Clarifying the Use of Ruxolitinib in Patients With Myelofibrosis
In this article, we provide updated data on ruxolitinib therapy for patients with myelofibrosis and offer expert opinion on the appropriate use of this agent in the community practice.
Myelofibrosis (MF) is a hematopoietic stem cell malignancy classified as a myeloproliferative neoplasm (MPN). The clinical course of individuals with MF is heterogeneous and characterized by constitutional symptoms, bone marrow myeloproliferation and fibrosis, progressive cytopenias, and symptomatic splenomegaly. Historically, patients with this debilitating disease have had limited treatment options, and disease-modifying agents were not available. Hematopoietic stem cell transplantation is the only potentially curative therapy, but it is only an option for select patients. The discovery of an activating point mutation in the Janus kinase 2 gene (JAK2V617F) in a significant portion of patients with MPNs led to improved understanding of the pathobiology of these disorders and prompted rapid development of JAK inhibitors. Ruxolitinib (Jakafi) is the first-in-class and only JAK inhibitor currently approved by the US Food and Drug Administration (FDA) for the treatment of patients with MF; approval was based on the results of the COMFORT (COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment) I and II studies. While not a curative option, ruxolitinib offers great palliative potential and results in significant reduction in splenomegaly and improvement in constitutional symptoms in the majority of treated patients, thus improving their quality of life and performance status. Additionally, ruxolitinib is the only agent that has demonstrated a survival benefit in patients with MF. The optimal use of ruxolitinib for MF patients is challenging and complex. In this article, we provide updated data on ruxolitinib therapy for patients with MF and offer expert opinion on the appropriate use of this agent in the community practice.
Introduction
The myeloproliferative neoplasms (MPNs) are a heterogeneous group of chronic hematological malignancies that are generally divided into the Philadelphia chromosome–positive (Ph-positive) MPNs, which refers to chronic myelogenous leukemia (CML) and the Philadelphia chromosome–negative (Ph-negative) MPNs. The World Health Organization (WHO) classifies polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) as Ph-negative MPNs.[1] PV and ET are both capable of progressing to a fibrotic stage that clinically resembles PMF, and collectively these three disease entities are termed myelofibrosis (MF).
The clinical course of individuals with MF is characterized by constitutional symptoms (fevers, night sweats, and weight loss), bone marrow myeloproliferation and reticulin/collagen fibrosis, worsening cytopenias, thrombosis, and progressive symptomatic splenomegaly. Extramedullary hematopoiesis (EMH) is likely the result of abnormal trafficking of hematopoietic stem cells (HSC) from the bone marrow to organs such as the spleen, liver, and lung, causing organomegaly and sometimes organ dysfunction.[2,3] Common MF symptoms include bone pain, debilitating fatigue, pruritus, abdominal pain, and bowel disturbances. Dyspnea can be due to anemia, pulmonary emboli, congestive heart failure, and/or the development of pulmonary artery hypertension secondary to EMH. Splenomegaly can result in early satiety that further adds to weight loss, abdominal bloating, and severe left-upper-quadrant abdominal pain from splenic infarcts.
An increased rate of thrombotic complications is associated with MF and can occur in the venous or arterial circulation. Conversely, bleeding episodes can also complicate the clinical course of MF and can be attributed to either thrombocytopenia or qualitative platelet dysfunction. Many patients develop anemia during the course of their disease and require red blood cell transfusion support. Often patients who present the biggest therapeutic challenge are those who develop profound transfusion-dependent thrombocytopenia and who in some cases become refractory to platelet transfusions.
