Ruxolitinib In Myelofibrosis Research Articles

Ruxolitinib in Myelofibrosis and Baseline Thrombocytopenia in Real Life: Results in Dutch Patients and Review of the Literature

BackgroundRuxolitinib is an approved treatment for myelofibrosis patients, but data regarding patients with baseline thrombocytopenia are limited. The EXPAND study recently suggested tolerability of ruxolitinib, with a maximum starting dose of 10 mg 2 times a day (BID). However, the small sample size and vigorous follow-up in this trial hamper direct translation of these results to routine practice. Patients and MethodsWe report retrospective data on Dutch ruxolitinib-treated myelofibrosis patients, focusing on those with baseline thrombocytopenia. Additionally, we reviewed current literature regarding ruxolitinib treatment in this subgroup. ResultsIn our cohort, 12 of 119 patients had a baseline platelet count of < 100 × 109/L. Spleen responses at a mean treatment duration of 25 weeks were documented in 1 of 6 and 15 of 47 patients with and without baseline thrombocytopenia, respectively. Despite a high rate of grade 3 or higher thrombocytopenia in thrombocytopenic versus nonthrombocytopenic patients (42% vs. 15%), no grade 3 or higher hemorrhage was reported. Median doses in thrombocytopenic patients were 15 and 10 mg BID at the start and after 12 weeks of treatment, respectively. Additionally, 238 thrombocytopenic patients were identified in the available literature, of whom 59 were treated in routine practice. Incidences of severe thrombocytopenia reported separately for patients with baseline thrombocytopenia were 30% to 59% (grade 3 or higher) and 4% to 60% (grade 4). Severe bleeding, pooled across our data and evaluable studies, occurred in 2.4%. ConclusionRuxolitinib treatment appears to be safe for patients with platelet counts of 50 to 100 × 109/L in real-life practice. We did not find any reason to discourage a starting dose of 10 mg BID in this subgroup.

PB2235 SYMPTOM BURDEN AND SPLEEN SIZE RESPONSE WITH RUXOLUTINIB IN A REAL‐LIFE TURKISH COHORT

Background:Myelofibrosis (MF) is a myeloproliferative disease that is characterized by variable life expectancy, cytopenia, splenomegaly, and constitutional symptoms. Although allogeneic stem cell transplantation can be a curative treatment, it carries a high risk of morbidity and mortality (1,2). Ruxolitinib, a JAK2 inhibitor, is a new treatment option which improves symptomatic splenomegaly in patients with intermediate and high risk myelofibrosis.Aims:In this retrospective study we documented our real life clinical experience with ruxolitinib in MF patients.Methods:We reviewed the data of 53 patients with MF who were treated with ruxolitinib. Primary endpoint is to identify the improvement in spleen size and symptoms of the patients. Secondary endpoint was to determine overall survival of the patients, treatment safety and tolerability. Spleen size was measured by using ultrasound examination. Myeloproliferative Neoplasm 10 (MPN‐10) disease‐specific questionnaire was used to evaluate the symptoms and quality of life.Results:Fifty three patients with a mean age of 63.5 years were evaluated. Mean follow‐up time on ruxolitinib treatment was 18.9 ± 17.3 months (range 1‐69 months). DIPSS plus score was Int‐1 in 33 patients (62.3%), Int‐2 in 16 patients (30.2%), high risk in 4 patients (7.5%). Baseline demographic data of the patients were summarized in Table 1. The median subcostal spleen size decreased from 80 (34‐272) mm to 49 (0‐210) mm in 28 (52%) patients. Median spleen size reduction was 45% (10‐100%) in these patients. Spleen size decreased by 35% in 17 (32%) patients (Figure 1). In six patients (11 %), there were no change in spleen size. Spleen size increased 29.5% in 12 patients (1.5‐ 85.7%). Percentage of the patients whose spleen length did not change or increase were relatively high in post ET‐MF patients compared to patients with primary MF (66% vs. 34 %, respectively, P &gt; 0.05). MPN‐10 reassessment data within the first 6‐12 months was documented in 15 patients and found to be improved in 10 of 15 patients (66%). Hematologic adverse events were found in %77.4 which includes 73.6% anemia, 28.3% thrombocytopenia. Grade 2‐3 anemia and grade 3 thrombocytopenia was seen in 50% and 13% of the patients, respectively. Non‐hematological adverse events were observed in 11.3% of patients. Overall survival of the cohort was 66.7 ± 46.3 (5‐206) months. A total of 10 patients died, in three of them the cause of death was leukemic transformation.Summary/Conclusion:Our results which are similar to previous studies show that ruxolitinib is associated with improvement in quality of life and splenomegaly (3). The most important hematological side effects are anemia and thrombocytopenia and non‐hematological side effects are acceptable. The main difference of our real‐life data from the previous randomized clinical studies is that the majority of our patients had intermediate‐I disease. In this real‐life data we showed that ruxolutinib is safe and effective in this group of patients.image

