Reduction In Palpable Spleen Length Research Articles

Efficacy and safety of a novel dosing strategy for ruxolitinib in the treatment of patients with myelofibrosis and anemia: the REALISE phase 2 study

Anemia is a frequent manifestation of myelofibrosis (MF) and there is an unmet need for effective treatments in anemic MF patients. The REALISE phase 2 study (NCT02966353) evaluated the efficacy and safety of a novel ruxolitinib dosing strategy with a reduced starting dose with delayed up-titration in anemic MF patients. Fifty-one patients with primary MF (66.7%), post-essential thrombocythemia MF (21.6%), or post-polycythemia vera MF (11.8%) with palpable splenomegaly and hemoglobin <10 g/dl were included. Median age was 67 (45–88) years, 41.2% were female, and 18% were transfusion-dependent. Patients received 10 mg ruxolitinib b.i.d. for the first 12 weeks, then up-titrations of up to 25 mg b.i.d. were permitted, based on efficacy and platelet counts. Overall, 70% of patients achieved a ≥50% reduction in palpable spleen length at any time during the study. The most frequent adverse events leading to dose interruption/adjustment were thrombocytopenia (17.6%) and anemia (11.8%). Patients who had a dose increase had greater spleen size and higher white blood cell counts at baseline. Median hemoglobin levels remained stable and transfusion requirements did not increase compared with baseline. These results reinforce the notion that it is unnecessary to delay or withhold ruxolitinib because of co-existent or treatment-emergent anemia.

A Phase II Trial of Azacitidine (AZA) in Combination with Ruxolitinib (RUX) in Myelodysplastic Syndrome/Myeloproliferative Neoplasms (MDS/MPNs)

A Phase II Trial of Azacitidine (AZA) in Combination with Ruxolitinib (RUX) in Myelodysplastic Syndrome/Myeloproliferative Neoplasms (MDS/MPNs)

Real-World Management of Myelofibrosis with Ruxolitinib: Initial Analysis of an Italian Observational Study (ROMEI)

Real-World Management of Myelofibrosis with Ruxolitinib: Initial Analysis of an Italian Observational Study (ROMEI)

A phase 1 study of the Janus kinase 2 (JAK2)V617F inhibitor, gandotinib (LY2784544), in patients with primary myelofibrosis, polycythemia vera, and essential thrombocythemia

Mutations in Janus kinase 2 (JAK2) are implicated in the pathogenesis of Philadelphia-chromosome negative myeloproliferative neoplasms, including primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Gandotinib (LY2784544), a potent inhibitor of JAK2 activity, shows increased potency for the JAK2V617F mutation. The study had a standard 3+3 dose-escalation design to define the maximum-tolerated dose. Primary objectives were to determine safety, tolerability, and recommended oral daily dose of gandotinib for patients with JAK2V617F-positive myelofibrosis, essential thrombocythemia, or polycythemia vera. Secondary objectives included estimating pharmacokinetic parameters and documenting evidence of efficacy by measuring clinical improvement. Thirty-eight patients were enrolled and treated (31 myelofibrosis, 6 polycythemia vera, 1 essential thrombocythemia). The maximum-tolerated dose of gandotinib was 120mg daily, based on dose-limiting toxicities of blood creatinine increase or hyperuricemia at higher doses. Maximum plasma concentration was reached 4h after single and multiple doses, and mean half-life on day 1 was approximately 6h. Most common treatment-emergent adverse events were diarrhea (55.3%) and nausea (42.1%), a majority of which were of grade 1 severity. Best response of clinical improvement was achieved by 29% of myelofibrosis patients. A ≥50% palpable spleen length reduction was observed at any time during therapy in 20/32 evaluable patients. Additionally, ≥50% reduction in the Total Symptom Myeloproliferative Neoplasm Symptom Assessment Form Score was seen in 11/21 (52%) and 6/14 patients (43%) receiving ≥120mg at 12 and 24 weeks respectively. Gandotinib demonstrated an acceptable safety and tolerability profile, and findings at the maximum-tolerated dose of 120mg supported further clinical testing. Clinicaltrials.gov identifier: NCT01134120.

Ruxolitinib (RUX) in combination with azacytidine (AZA) in patients (pts) with myelodysplastic/myeloproliferative neoplasms (MDS/MPNs).