TABLE 1
Dynamic International Prognostic Scoring System
Thrombotic complications involving the venous and arterial vasculature; bone marrow failure leading to transfusion dependence, increased bleeding, and infection risk; and transformation to acute leukemia contribute to reduced survival in MF patients.[4] The clinical course of MF patients is variable, and risk stratification systems are used to estimate predicted survival in order to select the most appropriate treatment approach for a given patient. The International Prognostic Scoring System (IPSS) incorporates five prognostic clinical variables derived from multivariate analysis, assigning a point each for age > 65 years, leukocyte count > 25 × 109/L, hemoglobin level < 10 g/dL, peripheral blood blast percentage ≥ 1%, and the presence of constitutional symptoms (see Table 1).[4] Four risk groups can be defined-low-risk (0 points), intermediate-1 (1 point), intermediate-2 (2 points), and high-risk (≥ 3 points)-with independent median survivals of 135, 95, 48, and 27 months, respectively. The IPSS score is calculated at time of diagnosis, and the dynamic IPSS (DIPSS) and DIPSS-plus can be used to calculate an individual MF patient’s risk-group status at any point during his or her clinical course.[5,6] DIPSS-plus also incorporates thrombocytopenia, transfusion-dependent anemia, and cytogenetic abnormalities as adverse prognostic markers in addition to the risk factors used in the IPSS. Karyotypic abnormalities are present in approximately 30% to 50% of MF patients, and unfavorable chromosomal abnormalities (complex abnormalities or sole or dual abnormalities that include +8, −7/7q−, i7/7q−, i(17q), −5/5q, 12p−, inv(3), or 11q23 rearrangements) have been incorporated in the DIPSS-plus as negative prognostic indicators. Patients with MF have a median survival of approximately 5 to 6 years from time of diagnosis, but recently a large retrospective study of MF patients from Europe has indicated an improvement in relative survival that is most significant in women, younger patients, and low/intermediate-1–risk subgroups.[4,7]
Therapeutic approaches that address the myeloproliferation (leukocytosis, thrombocytosis) and organomegaly (splenomegaly and hepatomegaly) associated with MF include chemotherapeutic agents such as hydroxyurea, melphalan, busulfan, and cladribine.[8] Radiotherapy can be employed to address symptomatic splenomegaly refractory to medical management, or in cases of EMH affecting the lung or peritoneum, or impinging on nerves. Anemia is common in MF patients and can be multifactorial in origin (possible causes include iron deficiency, B12 deficiency, folate deficiency, ineffective erythropoiesis, splenic sequestration, and hemolysis) and leads to red blood cell transfusion–dependence in many patients. Multiple approaches to the anemia have been evaluated and include erythropoiesis-stimulating agents (ESAs); immunomodulatory agents such as thalidomide (Thalomid), lenalidomide (Revlimid), and pomalidomide (Pomalyst) alone or in combination with prednisone; danazol (Danocrine); and occasionally corticosteroids alone, which can be effective if the anemia is due to an autoimmune hemolytic process.
Stem cell transplantation (SCT) is the only therapeutic option that offers the potential for cure in patients with MF.[9] Although it is generally agreed that MF patients with intermediate-2/high-risk disease are appropriate for consideration of SCT, advanced patient age, significant comorbid conditions, and lack of optimal donor options exclude the majority of patients. SCT utilizing reduced-intensity conditioning (RIC) broadens the eligibility for this definitive approach to include MF patients who are less fit, who have more competing co-morbidities, and are older.[10] The use of alternative donor sources such as haploidentical and cord blood, the role of autologous SCT, and the benefit of preconditioning with a Janus kinase 2 (JAK2) inhibitor are approaches being evaluated in MF patients in a variety of clinical trials.[11,12]
FIGURE
Increased JAK/STAT Signaling in Myelofibrosis
Janus Kinase 2 and MF
