Ruxolitinib for Myelofibrosis – An Update of Its Clinical Effects

Abstract

Myelofibrosis (MF), associated with a Philadelphia chromosome-negative myeloproliferative neoplasms, is characterized by progressive bone marrow fibrosis and ineffective hematopoiesis. Clinical hallmarks include splenomegaly, anemia, and debilitating symptoms. In two randomized phase III studies, the JAK1/JAK2 inhibitor ruxolitinib demonstrated significant improvement in splenomegaly and disease-related symptoms compared with placebo (COMFORT-I) or best-available therapy (COMFORT-II) in patients with intermediate-2 or high-risk MF. Although ruxolitinib was associated with dose-dependent anemia and thrombocytopenia, adverse events were manageable and rarely led to treatment discontinuation. Here, we provide an update of the clinical effects of ruxolitinib in patients with MF, based on original articles and meeting abstracts published after the primary publication of the COMFORT trials in March 2012. Long-term follow-up data from the COMFORT trials and clinical experience with ruxolitinib in unselected patient populations confirmed the previously established improvement of splenomegaly and symptoms, including the durability of these effects. Analyses suggest that patients benefit from ruxolitinib therapy across subgroups defined by age, MF type, risk category, performance status, JAK2 V617F mutation status, extent of splenomegaly, or presence of cytopenias. Additional analyses from COMFORT-I showed that with dose adjustments, platelet counts stabilized. Hemoglobin gradually recovered to levels slightly below baseline after the first 8–12 weeks of therapy. After initial increases, the need for red blood cell transfusions decreased to a level similar to placebo. Two-year follow-up data from the COMFORT trials suggest that patients with intermediate-2 or high-risk MF receiving ruxolitinib therapy may have improved survival compared with those receiving no (placebo) or traditional therapy.

Introduction

Myelofibrosis (MF) is a pathologic entity occurring in the course of primary MF, post polycythemia vera (PV) MF or post essential thrombocythemia (ET) MF. Thus, as a clinical syndrome MF comprises a group of related disorders that constitute or develop from a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN). MF is characterized by progressive bone marrow fibrosis and ineffective hematopoiesis.^1–3 Although PMF, PV, and ET have distinct disease characteristics and diagnostic criteria,⁴ secondary development of MF in patients with PV or ET results in disorders with clinical and laboratory characteristics virtually indistinguishable from those of PMF.^1,3 Typical clinical manifestations of MF include anemia and splenomegaly, which are consequences of ineffective and extramedullary hematopoiesis, and debilitating symptoms (e.g., fatigue, night sweats, bone pain, fever, pruritus, and weight loss) resulting from disease-related systemic inflammation and excessive catabolism.^2,3,5,6 The estimated prevalence of MF — including PMF and secondary development from PV or ET — in the United States is 3.6 to 5.7 cases per 100,000 persons.⁷ For patients with PMF, the median age at the time of diagnosis is around 65 years.^8,9

A hallmark of MPNs, including PMF, is aberrant myeloproliferation associated with dysregulated JAK-STAT signaling.¹⁰ Patients with MPNs carry somatic mutations in hematopoietic stem cells that result in constitutive or overactivation of JAK-STAT pathways,^11,12 which are essential in normal hematopoiesis.¹³ Although the gain-of-function mutation JAK2 V617F is the most prevalent of these mutations — present in approximately 60% of patients with PMF and ET, and at least 95% of patients with PV¹¹ — an increasing number of mutations that directly or indirectly affect JAK-STAT signaling, including mutations in genetic and epigenetic regulators, have been associated with MPNs, and patients may have multiple neoplastic stem cell clones.^11,12,14 When present, the JAK2 V617F mutation appears not to be the disease-initiating event,¹⁵ but it may contribute to MPN disease phenotype and manifestations.^16–18 In patients with MF, dysregulated JAK-STAT signaling is not only involved in the pathogenesis of myeloproliferation but also appears to be associated with secondary pathogenic phenomena, particularly the excess production of inflammatory cytokines, which is believed to be associated with MF-related symptoms and is sensitive to JAK inhibition.^19,20

