ABSTRACT
Development of Janus-kinase (JAK) inhibitors has revolutionized the therapeutic landscape for patients with myeloproliferative neoplasia (MPN). Following approval of the first JAK1/2-inhibitor Ruxolitinib, symptoms of this inflammatory disease, characterized by splenomegaly, release of inflammatory cytokines and appearance of thrombosis, could be effectively reduced for the first time. However, JAK-inhibitor treatment is limited in several aspects: 1) duration of response: 3 years after initiation of therapy more than 50% of patients have discontinued JAK-inhibitor treatment due to lack of efficacy or resistance; 2) reduction of disease burden: while effective in reducing inflammation and constitutional symptoms, JAK-inhibitors fail to reduce the malignant clone in the majority of patients and therefore lack long-term efficacy. Early clinical trials for patients with myelofibrosis (MF) have tried to address these issues for patients with suboptimal response to Ruxolitinib therapy while combination therapies with Fedratinib are rare. Recent reports provided first evidence on how the JAK2-V617F mutated myeloid cells may influence T-cell responses. JAK2-V617F promoted the synthesis of PD-L1 in MPN cells leading to limited anti-neoplastic T-cell responses, metabolic changes in T-cells and eventually JAK2-V617F-driven immune-escape of MPN cells. These findings may facilitate the use of immunotherapeutic approaches for JAK-mutated clones. Immune checkpoints refer to a variety of inhibitory pathways that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. The FRACTION study is a single arm, open label Phase II trial investigating the combination of Fedratinib with the PD-1 inhibitor Nivolumab in patients with myelofibrosis and suboptimal or lack of response to JAK-inhibitor therapy. Over a 12 months period the trial assesses longer term outcomes, particularly the effects on clinical outcomes, such as induction of clinical remissions, quality of life and improvement of anemia. No prospective clinical trial data exist for combinations of JAK- and immune-checkpoint-inhibitors in the planned MF study population and this study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives.
Subject(s)
Janus Kinase Inhibitors , Nivolumab , Primary Myelofibrosis , Pyrrolidines , Humans , Primary Myelofibrosis/drug therapy , Janus Kinase Inhibitors/therapeutic use , Pyrrolidines/therapeutic use , Nivolumab/therapeutic use , Nivolumab/administration & dosage , Sulfonamides/therapeutic use , Sulfonamides/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Male , Middle Aged , Aged , Germany , Myeloproliferative Disorders/drug therapy , Nitriles/therapeutic use , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/genetics , Pyrimidines/therapeutic use , Pyrazoles/therapeutic use , BenzenesulfonamidesABSTRACT
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.
Subject(s)
Interferon alpha-2 , Interferon-alpha , Polyethylene Glycols , Recombinant Proteins , Thrombocythemia, Essential , Humans , Thrombocythemia, Essential/drug therapy , Polyethylene Glycols/therapeutic use , Polyethylene Glycols/adverse effects , Polyethylene Glycols/administration & dosage , Recombinant Proteins/therapeutic use , Recombinant Proteins/adverse effects , Recombinant Proteins/administration & dosage , Interferon alpha-2/therapeutic use , Interferon alpha-2/adverse effects , Interferon-alpha/therapeutic use , Interferon-alpha/adverse effects , Prospective Studies , Male , Female , Treatment Outcome , Adult , Middle Aged , AgedABSTRACT
Patients (pts) with polycythemia vera (PV) suffer from pruritus, night sweats, and other symptoms, as well as from thromboembolic complications and progression to post-PV myelofibrosis. Ruxolitinib (RUX) is approved for second-line therapy in high-risk PV pts with hydroxyurea intolerance or resistance. The RuxoBEAT trial (NCT02577926, registered on October 1, 2015, at clinicaltrials.gov) is a multicenter, open-label, two-arm phase-IIb trial with a target population of 380 pts with PV or ET, randomized to receive RUX or best available therapy. This pre-specified futility analysis assesses the early clinical benefit and tolerability of RUX in previously untreated PV pts (6-week cytoreduction was allowed). Twenty-eight patients were randomly assigned to receive RUX. Compared to baseline, after 6 months of treatment, there was a significant reduction of median hematocrit (46 to 41%), the median number of phlebotomies per year (4.0 to 0), and median patient-reported pruritus scores (2 to 1), and a trend for reduced night sweat scores (1.5 to 0). JAK2V617F allele burden, as part of the scientific research program, also significantly decreased. One hundred nine adverse events (AEs) occurred in 24/28 patients (all grade 1 to 3), and no pt permanently discontinued treatment because of AEs. Thus, treatment with ruxolitinib in untreated PV pts is feasible, well-tolerated, and efficient regarding the above-mentioned endpoints.
