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Rates of grade ≥3 thrombocytopenia and anemia in COMFORT-I. (From Verstovsek, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis 16. © 2012 Massachusetts Medical Society. Reprinted with permission from the Massachusetts Medical Society). Shown are mean percentages of (A) grade ≥3 thrombocytopenia and (B) grade ≥3 anemia per month over time.
Source publication
Ruxolitinib, an oral JAK1 and JAK2 inhibitor, is approved in the US for patients with intermediate or high-risk myelofibrosis (MF), a chronic neoplasm associated with aberrant myeloproliferation, progressive bone marrow fibrosis, splenomegaly, and burdensome symptoms. Phase III clinical studies have shown that ruxolitinib reduces splenomegaly and a...
Contexts in source publication
Context 1
... and thrombocytopenia were the most common adverse events associated with ruxolitinib treatment and typically occurred early in the course of therapy [16,17,21]. As shown in Figure 1A and 1B, grade 3 or 4 anemia and thrombocytopenia were greatest in the first 8-12 weeks of treatment [16]. Similarly, hemoglobin levels and platelet counts decreased during the same time frame (Figure 2A and 2B) [22]. ...
Context 2
... decreasing from a baseline value of 109.3 g/L to a nadir of 94.1 g/L approximately 12 weeks after treat- ment initiation, mean hemoglobin levels in the ruxolitinib arm of COMFORT-II reached a steady-state value of 101.8 g/L by week 24 [17]. Monthly rates of grade 3 or 4 anemia and thrombocytopenia in COMFORT-I de- creased over time to levels similar to those observed in the placebo group (Figure 1) [16]. In addition, grade 3 or 4 episodes of bleeding with ruxolitinib were uncommon (2.6% and 1.3%, respectively) and occurred at rates simi- lar to those with placebo (2.0% and 1.3%, respectively), an indication that the mandatory dose reductions and treat- ment interruptions allowed for effective management of thrombocytopenia [16]. ...
Similar publications
The JAK1/JAK2 inhibitor ruxolitinib produced significant reductions in splenomegaly and symptomatic burden and improved survival in patients with myelofibrosis (MF), irrespective of their JAK2 mutation status, in 2 phase III studies against placebo (COMFORT-I) and best available therapy (COMFORT-II). We performed a comprehensive mutation analysis t...
Citations
... The observational, longitudinal RUXOREL-MF study showed the impact of ruxolitinib dose on clinical benefit: a shorter OS was associated with doses < 20 mg bid, and a suboptimal starting dose was often associated with patients not reaching the recommended 20-mg bid dose in the study [50]. Analyses from COMFORT-I also underscored that doses ≥ 10 mg bid led to better clinical outcomes, including reductions in spleen volume and symptom improvement [51,52], and spleen responses to ruxolitinib have separately been demonstrated to correlate with survival [53][54][55]. An important exception to initiating patients at ruxolitinib doses ≥ 10 mg bid comes from the REALISE study, which showed that patients with anemia (baseline hemoglobin < 10 g/dL) can be effectively treated with a strategy of initiating ruxolitinib treatment at lower doses (10 mg bid) and titrating up based on tolerance after 12 weeks [44,56]. ...
Purpose of Review
Summarize best practices for management of patients with early myelofibrosis (MF).
Recent Findings
Myelofibrosis is a progressive myeloproliferative neoplasm (MPN) that generally produces burdensome symptoms and ultimately leads to worse overall survival than that observed in healthy controls or patients with other MPNs. Several Janus kinase inhibitors and various interferon formulations are now available for treatment of MF, with ruxolitinib notable for extending overall survival in addition to improving MF signs and symptoms.
Summary
The chronic nature of the disease can lead some patients to avoid immediate treatment in favor of a watch-and-wait approach. This review summarizes the patient management approach taken in my practice, providing guidance and a discussion of best practices with an emphasis on the importance and clinical benefits of active treatment in early MF. In particular, a case is made to consider treatment with ruxolitinib for patients with intermediate-1 risk disease and to minimize delay between diagnosis and treatment initiation for patients with intermediate or high-risk disease.