The prognosis of patients with PMF varies widely depending on age, presence of symptoms and anemia, leukocyte and platelet counts, percentage of circulating blasts, and karyotype.^8,21,22 Based on the number of prognostic factors, a patient’s risk status is classified as low (no risk factors), intermediate-1, intermediate-2, or high. Although risk classification and prognostic estimates vary with the prognostic scoring system used, the median survival time is less than 2 years for high-risk patients and 3 to 7 years for intermediate-risk patients with PMF.^8,21,22

Before the recognition of the critical role of aberrant JAK-STAT signaling in the pathophysiology of MF, available treatment options in general were palliative and associated with limited and transient responses.²³ The oral JAK1/JAK2 inhibitor ruxolitinib has been evaluated in patients with intermediate-2 or high-risk MF, including PMF, post- PV MF, and post-ET MF in 2 large randomized phase III studies, the 24-week double-blind placebo-controlled COMFORT-I study²⁴ and the 48-week COMFORT-II study, which compared the effects of ruxolitinib and best available therapy (BAT).²⁵ In both studies, ruxolitinib was associated with significant improvements in splenomegaly and MF-associated symptoms compared with the controls. Mean reductions from baseline in spleen volume with ruxolitinib were approximately 30% in both studies, whereas spleen volumes increased with placebo in COMFORT-I and BAT in COMFORT-II.^24,25 In COMFORT-I, ruxolitinib also was associated with a mean decrease of 46% in MF-related symptoms, based on Total Symptom Score (TSS) assessed using the modified MF Symptom Assessment Form v2.0 — compared with a 42% increase in TSS with placebo.²⁴ Furthermore, compared with placebo, ruxolitinib therapy was associated with significant improvements in measures of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30), including global health status/quality of life and physical, role, emotional, and social functioning.²⁴ Patients treated with ruxolitinib in COMFORT-II experienced clinically significant improvements in symptoms and quality of life as measured using the EORTC QLQ-30, including fatigue, dyspnea, insomnia, appetite loss, and physical and role functioning scales, whereas BAT was generally associated with no change or symptom worsening.^25,26 Symptom improvements with ruxolitinib were accompanied by decreases in the plasma levels of pro-inflammatory biomarkers.^24,25 No major changes in bone marrow histomorphology were observed.²⁵ Although ruxolitinib was generally well tolerated in both trials, patients in the ruxolitinib groups experienced increased rates of dose-dependent anemia and thrombocytopenia compared with the control groups; however, these events rarely led to treatment discontinuations.^24,25

The purpose of this review is to provide an update of the clinical effects of ruxolitinib in patients with myelofibrosis. The updated information was obtained from original articles and abstracts from professional society presentations published during the 12 months following the primary publication of the clinical data from the COMFORT trials in March 2012.

Discussion

Effect on Survival

In the publications of the primary results of the COMFORT studies, 1-year follow-up data from COMFORT-I suggested that ruxolitinib therapy was associated with improved survival in patients with intermediate-2 or high-risk MF relative to placebo.²⁴ However, this was not seen with ruxolitinib versus BAT in COMFORT-II (Table 1).²⁵ Two-year follow-up data from both COMFORT studies were presented at the annual meeting of the American Society of Hematology in December 2012.^27,28 Kaplan-Meier analyses of overall survival were based on the intended treatment at randomization and did not take into account crossover of patient from the control to the ruxolitinib groups, which was permitted in both trials according to protocol-specified criteria of disease progression. In both trials the 2-year analyses showed a reduction in the risk of death for patients randomized to ruxolitinib compared with those randomized to the control groups (Table 1). The 2-year survival data from COMFORT-I confirmed those reported after 1 year of follow-up, suggesting that ruxolitinib therapy relative to placebo may be associated with prolonged survival in patients with intermediate-2 or high-risk MF.²⁴ Improved survival was seen, although all patients originally randomized to placebo had discontinued or crossed over to ruxolitinib at the time of the 2-year analysis. The 2-year survival data from COMFORT-II^28,29 are the first indication of improved survival of patients who received ruxolitinib therapy rather than BAT (Table 1). Possible reasons that improved survival with ruxolitinib relative to BAT was not observed at earlier follow-up times²⁵ include the 2:1 randomization scheme in favor of ruxolitinib and potentially biased survival estimates caused by the relatively high proportion of patients in the BAT arm who were censored (27.4% versus 14.4% in the ruxolitinib arm) because of a lack of relevant follow-up information.²⁹

Table 1.

