Overcoming treatment challenges in myelofibrosis and polycythemia vera: the role of ruxolitinib

MF is a chronic disease marked by progressive bone marrow fibrosis, ineffective erythropoiesis, excess production of dysplastic megakaryocytes, extramedullary hematopoiesis, systemic inflammation with excess circulating levels of proinflammatory cytokines, cachexia, and shortened survival [16, 25‐27]. The development and progression of fibrosis in the marrow is likely a reaction by stromal cells to the malignant hematopoietic stem cell clones and eventually leads to cytopenias (ineffective hematopoiesis) and/or to extramedullary hematopoiesis as compensation for the diminished capacity of the bone marrow [28, 29]. The main clinical manifestations of MF include splenomegaly and a variety of troublesome symptoms (Fig. 2) [25, 26, 30, 31], which are a major source of morbidity and poor quality of life (QoL) [32‐35]. Common symptoms include abdominal discomfort, early satiety, itching, bone pain, muscle pain, fatigue, dyspnea, and insomnia [31, 35]. Many patients also experience anemia, which may necessitate red blood cell transfusions [25, 32‐34], and hepatomegaly is common among patients who underwent palliative splenectomy [36‐38]. Patients with MF have an increased risk of developing secondary acute myeloid leukemia [39]. Leukemic transformation is thought to result from the accumulation of deleterious genetic events in addition to the mutations affecting JAK–STAT signaling, but the precise contribution of individually acquired mutations to the process of transformation is not well understood [40].

Among patients with MPNs, those with PMF have the worst prognosis, with a median life expectancy of 6 years at the time of diagnosis [14]. Patients with MF may die from a variety of complications related to disease progression [32, 41]. Risk factors for shortened survival that have been validated in various prognostic models include age >65 years, constitutional symptoms (fever, night sweats, weight loss), hemoglobin <10 g/dL, leukocytes >25 × 10⁹/L, circulating blasts ≥1 % [32, 34], unfavorable karyotype, platelets <100 × 10⁹/L, and the need for red blood cell transfusions [33]. Median survival varies from approximately 11 years for those with low-risk disease to 2 years for those with high-risk disease [32]. Additional variables that have demonstrated prognostic value outside of these models include mutations associated with worse (ASXL1) or better (CALR) prognosis [15, 42, 43], the number of mutations present [43], and the levels of circulating cytokines [44]. Current prognostic models also do not consider the potential impact of splenomegaly, fibrosis grade, low cholesterol, or comorbidities on survival [45‐49].

Allogeneic hematopoietic stem cell transplantation is the only potentially curative option for MF and provides resolution of bone marrow fibrosis in the majority of successful transplants [26, 50, 51]. However, because of the high risks of treatment-related morbidity and mortality, allogeneic hematopoietic stem cell transplantation is generally limited to younger patients with a survival expectancy of <5 years, with consideration of the patient’s overall benefit-risk profile [26, 52]. Before the development of targeted inhibitors, conventional therapies addressing specific signs or symptoms of MF were used in a multimodal approach essentially intended to provide palliation. Treatment with immunomodulatory agents such as thalidomide, lenalidomide, or pomalidomide may benefit some patients with MF and anemia; however, recent studies suggest that these agents often have modest activity and/or provide limited long-term benefit with no or marginal effects on splenomegaly [53‐57]. Chemotherapies such as hydroxyurea, melphalan, busulfan, and cladribine have been used mainly for the treatment of symptomatic splenomegaly; however, their efficacy was also modest and their use was associated with an increased burden of adverse events [58]. Importantly, conventional therapies have not demonstrated alleviation of constitutional symptoms such as fatigue [35] and have not been shown to result in improved overall survival or disease modification.

For patients with symptomatic splenomegaly who are intolerant of or refractory to pharmacotherapy, splenic irradiation and splenectomy are alternative palliative treatment options. However, both options have significant limitations. Palliative cytoreductive radiotherapy to the spleen, liver, or other sites of extramedullary hematopoiesis often provides nondurable responses and may cause or exacerbate cytopenias [59]. Splenectomy is associated with increased risk of complications and poor postoperative prognosis [37, 60]. Therefore, splenectomy should be considered only for patients who have splenomegaly associated with portal hypertension, severe cytopenias, or other severe symptom, and who have no other treatment options.