Synergistic Effect of Imatinib and Ruxolitinib in a Patient with JAK2V617F positive Myelofibrosis and Concomitant BCR-ABL1 positive Chronic Myeloid Leukemia

Introduction:JAK2V617Fmutation is present in majority of polycythemia vera (PV) and in 50-60% of patients with primary myelofibrosis (MF). JAK1/2 inhibitor ruxolitinib (RUX) is approved for treatment of both PV and intermediate/high risk MF. Two independent randomized studies showed the benefit of RUX in MF with significant reduction in spleen volume and improvement in constitutional symptoms compared to best supportive care. Clonal evolution may occur in PV and MF upon acquisition of new mutations and transformation to acute myeloid leukemia. Rarely, patients with JAK2V617Fpositive PV or MF have also concomitant BCR-ABL1 fusion gene with phenotype of chronic myelogenous leukemia (CML). Imatinib, a BCR-ABL1 inhibitor, induces long-term cytogenetic and molecular remissions in CML. Single agent imatinib has shown no clinical benefit in MF patients despite in vitro efficacy (Gaikwad et al Exp. Hematol. 2007). We describe here a patient with JAK2V617F positive post-PV MF who later developed concomitant BCR-ABL+ CML. Splenomegaly was initially resolved by RUX but returned coincidently with the diagnosis of CML and was again normalized by imatinib alone. Massive splenomegaly reappeared along with elevated hematocrit on imatinib and was resolved by the addition of low dose RUX.Case report: A 71-year old woman initially presented in September 2011 with isolated erythrocytosis and splenomegaly. A diagnosis of PV was established based on the presence of the JAK2V617Fmutation and hypercellular marrow. Bone marrow karyotype was normal (Table 1). The patient was randomized to pegylated interferon arm in the MPD Consortium study. A complete hematologic response was achieved after nearly 2 years on maximal dose 180 mcg weekly. In early 2015, she developed constitutional symptoms, and progressive splenomegaly. Progression to post-PV MF was confirmed on bone marrow evaluation. The patient was taken off study and started on RUX 20 mg BID. She developed severe anemia 4 months later requiring dose reduction to 10 mg BID. The anemia markedly improved, while JAK2V617F allele burden remained high at 88% with normal cytogenetics. In December 2017, the patient developed anemia, fatigue and rapid regrowth of spleen. Marrow karyotype showed Philadelphia (Ph) chromosome in 25% of the cells analyzed, PCR was positive for BCR-ABL1 p210, and JAK2V617F allele burden was reduced to 56.4%. In January 2018, she started imatinib 400 mg daily and RUX was discontinued due to toxicity concerns. In April 2018, her hematocrit increased and massive splenomegaly returned. Restart of initial RUX 20 mg BID was followed by severe pancytopenia which normalized when RUX was reduced to 5 mg BID with continuing imatinib regimen. After 8 weeks, splenomegaly completely resolved (Figure 1). A complete cytogenetic response and major molecular response were achieved after 3 months and 6 months of combination therapy respectively.Methods: Mononuclear cells from peripheral blood collected in June 2018 were plated in methylcellulose without erythropoietin or other cytokines. After 14 days, colonies were plucked, with ½ of each colony used for JAK2V617F allele-specific PCR and ½ prepared as cytospins for BCR-ABL fluorescent in situ hybridization (FISH) with the Vysis LSI BCR/ABL Dual Color, Dual Fusion Translocation Probe from Abbott Laboratories.Results: Analysis of 3-6 EPO-independent colonies of each CFU-E, G, M, GM, GEMM, BFU-E showed no BCR-ABL1 positive cells, while a single CFU-GEMM colony was positive and also homozygous for JAK2V617F. Frozen marrow cells from the time of the original diagnosis are being analyzed.Conclusion: The recurrence of splenomegaly in this patient following single agent RUX indicates emergence of novel BCR-ABL1+ clone. While single agent imatinib temporarily normalized the splenomegaly and leukocytosis for several months, MF phenotype reoccurred. Splenomegaly resolved completely in 8 weeks with the addition of very low dose RUX to standard dose imatinib, providing the first clinical observation of in vivo synergism of RUX and imatinib. We are investigating serial samples during her course, which will be presented at the meeting. The analysis of a single clone demonstrate that BCR-ABL1 mutation did not occur in previously normal dormant stem cell but in JAK2V617F positive progenitors and represent in this pts a novel subclone of previous PV/MF stem cell. DisclosuresDeininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy.

Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses

BackgroundMyelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF.MethodsThis was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. Overall survival (OS; a secondary endpoint in both trials) was evaluated using pooled intent-to-treat data from patients randomized to ruxolitinib or the control groups. OS was also evaluated in subgroups stratified by baseline anemia and transfusion status at week 24.ResultsA total of 528 patients were included in this analysis; 301 were originally randomized to ruxolitinib (COMFORT-I, n = 155; COMFORT-II, n = 146) and 227 to control (n = 154 and n = 73, respectively). The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio [HR], 0.70 [95% CI, 0.54–0.91]; P = 0.0065). After correcting for crossover using a rank-preserving structural failure time (RPSFT) method, the OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib (median OS, 5.3 vs 2.3 years; HR [ruxolitinib vs RPSFT], 0.35 [95% CI, 0.23–0.59]). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged OS compared with control (median OS, 5.3 vs 2.4 years; HR [ruxolitinib vs censored at crossover], 0.53 [95% CI, 0.36–0.78]; P = 0.0013). The survival benefit with ruxolitinib was observed irrespective of baseline anemia status or transfusion requirements at week 24.ConclusionsThese findings support ruxolitinib treatment for patients with int-2 or high-risk MF, regardless of anemia or transfusion status. Further analyses will be important for exploring ruxolitinib earlier in the disease course to assess the effect on the natural history of MF.Trial registrationClinicalTrials.gov identifiers, NCT00952289 and NCT00934544.

Developmental Therapeutics in Myeloproliferative Neoplasms.

The unprecedented success of the Janus kinase (JAK) 1/2 inhibitor ruxolitinib in myelofibrosis (MF) provided much-needed impetus for clinical drug development for the Philadelphia chromosome-negative myeloproliferative neoplasms. The survival benefit conferred by this agent, along with its marked efficacy with regard to spleen volume and symptom reduction, have made ruxolitinib the cornerstone of drug therapy in MF. However, there remain significant unmet needs in the treatment of patients with MF, and many novel classes of agents continue to be investigated in efforts to build on the progress made with ruxolitinib. These include inhibitors of histone deacetylases (HDACs) and DNA methyltransferases, phosphatidylinositol-3-kinase isoforms, heat shock protein 90, cyclin-dependent kinases 4/6, and Hedgehog signaling, among others. In parallel, other JAK inhibitors with potential for less myelosuppression or even improvement of anemia, greater selectivity for JAK1 or JAK2, and the ability to overcome JAK inhibitor persistence are in various stages of development. First-in-class agents such as the activin receptor IIA ligand trap sotatercept (for anemia of MF), the telomerase inhibitor imetelstat, and the antifibrotic agent PRM-151 (recombinant human pentraxin-2) are also in clinical trials. In polycythemia vera, a novel interferon administered every 2 weeks is being developed for front-line therapy in high-risk individuals, and inhibitors of human double minute 2 (HDM2) have shown promise in preclinical studies, as have HDAC inhibitors such as givinostat (both in the laboratory and in the clinic). Ruxolitinib is approved for second-line therapy of polycythemia vera and is being developed for essential thrombocythemia.

Ruxolitinib in myelofibrosis: to be or not to be an immune disruptor

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm classified according to the 2016 revision of World Health Organization Classification of Tumors and Haematopoietic and Lymphoid Tissue. Ruxolitinib is an oral inhibitor of Janus kinase approved in the USA for the treatment of intermediate or high-risk PMF and approved in Europe for the treatment of splenomegaly and constitutional symptoms of the disease. More recently, case reports described serious opportunistic infections in this neoplasm treated with ruxolitinib. Research studies demonstrated the immunological derangement of this compound mainly based on T, dendritic, and natural killer cell defects. The purpose of this review of the literature was to analyze the relationship among ruxolitinib, immune system and bacterial, viral, fungal, and protozoan infections. A literature search was conducted using PubMed articles published between January 2010 and November 2016. The efficacy of drug in patients with PMF was demonstrated in two phase III studies, Controlled MyeloFibrosis Study with ORal Jak inhibitor Treatment (COMFORT-I and COMFORT-II). Grade 3 and 4 neutropenia were recognized in 7.1% and 2% of patients in the ruxolitinib and placebo arm of COMFORT-I. Grade 3 or 4 neutropenia or leukopenia were observed in 8.9% and 6.3% of ruxolitinib treated patients of 5-year follow-up of COMFORT-II. In addition, leukocyte subpopulations, lymphocyte functions, or antibody deficiency were not documented in either of the studies. The complex interactions between ruxolitinib, bone marrow, immune system, and infections in PMF need further investigation, robust data from a randomized clinical trial, registry, or large case-series.

