Ruxolitinib Group Research Articles

The Impact of Allogeneic Hematopoietic Cell Transplantation (HCT) and Treatment with Ruxolitinib on Survival in Patients with Myelofibrosis

Allogeneic HCT is curative in myelofibrosis (MF) with a survival (OS) advantage compared to non-JAK-inhibitor treatments in patients (pts) with Int-2/high-risk DIPSS (Kroeger et al, Blood 2015). On the other hand, data demonstrate a OS benefit of the JAK1/JAK2 inhibitor ruxolitinib (RUX) in intermediate (Int)-2/high-risk IPSS (Cervantes et al, Blood 2013; Verstovsek et al, Haematologica 2015). Yet, comparative data to the impact of RUX and HCT on OS are lacking. This was pursued retrospectively at the University of Leipzig in light of clinical-, cytogenetic-, phenotype-driver-, and somatic mutations-based prognostic variables.Patient and Methods: RUX became available in November, 2009. MF pts (n=137; median age 58y) seen afterwards were included with the exception of MPL + pts (small number). Characteristics are shown in table 1. RUX was given for spleenomegaly and/or constitutional symptoms [n=76 (55%)]. Irrespective of RUX, a donor search was initiated in int-2 and high-risk IPSS pts < 70 y and HCT performed if a suitable donor identified. Based on this biologic randomization, 50 (37%) received HCT, 58 (42%) continued with RUX (median exposure 19 months), and 29 (21%) pts had other options. The RUX- and HCT-groups were balanced in terms of IPSS, platelets, cytogenetic-, and epigenetic molecular-risks. Treatment was initiated within the first year (median 10 months), thus probability of OS 5 years after diagnosis was calculated (SPSS20 software). Cytogenetic-risk was conducted according to Caramazza et al. Leukemia 2011. Somatic mutations detected by NGS were used to calculate molecular-risk (Vannucchi et al. Leukemia 2013).Results: Median OS time was 6.8 y. The RUX-group was older (median age 64 y) with profound spleenomegaly and a higher JAK2 V617F allele burden compared to the HCT group (median age 55 y) (p<0.0005). The 56% OS at 5 years in the RUX group was comparable to that after HCT (60%; p=0.5). In the transplant setting, prior RUX-treatment (n=21; OS 65%) had no negative impact compared to up-front HCT (n=29; OS 55%) (p=0.9). Whilst IPSS low-/int-1-risk retained its survival impact (p=0.04), OS at 5 years was comparable for int-2 and high-risk. OS in the HCT and RUX groups for int-2 was 59% and 62% respectively (p=0.4) and for high-risk IPSS 54% and 50% respectively (p=0.2). Advanced age was associated with an inferior OS (p=0.002) and correlated with higher IPSS, transfusion-dependency and thrombocytopenia. In the HCT group, OS in pts <50 y was 91% vs. 49% in pts >50 y (p=0.001). In the RUX group, age <60 and not <50 y was OS-relevant [79% in pts <60y vs. 43% in those >60 y (p=0.02)]. No prognostic implication of anemia, WBC, peripheral blasts, and constitutional symptoms could be detected with both treatments. OS in JAK2 + pts was similar to CALR + pts in both therapy cohorts (p=0.3). Triple negativity retained its detrimental influence (p<0.0001) even after HCT, with frequent AML-typical mutations (transcription and/or signaling genes) and a leukemic transformation (LT) rate of 35%. Although spliceosome mutations were associated with anemia (p=0.004)/transfusion-dependency (p=0.006) and mutations in chromatin modifiers (ASXL1, EZH2) with splenomegaly(p=0.02),high-molecular epigenetic risk had no impact on OS or LT in the treatment groups. Unfavourable cytogenetics were associated with LT (p=0.04) but not OS in the two groups. Of the 24 pts with a LT, 15 (62%) received no RUX and no HCT.Conclusions: Our data imply that, besides allogeneic HCT, a prolonged JAK1/JAK2 inhibition could, at least partly, attenuate most of the prognostic detrimental parameters. Pre-treatment with ruxolitinib prior to HCT does not seem to have a negative impact on survival. It is the first time where outcome with a non-transplant procedure is shown to be comparable to that after HCT in MF, even in high-risk disease. This needs to be verified in prospective randomized trials to define the role of allogeneic HCT in the era of JAK1/JAK2 inhibition.Table 1Patients characteristics ( n = 137 )VariableImpact on OSImpact on LTMedian age (years)580.0020.6JAK2+/CALR+/Double negative (%)63 / 20 / 17<0.00050.04Median number of MF-related mutations (range)1 (0-5)0.40.07High-molecular risk profile (%)(ASXL1, EZH2, SRSF2, IDH1/2)33.60.80.7Mutations in transcription/signaling genes (%)280.30.008Unfavorable cytogenetics (%)300.10.04IPSS (Int-2 / high-risk) (%)34 / 410.040.2 DisclosuresRoskos:Novartis: Honoraria. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Ruxolitinib versus Standard Therapy for the Treatment of Polycythemia Vera

BackgroundRuxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea.MethodsWe randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging.ResultsThe primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy; 38% and 1% of patients in the two groups, respectively, had at least a 35% reduction in spleen volume. A complete hematologic remission was achieved in 24% of patients in the ruxolitinib group and 9% of those in the standard-therapy group (P=0.003); 49% versus 5% had at least a 50% reduction in the total symptom score at week 32. In the ruxolitinib group, grade 3 or 4 anemia occurred in 2% of patients, and grade 3 or 4 thrombocytopenia occurred in 5%; the corresponding percentages in the standard-therapy group were 0% and 4%. Herpes zoster infection was reported in 6% of patients in the ruxolitinib group and 0% of those in the standard-therapy group (grade 1 or 2 in all cases). Thromboembolic events occurred in one patient receiving ruxolitinib and in six patients receiving standard therapy.ConclusionsIn patients who had an inadequate response to or had unacceptable side effects from hydroxyurea, ruxolitinib was superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with polycythemia vera. (Funded by Incyte and others; RESPONSE ClinicalTrials.gov number, NCT01243944.)

Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I.

In the phase III COMFORT-I study, the Janus kinase 1 (JAK1)/JAK2 inhibitor ruxolitinib provided significant improvements in splenomegaly, key symptoms, and quality-of-life measures and was associated with an overall survival benefit relative to placebo in patients with intermediate-2 or high-risk myelofibrosis. This planned analysis assessed the long-term efficacy and safety of ruxolitinib at a median follow-up of 149 weeks. At data cutoff, approximately 50% of patients originally randomized to ruxolitinib remained on treatment whereas all patients originally assigned to placebo had discontinued or crossed over to ruxolitinib. At week 144, mean spleen volume reduction was 34% with ruxolitinib. Previously observed improvements in quality-of-life measures were sustained with longer-term ruxolitinib therapy. Overall survival continued to favor ruxolitinib despite the majority of placebo patients crossing over to ruxolitinib [hazard ratio 0.69 (95% confidence interval: 0.46-1.03); P = 0.067]. Exploratory analyses suggest that crossover may have contributed to an underestimation of the true survival difference between the treatment groups. Ruxolitinib continued to be generally well tolerated; there was no pattern of worsening grade ≥ 3 anemia or thrombocytopenia with longer-term ruxolitinib exposure. These longer-term data continue to support the efficacy and safety of ruxolitinib in patients with myelofibrosis. The study is registered at clinicaltrials.gov: NCT00952289.

The Efficacy and Safety of Continued Hydroxyurea Therapy Versus Switching to Ruxolitinib in Patients with Polycythemia Vera: A Randomized, Double-Blind, Double-Dummy, Symptom Study (RELIEF)

The Efficacy and Safety of Continued Hydroxyurea Therapy Versus Switching to Ruxolitinib in Patients with Polycythemia Vera: A Randomized, Double-Blind, Double-Dummy, Symptom Study (RELIEF)

Ruxolitinib Overcomes the Adverse Prognostic Effect of Anemia in Patients with Myelofibrosis (MF)