Patients with intermediate-2 or high-risk MF, platelet counts ≥100 × 10⁹/L, and splenomegaly received ruxolitinib or placebo in a randomized double-blind study (COMFORT-I), or ruxolitinib or best available therapy (BAT, most commonly hydroxyurea, 47 % of patients) in a randomized open-label study (COMFORT-II) [21, 61]. Based on assessments by magnetic resonance imaging or computed tomography, the primary endpoint, a ≥35 % reduction in total spleen volume (from baseline to week 24 for COMFORT-I and week 48 for COMFORT-II), was achieved by 41.9 % of patients in the ruxolitinib group versus 0.7 % in the placebo group in COMFORT-I and in 28 % in the ruxolitinib group versus 0 % in the BAT group in COMFORT-II [21, 61]. Overall, 97 % of patients in both studies experienced some degree of reduction in spleen volume upon treatment with ruxolitinib [21, 61]. Long-term ruxolitinib therapy was associated with marked and durable reductions in splenomegaly. In COMFORT-I, the median reduction from baseline in spleen volume was 34.9 % at week 96 and 34.1 % at week 144 in patients randomized to ruxolitinib [41, 62]. Patients in COMFORT-II who achieved a ≥35 % reduction in spleen volume had a 50 % probability of maintaining this level of improvement at week 144 [63]. At the time of the 3-year analyses, 49.7 and 45 % of patients randomized to ruxolitinib in COMFORT-I and COMFORT-II, respectively, were still being treated [41, 62, 63].

An important secondary objective of the COMFORT trials was the assessment of changes in symptom burden, which is poorly addressed with traditional therapies. In COMFORT-I, 45.9 % of patients who received ruxolitinib versus 5.3 % of those who received placebo (P < 0.001) achieved a ≥50 % improvement in total symptom score at week 24, as assessed by the modified Myelofibrosis Symptom Assessment Form version 2 [21]. Marked improvements in role functioning and QoL per the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life questionnaire core model (QLQ-C30) were also noted in ruxolitinib-treated patients (Fig. 3) [21, 64]. Similarly, in COMFORT-II, patients treated with ruxolitinib experienced mean improvements in fatigue, pain, dyspnea, insomnia, and appetite loss at week 48 per their responses on the EORTC-QLQ-C30, whereas patients treated with BAT experienced mean worsening of those symptoms (Fig. 3) [61]. Some of the reduction in symptom burden may be due to a decrease in the proinflammatory state, because ruxolitinib has been shown to decrease cytokine levels in patients with MF, which coincided with improvement in symptoms and splenomegaly [16, 65, 66]. Ruxolitinib-mediated symptom improvement and QoL benefits were durable among patients remaining on therapy based on recent 2- and 3-year follow-up data from the COMFORT studies [41, 62, 63].

In both COMFORT studies, efficacy was not dependent on the presence of the JAK2V617F mutation [21, 61]. Moreover, the rapid reductions in splenomegaly and symptom burden seen with ruxolitinib were not reflected by corresponding changes in allele burden, which generally were modest at the time of the primary analyses of COMFORT-I and COMFORT-II [21, 61, 63]. The absence of JAK2V617F should not preclude treatment with ruxolitinib and change in JAK2V617F allele burden is not useful as an indicator or predictor of short-time treatment success or as a surrogate measure of spleen size or symptom burden reduction.

A hallmark of advanced MF is the preponderance of cachexia and systemic inflammation, manifested by unwanted weight loss, hypocholesterolemia, low-grade fever, fatigue, and other constitutional symptoms [31, 45, 67]. In addition, MF is characterized by increased plasma levels of proinflammatory cytokines such as IL-6, IL-8, TNF-α, and lipocalin-2 [16, 44, 68]. Some of these cytokines, such as lipocalin-2 and IL-8, have been implicated directly in MF pathogenesis. Increased IL-8 expression in megakaryocytes derived from malignant stem cells may contribute to excess fibroblast proliferation in the bone marrow [69], whereas lipocalin-2 may promote oxidative damage of normal but not malignant CD34+ cells as well as osteoclastogenesis and fibrosis [68]. IL-6 is recognized as a mediator of cancer-related cachexia [70] and thus may be a driver of cachexia in MF.