Subject(s)
Janus Kinases , Polycythemia Vera , Humans , Hydroxyurea/therapeutic use , Medical Futility , Nitriles/therapeutic use , Polycythemia Vera/diagnosis , Polycythemia Vera/drug therapy , Polycythemia Vera/genetics , Pyrimidines/therapeutic use , Janus Kinases/therapeutic useABSTRACT
Patients with Philadelphia-negative myeloproliferative neoplasm (MPN) are prone to the development of second cancers, but the factors associated with these events have been poorly explored. In an international nested case-control study, we recruited 647 patients with carcinoma, nonmelanoma skin cancer, hematological second cancer, and melanoma diagnosed concurrently or after MPN diagnosis. Up to 3 control patients without a history of cancer and matched with each case for center, sex, age at MPN diagnosis, date of diagnosis, and MPN disease duration were included (n = 1234). Cases were comparable to controls for MPN type, driver mutations and cardiovascular risk factors. The frequency of thrombosis preceding MPN was similar for cases and controls (P = .462). Thrombotic events after MPN and before second cancer were higher in cases than in controls (11.6% vs 8.1%; P = .013), because of a higher proportion of arterial thromboses (6.2% vs 3.7%; P = .015). After adjustment for confounders, the occurrence of arterial thrombosis remained independently associated with the risk of carcinoma (odds ratio, 1.97; 95% confidence interval, 1.14-3.41), suggesting that MPN patients experiencing arterial events after MPN diagnosis deserve careful clinical surveillance for early detection of carcinoma. This study was registered at www.clinicaltrials.gov as NCT03745378.
Subject(s)
Arteries/pathology , Myeloproliferative Disorders/pathology , Neoplasms, Second Primary/pathology , Philadelphia Chromosome , Thrombosis/pathology , Case-Control Studies , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Multivariate AnalysisABSTRACT
In patients with bcr-abl-negative myeloproliferative neoplasms (MPN), concerns are often raised about the use of anticoagulants because of an increased bleeding risk. However, there are few MPN studies focusing on bleeding. To investigate bleeding complications in MPN, we report our retrospective, single-center study of 829 patients with a median follow-up of 5.5 years (range: 0.1-35.6). A first bleeding event occurred in 143 of 829 patients (17.2%), corresponding to an incidence rate of 2.29% per patient/year. During the follow-up period, one out of 829 patients (0.1%) died due to bleeding. Regarding anticoagulation, most bleeding occurred in patients on antiplatelet therapies (60.1%), followed by patients on anticoagulation therapies (20.3%) and patients not on anticoagulation (19.6%). In multivariate analysis, administration of antiplatelet (HR 2.31 [1.43, 3.71]) and anticoagulation therapies (HR 4.06 [2.32, 7.09]), but not age, gender or mutation status, was associated with an increased bleeding risk. Comparing the "probability of bleeding-free survival" between the MPN subtypes, no significant difference was observed (p = 0.91, log-rank test). Our retrospective study shows that antiplatelet and anticoagulation therapies significantly increase the risk of bleeding in MPN patients without affecting mortality. However, there is no reason to refrain from guideline-conform primary or secondary anticoagulation in MPN patients.
Subject(s)
Hemorrhage/epidemiology , Hemorrhage/etiology , Myeloproliferative Disorders/complications , Myeloproliferative Disorders/epidemiology , Adolescent , Adult , Aged , Anticoagulants/therapeutic use , Biomarkers , Biomarkers, Tumor , Biopsy , Blood Coagulation , Bone Marrow , Child , Disease Management , Disease Susceptibility , Female , Fusion Proteins, bcr-abl/genetics , Hemorrhage/diagnosis , Hemorrhage/therapy , Humans , Incidence , Male , Middle Aged , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/genetics , Prognosis , Risk Assessment , Risk Factors , Survival Rate , Young AdultABSTRACT
Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) have poor outcomes to current treatment. A phase 2 hypothesis-generating trial was conducted to determine whether the addition of the multitargeted kinase inhibitor midostaurin to intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (alloHCT) and single-agent maintenance therapy of 12 months is feasible and favorably influences event-free survival (EFS) compared with historical controls. Patients 18 to 70 years of age with newly diagnosed AML and centrally confirmed FLT3-ITD were eligible: 284 patients were treated, including 198 younger (18-60 years) and 86 older (61-70 years) patients. Complete remission (CR) rate, including CR with incomplete hematological recovery (CRi) after induction therapy, was 76.4% (younger, 75.8%; older, 77.9%). The majority of patients in CR/CRi proceeded to alloHCT (72.4%). Maintenance therapy was started in 97 patients (34%): 75 after alloHCT and 22 after consolidation with high-dose cytarabine (HiDAC). Median time receiving maintenance therapy was 9 months after alloHCT and 10.5 months after HiDAC; premature termination was mainly a result of nonrelapse causes (gastrointestinal toxicity and infections). EFS and overall survival at 2 years were 39% (95% confidence interval [CI], 33%-47%) and 34% (95% CI, 24%-47%) and 53% (95% CI, 46%-61%) and 46% (95% CI, 35%-59%) in younger and older patients, respectively. EFS was evaluated in comparison with 415 historical controls treated within 5 prospective trials. Propensity score-weighted analysis revealed a significant improvement of EFS by midostaurin (hazard ratio [HR], 0.58; 95% CI, 0.48-0.70; P < .001) overall and in older patients (HR, 0.42; 95% CI, 0.29-0.61). The study was registered at www.clinicaltrials.gov as #NCT01477606.