Effect of Ruxolitinib on Overall Survival in COMFORT-I and COMFORT-II

Study	Treatment Group	Median Follow-up, Weeks	HR (95% CI)	P
COMFORT-I24,27	Ruxolitinib (n = 155)	3224	0.67 (0.30–1.50)	.33
	vs. placebo (n = 154)	5124	0.50 (0.25–0.98)	.04a
		10227	0.58 (0.36–0.95)	.028a
COMFORT-II25,28	Ruxolitinib (n = 146)	5225	0.70 (0.20–2.49)
	vs. BAT (n = 73)	6125	1.01 (0.32–3.24)
		11228,29	0.51 (0.27–0.99)	.041a

^aP values for this unplanned analysis are descriptive and not adjusted for multiple comparisons.

Abbreviations: BAT = best available therapy; CI = confidence interval; HR = hazard ratio.

Cachexia-related persistent weight loss and decreases in total cholesterol are common in patients with MF and are associated with shortened survival.^8,30,31 In both COMFORT studies, ruxolitinib was associated with substantial median weight gains, whereas placebo and BAT were associated with weight decreases and no substantial changes in weight, respectively.^24,25 A post hoc analysis of longer-term COMFORT-I data presented at the 53rd annual meeting of the American Society of Hematology in December 2012 suggests that ruxolitinib-mediated alleviation of cachexia and improvement in total cholesterol may contribute to the improved survival seen in patients receiving ruxolitinib therapy. Patients in the ruxolitinib group with greater than median weight gains had a reduced risk of death compared with those who achieved smaller weight gains (hazard ratio [HR] 0.40; 95% confidence interval [CI] 0.18–0.90; P = .022).³² Furthermore, 97% of patients randomized to ruxolitinib experienced metabolic improvement in the form of an increase in total cholesterol, and greater than median increases in total cholesterol were associated with improved survival prognosis compared with smaller increases (HR 0.46; 95% CI 0.21–1.01; P = .048).³²

Efficacy in spleen size reduction and symptom improvement

Durability of treatment response

Two-year follow-up data from the 2 COMFORT trials demonstrated that ruxolitinib-mediated reductions in splenomegaly and symptom burden were durable.^27,28 In COMFORT-I, 134 of 155 patients originally randomized to ruxolitinib continued treatment after the primary data analysis at Week 24, and 100 patients remained on treatment at the time of the 2-year analysis.²⁷ Patients randomized to ruxolitinib who were followed for a median period of 102 weeks had mean reductions from baseline in spleen volume of 32% at Week 24 and 35% at Week 96 (Table 2), and for those who originally met the primary endpoint of a ≥35% reduction in spleen volume at Week 24, the median response duration was 108 weeks. The mean increase from baseline in EORTC QLQ-C30 Global Health Status/Quality of Life (QoL) was 12.3 points at Week 24 and 13.0 points at Week 96 (Table 2), with an increase by at least 10 points indicating a clinically meaningful improvement.²⁷

Table 2.

Long-term Effects of Ruxolitinib on Spleen Volume and EORTC QLQ-C30 Global Health Status/QoL in COMFORT-I²⁷

	Week	Change From Baseline, Mean (SEM)
		Ruxolitinib	Placebo
Spleen volume
	24	−31.6 (1.6)	8.2 (1.5)
	48	−31.6 (2.1)	NA
	72	−34.1 (2.5)	NA
	96	−34.9 (3.0)	NA
EORTC QLQ-C30 Global Health Status/QoLa
	24	12.3 (2.2)	−3.7 (2.1)
	48	13.6 (2.2)	NA
	72	14.1 (2.5)	NA
	96	13.0 (2.4)	NA

^aIncrease by more than 10 points indicates clinically meaningful improvement.