Impact of Genomic Alterations on Outcomes in Myelofibrosis Patients Undergoing JAK1/2 Inhibitor Therapy

Introduction:The advent of next generation sequencing (NGS) has brought intense interest to the complex genetic landscape of myeloproliferative neoplasms (MPN). However, data regarding clinical outcomes in the context of novel MPN therapies such as JAK inhibitors are scarce. Limited data indicate that high molecular risk signature (HMR, presence of at least one mutation in ASXL1, EZH2, IDH1/2, SRSF2) or multiple mutations may be associated with decreased spleen response and a shorter time to discontinuation of Ruxolitinib in myelofibrosis (Patel et al, Blood 2015).Methods:All myelofibrosis patients seen in the MPN program at Princess Margaret Hospital between November 2009 and May 2016 and treated with JAK1/2 inhibitor therapy were identified. NGS molecular profiling of 54 genes (39 hotspot region; 15 complete coding region coverage) was performed on peripheral blood or bone marrow samples using the TruSight Myeloid Sequencing Panel. Reporting was restricted to well-covered, exonic nonsynonymous, intronic splice site, and known pathogenic synonymous variants. Variants with global mean allele frequency >1% were identified using multiple population databases (1000 genomes, ESP, ExAC) and excluded. The primary endpoint was time from start of JAK1/2 inhibitor therapy to treatment failure (TTF) defined as treatment discontinuation, progression to accelerated phase or leukemic transformation, spleen progression or death. Secondary endpoints included best spleen, anemia and IWG response achieved by 48 weeks of treatment and overall survival. Response was assessed according to the 2013 revised IWG-MRT criteria. Transfusion dependency was assessed as any transfusion in 12 weeks prior to treatment or being identified as transfusion dependent in medical history.Results:Of 159 patients treated with JAK1/2 inhibitors at our institution, 102 met the inclusion criteria (see Table 1). Patients were excluded if; no sample was available for analysis (19), short use of JAK inhibitor prior to transplant (9), active clinical trial (5), in accelerated phase/acute leukemia (4) and others (20). First JAK inhibitor used was ruxolitinib in 77 patients and momelotinib in 25. At least one mutation was identified in every patient. Twenty (20%) patients had one mutation, 32 (31%) had 2 mutations and 50 (49%) patients had ≥ 3 mutations. Eighty (82%) patients had the JAK2V617F mutation, 15 (15%) had mutations in CALR, 4 (4%) had MPL mutations and one patient was triple negative. One patient had mutations in both CALR and JAK2 while another had mutations in MPL and CALR. Forty-eight (47%) patients had mutations consistent with HMR profile. Mutation profile is summarized in Table 2.With median follow-up of 2.5 years, 51 (50%) patients experienced treatment failure. On univariate analysis, TTF was associated with DIPSS, pre-treatment transfusion status and Hb <100 prior to initiating JAK inhibitor therapy. However, TTF was not associated with specific driver mutations, the number of mutations or HMR profile. Exploratory analysis of genes mutated in ≥5% of the population showed EZH2 (p=0.004) and CBL (p=0.005) mutated patients had shorter TTF. Multi-variable analysis employing anemia <100 and DIPSS with either of the number of mutations or HMR profile did not show any association with TTF. There was a trend towards TTF in patients with Hb<100 (HR 2.21, 95%CI: 0.99-4.95, p=0.05). Of 102 patients, 91 were evaluable for spleen response with 43 (47%) achieving a spleen response by 48 weeks of treatment. Twelve (23%) of the 53 patients evaluated met criteria for anemia response. Neither spleen nor anemia response was associated with the use of a particular JAK inhibitor. Of the 95 patients with at least 48-week follow-up, best response while on treatment was clinical improvement and spleen response in 29 (31%) and 19 (20%) patients respectively.Conclusions:In this study of myelofibrosis patients treated with JAK inhibitors, EZH2 and CBL mutated patients had shorter TTF. We did not find any association between TTF and number of mutations or other high risk mutations such as ASXL1/SRSF2. Anemia was the only significant independent predictor of shorter TTF. Our findings highlight the need for multicenter collaborative studies on a large number of patients and cautious use of mutation profiling results in routine clinical decision making with current treatment approaches.Spiegel and McNamara are co-primary authors. [Display omitted] [Display omitted] DisclosuresPanzarella:Cellgene: Consultancy. Schimmer:Novartis: Honoraria. Schuh:Amgen: Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kamel-Reid:BMS: Research Funding. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.