Results from clinical studies of ruxolitinib in MF demonstrated that ruxolitinib not only mitigated cachexia but also had a positive effect on various markers of inflammation. In the phase 1/2 study of ruxolitinib in MF, ruxolitinib promoted rapid reductions in plasma levels of a large number of inflammatory markers, including but not limited to IL-6, TNF-α, and C-reactive protein, an acute-phase marker of inflammation [16]. In COMFORT-I, ruxolitinib versus placebo was associated with significant improvements in weight (mean weight gain of 3.9 kg with ruxolitinib vs mean weight loss of 1.9 kg with placebo, P < 0.0001) and metabolic status (e.g., mean increase in total cholesterol of 26.4 % vs mean decrease in 3.3 %, P < 0.0001) at 24 weeks, and sustained improvement was observed with long-term therapy [71]. These metabolic improvements were accompanied by median reductions in plasma levels of close to 40 % for IL-6 and TNF-α and more than 70 % for C-reactive protein at week 24 [21]. In contrast, inflammation markers showed no (TNF-α) or marginal improvement (IL-6, C-reactive protein) with placebo. Furthermore, median plasma leptin levels increased approximately twofold with ruxolitinib and decreased slightly with placebo [21].

Results from animal models of MF suggest that increased production of proinflammatory cytokines originates not only from malignant cells but also from nonmalignant cells and is rapidly and potently inhibited by ruxolitinib [17]. Of note, deletion of STAT3 in mutant clones has been shown to be insufficient to suppress inflammatory signaling [17]. This finding supports the importance of inhibiting JAK–STAT signaling in nonmalignant cells to mitigate inflammation-related symptoms and would explain the effectiveness of ruxolitinib in providing rapid symptom mitigation without clinically significant reduction in mutant allele burden.

Overall, data from the COMFORT studies suggest that ruxolitinib was associated with improved overall survival compared with placebo or BAT in patients with MF [21, 41, 61, 72, 73]. Kaplan–Meier analyses of overall survival based on the intention-to-treat principle showed hazard ratios in favor of ruxolitinib versus placebo or BAT despite a potential bias in favor of the control arms caused by patient crossover to ruxolitinib [21, 61‐63, 74]. In COMFORT-II, the survival advantage observed was independent of the mutation profile, including prognostically detrimental mutations [75]. Furthermore, an ad hoc comparison of COMFORT-II data with those from a historical control group determined that patients with PMF receiving ruxolitinib had longer overall survival from the time of diagnosis than patients receiving conventional therapy [median survival 5 vs 3.5 years; hazard ratio (95 % CI) 0.61 (0.41–0.91), P = 0.0148], suggesting that ruxolitinib may modify the natural history of PMF [76]. This hypothesis is supported by long-term follow-up data from the phase II and III trials of ruxolitinib in MF showing treatment-associated changes in bone marrow fibrosis and/or allele burden. Comparative analyses of bone marrow biopsies from patients enrolled in the ruxolitinib phase II study and a matched cohort treated with BAT showed that the proportions of patients who had improved or stabilized bone marrow fibrosis after 1–5 years of treatment was greater with ruxolitinib than BAT [77]. Conversely, the odds of worsening fibrosis were lower with ruxolitinib versus BAT [odds ratio at 5 years (95 % CI) 0.07 (0.01–0.34)] [77]. A recent post hoc analysis from the COMFORT-I study further showed that long-term therapy with ruxolitinib resulted in partial or complete molecular remission of JAK2V617F allele burden in 20 and six patients, respectively [78]. Of note, complete resolution of bone marrow fibrosis documented in two case reports of patients with post-PV MF appeared to be accompanied by complete molecular remission [79, 80]. Together, these findings suggest that long-term therapy can result in profound disease modification, including sustained remission of bone marrow fibrosis and malignant clonal burden. Nevertheless, the general prolongation of survival observed with ruxolitinib versus placebo or BAT in the COMFORT trials may be the result of overall improvement in patients’ health status, including the reduction of cachexia (unwanted weight loss) and other constitutional symptoms, which are known prognostic factors in MF [32].