The JAK2 tyrosine kinase is a member of a family of key intracellular signaling proteins associated with cytokine receptors such as erythropoietin (EPO), thrombopoietin (TPO), and granulocyte colony–stimulating factor (G-CSF).[13] Binding of the cytokine to the appropriate receptor results in phosphorylation and activation of the JAK kinase, as well as cytokine receptor phosphorylation, recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins, and the activation of multiple downstream signaling events (see Figure). Phosphorylation of STAT in turn leads to the transcription of genes related to survival and proliferation. In 2005, an activating point mutation in the JAK2 gene was identified by four independent groups, providing the first association between a genetic event and Ph-negative MPN pathogenesis.[14-17] A G-to-T point mutation in exon 14 of JAK2, located on chromosome 9p24, is the most commonly observed mutation in Ph-negative MPNs. Expression of JAK2V617F confers cytokine hypersensitivity and cytokine-independent growth of hematopoietic cells. Approximately 50% of MF patients have this mutation. Additionally, mutations of the thrombopoietin receptor (MPL515L/K) have been identified in approximately 3% to 5% of MF patients and represent an upstream event that also leads to constitutive JAK-STAT pathway activation.[18]
It is now recognized that JAK2V617F is not a disease-initiating genetic event, nor is there clear prognostic significance for this mutation in patients with MF.[19] Although JAK2V617F appears to be associated with a higher hemoglobin level and less need for transfusion in MF patients as well as with older age, thrombocytosis, leukocytosis, and splenomegaly, it has not been reported to uniformly influence risk of thrombosis, leukemic transformation, or survival.[20-23] However, low JAK2V617F allele burden may predict for shorter overall and leukemia-free survival compared with patients who have a high burden or JAK2 wild-type.[24]
In recent years a number of mutated genes have been identified in patients with MF and include TET2, ASXL1, IDH1, IDH2, EZH2, LNK, and CBL.[25] Mutations in these genes can co-exist, are found in low frequency, and affect various aspects of hematopoietic cell function and survival. A complex interaction of acquired genetic and epigenetic lesions likely contributes to the molecular pathogenesis, clinical phenotype, and events leading to leukemic transformation.[26] Ongoing laboratory efforts are focused on elucidating the inciting molecular events at the level of the MF hematopoietic stem cell, and ultimately on the identification of therapeutic targets.
There are currently over a dozen oral JAK inhibitors in clinical development for the treatment of MPN.[27-29] These agents differ primarily in their selectivity for JAK2 inhibition and have all been shown to reduce splenomegaly and improve symptoms to varying degrees. Whether significant reduction in JAK2 allele burden, improvement in cytopenias, and restoration of normal polyclonal hematopoiesis are achieved with these agents has not yet been fully documented. Ultimately, whether one agent is superior to the rest is currently unknown and will require a rigorous evaluation in controlled prospective studies.
Other therapies being evaluated for the treatment of MF include interferon-alpha (IFN-α), histone deacetylase inhibitors (HDACi), heat shock protein 90 (HSP90) inhibitors, monoclonal antibodies to transforming growth factor beta (TGF-beta) and lysyl oxidase–like 2 (LOXL2), inhibitors of mammalian target of rapamycin (mTOR), and small molecule inhibitors of the Hedgehog pathway.[30,31] Given the apparently complex pathobiological underpinnings of MF, combinations of agents targeting multiple dysregulated pathways and epigenetic alterations are being evaluated in clinical trials.[32]
Ruxolitinib
In November 2011, ruxolitinib (Jakafi) was approved by the US Food and Drug Administration (FDA) for the treatment of intermediate- and high-risk MF patients, based on the results of two pivotal phase III trials. Ruxolitinib is the only FDA-approved drug for the treatment of this hematopoietic stem cell malignancy, and it has dramatically changed the treatment landscape.[33] As an oral agent that can be prescribed in the community, ruxolitinib offers many patients who did not have access to clinical trials at tertiary care centers an effective treatment option that addresses splenomegaly and other disease-related symptoms.
Dysregulated JAK-STAT activity is present in MF patients, regardless of JAK2 mutational status.[34] Consequently, JAK1 and JAK2 have become the focus of study for pharmacologic intervention in MF. Ruxolitinib is a first-in-class oral small-molecule inhibitor of JAK1/JAK2. Pharmacodynamic assessments performed during preclinical and phase I studies have demonstrated the molecular-biological effect of JAK 1/2 inhibition as manifested by down-regulation of phosphorylated STAT-3 and pro-inflammatory cytokines from patient blood samples after administration of the drug.[34,35] It is believed that reduction in circulating inflammatory cytokines with ruxolitinib therapy is a consequence of JAK1 signaling inhibition and correlates with improvement in constitutional and MF-related symptoms.
