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Ruben A Mesa - One of the best experts on this subject based on the ideXlab platform.

  • Management of myelofibrosis after Ruxolitinib failure
    2020
    Co-Authors: Claire N Harrison, Nicolaas Schaap, Ruben A Mesa
    Abstract:

    Myelofibrosis is a BCR-ABL1–negative myeloproliferative neoplasm characterized by anemia, progressive splenomegaly, extramedullary hematopoiesis, bone marrow fibrosis, constitutional symptoms, leukemic progression, and shortened survival. Constitutive activation of the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway, and other cellular pathways downstream, leads to myeloproliferation, proinflammatory cytokine expression, and bone marrow remodeling. Transplant is the only curative option for myelofibrosis, but high rates of morbidity and mortality limit eligibility. Several prognostic models have been developed to facilitate treatment decisions. Until the recent approval of fedratinib, a JAK2 inhibitor, Ruxolitinib was the only available JAK inhibitor for treatment of intermediate- or high-risk myelofibrosis. Ruxolitinib reduces splenomegaly to some degree in almost all treated patients; however, many patients cannot tolerate Ruxolitinib due to dose-dependent drug-related cytopenias, and even patients with a good initial response often develop resistance to Ruxolitinib after 2–3 years of therapy. Currently, there is no consensus definition of Ruxolitinib failure . Until fedratinib approval, strategies to overcome Ruxolitinib resistance or intolerance were mainly different approaches to continued Ruxolitinib therapy, including dosing modifications and Ruxolitinib rechallenge. Fedratinib and two other JAK2 inhibitors in later stages of clinical development, pacritinib and momelotinib, have been shown to induce clinical responses and improve symptoms in patients previously treated with Ruxolitinib. Fedratinib induces robust spleen responses, and pacritinib and momelotinib may have preferential activity in patients with severe cytopenias. Reviewed here are strategies to ameliorate Ruxolitinib resistance or intolerance, and outcomes of clinical trials in patients with myelofibrosis receiving second-line JAK inhibitors after Ruxolitinib treatment.

  • real world outcomes of Ruxolitinib treatment for polycythemia vera
    2020
    Co-Authors: Alexander Coltoff, Ruben A Mesa, Jason Gotlib, Jessica Shulman, Raajit K Rampal, Olivia Siwoski, Abdulraheem Yacoub, Alison R Moliterno, Anna Yang, Evan M Braunstein
    Abstract:

    Abstract Introduction Ruxolitinib is approved for the treatment of polycythemia vera (PV) with hydroxyurea resistance or intolerance. Approval was based on the phase III RESPONSE trial, which demonstrated efficacy in a highly selected patient population. Materials and Methods To characterize the tolerability and outcomes of Ruxolitinib outside of a clinical trial, we performed a multi-center retrospective analysis of patients with PV treated with Ruxolitinib at 11 participating sites across the United States. Outcomes of interest included change in phlebotomy requirements after starting Ruxolitinib and spleen response, as these were included in the primary composite outcome in the RESPONSE trial. Results One hundred twenty-six patients met eligibility criteria, and the median duration of follow-up was 22.4 months (range, 0-63.0 months). At 32 weeks after starting Ruxolitinib, the percentage of patients who received at least 1 phlebotomy was significantly decreased compared with before Ruxolitinib (37% vs. 56%; relative risk [RR], 0.66; 95% confidence interval [CI], 0.52-0.84; P  Conclusion These real-world results are similar to those reported from the RESPONSE trial, although additional follow-up is necessary to assess long-term outcomes and potential for late-onset toxicity.

  • long term survival in patients treated with Ruxolitinib for myelofibrosis comfort i and ii pooled analyses
    2017
    Co-Authors: Srdan Verstovsek, Ruben A Mesa, Jason Gotlib, Claire N Harrison, Alessandro M Vannucchi, Jeanjacques Kiladjian, Francisco Cervantes, Ronald Paquette, William Sun, Ahmad Naim
    Abstract:

    Myelofibrosis (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. This 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. A 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. These 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. ClinicalTrials.gov identifiers, NCT00952289 and NCT00934544 .

  • simplify 1 a phase iii randomized trial of momelotinib versus Ruxolitinib in janus kinase inhibitor naive patients with myelofibrosis
    2017
    Co-Authors: Ruben A Mesa, John Catalano, Jeanjacques Kiladjian, Timothy Devos, Miklos Egyed, Andrzei Hellmann, Donal P Mclornan, Kazuya Shimoda, Elliott F Winton, Wei Deng
    Abstract:

    Purpose We evaluated the efficacy and safety of momelotinib, a potent and selective Janus kinase 1 and 2 inhibitor (JAKi), compared with Ruxolitinib, in JAKi-naive patients with myelofibrosis. Patients and Methods Patients (N = 432) with high risk or intermediate-2 risk or symptomatic intermediate-1 risk myelofibrosis were randomly assigned to receive 24 weeks of treatment with momelotinib 200 mg once daily or Ruxolitinib 20 mg twice a day (or per label), after which all patients could receive open-label momelotinib. The primary end point was a ≥ 35% reduction in spleen volume at 24 weeks of therapy. Secondary end points were rates of symptom response and effects on RBC transfusion requirements. Results A ≥ 35% reduction in spleen volume at week 24 was achieved by a similar proportion of patients in both treatment arms: 26.5% of the momelotinib group and 29% of the Ruxolitinib group (noninferior; P = .011). A ≥ 50% reduction in the total symptom score was observed in 28.4% and 42.2% of patients who received momelotinib and Ruxolitinib, respectively, indicating that noninferiority was not met ( P = .98). Transfusion rate, transfusion independence, and transfusion dependence were improved with momelotinib (all with nominal P ≤ .019). The most common grade ≥ 3 hematologic abnormalities in either group were thrombocytopenia and anemia. Grade ≥ 3 infections occurred in 7% of patients who received momelotinib and 3% of patients who received Ruxolitinib. Treatment-emergent peripheral neuropathy occurred in 10% of patients who received momelotinib (all grade ≤ 2) and 5% of patients who received Ruxolitinib (all grade ≤ 3). Conclusion In JAKi-naive patients with myelofibrosis, 24 weeks of momelotinib treatment was noninferior to Ruxolitinib for spleen response but not for symptom response. Momelotinib treatment was associated with a reduced transfusion requirement.

  • a phase 2 study of simtuzumab in patients with primary post polycythaemia vera or post essential thrombocythaemia myelofibrosis
    2017
    Co-Authors: Srdan Verstovsek, Ruben A Mesa, Michael R Savona, Hua Dong, Julia D Maltzman, Shringi Sharma, Jeffrey A Silverman, Jason Gotlib
    Abstract:

    Summary Simtuzumab, a monoclonal antibody inhibitor of extracellular matrix enzyme lysyl oxidase-like-2, showed preclinical promise and was well tolerated in clinical studies. A phase 2, open-label study of simtuzumab was conducted in patients with primary myelofibrosis (MF), post-polycythaemia vera MF and post-essential thrombocythaemia MF. Fifty-four patients were randomized to receive simtuzumab alone (200 or 700 mg [n = 12 each group]) or simtuzumab (200 or 700 mg) with Ruxolitinib (n = 15 each group) for 24 weeks. Simtuzumab alone or in combination with Ruxolitinib showed no clinical benefit at 24 weeks. The mean serum simtuzumab trough concentrations appeared to increase dose-proportionally between the 200-mg and 700-mg treatment groups. Therapy-related serious adverse events were pyrexia, pain in extremity (both in 1 patient) and infusion reaction (in another patient). Bone marrow fibrosis (BMF) score was reduced at 24 weeks in 2 patients (16·7%) in the simtuzumab 700-mg group, 1 (6·7%) in the simtuzumab 200-mg + Ruxolitinib group, and 2 (13·3%) in the simtuzumab 700-mg + Ruxolitinib group; similar numbers of patients had increased BMF. Simtuzumab alone or with Ruxolitinib was well tolerated but did not produce clinical benefit nor consistently reduce BMF in patients with MF by 24 weeks.

Pooja Khandelwal - One of the best experts on this subject based on the ideXlab platform.

  • Ruxolitinib as salvage therapy in steroid refractory acute graft versus host disease in pediatric hematopoietic stem cell transplant patients
    2017
    Co-Authors: Pooja Khandelwal, Ashley Teusinkcross, Adam S Nelson, Christopher E Dandoy, Stella M Davies, Javier Elbietar
    Abstract:

    Abstract We describe our retrospective clinical experience with Ruxolitinib for steroid-refractory acute graft-versus-host disease (GVHD) in pediatric allogeneic hematopoietic stem cell transplant (HSCT) patients. Ruxolitinib was administered orally at 5 mg twice daily for children ≥ 25 kg or 2.5 mg twice daily if

  • Ruxolitinib as salvage therapy in steroid refractory acute graft versus host disease in pediatric hematopoietic stem cell transplant patients
    2017
    Co-Authors: Pooja Khandelwal, Ashley Teusinkcross, Adam S Nelson, Christopher E Dandoy, Stella M Davies, Javier Elbietar
    Abstract:

    We describe our retrospective clinical experience with Ruxolitinib for steroid-refractory acute graft-versus-host disease (GVHD) in pediatric allogeneic hematopoietic stem cell transplant (HSCT) patients. Ruxolitinib was administered orally at 5 mg twice daily for children ≥ 25 kg or 2.5 mg twice daily if <25 kg. We excluded patients who received new immune suppressive agents within 2 weeks before initiation of Ruxolitinib from response analysis. Patients were called a treatment failure if Ruxolitinib was stopped before completion of 4 weeks of therapy because of adverse effects and not because of progression of acute GVHD. Thirteen patients received Ruxolitinib, and 11 patients were assessable for response. One patient achieved a complete response, 4 had a partial response, and 2 had no response at 4 weeks after the first Ruxolitinib dose. Four patients were treatment failures. Overall response rate was 45%. Adverse effects (n = 13) included grades 3 to 4 elevated alanine transaminase (n = 7), grades 3 to 4 neutropenia (n = 5), and grade 4 thrombocytopenia (n = 3). Infectious complications in patients included for response analysis (n = 11) were Epstein-Barr viremia (n = 2), adenovirus (n = 2), BK (n = 3), bacterial infections (n = 6), and fungal infections (n = 1). Seven of 13 patients were alive at a median follow-up of 401 days (range, 219 to 969) after HSCT. We observed a high rate of reversible adverse effects in children with steroid-refractory acute GVHD and a fair overall response of Ruxolitinib as a salvage therapeutic agent. Further pharmacokinetic studies are needed to determine the best-tolerated dose of Ruxolitinib that will achieve efficacy without significant adverse effects.