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Maintenance Chemotherapy , Staurosporine/analogs & derivatives , fms-Like Tyrosine Kinase 3/genetics , Adolescent , Adult , Aged , Allografts , Disease-Free Survival , Female , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Staurosporine/administration & dosage , Survival RateABSTRACT
Ruxolitinib, a potent Janus kinase 1/2 inhibitor, has demonstrated durable improvements in patients with myelofibrosis. In this analysis of the Phase 3b JUMP study, which included patients aged ≥18 years with a diagnosis of primary or secondary myelofibrosis, we assessed the safety and efficacy of ruxolitinib in patients stratified by Dynamic International Prognostic Scoring System (DIPSS) risk categories. Baseline characteristic data were available to assess DIPSS status for 1844 of the 2233 enrolled patients; 60, 835, 755, and 194 in the low-, intermediate (Int)-1-, Int-2-, and high-risk groups, respectively. Ruxolitinib was generally well tolerated across all risk groups, with an adverse-event (AE) profile consistent with previous reports. The most common hematologic AEs were thrombocytopenia and anemia, with highest rates of Grade ≥3 events in high-risk patients. Approximately, 73% of patients experienced ≥50% reductions in palpable spleen length at any point in the ≤24-month treatment period, with highest rates in lower-risk categories (low, 82.1%; Int-1, 79.3%; Int-2, 67.1%; high risk, 61.6%). Median time to spleen length reduction was 5.1 weeks and was shortest in lower-risk patients. Across measures, 40%-57% of patients showed clinically meaningful symptom improvements, which were observed from 4 weeks after treatment initiation and maintained throughout the study. Overall survival (OS) was 92% at Week 72 and 75% at Week 240 (4.6 years). Median OS was longer for Int-2-risk than high-risk patients (253.6 vs. 147.3 weeks), but not evaluable in low-/Int-1-risk patients. By Week 240, progression-free survival (PFS) and leukemia-free survival (LFS) rates were higher in lower-risk patients (PFS: low, 90%; Int-1, 82%; Int-2, 46%; high risk, 15%; LFS: low, 92%; Int-1, 86%; Int-2, 58%; high risk, 19%). Clinical benefit was seen across risk groups, with more rapid improvements in lower risk patients. Overall, this analysis indicates that ruxolitinib benefits lower-risk DIPSS patients in addition to higher risk.
Subject(s)
Janus Kinases/therapeutic use , Primary Myelofibrosis/classification , Primary Myelofibrosis/drug therapy , Pyrazoles/therapeutic use , Adult , Aged , Female , Humans , Janus Kinases/pharmacology , Male , Middle Aged , Nitriles , Pyrazoles/pharmacology , PyrimidinesABSTRACT
In patients with BCR-ABL-negative myeloproliferative neoplasms (MPN), arterial or venous thromboembolic events (ATE/VTE) are a major burden. In order to control these complications, vitamin K antagonists (VKA) are widely used. There is no robust evidence supporting the use of direct oral anticoagulants (DOAC) in MPN patients. We therefore compared the efficacy and safety of both anticoagulants in 71 cases from a cohort of 782 MPN patients. Seventy-one of 782 MPN patients (9.1%) had ATE/VTE with nine ATE (12.7%) and 62 VTE (87.3%). Forty-five of 71 ATE/VTE (63.4%) were treated with VKA and 26 (36.6%) with DOAC. The duration of anticoagulation therapy (p = 0.984), the number of patients receiving additional aspirin (p = 1.0), and the proportion of patients receiving cytoreductive therapy (p = 0.807) did not differ significantly between the VKA and DOAC groups. During anticoagulation therapy, significantly more relapses occurred under VKA (n = 16) compared to DOAC treatment (n = 0, p = 0.0003). However, during the entire observation period of median 3.2 years (0.1-20.4), ATE/VTE relapse-free survival (p = 0.2) did not differ significantly between the two anticoagulants. For all bleeding events (p = 0.516) or major bleeding (p = 1.0), no significant differences were observed between VKA and DOAC. In our experience, the use of DOAC was as effective and safe as VKA, possibly even potentially beneficial with a lower number of recurrences and no increased risk for bleedings. However, further and larger studies are required before DOAC can be routinely used in MPN patients.