▪BACKGROUND: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor that has demonstrated rapid and durable reductions in splenomegaly, improvements in MF-related symptoms and quality-of-life measures, and prolonged survival in 2 phase 3 studies (COMFORT-I and -II). RUX is generally well tolerated, with low rates of nonhematologic adverse events (AEs). As expected based on the mechanism of action of JAK1/JAK2 inhibition, anemia and thrombocytopenia are frequent, but manageable, AEs with RUX. Anemia is a known adverse prognostic factor in MF patients (pts) not receiving JAK inhibitor therapy; however, the prognostic impact of anemia in pts receiving RUX has not been determined. Here, we characterize the dynamics of hemoglobin (Hb) changes with RUX treatment and assess prognostic effects.METHODS: Data from the COMFORT studies, in which pts with MF were treated with RUX 15 or 20 mg bid based on their baseline platelet counts (PLTs), were used to define Hb changes during the course of treatment. Baseline characteristics were evaluated against observed patterns of Hb changes. A multivariate Cox proportional hazards regression model was used to assess the impact of baseline Hb on overall survival (OS) and to evaluate the effect of Hb decreases at wk 12 on observed OS to assess whether on-treatment Hb changes with RUX retain the same prognostic effects as pre-treatment Hb levels in pts with MF in the landmark analysis at wk 12. The models were fit by treatment arm and were adjusted for baseline white cell count, PLT count, age, MF subtype, sex, and spleen length.RESULTS: 301 pts were randomized to RUX and 227 pts to the control group (placebo, n = 154; best available therapy [BAT], n = 73). Median (range) Hb at baseline was 105 g/L (66-170 g/L) and 106 g/L (65-162 g/L) in the RUX groups of COMFORT-I and -II, 105 g/L (35-173 g/L) in the placebo group, and 103 g/L (54-154 g/L) in the BAT group.At wk 12, 82% of pts (247/301) had an Hb decrease of ≥ 3 g/dL from baseline with RUX. This ≥ 3-g/dL decrease was seen in pts with baseline Hb levels of ≥ 10 and < 10 g/dL (72% and 88%, respectively). Baseline spleen volume was also similar for pts with Hb decreases of ≥ 3 and < 3 g/dL, respectively. In pts who did not receive transfusions up to wk 12, mean spleen volume reductions from baseline at wk 24 were −30%, −32%, and −26% for pts with no decrease (n = 14), ≥ 3-g/dL decrease (n = 119), and < 3-g/dL decrease (n = 7) in Hb, respectively. Higher dose intensity during the first 12 wk of RUX treatment not only correlated with more pronounced spleen responses but was also associated with larger decreases in Hb. As reported elsewhere, following the nadir at wk 12, mean Hb levels in the overall population increased to levels similar to those in the control arm (Figure 1). Hb improvement beyond wk 12 was observed despite maintaining pre-nadir dose intensities. Analyses regarding the correlation of reticulocyte count with on-treatment Hb changes will be presented.At the 3-year update, in multivariate models for nontransfused pts, baseline Hb level (per 1 g/dL) was prognostic for OS in the control arm (hazard ratio [HR] = 0.66; 95% CI, 0.54-0.81) but not in the RUX arm (HR = 0.94; 95% CI, 0.74-1.20). Additionally, Hb decreases of ≤ 3 g/dL vs > 3 g/dL at wk 12 were not associated with OS in either arm (control, HR = 0.72; 95% CI, 0.34-1.49; RUX, HR = 0.85; 95% CI, 0.27-2.69). These findings were reproducible in the overall population independent of transfusion requirements (Figure 2).CONCLUSIONS:Similar to previous observations in pts with MF, baseline Hb levels in the control arm of the COMFORT studies were prognostic for OS. However, the introduction of RUX appears to dilute the negative prognostic effect of lower Hb on OS, while Hb decreases that occur on treatment do not adversely affect the treatment-related survival benefit. Hb decreases, likely with RUX treatment during the first 12 wks, are dose-dependent but independent of baseline spleen volume and baseline Hb. However, observations here suggest that Hb changes on RUX treatment do not bear the same prognostic implications as Hb changes that occur as a consequence of MF pathology. Together, these data suggest that transient Hb changes during treatment initiation should not lead to premature interruption or discontinuation, although appropriate supportive care and dose titration should be adapted based on a patient’s immediate needs. [Display omitted] [Display omitted] DisclosuresAl-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Stalbovskaya:Novartis: Employment, Equity Ownership. Gopalakrishna:Novartis: Employment. Perez Ronco:Novartis: Employment. Foltz:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Janssen: Consultancy.

Descriptive, Comparative Study of Filipino Myelofibrosis Patients: An Agematched Comparison of Patients on Ruxolitinib vs. Best Available Therapy

Introduction: Myelofibrosis is characterized by bone marrow fibrosis, cytopenias and extramedullary hematopoiesis. Ruxolitinib is a Janus Kinase-2 inhibitor recently approved for myelofibrosis. In the Philippines, it was made available through the compassionate use program. Methods: This is a multicentre, retrospective case series of eleven patients in the compassionate use program and eleven age-matched historical controls on best available therapy. Results: The median age was 54.5+7.33, 82% females. Using the International Working Group on Myelofibrosis Research and Treatment (IWG-MRT) consensus criteria of 2013, 1 out of the 11 patients had both spleen response and anemia response, achieving transfusion independence for > 12 weeks. Nine patients experienced clinical improvement specifically spleen response. Decrease in spleen size was seen in the first 3 months of ruxolitinib use with a mean of 53.5% from baseline. Hematologic toxicities were anemia and thrombocytopenia while nonhematologic were gastrointestinal disorders 5(45%) and hepatic dysfunction 4(36%). These patients were matched by age with historical controls on best available therapy. There was a remarkable decrease in spleen size with ruxolitinib (53.5%) compared to BAT group (18% from baseline). Thrombocytopenia and anemia occurred more frequently in the ruxolitinib group. Conclusion: Ruxolitinib is a viable treatment option for Intermediate-2 to high risk myelofibrosis with massive splenomegaly. Anemia and thrombocytopenia were common hematologic toxicities during therapy.

Identification Of AML Subtype-Selective Drugs By Functional Ex Vivo Drug Sensitivity and Resistance Testing and Genomic Profiling