Drug Development Pipeline for Myeloproliferative Neoplasms: Potential Future Impact on Guidelines and Management

The unprecedented success of ruxolitinib in myelofibrosis (MF) has paved the way for the development of other Janus kinase (JAK) inhibitors and other agents representing diverse drug classes and mechanisms of action in myeloproliferative neoplasms (MPNs). In particular, the symptomatic benefits afforded by ruxolitinib have led to the recognition of "clinical improvement" in symptoms and the spleen in international consensus response criteria for MF. Ruxolitinib is also approved for the second-line treatment of polycythemia vera and is being developed for essential thrombocythemia. Appreciation of the universal role of activated JAK/signal transducer and activator of transcription (STAT) signaling in MPNs and improved understanding of the canonical and noncanonical actions of JAK2 have yielded a number of drug targets beyond JAK2 in MPNs, which form the basis for a number of ruxolitinib-based rational combinations that are being explored in MF. Other JAK inhibitors with the potential for significantly less myelosuppression or even improvement of anemia continue to be tested. Finally, agents with very distinct mechanisms of action, such as novel interferon formulations, antifibrotic agents, and telomerase inhibitors, are being pursued in polycythemia vera and MF, respectively. This article reviews the current landscape of clinical drug development in MPNs, focusing on the most promising agents and combinations.

Creating clinical trial designs that incorporate clinical outcome assessments.

Clinical outcome assessments (COAs) are increasingly being used in determining the efficacy of new treatment regimens. This was typified in the recent use of a symptom-based instrument combined with an organ-based measure of response for the approval of ruxolitinib in myelofibrosis. There are challenges in incorporating these COAs into clinical trials, including designating the level of priority, incorporating these measures into a combined or composite endpoint, and dealing with issues related to compliance and interpretation of results accounting for missing data. This article describes the results of a recent panel discussion that attempted to address these issues and provide guidance to the incorporation of COAs into clinical trials, including novel statistical designs, so that the testing of new treatments in patients with cancers of the central nervous system can incorporate these important clinical endpoints.

Abstract A179: NMS-P113, a novel orally available JAK2 selective inhibitor

Abstract The Janus Kinases (JAK1, JAK2, JAK3, TYK2) are non-receptor tyrosine kinases that play important roles in hematopoiesis and immune response. In particular, gene ablation of JAK1 or JAK2 in the mouse is incompatible with life, due to neurological defects/immunodeficency and lack of erythropoiesis, respectively, whereas that of JAK3 or TYK2 is associated with severe immunodeficiency. Activating mutations of JAKs are found in association with malignant transformation. The best characterized gain-of-function mutation, JAK2-V617F in the pseudo-kinase domain of JAK2, is present in hematopoietic cells of patients with myeloproliferative disorders (MPD). In particular, the JAK2-V617F mutation is found in &amp;gt;95% of patients with polycythemia vera (PV), circa 50% of patients with essential thrombocythemia (ET), and circa 50% of myelofibrosis (MF) patients. Recently, a central role of JAK2 has been described in upregulation of the immune checkpoint component PD-L1 mediated by IFN-γ or by chromosome 9p24.1 amplification, suggesting that its inhibition might provide a new strategy to increase immune-mediated tumor inhibition in specific contexts. Although JAK inhibitors have been approved in oncological and autoimmune settings (e.g. the JAK1/JAK2 inhibitor ruxolitinib in MF and the pan-JAK inhibitor tofacitinib in rheumatoid arthritis) and multiple agents are in clinical testing, JAK2 selective compounds might be provide an advantage for long-term MPD therapy or in association with immunotherapy, given that inhibition of other JAK family members leads to immunosuppressive effects. Due to high homology amongst JAK family kinases within the ATP binding pocket, discovery of selective JAK2 inhibitors has represented a significant challenge. Here, we report the characterization of NMS-P113, a potent and selective JAK2 inhibitor. Screening of the NMS compound collection led to the identification of a pyrrole series with promising activity against JAK2. An optimization program led to identification of the potent and orally bioavailable JAK2 inhibitor NMS-P113. In biochemical assay this compound possesses low nanomolar potency against JAK2 (IC50 3 nM), with preferential activity over other JAK family members and high selectivity against a panel of 60 further kinases. In cellular assay, NMS-P113 potently inhibits proliferation of the JAK2 dependent SET-2 human megakaryoblastic leukemia line, derived from an ET patient and which harbors the JAK2-V617F mutation, as well as of Ba/F3 cells engineered to express constitutively activated JAK2 (IC50s circa 200 nM). NMS-P113 is 10-fold less active against the DERL-7 T-cell lymphoma cell line (which is dependent upon JAK1/JAK3) and has poor antiproliferative activity in JAK independent lines. Oral administration of NMS-P113 results in dose-related normalization of spleen weight and erythrocyte precursors count in an erythropoietin-induced model of PV in the mouse. Mechanism of action of NMS-P113, as assessed by inhibition of P-STAT5, was confirmed in vitro and in vivo. A favorable ADME profile with high oral bioavailability, together with permissive therapeutic safety margins in test species, indicate that NMS-P113 is suitable for further development, affording the possibility of reduced undesirable immunosuppressive activities compared to inhibitors that target multiple members of the JAK family. Citation Format: Paola Gnocchi, Maria Gabriella Brasca, Nadia Amboldi, Nilla Avanzi, Simona Bindi, Giulia Canevari, Daniele Casero, Roberta Ceruti, Marina Ciomei, Sabrina Cribioli, Cinzia Cristiani, Marcella Nesi, Wilma Pastori, Veronica Patton, Cinzia Pellizzoni, Gemma Texido, Elena Ardini, Eduard R. Felder, Antonella Isacchi, Daniele Donati, Arturo Galvani. NMS-P113, a novel orally available JAK2 selective inhibitor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A179.