Subject(s)
Factor Xa Inhibitors/therapeutic use , Myeloproliferative Disorders/complications , Secondary Prevention , Thromboembolism/prevention & control , Adult , Aged , Aged, 80 and over , Factor Xa Inhibitors/adverse effects , Female , Hemorrhage/chemically induced , Humans , Male , Middle Aged , Thromboembolism/etiology , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & control , Young AdultABSTRACT
Recently, there has been increased concern about a risk of secondary malignancies (SM) occurring in myelofibrosis (MF) patients receiving ruxolitinib (RUX). In polycythemia vera (PV), on the other hand, only limited data on the risk of SM under RUX treatment are available. To investigate the association between RUX therapy in PV and SM, we conducted a retrospective, single-center study that included 289 PV patients. RUX was administered to 32.9% (95/289) of patients for a median treatment duration of 48.0 months (range 1.0-101.6). Within a median follow-up of 97 months (1.0-395.0) after PV diagnosis, 24 SM occurred. Comparing the number of PV patients with RUX-associated SM (n = 10, 41.7%) with the 14 (58.3%) patients who developed SM without RUX, no significant difference (p = 0.34, chi square test) was found. No increased incidences of melanoma, lymphoma, or solid "non-skin" malignancies were observed with RUX (p = 0.31, p = 0.60, and p = 0.63, respectively, chi square test). However, significantly more NMSC occurred in association with RUX treatment (p = 0.03, chi-squared test). The "SM-free survival" was not significantly different by log rank test for all 289 patients (p = 0.65), for the patients (n = 208; 72%) receiving cytoreductive therapy (p = 0.48) or for different therapy sequences (p = 0.074). In multivariate analysis, advanced age at PV diagnosis (HR 1.062 [95% CI 1.028, 1.098]) but not administration of RUX (HR 1.068 [95% CI 0.468, 2.463]) was associated with an increased risk for SM (p = 0.005). According to this retrospective analysis, no increased risk of SM due to RUX treatment could be substantiated for PV.
Subject(s)
Neoplasms, Second Primary/chemically induced , Polycythemia Vera/drug therapy , Pyrazoles/adverse effects , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Hydroxyurea/adverse effects , Hydroxyurea/therapeutic use , Incidence , Janus Kinase 2/genetics , Lymphoma/chemically induced , Lymphoma/epidemiology , Male , Middle Aged , Mutation, Missense , Neoplasms, Second Primary/epidemiology , Nitriles , Polycythemia Vera/genetics , Primary Myelofibrosis/chemically induced , Primary Myelofibrosis/etiology , Proportional Hazards Models , Pyrazoles/therapeutic use , Pyrimidines , Retrospective Studies , Risk , Skin Neoplasms/chemically induced , Skin Neoplasms/epidemiologyABSTRACT
OBJECTIVES: Pregnancies in women with polycythemia vera (PV) are associated with an increased risk of PV-related maternal complications and often result in miscarriage. Recommendations for the management of PV pregnancies are mainly based on studies with a small number of patients. A correlation between pregnancy outcome and postpartum course has been reported for essential thrombocythemia, but corresponding data for PV are lacking so far. METHODS: In 41 PV pregnancies, the pregnancy outcome, the use of PV-specific therapies (ie, acetylsalicylic acid, low-molecular weight heparin and/or interferon-alpha), and the postpartum PV course were investigated. RESULTS: A live birth rate of 51.2% (21/41 pregnancies) was observed. 43.9% of pregnancies ended in spontaneous abortion and 4.9% in stillbirth. A significantly increased live birth rate occurred in pregnancies with PV-specific therapies compared to standard antenatal care (69.0% vs. 8.3%; P < .0019). The use of PV-specific therapy significantly increased the number of maternal hemorrhages (P = .021) without increasing the risk of fetal complications. During the median postpartum follow-up period of 1.2 years (range 0.1-13.7), complicated postpartum PV occurred significantly more often after miscarriages (P = .035). CONCLUSIONS: According to our analysis, PV-specific therapy improved the live birth rate. Significantly more complicated postpartum PV courses were observed after miscarriages.