Abbreviations: EORTC = European Organisation for Research and Treatment of Cancer; QoL = quality of life; QLQ = quality of life questionnaire; SEM = standard error of the mean.

In COMFORT-II, 81 of 146 patients originally randomized to ruxolitinib remained on treatment at the time of the 2-year analysis.²⁸ At a median follow-up of 112 weeks, a total of 70 patients (48%) achieved a ≥35% reduction in spleen volume at any time during the trial. These reductions were sustained with continued therapy. With the median duration of spleen response not reached at the time of the analysis, the estimated probabilities of maintaining response at Weeks 48 and 84 were 75% (95% CI 61%–84%) and 58% (95% CI 35%–76%), respectively.²⁸

Clinical benefits in specific patient populations

Results of recent COMFORT-I subgroup analyses show that patients treated with ruxolitinib experienced improvements in spleen size and TSS across subgroups defined by MF subtype, age group, International Prognostic Scoring System (IPSS) risk, Janus kinas 2 (JAK2) V617F mutation status or various baseline parameters, such as Eastern Cooperative Oncology Group (ECOG) performance status, hemoglobin value, platelet count, palpable spleen size, spleen volume quartile, or TSS quartile (Figure 1).³³ Across COMFORT-I subgroups, mean reductions from baseline in spleen volume in patients treated with ruxolitinib ranged from 29.2% to 33.9%, whereas mean reductions from baseline in TSS ranged from 36.2% to 56.7%.³³ Previous results from COMFORT-II showed that ruxolitinib overall was more effective than BAT at reducing spleen volume across subgroups defined by gender, age, mutation status, IPSS risk category, baseline spleen size, MF subtype, or ruxolitinib starting dose results.³⁴ In a post hoc analysis of spleen volume reductions and patient reported outcomes in COMFORT-I, ruxolitinib-treated patients achieving ≥10% reduction in spleen size had significant improvements versus placebo in TSS, total abdominal and nonabdominal symptoms, and other patient-reported outcomes, including global health status/QoL, Patient Global Impression of Change (PGIC) scores, and Patient Reported Outcomes Measurement Information System (PROMIS) fatigue scores.³⁵ However, even patients with <10% reduction in spleen size experienced clinically meaningful improvements in TSS, total abdominal and nonabdominal symptoms, and PGIC scores with ruxolitinib versus placebo.³⁵

Figure 1. Percentage Change in Spleen Volume (A) and Total Symptom Score (B) From Baseline to Week 24, by COMFORT-I Patient Subgroup³³.

Dashed lines represent the mean percentage change from baseline for overall treatment group.²⁴

Abbreviations: ECOG PS = Eastern Cooperative Oncology Group performance status; Hb = hemoglobin; Int-2 = Intermediate-2; IPSS = International Prognostic Scoring System; JAK = Janus kinase; MF = myelofibrosis; PET = post-essential thrombocythemia; PMF = primary myelofibrosis; PPV = post-polycythemia vera; SEM = standard error of the mean.

(From Verstovsek et al. The clinical benefit of ruxolitinib across patient subgroups: analysis of a placebo-controlled, Phase III study in patients with myelofibrosis.³³ © 2013 Blackwell Publishing Ltd. Reprinted with permission from Blackwell Publishing Ltd.)

An analysis of COMFORT-I patients stratified by baseline values of palpable spleen length or TSS showed that ruxolitinib therapy was effective in reducing spleen volume and symptom burden regardless of spleen size or symptom severity, whereas patients receiving placebo experienced disease progression across all subgroups.³⁶ For this analysis, a nonlinear mixed model that best fitted individual patient data was used to predict placebo-associated changes in spleen volume for patients who crossed over to ruxolitinib therapy, whereas last observations were carried forward to impute missing TSS data. Based on this analysis, patients in COMFORT-I who initiated ruxolitinib therapy at a less advanced stage of the disease were likely to achieve a better clinical status at a given time point in terms of absolute spleen size and symptom severity than those initiating therapy at a more advanced disease stage.³⁶ The results of this hypothesis-generating analysis seem to suggest that patients with clinically significant splenomegaly and/or MF-related symptoms generally may benefit from early intervention, but further prospective studies are needed.