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.

What Is the True Response Rate to Ruxolitinib in Persons with Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis (MF) Needing Therapy for Splenomegaly ?

Data from COMFORT-I and COMFORT-II trials indicate that the JAK1/JAK2 inhibitor ruxolitinib is effective in reducing splenomegaly and reversing symptoms in patients with MPN-associated MF (Verstovsek S. et al, NEJM 2012;366:799; Harrison C. et al. NEJM 2012;366:787). However, not all subjects in these studies needed therapy for splenomegaly according newly-reported criteria (Barosi et al, Leuk Res 2014;38:155). Moreover, splenomegaly response was defined as 35% reduction in spleen volume by magnetic resonance imaging, which does not always correspond to a clinically relevant response as defined by the IWG-MRT/ELN revised response criteria (Tefferi et al. Blood 2012;122:1395).We evaluated response in 57 subjects with a spleen > 10 cm from the costal margin or with a progressive splenomegaly. Patients had been enrolled in clinical trials, or in individual patient care. The majority of patients were males (32/57, 56.1%), and the median patient age was 57 years (range: 30–81 years). The disease conditions included primary MF in 45 patients (78.9%), post-ET or post- PV MF (12 patients, 21.1%). Genotype was JAK2V617F in 37, 26 with > 50% (45.6%) and 11 (19.3%) with 50% or less allele burden. Fifteen (26.3%) had a CALR mutation, 4 a MPL mutation (7%), and 1 no detectable mutation. Starting dose of ruxolitinib given twice daily was: 20 mg in 32, 15 mg in 22, and 10 mg in 3. Doses were adjusted as appropriate. Median actuarial follow-up was 23.3 months. Thirteen subjects (37%) had a dose-reduction at a median time of 34 days (range 8-510 days). Twenty-eight (49.1%) discontinued therapy at a median of 17. months: 3-month and 1-,2-, and 3-year discontinuation rates were 22%, 40%, 55%, and 67%, respectively. Reasons for therapy-discontinuation were lack of response/progression (N=14), or toxicity/adverse events (N=14).Nineteen subjects (33%) responded according to the IWG-MRT/ELN response criteria at a median time of 3.9 months (range, 12 days - 21 months). However, 7 subsequently lost their response after a median time of 2.3 months (range, 1-35 months). 3-year continuous response rate was 24%.We next estimated failure-free survival (FFS), defined as continuing on ruxolitinib, no start of another therapy for splenomegaly, and/or no disease progression. This composite endpoint is more relevant than the individual components, but its validity after ruxolitinib in MF has not been evaluated. Actuarial FFS was 84% at 3 months, 71% at 6 months, 61% at 12 months, 44% at 2 years, and 36% at 3 years. Subjects with a JAK2V617F allele burden >50%, or with a liver <5 cm="" had="" significantly="" longer="" ffs="" log="" rank="" test="" p=".05," and="" respectively="" multivariate="" analysis="" identified="" jak2v617f="" allele="" burden="">50% as independently associated with FFS. Relative failure risk of subjects with >50% JAK2V617F allele burden was 0.28 (95% CI = 0.12 to 0.66), P=0.003 relative to all other genotypes (Figure). There was no significant association between FFS and age, gender, type of MF, hemoglobin concentration, white blood cells, platelet count, reason for starting therapy, spleen size, CD34+ levels, starting dose, or dose reductions.In conclusion, ruxolitinib produced a 3-year IWG-MRT/ELN response rate of 24% in persons needing therapy for splenomegaly. However, actuarial 3-year FFS was 36%. Patients with JAK2V617F and more than 50% allele burden had significantly better FFS than other genotypes, perhaps reflecting a greater sensitivity to inhibition of JAK1/JAK2 by ruxolitinib. These results may help define which persons with MPN-associated MF and splenomegaly needing therapy are most likely to benefit from ruxolitinib. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Ruxolitinib Discontinuation In Patients With Myelofibrosis: An Analysis From Clinical Practice