The dose-escalation phase I/II study of ruxolitinib in JAK2V617F-positive and JAK2V617F-negative MF patients established 25 mg twice-daily or 100 mg once-daily as the maximum tolerated dose, based on the dose-limiting toxicity of reversible thrombocytopenia.[35] Ruxolitinib at a dose of 15 mg twice-daily was associated with sustained reductions of splenomegaly and constitutional symptoms, with an associated improvement in exercise tolerance, performance status, and meaningful weight gain in MF patients, irrespective of JAK2 mutational status. Approximately half of treated patients achieved a 50% reduction in splenomegaly for ≥ 12 months, and tumor lysis syndrome was rarely seen. Marked suppression of the heightened expression of pro-inflammatory cytokines (interleukin [IL]-6, IL-1ra, macrophage inflammatory protein [MIP]-1β, tumor necrosis factor [TNF]α, and C-reactive protein [CRP]) was seen with ruxolitinib treatment and correlated with improvement in night sweats, fevers, fatigue, weight loss, and pruritus. After 12 cycles of ruxolitinib therapy, a mean maximal suppression of JAK2V617F allele burden of 13% was observed.
Five of the 47 MF patients (11%) treated at Mayo Clinic Rochester experienced a withdrawal syndrome after rapid discontinuation of ruxolitinib.[36] In some cases this was reportedly associated with hemodynamic compromise and a septic-like state.
COMFORT-I and COMFORT-II Trials
COMFORT-I was a pharmaceutical company (Incyte, Wilmington, Delaware)-sponsored, randomized (1:1), double-blind, placebo-controlled phase III study of ruxolitinib in 309 intermediate-2 or high-risk MF patients with palpable splenomegaly at least 5 cm below the costal margin and a baseline platelet count of ≥ 100 × 109/L.[37] Based on the patients’ platelet count at study entry, ruxolitinib was dosed at either 15 mg or 20 mg twice-daily for platelet counts < 200 × 109/L and > 200 × 109/L, respectively. Of note, patients were not allowed to receive concomitant hydroxyurea or radiation. The primary endpoint was the proportion of treated patients achieving a reduction in spleen volume of at least 35% by MRI. Duration of spleen reduction and improvement in disease-related symptoms according to the Myelofibrosis Symptom Assessment Form (MFSAF) were key secondary endpoints.[38]
As predicted with this class of medications, hematologic toxicity was frequent. Grade 3/4 anemia, thrombocytopenia, and neutropenia were observed in 45% vs 19.2%, 12.9% vs 1.3%, and 7.1% vs 2% of patients in the ruxolitinib vs placebo arms, respectively. The most common nonhematologic adverse events seen in the ruxolitinib-treated group were headache, dizziness, and easy bruisability independent of platelet count, all of which were low grade and did not lead to study drug discontinuation.
At 24 weeks, nearly 42% of patients treated with ruxolitinib experienced a ≥ 35% reduction in spleen volume, compared with 0.7% of patients who received placebo, and nearly 46% of the ruxolitinib-treated patients experienced a ≥ 50% improvement in constitutional symptoms, as compared with 5.3% in the placebo group. Patients with wild-type JAK2 and JAK2V617F-positive disease experienced similar response rates.
The responses described above were durable at a median follow-up of 102 weeks, with continuing symptom improvement and spleen volume reduction.[39] By week 36, the proportion of ruxolitinib-treated patients receiving transfusions decreased to that which was observed in the placebo arm. A continued overall survival benefit in favor of ruxolitinib treatment (hazard ratio [HR] = 0.58; 95% confidence interval [CI], 0.36–0.95; P = .028) remained constant across all MF subgroups analyzed.
COMFORT-II was a randomized (2:1), pharmaceutical company–sponsored (by Incyte), open-label, phase III clinical trial that was conducted in nine European countries. It compared ruxolitinib with best available therapy (BAT)[40] in 219 intermediate- and high-risk MF patients with a median age of 66 years. BAT, determined by the treating physician, included hydroxyurea (46.6%), corticosteroids (16.4%), and supportive therapy (32.9%).