  • jak1 2 inhibition as a salvage therapy for steroid refractory acute and chronic graft versus host disease in pediatric allogeneic hematopoietic stem cell transplant recipients
    2016
    Co-Authors: Pooja Khandelwal, Ashley Teusinkcross, Adam S Nelson, Christopher E Dandoy, Javier Elbietar, Rebecca A Marsh, Ashish Kumar, Michael Grimley, Sonata Jodele, Stella M Davies
    Abstract:

    Introduction: The Jak1/2 inhibitor, Ruxolitinib, is effective as a salvage therapy for steroid refractory (SR) graft versus host disease (GVHD) in adult allogeneic hematopoietic stem cell transplant (HSCT) recipients. The effectiveness of Ruxolitinib for the salvage of SR-GVHD in pediatric HSCT patients has not been studied. Objective: To evaluate ruxolitnib as a salvage therapy for SR- acute GVHD (aGVHD) and chronic GVHD (cGVHD) in pediatric HSCT recipients. Methods: We conducted a retrospective review of pediatric HSCT recipients who received Ruxolitinib for treatment of SR-GVHD at our center. SR aGVHD and cGVHD were defined as lack of response to high dose corticosteroids (1-2 mg/kg/day) for 1 and 3 weeks, respectively. Ruxolitnib was administered orally at 5 mg twice daily for patients weighing ≥ 25 kg or 2.5 mg twice daily if Results: Fifteen patients of median age 8.5 years (range 1.6-16.5 years) received Ruxolitinib for acute (n=13) and chronic (n=2) GVHD. Transplant characteristics are shown in table 1. aGVHD patients: Grades of aGVHD at time of Ruxolitinib administration were grade II (n=2), III (n=9) and IV (n=2). Forty-seven percent (n=6) of patients had acute gastrointestinal (GI) GVHD, 6% (n=1) had acute skin GVHD and the remaining 47% (n=6) had multiple organ involvement. aGVHD was diagnosed at a median of 41 days (20-169 days) and Ruxolitinib was started at a median of 147 days (range 55-538 days) after HSCT. Patients received a median of 4 immune suppressive medications (range 1-6) prior to starting Ruxolitinib. The median initial dose of Ruxolitinib was 5 mg twice daily (range 2.5 mg daily- 5 mg twice daily). Doses were escalated in 11/15 patients, and 9/15 patients reached a maximum dose of 10 mg twice daily. Ruxolitinib was discontinued in 28% (n=3) of patients after 2-9 days and these patients were excluded from response analysis. Patients who received additional immune suppressive agents either 2 weeks prior to starting ruxolitnib (n=2) or after 2 weeks after initiation of Ruxolitinib (n=1) were also excluded. Of the 7 evaluable aGVHD patients, 14% (n=1) had CR and 72% (n=5) had PR at a median of 20.5 days from initiation of Ruxolitinib. NR was observed in 14 %( n=1) patients. Overall response rate of Ruxolitinib was 86%. Durable responses were observed in 43% (n=3) of patients. cGVHD patients: Two patients with severe cGVHD involving skin, eye and GI (n=1), and skin, joints and liver (n=1) received Ruxolitinib at 1486 and 2177 days after HSCT, respectively, at a maximum dose of 10 mg twice daily. One patient had PR in 2.5 weeks and one had NR. Adverse effects in all 15 patients included elevated liver enzymes (n=5; 30%), neutropenia (n=8; 53%) and thrombocytopenia (n=4; 26%) leading to discontinuation of Ruxolitinib in 10/15 patients. Infectious complications in the 9 patients who were evaluated for responses included EBV viremia (n=2; 22%), adenovirus viremia (n=1; 11%), BK viremia (n=3; 33%), bacterial infections (n=5; 55%) and fungal infections (n=1; 11%). At a median follow up of 341 days (range 260-2331 days) after HSCT 55% (n=5) of patients were alive. Conclusion: Ruxolitinib may have a limited role in the durable salvage of acute and chronic SR-GVHD in pediatric HSCT patients and should be used cautiously in patients with pre-existing liver dysfunction or cytopenia. Future large scale studies may be needed to assess the effectiveness of Ruxolitinib in pediatric HSCT patients with SR-GVHD. Disclosures Davies:Novartis: Honoraria.

Javier Elbietar - One of the best experts on this subject based on the ideXlab platform.