Subject(s)
Hemorrhage/etiology , Polycythemia Vera/physiopathology , Polycythemia Vera/therapy , Pregnancy Complications/physiopathology , Pregnancy Complications/therapy , Abortion, Spontaneous , Adolescent , Adult , Female , Heparin, Low-Molecular-Weight , Humans , Polycythemia Vera/complications , Pregnancy , Pregnancy Outcome , Retrospective Studies , Thrombocythemia, Essential/therapy , Treatment Outcome , Young AdultABSTRACT
Ruxolitinib is a potent Janus kinase (JAK) 1/JAK2 inhibitor approved for the treatment of myelofibrosis (MF). Ruxolitinib was assessed in JUMP, a large (N = 2233), phase 3b, expanded-access study in MF in countries without access to ruxolitinib outside a clinical trial, which included patients with low platelet counts (<100 × 109 /l) and patients without splenomegaly - populations that have not been extensively studied. The most common adverse events (AEs) were anaemia and thrombocytopenia, but they rarely led to discontinuation (overall, 5·4%; low-platelet cohort, 12·3%). As expected, rates of worsening thrombocytopenia were higher in the low-platelet cohort (all grades, 73·2% vs. 53·5% overall); rates of anaemia were similar (all grades, 52·9% vs. 59·5%). Non-haematologic AEs, including infections, were mainly grade 1/2. Overall, ruxolitinib led to meaningful reductions in spleen length and symptoms, including in patients with low platelet counts, and symptom improvements in patients without splenomegaly. In this trial, the largest study of ruxolitinib in patients with MF to date, the safety profile was consistent with previous reports, with no new safety concerns identified. This study confirms findings from the COMFORT studies and supports the use of ruxolitinib in patients with platelet counts of 50-100 × 109 /l. (ClinicalTrials.gov identifier NCT01493414).
Subject(s)
Primary Myelofibrosis/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Anemia/chemically induced , Female , Humans , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/etiology , Male , Middle Aged , Neoplasms/etiology , Nitriles , Platelet Count , Primary Myelofibrosis/blood , Primary Myelofibrosis/complications , Progression-Free Survival , Proportional Hazards Models , Protein Kinase Inhibitors/adverse effects , Pyrazoles/adverse effects , Pyrimidines , Spleen/pathology , Splenomegaly/etiology , Thrombocytopenia/chemically induced , Young AdultABSTRACT
One out of ten patients with Philadelphia-negative myeloproliferative neoplasms (MPN) develop a second cancer (SC): in such patients we aimed at assessing the survival impact of SC itself and of MPN-specific therapies. Data were therefore extracted from an international nested case-control study, recruiting 798 patients with SC diagnosed concurrently or after the MPN. Overall, 2995 person-years (PYs) were accumulated and mortality rate (MR) since SC diagnosis was 5.9 (5.1-6.9) deaths for every 100 PYs. A "poor prognosis" SC (stomach, esophagus, liver, pancreas, lung, ovary, head-and-neck or nervous system, osteosarcomas, multiple myeloma, aggressive lymphoma, acute leukemia) was reported in 26.3% of the patients and was the cause of death in 65% of them (MR 11.0/100 PYs). In contrast, patients with a "non-poor prognosis" SC (NPPSC) incurred a MR of 4.6/100 PYs: 31% of the deaths were attributed to SC and 15% to MPN evolution. At multivariable analysis, death after SC diagnosis was independently predicted (HR and 95% CI) by patient age greater than 70 years (2.68; 1.88-3.81), the SC prognostic group (2.57; 1.86-3.55), SC relapse (1.53; 10.6-2.21), MPN evolution (2.72; 1.84-4.02), anemia at SC diagnosis (2.32; 1.49-3.59), exposure to hydroxyurea (1.89; 1.26-2.85) and to ruxolitinib (3.63; 1.97-6.71). Aspirin was protective for patients with a NPPSC (0.60; 0.38-0.95). In conclusion, SC is a relevant cause of death competing with MPN evolution. Prospective data are awaited to confirm the role of cytoreductive and anti-platelet drugs in modulating patient survival after the occurrence of a SC.
Subject(s)
Hematologic Neoplasms/mortality , Myeloproliferative Disorders/mortality , Neoplasms, Second Primary/mortality , Age Factors , Aged , Case-Control Studies , Disease-Free Survival , Female , Follow-Up Studies , Humans , Male , Middle Aged , Survival RateABSTRACT
Thromboembolic events and cardiovascular disease are the most prevalent complications in patients with polycythemia vera (PV) compared with other myeloproliferative disorders and are the major cause of morbidity and mortality in this population. Moreover, a vascular complication such as arterial or venous thrombosis often leads to the diagnosis of PV. The highest rates of thrombosis typically occur shortly before or at diagnosis and decrease over time, probably due to the effects of treatment. Important risk factors include age (≥ 60 years old) and a history of thrombosis; elevated hematocrit and leukocytosis are also associated with an increased risk of thrombosis. The goal of therapy is to reduce the risk of thrombosis by controlling hematocrit to < 45%, a target associated with reduced rates of cardiovascular death and major thrombosis. Low-risk patients (< 60 years old with no history of thrombosis) are managed with phlebotomy and low-dose aspirin, whereas high-risk patients (≥ 60 years old and/or with a history of thrombosis) should be treated with cytoreductive agents. Interferon and ruxolitinib are considered second-line therapies for patients who are intolerant of or have an inadequate response to hydroxyurea, which is typically used as first-line therapy. In this review, we discuss factors associated with thrombosis and recent data on current treatments, including anticoagulation, highlighting the need for more controlled studies to determine the most effective cytoreductive therapies for reducing the risk of thrombosis in patients with PV.