7064 Background: Clinical trials exclusively focusing on pts with MDS/MPNs are lacking. Combining RUX and AZA may target distinct manifestations of MDS/MPNs. Methods: Pts were treated with single-agent RUX 15 mg or 25 mg (based on platelets count) orally twice daily continuously in 28-day cycles for the first 3 cycles. AZA 25 mg/m2 (day 1-5) was added on each cycle starting cycle 4 and could be increased to 75 mg/m2 (maximum) or started earlier than cycle 4 and/or at higher dose in pts with proliferative features or high blasts. Results: 35 pts with med age 70 years (range, 43-79) were enrolled (MDS/MPN-U, n = 14; CMML, n = 17; atypical CM (aCML), n = 4), 28 (80%) were Int-2/High per MF DIPSS, 14 (41%) had splenomegaly &gt; 5 cm, and 12 (34%) had EUMNET MF-2/MF-3 fibrosis. Common mutations on a 28-gene sequencing panel included JAK2 (29%), RAS (27%), ASXL1 (21%), TET2 (18%), and DNMT3A (12%). All 35 pts were evaluable for response per MDS/MPN IWG criteria and 17 (49%) responded. 6/17 (35%) IWG responses occurred after the addition of AZA (med time after AZA = 1.8 months). JAK2 mutated pts had a trend to higher responses vs those with non-mutated pts (8/10 vs 9/25, P = 0.19). Ten pts had &gt; 5% pretreatment BM blasts and 7 achieved a reduction in blasts to &lt; 5% (70%). A &gt; 50% reduction in palpable spleen length reduction at 24 weeks was seen in 9/12 (75%) pts. New grade 3/4 anemia and thrombocytopenia occurred in 18 pts (51%) and 19 (54%) pts but were manageable with dose modifications. Only one pt discontinued therapy due to cytopenias. At a med follow-up of 17.4 mo (range, 1.2-36.8+), 14 (40%) pts died: pneumonia (n = 4), sepsis (n = 4), progression to AML (n = 4), and cardiac arrest (n = 1). The med survival for all pts was 16.6 mo (1.0 - 36.8). Compared to CMML and aCML, MDS/MPN-U pts had significantly better med survival (26.4+ vs 15.0+ vs 1.5+ mo, respectively; p = 0.01). Conclusions: The combination of RUX and AZA showed an IWG-response rate of 49% in pts with MDS/MPNs, and was well-tolerated. The benefit appears more profound in pts with MDS/MPN-U. This study is ongoing. (ClinicalTrials.gov Identifier: NCT01787487).

Ruxolitinib (RUX) in Combination with 5-Azacytidine (AZA) As Therapy for Patients (pts) with Myelofibrosis (MF)

Ruxolitinib (RUX) in Combination with 5-Azacytidine (AZA) As Therapy for Patients (pts) with Myelofibrosis (MF)

Assessing the Safety and Efficacy of Ruxolitinib in a Multicenter, Open-Label, Expanded-Access Study in Japanese Patients with Myelofibrosis (MF)

Assessing the Safety and Efficacy of Ruxolitinib in a Multicenter, Open-Label, Expanded-Access Study in Japanese Patients with Myelofibrosis (MF)

Phase 1b/2 Study of the Efficacy and Safety of Sonidegib (LDE225) in Combination with Ruxolitinib (INC424) in Patients with Myelofibrosis

Phase 1b/2 Study of the Efficacy and Safety of Sonidegib (LDE225) in Combination with Ruxolitinib (INC424) in Patients with Myelofibrosis

An Open-Label, Multicenter, 2-Arm, Dose-Finding, Phase 1b Study of the Combination of Ruxolitinib and Buparlisib (BKM120) in Patients with Myelofibrosis: Results from HARMONY Study

An Open-Label, Multicenter, 2-Arm, Dose-Finding, Phase 1b Study of the Combination of Ruxolitinib and Buparlisib (BKM120) in Patients with Myelofibrosis: Results from HARMONY Study

Ruxolitinib (RUX) in combination with 5-Azacytidine (AZA) as therapy for patients with myelofibrosis (MF)

Ruxolitinib (RUX) in combination with 5-Azacytidine (AZA) as therapy for patients with myelofibrosis (MF)

Response to ruxolitinib in patients with intermediate‐1–, intermediate‐2–, and high‐risk myelofibrosis: results of the UK ROBUST Trial

Myelofibrosis is characterized by splenomegaly and debilitating constitutional symptoms that negatively impact patients' quality of life. ROBUST, a UK, open-label, phase II study, evaluated the safety and efficacy of ruxolitinib in patients with myelofibrosis (N = 48), including intermediate-1 risk patients. The primary composite endpoint was the proportion of patients achieving treatment success [≥ 50% reduction in palpable spleen length and/or a ≥ 50% decrease in Myelofibrosis Symptom Assessment Form Total Symptom Score (MF-SAF TSS)] at 48 weeks. This was the first time that efficacy of ruxolitinib in myelofibrosis has been evaluated based on these criteria and the first time the MF-SAF was used in a population of patients solely from the United Kingdom. Overall, 50% of patients and 57% of intermediate-1 risk patients, achieved treatment success; reductions in spleen length and symptoms were observed in all risk groups. The majority of patients (66.7%) experienced ≥ 50% reductions from baseline in spleen length at any time. Improvements in MF-SAF TSS were seen in 80.0%, 72.7%, and 72.2% of intermediate-1, intermediate-2, and high-risk patients, respectively. Consistent with other studies of ruxolitinib, the most common haematological adverse events were anaemia and thrombocytopenia. Results indicate that most patients with myelofibrosis, including intermediate-1 risk patients, may benefit from ruxolitinib treatment.