... Cytopenias, in particular anemia and thrombocytopenia, are the most frequent adverse events (AEs) with ruxolitinib in patients with MF (Table 1) [2,3]. This outcome is unsurprising based on inhibition of JAK2, which regulates thrombopoietin and erythropoietin signaling [10,11]. In the pivotal phase 3 COMFORT-I study (ClinicalTrials.gov ...
Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, anemia, extramedullary hematopoiesis, and splenomegaly. Patients with MF are at risk for reduced survival versus the general population and often experience burdensome signs and symptoms that reduce quality of life. The oral Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib was initially approved by the US Food and Drug Administration in 2011 for the treatment of patients with intermediate or high-risk MF, including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF, based on efficacy and safety findings from the randomized, controlled, phase 3 COMFORT trials. Over a decade later, ruxolitinib continues to be the standard of care in higher-risk MF, and dose optimization and management remain crucial for safely maximizing clinical benefits of ruxolitinib. This review summarizes the safety profile of ruxolitinib in patients with MF in the COMFORT trials leading up to approval and in the subsequent JUMP, ROBUST, EXPAND, and REALISE trials; in pooled analyses; and in postmarketing analyses in the 10 years following approval. There is a focus on the occurrence of common hematologic and nonhematologic adverse events, with guidance provided on the management of patients with anemia or thrombocytopenia, including dosing strategies based on findings from the REALISE and EXPAND trials. Finally, to ensure a greater understanding of the safety profile of ruxolitinib, practical considerations are discussed.
... 34 Furthermore, cytopenias are a key reason why many patients with MF cannot continue to receive effective doses of ruxolitinib. 13,35 A randomized safety study (ORAL Surveillance) has also shown a signal for MACE and malignancies with the JAK inhibitor tofacitinib, which is used in the treatment of rheumatoid arthritis. 36 Notably, the 3 pooled phase 3 studies of momelotinib in the present analysis represent a much smaller patient sample than that in the ORAL Surveillance study of tofacitinib; however, a review of the safety data suggests that momelotinib does not increase the risk of MACE or malignancies. ...
Momelotinib is the first inhibitor of Janus kinase 1 (JAK1) and JAK2 shown to also inhibit activin A receptor type 1 (ACVR1), a key regulator of iron homeostasis, and has demonstrated improvements in splenomegaly, constitutional symptoms, and anemia in myelofibrosis. This long-term analysis pooled data from 3 randomized phase 3 studies of momelotinib (MOMENTUM, SIMPLIFY-1, SIMPLIFY-2), representing myelofibrosis disease from early (JAK inhibitor-naive) to late (JAK inhibitor-experienced) stages. Patients in the control arms (danazol in MOMENTUM; ruxolitinib in SIMPLIFY-1; best available therapy in SIMPLIFY-2) could cross over to receive momelotinib at the end of the 24-week randomized period, and all patients could continue momelotinib treatment after the completion of these studies via an extended access protocol. Across these studies, 725 patients with myelofibrosis received momelotinib; 12% remained on therapy for ≥5 years, with a median treatment exposure of 11.3 months (range, 0.1-90.4 months). The most common nonhematologic treatment-emergent adverse event (AE) occurring in ≥20% of patients was diarrhea (any grade, 27%; grade ≥3, 3%). Any-grade thrombocytopenia, anemia, and neutropenia occurred in 25%, 23%, and 7% of patients, respectively. The most common reason for momelotinib discontinuation was thrombocytopenia (4% rate of discontinuation). Incidence of AEs of clinical importance (eg, infections, malignant transformation, peripheral neuropathy, hemorrhage) did not increase over time. This analysis of one of the largest randomized trial databases for a JAK inhibitor to date in myelofibrosis demonstrated a consistent safety profile of momelotinib without long-term or cumulative toxicity.