  • Ruxolitinib as salvage therapy in steroid refractory acute graft versus host disease in pediatric hematopoietic stem cell transplant patients
    2017
    Co-Authors: Pooja Khandelwal, Ashley Teusinkcross, Adam S Nelson, Christopher E Dandoy, Stella M Davies, Javier Elbietar
    Abstract:

    Abstract We describe our retrospective clinical experience with Ruxolitinib for steroid-refractory acute graft-versus-host disease (GVHD) in pediatric allogeneic hematopoietic stem cell transplant (HSCT) patients. Ruxolitinib was administered orally at 5 mg twice daily for children ≥ 25 kg or 2.5 mg twice daily if

  • Ruxolitinib as salvage therapy in steroid refractory acute graft versus host disease in pediatric hematopoietic stem cell transplant patients
    2017
    Co-Authors: Pooja Khandelwal, Ashley Teusinkcross, Adam S Nelson, Christopher E Dandoy, Stella M Davies, Javier Elbietar
    Abstract:

    We describe our retrospective clinical experience with Ruxolitinib for steroid-refractory acute graft-versus-host disease (GVHD) in pediatric allogeneic hematopoietic stem cell transplant (HSCT) patients. Ruxolitinib was administered orally at 5 mg twice daily for children ≥ 25 kg or 2.5 mg twice daily if <25 kg. We excluded patients who received new immune suppressive agents within 2 weeks before initiation of Ruxolitinib from response analysis. Patients were called a treatment failure if Ruxolitinib was stopped before completion of 4 weeks of therapy because of adverse effects and not because of progression of acute GVHD. Thirteen patients received Ruxolitinib, and 11 patients were assessable for response. One patient achieved a complete response, 4 had a partial response, and 2 had no response at 4 weeks after the first Ruxolitinib dose. Four patients were treatment failures. Overall response rate was 45%. Adverse effects (n = 13) included grades 3 to 4 elevated alanine transaminase (n = 7), grades 3 to 4 neutropenia (n = 5), and grade 4 thrombocytopenia (n = 3). Infectious complications in patients included for response analysis (n = 11) were Epstein-Barr viremia (n = 2), adenovirus (n = 2), BK (n = 3), bacterial infections (n = 6), and fungal infections (n = 1). Seven of 13 patients were alive at a median follow-up of 401 days (range, 219 to 969) after HSCT. We observed a high rate of reversible adverse effects in children with steroid-refractory acute GVHD and a fair overall response of Ruxolitinib as a salvage therapeutic agent. Further pharmacokinetic studies are needed to determine the best-tolerated dose of Ruxolitinib that will achieve efficacy without significant adverse effects.

  • jak1 2 inhibition as a salvage therapy for steroid refractory acute and chronic graft versus host disease in pediatric allogeneic hematopoietic stem cell transplant recipients
    2016
    Co-Authors: Pooja Khandelwal, Ashley Teusinkcross, Adam S Nelson, Christopher E Dandoy, Javier Elbietar, Rebecca A Marsh, Ashish Kumar, Michael Grimley, Sonata Jodele, Stella M Davies
    Abstract:

    Introduction: The Jak1/2 inhibitor, Ruxolitinib, is effective as a salvage therapy for steroid refractory (SR) graft versus host disease (GVHD) in adult allogeneic hematopoietic stem cell transplant (HSCT) recipients. The effectiveness of Ruxolitinib for the salvage of SR-GVHD in pediatric HSCT patients has not been studied. Objective: To evaluate ruxolitnib as a salvage therapy for SR- acute GVHD (aGVHD) and chronic GVHD (cGVHD) in pediatric HSCT recipients. Methods: We conducted a retrospective review of pediatric HSCT recipients who received Ruxolitinib for treatment of SR-GVHD at our center. SR aGVHD and cGVHD were defined as lack of response to high dose corticosteroids (1-2 mg/kg/day) for 1 and 3 weeks, respectively. Ruxolitnib was administered orally at 5 mg twice daily for patients weighing ≥ 25 kg or 2.5 mg twice daily if Results: Fifteen patients of median age 8.5 years (range 1.6-16.5 years) received Ruxolitinib for acute (n=13) and chronic (n=2) GVHD. Transplant characteristics are shown in table 1. aGVHD patients: Grades of aGVHD at time of Ruxolitinib administration were grade II (n=2), III (n=9) and IV (n=2). Forty-seven percent (n=6) of patients had acute gastrointestinal (GI) GVHD, 6% (n=1) had acute skin GVHD and the remaining 47% (n=6) had multiple organ involvement. aGVHD was diagnosed at a median of 41 days (20-169 days) and Ruxolitinib was started at a median of 147 days (range 55-538 days) after HSCT. Patients received a median of 4 immune suppressive medications (range 1-6) prior to starting Ruxolitinib. The median initial dose of Ruxolitinib was 5 mg twice daily (range 2.5 mg daily- 5 mg twice daily). Doses were escalated in 11/15 patients, and 9/15 patients reached a maximum dose of 10 mg twice daily. Ruxolitinib was discontinued in 28% (n=3) of patients after 2-9 days and these patients were excluded from response analysis. Patients who received additional immune suppressive agents either 2 weeks prior to starting ruxolitnib (n=2) or after 2 weeks after initiation of Ruxolitinib (n=1) were also excluded. Of the 7 evaluable aGVHD patients, 14% (n=1) had CR and 72% (n=5) had PR at a median of 20.5 days from initiation of Ruxolitinib. NR was observed in 14 %( n=1) patients. Overall response rate of Ruxolitinib was 86%. Durable responses were observed in 43% (n=3) of patients. cGVHD patients: Two patients with severe cGVHD involving skin, eye and GI (n=1), and skin, joints and liver (n=1) received Ruxolitinib at 1486 and 2177 days after HSCT, respectively, at a maximum dose of 10 mg twice daily. One patient had PR in 2.5 weeks and one had NR. Adverse effects in all 15 patients included elevated liver enzymes (n=5; 30%), neutropenia (n=8; 53%) and thrombocytopenia (n=4; 26%) leading to discontinuation of Ruxolitinib in 10/15 patients. Infectious complications in the 9 patients who were evaluated for responses included EBV viremia (n=2; 22%), adenovirus viremia (n=1; 11%), BK viremia (n=3; 33%), bacterial infections (n=5; 55%) and fungal infections (n=1; 11%). At a median follow up of 341 days (range 260-2331 days) after HSCT 55% (n=5) of patients were alive. Conclusion: Ruxolitinib may have a limited role in the durable salvage of acute and chronic SR-GVHD in pediatric HSCT patients and should be used cautiously in patients with pre-existing liver dysfunction or cytopenia. Future large scale studies may be needed to assess the effectiveness of Ruxolitinib in pediatric HSCT patients with SR-GVHD. Disclosures Davies:Novartis: Honoraria.