Introduction Adult acute myeloid leukemia (AML) exemplifies the challenges of modern cancer drug discovery and development in that molecularly targeted therapies are yet to be translated into clinical use. No effective second-line therapy exists once standard chemotherapy fails. While many genetic events have been linked with the onset and progression of AML, the fundamental disease mechanisms remain poorly understood. There is significant genomic and molecular heterogeneity among patients. Several targeted therapies have been investigated for improved second-line AML therapy but none has been approved for clinical use to date. It would be critically important to identify patient subgroups that would benefit from such therapies and to identify combinations of drugs that are likely to be effective. Methods To identify and optimize novel therapies for AML, we studied 28 samples from 18 AML patients with an individualized systems medicine (ISM) approach. The ISM platform includes functional profiling of AML patient cells ex vivo with drug sensitivity and resistance testing (DSRT), comprehensive molecular profiling as well as clinical background information. Data integration was done to identify disease- and patient-specific molecular vulnerabilities for translation in the clinic. The DSRT platform comprises 306 anti-cancer agents, each tested in a dose response series. We calculated differential drug sensitivity scores by comparing AML responses to those of control cells in order to distinguish cancer-specific drug effects. Next generation RNA- and exome-sequencing was used to identify fusion transcripts and mutations that link to drug sensitivities. Results Individual AML patient samples had a distinct drug sensitivity pattern, but unsupervised hierarchical clustering of the drug sensitivity profiles of the 28 AML patient samples identified 5 functional AML drug response subtypes. Each subtype was characterized by distinct combinations of sensitivities: Bcl-2 inhibitors (e.g. navitoclax; Group 1), JAK inhibitors (e.g. ruxolitinib) (Group 2) and MEK inhibitors (e.g. trametinib) (Groups 2 and 4), PI3K/mTOR inhibitors (e.g. temsirolimus; Groups 4 and 5), broad spectrum receptor tyrosine kinase inhibitors (e.g. dasatinib) (Groups 3, 4 and 5) and FLT3 inhibitors (e.g. quizartinib, sunitinib) (Group 5). Correlation of overall drug responses with genomic profiles revealed that RAS and FLT3 mutations were significantly linked with the drug response subgroups 4 and 5, respectively. Activating FLT3 mutations contributed to sensitivity to FLT3 inhibitors, as expected, but also to tyrosine kinase inhibitors not targeting FLT3, such as dasatinib. Hence, these data point to the potential synergistic combinatorial effects of FLT3 inhibitors with dasatinib for improved therapy outcome (Figure). Early clinical translational results based on compassionate use support this hypothesis. Therefore, by combinations of drugs we expect to see synergistic drug responses that can be translated into efficacious and safe therapies for relapsed AML cases in the clinic. Clinical application of DSRT results in the treatment of eight recurrent chemorefractory patients led to objective responses in three cases according to ELN criteria, whereas four of the remaining five patients had meaningful responses not meeting ELN criteria. After disease progression, AML patient cells showed ex vivo resistance to the drugs administered to the patients, as well as significant changes in clonal architecture during treatment response. Furthermore, we saw genomic alterations potentially explaining drug resistance, such as appearance of novel fusion genes. Summary The ISM approach represents an opportunity for improving therapies for cancer patients, one patient at the time. We show that the platform can be used to identify functional groups of AML linking to vulnerabilities to single targeted drugs and, importantly, unexpected drug combinations. This information can in turn be used for personalized medicine strategies and for creating hypotheses to be explored in systematic clinical trials, both for approved and investigational drugs. Disclosures: Off Label Use: Many of the compounds included in our DSRT platform are not indicated for AML therapy. Mustjoki:BMS: Honoraria, Research Funding; Novartis: Honoraria. Porkka:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Kallioniemi:Medisapiens: Membership on an entity’s Board of Directors or advisory committees; Roche: Research Funding.

Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I

COMFORT-I is a randomized, double-blind, placebo-controlled trial of the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib in 309 patients with intermediate-2 or high-risk myelofibrosis. This analysis of COMFORT-I describes the long-term efficacy and safety of ruxolitinib (median follow-up, 2 years). Spleen volume was measured by magnetic resonance imaging, and quality of life was evaluated using the EORTC QLQ-C30. Overall survival was determined according to randomized treatment group. At the time of this analysis, 100 of 155 patients randomized to ruxolitinib were still receiving treatment. All patients randomized to placebo crossed over to ruxolitinib or discontinued within 3 months of the primary analysis (median time to crossover, 41 weeks). Mean spleen volume reductions in the ruxolitinib group were 31.6% at week 24 and 34.9% at week 96; improvements in quality of life measures were also maintained. Improved survival was observed for ruxolitinib (n=27 deaths) versus placebo (n=41 deaths) (hazard ratio=0.58; 95% confidence interval: 0.36, 0.95; P=0.03). The incidence of new-onset grade 3 or 4 anemia and thrombocytopenia decreased over time to levels observed in patients receiving placebo. These data indicate that ruxolitinib treatment provides durable reductions in spleen volume and improvements in quality of life and suggest a continued survival advantage for ruxolitinib over placebo.

Ruxolitinib in clinical practice for therapy of myelofibrosis: Single USA center experience following Food and Drug Administration approval