... However, certain clinical situations may support initiation of ruxolitinib at a lower dose (5 mg twice daily) with subsequent dose modifications based on CBC, which must be performed before initiating ruxolitinib and monitored every 2 to 4 weeks until the dose is stabilized, and then as clinically indicated. 182,184 Dose modifications based on insufficient response includes increasing the dose as tolerated, at 4-week intervals, in 5 mg twice daily increments to a maximum of 10 mg twice daily (if platelet count ,100 3 10 9 /L) and 25 mg twice daily (if platelet count $100 3 10 9 /L). 185 See "Special Considerations for the Use of JAK Inhibitors: Ruxolitinib" (MPN-G 2 of 7, available at NCCN.org) for dose modifications for the management of hematologic toxicities. ...
The classic Philadelphia chromosome–negative myeloproliferative neoplasms (MPN) consist of myelofibrosis, polycythemia vera, and essential thrombocythemia and are a heterogeneous group of clonal blood disorders characterized by an overproduction of blood cells. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the goal of providing recommendations for the management of MPN in adults. The Guidelines include recommendations for the diagnostic workup, risk stratification, treatment, and supportive care strategies for the management of myelofibrosis, polycythemia vera, and essential thrombocythemia. Assessment of symptoms at baseline and monitoring of symptom status during the course of treatment is recommended for all patients. This article focuses on the recommendations as outlined in the NCCN Guidelines for the diagnosis of MPN and the risk stratification, management, and supportive care relevant to MF.
... 89% of patients discontinue ruxolitinib within 3 years, with common reasons for discontinuation being adverse events, disease progression and death [12,[16][17][18]. Management of ruxolitinib-related adverse events (e.g., cytopenias) may require close monitoring and subsequent ruxolitinib dose adjustment while not compromising treatment efficacy [19]. Until the recent approval of fedratinib, dose modification and ruxolitinib rechallenge were potential approaches to managing MF in patients whose disease progressed while on ruxolitinib treatment [20]. ...
... These data suggest that extended treatment with ruxolitinib may be possible with different dosing regimens. However, differential dosing with ruxolitinib remains controversial; while some evidence suggests that individualized dosing strategies can help manage adverse effects while maintaining efficacy, the effects of ruxolitinib have been clearly documented to be dose dependent [19,24,25]. Ruxolitinib doses are most commonly adjusted to manage cytopenias but are often increased stepwise following symptom management [19]. ...
... However, differential dosing with ruxolitinib remains controversial; while some evidence suggests that individualized dosing strategies can help manage adverse effects while maintaining efficacy, the effects of ruxolitinib have been clearly documented to be dose dependent [19,24,25]. Ruxolitinib doses are most commonly adjusted to manage cytopenias but are often increased stepwise following symptom management [19]. The JUMP trial, which analyzed the response to ruxolitinib, found that spleen response is dose dependent, but symptom improvements may not be [26]. ...
Aim: To assess real-world ruxolitinib treatment patterns and outcomes in patients diagnosed with primary or secondary myelofibrosis. Materials & methods: Patient medical records were reviewed in six countries. Results: Eligible patients (n = 469) had a mean age of 63.5 years, and most were male (66.5%) with primary myelofibrosis (78.5%). Median duration of ruxolitinib treatment was 13.1 months; 40% of patients initiated treatment at the recommended dose. The Kaplan–Meier estimate of median survival from ruxolitinib initiation was 44.4 months (95% CI, 38.8–50.2 months). Approximately one quarter (23%) of patients continued ruxolitinib after progression. Conclusion: These results suggest an unmet need for more effective treatments for patients with myelofibrosis who failed ruxolitinib.