Subject(s)
Polycythemia Vera , Thromboembolism , Age Factors , Anticoagulants/therapeutic use , Aspirin/therapeutic use , Humans , Hydroxyurea/adverse effects , Hydroxyurea/therapeutic use , Interferons/therapeutic use , Nitriles , Phlebotomy , Polycythemia Vera/complications , Polycythemia Vera/diagnosis , Polycythemia Vera/therapy , Pyrazoles/therapeutic use , Pyrimidines , Risk Factors , Thromboembolism/diagnosis , Thromboembolism/etiology , Thromboembolism/therapy , Thrombosis/diagnosis , Thrombosis/etiology , Thrombosis/therapyABSTRACT
Venous thromboembolism (VTE) is a major burden in patients with BCR-ABL-negative myeloproliferative neoplasms (MPN). In addition to cytoreductive treatment anticoagulation is mandatory, but optimal duration of anticoagulation is a matter of debate. In our single center study, we retrospectively included 526 MPN patients. In total, 78 of 526 MPN patients (14.8%) had 99 MPN-associated VTE. Median age at first VTE was 52.5 years (range 23-81). During a study period of 3497 years, a VTE event rate of 1.7% per patient/year was detected. 38.4% (38/99) of all VTEs appeared before or at MPN diagnosis and 55.6% (55/99) occurred at "uncommon" sites like splanchnic or cerebral veins. MPN patients with VTEs were significantly more female (p = 0.028), JAK2 positive (p = 0.018), or had a polycythemia vera (p = 0.009). MPN patients without VTEs were more often CALR positive (p = 0.023). Total study period after first VTE was 336 years with 20 VTE recurrences accounting for a recurrence rate of 6% per patient/year. In 36 of 71 MPN patients with anticoagulation therapy after first VTE event (50.7%), prophylactic anticoagulation was terminated after a median time of 6 months (range 1-61); 13 of those 36 patients (36.1%) had a VTE recurrence after a median of 13 months (range 4-168). In contrast, only three of 35 (8.6%) patients with ongoing anticoagulation had a VTE recurrence (p = 0.0127). Thus, termination of prophylactic anticoagulation was associated with a significantly higher risk of VTE recurrence. Our data suggest that in MPN patients with VTE, a prolonged duration of anticoagulation may be beneficial.
Subject(s)
Anticoagulants/administration & dosage , Hematologic Neoplasms , Myeloproliferative Disorders , Venous Thromboembolism , Adolescent , Adult , Aged , Aged, 80 and over , Anticoagulants/adverse effects , Child , Female , Fusion Proteins, bcr-abl , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/epidemiology , Humans , Male , Middle Aged , Myeloproliferative Disorders/drug therapy , Myeloproliferative Disorders/epidemiology , Recurrence , Retrospective Studies , Risk Factors , Sex Factors , Venous Thromboembolism/epidemiology , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & controlABSTRACT
Standard first-line treatment of aggressive B cell lymphoma comprises six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus eight doses of rituximab (R). Whether adding two doses of rituximab to six cycles of R-CHOP is of therapeutic benefit has not been systematically investigated. The Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial investigated the ability of [18F]-fluorodesoxyglucose PET scanning to guide treatment in aggressive non-Hodgkin lymphomas. Patients with B cell lymphomas and a negative interim scan received six cycles of R-CHOP with or without two extra doses of rituximab. For reasons related to trial design, only about a third underwent randomization between the two options. Combining randomized and non-randomized patients enabled subgroup analyses for diffuse large B cell lymphoma (DLBCL; n = 544), primary mediastinal B cell lymphoma (PMBCL; n = 37), and follicular lymphoma (FL) grade 3 (n = 35). With a median follow-up of 52 months, increasing the number of rituximab administrations failed to improve outcome. A non-significant trend for improved event-free survival was seen in DLBCL high-risk patients, as defined by the International Prognostic Index, while inferior survival was observed in female patients below the age of 60 years. Long-term outcome in PMBCL was excellent. Differences between FL grade 3a and FL grade 3b were not apparent. The results were confirmed in a Cox proportional hazard regression model and a propensity score matching analysis. In conclusion, adding two doses of rituximab to six cycles of R-CHOP did not improve outcome in patients with aggressive B cell lymphomas and a fast metabolic treatment response.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Fluorodeoxyglucose F18/administration & dosage , Lymphoma, B-Cell , Positron-Emission Tomography , Rituximab/administration & dosage , Adolescent , Adult , Aged , Aged, 80 and over , Cyclophosphamide/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Female , Follow-Up Studies , Humans , Lymphoma, B-Cell/diagnostic imaging , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/mortality , Male , Middle Aged , Prednisone/administration & dosage , Survival Rate , Vincristine/administration & dosageABSTRACT
BACKGROUND: Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea. METHODS: We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging. RESULTS: The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy; 38% and 1% of patients in the two groups, respectively, had at least a 35% reduction in spleen volume. A complete hematologic remission was achieved in 24% of patients in the ruxolitinib group and 9% of those in the standard-therapy group (P=0.003); 49% versus 5% had at least a 50% reduction in the total symptom score at week 32. In the ruxolitinib group, grade 3 or 4 anemia occurred in 2% of patients, and grade 3 or 4 thrombocytopenia occurred in 5%; the corresponding percentages in the standard-therapy group were 0% and 4%. Herpes zoster infection was reported in 6% of patients in the ruxolitinib group and 0% of those in the standard-therapy group (grade 1 or 2 in all cases). Thromboembolic events occurred in one patient receiving ruxolitinib and in six patients receiving standard therapy. CONCLUSIONS: In patients who had an inadequate response to or had unacceptable side effects from hydroxyurea, ruxolitinib was superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with polycythemia vera. (Funded by Incyte and others; RESPONSE ClinicalTrials.gov number, NCT01243944.).