The most common nonhematologic adverse reactions occurring in a greater proportion of patients receiving ruxolitinib versus placebo were ecchymosis, dizziness, and headache (mostly grade 1 or 2), whereas abdominal pain and fatigue, which are typical disease-related symptoms, occurred less frequently in the ruxolitinib arm versus the placebo arm (Table 1) [21]. In COMFORT-II, the most common nonhematologic adverse events occurring in more patients treated with ruxolitinib versus BAT were diarrhea (23 vs 12 %) and asthenia (18 vs 10 %); most nonhematologic adverse events were grade 1 or 2 [61].

Ruxolitinib inhibits normal erythropoietin and thrombopoietin signaling through JAK2 (through the erythropoietin and thrombopoietin receptors, respectively) [6], often resulting in dose-dependent anemia and thrombocytopenia [21, 61]. Indeed, in the COMFORT studies, the most common hematologic adverse reactions with ruxolitinib were thrombocytopenia and anemia, some of which were grade 3 or 4 (Table 2) [21, 61]. However, of 301 patients randomized to ruxolitinib treatment in the two trials, only 1 patient discontinued ruxolitinib for anemia and 2 patients discontinued ruxolitinib for thrombocytopenia. Instead, cytopenias were managed by dose modifications and treatment interruptions or with red blood cell transfusions for anemia [21, 61]. In COMFORT-I, 77 % of patients with a baseline platelet count of 100–200 × 10⁹/L and 39 % of patients with a baseline platelet count >200 × 10⁹/L were receiving a lower dose at week 24 than at baseline [81]. Overall the incidence of adverse events decreased over time, with most occurring during the first 12 weeks of treatment [21, 41, 61, 63]. In both trials, mean hemoglobin levels decreased initially, but recovered after the first 8–12 weeks to new steady-state levels slightly lower than baseline [21, 61]. Similarly, ruxolitinib-treated patients initially required more blood transfusions than placebo-treated patients, but transfusion rates gradually returned close to baseline values when assessed over a 36-week period [21]. In COMFORT-I, patients treated with ruxolitinib who experienced grade 3 or 4 anemia had similar improvements in symptoms as those who did not have anemia [21]. Mandatory dose reductions for thrombocytopenia occurred mostly during the first 8–12 weeks of treatment when mean platelet count decreased; after this period, a stabilization of mean platelet counts was observed [82].

In COMFORT-I, at the 3-year follow-up, four patients originally randomized to ruxolitinib and four patients randomized to placebo experienced disease progression to secondary acute myeloid leukemia [21, 41, 62]. In COMFORT-II, at the 3-year follow-up, five patients (3.4 %) in the ruxolitinib arm and four patients (5.5 %) in the BAT arm experienced leukemic transformation [73].

Although rare adverse events of fever, respiratory distress, hypotension, and multi-organ failure have been reported after treatment discontinuation [20], experience from the placebo-controlled COMFORT-I study provided no evidence that treatment discontinuation per se was associated with serious adverse events [21, 41]. If a patient experiences one of these adverse events after the drug has been withdrawn or while tapering the dose, the intercurrent illness should be evaluate and treated, and restarting or increasing the dose of ruxolitinib should be considered [20]. If a patient needs to discontinue the use of ruxolitinib for a reason other than cytopenia, a gradual tapering of the dose by 5 mg twice daily each week may be considered to reduce the severity of returning symptoms [20]. Furthermore, the use of corticosteroids following discontinuation of ruxolitinib may be considered in specific cases where tapering of ruxolitinib is not possible (e.g., in cases of severe thrombocytopenia requiring immediate treatment discontinuation) and abrupt ruxolitinib withdrawal results in an acute return of systemic inflammatory symptoms.

The recommended starting and maintenance dose of ruxolitinib for the treatment of patients with MF is dependent on the baseline platelet count (Table 3) [20]. If response is insufficient, the dose may be increased beginning 4 weeks after initiation of therapy to a maximum of 25 mg twice daily for patients with starting platelet counts ≥100 × 10⁹/L and to a maximum of 10 mg twice daily for patients with starting platelet counts of 50 to <100 × 10⁹/L [82]. These increases may be undertaken in patients who fail to achieve a ≥50 % reduction in palpable spleen length or a ≥35 % reduction in spleen volume, as long as adequate platelet and absolute neutrophil counts are maintained [20]. Once-daily doses are not as effective as twice-daily dosing and should not be used unless specifically indicated [20]. If a dose is missed, the patient should take the next scheduled dose at the regular time [20]. Dose modifications should not be implemented on the basis of allele burden, because, as discussed above, allele burden reduction is not a clinically validated outcome marker in MF.