... In clinical studies, approximately 80% of ruxolitinib-treated patients reported thrombocytopenia [35]. Decreases in platelet levels are expected in the first 4-12 weeks of treatment, but levels remain stable afterwards [22,46]. An analysis on 2233 patients (138 patients with platelet levels <100 × 10 9 /L) from the JUMP study showed that grade 3-4 thrombocytopenia led to treatment discontinuation in only 3.4% of cases (10.1% of patients with low platelet levels) [21]. ...
Objectives
Myelofibrosis is a rare bone marrow disorder associated with a high symptom burden, poor prognosis, and shortened survival. While allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for myelofibrosis, the only approved and reimbursed pharmacotherapy for non-HSCT candidates in Belgium is ruxolitinib.
Methods
These updated recommendations are based on a consensus reached during two meetings and provide guidance for ruxolitinib administration in myelofibrosis patients considering the particularities of Belgian reimbursement criteria.
Results and Discussion
In Belgium, ruxolitinib is indicated and reimbursed for transplant-ineligible myelofibrosis patients from intermediate-2- and high-risk groups and from the intermediate-1-risk group with splenomegaly. Our recommendation is to also make ruxolitinib available in the pre-transplant setting for myelofibrosis patients with splenomegaly or heavy symptom burden. Before ruxolitinib initiation, complete blood cell counts are recommended, and the decision on the optimal dosage should be based on platelet count and clinical parameters. In anemic patients, we recommend starting doses of ruxolitinib of 10 mg twice daily for 12 weeks and we propose the use of erythropoiesis-stimulating agents in patients with endogenous erythropoietin levels ≤500 mU/mL. Increased vigilance for opportunistic infections and second primary malignancies is needed in ruxolitinib-treated myelofibrosis patients. Ruxolitinib treatment should be continued as long as there is clinical benefit (reduced splenomegaly or symptoms), and we recommend progressive dose tapering when stopping ruxolitinib.
Conclusion
Based on new data and clinical experience, the panel of experts discussed ruxolitinib treatment in Belgian myelofibrosis patients with a focus on dose optimization/monitoring, adverse events, and interruption/rechallenge management.
... However, genetic polymorphisms or drugdrug interactions may affect the therapeutic efficacy and tolerability of type I JAK inhibitors, including RUX. Therefore, studies on the development of rapid and reliable methods for the determination of RUX concentration in biological fluids have gained importance [10,11]. ...
A novel methodology has been applied to generate a porous molecularly imprinted material for highly selective and sensitive recognition of Janus kinase inhibitor ruxolitinib (RUX). The porous material-based nucleobase-derivative functional monomer was developed by a photopolymerization method. The thymine methacrylate (ThyM) as a functional monomer was synthesized and copolymerized with 2-hydroxyethyl methacrylate (HEMA) in the presence of ethylene glycol dimethacrylate (EGDMA) onto the glassy carbon electrode [glassy carbon electrode/molecularly imprinted [email protected](2-hydroxyethyl methacrylate-co-thymine methacrylate), (GCE/[email protected])] for the first time. The presence of ThyM results in the functional groups in imprinting binding sites, while the presence of poly(vinyl alcohol) (PVA) allows to generate porous materials for sensitive sensing. The characterization of GCE/[email protected] was investigated by Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), and impedance spectroscopy technique. Then, the porous MIP modified glassy carbon electrode was optimized with effecting parameters including removal agent, removal time, and incubation time to get a better response for RUX. Under well-controlled optimum conditions, the GCE/[email protected] linearly responded to the RUX concentration up to 0.01 pM at the limit of detection (LOD) of 0.00191 pM. The non-imprinted polymer (NIP) was also prepared to serve as a control in the same way but without the template. The proposed method improves the accessibility of binding sites by generating the porous material resulting in highly selective and sensitive recognition of drugs in the pharmaceutical dosage form and synthetic human serum samples.