IntroductionThe objective of this study is to evaluate the persistence patterns and discontinuation rates from ruxolitinib in clinical practice. Ruxolitinib was the first Janus kinase (JAK) inhibitor approved for treating intermediate-risk or high-risk myelofibrosis, including primary myelofibrosis, post‒polycythemia vera myelofibrosis, and post‒essential thrombocythemia myelofibrosis. Ruxolitinib was investigated in 2 randomized, controlled, phase 3 efficacy trials in patients diagnosed with myelofibrosis (COMFORT-I and COMFORT-II). MethodsA retrospective database inception cohort study is developed from 2 large US claims databases, the IMS Health® database containing National Council for Prescription Drug Programs pharmacy-dispensed prescription claims and the MarketScan® database containing patient-level data from approximately 100 health plans (data from active employees, early retirees, COBRA continues, and dependents) and from Medicare Supplemental data. We identify a cohort of myelofibrosis patients who were prescribed ruxolitinib between November 1, 2011 and August 31, 2012 in the IMS database and between November 1, 2011 and June 30, 2012 from the MarketScan database. Patients are followed from the date of the first ruxolitinib claim, defined as the index date, until the last enrollment date or date of last claim recorded if greater than the last enrollment date in the MarketScan database or for a fixed 3- and 6-month period in the IMS database. When analyzing treatment discontinuation, patients with primary or secondary myelofibrosis are required to have ≥1 ruxolitinib dispensed prescription(s) and to have ≥3 months of pre-index data and ≥3 or 6 months of follow-up post-index data. Discontinuation of ruxolitinib was defined as a >30-day gap from the last day of supply from the prior prescription fill. Demographic and ruxolitinib discontinuation rates at 3 and 6 months post-index date for patients in each database are reported in this analysis with the Clopper-Pearson confidence interval. ResultsIn patients prescribed ruxolitinib in the IMS database, mean (SD) age at the index date was 63.4 (13.2) years for patients followed for 3 months (n=183) and 63.3 (13.6) years for patients followed for 6 months (n=115). The MarketScan database inception cohort comprised 161 patients with mean (SD) age of 66.8 (12.2) years. Age was comparable and not substantially different across the 2 databases. Discontinuation rates in the IMS database were 60.9% and 73.0% at 3 and 6 months follow-up, respectively; in the MarketScan database, discontinuation rates were 41.1% and 48.4% for patients with a minimum of 3 and 6 months follow-up, respectively. ConclusionsThese analyses indicate that the discontinuation rates for patients receiving treatment with ruxolitinib for myelofibrosis are not low and are most pronounced within the first 3 months of treatment. Results suggest the magnitude of unmet need in myelofibrosis and for additional medications that can improve treatment outcomes.Limitations of this study pertain to a traditional claims database inquiry. As patients were identified from 2 distinct databases, there may be some data overlap. Diagnostic information on the basis of claims databases is not always accurate. Future research using rich clinical data from chart reviews is needed to identify clinical determinants of persistence/discontinuation. The discontinuation rates observed from these 2 large representative databases are substantial, reflecting inherent variability of point estimates and differences in data collection for the 2 data sources. Future studies should examine the reasons for discontinuation so that findings may be incorporated into disease/medication adherence management programs. Disclosures:Fonseca:IMS Health - a company that received funds from Sanofi to conduct the study: Employment. Silver:Sanofi : Consultancy, Research Funding. Kazis:Sanofi and IMS: Consultancy. Iqbal:Sanofi: Employment, Equity Ownership. Rose:Sanofi: Employment. Khan:IMS Health: Employment.Table. Discontinuation Rates From RuxolitinibDatabaseFollow-up Time% [95% CI]IMS®3 months60.9 [53.2-67.8]6 months73.0 [64.0-80.9]MarketScan®≥3 monthsa41.1 [32.9-49.7]≥6 monthsb48.4 [37.9-59.0]Median follow-up time is a207 days and b241 days.This study was sponsored by Sanofi.

Ruxolitinib for Myelofibrosis–An Update of Its Clinical Effects

Myelofibrosis (MF), a Philadelphia chromosome-negative myeloproliferative neoplasm, is characterized by progressive bone marrow fibrosis and ineffective hematopoiesis. Clinical hallmarks include splenomegaly, anemia, and debilitating symptoms. In 2 randomized phase III studies, the Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib significantly improved splenomegaly and disease-related symptoms compared with placebo (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment [COMFORT-I]) or best available therapy (COMFORT-II) in patients with intermediate-2 or high-risk MF. Although ruxolitinib therapy was associated with dose-dependent anemia and thrombocytopenia, these adverse events rarely led to treatment discontinuation. This update of the clinical effects of ruxolitinib in patients with MF was based on original articles and meeting abstracts published after the primary publication of the COMFORT trials in March 2012. Long-term follow-up data from the COMFORT trials and clinical experience with ruxolitinib in unselected patient populations suggest that improvement of splenomegaly and symptoms is durable. Patients benefit from ruxolitinib therapy across subgroups defined by age, MF type, risk category, performance status, JAK2 V617F mutation status, extent of splenomegaly, or presence of cytopenias. In COMFORT-I, platelet counts stabilized with dose adjustments, and hemoglobin levels gradually recovered to slightly below baseline after the first 8 to 12 weeks of therapy. After initial increases, the need for red blood cell transfusions decreased to a level similar to that found in the placebo group. The 2-year follow-up data from the COMFORT trials suggest that patients with intermediate-2 or high-risk MF receiving ruxolitinib therapy may have improved survival compared with those receiving no (placebo) or traditional therapy.