Practical Measures of Clinical Benefit with Ruxolitinib Therapy: An Exploratory Analysis of COMFORT-I

Background: In 2 phase III studies comparing the Janus kinase (JAK) 1 and JAK2 inhibitor ruxolitinib with placebo (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment I [COMFORT-I]) or best available therapy (COMFORT-II), ruxolitinib treatment was associated with rapid and durable reductions in spleen volume, improved myelofibrosis (MF)-related symptoms and quality of life measures, and prolonged survival. However, the key measures of efficacy used in the COMFORT studies—magnetic resonance imaging/computed tomography (MRI/CT) to measure change in spleen volume and the modified Myelofibrosis Symptom Assessment Form v2.0 to assess change in MF-related symptoms—are not commonly used in clinical practice. Therefore, we analyzed the efficacy of ruxolitinib in COMFORT-I using practical, community-based measures of clinical benefit (spleen palpation and the Patient Global Impression of Change [PGIC] questionnaire).Methods: In COMFORT-I, patients (N = 309) with primary MF, post–polycythemia vera MF or post–essential thrombocythemia MF were randomized to receive ruxolitinib (n = 155) or placebo (n = 154). For this analysis, patients were divided into groups by degree of palpable spleen reduction and symptom improvement at week 12 as follows: patients with clinically relevant reductions in palpable spleen as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus criteria (SPL), patients with “much improved” or “very much improved” symptoms as measured by the PGIC (PGIC), or patients who did not achieve SPL or PGIC (Neither). The Neither group encompassed patients with “minimally improved” symptoms with no worsening in palpable spleen or patients who achieved 10% reduction in palpable spleen with no worsening in symptoms (Minor), and patients who did not achieve any palpable spleen reduction or PGIC-assessed symptom improvement (None). Nonevaluable patients (4/155 for ruxolitinib and 13/154 for placebo) were not included in the analysis. Additional measures of clinical benefit assessed at week 12 included changes in spleen volume and changes in white blood cell (WBC) count. Durability of all measures of clinical benefit with longer-term ruxolitinib therapy was also evaluated.Results: At week 12, the majority (91.4%) of patients randomized to ruxolitinib achieved some clinical benefit as measured by palpable spleen reduction and/or PGIC-assessed symptom improvement, vs 31.9% of those assigned to placebo (Figure 1). Benefits in palpable spleen length reduction and PGIC-assessed symptom improvement achieved at week 12 with ruxolitinib were sustained at week 24. Benefits in palpable spleen length reduction were sustained with longer-term ruxolitinib therapy (median follow-up: 149 weeks). At week 12, ruxolitinib treatment was associated with meaningful reductions in spleen volume by MRI or CT and WBC count in patients who achieved SPL and PGIC criteria, while worsening spleen volume and WBC count was observed with placebo (Figure 2); these effects were durable with longer-term therapy. Patients who achieved neither SPL nor PGIC criteria by week 12 (n = 47; 31.1%) achieved a clinically meaningful reduction in spleen volume by MRI or CT (mean change, −25.6%) and decreased WBC counts (mean change, −7.4%) at week 12 (Figure 2). Patients who did not achieve any palpable spleen reduction or PGIC-assessed symptom improvement (n = 13; 8.6%) were generally older, more likely to have high-risk MF as assessed by the International Prognostic Scoring System, and had higher WBC counts, lower platelet counts, and worse fibrosis grade at baseline compared with those achieving defined palpable spleen length reduction and/or PGIC-assessed symptom improvement with ruxolitinib.Conclusions: Nearly all patients treated with ruxolitinib achieved some clinical benefit as assessed by practical measures of assessing efficacy (ie, palpable spleen reduction or PGIC-assessed symptom improvement) within 12 weeks of treatment initiation. Meaningful reductions in spleen volume and WBC count were observed in patients receiving ruxolitinib whether or not they achieved palpable spleen reduction by IWG-MRT/ELN consensus criteria or PGIC symptom improvement (“much improved” or “very much improved”) at week 12; these reductions were durable with long-term ruxolitinib therapy. [Display omitted] [Display omitted] DisclosuresMiller:Incyte Corporation: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Komrokji:Incyte Corporation: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Mesa:CTI: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; Celgene: Research Funding. Sun:Incyte Corporation: Employment. Montgomery:Incyte Corporation: Employment. Verstovsek:Incyte Corporation: Research Funding.