... [6,7] Although the United States Food and Drug Administration (FDA) label for ruxolitinib extends to patients with platelet count 50 3 10 9 /L, doses recommended for thrombocytopenic patients are associated with fewer clinical responses. [8,9] Beyond pretreatment thrombocytopenia, ruxolitinib treatment often leads to a decrease in platelet count and dose modification is frequently required. [9] Thrombocytopenia of any grade was seen in 69.7 and 60.0% on the COMFORT-I and COMFORT-II studies, respectively, with grade 3 or worse thrombocytopenia seen in 12.9 and 8.0%, respectively. ...
Myelofibrosis (MF) is a myeloproliferative neoplasm hallmarked by uncontrolled blood counts, constitutional symptoms, extramedullary hematopoiesis, and an increased risk of developing acute myeloid leukemia. Janus kinase (JAK) inhibitors are the most common treatment for MF due to their ability to reduce spleen size and improve disease-related symptoms; however, JAK inhibitors are not suitable for every patient and their impact on MF is limited in several respects. Novel JAK inhibitors and JAK inhibitor combinations are emerging that aim to enhance the treatment landscape, providing deeper responses to a broader population of patients with the continued hope of providing disease modification and improving long-term outcomes. In this review, we highlight several specific areas of unmet need within MF. Subsequently, we review agents that target those areas of unmet need, focusing specifically on the JAK inhibitors, momelotinib, pacritinib, itacitinib, and NS-018 as well as JAK inhibitor combination approaches using CPI-0610, navitoclax, parsaclisib, and luspatercept.
... Both anemia and platelet values improved in the next stages of the treatment. Several studies showed that anemia and thrombocytopenia may develop in the early stages of treatment, but this condition improves in the next weeks of the treatment continuation [19,23,24]. ...
... Effective management of fedratinib-related TEAEs can facilitate long-term therapy. Hematologic events are anticipated with JAK2 inhibitors due to their mechanism of action [90]. These events typically occur within the first 3-4 months of initiating fedratinib therapy and hematology counts tend to improve over time during treatment [34,35,55]. ...
Myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) is characterized by cytopenias, marrow fibrosis, constitutional symptoms, extramedullary hematopoiesis, splenomegaly, and shortened survival. Constitutive activation of the janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in MF leads to cell proliferation, inhibition of cell death, and clonal expansion of myeloproliferative malignant cells. Fedratinib is a selective oral JAK2 inhibitor recently approved in the United States for treatment of adult patients with intermediate-2 or high-risk MF. In mouse models of JAK2V617F-driven myeloproliferative disease, fedratinib blocked phosphorylation of STAT5, increased survival, and improved MF-associated disease features, including reduction of white blood cell counts, hematocrit, splenomegaly, and fibrosis. Fedratinib exerts off-target inhibitory activity against bromodomain-containing protein 4 (BRD4); combination JAK/STAT and BRD4 inhibition was shown to synergistically block NF-kB hyperactivation and inflammatory cytokine production, attenuating disease burden and reversing bone marrow fibrosis in animal models of MPNs. In patients, fedratinib is rapidly absorbed and dosed once daily (effective half-life 41 h). Fedratinib showed robust clinical activity in JAK-inhibitor-naïve patients and in patients with MF who were relapsed, refractory, or intolerant to prior ruxolitinib therapy. Fedratinib is effective regardless of JAK2 mutation status. Onset of spleen and symptom responses are typically seen within the first 1–2 months of treatment. The most common adverse events (AEs) with fedratinib are grades 1–2 gastrointestinal events, which are most frequent during early treatment and decrease over time. Treatment discontinuation due to hematologic AEs in clinical trials was uncommon (~3%). Suspected cases of Wernicke’s encephalopathy were reported during fedratinib trials in ~1% of patients; thiamine levels should be monitored before and during fedratinib treatment as medically indicated. Phase III trials are ongoing to assess fedratinib effects on long-term safety, efficacy, and overall survival. The recent approval of fedratinib provides a much-needed addition to the limited therapeutic options available for patients with MF.