In light of the efficacy of ruxolitinib in reducing splenomegaly and symptom burden, a retrospective analysis across ruxolitinib clinical trials (phase I/II open-label and the 2 phase III COMFORT studies) was conducted to assess whether ruxolitinib therapy affected the incidence of splenectomy.³⁷ The results showed that the incidence of splenectomy among patients treated with ruxolitinib was almost 3 times lower than that among patients randomized to placebo or BAT in the COMFORT trials (Table 3).³⁷ This analysis, which was based on intent-to-treat populations, likely underestimated the true incidence of splenectomy associated with placebo and BAT because of the large proportion of patients in the COMFORT studies who crossed over from the control arms to ruxolitinib therapy.^24,25 The findings of this analysis suggest that ruxolitinib therapy may prevent or delay the potential need for splenectomy in patients with severe spleen-related symptoms.

Table 3.

Incidence of Splenectomy During Clinical Studies of Ruxolitinib³⁷

Patient group	n	Patient-years	Splenectomies, n	Splenectomies per 100 patient-years, n
Assigned to ruxolitinib	459	818.0	9	1.10
BAT or placebo	224	170.7	5	2.93

Abbreviation: BAT = best available therapy.

Effects of dose modifications

A dose-response post hoc analysis from COMFORT-I showed that most patients randomized to ruxolitinib achieved a final titrated dose (defined as average daily dose from Weeks 21 to 24) of 10 mg twice daily (b.i.d.) or higher, including the majority of patients with platelet counts of 100 to 200 × 10⁹/L at baseline.³⁸ Reductions in splenomegaly and symptom burden similar to those observed in the primary analysis were seen in patient groups with mean final titrated doses of 10 mg b.i.d. and higher. The authors concluded that patients who received a dose of at least 10 mg b.i.d. achieved clinically meaningful reductions in spleen size and improvements in fatigue as well as other MF-related symptoms.³⁸

Safety and tolerability

Although risks of anemia and thrombocytopenia remain main concerns in the treatment of patients with ruxolitinib, the 2-year safety data from the COMFORT studies showed that there were no unexpected safety or tolerability issues with longer-term therapy past the time frame for the primary analysis.^27,28 Among all patients randomized to ruxolitinib in COMFORT-I, grade 3 or 4 anemia regardless of baseline hemoglobin was reported in 37.4% and 14.8% of patients, respectively, at a median follow-up of 102 weeks. Grade 3 or 4 thrombocytopenia was reported in 11.0% and 5.2% of patients, respectively. These rates were similar to those reported in the primary analysis at a median follow-up of 32 weeks, i.e., grade 3 or 4 anemia in 45.2% and grade 3 or 4 thrombocytopenia in 12.9% of patients.²⁴ Rates of nonhematologic adverse events adjusted for increased follow-up duration were similar to those seen at the time of the primary data analysis. After the report of 2 cases of secondary AML among patients treated with ruxolitinib at the time of the primary analysis, no additional cases of AML in this patient group were reported.²⁷

At a median follow-up of 112 weeks, the most common new or worsened grade 3 or 4 hematologic abnormalities during randomized treatment in COMFORT-II were anemia (ruxolitinib, 40.4%; BAT, 23.3%), lymphopenia (22.6%; 31.5%), and thrombocytopenia (9.6%; 9.6%).²⁸ In the ruxolitinib arm, mean hemoglobin levels decreased over the first 12 weeks of treatment and then recovered after Week 24 to levels were similar to those observed with BAT. Mean monthly red blood cell transfusion rates also were similar in the two treatment groups. Most nonhematologic adverse events were grade 1 or 2. There were no new nonhematologic adverse events associated with ruxolitinib therapy that occurred in ≥10% of patients beyond those that were observed previously. This analysis included ruxolitinib treatment during the extension phase of patients originally randomized to BAT.²⁸