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

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

Long-Term Outcome of Treatment with Ruxolitinib in Myelofibrosis

Abstract 1752▪▪This icon denotes a clinically relevant abstract Background:Patients with primary (PMF) or post-polycythemia vera/essential thrombocythemia (post-PV/ET MF) myelofibrosis often harbor a JAK2 mutation and also display abnormally increased inflammatory cytokines (J Clin Oncol. 2011;29:1356). Therefore, JAK-STAT is an appealing drug target in such patients. Ruxolitinib (INCB018424) is a small molecule ATP mimetic that inhibits both JAK1 and JAK2 and has been evaluated for its therapeutic activity in MF, in the setting of phases 1, 2, and 3 clinical trials. Methods:The first phase-1/2 MF study using ruxolitinib was conducted at the MD Anderson Cancer Center and Mayo Clinic. A total of 153 patients were included in the study whose first line results were published in September, 2010 (NEJM 2010;363:1117). The current report constitutes a sponsor-independent analysis of long-term outcome in the 51 Mayo Clinic patients who participated in the particular clinical trial. Results I: Baseline characteristics:The 51 patients (37 males) from the Mayo Clinic were enrolled between October, 2007 and February 2009. The median time from treatment initiation is now 3.5 years. MF subtype distributions were PMF 60%, post-PV MF 32% and post-ET MF 10%. Median (range) values were age 61 years (39–79), hemoglobin 10.6 g/dL (7.4-15.3), leukocyte count 15.8 (2.0–136), and palpable spleen size 19 cm (0–32). The proportion of patients with red cell transfusion dependency was 24%, hemoglobin <10 g/dL 38%, unfavorable karyotype 18%, pruritus 24%, night sweats 26%, and JAK2V617F 84%. DIPSS-plus risk distributions were high 18%, intermediate-2 48%, intermediate-1 22% and low 14%. Results II: Response and treatment duration:According to the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria, spleen response rate was 29% and anemia response rate 21%. Responses were also seen in constitutional symptoms (63%) and pruritus (92%). To date, treatment has been discontinued in 47 (92%) patients. The treatment discontinuation rates at 1, 2 and 3 years were 51%, 72% and 89%, respectively. For the 47 patients who were taken off study, median duration of treatment was 9.2 months (range 1.3–42 months). Reasons for treatment discontinuation included loss or lack of response/disease progression (∼40%), toxicity with and without lack of response/disease progression (∼34%), patient/physician choice often associated with lack of response (13%), and death on study (∼4%). Results III: Toxicity:Grade ≥2 thrombocytopenia and anemia occurred in 26% and 33% of patients and persisted in the majority of afflicted patients after drug discontinuation. To date, 18 deaths (36%) and 5 (10%) leukemic transformations have been recorded. Serious adverse events occurred upon drug discontinuation in 6 cases (13%) and were characterized by immediate relapse of symptoms, rapid and painful enlargement of spleen sometimes associated to splenic infarct, and acute hemodynamic decompensation occasionally leading to a septic shock-like syndrome. Results IV: Survival:There was no significant difference in the survival of the 51 ruxolitinib-treated patients compared to that of a cohort of 410 cases of PMF seen at the Mayo Clinic in the most recent 10-year period: unadjusted (Figure 1; p=0.43) and adjusted for DIPSS-plus (Figure 2; p=0.58). [Display omitted] [Display omitted] Conclusions:Ruxolitinib is effective in alleviating constitutional symptoms in the majority of patients with MF. Its activity in reducing spleen size is modest and not always durable. It is imperative that patients be alerted about important drug adverse events including potentially irreversible thrombocytopenia, worsening of anemia, and potentially catastrophic withdrawal symptoms. Ruxolitinib therapy does not appear to affect survival in MF. Disclosures:No relevant conflicts of interest to declare.

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.

Long-Term Outcome of Treatment with Ruxolitinib in Myelofibrosis

The initial encouraging activity of ruxolitinib in myelofibrosis appears to need some caveats when long-term efficacy is examined. The control of splenomegaly may not be durable, and the likelihood of leukemic progression or death is not dramatically lowered.