Srdan Verstovsek - One of the best experts on this subject based on the ideXlab platform.

  • characteristics and outcome of myelofibrosis patients on long term Ruxolitinib therapy 3 years
    2020
    Co-Authors: Lucia Masarova, Hagop M. Kantarjian, Prithviraj Bose, Zeev Estrov, Sherry Pierce, Naveen Pemmaraju, Lingsha Zhou, Srdan Verstovsek
    Abstract:

    Introduction: The JAK1/2 inhibitor, Ruxolitinib, was approved in the USA in 2011 for the treatment of patients with myelofibrosis (MF) with intermediate and high-risk IPSS score (International Prognostic Scoring System). In the approval phase 3 COMFORT 1 - 2 studies, about 50% patients were taking Ruxolitinib for at least 3 years, respectively. Objective: We sought to evaluate the characteristics and outcome of MF patients on long-term Ruxolitinib therapy (≥3 years) at our center. Methods: We retrospectively reviewed the charts of patients with MF who were treated with Ruxolitinib for ≥3 years. Cytogenetic were classified into risks according to Gangat et all, JCO, 2011. Descriptive statistics were used for nominal and continues variables, captured at the time of Ruxolitinib start. Duration of therapy and overall survival (OS) were estimated using the Kaplan-Meier method, from the start of Ruxolitinib initiation until the last day of initial Ruxolitinib therapy, the date of last follow-up or death, respectively. Response to therapy was according to IWG-MRT 2013 criteria. Results: Among 437 patients who initiated therapy with Ruxolitinib at our center, 136 (31%) remained on therapy for ≥3 years and represent current cohort. Ninety-one patients (67%) were newly diagnosed; the remaining patients presented after a median of 28 months (range, 4-228) from MF diagnosis. Median time to initiate Ruxolitinib from presentation to our center was 1 month (range, 0.3-123) for all patients. However, the time was longer for patients who presented > 3 months from MF diagnosis (median of 11.5 months; range, 3.5-123). Patient’s characteristics (n = 136) at the time of Ruxolitinib initiation are summarized in Table 1. Median age was 67 years (range, 32-84), and 76 (56%) of patients were males. Half of the patients had high risk IPSS score, > 80% had systemic symptoms or splenomegaly. Eighty six percent of patients had diploid or favorable karyotype. JAK2 mutation was detected in 87% of tested patients. Median duration of Ruxolitinib therapy was 72 months (95% CI: 66-78). Over the median follow-up of 83 months (range, 36-174), 63 patients (46%) died. Currently, 48 (35%) patients are still on Ruxolitinib; 88 discontinued therapy after a median time of 55 months (range, 47-63). By 5th and 7th year of therapy, out of 136 patients that were treated for at least 3 years, 35% and 65% percent of patients discontinued treatment. The reasons for discontinuation included allogeneic stem cell transplantation (SCT, n 5), cytopenia (n 6), progression of MF (n 38), progression to accelerate phase (n 2) or acute leukemia (n 7), patient's choice (n 11), and death (n 23: infection 4, cardiac 3, cancer 3, others 16). Overall, 101 patients (74%) achieved IWG-MRT response, represented in majority by clinical improvement (CI) in spleen (n 90, 84%) and CI in TSS (n 51, 71%), respectively. The remaining patients achieved clinical benefit not qualifying for overall IWG-MRT response. Median duration of IWG-MRT response was 55 months (95% CI: 48-63). Responses were ongoing in 29 patients (29% of initial responders) at the time of last follow-up. Median duration of therapy was 75 months (95% CI: 68-82) for responders vs 60 months (95% CI: 39-79) for non-responders, p = 0.74. Median OS from the start of Ruxolitinib was 90 months (95% CI: 76-104), Figure 1. Median OS for patients who were on Ruxolitinib for ≥5 years (n = 73) was 106 months (95% CI: 80-137). Univariate and multivariate analysis for factors associated with OS is shown in Table 2. After Ruxolitinib discontinuation, 25 patients received subsequent treatment at our center: SCT in 6, another JAK inhibitor in 11, other investigational agents in 3, chemotherapy in 5 patients. Median OS from Ruxolitinib discontinuation was 20 months (95% CI: 12-28). Conclusion: Our data with the longest follow-up of patients receiving Ruxolitinib for ≥3 years confirm the long-term benefit of this therapy with a median OS approaching 8 years since Ruxolitinib treatment initiation. Download : Download high-res image (359KB) Download : Download full-size image Disclosures Bose: Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Blueprint Medicines Corporation: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Pfizer, Inc.: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; CTI BioPharma: Honoraria, Research Funding; NS Pharma: Research Funding. Pemmaraju: AbbVie: Honoraria, Research Funding; Incyte Corporation: Honoraria; MustangBio: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Plexxikon: Research Funding; Celgene: Honoraria; Blueprint Medicines: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Novartis: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; LFB Biotechnologies: Honoraria; Roche Diagnostics: Honoraria; SagerStrong Foundation: Other: Grant Support; DAVA Oncology: Honoraria; Samus Therapeutics: Research Funding; Cellectis: Research Funding. Kantarjian: Daiichi-Sankyo: Research Funding; Ariad: Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Jazz Pharma: Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding. Verstovsek: Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; AstraZeneca: Research Funding; Roche: Research Funding; Genentech: Research Funding; Novartis: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Blueprint Medicines Corp: Research Funding; PharmaEssentia: Research Funding; Sierra Oncology: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding.