Subject(s)
Antineoplastic Agents/therapeutic use , Janus Kinases/antagonists & inhibitors , Polycythemia Vera/drug therapy , Pyrazoles/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Blood Cell Count , Female , Humans , Hydroxyurea/adverse effects , Hydroxyurea/therapeutic use , Kaplan-Meier Estimate , Male , Middle Aged , Nitriles , Organ Size/drug effects , Pyrazoles/adverse effects , Pyrazoles/pharmacology , Pyrimidines , Remission Induction , Spleen/drug effects , Spleen/pathology , Thrombocytopenia/chemically inducedABSTRACT
Evaluation of Anagrelide (Xagrid®) Efficacy and Long-term Safety, a phase IV, prospective, non-interventional study performed in 13 European countries enrolled high-risk essential thrombocythemia patients treated with cytoreductive therapy. The primary objectives were safety and pregnancy outcomes. Of 3721 registered patients, 3649 received cytoreductive therapy. At registration, 3611 were receiving: anagrelide (Xagrid®) (n=804), other cytoreductive therapy (n=2666), or anagrelide + other cytoreductive therapy (n=141). The median age was 56 vs. 70 years for anagrelide vs. other cytoreductive therapy. Event rates (patients with events/100 patient-years) were 1.62 vs. 2.06 for total thrombosis and 0.15 vs. 0.53 for venous thrombosis. Anagrelide was more commonly associated with hemorrhage (0.89 vs. 0.43), especially with anti-aggregatory therapy (1.35 vs. 0.33) and myelofibrosis (1.04 vs. 0.30). Other cytoreductive therapies were more associated with acute leukemia (0.28 vs. 0.07) and other malignancies (1.29 vs. 0.44). Post hoc multivariate analyses identified increased risk for thrombosis with prior thrombohemorrhagic events, age ≥65, cardiovascular risk factors, or hypertension. Risk factors for transformation were prior thrombohemorrhagic events, age ≥65, time since diagnosis, and platelet count increase. Safety analysis reflected published data, and no new safety concerns for anagrelide were found. Live births occurred in 41/54 pregnancies (76%). clinicaltrials.gov Identifier: 00567502.
Subject(s)
Quinazolines/therapeutic use , Thrombocythemia, Essential/therapy , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers , Cell Transformation, Neoplastic , Disease Management , Disease Progression , Europe/epidemiology , Female , Humans , Male , Middle Aged , Mortality , Pregnancy , Pregnancy Complications, Hematologic , Prospective Studies , Quinazolines/administration & dosage , Quinazolines/adverse effects , Risk Assessment , Thrombocythemia, Essential/diagnosis , Thrombocythemia, Essential/epidemiology , Treatment Outcome , Young AdultABSTRACT
RESPONSE-2 is a phase 3 study comparing the efficacy and safety of ruxolitinib with the best available therapy (BAT) in hydroxyurea-resistant/hydroxyurea-intolerant polycythemia vera (PV) patients without palpable splenomegaly. This analysis evaluated the durability of the efficacy and safety of ruxolitinib after patients completed the visit at week 80 or discontinued the study. Endpoints included proportion of patients achieving hematocrit control (< 45%), proportion of patients achieving complete hematologic remission (CHR) at week 28, and the durability of hematocrit control and CHR. At the time of analysis, 93% (69/74) of patients randomized to ruxolitinib were receiving ruxolitinib; while in the BAT arm, 77% (58/75) of patients crossed over to ruxolitinib after week 28. No patient remained on BAT by week 80. Among patients who achieved a hematocrit response at week 28, the probability of maintaining response up to week 80 was 78% in the ruxolitinib arm. At week 80, durable CHR was achieved in 18 patients (24%) in the ruxolitinib arm versus 2 patients (3%) in the BAT arm. The safety profile of ruxolitinib was consistent with previous reports. These data support that ruxolitinib treatment should be considered also as a standard of care for hydroxyurea-resistant/hydroxyurea-intolerant PV patients without palpable splenomegaly.