Experience from the COMFORT studies showed that careful monitoring of complete blood counts and adjustment of the dosing regimen accordingly are key to long-term therapeutic success in patients with MF, as adherence to therapy and avoidance of extended interruptions are important factors in maintaining response to therapy [21, 61]. If ruxolitinib needs to be stopped, symptoms can be expected to return within 1 week, usually to pretreatment levels [20]. Therefore, timely management of cytopenias with dose reductions, particularly during the first 3 months of therapy, is generally preferable to the risk of extended treatment interruptions that may reverse treatment gains. Prior to initiating ruxolitinib, a complete blood count must be performed, with subsequent monitoring during therapy every 2–4 weeks until doses stabilize, and then as clinically indicated [20, 82]. For patients with a starting platelet count of ≥100 × 10⁹/L, if at any point the platelet count falls below 50 × 10⁹/L, treatment should be interrupted until the count recovers; for patients with a baseline platelet count of 50 to <100 × 10⁹/L, treatment should be interrupted if platelet count falls below 25 × 10⁹/L [20]. Frequent monitoring and prompt dose adjustments should be employed to avoid these occurrences. Detailed dosing recommendations for cytopenias can be found in the prescribing information [20, 82].

In patients requiring modifications from the starting dose, clinical evidence suggests that ruxolitinib can be effective long-term at titrated doses as low as 10 mg twice daily [82‐84]. In trials of patients with MF with low platelet counts (between 50 and 100 × 10⁹/L), dosing of ruxolitinib was initiated at 5 mg twice daily followed by escalation by 5 mg daily every 4 weeks to 10 mg twice daily or higher in patients with adequate platelet counts [83, 85]. Preliminary findings suggest that this dosing strategy is effective in reducing spleen volume and improving symptoms [83]. Although there are no contraindications for the use of ruxolitinib, treatment is not recommended in patients with baseline platelet counts <50 × 10⁹/L [20].

Patients developing anemia may require blood transfusions and/or dose modifications of ruxolitinib. Patients treated with ruxolitinib in COMFORT-II who also received erythropoietin-stimulating agents (ESA) had a decrease in the rate of grade 3 or 4 anemia within 6 weeks of the first administration of ESA, and administration of ESA did not appear to affect the efficacy of ruxolitinib in reducing spleen volume [86]. Severe neutropenia (absolute neutrophil count <0.5 × 10⁹/L) is generally reversible with interruption of ruxolitinib therapy [81], which may be restarted once absolute neutrophil count recovers [20].

By definition [87], patients with PV have no or only minor degrees of bone marrow fibrosis, and with a median life expectancy of 13.5 years from the time of diagnosis, their prognosis is much more favorable than that of patients with PMF [14]. However, patients with PV who have some degree of bone marrow fibrosis at diagnosis have a 22 % chance of developing post-PV MF within 10 years, compared with a 7 % chance for patients with no bone marrow fibrosis at diagnosis [88]. Patients with PV typically have high levels of red blood cell mass, and keeping hematocrit levels below 45 % has been shown to be instrumental in minimizing the risk of cardiovascular death and major thrombosis [89]. However, although controlling hematocrit levels is the main concern in patients with PV, the disease is also associated with splenomegaly in approximately 40 % of patients [90], and with a considerable symptom burden, including high prevalence of fatigue (92 %) and pruritus (65 %) reported in a large survey (Fig. 2) [31].

Low-dose aspirin is the therapy of choice to reduce the overall risk of vascular events [91], and phlebotomy and/or cytoreductive therapy are commonly used to maintain hematocrit levels of <45 % [89]. Hydroxyurea is the most common first-line cytoreductive therapy for patients at high risk of thrombosis who cannot undergo phlebotomy, require frequent phlebotomy, and/or have splenomegaly or PV-related symptoms [19]. However, some evidence suggests that hydroxyurea is possibly leukemogenic [92] and some patients may not tolerate hydroxyurea or may develop clinical resistance to hydroxyurea [93]. In addition to hydroxyurea, pegylated interferon is frequently used as first-line therapy for patients with PV, based on phase II clinical results that showed high rates of hematologic and molecular responses [94, 95].