Myelofi brosis is a myeloproliferative neoplasm (MPN) characterized by increased bone marrow fi brosis, abnormal blood counts with peripheral cytopenias, extramedullary hematopoiesis, splenomegaly and profound constitutional symptoms [1,2]. Presenting as a primary disease or arising from polycythemia vera or essential thrombocythemia, myelofi brosis incurs a signifi cant symptom burden for patients, and results in a reduced survival of 2 – 11 years [3 – 7]. Amongst MPNs, myelofi brosis has represented a unique challenge to eff orts aimed at palliating symptoms or impacting disease course. Th e 2005 discovery of the gain-of-function JAK2V617F mutation present in a signifi cant proportion of patients with polycythemia vera, essential thrombocythemia and myelofi brosis opened a new avenue of investigation into potential novel therapies [8,9]. Among the various JAK2 inhibitor agents that have been developed, ruxolitinib was the fi rst to receive Food and Drug Administration (FDA) approval in the USA for the treatment of intermediate- and high-risk myelofi brosis. Th e Controlled Myelofi brosis Study with Oral JAK Inhibitor Treatment Trials compared ruxolitinib therapy in patients with intermediate-2 or high-risk myelofi brosis with placebo (COMFORT-I) and with best available therapy (COMFORT-II) [10,11]. In both trials, patients in the ruxolitinib group experienced signifi cant clinical benefi ts, including reduction in spleen size and amelioration of debilitating symptoms coupled with a tolerable side-eff ect profi le. In this study, we report the initial clinical experience with ruxolitinib outside of the clinical trial setting at our high-volume MPN program. Approval for the analysis was obtained from the Mayo Clinic Institutional Review Board. Patients with myelofi brosis including primary myelofi brosis (PMF), post-polycythemia vera (post-PV MF) and post-essential thrombocythemia (post-ET MF) were included. All patients had a Dynamic International Prognostic Scoring System (DIPSS) score of intermediate-1/2 risk or high risk at the start of therapy [12]. Clinical and hematopathological data, including bone marrow biopsy, were reviewed in all cases, and the diagnosis was made in accordance with the 2008 World Health Organization criteria. Baseline patient information, physical examination results, laboratory data, hematopathology reports and interim follow-up information were acquired via chart review, with baseline obtained within 1 month of initiating therapy. All patients were prescribed ruxolitinib within 6 months of FDA approval. Ruxolitinib was started at 20 mg twice daily for patients with platelet counts of 200 10 9 /L or hemoglobin concentrations 10 g/dL. Patients with values below these were started on lower doses at the discretion of the providing physician. Doses were adjusted for lack of effi cacy or excess toxicity. Complete blood counts were checked on a weekly basis for the fi rst 2 months, then monthly thereafter. Drug effi cacy and toxicity were determined at follow-up visits and through telephone conversations with patients. Symptoms were assessed through a verbal response during review of systems questioning. Spleen size was determined by physical examination. Descriptive statistics were determined using means, medians, ranges and standard deviations for continuous variables. Categorical variables were evaluated using frequencies and relative frequencies.

Ruxolitinib changes the natural course of myelofibrosis and its transplant outcome

THE AUTHORS' REPLY: In his letter referring to Will JAK1/2 inhibitors change the standard of care for myelofibrosis (MF)?, Dr. Raut raised two important issues about ruxolitinib: (1) its mechanism of action and (2) its beneficial effect on the outcome of hematopoietic stem cell transplantation (HSCT) in MF patients. The first issue was about how ruxolitinib improved survival without causing any significant effect on disease biology parameters such as the peripheral blast count, marrow fibrosis, cytogenetic response, and JAK2 V617F allele burden. At the last annual meeting of the American Society of Hematology, long-term outcome data of COMFORT-I and COMFORT-II trials that either showed significantly improved survival of ruxolitinib group compared to placebo (hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.36-0.95) or best supportive care (HR 0.52, 95% CI, 0.27-1.00) were presented. Since peripheral blast counts, marrow fibrosis, and cytogenetics were not investigated in those trials, it is difficult to explain the survival advantage on those parameters. However, with the use of ruxolitinib, the two studies showed significant sustained reduction of the JAK2 V617F allele burden. In COMFORT-I trials, ruxolitinib resulted in reduction of JAK2 mutant allele burden by a mean of 10.9% at week 24 (P<0.0001) and -21.5% at week 48 (P<0.0002) that were independent of baseline JAK2 V617F levels [1]. COMFORT-II trials also showed significant reduction in allele burden (median reduction rate of -7.0% at 48 weeks and -8.7% at 72 weeks), which was associated with spleen response [2]. Verstovsek et al. reported that 50% reduction in palpable spleen length was associated with prolonged survival in ruxolitinib treated patients [3]. These observations suggest that ruxolitinib could alter MF prognosis through reduction of JAK2 V617F allele burden and spleen volume. However, we should note that survival improvement was not great and longer follow-ups are required. The relationship between JAK2 V617F allele burden and the survival is also unclear. The second issue was regarding pre-transplant ruxolitinib and the improvement of HSCT outcome by decreasing proinflammatory cytokines. Several convergent lines of evidence suggested that inflammatory cytokines act as mediators of acute GVHD and cause debilitating symptoms in MF. Ruxolitinib significantly decreased tumor necrosis factor-alpha and interleukin-6 levels for a prolonged time in patients with MF through anti-JAK1-mediated downregulation [1]. In a mouse allogeneic transplant model, ruxolitinib decreased alloreactive CD4+ T cells, expression of CXCR3 in activated T cells and GVHD, leading to improved survival [4]. Poor performance status is associated with poor outcome with HSCT in MF, whereas the reduction in symptomatic burden with JAK1/2 inhibitors may have the potential of improving transplant outcome. Massive splenomegaly is reported to be associated with delayed neutrophil and platelet recovery, suggesting that reduction of spleen volume may induce faster marrow recovery after HSCT [5]. Although these are indirect evidences, they support the suggestion that JAK1/2 inhibitors prior to HSCT may have a beneficial effect on the transplant outcome. Whether pre-transplant JAK1/2 inhibitors decrease GVHD and improve survival in HSCT should be addressed through a prospective trial.