Subject(s)
Drug Resistance, Neoplasm/drug effects , Polycythemia Vera/drug therapy , Pyrazoles/therapeutic use , Aged , Cross-Over Studies , Female , Follow-Up Studies , Hematocrit , Humans , Male , Middle Aged , Nitriles , Phlebotomy/statistics & numerical data , Polycythemia Vera/epidemiology , Polycythemia Vera/pathology , Pyrazoles/adverse effects , Pyrimidines , Splenomegaly , Treatment OutcomeABSTRACT
Ruxolitinib was well tolerated and superior to best available therapy (including interferon [IFN]) in controlling hematocrit without phlebotomy eligibility, normalizing blood counts, and improving polycythemia vera-related symptoms in the Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care (RESPONSE) studies. This ad hoc analysis focuses on ruxolitinib in relation to IFN in the RESPONSE studies, with attention on the following: (1) safety and efficacy of ruxolitinib and best available therapy in patients who received IFN before study randomization, (2) safety and efficacy of IFN during randomized treatment in best available therapy arm, and (3) use of ruxolitinib after crossover from best available therapy in IFN-treated patients. IFN exposure before randomization had little effect on the efficacy or safety of ruxolitinib. In the randomized treatment arms, ruxolitinib was superior to IFN in efficacy [hematocrit control (RESPONSE = 60% of ruxolitinib vs 23% of IFN patients; RESPONSE-2 = 62% of ruxolitinib vs 15% of IFN patients)] and was tolerated better in hydroxyurea-resistant or hydroxyurea-intolerant patients. After crossing over to receive ruxolitinib, patients who had initially received IFN and did not respond had improved hematologic and spleen responses (62% of patients at any time after crossover) and an overall reduction in phlebotomy procedures. Rates and incidences of the most common adverse events decreased after crossover to ruxolitinib, except for infections (primarily grade 1 or 2). These data suggest that ruxolitinib is efficacious and well tolerated in patients who were previously treated with IFN. The RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) studies were registered at clinicaltrials.gov .
Subject(s)
Antineoplastic Agents/therapeutic use , Interferons/therapeutic use , Janus Kinases/antagonists & inhibitors , Polycythemia Vera/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Adult , Aged , Antineoplastic Agents/adverse effects , Bloodletting/adverse effects , Combined Modality Therapy/adverse effects , Cross-Over Studies , Drug Monitoring , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Female , Humans , Hydroxyurea/adverse effects , Hydroxyurea/therapeutic use , Interferons/adverse effects , Janus Kinases/metabolism , Male , Middle Aged , Nitriles , Polycythemia Vera/metabolism , Polycythemia Vera/physiopathology , Polycythemia Vera/therapy , Practice Patterns, Physicians' , Protein Kinase Inhibitors/adverse effects , Pyrazoles/adverse effects , Pyrimidines , Reproducibility of Results , Splenomegaly/etiology , Splenomegaly/prevention & controlABSTRACT
OBJECTIVES: To present the Central European Myeloproliferative Neoplasm Organisation (CEMPO) treatment recommendations for polycythaemia vera (PV). METHODS: During meetings held from 2015 through 2017, CEMPO discussed PV and its treatment and recent data. RESULTS: PV is associated with increased risks of thrombosis/thrombo-haemorrhagic complications, fibrotic progression and leukaemic transformation. Presence of Janus kinase (JAK)-2 gene mutations is a diagnostic marker and standard diagnostic criterion. World Health Organization 2016 diagnostic criteria for PV, focusing on haemoglobin levels and bone marrow morphology, are mandatory. PV therapy aims at managing long-term risks of vascular complications and progression towards transformation to acute myeloid leukaemia and myelodysplastic syndrome. Risk stratification for thrombotic complications guides therapeutic decisions. Low-risk patients are treated first line with low-dose aspirin and phlebotomy. Cytoreduction is considered for low-risk (phlebotomy intolerance, severe/progressive symptoms, cardiovascular risk factors) and high-risk patients. Hydroxyurea is suspected of leukaemogenic potential. IFN-α has demonstrated efficacy in many clinical trials; its pegylated form is best tolerated, enabling less frequent administration than standard interferon. Ropeginterferon alfa-2b has been shown to be more efficacious than hydroxyurea. JAK1/JAK2 inhibitor ruxolitinib is approved for hydroxyurea resistant/intolerant patients. CONCLUSIONS: Greater understanding of PV is serving as a platform for new therapy development and treatment response predictors.