Phase 1b Dose-Escalation Study of Sonidegib (LDE225) in Combination with Ruxolitinib (INC424) in Patients with Myelofibrosis

Background: Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, has been shown to effectively reduce splenomegaly, manage myelofibrosis (MF)-related symptoms, and improve survival, but has limited anticlonal activity. Inhibition of hedgehog signaling via therapy with sonidegib, a selective inhibitor of smoothened (SMO), in combination with ruxolitinib reduced white blood cell (WBC) and platelet counts, JAK2 mutant allele burden, and bone marrow (BM) fibrosis in preclinical MF models more than ruxolitinib alone (Bhagwat, ASH 2013). The maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of sonidegib in combination with ruxolitinib for patients (pts) with MF is being assessed in the phase 1b portion of this phase 1b/2 study (NCT01787552). The safety-expansion cohort is currently ongoing; updated data will be presented. Methods: Adults with primary or secondary (post–polycythemia vera or –essential thrombocythemia) intermediate- or high-risk MF with palpable splenomegaly not previously treated with JAK or SMO inhibitors were eligible. Pts received oral doses of sonidegib once daily (QD) and ruxolitinib twice daily (BID). The first dose level enrolled was sonidegib 400 mg QD + ruxolitinib 10 mg BID. Dose escalations were guided by a Bayesian logistic regression model. In addition to safety and pharmacokinetics (PK), spleen length was assessed by palpation at screening, wk 1, every 2 wk until wk 13, monthly after wk 13, and at the end of treatment. BM fibrosis was assessed in biopsies collected every 24 wk. Results: As of March 26, 2014, 23 pts (16 male) with a median age of 67 y (range, 42-77 y) were treated at 3 dose levels (1: sonidegib 400 mg QD + ruxolitinib 10 mg BID [n = 8]; 2: sonidegib 400 mg QD + ruxolitinib 15 mg BID [n = 10]; 3: sonidegib 400 mg QD + ruxolitinib 20 mg BID [n = 5]). Median (range) levels for hemoglobin, platelet count, and WBC count at baseline (BL) were 102 g/L (64-142 g/L), 232 × 109/L (81-900 × 109/L) and 21 x 109/L (2-59 x 109/L), respectively. Median (range) palpable spleen size at BL was 13 cm (5-38 cm) below costal margin. According to the International Prognosis Scoring System, 5, 7, and 11 pts were intermediate-1, intermediate-2, and high-risk, respectively. At data cutoff, 4 pts had discontinued treatment due to an adverse event (AE), physician decision, progressive disease, or patient decision (n = 1 each). PK parameters and trough levels for both agents generally aligned with single-agent data. Fatigue was the most commonly reported AE regardless of causality (Table). Six serious AEs were reported, 4 at dose level 1 (face edema, hyponatremia, pyrexia, right ventricular failure; n = 1 each) and 2 at dose level 2 (blood creatine kinase [CK] increased; n = 2). Dose-limiting toxicities of grade 3 and 4 CK elevations were reported in 2 pts at dose level 2. At data cutoff, 65% of pts achieved a ≥ 50% reduction in palpable spleen length from BL and 9 pts had resolution of splenomegaly. Conclusions: The evaluated combination doses of sonidegib and ruxolitinib were generally well tolerated in pts with MF, and preliminary efficacy data appear promising. Sonidegib and ruxolitinib in combination did not appear to affect the PK of either agent. Once the MTD and/or RP2D are determined, the safety and efficacy of this combination will be further evaluated in the phase 2 study. Disclosures Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Koschmieder:Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Travel, Accomodation, Expenses Other; Novartis Foundation: Research Funding. Harrison:SBio: Consultancy; Gilead: Honoraria; CTI: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Shire: Speakers Bureau. Cervantes:Novartis: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Membership on an entity9s Board of Directors or advisory committees; Gilead: Membership on an entity9s Board of Directors or advisory committees. Heidel:Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Drummond:Novartis: Consultancy, Honoraria, Speakers Bureau. Rey:Novartis: Consultancy. Hurh:Novartis NIBR: Employment. Bao:Novartis Pharmaceuticals Corporation: Employment. Rampersad:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Kalambakas:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Vannucchi:Novartis: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Phase I Study Of LY2784544, a JAK2 Selective Inhibitor, In Patients With Myelofibrosis (MF), Polycythemia Vera (PV), and Essential Thrombocythemia (ET)