Long-Term Safety, Efficacy, and Survival Findings From Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF)

Long-Term Safety, Efficacy, and Survival Findings From Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF)

Reductions in JAK2 V617F Allele Burden with Ruxolitinib Treatment in Comfort-II, a Phase 3 Study Comparing the Safety and Efficacy of Ruxolitinib with Best Available Therapy (BAT)

Abstract 802 Background: Ruxolitinib is a potent oral JAK1 & JAK2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of MF. In the two phase 3 studies, ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms and quality of life compared with placebo (COMFORT-I) and best available therapy (BAT; COMFORT-II) for pts with or without the JAK2 V617F mutation. Change in JAK2 V617F allele burden (%V617F) as a metric of molecular response to treatment in JAK2 V617 F–positive pts was investigated as an exploratory endpoint. Previously, we reported allele burden reductions in pts receiving ruxolitinib in the COMFORT-II study and demonstrated a positive correlation with reduction in spleen volume after 24 and 48 wk of treatment (Vannucchi, et al. Haematologica.2012); here, we evaluate the correlation between changes in %V617F and spleen size reduction after 72 wk of ruxolitinib therapy. Methods: COMFORT-II is a randomized (2:1), open-label, phase 3 study evaluating the safety and efficacy of ruxolitinib (n = 146) compared with BAT (n = 73) in pts with primary MF (PMF), post–polycythemia vera MF (PPV-MF), and post–essential thrombocythemia MF (PET-MF). Allele burden was measured from blood samples using allele-specific quantitative real-time polymerase chain reaction (qPCR) using the method outlined in Levine et al, 2006, using an Applied Biosystems ABI 7900 real-time PCR analyzer. Pts were stratified by absolute reduction in %V617F ( Results: Overall, 110 (76%) pts in the ruxolitinib group and 49 (71%) pts in the BAT group were JAK2V617 F–positive at baseline. More pts in the ruxolitinib arm had ≥ 10% V617F reductions compared with BAT at wk 48 (Table; 41% \(2868\) vs 5% \(122\) ) and at wk 72 (40% \(2153\) vs 0). The majority of reductions ≥ 20% were gradual and progressive over the course of the study (Figure); 2 pts had rapid initial reductions in allele burden that were sustained over 72 wk, from absolute %V617F of 48% and 45% at baseline to 20% reduction at wk 48 but the data were not available at the time of the 48-wk analysis, 2 pts did not have data at wk 48, and 1 pt achieved a 15% reduction at wk 48 that improved to a 21% reduction by wk 72. Among pts who achieved a ≥ 20% reduction in allele burden, 39% had PMF, 39% had PPV-MF, and 22% had PET-MF; this distribution was similar to that of the overall study population. In the ruxolitinib arm, significantly more pts with a ≥ 20% V617F reduction achieved a 9 35% reduction from baseline in spleen volume compared with pts with a Conclusions: Patients who received ruxolitinib had larger reductions in JAK2 V617F allele burden compared with BAT. %V617F reductions were gradual over the course of the study and continued between wk 48 and 72 in some pts. In JAK2 V617 F–positive pts, reductions in %V617F were associated with spleen responses; in pts with a ≥ 20% reduction, spleen volume reductions were sustained out to 72 wk. These results, along with findings from COMFORT-I and the phase 1/2 study, suggest that ruxolitinib has the potential to alter the course of disease through a reduction in the burden of JAK2V671 F–mutated cells. Disclosures: Vannucchi:Novartis: Membership on an entity9s Board of Directors or advisory committees. Passamonti:Sanofi: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Al-Ali:Sanofi Aventi: Consultancy, Honoraria; celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau. Sirulnik:Novartis: Employment. Stalbovskaya:Novartis: Employment, Equity Ownership. Squires:Novartis : Employment. Burn:Incyte: Employment, Equity Ownership. Knoops:Novartis: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Cervantes:Bristol-Myers Squibb: Speakers Bureau; Teva Pharmaceuticals: Advisory Board, Advisory Board Other; Pfizer: Advisory Board, Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Sanofi-Aventis: Advisory Board, Advisory Board Other; Novartis: AdvisoryBoard Other, Speakers Bureau. Barbui:Novartis: Honoraria. Gisslinger:Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; AOP Orphan Pharma AG: Consultancy, Speakers Bureau. Kiladjian:Incyte: Membership on an entity9s Board of Directors or advisory committees; Shire: Membership on an entity9s Board of Directors or advisory committees; Novartis: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Research Funding.