  • A phase Ib study to assess the efficacy and safety of vismodegib in combination with Ruxolitinib in patients with intermediate- or high-risk myelofibrosis
    2018
    Co-Authors: Stephen Couban, Srdan Verstovsek, Steffen Koschmieder, Giulia Benevolo, William Donnellan, Jennifer Cultrera, Gregory Hooper, Christian Hertig, Maneesh Tandon, Natalie Dimier
    Abstract:

    Abstract Background The JAK inhibitor (JAKi) Ruxolitinib is standard treatment for myelofibrosis (MF), but some patients are unresponsive. Pre-clinical and clinical data suggest that addition of a Hedgehog pathway inhibitor (HPI) to Ruxolitinib might improve response. Vismodegib is an HPI approved for treatment of locally advanced and metastatic basal cell carcinoma. The MYLIE study assessed the safety and efficacy of combining Ruxolitinib with vismodegib in Ruxolitinib-naive patients with MF and characterized the pharmacokinetics (PK) of vismodegib in this setting. Methods In this phase Ib study, ten patients with intermediate- or high-risk primary or secondary MF received open-label vismodegib (150 mg/day orally) and Ruxolitinib (15 or 20 mg orally twice daily, depending on baseline platelet count) for up to 48 weeks, or until withdrawal or discontinuation. PK samples were collected throughout the study for comparison with other patient populations. Efficacy outcomes at week 24 included spleen response (≥ 35% reduction in volume by imaging) and improvement in bone marrow fibrosis by central and investigator assessment, symptom response (≥ 50% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom score), and anemia response (per International Working Group for Myeloproliferative Neoplasms Research and Treatment revised response criteria). Results As of November 17, 2017, eight patients had completed 48 weeks of treatment with vismodegib and Ruxolitinib; two discontinued treatment early. At week 24 (± 1 week), three patients experienced a spleen response by central review and no patients showed a 1-grade improvement in bone marrow fibrosis by central review. Five patients experienced symptom response at week 24, and no patients experienced an anemia response. The most common adverse events were muscle spasm (100% of patients), alopecia (70%), dysgeusia (50%), thrombocytopenia (50%), and nausea (40%); these events were predominantly grade 1/2. Three patients experienced a total of six serious adverse events. Conclusions The combination of vismodegib and Ruxolitinib was tolerable and no new safety signals were seen, but there was no evidence that the addition of vismodegib to Ruxolitinib improved any of the efficacy outcome measures assessed. Further evaluation of this combination will not be pursued. Trial registration ClinicalTrials.gov, NCT02593760. Registered November 2, 2015

  • long term survival in patients treated with Ruxolitinib for myelofibrosis comfort i and ii pooled analyses
    2017
    Co-Authors: Srdan Verstovsek, Ruben A Mesa, Jason Gotlib, Claire N Harrison, Alessandro M Vannucchi, Jeanjacques Kiladjian, Francisco Cervantes, Ronald Paquette, William Sun, Ahmad Naim
    Abstract:

    Myelofibrosis (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. This 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. A 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. These 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. ClinicalTrials.gov identifiers, NCT00952289 and NCT00934544 .

  • a phase 2 study of simtuzumab in patients with primary post polycythaemia vera or post essential thrombocythaemia myelofibrosis
    2017
    Co-Authors: Srdan Verstovsek, Ruben A Mesa, Michael R Savona, Hua Dong, Julia D Maltzman, Shringi Sharma, Jeffrey A Silverman, Jason Gotlib
    Abstract:

    Summary Simtuzumab, a monoclonal antibody inhibitor of extracellular matrix enzyme lysyl oxidase-like-2, showed preclinical promise and was well tolerated in clinical studies. A phase 2, open-label study of simtuzumab was conducted in patients with primary myelofibrosis (MF), post-polycythaemia vera MF and post-essential thrombocythaemia MF. Fifty-four patients were randomized to receive simtuzumab alone (200 or 700 mg [n = 12 each group]) or simtuzumab (200 or 700 mg) with Ruxolitinib (n = 15 each group) for 24 weeks. Simtuzumab alone or in combination with Ruxolitinib showed no clinical benefit at 24 weeks. The mean serum simtuzumab trough concentrations appeared to increase dose-proportionally between the 200-mg and 700-mg treatment groups. Therapy-related serious adverse events were pyrexia, pain in extremity (both in 1 patient) and infusion reaction (in another patient). Bone marrow fibrosis (BMF) score was reduced at 24 weeks in 2 patients (16·7%) in the simtuzumab 700-mg group, 1 (6·7%) in the simtuzumab 200-mg + Ruxolitinib group, and 2 (13·3%) in the simtuzumab 700-mg + Ruxolitinib group; similar numbers of patients had increased BMF. Simtuzumab alone or with Ruxolitinib was well tolerated but did not produce clinical benefit nor consistently reduce BMF in patients with MF by 24 weeks.

  • long term treatment with Ruxolitinib for patients with myelofibrosis 5 year update from the randomized double blind placebo controlled phase 3 comfort i trial
    2017
    Co-Authors: Srdan Verstovsek, Ruben A Mesa, Jason Gotlib, Vikas Gupta, John F Dipersio, John Catalano, Michael W Deininger, Carole B Miller, Richard T Silver, Moshe Talpaz
    Abstract:

    The randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial evaluated the JAK1/JAK2 inhibitor Ruxolitinib in patients with intermediate-2/high-risk myelofibrosis. The primary and planned 3-year analyses of COMFORT-I data demonstrated that Ruxolitinib—the first myelofibrosis-approved therapy—reduced splenomegaly and prolonged overall survival versus placebo. Here, we present the final 5-year results. Patients managed in Australia, Canada, and the USA were randomized centrally (interactive voice response system) 1:1 to oral Ruxolitinib twice daily (15 or 20 mg per baseline platelet counts) or placebo. Investigators and patients were blinded to treatment. The secondary endpoints evaluated in this analysis were durability of a ≥35% reduction from baseline in spleen volume (spleen response) and overall survival, evaluated in the intent-to-treat population. Safety was evaluated in patients who received study treatment. Patients were randomized (September 2009–April 2010) to Ruxolitinib (n = 155) or placebo (n = 154). At termination, 27.7% of Ruxolitinib-randomized patients and 25.2% (28/111) who crossed over from placebo were on treatment; no patients remained on placebo. Patients randomized to Ruxolitinib had a median spleen response duration of 168.3 weeks and prolonged median overall survival versus placebo (Ruxolitinib group, not reached; placebo group, 200 weeks; HR, 0.69; 95% CI, 0.50–0.96; P = 0.025) despite the crossover to Ruxolitinib. The Ruxolitinib safety profile remained consistent with previous analyses. The most common new-onset all-grade nonhematologic adverse events starting <12 versus ≥48 months after Ruxolitinib initiation were fatigue (29.0 vs 33.3%) and diarrhea (27.8 vs 14.6%). New-onset grade 3 or 4 anemia and thrombocytopenia both primarily occurred within the first 6 months, with no cases after 42 months. The most common treatment-emergent adverse event-related deaths in the Ruxolitinib-randomized group were sepsis (2.6%), disease progression (1.9%), and pneumonia (1.9%). The final COMFORT-I results continue to support Ruxolitinib as an effective treatment for patients with intermediate-2/high-risk MF. ClinicalTrials.gov, NCT00952289

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  • Ruxolitinib as salvage therapy in steroid refractory acute graft versus host disease in pediatric hematopoietic stem cell transplant patients
    2017
    Co-Authors: Pooja Khandelwal, Ashley Teusinkcross, Adam S Nelson, Christopher E Dandoy, Stella M Davies, Javier Elbietar
    Abstract:

    Abstract We describe our retrospective clinical experience with Ruxolitinib for steroid-refractory acute graft-versus-host disease (GVHD) in pediatric allogeneic hematopoietic stem cell transplant (HSCT) patients. Ruxolitinib was administered orally at 5 mg twice daily for children ≥ 25 kg or 2.5 mg twice daily if

  • Ruxolitinib as salvage therapy in steroid refractory acute graft versus host disease in pediatric hematopoietic stem cell transplant patients
    2017
    Co-Authors: Pooja Khandelwal, Ashley Teusinkcross, Adam S Nelson, Christopher E Dandoy, Stella M Davies, Javier Elbietar
    Abstract:

    We describe our retrospective clinical experience with Ruxolitinib for steroid-refractory acute graft-versus-host disease (GVHD) in pediatric allogeneic hematopoietic stem cell transplant (HSCT) patients. Ruxolitinib was administered orally at 5 mg twice daily for children ≥ 25 kg or 2.5 mg twice daily if <25 kg. We excluded patients who received new immune suppressive agents within 2 weeks before initiation of Ruxolitinib from response analysis. Patients were called a treatment failure if Ruxolitinib was stopped before completion of 4 weeks of therapy because of adverse effects and not because of progression of acute GVHD. Thirteen patients received Ruxolitinib, and 11 patients were assessable for response. One patient achieved a complete response, 4 had a partial response, and 2 had no response at 4 weeks after the first Ruxolitinib dose. Four patients were treatment failures. Overall response rate was 45%. Adverse effects (n = 13) included grades 3 to 4 elevated alanine transaminase (n = 7), grades 3 to 4 neutropenia (n = 5), and grade 4 thrombocytopenia (n = 3). Infectious complications in patients included for response analysis (n = 11) were Epstein-Barr viremia (n = 2), adenovirus (n = 2), BK (n = 3), bacterial infections (n = 6), and fungal infections (n = 1). Seven of 13 patients were alive at a median follow-up of 401 days (range, 219 to 969) after HSCT. We observed a high rate of reversible adverse effects in children with steroid-refractory acute GVHD and a fair overall response of Ruxolitinib as a salvage therapeutic agent. Further pharmacokinetic studies are needed to determine the best-tolerated dose of Ruxolitinib that will achieve efficacy without significant adverse effects.

  • jak1 2 inhibition as a salvage therapy for steroid refractory acute and chronic graft versus host disease in pediatric allogeneic hematopoietic stem cell transplant recipients
    2016
    Co-Authors: Pooja Khandelwal, Ashley Teusinkcross, Adam S Nelson, Christopher E Dandoy, Javier Elbietar, Rebecca A Marsh, Ashish Kumar, Michael Grimley, Sonata Jodele, Stella M Davies
    Abstract:

    Introduction: The Jak1/2 inhibitor, Ruxolitinib, is effective as a salvage therapy for steroid refractory (SR) graft versus host disease (GVHD) in adult allogeneic hematopoietic stem cell transplant (HSCT) recipients. The effectiveness of Ruxolitinib for the salvage of SR-GVHD in pediatric HSCT patients has not been studied. Objective: To evaluate ruxolitnib as a salvage therapy for SR- acute GVHD (aGVHD) and chronic GVHD (cGVHD) in pediatric HSCT recipients. Methods: We conducted a retrospective review of pediatric HSCT recipients who received Ruxolitinib for treatment of SR-GVHD at our center. SR aGVHD and cGVHD were defined as lack of response to high dose corticosteroids (1-2 mg/kg/day) for 1 and 3 weeks, respectively. Ruxolitnib was administered orally at 5 mg twice daily for patients weighing ≥ 25 kg or 2.5 mg twice daily if Results: Fifteen patients of median age 8.5 years (range 1.6-16.5 years) received Ruxolitinib for acute (n=13) and chronic (n=2) GVHD. Transplant characteristics are shown in table 1. aGVHD patients: Grades of aGVHD at time of Ruxolitinib administration were grade II (n=2), III (n=9) and IV (n=2). Forty-seven percent (n=6) of patients had acute gastrointestinal (GI) GVHD, 6% (n=1) had acute skin GVHD and the remaining 47% (n=6) had multiple organ involvement. aGVHD was diagnosed at a median of 41 days (20-169 days) and Ruxolitinib was started at a median of 147 days (range 55-538 days) after HSCT. Patients received a median of 4 immune suppressive medications (range 1-6) prior to starting Ruxolitinib. The median initial dose of Ruxolitinib was 5 mg twice daily (range 2.5 mg daily- 5 mg twice daily). Doses were escalated in 11/15 patients, and 9/15 patients reached a maximum dose of 10 mg twice daily. Ruxolitinib was discontinued in 28% (n=3) of patients after 2-9 days and these patients were excluded from response analysis. Patients who received additional immune suppressive agents either 2 weeks prior to starting ruxolitnib (n=2) or after 2 weeks after initiation of Ruxolitinib (n=1) were also excluded. Of the 7 evaluable aGVHD patients, 14% (n=1) had CR and 72% (n=5) had PR at a median of 20.5 days from initiation of Ruxolitinib. NR was observed in 14 %( n=1) patients. Overall response rate of Ruxolitinib was 86%. Durable responses were observed in 43% (n=3) of patients. cGVHD patients: Two patients with severe cGVHD involving skin, eye and GI (n=1), and skin, joints and liver (n=1) received Ruxolitinib at 1486 and 2177 days after HSCT, respectively, at a maximum dose of 10 mg twice daily. One patient had PR in 2.5 weeks and one had NR. Adverse effects in all 15 patients included elevated liver enzymes (n=5; 30%), neutropenia (n=8; 53%) and thrombocytopenia (n=4; 26%) leading to discontinuation of Ruxolitinib in 10/15 patients. Infectious complications in the 9 patients who were evaluated for responses included EBV viremia (n=2; 22%), adenovirus viremia (n=1; 11%), BK viremia (n=3; 33%), bacterial infections (n=5; 55%) and fungal infections (n=1; 11%). At a median follow up of 341 days (range 260-2331 days) after HSCT 55% (n=5) of patients were alive. Conclusion: Ruxolitinib may have a limited role in the durable salvage of acute and chronic SR-GVHD in pediatric HSCT patients and should be used cautiously in patients with pre-existing liver dysfunction or cytopenia. Future large scale studies may be needed to assess the effectiveness of Ruxolitinib in pediatric HSCT patients with SR-GVHD. Disclosures Davies:Novartis: Honoraria.