BackgroundMF, PV, and ET are neoplasms characterized by activation of JAK2 signaling, and the majority of cases are associated with the gain of function JAK2 V617F mutation. Given that wild-type JAK2 plays a pivotal role in multiple stages of hematopoiesis it is desirable to treat JAK2V617F-positive cases by selectively inhibiting JAK2 V617F while minimizing inhibition of wild-type JAK2 in order not to impede normal marrow function. LY2784544 is a selective inhibitor of JAK2 which demonstrates dose dependent selectivity for JAK2 V617F/STAT5 signaling. LY2784544 entered clinical testing in a Phase I trial in MF, PV, and ET patients (I3X-MC-JHTA, NCT01134120). We have previously reported early interim analysis from this study and provide here an update following completion of study enrollment. MethodsThe study's primary objectives were to determine the safety and tolerability of LY2784544 and define a recommended oral daily dose for further study in patients with JAK2 V617F-positive MF, ET, or PV. Secondary objectives included determination of pharmacokinetics and evaluation of response using the IWG-MRT response criteria (2006), European Leukemia Net response criteria for PV and ET (EULN 2009), and symptom burden using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) (Scherber et. al. Blood 2011). Study design included a standard 3+3 dose-escalation to define the maximum tolerated dose (MTD) and was amended to allow cohort expansions at multiple doses demonstrating potential clinical merit. ResultsPatients Prior to closing to enrollment, 47 patients were consented; 9 did not meet eligibility screening. The 38 treated patients included 31 MF (22 pMF, 6 post-PV MF and 3 post-ET MF), 6 PVs, and 1 ET patient(s), and 86% had received prior systemic therapy for their MPN.Dosing and tolerability of LY2784544: Systemic exposures were approximately dose proportional across the tested range from 30 to 300 mg. Daily doses of 200 mg or greater were associated with CTCAE Grade 3 increases in serum creatinine. In general, increases in serum creatinine occurred within the first 2 weeks of either starting treatment or after an increase in study drug dose. With the available data, the elevations in serum creatinine appear to be fully reversible after dose reduction or drug holiday in the majority of patients. The maximum tolerated daily dose of LY2784544 when given on a continuous daily basis was determined to be 120 mg per day.Serious AEs, across all grades and doses, included increased creatinine/acute renal insufficiency (4 grade 3, 5 grade 2, 1 grade 1), hyperuricemia (2 grade 4, 1 grade 1), hyperkalemia (1 grade 1), and anemia (1 grade 3). This study allowed intrapatient dose escalation, and 34 patients received 120 mg during their study participation. There were 4 patients dosed at 120 mg with SAEs but all were unrelated to study drug treatment (anemia, influenza, enterococcal bacteremia, hematuria and pneumonia). At 120 mg, the most frequently reported drug-related AEs across all grades were diarrhea (44%), nausea (29%), increased creatinine (21%), and anemia, vomiting, fatigue (9% each). Of these related AEs at 120 mg, there was 1 Grade 3 anemia, 3 Grade 3 increased creatinine, and 2 Grade 3 fatigue. There were no Grade 4 AEs. EfficacyAmong a cohort of 10 MF patients who only received 120 mg, 3 achieved a clinical improvement. Analyzing across dose levels, a palpable spleen length reduction of ≥50% was seen in 15 of 27 evaluable patients (56%) at any time. The median duration of these responses was 18.3 weeks (range from 0.7 to 148.1 weeks). At 12 weeks, 56% of patients (15/27) reported a ≥50% improvement in Total Symptom Score on the MPN-SAF. Of the 6 PV patients, 3 achieved a clinicohematologic PR. Findings from a central pathology review of serial bone marrow samples will be presented at the meeting. ConclusionsA recommended phase II dose for daily dosing of LY2784544 was identified as 120 mg. This dose has been well tolerated and associated with clinical improvements, supporting ongoing Phase II testing of LY2784544 in MPNs. Disclosures:Verstovsek:Eli Lilly and Co: Research Funding. Mesa:Eli Lilly and Co: Research Funding; Genetech: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Sanofi: Research Funding; NS pharma: Research Funding; Celgene: Research Funding. Salama:Eli Lilly and Co: Research Funding. Giles:Eli Lilly and Co: Employment. Pitou:Eli Lilly and Co: Employment. Hayden Zimmermann:Eli Lilly and Co: Employment. Price:Eli Lilly and Co: Employment. Walgreen:Eli Lilly and Co: Employment. Prchal:Eli Lilly and Co: Research Funding.

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.

An open-label, multicenter, expanded access study assessing the safety and efficacy of oral ruxolitinib administered to patients with primary myelofibrosis (PMF), post-polycythemia myelofibrosis (PPV MF) or post-essential thrombocythemia myelofibrosis (PET-MF).