Improvement in Weight and Total Cholesterol and Their Association with Survival in Ruxolitinib-Treated Patients with Myelofibrosis From COMFORT-I

Abstract 1733 Background:Patients with myelofibrosis (MF) suffer from cytopenias, debilitating symptoms, and splenomegaly, all of which may contribute to shortened life expectancy. Cachexia is a common manifestation of MF. Its causes are multifactorial and include elevated inflammatory cytokines and mechanical effects of splenomegaly. It is a predictor of poor survival in patients with MF. Cachexia manifests as weight loss with low body-mass index (BMI; <20–21 kg/m2) (Strasser F. Sixth Research Congress of the European Association of Palliative Care; Wagner PD. Eur Respir J. 2008;31:492–501) and with metabolic indicators of poor nutritional status including hypocholesterolemia (total cholesterol <150 mg/dL or <3.89 mmol/L), which has been linked to poor prognosis in MF (Mesa et al. Blood 2007;110:abstract 2548).In the phase III, placebo-controlled, COMFORT-I study, ruxolitinib treatment significantly reduced spleen volume, improved MF-related symptoms, and exhibited a survival advantage compared with placebo in patients with MF. In this post hoc analysis, we investigated the effects of ruxolitinib treatment on weight and total cholesterol and the association of these changes with survival in COMFORT-I. Methods:Eligible patients in COMFORT-I were randomized to receive placebo (n=154) or ruxolitinib (n=155) at starting doses of 15 and 20 mg PO BID depending on baseline platelet count. Body weight was measured at baseline, and weeks 4, 8, 12, 16, and 24 and then every 12 weeks thereafter. Total serum cholesterol was measured at baseline and weeks 4, 12, 24, and then every 24 weeks thereafter. All patients receiving PBO completed crossover or discontinued within 3 months of the primary data analysis (when all patients completed 24 weeks and when half the patients remaining on study completed 36 weeks of treatment); thus, data for these patients were available for up to week 36 for weight and week 24 for total cholesterol. Kaplan-Meier analyses of overall survival were conducted in patients randomized to ruxolitinib stratified into 2 groups based on the median values separately for maximum weight gain and for maximum increase in total cholesterol during randomized treatment. Results:At baseline, mean body weight was similar between the treatment groups (72 kg, both) and mean total cholesterol was low (<150 mg/dL) in both treatment groups (ruxolitinib: 118 mg/dL; placebo: 115 mg/dL). The proportion of patients with BMI <22 were similar between the treatment groups (ruxolitinib: 23%; placebo: 28%) as was the proportion with total cholesterol <150 mg/dL (82%, both). Patients randomized to ruxolitinib experienced a gradual increase in body weight that stabilized by week 36 of treatment whereas patients receiving placebo experienced decreases in body weight over time (Figure 1). Similarly, total cholesterol increased in patients randomized to ruxolitinib and decreased in patients receiving placebo (Figure 2). Although total cholesterol increased over time in ruxolitinib-treated patients, increases did not exceed the upper limit of normal (199 mg/dL or 5.15 mmol/L). Nearly all patients randomized to ruxolitinib experienced weight gain (96% of patients) or an increase in total cholesterol (97% of patients). In patients randomized to ruxolitinib, weight gain above the median was associated with prolonged survival relative to lesser degrees of weight gain (HR=0.40; 95% CI: 0.18, 0.90; P=0.022; Figure 3). Similarly, increase in total cholesterol above the median was also associated with prolonged survival relative to a lesser degree of total cholesterol increase (HR=0.46; 95% CI: 0.21, 1.01; P=0.048; Figure 4). Meaningful comparisons with the placebo group based on the same stratification criteria could not be conducted as the majority of such patients experienced weight loss and decreases in total cholesterol while on the study; however, overall survival favored both ruxolitinib groups relative to all patients randomized to placebo even for ruxolitinib-treated patients with lower than median levels of weight gain or increase in total cholesterol. Conclusions:Ruxolitinib therapy promotes weight gain and improves total cholesterol in MF patients. These results suggest that the survival advantage exhibited by ruxolitinib over placebo in MF patients may be partly explained by reversal of the catabolic state and cachexia. [Display omitted] [Display omitted] [Display omitted] Disclosures:Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding. Verstovsek:Incyte Corporation: Research Funding. Gupta:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; YM Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi#x2610;#x0025; Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mascarenhas:Incyte Corporation: Consultancy; Novartis: Clinical Trial Support, Clinical Trial Support Other. Atallah:Incyte: Consultancy, Research Funding. Sun:Incyte Corporation: Employment, Equity Ownership. Sandor:Incyte Corporation: Employment, Equity Ownership. Gotlib:Incyte Corporation: Consultancy, Honoraria, Support for travel to meeting for the study or other purposes from Incyte Other.

A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis

BackgroundRuxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis.MethodsIn this double-blind trial, we randomly assigned patients with intermediate-2 or high-risk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival.ResultsThe primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.25 to 0.98; P=0.04). The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (in one patient for each event). Two patients had transformation to acute myeloid leukemia; both were in the ruxolitinib group.ConclusionsRuxolitinib, as compared with placebo, provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival. These benefits came at the cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. (Funded by Incyte; COMFORT-I ClinicalTrials.gov number, NCT00952289.)

JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis

BackgroundTreatment options for myelofibrosis are limited. We evaluated the efficacy and safety of ruxolitinib, a potent and selective Janus kinase (JAK) 1 and 2 inhibitor, as compared with the best available therapy, in patients with myelofibrosis.MethodsWe assigned 219 patients with intermediate-2 or high-risk primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis to receive oral ruxolitinib or the best available therapy. The primary end point and key secondary end point of the study were the percentage of patients with at least a 35% reduction in spleen volume at week 48 and at week 24, respectively, as assessed with the use of magnetic resonance imaging or computed tomography.ResultsA total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48, as compared with 0% in the group receiving the best available therapy (P<0.001); the corresponding percentages at week 24 were 32% and 0% (P<0.001). At 48 weeks, the mean palpable spleen length had decreased by 56% with ruxolitinib but had increased by 4% with the best available therapy. The median duration of response with ruxolitinib was not reached, with 80% of patients still having a response at a median follow-up of 12 months. Patients in the ruxolitinib group had an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis. The most common hematologic abnormalities of grade 3 or higher in either group were thrombocytopenia and anemia, which were managed with a dose reduction, interruption of treatment, or transfusion. One patient in each group discontinued treatment owing to thrombocytopenia, and none discontinued owing to anemia. Nonhematologic adverse events were rare and mostly grade 1 or 2. Two cases of acute myeloid leukemia were reported with the best available therapy.ConclusionsContinuous ruxolitinib therapy, as compared with the best available therapy, was associated with marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects. An influence on overall survival has not yet been shown. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT00934544.)

Comparison of Outcomes of Advanced Myelofibrosis Patients Treated with Ruxolitinib (INCB018424) to Those of a Historical Control Group: Survival Advantage of Ruxolitinib Therapy

Abstract 793▪FN2▪This icon denotes a clinically relevant abstract Background:Myelofibrosis (MF) is a myeloproliferative neoplasm associated with splenomegaly, debilitating symptoms, cytopenias and progressive bone marrow fibrosis that leads to early death. Patients (pts) with high-risk MF according to International Prognosis Scoring System (IPSS) have particularly poor outcome with a median survival of 2 years (yrs). No approved or effective therapy exists. Ruxolitinib is a JAK1 and JAK2 inhibitor with established clinical benefit in the treatment of pts with MF by reducing spleen size and improving quality of life. Objective:The objective of this analysis was to compare assorted outcomes of MF pts receiving ruxolitinib to those of a matched historical control group. Methods:Overall survival (OS) of 107 pts enrolled in a Phase I/II trial (INCB18424-251; NCT00509899) and followed at the MD Anderson Cancer Center (MDACC) was compared to that of 310 pts with MF identified in 3 large databases (MDACC, U. of Pavia and Hospital Niguarda cà Granda, Milano) with characteristics that would have allowed them to enroll in INCB18424-251. Thus, the pt features between the 2 groups were matched based on enrollment criteria. Among 107 ruxolitinib treated pts, 63 had high risk, 34 intermediate (int)-2 and 10 int-1 risk according to IPSS. In the control group (n=310), 165 pts had high and 145 pts int-2 risk; most pts were treated with conventional or investigational therapies during follow-up. Results:Ruxolitinib-treated pts had a median age of 66 yrs, hemoglobin (Hb) of 10.2 g/dL, WBC of 19×10^9/L, platelets of 277×10^9/L, and palpable spleen of 19 cm. Control pts had a median age of 70 yrs, Hb of 9.7 g/dL, WBC of 12×10^9/L, platelets of 265×10^9/L, and palpable spleen of 6 cm. Baseline characteristics that differed between 2 groups included: significantly more int-2 vs high-risk pts (according to both IPSS and dynamic IPSS [DIPSS]), older age and lower Hb in the controls, as contrasted to higher WBC and larger spleen in those on ruxolitinib. There were no differences between the groups with regard to male:female ratio, platelet count, and cytogenetic characteristics. With regard to OS comparison between the 2 groups, a significant difference was seen in favor of ruxolitinib (p=0.022). Indeed, 33 of 107 pts (30.8%) in the ruxolitinib group vs. 189 of 310 (60.9%) in the control group died, after a median follow-up of 32 and 22 months, respectively. The difference in OS was highly significant in the high-risk pt subgroup (p=0.006), in that 21/63 (33.3%) vs. 112/165 (67.9%) died in the ruxolitinib and control groups, respectively. In the univariate analysis, significant factors associated with longer OS were int-2 (vs. high) risk (per IPSS/ DIPSS), platelets >400×10^9/L, and age <65 years, but not gender, abnormal cytogenetics, high WBC (>25×10^9/L), anemia (Hb <10g/dL), or spleen size. In the multivariate analysis, using age and blood cell counts as continuous variables, independent significant factors for better survival were IPSS int-2 risk, younger age, higher platelets, and treatment with ruxolitinib (p=0.02; HR=0.63). Conclusions:We have identified a historical control group of pts with clinical characteristics that would have allowed them to participate in the Phase I/II study of ruxolitinib in MF. We compared their survival to 107 pts who participated in that trial, and were followed at the MDACC. The survival of pts with high-risk MF that were treated with ruxolitinib was found to be significantly longer than that of the matched control group. Further, ruxolitinib therapy was identified as an independent factor influencing better survival in the multivariate analysis. Our data suggest the potential of ruxolitinib to change the natural progression of MF pts with advanced disease. [Display omitted] Disclosures:Verstovsek:Incyte Corporation: Research Funding.