitinib could reduce the incidence of arterial thrombosis, but a disease-modifying effect could not be demonstrated for ruxolitinib in this patient population.
Subject(s)
Leukemia, Myeloid, Acute , Neoplasms, Second Primary , Polycythemia Vera , Primary Myelofibrosis , Thrombosis , Hemorrhage/chemically induced , Humans , Hydroxyurea/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Neoplasms, Second Primary/drug therapy , Nitriles , Polycythemia Vera/drug therapy , Primary Myelofibrosis/drug therapy , Pyrazoles , Pyrimidines , Retrospective Studies , Thrombosis/chemically induced , Thrombosis/drug therapy , Thrombosis/prevention & controlABSTRACT
Myeloproliferative neoplasm (MPN)-unclassifiable (MPN-U) or not otherwise specified represents a rare, poorly defined and heterogeneous group of MPNs. Disease incidence is difficult to define but likely represents close to 5% of all MPNs when strict World Health Organisation (WHO) criteria are applied. Dynamic review over time is required to assess if the disease can be re-classified into another MPN entity. A diagnosis of MPN-U leads to many challenges for both the patient and physician alike including lack of agreed monitoring and therapeutic guidelines, validated prognostic markers and licenced therapies coupled with exclusion from clinical trials. MPN-U has an inherent risk of an aggressive clinical course and transformation in some but who, and when to treat in the chronic phase, including identifying who may require more aggressive therapy at an earlier stage, remains elusive. Moreover, despite the significant thrombotic risk, there is no agreement on systematic primary thromboprophylaxis. We hereby provide a contemporary overview of MPN-U in addition to four illustrative cases providing our collective suggested approaches to clinical challenges.
Subject(s)
Myeloproliferative Disorders , Neoplasms , Venous Thromboembolism , Anticoagulants , Humans , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/therapyABSTRACT
Available data have proved insufficient to develop consensus recommendations on the prevention of thrombosis and bleeding in myelofibrosis (MF). We evaluated the incidence and risk factors of vascular complications in 1613 patients from the Spanish Myelofibrosis Registry. Over a total of 6981 patient-years at risk, 6.4% of the study population had at least one thrombotic event after MF diagnosis, amounting to an incidence rate of 1.65 per 100 patient-years. Prior history of thrombosis, the JAK2 mutation, and the intermediate-2/high-risk International Prognostic Scoring System (IPSS) categories conferred an increased thrombotic risk after adjustment for the risk-modifying effect of anti-thrombotic and cytoreductive treatments. History of thrombosis and the JAK2 mutation allowed us to pinpoint a group of patients at higher risk of early thrombosis. No decreased incidence of thrombosis was observed while patients were on anti-thrombotic or cytoreductive treatment. An increased risk of venous thrombosis was found during treatment with immunomodulatory agents. A total of 5.3% of patients had at least one episode of major bleeding, resulting in an incidence rate of 1.5 events per 100 patient-years. Patients in the intermediate-2/high-risk IPSS categories treated with anti-coagulants had an almost sevenfold increased risk of major bleeding. These findings should prove useful for guiding decision-making in clinical practice.
Subject(s)
Primary Myelofibrosis , Thrombocythemia, Essential , Thrombosis , Humans , Primary Myelofibrosis/complications , Primary Myelofibrosis/drug therapy , Primary Myelofibrosis/genetics , Thrombocythemia, Essential/genetics , Thrombosis/epidemiology , Thrombosis/etiology , Thrombosis/diagnosis , Hemorrhage/diagnosis , Registries , Risk FactorsABSTRACT
Hematological control, incidence of complications, and need for cytoreduction were studied in 453 patients with low-risk polycythemia vera (PV) treated with phlebotomies alone. Median hematocrit value decreased from 54% at diagnosis to 45% at 12 months, and adequate hematocrit control over time (< 45%) was observed in 36%, 44%, and 32% of the patients at 6, 12, and 24 months, respectively. More than 5 phlebotomies per year in the maintenance phase were required in 19% of patients. Worsening thrombocytosis, age > 60 years, and microvascular symptoms constituted the main indications for starting cytoreduction. Median duration without initiating cytoreduction was significantly longer in patients younger than 50 years (< 0.0001). The incidence rate of thrombosis under phlebotomies alone was 0.8% per year and the estimated probability of thrombosis at 10 years was 8.5%. The probability of arterial thrombosis was significantly higher in patients with arterial hypertension whereas there was a trend to higher risk of venous thrombosis in cases with high JAK2V617F allele burden. Rates of major bleeding and second primary neoplasm were low. With a median follow-up of 9 years, survival probability at 10 years was 97%, whereas the probability of myelofibrosis at 10 and 20 years was 7% and 20%, respectively. Progression to acute myeloid leukemia was documented in 3 cases (1%). Current management of low-risk PV patients is associated with low rate of thrombosis and long survival. New treatment strategies are needed for improving hematological control and, in the long term, reducing progression to myelofibrosis.
Subject(s)
Leukemia, Myeloid, Acute , Polycythemia Vera , Primary Myelofibrosis , Thrombosis , Humans , Leukemia, Myeloid, Acute/complications , Middle Aged , Phlebotomy/adverse effects , Polycythemia Vera/complications , Polycythemia Vera/diagnosis , Polycythemia Vera/surgery , Primary Myelofibrosis/diagnosis , Registries , Thrombosis/complications , Thrombosis/etiologyABSTRACT
BACKGROUND: To investigate the multi-drug resistant bacteria (MDRB) colonization rate in hematological patients hospitalized for any cause using a multi-body-site surveillance approach, and determine the extent to which this screening strategy helped anticipate MDRB bloodstream infections (BSI). METHODS: Single-center retrospective observational study including 361 admissions documented in 250 adult patients. Surveillance cultures of nasal, pharyngeal, axillary and rectal specimens (the latter two combined) were performed at admission and subsequently on a weekly basis. Blood culture samples were incubated in an automated continuous monitoring blood culturing instrument (BACTEC FX). RESULTS: In total, 3463 surveillance cultures were performed (pharyngeal, n = 1201; axillary-rectal, n = 1200; nasal, n = 1062). MDRB colonization was documented in 122 out of 361 (33.7%) admissions corresponding to 86 patients (34.4%). A total of 149 MDRB were isolated from one or more body sites, of which most were Gram-negative bacteria, most frequently non-fermenting (n = 83) followed by Enterobacterales (n = 51). BSI were documented in 102 admissions (28%) involving 87 patients. Overall, the rate of BSI caused by MDRB was significantly higher (p = 0.04) in the presence of colonizing MDRB (16 out of 47 admissions in 14 patients) than in its absence (9 out of 55 admissions in 9 patients). Colonization by any MDRB was independently associated with increased risk of MDRB-BSI (HR, 3.70; 95% CI, 1.38-9.90; p = 0.009). CONCLUSION: MDRB colonization is a frequent event in hematological patients hospitalized for any reason and is associated with an increased risk of MDRB BSI. The data lend support to the use of MDRB colonization surveillance cultures for predicting the occurrence of MDRB BSI in this cohort.
Subject(s)
Bacteremia , Pharmaceutical Preparations , Sepsis , Adult , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Bacteremia/drug therapy , Drug Resistance, Multiple, Bacterial , Gram-Negative Bacteria , Humans , Retrospective Studies , Sepsis/drug therapyABSTRACT
The present study assessed the criteria for initiating cytoreduction and response to conventional therapies in 1446 patients with essential thrombocythemia (ET), 267 (17%) of which were CALR-mutated. In low risk patients, time from diagnosis to cytoreduction was shorter in CALR-positive than in the other genotypes (2·8, 3·2, 7·4 and 12·5 years for CALR, MPL, JAK2V617F and TN, respectively, P < 0·0001). A total of 1104 (76%) patients received cytoreductive treatment with hydroxycarbamide (HC) (n = 977), anagrelide (n = 113), or others (n = 14). The estimated cumulative rates of complete haematological response (CR) at 12 months were 40 % and 67% in CALR and JAK2V617F genotypes, respectively. Median time to CR was 192 days for JAK2V617F, 343 for TN, 433 for MPL, and 705 for CALR genotypes (P < 0·0001). Duration of CR was shorter in CALR-mutated ET than in the remaining patients (P = 0·003). In CALR-positive patients, HC and anagrelide had similar efficacy in terms of response rates and duration. CALR-mutated patients developed resistance/intolerance to HC more frequently (5%, 23%, 27% and 15% for JAK2V617F, CALR, MPL and TN, respectively; P < 0·0001). In conclusion, conventional cytoreductive agents are less effective in CALR-mutated ET, highlighting the need for new treatment modalities and redefinition of haematologic targets for patients with this genotype.
Subject(s)
Calreticulin/genetics , Genotype , Hydroxyurea/administration & dosage , Mutation, Missense , Quinazolines/administration & dosage , Registries , Thrombocythemia, Essential , Adolescent , Adult , Aged , Aged, 80 and over , Amino Acid Substitution , Child , Female , Follow-Up Studies , Humans , Janus Kinase 2/genetics , Male , Middle Aged , Spain , Thrombocythemia, Essential/drug therapy , Thrombocythemia, Essential/geneticsABSTRACT
Monitoring of alphatorquevirus (torque teno virus [TTV]) DNA in plasma may prove to be useful to assess the net state of immune competence following allogeneic hematopoietic stem cell transplantation (allo-HSCT). There are scarce data published on the prevalence of beta (torque teno mini virus [TTMV]) and gammatorqueviruses (torque teno midi virus [TTMDV]) and, in particular, on the dynamics of anelloviruses in allo-HSCT patients. Twenty-five allo-HSCT recipients with available plasma specimens obtained before conditioning and after engraftment were included. Degenerated primers targeting a highly conserved genomic sequence across all anelloviruses were designed for genomic amplification and high-throughput sequencing. Co-detection of TTV, TTMV, and TTMDV both in pre-transplant and post-engraftment plasma specimens was documented in more than two-thirds of patients. The use of quantitative real-time polymerase chain reaction (PCR) assays targeting TTMV and TTMDV in addition to TTV may add value to TTV-specific PCR assays in the inference of the net state of immunosuppresion or immune competence in this clinical setting.
Subject(s)
Anelloviridae/genetics , DNA Virus Infections/virology , Hematopoietic Stem Cell Transplantation , Adult , Aged , Anelloviridae/classification , Anelloviridae/isolation & purification , DNA Virus Infections/blood , DNA Virus Infections/immunology , DNA, Viral/blood , DNA, Viral/genetics , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Male , Middle Aged , Plasma/virology , Transplantation, HomologousABSTRACT
OBJECTIVE: To compare the efficacy and safety of CD34+ selected ex vivo T-cell depletion (TCD) vs post-transplant cyclophosphamide, sirolimus, and mycophenolate mofetil (PTCy-Sir-MMF) as graft-vs-host disease (GVHD) prophylaxis. METHODS: We retrospectively included patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with either TCD (n = 38) or PTCy-Sir-MMF (n = 91). RESULTS: Cumulative incidence of neutrophil and platelet recovery was 92% vs 99% (P = .06) and 89% vs 97% (P = .3) in TCD and PTCy-Sir-MMF, respectively. Cumulative incidences of aGHVD grade II-IV, III-IV, and moderate to severe cGVHD were 11% vs 19% (P = .2), 3% vs 2% (P = .9), and 3% vs 36% (P < .001) in TCD and PTCy-Sir-MMF, respectively. The 2-year non-relapse mortality, relapse, disease-free and overall survival were 25% vs 8% (P = .01), 20% vs 16% (P = .2), 55% vs 76% (P = .004), 57% vs 83% (P = .004) for TCD and PTCy-Sir-MMF, respectively. Cumulative incidence of cytomegalovirus and Epstein-Barr infection requiring therapy was 76% vs 40% (P < .001) and 32% vs 0% (P < .001) in TCD and PTCy-Sir-MMF, respectively. PTCy-Sir-MMF platform showed faster T-cell reconstitution. CONCLUSIONS: PTCy-Sir-MMF provides better survival outcomes but is associated with higher risk of cGVHD compared to TCD.