TPS6640 Background: Myelofibrosis (MF) can be primary in origin or can progress from polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). MF is characterized by cytopenias, reactive bone marrow fibrosis, splenomegaly, and constitutional symptoms including weight loss, fever, and night sweats. MF is associated with dysregulation of the Janus kinase pathway, irrespective of JAK2V617F mutation status. Recently, ruxolitinib (INCB018424) was approved for the treatment of MF on the basis of results from 2 phase 3 trials (COMFORT-I and -II). These trials demonstrated marked reductions in splenomegaly and symptom burden, and improvements in health-related quality of life (QoL) measures. Methods: JAK Inhibitor rUxolitinib in Myelofibrosis Patients (JUMP) is a global, phase 3b expanded access trial (NCT01493414) designed to assess the safety and efficacy of ruxolitinib in adult pts with PMF, PPV-MF or PET-MF who are treatment naïve, and are intolerant of, or had progressed on any prior therapy. Inclusion criteria: peripheral blast count of &lt;10%, adequate liver and renal function and intermediate-2 or high risk MF according to IPSS criteria or intermediate-1 risk MF with palpable spleen length ≥ 5 cm. The primary endpoint is to assess the safety of ruxolitinib. Additional endpoints include the proportion of pts with a &gt; 50% reduction in palpable spleen length, % change in white blood cell and platelet counts from baseline (BL), and change in packed red blood cell transfusion requirements. Changes from BL in QoL scores will be assessed using validated ECOG PS, FACT-Lymphoma, and FACIT instruments. Pts with a BL platelet count &gt; 200,000/μL will receive oral ruxolitinib 20 mg BID; pts with a BL platelet count of 100,000/μL to 200,000/μL will receive 15 mg BID; dose modifications are permitted for safety and efficacy. Global enrollment is open and currently includes 277 pts. This is planned to be the largest study ever conducted in pts with MF. [Table: see text]

The MD Anderson Cancer Center (MDACC) Experience with Ruxolitinib, An Oral JAK1 and JAK2 Inhibitor, in Myelofibrosis: Long-Term Follow-up Outcomes of 107 Patients From a Phase I/II Study,

Abstract 3851▪▪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. Survival in MF is poor, and effective therapy is lacking. Ruxolitinib (INCB18424) is a JAK1 and JAK2 inhibitor with established clinical benefit in patients (pts) with MF (Verstovsek S. J Clin Oncol 29: [suppl; abstr 6500], 2011) by reducing spleen size and improving MF symptoms & quality of life. Objective:Aim was to identify potential correlates of overall survival (OS) of MF pts receiving ruxolitinib. This study was based on a subset analysis of an open-label single-arm phase I/II trial (INCB18424–251; NCT00509899). Methods:158 adult pts with primary or secondary MF were enrolled in the parent trial; most received ruxolitinib at doses of 10–25 mg PO twice daily. This updated analysis focuses on 107 pts enrolled at MDACC: 63 were high, 34 intermediate (int)-2 and 10 int-1 risk, according to the International Prognosis Scoring System (IPSS), and assesses their survival and correlates thereof. For log-rank survival analysis, events were censored at the later of last dose, last visit, or last follow-up date. Results:Efficacy and safety findings of the parent trial have been published (Verstovsek S. N Engl J Med 363:1117, 2010): ruxolitinib treatment led to a rapid and sustained reduction in splenomegaly and improvements in MF symptoms; anemia and thrombocytopenia were the most common adverse events. After a median follow-up of 32 months, 58 of 107 pts (54%) were still receiving therapy. The corresponding overall survival (OS) was 69% (33 pts died, none due to therapy-related reasons: 14 while on therapy/within 30 days (d) of discontinuation (dc), and 19 off-study). Accounting for deaths occurring on the study, the 2-yr actuarial survival of int-2 and high-risk pts was 92% and 88%, respectively. However, the 2-yr survival of 13 int-2 and 21 high-risk pts who had discontinued therapy and were subsequently followed was 32% and 21%, respectively. MF transformed to acute leukemia in 9 pts: 5 while on therapy/within 30 d of dc, and 4 off-study; the transformation rate was 0.036/pt years. Pts with normal baseline cytogenetics did not have better survival than those with aberrations (Hazard ratio [HR]=1.52; p=0.24). However, pts with a baseline bone marrow fibrosis score of 2 had greater survival than those with a score of 3 (HR=2.21; p=0.031). Other evaluable baseline pt characteristics (gender, age, anemia, WBC and splenomegaly, did not affect survival. Surprisingly, high-risk pts (per either IPSS or dynamic IPSS [DIPSS]) did not have significantly worse survival than int-2 pts. Importantly, reduction in palpable spleen length while on ruxolitinib was noted to be the most robust predictor for survival: pts who had a ≥50% reduction in spleen size (n=62) had significantly prolonged survival vs. those with a <25% reduction (n=20) (Fig. 1; HR=4.94; p<0.0001). [Display omitted] Conclusions:Most MDACC pts with advanced MF in the phase I/II ruxolitinib study are still receiving therapy, demonstrating an OS of 69% after a median of 32 months. The 2-yr survival of pts who remained on therapy was 3–4-fold greater than those who discontinued therapy. Among baseline pt characteristics, only a lower bone marrow fibrosis score correlated with better survival. Conversely, achievement of ≥50% reduction in spleen size while on ruxolitinib resulted in greater survival (vs. <25% reduction). Our data suggest that the most important factors that influence survival of MF pts receiving ruxolitinib are continuous active therapy and a degree of the spleen response, not pt pretherapy characteristics. Disclosures:Verstovsek:Incyte Corporation: Research Funding.