The primary endpoint again was reduction of ≥ 35% of spleen volume, as assessed by MRI or CT imaging at 48 weeks. This primary endpoint was achieved in 28.5% of patients treated with ruxolitinib and in 0% of patients in the BAT arm (P < .0001). The secondary endpoint of spleen reduction at 24 weeks was achieved in 31.9% and 0% of patients in the ruxolitinib and BAT arms, respectively. A beneficial effect on other secondary endpoints with ruxolitinib treatment was observed, including an improvement in quality of life measures and a reduction in MF symptom burden.
As was seen in COMFORT-I, hematologic toxicity of all grades was frequent with ruxolitinib (44.5% thrombocytopenia and 40.4% anemia). Grade 3/4 thrombocytopenia and anemia were seen in 7.5% vs 4.1% and in 11% vs 4.1% of the ruxolitinib vs BAT arms, respectively. The most frequent nonhematologic adverse event was diarrhea (all grades), which was seen in 23% of ruxolitinib-treated patients; grade 3/4 diarrhea was observed in only 1% of patients who received ruxolitinib.
Initially, a statistically significant difference between the two treatment arms in terms of progression-free survival, leukemia-free survival, and overall survival was not observed, presumably due to inadequate follow-up of patients in whom the drug was discontinued, cross-over from BAT, and the low frequency of observed events at the time of analysis. However, in an updated and unplanned analysis after a median follow-up of 112 weeks of ruxolitinib therapy, a statistically significant advantage in overall survival was detected in MF patients in the ruxolitinib arm compared with the BAT arm (HR = 0.52; 95% CI, 0.27–1.00).[41] It is important to note that this analysis was done with an intention-to-treat principle, and even patients randomly assigned to BAT who ultimately crossed over to ruxolitinib were still evaluated.
In both trials, ruxolitinib therapy was uniformly ineffective at reversing bone marrow histopathological abnormalities, at eliminating cytogenetic abnormalities, and at significantly reducing the JAK2V617F allele burden to the degree that is achieved with tyrosine kinase inhibitor therapy in CML patients. However, recent reports of long-term follow-up of COMFORT-II patients demonstrate that patients who received ruxolitinib had larger reductions in JAK2V617F allele burden compared with those who received BAT.[42] Moreover, in the ruxolitinib arm, significantly more patients with > 20% decrease in allele burden achieved a 35% reduction in spleen volume compared with patients with < 10% decrease in allele burden, at both week 48 (79% vs 30%) and week 72 (69% vs 31%). The significance of such modest reductions in JAK2V617F allele burdens on disease progression is yet to be determined.
It cannot be overemphasized that both the COMFORT-I and COMFORT-II studies included only a subset of patients with MF who had baseline platelet counts of 100 × 109/L or higher. These inclusion criteria prevented a significant proportion of MF patients with thrombocytopenia from entering this trial and remains a point of difficulty for practitioners who are treating such patients. Ongoing trials have been designed to assess the effectiveness and safety of ruxolitinib in patients with platelet counts between 50 and 100 × 109/L.[43,44] In these trials, dosing of ruxolitinib is initiated at 5 mg twice daily and then escalated by a total of 5 mg daily every 4 weeks to a maximum of 10 mg twice daily in patients with adequate platelet counts. Preliminary findings suggest that this dosing strategy is effective in reducing spleen volume and improving symptoms to a degree that is comparable to what was reported in the COMFORT trials. None of the patients at this time have had to withdraw from the study because of progressive thrombocytopenia or bleeding events. Since these data are preliminary, the extension of ruxolitinib therapy to MF patients with low platelet counts should be considered experimental and pursued in the context of a clinical trial.
Expert Opinion: Our Recommendations for Practice
Patients with PMF and PV/ET-related MF, regardless of their JAK2 mutational status, should be considered for treatment with ruxolitinib to address symptomatic splenomegaly and/or MF-related symptoms, including intractable pruritus. The phase I/II study and COMFORT studies excluded patients with a baseline platelet count of < 100 × 109/L, established a very clear toxicity profile, and identified thrombocytopenia as a dose-limiting toxicity. However, the preliminary results from the ongoing low-platelet study have shown that patients can be treated safely, with lower daily doses of ruxolitinib, at platelet counts as low as 50 × 109/L and can still achieve and maintain responses in spleen reduction and symptom improvement.
Based on the available data, we would not recommend treating MF patients in the community with baseline platelet counts below 50 × 109/L. For patients with thrombocytopenia but platelet count above 50 × 109/L, we would favor starting patients at low doses of ruxolitinib (5 mg twice daily) and titrating upwards on a monthly basis to achieve maximal spleen reduction and symptom response without bringing the platelet count below 35 × 109/L. One must also be wary of incurring treatment-emergent anemia; this can be particularly troubling to patients who were previously transfusion-independent. Unlike disease-related anemia, there is no indication that therapy-induced anemia is a negative prognostic indicator, and subgroup analysis from the COMFORT studies demonstrated that the frequency of spleen and symptom responses was similar in patients who developed anemia compared with those who did not. However, the goals of treatment should be discussed with the patient prior to initiating therapy, and expectations of response and possible toxicities should be made clear. For some MF patients, the possibility of developing worsening anemia even in the face of improvement in symptoms can cause anxiety, and the requirement for transfusional support can negate the benefit for certain patients.
TABLE 2
Suggested Ruxolitinib (Jakafi) Dosing Nomogram for Starting Dose and Dose Modifications
Thrombocytopenia can limit the treatment of patients with ruxolitinib, and this is the most common toxicity we observe in our patients. We would recommend following blood counts weekly for the first month for MF patients with platelet counts less than 100 × 109/L and biweekly for those above 100 × 109/L. Careful monitoring of the platelet count can ensure patient safety and allow for appropriate dose reductions to avoid abrupt cessation of therapy. Table 2 provides a dosing strategy based on starting platelet counts and dosing modifications based on current platelet counts and dose of ruxolitinib.
Because of concern for the development of a rebound of symptoms and splenomegaly that had been successfully treated with ruxolitinib, one should not abruptly stop therapy with the drug. Although this scenario was rarely observed in patients who discontinued therapy in the COMFORT studies, and symptoms were reported to gradually return to their baseline within 7 to 10 days of stopping ruxolitinib, a single institution has reported a cytokine storm effect and even cases of hemodynamic instability with abrupt drug cessation. On occasion, we have also seen MF patients develop rapid return of symptoms, leukocytosis, splenomegaly, and even pulmonary insufficiency after abrupt discontinuation of ruxolitinib. Therefore, we would recommend tapering the dose of ruxolitinib when possible and use of a short course of prednisone starting at 20 mg daily, with tapering of the dose over a week to blunt the effects of returning symptoms and possible consequences of a cytokine storm. This may be especially important for patients with hyperproliferative disease and high leukocyte counts.
Although the COMFORT studies only included intermediate-2 and high-risk MF patients, the approval for commercial use of ruxolitinib also includes intermediate-1 patients, as they can also have constitutional symptoms and splenomegaly that warrant therapy.
Considerations when making ruxolitinib dosing determinations also include renal and hepatic impairment, as well as the use of concomitant CYP3A4 inhibitors. Metabolism and excretion of ruxolitinib are mainly via the kidney, with 74% of drug excreted in urine and 22% excreted in feces.[45] For patients who have moderate or severe renal impairment, dose reduction is recommended based on the platelet count, as described in the package insert.
It is not recommended to follow the JAK2V617F allele burden in MF patients treated with ruxolitinib, since dramatic changes in this molecular marker are not anticipated. Unless there is a clinical indication of progressive disease while on ruxolitinib, such as an expanding spleen, worsening symptoms, or rising peripheral blood blast count, there is no indication to perform serial bone marrow biopsies to assess response. Although the primary endpoint in the COMFORT studies was reduction in spleen volume as measured by MRI, MRI monitoring is not necessary in clinical practice. A 35% reduction in spleen volume has been shown to correlate with a 50% reduction in palpable splenomegaly, and in clinical practice simply assessing response by physical examination is sufficient and far more economical.
It is important to consider that many MF patients are not fully aware of all the symptoms or the degree of symptoms they may experience that are attributable to MF. For example, it is not uncommon to find that patients treated with ruxolitinib find improvement in energy level and fatigue even if those were not their presenting complaints. They grew so accustomed to the reduced energy level that only after improvement with ruxolitinib treatment do they become aware of their new baseline.
Patients with peripheral or bone marrow blasts of > 20% (termed MPN-blast phase [MPN-BP]) have an acute form of leukemia with a dismal prognosis and a median survival of approximately 3 to 5 months.[46,47] These patients should be considered for experimental therapy, since conventional induction chemotherapy for acute myeloid leukemia has not been shown to be effective. Although treatment with higher doses of ruxolitinib in patients with an MPN-BP was reported to lead to a modest response rate in a phase II study from MD Anderson Cancer Center, treatment of such patients in the community with ruxolitinib is not recommended.[48] Our group has had the most success in treating MPN-BP patients with hypomethylating agents such as decitabine.[49] This and other novel approaches need to be evaluated in prospective clinical trials. As with other hematologic malignancies, combination treatments targeting different disease pathways are likely to have an even more significant impact on altering the natural history of MF. With this in mind, the Myeloproliferative Disorders Research Consortium (MPD-RC) will be opening a trial of combination ruxolitinib and decitabine in patients with MPN-BP in the near future. Because SCT remains the only curative option for patients with MPN-BP, this combination regimen may be most useful as a potential bridge to SCT-eligible patients.
The use of ruxolitinib in combination with other MF-directed therapies remains investigational and should not be tested outside of a clinical trial in an individual patient. We urge physicians to refer MF patients being treated with ruxolitinib who have either loss of previous spleen/symptom response, worsening anemia beyond 3 months of therapy, increasing peripheral blood blast count, or nonresponse after a minimum of 3 months of therapy to an institution with a dedicated MPN program for further evaluation and consideration for experimental therapy.
Since ruxolitinib has largely palliative effects and is not a curative approach, it is important to emphasize that younger patients who have advanced forms of the disease and have an acceptable donor option should proceed with allogeneic SCT. SCT should still be considered the primary therapy even though ruxolitinib results in symptomatic improvement. The role of ruxolitinib prior to SCT is the focus of an ongoing MPD-RC clinical trial in patients with MF. The primary objective of this trial is to determine transplant outcome success at day 100, as well as the effect of pretreatment with ruxolitinib on time to engraftment, incidence and severity of acute and chronic graft-versus-host disease, and infectious complications.
Important questions still remain concerning ruxolitinib therapy for MF. Is there a role for the use of ruxolitinib earlier in the clinical course before patients have developed splenomegaly or symptoms? Will treatment with ruxolitinib in patients with less advanced MF offer an increased survival advantage? Will the use of ruxolitinib in combination with established MF therapies, such as erythropoietin, danazol, or IMiDs (small-molecule immunomodulatory drugs that are structural and functional analogues of thalidomide) directed towards achieving improvement in disease-related anemia be safe, tolerable, and effective? We do not yet know if all JAK inhibitors are created equal and await the results of multiple ongoing phase II and III trials of these other therapeutic agents. There are claims that some of these other JAK inhibitors still in development may be less myelosuppressive and more selective for JAK2V617F, and may result in improvement of cytopenias. Whether the efficacy of these agents is comparable or superior to ruxolitinib will likely be the subject of numerous future reports that should be closely monitored. At this time, very few patients have been treated with ruxolitinib for more than 5 years, and the long-term durability of the achieved responses remains unknown. Another theoretical concern is whether long-term therapy with ruxolitinib may eventually allow for escape of a subclone that has the potential for leukemic transformation. All of these questions remain unanswered but are the focus of ongoing investigations.
Financial Disclosure:Dr. Mascarenhas serves on the advisory board of, and is a consultant for, Incyte. The remaining authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
References:
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