In the open-label, multicenter phase III Randomized Study of Efficacy and Safety in Polycythemia Vera with JAK Inhibitor INCB018424 versus Best Supportive Care (RESPONSE), 222 patients with PV and resistance to or intolerance of hydroxyurea were randomized to receive ruxolitinib (starting dose: 10 mg twice daily) or standard therapy. Standard therapy consisted of hydroxyurea (at tolerated doses) in 58.9 %, interferon in 11.6 %, pipobroman in 1.8 %, anagrelide in 7.1 %, immunomodulators (e.g., lenalidomide, thalidomide) in 4.5 %, and no medication in 15.2 % of patients in this treatment arm [98]. Per inclusion criteria, patients had splenomegaly, exhibited phlebotomy dependence (defined as two or more phlebotomies during the 24 weeks before screening and one or more phlebotomies during the 16 weeks before screening), and did not receive prior treatment with a JAK inhibitor. The composite primary endpoint was the proportion of patients with both hematocrit control and a ≥35 % reduction in spleen volume from baseline to week 32. To achieve the endpoint of hematocrit control, a patient had to have ≤1 instance of phlebotomy eligibility during the first 8 weeks after randomization and no instance of phlebotomy eligibility during the remainder of the 32-week study period.

The composite primary endpoint was achieved by 20.9 % of patients in the ruxolitinib arm compared with 0.9 % in the standard therapy arm (P < 0.001). Further analysis of the individual components of the primary endpoint showed that 60.0 % of patients in the ruxolitinib arm versus 19.6 % in the standard therapy arm had hematocrit control and 38.2 % in the ruxolitinib versus 0.9 % in the standard therapy arm (i.e., a single patient who received hydroxyurea) had a ≥35 % reduction in spleen volume from baseline to week 32. In addition, 49 % of patients receiving ruxolitinib compared with 5 % receiving standard therapy had a ≥50 % reduction in total symptom score, as assessed with a 14-item MPN Symptom Assessment Form patient diary. Median reductions in symptom score from baseline to week 32 for each of the 14 symptoms ranged from 37.1 % (numbness or tingling in hands or feet) to >90 % (itching, night sweats, sweating while awake, and early satiety). In contrast, standard therapy was associated with no or minimal symptom improvement or with symptom worsening (Fig. 4). The difference in efficacy between the two arms was reflected in the mean changes from baseline in EORTC-QLQ-C30 QoL and functioning scores, whereas ruxolitinib therapy resulted in overall improvement, standard therapy was associated with worsening (Fig. 5) [98]. Recent longer-term follow-up data suggest that the benefits of ruxolitinib therapy are durable. Among patients who achieved the composite primary endpoint, only one patient had lost response at the 80-week follow-up, and 82.7 % of patients were still receiving ruxolitinib after a median exposure of 111 weeks [99].

The superior benefit of ruxolitinib versus standard therapy was also reflected in the discontinuation rates for the two treatment arms. After a median treatment exposure of 81 weeks in the ruxolitinib arm, 15.5 % of patients had discontinued and none discontinued for protocol-defined lack of efficacy. In contrast, 96.4 % of patients randomized to standard therapy discontinued treatment or crossed over to ruxolitinib after a median treatment exposure of 34 weeks, and 87.5 % did so for lack of efficacy.

The hematologic safety profile in the RESPONSE study was similar for both treatment arms (Table 4) [98]. The most common grade 3 and 4 hematologic events were lymphopenia (ruxolitinib: 15.5 % and 0.9 %, respectively; standard therapy: 16.2 and 1.8 %, respectively). Two patients in the ruxolitinib arm (1.8 %) and no patients receiving standard therapy experienced grade 3 or 4 anemia. Grade 3 or 4 thrombocytopenia occurred in six (5.4 %) patients receiving ruxolitinib and four (3.6 %) patients receiving standard therapy.

Nonhematologic adverse events were generally grade 1 or 2 in both treatment arms [98]. Adverse events that were more common in the ruxolitinib versus the standard therapy arm (all-grade rates) included diarrhea (14.5 vs 7.2 %), muscle spasms (11.8 vs 4.5 %), and dyspnea (10.0 vs 1.8 %). In contrast, adverse events of pruritus, one of the most common symptoms of PV, occurred less frequently in the ruxolitinib versus the standard therapy arm (13.6 vs 22.5 %), likely reflecting the superior efficacy of ruxolitinib in symptom mitigation.