Phase I Study of the JAK2 V617F Inhibitor, LY2784544, in Patients with Myelofibrosis (MF), Polycythemia Vera (PV), and Essential Thrombocythemia (ET)

Abstract▪2814▪This icon denotes a clinically relevant abstract Background:The majority of primary and secondary MF, PV, and ET neoplasms are characterized by gain-of-function activation of JAK2 V617F/STAT5 signaling. Given that wild-type JAK2 plays a pivotal role in multiple stages of hematopoiesis it is desirable to treat JAK2 V617F-positive cases by selectively inhibiting JAK2 V617F while minimizing inhibition of wild-type JAK2 in order not to impede normal marrow function. In murine MPN models and in vitro cell based assays, a novel JAK2 inhibitor, LY2784544, demonstrates selective inhibition of JAK2 V617F/STAT5 signaling and mutant cell proliferation (Ma et al. Abstract 4087 ASH 2010). These results provided the basis for the LY2784544 Phase I trial in MF, PV, and ET patients (I3X-MC-JHTA, NCT01134120). Methods:The primary objectives are to determine the safety and tolerability of LY2784544 and define a recommended oral daily dose for further study in patients with JAK2 V617F-positive MF, ET, or PV. Secondary objectives include determination of pharmacokinetics and evaluation of response using the IWG-MRT response criteria, European Leukemia Net response criteria for PV and ET (EULN), and symptom burden using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) (Scherber et. al. Blood 2011). The study has a standard 3+3 dose-escalation design to define the maximum tolerated dose (MTD). The study was recently amended to allow cohort expansions at lower than MTD doses demonstrating potential clinical merit. Results:To date, 19 patients have been treated: 1 PV, 1 post-ET MF, and 17 MF patients. Four patients discontinued therapy, 1 for each of the following: Adverse Event, progressive disease, investigator decision, and subject's decision. Reported drug-related serious adverse events were seen in 4 patients, and include: creatinine increase (n=4 grade 2), hyperuricemia (2 grade 4), and hyperkalemia (1 grade 1). All resolved within 14 days with temporary treatment interruption. Analysis of collected laboratory studies using the definitions of Cairo and Bishop (BJH 2004, 2010) demonstrated that 1 instance of laboratory tumor lysis syndrome (LTLS) and 3 instances of Grade 2 clinical tumor lysis syndrome (CTLS) occurred. Hyperuricemia and creatinine increases in cases of TLS were reported as dose-limiting toxicities at 240 and 200 mg with 1 and 3 instances at each respective dose. The most frequently reported drug-related AEs across all grades were diarrhea (3 grade 2, 5 grade 1), nausea (3 grade 2, 4 grade 1), transient increased creatinine (4 grade 2), anemia (3 grade 2, 1 grade 1), and hyperuricemia (2 grade 4).A palpable spleen length reduction of at least 35% was seen in 13 of 17 evaluable patients (76% including 16 MF and 1PV). A partial response by EULN for PV involving 100% reduction in spleen size was observed for >10 months. In MF, 7 patients had a ≥50% reduction, including 4 with sufficient stability or duration of follow-up to qualify as a clinical improvement by IWG-MRT. After 5 cycles of therapy, a reduction in bone marrow fibrosis grade was observed in 3 of the 5 MF patients for whom follow-up biopsy results are available. Using the MPN-SAF questionnaire, patients reported improvements in symptom burden within the first 2 cycles of therapy. Fifty-nine percent (59%) reported a ≥50% improvement in the Key MPN Related Symptoms, and 47% reported a ≥50% improvement in the categories of Fatigue-Enjoyment of Life, Fatigue-Walking Ability, itching, and early satiety. A similar level of improvement was reported by 65% of patients for inactivity, while 35% had improvements in bone pain and night sweats. At tested doses, a reduction in mutant allele burden has not been observed. Conclusions:An MTD for daily dosing of LY2784544 was identified as 120 mg. Based on PK analysis, exposure from doses associated with TLS appear to overlap the lower boundary of the predicted biologically efficacious dose (BED) range established in murine JAK2 V617F models. To allow testing of doses within the BED, the dosing regimen has been amended to include a lower dose lead-in period, intended to reduce tumor burden, prior to further testing of dose escalation. This trial amendment will also further evaluate the bone marrow fibrosis response. Disclosures:Verstovsek:Eli Lilly: Research Funding. Off Label Use: Study of LY2784544 - Purpose is to present results of a study. Mesa:NS Pharma: Research Funding; Astra Zeneca: Research Funding; SBio: Research Funding; Lilly: Research Funding; Incyte: Research Funding; Celgene: Research Funding. Kloeker Rhoades:Eli Lilly: Employment, Equity Ownership. Giles:Eli Lilly: Employment, Equity Ownership. Pitou:Eli Lilly: Employment, Equity Ownership. Jones:Eli Lilly: Employment, Equity Ownership. Walgren:Eli Lilly: Employment, Equity Ownership.