The dose-dependent risks of anemia and thrombocytopenia associated with ruxolitinib are a consequence of the drug’s mechanism of action, as erythropoietin and thrombopoietin both signal through JAK2.¹⁰ However, results from COMFORT-I showed that treatment-related events of anemia or thrombocytopenia generally can be managed effectively using dose reductions, brief treatment interruptions, and RBC transfusions (for anemia) without compromising efficacy or leading to permanent treatment discontinuation.^24,39 Time course analyses showed that most grade ≥3 anemia or thrombocytopenia occurred during the first 8 to 12 weeks of treatment with ruxolitinib, parallel to mean decreases in platelet counts and hemoglobin levels.^24,39 Mean platelet counts subsequently stabilized. and hemoglobin values gradually recovered to levels slightly below baseline values (Figure 2). Consistent with the recovery of hemoglobin values, the proportion of patients receiving red blood cell transfusions gradually decreased to the level seen with placebo, after increasing during the first 8 weeks of treatment.^24,39

Figure 2. Mean Percentage Change From Baseline in (A) Platelet Counts and (B) Hemoglobin Levels Over Time³⁹.

Abbreviation: b.i.d. = twice daily.

Isolated cases of a ruxolitinib withdrawal syndrome during the ruxolitinib phase I/II study were reported based on the occurrence of acute or severe disease-related symptoms after treatment discontinuation.⁴⁰ However, these cases included patients who discontinued ruxolitinib therapy during acute intercurrent illnesses, and it has not been established whether discontinuation of therapy contributed to the clinical course in these patients.^40,41 In the COMFORT-I primary analysis, myelofibrosis-related symptom burden, as measured by TSS, was shown to return to baseline levels over a period of approximately 1 week following treatment interruption; however, a closer inspection of the pattern of adverse events following treatment interruption or discontinuation suggested that ruxolitinib was not associated with a withdrawal syndrome.⁴² No cases of a ruxolitinib withdrawal syndrome were reported in the 2-year follow-up as well.²⁷ Nonetheless, because it may be difficult to distinguish between symptoms returning or worsening due to drug withdrawal and symptoms of disease progression, gradual tapering of the dose of ruxolitinib should be considered when discontinuing therapy for reasons other than thrombocytopenia.⁴¹

Ruxolitinib therapy in patients with low platelet counts

The COMFORT studies excluded patients with baseline platelet counts below 100 × 10⁹/L. Two early-phase clinical studies are underway to determine the optimal dosing strategy for ruxolitinib in patients with platelet counts of 50 to 100 × 10⁹/L.^43,44 Interim results of a phase II study in patients with baseline platelet counts of 50 to 100 × 10⁹/L (Study 258, NCT01348490), who received a starting dose of 5 mg b.i.d., showed that most patients who complete 24 weeks of treatment attained final doses of 10 mg b.i.d. or higher,⁴³ a dosage regimen that has been shown to provide clinically meaningful reductions in spleen size and improvements in fatigue and other MF-related symptoms.³⁸ No treatment discontinuations attributable to thrombocytopenia or bleeding events occurred, and the preliminary efficacy results for ruxolitinib are consistent with the findings from COMFORT-I (Table 4).⁴³ The authors concluded that using a low starting dose (5 mg b.i.d.) with subsequent up-titration to ≥10 mg b.i.d. under careful monitoring may be a useful strategy to optimize tolerability and maximize benefit of ruxolitinib in patients with low platelet counts.⁴³ Preliminary findings from EXPAND, an ongoing phase Ib dose-finding study of ruxolitinib in patients with platelet counts of 50 to 99 × 10⁹/L, revealed no dose-limiting toxicities at the doses tested to date (i.e., up to 10 mg b.i.d. in patients with platelet counts of 75 to 99 × 10⁹/L and 5 mg b.i.d. in patients with platelet counts of 50 to 74 × 10⁹/L).⁴⁴

Table 4.

Summary of Hematology and Efficacy in Study 258 (Interim Results)⁴³ and COMFORT-I²⁴

	Ruxolitinib		Placebo
	Study 258 N=41	COMFORT-I n=155	COMFORT-I n=154
Total daily dose at Week 12/Week 24, mg	15.1/19.1	30.4/29.6	0
Hematology
Mean baseline values
Platelet count, ×109/L	73	321	280
Hemoglobin in patients with no transfusions, g/L	108	123	115
Mean change from baseline to Week 12/Week 24
Platelet count, ×109/L	−1.0/−5.3	−130/−159	−9.1/−11.2
Hemoglobin, g/L	−1.8/−0.2	−18/−11	+1.3/+1.9
Efficacy
Percent of patients
≥50% reduction in TSS	36	46	5.3
≥35% reduction in spleen volume	33	42	0.7
“Much” or “very much improved” on PGIC	59	67	11
Mean change from baseline
EORTC QLQ-C30 Fatigue Subscalea	−23.4	−14.8	1.8
EORTC QLQ-C30 Global	16.2	12.3	−3.4
Health/Quality of Lifeb

^aNegative values indicate improvement.

^bPositive values indicate improvement.

Abbreviations: EORTC = European Organisation for the Treatment of Cancer; PGIC = Patient Global Impression of Change; QLQ = quality of life questionnaire.

Experience with ruxolitinib in clinical practice

Important insight into the treatment effects of ruxolitinib in patients with MF has recently come from clinical experience at both single institutions inside the United States, including Mayo Clinic, Scottsdale,⁴⁵ and Stanford University School of Medicine,⁴⁶ and large support programs outside the United States, including a compassionate use program by the French Intergroup of Myeloproliferative Neoplasms (FIM)⁴⁷ and the international Individual Patient Supply Program (IPSP).⁴⁸ Overall, the clinical experience with these unselected patient populations confirms the clinical benefits of ruxolitinib observed in the phase III COMFORT trials. The IPSP, which included requests for ruxolitinib by more than 800 physicians in 48 countries, approved access to the drug for at least 1240 patients by December 2012. Of 639 patients enrolled before February 2012, 381 had available follow-up data. Most of these patients experienced reductions in spleen size (201 of 247 evaluable patients [81.4%]) and/or constitutional symptoms (151 of 203 [74.4%]), and most patients who experienced reductions in spleen size also experienced symptom improvement (131 of 162 [80.1%]).⁴⁸ Safety profiles were comparable with those reported in the COMFORT trials.⁴⁸

Conclusion

Since the publication of the primary analysis data from the COMFORT trials in March 2012, both long-term follow-up data from these trials and increasing clinical practice experience with ruxolitinib therapy in unselected patient populations with MF confirm the previously established efficacy and tolerability profile of ruxolitinib, i.e., clinically meaningful improvement of disease-associated splenomegaly and symptoms, improvement in health-related QOL measures, and overall good tolerability. In general, dose modifications and red blood cell transfusions appear to be effective in managing treatment-related thrombocytopenia and anemia. Preliminary data from ongoing studies^43,44 suggest that up-titration from a low dose (5 mg b.i.d.) may be a promising strategy in patients with low platelet counts to achieve final doses of ruxolitinib that are both effective and well tolerated. Updated results from the ongoing phase II study of ruxolitinib in patients with MF who have low platelet counts provided the basis for the recent approval by the United States Food and Drug Administration of a new recommended starting dose of ruxolitinib 5 mg b.i.d. for patients with baseline platelet counts of at least 50 × 10⁹/L but less than 100 × 10⁹/L.^41,49 The prescribing information updated in June 2013 also provides flexibility for subsequent dose modifications in this patient population based on safety and efficacy.⁴¹ The results of the 2-year follow-up data from the COMFORT studies in patients with platelet counts ≥100 × 10⁹/L further suggest that long-term ruxolitinib therapy provided durable efficacy and was not associated with unexpected adverse events. In addition, there was no evidence of a withdrawal syndrome in patients who discontinued treatment. New, 2-year survival data from the 2 COMFORT trials also suggest that ruxolitinib therapy may be associated with a survival advantage for patients with intermediate-2 and high-risk MF over those receiving no treatment (placebo) and over those receiving traditional therapy (BAT). In COMFORT-I, prolonged survival may in part be associated with the metabolic improvements and weight gains observed in ruxolitinib-treated patients, suggesting that alleviation of cachexia may be one of the underlying mechanisms. Given the significant improvement in symptoms seen with ruxolitinib therapy, a ruxolitinib-mediated survival advantage also would be consistent with the established prognostic value of presence of symptoms in patients with MF.^8,21,22