Within the 32-week study period, one patient treated with ruxolitinib versus six patients receiving standard therapy experienced thromboembolic events. Two patients died after crossover from standard therapy to ruxolitinib. The causes of death were central nervous system hemorrhage and multi-organ failure-associated hypovolemic shock and a sudden unexplained decrease in hemoglobin [98].

The recommended starting dose of ruxolitinib for the treatment of patients with PV is 10 mg twice daily. Because of the different hematologic characteristics of PV and advanced MF, ruxolitinib-induced anemia and thrombocytopenia are much less common in patients with PV than they are in patients with intermediate- or high-risk MF. In the ruxolitinib arm of the RESPONSE study, only 10 of 98 patients assessed at week 32 received doses that were lower than the starting dose, whereas 55 patients received higher doses (15, 20, or 25 mg twice daily) [98]. Dose reduction should be considered when a patient has a hemoglobin value in the range of 100 to <120 g/L and a platelet count of 75 to <100 × 10⁹/L. Dose reductions and interruptions are recommended if hemoglobin is >100 and >80 g/L, respectively, or platelet count is <75 × 10⁹ and <50 × 10⁹/L, respectively (for additional detail, see full prescribing information [20]).

Patients with renal or hepatic impairment exhibit altered pharmacokinetic properties of ruxolitinib and/or its metabolites [100]. Renal impairment had no effect on ruxolitinib pharmacokinetics but increased the exposure of ruxolitinib metabolites, with the greatest effect seen in patients with end-stage renal disease. Because these changes were associated with increased pharmacodynamic activity (inhibition of STAT3 phosphorylation) [100], dose reductions are recommended for patients with moderate or severe renal disease. Ruxolitinib is not recommended for patients with end-stage renal disease, unless they are on dialysis (Table 5) [20]. Hepatic impairment did not affect maximal serum concentration but increased exposure (by a factor of approximately 1.5–2) and decreased clearance, with no obvious quantitative relationship to the severity of impairment [100]. Accordingly, lower starting doses are recommended for all patients with MF or PV who have mild to severe hepatic impairment (Table 5) [20].

In vitro and ex vivo evidence of inhibition of dendritic cell function and downregulation of T regulatory cells with ruxolitinib [101‐103] suggests that ruxolitinib may have immunosuppressive activity. However, ruxolitinib does not appear to inhibit the formation of T cells, as evidenced by the successful immune reconstitution experienced by patients who received ruxolitinib and stem cell transplantation [104]. Nonetheless, isolated cases of serious infections have been noted in patients with MF who were treated with ruxolitinib in clinical practice, including progressive multifocal leukoencephalopathy [105], increase in hepatitis B viral titers [106], reactivation of herpes simplex virus [107], and disseminated tuberculosis [108]. Furthermore, herpes zoster and urinary tract infections occurred in patients treated with ruxolitinib in phase 3 trials in MF and PV [20]. Because of the potential for bacterial, fungal, or viral infections to occur or be reactivated in patients receiving ruxolitinib, special care should be taken when treating patients with MF who have an already compromised immune system due to other underlying medical problems or comorbidities, or those who have a history of atypical infections. Patients should be observed for signs of infection so that proper treatment can begin promptly, and ruxolitinib should not be started until serious infections have resolved. Patients at risk of tuberculosis (i.e., patients who have a history of tuberculosis, have lived in or traveled to countries with a high prevalence of tuberculosis, or have had close contact with a person with active tuberculosis) should be tested for latent infection prior to starting ruxolitinib. Those who test positive should consult with their physician regarding the use of ruxolitinib based on their overall benefit-risk ratio [20].

The effect of single-dose ruxolitinib (25 and 200 mg) on the QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 47 healthy human participants [109]. In this study, which had a demonstrated ability to detect small effects, the upper bound of the one-sided 95 % CI for the largest placebo-adjusted, baseline-corrected QTc (Fridericia correction method) was <10 ms, which is below the level of regulatory concern. The dose of 200 mg is adequate to represent the high-exposure clinical scenario [20].