Durable Responses with the JAK1/ JAK2 Inhibitor, INCB018424, In Patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET) Refractory or Intolerant to Hydroxyurea (HU)

AbstractAbstract 313 Background:While advanced PV and ET patients at high thrombotic risk are managed primarily with HU, patients who are intolerant or refractory to HU have limited therapeutic options. Identification of a dominant gain-of-function mutation in the JAK2 kinase, V617F, in myeloproliferative neoplasms (MPNs), including PV and ET, provided a key rationale for the development of a molecularly targeted therapy for these diseases. Long term follow-up data from an ongoing trial of INCB018424, a selective JAK 1/ JAK 2 inhibitor, in PV and ET patients refractory or intolerant to HU are presented. Methods:Study 18424-256 is an uncontrolled open-label Phase 2 study being conducted at 6 sites in the United States and Italy. An initial 8-week run-in evaluation established 10-mg and 25-mg twice daily as starting doses for expansion cohorts in PV and ET, respectively; dose adjustments for safety and efficacy are allowed so that each subject is titrated to their most appropriate dose. For PV, response is defined based on Hct control in the absence of phlebotomy, improvement or elimination of palpable splenomegaly when present, and normalization of leukocytosis and thrombocytosis. For ET, response is defined based on improvement or normalization of WBC and platelet counts and, when present, elimination of palpable splenomegaly. PV results (n=34; median 108 months from diagnosis):After a median follow-up of 15 months (range 8–21), 97% of enrolled subjects achieved Hct control to <45% in the absence of phlebotomy, and all continued to maintain phlebotomy-independence at the time of last follow-up visit. Splenomegaly was present in 74% of subjects at entry: 59% of those achieved ≥ 50% reduction in palpable spleen length, or the spleen became non-palpable with all maintaining spleen response at the time of the last follow-up visit. Leukocytosis > 15×109/L was present in 47% of subjects and improved (≤ 15×109/L) or normalized (≤ upper limit of normal) in 88% and 63%, respectively. Thrombocytosis > 600×109/L was present in 38% of subjects and improved (≤ 600×109/L) or normalized (≤ upper limit of normal) in 92% and 69%, respectively. 59% of subjects achieved phlebotomy independence, resolution of splenomegaly and normalization of leukocytosis and thrombocytosis. 6 patients discontinued therapy (3 due to AEs, 2 withdrew consent, 1 for no response). Grade 3 AEs potentially related to study medication included thrombocytopenia (2 patients), neutropenia (1), renal tumor (1), asthenia (1), viral infection (1), and atrial flutter (1). No Grade 4 drug-related AEs have occurred. ET results (n=39; median 84 months from diagnosis):After a median follow-up of 15 months (range 4–21), 49% of enrolled subjects normalized platelet counts to ≤ upper limit of normal after a median of 0.5 months and for a median duration of 3.5 months. 82% maintained platelet counts < 600×109/L, for a median duration of 9.8 months. Of 14 patients with baseline platelet counts > 1000×109/L, 13 have experienced > 50% reduction. 88% maintained normal WBC (median duration 14.5 months). Palpable spleens resolved in 3 of 4 subjects; 1 reduced >50% from baseline. 49% of subjects achieved normalization of WBC and platelet counts in the presence of non-palpable splenomegaly. 9 patients discontinued therapy (4 due to AEs, 2 withdrew consent, 3 for no response). Grade 3 AEs potentially related to study medication included leukopenia (2 patients), GI disorder (1), and peripheral neuropathy (1). No Grade 4 drug-related AEs have occurred. Both patient groups demonstrated reductions in patient-reported symptom scores for pruritus, night sweats, and bone pain. Of 26 PV patients reporting pruritus at baseline (median score of 6 on a 10-point scale), 24 reported scores of 0 after a median duration of 1 month and for a median duration of 7 months. 42% of PV and 56% of ET patients had at least a 20% decrease in JAK2V617F allele burden; 6% of PV and 12% of ET had >50% decrease. Clinical responses were unrelated to the presence/absence of JAK2V617F mutation at entry or to the allele burden changes following treatment. Conclusions:Rapid and durable clinical benefits (normalization of hematological parameters, resolution of splenomegaly and alleviation of symptoms) have been demonstrated in advanced PV and ET patients with >1 year of follow-up. In this study, INCB018424 continues to be a well tolerated, effective therapy in patients with PV and ET refractory or intolerant to hydroxyurea. Disclosures:Verstovsek:Incyte Corporation: Research Funding. Levy:Incyte Corporation: Employment, Equity Ownership. Bradley:Incyte Corporation: Employment. Garrett:Incyte Corporation: Employment. Vaddi:Incyte corporation: Employment. Huber:Incyte Corporation: Employment, Equity Ownership. Schacter:Pfizer Corporation: Employment. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees.