Post-essential Thrombocythemia Myelofibrosis Research Articles

Abstract CT253: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Parsaclisib Plus Ruxolitinib in Patients with Myelofibrosis Who Have Suboptimal Response to Ruxolitinib

Abstract Background: Ruxolitinib (JAK1/JAK2 inhibitor) is indicated for the treatment of adults with intermediate (INT) or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF, but a subset of patients may exhibit a suboptimal response due to possible persistent PI3K/AKT activation. Targeting PI3K/AKT signaling may therefore have clinically relevant effects on MF disease burden. This phase 3, randomized, double-blind, placebo-controlled study will determine the effect of add-on parsaclisib, a highly selective PI3Kδ inhibitor, on signs and symptoms of MF in patients with suboptimal or declining response to stable ruxolitinib treatment (INCB 50465-304; NCT04551053). Methods: Eligible patients are aged ≥18 years with a diagnosis of at least INT-1-risk category according to the Dynamic International Prognostic Scoring System (DIPSS; Passamonti. Blood. 2010;115:1703-1708) primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF, have received ruxolitinib for ≥3 months with a stable dose (5-25 mg twice daily) for ≥8 weeks prior to receiving the first dose of study drug (Day 1), have evidence of suboptimal response to ruxolitinib (palpable spleen ≥5 cm below left subcostal margin, and total symptom score ≥10), and ECOG PS ≤2. Patients are excluded if they received prior therapy with any PI3K inhibitor, experimental or standard drug therapy for MF (except ruxolitinib) within 3 months of starting study drug, or have platelet count <50×109/L, recent history of inadequate bone marrow reserve, or inadequate liver or renal function at screening. Approximately 212 patients on a stable dose of ruxolitinib will be randomized (1:1) to receive add-on parsaclisib 5 mg daily or matching placebo beginning on Day 1, with stratification by platelet count (≥100×109/L or 50 to <100×109/L) and DIPSS risk category (high, INT-2, or INT-1) at randomization. Treatment will continue as long as tolerated and discontinuation criteria are not met. Upon patient completion of 24 weeks of treatment, he/she will be unblinded and if randomized to ruxolitinib plus placebo and with adequate hematology parameters, the patient will be able to crossover to receive ruxolitinib plus add-on parsaclisib. The primary objective is to evaluate and compare the efficacy of add-on parsaclisib versus placebo on spleen volume at Week 24. Secondary objectives are to evaluate and compare the effect of add-on parsaclisib versus placebo on: patient-reported MF symptoms, overall survival, time to onset and duration of spleen volume response, and safety and tolerability. Sites are opening throughout the US, EU, China and Japan. Citation Format: Abdulraheem Yacoub, Michael Stouffs, Feng Zhou, Albert Assad. A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Parsaclisib Plus Ruxolitinib in Patients with Myelofibrosis Who Have Suboptimal Response to Ruxolitinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT253.

Abstract CT252: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Ruxolitinib Plus Parsaclisib in Patients with JAK- and PI3K-Inhibitor Treatment-Naïve Myelofibrosis

Abstract Background: Ruxolitinib (JAK1/JAK2 inhibitor) significantly improves outcomes in patients with myelofibrosis (MF); however, a subset of patients may experience a suboptimal response. Recent phase 2 data showed that addition of PI3Kδ inhibitor parsaclisib to ruxolitinib monotherapy resulted in additional alleviation of MF symptoms and splenomegaly in patients with MF (Yacoub. EHA2020. S216). This phase 3, randomized, double-blind study (INCB 50465-313; NCT04551066), evaluates the combination of ruxolitinib and parsaclisib in patients with MF who are naïve to Janus kinase (JAK) and PI3K inhibitor therapies. Methods: Eligible patients are aged ≥18 years with a diagnosis of primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, have a Dynamic International Prognostic Scoring System (DIPSS; Passamonti. Blood. 2010;115:1703-1708) risk category of at least Intermediate (INT)-1, palpable spleen ≥5 cm below left subcostal margin, total symptom score ≥10 at screening, ECOG PS 0-2, and life expectancy ≥24 weeks. Patients will be excluded if they previously received therapy with any JAK inhibitor, any PI3K inhibitor, any experimental or standard drug therapy for MF within 3 months of first study dose and/or lack of recovery from all toxicities related to previous therapies to grade ≤1, have recent history of inadequate bone marrow reserve (eg, platelet count <50×109/L) or have inadequate liver or renal function at screening. Approximately 440 patients will be randomized (1:1) to ruxolitinib plus parsaclisib 5 mg QD or ruxolitinib plus matching placebo, with stratification at randomization by DIPSS risk category (high vs INT-2 vs INT-1) and platelet count (≥100×109/L vs 50 to <100×109/L inclusive). Treatment will begin on Day 1, with starting ruxolitinib dose level determined by baseline platelet count, and will continue as long as treatment is tolerated and discontinuation criteria are not met. When the last enrolled patient has completed 24 weeks of treatment, the study will be unblinded and patients randomized to ruxolitinib plus placebo who have adequate hematology parameters will be able to crossover to receive parsaclisib together with continued ruxolitinib. The primary objective is the evaluation and comparison of spleen volume at Week 24 for patients who received ruxolitinib plus parsaclisib versus ruxolitinib plus placebo. Secondary objectives include evaluation and comparison of patient-reported MF symptoms, overall survival, time to onset and duration of response in spleen volume, and safety and tolerability for ruxolitinib plus parsaclisib versus ruxolitinib plus placebo. Sites are opening across the US, Canada, EU, and Asia. Citation Format: Abdulraheem Yacoub, Sue Erickson-Viitanen, Feng Zhou, Albert Assad. A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Ruxolitinib Plus Parsaclisib in Patients with JAK- and PI3K-Inhibitor Treatment-Naïve Myelofibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT252.

Abstract CT236: A Two-Part Phase 2 Study of Itacitinib Immediate Release in Patients with Primary or Secondary Myelofibrosis Who Have Received Prior Ruxolitinib and/or Fedratinib Monotherapy

Abstract Background: Ruxolitinib (JAK1/JAK2 inhibitor) and fedratinib (JAK2/FLT3 inhibitor) are indicated in the US for myelofibrosis (MF); however, some patients fail to achieve adequate/sustained response to initial JAK-inhibitor therapy. Itacitinib is a potent JAK inhibitor selective for JAK1 over JAK2 when administered as a once-daily sustained-release (SR) formulation. In prior clinical trials, the SR formulation improved MF-related symptoms but had less effect with respect to spleen volume reduction. When dosed as a twice-daily (BID) immediate release (IR) formulation, itacitinib may offer increased JAK2 inhibition (in addition to JAK1 inhibition) to better address the JAK2-mediated myeloproliferative features of MF. This open-label phase 2 study is designed to determine a tolerable and safe dose of itacitinib IR that results in clinically significant reductions in symptoms and spleen volume in patients with MF who have previously received ruxolitinib and/or fedratinib monotherapy (INCB 39110-213; NCT04629508). Methods: Eligible patients are aged ≥18 years, diagnosed with at least INT-1 risk (Dynamic International Prognostic Scoring System [Passamonti. Blood. 2010;115:1703-1708]) primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF and have received ruxolitinib and/or fedratinib monotherapy. Patients must also have palpable splenomegaly and platelets ≥50×109/L at screening. Exclusion criteria include receipt of a JAK inhibitor other than ruxolitinib or fedratinib, ≥10% myeloid blasts in peripheral blood or bone marrow, or inability to taper ruxolitinib/fedratinib over 14 days without use of other agents. Two itacitinib IR dose levels (DLs) will be evaluated in part 1 following a Bayesian optimal interval design algorithm: 3-9 patients will be enrolled at DL1 (300 mg BID) and observed for 28 days for dose-limiting toxicity before enrollment at DL2 (600 mg BID). Part 2 will enroll ~55 patients at the recommended phase 2 dose (RP2D) determined in part 1. Patients may remain on treatment until week 48 if they are receiving clinical benefit and have not met study withdrawal criteria. A safety follow-up will occur 30 days after treatment completion. Primary objectives: part 1 - evaluate safety and tolerability of itacitinib IR and select the RP2D; part 2 - evaluate efficacy of itacitinib IR at the RP2D based on spleen volume reduction at week 24. Secondary objectives (part 2 only): evaluate safety and tolerability of itacitinib IR; evaluate efficacy of itacitinib IR with respect to MF symptom improvement at week 24 in patients with baseline total symptom score ≥10, quality-of-life improvement, and patient global impression of change. Sites are opening in the US and EU. Citation Format: Andrew T. Kuykendall, Lea Burke, Mani Lakshminarayanan, Philomena Colucci. A Two-Part Phase 2 Study of Itacitinib Immediate Release in Patients with Primary or Secondary Myelofibrosis Who Have Received Prior Ruxolitinib and/or Fedratinib Monotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT236.

Sotatercept (ACE-011) Alone and in Combination with Ruxolitinib in Patients (pts) with Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis (MF) and Anemia

Sotatercept (ACE-011) Alone and in Combination with Ruxolitinib in Patients (pts) with Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis (MF) and Anemia

Validation of the Myelofibrosis Secondary to PV and ET-Prognostic Model in Patients with Post-Polycythemia Vera and Post-Essential Thrombocythemia Myelofibrosis: MD Anderson Cancer Center

Validation of the Myelofibrosis Secondary to PV and ET-Prognostic Model in Patients with Post-Polycythemia Vera and Post-Essential Thrombocythemia Myelofibrosis: MD Anderson Cancer Center

Incidence of Infections and Second Cancers in Philadelphia Chromosome-Negative Patients with Myeloproliferative Neoplasms Treated with Ruxolitinib

Introduction:This is a retrospective, case-control study evaluating the incidence of infections and second cancers in Philadelphia-chromosome negative (Ph-) myeloproliferative neoplasm (MPN) patients treated with ruxolitinib, a JAK1/JAK2 tyrosine kinase inhibitor approved for treating patients with polycythemia vera (PV), primary myelofibrosis (PMF), post-essential thrombocythemia myelofibrosis (PET-MF), and post-polycythemia vera myelofibrosis (PPV-MF) [1]. These patients are at significant risk for infections and second cancers when treated with long-term ruxolitinib. Similar observations have been reported in the COMFORT-II clinical trial findings, which studied ruxolitinib use in myelofibrosis (MF) patients [2], and have real-world clinical implications.Methods:128 MPN patients treated with ruxolitinib were studied and matched with 122 control patients based on gender, disease subtype, and age at the beginning of an MPN treatment (± 5 years). All evidence of infections and second cancers during this treatment regimen were recorded.Results:MPN patients whose mean age was 67.2±11.2 years when starting ruxolitinib treatment were studied, among whom myelofibrosis (38.3%) and PV (33.6%) were the leading subtypes. Of patients in the ruxolitnib cohort, 60/128 (46.9%) presented with ≥1 infection and a second cancer occurred in 13/128 (10.2%) patients. Of patients in the control cohort, 37/122 (30.3%) presented with ≥1 infection and a second cancer occurred in 6/122 (4.9%) patients. The difference of these proportions was significant for both infections (p=0.0072, RR=1.5456) and second cancers (p=0.0006, RR=2.0651) (Graph 1). Types of infections and cancers are summarized in Table 1a, Table 1b, and Table 2 . Of note, 2 patients treated with ruxolitinib had tuberculosis (TB) reactivations and 1 patient had pulmonary aspergillosis. All 13 of the patients that were diagnosed with a second cancer after being treated with ruxolitinib were found to have ≥1 skin cancer.Stratification of the incidence of these events by gender shows a trend for females treated with ruxolitinib with a higher relative risk (RR) of developing cancer than males of the same cohort (RR: 6.8971 for females, 0.4385 for males) (Table 3) . Serial upper respiratory infections (URIs) and urinary tract infections (UTIs) were of higher incidence in the ruxolitinib cohort than in the control cohort. In the ruxolitinib cohort, 7/21 (33.3%) and 5/12 (41.7%) experienced serial URIs and UTIs, respectively. In the control cohort, 1/9 (11.1%) and 0/8 (0.0%) experienced serial URIs and UTIs, respectively. 29/128 (22.7%) of the ruxolitinib cohort and 14/123 (11.4%) of the control cohort developed ≥2 different types of infections (p=0.0217, RR=1.9905).When compared to the control cohort, patients in the ruxolitinib cohort were found to have a higher incidence of recurring neutropenia (ruxolitinib: 35/128 (27.3%), control: 22/123 (17.9%), p=0.0782, RR=1.5288). The ruxolitnib cohort had a higher incidence of elevated ferritin than the control cohort (ruxolitinib: 26/128 (20.3%), control: 6/123 (4.9%), p=0.0010, RR=4.1641). Elevated ferritin could be a factor contributing to the increased risk of developing certain types of infections owing to iron overload [3].Conclusions:Long-term ruxolitinib treatment in Ph- MPN patients has resulted in an increased risk of infections and second cancers when compared to a matched control cohort. Those patients also had significantly higher ferritin levels which may contribute to the increased risk of certain infections. The risk of secondary cancer was much higher in the ruxolitinib group and especially in females. The significant proportion of ruxolitinib-treated patients who developed skin cancer (13/128, 10.2%) emphasizes the importance of skin cancer screening in these patients. [Display omitted] DisclosuresRitchie:Astellas Pharma: Other: Research funding to my institution; NS Pharma: Other: Research funding to my institution; Bristol-Myers Squibb: Other: Research funding to my institution; Celgene: Consultancy, Other: Travel, Speakers Bureau; Pfizer: Consultancy, Other: Research funding to my institution; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Research funding to my institution, and travel, Speakers Bureau. Roboz:Cellectis: Research Funding; AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy. Lee:Amgen: Consultancy; Baxalta: Consultancy; Alexion Pharmaceuticals: Consultancy; Clinipace: Consultancy.

The Relationship between Cause of Death in Myelofibrosis and the Dynamic International Prognostic Scoring System

Background:The Dynamic International Prognostic Scoring System (DIPSS) and DIPSS Plus are well established systems for providing prognoses to patients with primary myelofibrosis. Five risk factors are included in the DIPSS: age > 65, hemoglobin < 10 g/dL, leukocyte count > 25 x 109/L, circulating blasts ≥ 1%, and presence of constitutional symptoms. The DIPSS plus score also factors in three additional variables: presence of an unfavorable karyotype, transfusion dependency, and platelet count < 100 x 109/L. The bulk of current research focuses on overall survival. The goal of this study was to examine if the presence of these risk factors were associated with cause of death (COD) in patients with myelofibrosis (MF).Methods:Follow-up information on 139 patients referred to Michigan Medicine with an initial diagnosis of myelofibrosis, who subsequently died between April 2007 and February 2017, was collected through retrospective chart review. Nine patients who had an unknown cause of death (COD), and 17 who died from complications due to BMT were excluded, leaving 113 evaluable patients (61 male, 52 female). DIPSS plus risk factors were collected at time of referral, though there was insufficient data available to include an analysis of transfusion-dependency or karyotype. P-values were obtained from a chi-squared test for independence between each variable and COD.PatientsThe median age at diagnosis was 70.7 years (IQR 63.0, 74.9), the median age at death was 73.1 years (IQR 65.8, 77.9), and the median time from diagnosis to death was 2.3 years (IQR 0.9, 4.0). 61.9% of patients had primary MF (n = 86), 23.0% had post-essential thrombocythemia MF (n = 32), and 14.4% had post-polycythemia vera MF (n = 20); one patient's history was unknown. 48.2% had a positive JAK2 mutation (n = 67), 24.5% were tested and negative (n = 34); 12 patient's JAK2 mutation status were unknown.Results:Seven causes of death were predefined, namely death from acute myeloid leukemia (n = 26), bone marrow failure (n = 21), congestive heart failure or pulmonary hypertension (n = 20), spleen or liver complications (n = 17), infection not related to cytopenias (n = 7), failure to thrive (n = 7), or any other COD (n = 15). Among the seven characteristics, a significant association was observed among patients with a platelet count < 100 x 109/L; disproportionately more died due to bone marrow failure and less died due to cardiac or pulmonary causes (p = 0.012). This should be interpreted in the context of no statistically significant associations between COD and the other five clinical risk factors. Overall DIPSS score ≥ intermediate-2 also did not lead to significant associations. Of the 113 patients, sixteen had missing DIPSS scores and/or unknown JAK2 status. Among the remaining 97, a larger-than-expected number of patients with a JAK2 mutation had an Intermediate-1 DIPSS risk; conversely, more patients without a JAK2 mutation had an Intermediate-2 risk. A statistical test for independence yielded a p = 0.009, suggesting that patients with JAK2 mutations have lower DIPSS-calculated risk.Conclusions:DIPSS Plus variables are often collected at referral to provide prognostic information to patients. It appears that the presence of thrombocytopenia is more likely to predict bone marrow failure as a patient's ultimate COD compared to the presence of anemia. Additionally, patients with JAK2 mutations seem to have lower DIPSS-calculated risk. Knowledge of this clinical information can aid management of myelofibrosis. DisclosuresTalpaz:ARIAD: Other: Travel, Research Funding; Pfizer Inc: Consultancy, Other: Travel, Research Funding.

Phase 2 Study of Pracinostat in Combination with Ruxolitinib in Patients (pts) with Myelofibrosis (MF)

Phase 2 Study of Pracinostat in Combination with Ruxolitinib in Patients (pts) with Myelofibrosis (MF)

Graft-Versus-Host Disease Prophylaxis with Posttransplantation Cyclophosphamide and Ruxolitinib in Patients with Myelofibrosis

Introduction. Allogeneic stem cell transplantation (alloHSCT) is currently the only treatment modality with curative potential in patients with myelofibrosis (MF), although transplant-associated complications and relapses significantly reduce the application of this method. JAK1/JAK2 inhibitor ruxolitinib is effective in reducing symptomatic splenomegaly and myelofibrosis-related symptoms. At the same time it has significant immunomodulatory effect and is used for the treatment of steroid-refractory acute and chronic graft-versus-host disease (GVHD). This study evaluated calcineurin inhibitor free GVHD prophylaxis regimen with ruxolitinib in combination with posttransplant cyclophosphamide (PTCy).Patients and methods. Pilot prospective study (NCT02806375) so far enrolled 13 patients with primary or secondary MF. One patient had post-essential thrombocythemia MF, 3 -post-polycythemia vera MF, 9 - primary MF. 11 patients had intermediate-2 risk and 2 had high risk according to DIPSSplus. Median age was 50 years (range 32-64). Nine patients were JAK2V617F positive, 1 patient MPL -positive, 2 patients CALR -positive before alloHSCT. 5 patients had pre-transplant splenectomy. Reduced intensity conditioning was performed with fludarabine 180 mg/m2 and busulfan 10 mg/kg (N Kröger et al., 2009). GVHD prophylaxis included PTCy 50 mg/kg at day +3, +4 and ruxolitinib 45 mg/day at days -7 to -2, and 15 mg/day at days +5 to +100. 4 patients were grafted from matched related donor, 6 from 10/10-matched unrelated donor, 1 from 9/10 matched unrelated donor and 2 from haploidentical donor. Peripheral blood stem cells were used as a graft source in 12/13 patients.Results. Median folow-up was 192 days (range 49-676). Engraftment was documented in all patients. Median time to neutrophil engraftment was 25 days (range 16-57 days), to platelet engraftment - 42 days (15-345). In two cases stem cell “boost” was administered due to poor graft function. Dose reduction of ruxolitinib to 10 mg/day due to poor graft function was performed in all but two patients. 12/13 are alive and with full donor chimerism. One died of Pseudomonas aeruginosa sepsis. In 5 patients near complete bone marrow fibrosis resolution (grade 1-0) was observed. No hematologic relapses of MF were documented.Two patients developed grade III acute GVHD and one grade II acute GVHD. 4/13 patients developed chronic GVHD, in two cases it was classified as moderate (NIH). In all but one patient, who required systemic steroids, GVHD was successfully treated with cyclosporine A.The regimen was well tolerated. Grade 3-4 toxicities included only toxic hepatitis in 3 and sepsis in 3 patients. Mild veno-occlusive disease was observed in one patient. Viral reactivations were relatively frequent, including CMV in 62%, HSV type 1,2 in 100%, HSV type 6 in 8% and BK virus in 23% of patients. Moderate hemorrhagic cystitis developed in 2 patients.Conclusion. GVHD prophylaxis with combination of PTCy and ruxolitinib is associated with good acute and chronic GVHD control and seems promising modality at least for MF patients. Further recruitment of patients and longer follow-up is required to draw more solid conclusions. DisclosuresNo relevant conflicts of interest to declare.

Phase 1b Results of a Study to Assess the Efficacy and Safety of Vismodegib in Combination with Ruxolitinib in Patients with Intermediate- or High-Risk Myelofibrosis

Background: The JAK inhibitor (JAKi) ruxolitinib is approved for treatment of myelofibrosis (MF). Treatment for 5 years or more may be necessary to improve or stabilize bone marrow fibrosis, and a fraction of patients do not respond to ruxolitinib. The Hedgehog signaling pathway is involved in primitive and definitive bone marrow hematopoiesis, and maintenance of hematopoietic precursors, suggesting that addition of a Hedgehog pathway inhibitor (HPI) to ruxolitinib might improve responses. In a murine model of MF, a combination of a JAKi and HPI reduced fibrosis in the bone marrow and spleen and decreased splenomegaly. Vismodegib is a HPI approved for treatment of locally advanced and metastatic basal cell carcinoma. The MYLIE study aimed to assess the safety and efficacy of combined ruxolitinib and vismodegib for the treatment of MF. The pharmacokinetics (PK) of vismodegib were characterized in patients with intermediate or high-risk MF.Methods: In this phase 1b study, 10 patients with intermediate- or high-risk MF (per Dynamic International Prognostic Scoring System) 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. PK sampling was designed to characterize the PK of total and unbound vismodegib in this study for comparison with PK data collected in other patient populations. Efficacy outcomes assessed for phase 1b included spleen response (≥35% reduction in volume by computed tomography or magnetic resonance imaging) per central and investigator assessment, improvement in bone marrow fibrosis per central and investigator assessment (using European consensus grading system), symptom response (≥50% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score [MPN-SAF TSS]) and anemia response (per International Working Group for Myeloproliferative Neoplasms Research and Treatment [IWG-MRT] revised response criteria). We report results from the planned analysis of the phase 1b study for efficacy and safety at week 24.Results: Six patients with primary MF, 1 with post-polycythemia vera MF and 3 with post-essential thrombocythemia MF were treated with vismodegib and ruxolitinib for a median of 294.0 days. As of the interim analysis data cutoff (March 29, 2017), 4 patients had completed 48 weeks of study treatment with ruxolitinib and vismodegib, 5 patients were still receiving treatment, and 1 had discontinued treatment because of a vismodegib-related adverse event (AE) (dysgeusia). The most common AEs were muscle spasm (100% of patients), dysgeusia (50%), alopecia (50%), thrombocytopenia (50%), and nausea (40%). All were grade 1/2, except for 2 instances of grade 3 thrombocytopenia in 2 patients. Three patients experienced serious AEs: infection (3 patients), lung infiltration (1 patient), and vomiting (1 patient); none were considered by the investigators to be related to vismodegib. Because of AEs, 7 patients modified or interrupted their ruxolitinib dose, and 4 patients interrupted their vismodegib dose. At week 24, three patients achieved a ≥35% reduction in spleen volume (including the patient who discontinued early because the assessment occurred within the week 24 visit window) by central review (a spleen response occurred in 1 patient per the investigator assessment). According to the central reviews, no patients had improvement in bone marrow fibrosis (1 patient had improvement in bone marrow fibrosis per investigator assessment). Five patients experienced symptom response, and no patients experienced an anemia response. A further central review of bone marrow biopsy specimens from 5 patients at week 48 continued to show no improvement in fibrosis.Conclusions: There was no clear benefit of the addition of vismodegib to ruxolitinib in any of the phase 1b efficacy outcome measures assessed. Given the lack of evidence of a disease-modifying effect with addition of vismodegib to ruxolitinib, further evaluation of this combination will not be pursued.Source of funding: F. Hoffmann-La Roche DisclosuresKoschmieder:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Roche: Other: Clinical Trial participation; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Verstovsek:Incyte: Research Funding; NS Pharma: Research Funding; Blueprint Medicines Corp: Research Funding; Blueprint Medicines Corp: Research Funding; Galena BioPharma: Research Funding; Celgene: Research Funding; NS Pharma: Research Funding; Seattle Genetics: Research Funding; Genentech: Research Funding; Lilly Oncology: Research Funding; CTI BioPharma Corp: Research Funding; Astrazeneca: Research Funding; Promedior: Research Funding; Pfizer: Research Funding; Astrazeneca: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Celgene: Research Funding; CTI BioPharma Corp: Research Funding; Galena BioPharma: Research Funding; Roche: Research Funding; Pfizer: Research Funding; Lilly Oncology: Research Funding; Roche: Research Funding. Hooper:Roche Products Ltd: Employment. Tandon:F. Hoffmann-La Roche: Employment. Dimier:F. Hoffmann-La Roche: Employment, Other: Stock.

Leukemic Transformation of Post-Essential Thrombocythemia Myelofibrosis: A Unique Case Presenting with Double MPL and CALR Mutations

Leukemic Transformation of Post-Essential Thrombocythemia Myelofibrosis: A Unique Case Presenting with Double MPL and CALR Mutations

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

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

A phase 3, randomized, double-blind, placebo-controlled study of ruxolitinib plus parsaclisib in patients with JAK- and PI3K-inhibitor treatment-naïve myelofibrosis.

TPS7058 Background: Ruxolitinib (JAK1/JAK2 inhibitor) significantly improves outcomes in patients with myelofibrosis (MF); however, a subset of patients may experience a suboptimal response. Recent phase 2 data showed that addition of PI3Kδ inhibitor parsaclisib to ruxolitinib monotherapy resulted in additional alleviation of MF symptoms and splenomegaly in patients with MF (Yacoub. EHA2020. S216). This phase 3, randomized, double-blind study (INCB 50465-313; NCT04551066), evaluates the combination of ruxolitinib and parsaclisib in patients with MF who are naïve to Janus kinase (JAK) and PI3K inhibitor therapies. Methods: Eligible patients are aged ≥18 years with a diagnosis of primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, have a Dynamic International Prognostic Scoring System (DIPSS; Passamonti. Blood. 2010;115:1703-1708) risk category of at least Intermediate (INT)-1, palpable spleen ≥5 cm below left subcostal margin; total symptom score ≥10 at screening, ECOG PS 0–2, and life expectancy ≥24 weeks. Patients will be excluded if they previously received therapy with any JAK inhibitor, any PI3K inhibitor, any experimental or standard drug therapy for MF ≤3 months of first study dose and/or lack of recovery from all toxicities related to previous therapies to grade ≤1, have recent history of inadequate bone marrow reserve (eg, platelet count = 50×109/L) or have inadequate liver or renal function at screening. Approximately 440 patients will be randomized (1:1) to ruxolitinib plus parsaclisib 5 mg QD or ruxolitinib plus matching placebo, with stratification at randomization by DIPSS risk category (high vs INT-2 vs INT-1) and platelet count (≥100×109/L vs 50 to = 100×109/L inclusive). Treatment will begin on Day 1, with starting ruxolitinib dose level determined by baseline platelet count, and will continue as long as treatment is tolerated and discontinuation criteria are not met. When the last enrolled patient has completed 24 weeks of treatment, the study will be unblinded and patients randomized to ruxolitinib plus placebo who have adequate hematology parameters will be able to crossover to receive parsaclisib together with continued ruxolitinib. The primary objective is the evaluation and comparison of spleen volume at Week 24 for patients who received ruxolitinib plus parsaclisib versus ruxolitinib plus placebo. Secondary objectives include evaluation and comparison of patient-reported MF symptoms, overall survival, time to onset and duration of response in spleen volume, and safety and tolerability for ruxolitinib plus parsaclisib versus ruxolitinib plus placebo. Sites are opening across the United States, Europe, Asia, and New Zealand. Clinical trial information: NCT04551066.

Novel findings of splenic extramedullary hematopoiesis during primary myelofibrosis, post-essential thrombocythemia, and post-polycythemia vera myelofibrosis.

BCR-ABL-fusion-negative myeloproliferative neoplasms (MPNs) with myelofibrosis (MF) include primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF. Clonal extramedullary hematopoiesis (EMH) can occur during MPN pathogenesis. Although histopathological bone-marrow (BM) features during clonal EMH have been investigated, those of the spleen have been poorly described. We analyzed splenectomy samples from 28 patients with MF and BM samples from 20 of them. Slides were stained with hematoxylin and eosin, reticulin, and trichrome, with immunohistochemical labeling of glycophorin A, myeloperoxidase, CD61, CD34, and CD117. We also subjected splenectomy and BM samples from six patients and spleen samples from seven patients to next-generation sequencing (NGS). Megakaryocyte-rich spleen nodules (MRSNs), seen in seven of the 28 patients, were significantly associated with megakaryocyte proliferation in the spleen (p = 0.04). We devised a grading system for spleen fibrosis (SF) and found that SF was increased in 20 of 28 patients. Notably, patients with SF were more likely to have MRSNs, suggesting that megakaryocytes might participate in SF, as previously described in BM. Comparisons of spleen and BM NGS findings of six patients' specimens revealed identical mutational status in the two organs for half of the patients. We observed additional mutations in the spleen of two patients. However, the meaning of this finding remains unknown since there was a long interval between BM and spleen samplings (68 and 82months, respectively).

Les myélofibroses

Myelofibrosis is a BCR-ABL1-negative chronic myeloproliferative neoplasm that includes primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. It is characterized by stem cell-derived clonal proliferation that is often, but not always, accompanied by somatic mutations, which are classified into driver mutations (JAK2, CALR, or MPL), subclonal mutations and fibrosis on bone marrow biopsy. Myelofibrosis commonly demonstrates splenomegaly, constitutional symptoms, anemia, thrombocytosis, or thrombocytopenia. Patients may also be asymptomatic. Complications as thromboembolic or hemorrhagic events can reveal the disease. Primary myelofibrosis is the least common myeloproliferative neoplasm but is associated with poor survival and acute leukemic transformation. In contrast to the significant progress made in understanding the disease's pathogenesis, treatment for myelofibrosis remains largely palliative. The JAK2 inhibitor, ruxolitinib is not sufficient in eliminating the underlying myeloid progenitor clone, as disease inevitably returns with therapy discontinuation. Allogeneic hematopoietic stem cell transplantation is the only therapeutic option that offers potential cure. The development of novel treatment strategies aimed at slowing or even reversing disease progression, prolonging patient survival and preventing evolution to blast-phase are still lacking.

Analysis of predictors of response to ruxolitinib in patients with myelofibrosis in the phase 3b expanded-access JUMP study

Data from the large, prospective, multinational, phase 3b JUMP study were analyzed to identify factors predictive of spleen and symptom responses in myelofibrosis patients receiving ruxolitinib. Factors associated with higher spleen response rates included International Prognostic Scoring System (IPSS) low/intermediate-1 risk vs intermediate-2/high risk (43.1% vs 30.6%; adjusted OR [aOR] 0.65 [95% CI 0.44–0.95]), ruxolitinib as first- vs second- or later-line therapy (40.2% vs 31.5%; aOR 0.53 [95% CI 0.38–0.75]), and a ruxolitinib total daily dose at Week 12 of >20 mg/day vs ≤20 mg/day (41.3% vs 30.4%; aOR 0.47 [95% CI 0.33–0.68]). No association was seen between baseline characteristics or total daily dose at Week 12 and symptom response. Ruxolitinib led to higher spleen response rates in patients with lower IPSS risk, and when used earlier in treatment. Higher doses of ruxolitinib were associated with higher spleen response rates, but not with symptom improvement. Trial registration INC424 for patients with primary myelofibrosis, post polycythemia myelofibrosis or post-essential thrombocythemia myelofibrosis (JUMP). 2010-024473-39; NCT01493414 Date of registration: 16 December 2011 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2010-024473-39 https://clinicaltrials.gov/ct2/show/NCT01493414

A Case of Traumatic Splenic Injury during Post-essential Thrombocythemia Myelofibrosis

A Case of Traumatic Splenic Injury during Post-essential Thrombocythemia Myelofibrosis

An Open-Label, Global, Multicenter, Phase 1b/2 Study of KRT-232, a First-in-Class, Oral Small-Molecule Inhibitor of Murine Double Minute 2 (MDM2), Combined with Ruxolitinib in Patients Who Have Myelofibrosis and a Suboptimal Response to Ruxolitinib

An Open-Label, Global, Multicenter, Phase 1b/2 Study of KRT-232, a First-in-Class, Oral Small-Molecule Inhibitor of Murine Double Minute 2 (MDM2), Combined with Ruxolitinib in Patients Who Have Myelofibrosis and a Suboptimal Response to Ruxolitinib

Trends in Allogeneic Stem Cell Transplantation for Myelofibrosis in Europe between 1995-2018: An EBMT Retrospective Analysis

Aim: Dynamic assessment of trends over time in patient- and transplant-specific characteristics and outcomes for patients undergoing 1st allogeneic haematopoietic cell transplant (allo-HCT) for Myelofibrosis (MF). Methods and Results: A total of 4142 MF patients were analysed who underwent allo-HCT between 1995-2018 (24-year period) across 278 centres based on data reported to the European Society for Blood and Marrow Transplantation. For analysis, 4 cohorts were considered based on year of allo-HCT: &amp;lt;2006 n=389 (9.4%), 2006-2010 n=910 (22%), 2011-2014 n=1148 (27.7%) and 2015-2018 n=1695 (40.9%). A steady increase in MF allo-HCT activity over time was apparent paralleled with increasing numbers of participating transplant centres. A total of 2603 (62.8%) patients were male, 3239 (78.2%) had Primary MF, 409 (9.9%) and 494 (11.9%) post-Polycythaemia Vera and post-Essential Thrombocythaemia MF, respectively. An increased median interval (lnterquartile range (IQR)) between diagnosis and transplant was evident over time (&amp;lt;2006 median 20.8 (8.9-62.2) months versus 36.2 (11.6-107.5) months in 2015-2018 period;p&amp;lt;0.001), potentially reflecting increased availability of therapeutics in recent eras (untreated patients &amp;lt;2006= 59.4% versus 2015-2018=23.7%). Median recipient age (IQR) increased over time by ~ a decade between earliest cohort and most recent: &amp;lt;2006, 49.4 years (43.1-55.3) versus 59.3 years (53.4-64.8)2015-2018. Prior to 2006, patients &amp;gt;60 years accounted for 8.7% of adults undergoing allo-HCT whereas for 2015-2018 this was 47%. Over time, increasing number of patients with a Karnofsky performance status (KPS) &amp;lt;90 underwent allo-HCT (&amp;lt;2006=19.7% versus 36.1% 2015-18; p&amp;lt;0.001). Peripheral Blood (PB) was the predominant stem cell source and utilisation increased over time, accounting for 74.8% &amp;lt;2006 and 92.2% within 2015-2018 cohort. Cord blood utilisation was limited to &amp;lt;1% throughout the 24-year study period. Significant shifts towards use of unrelated donors (URD) in more recent periods was apparent (p&amp;lt;0.001). Moreover, increased use of mismatched related donors (MMRD) was particularly evident in 2015-2018 cohort; n=152 (9%) versus n=74 (3%) cumulative for other 3 cohorts combined; p&amp;lt;0.001. Decreased use of myeloablative and TBI- based conditioning was evident over time (p&amp;lt;0.001). Specifically, there was increased use of busulphan-based regimens (&amp;lt;2006: 44.2% versus 2015-2018: 72%). Regarding T cell depletion, trends demonstrated increased use of anti-thymocyte globulin (ATG) over time (&amp;lt;2006=37.3% vs 69.9% 2015-2018; p&amp;lt;0.001). Median time to both neutrophil (median 18 days across all cohorts) and platelet engraftment was similar in all 4 cohorts, with no significant variation when stratified by period of transplantation. Allo-HCT outcomes, survival, GVHD and relapse endpoints are shown for all 4 cohorts in Table 1. Overall for the entire group, significant factors associated with worse OS, RFS and NRM remained older age and a poor KPS (&amp;lt;90). No significant differences between cohorts were noted for either estimated 3-year OS (&amp;lt;2006=55% (50-60%), 2006-2010=60% (56-63%), 2011-2014 and 2015-2018= 58% (55-61%); p=0.299) or non-relapse mortality (NRM (Table 1); p=0.523), despite increasing numbers of older, less fit patients, and more frequent HLA-mismatched transplants over time. To investigate survival findings in more detail an adjusted model will be presented including period of allo-HCT and transplant-related variables. Cumulative incidence of relapse at 3 years was similar across all cohorts, suggesting no significant changes with time. Most common causes of death across all 4 cohorts remained GVHD and infection. Of note, rates of acute (a)GVHD grade II-IV by day +100 decreased from the earliest cohort &amp;lt;2006 compared to the later groups (p=0.027) as did rates of overall chronic (c) GVHD whereby this was evident in 57% (95% CI 52-62%) &amp;lt;2006 cohort compared to 44% (95% CI 42-47%) in the 2015-2018 group, predominantly reflected by reductions in extensive cGVHD (Table 1). Conclusions: Despite a marked increase over this 24-year period in recipient age, RIC regimen utilisation and use of both URD and MMRD, this comprehensive analysis demonstrates stable OS and EFS rates. However, rates of GVHD have decreased over time, in particular extensive cGVHD. Further work is required to improve both the considerable NRM and relapse rates which remain significant. Disclosures McLornan: JAZZ PHARMA: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau; NOVARTIS: Honoraria, Speakers Bureau. Platzbecker:Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Chevallier:Incyte Corporation: Honoraria. Martínez-Lopez:Altum, Hosea: Membership on an entity's Board of Directors or advisory committees, Patents &amp; Royalties; Vivia Biotech: Honoraria; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding. Yakoub-Agha:Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria.

Ruxolitinib Treatment Is Associated with Increased Incidence of Infections and Higher Risk of HSV/Vzv Recurrence in Patients with Myeloproliferative Neoplasm (MPN) Related Myelofibrosis (MF)

Introduction: Ruxolitinib (RUX) is a JAK 1/2 inhibitor approved for the treatment of intermediate and high-risk primary or secondary MF. In addition to the intrinsic immune system modulation in MF patients, JAK inhibition exerts an immunosuppressive effect that may increase the risk of infections (Heine A et al., Blood, 2013). We aimed to investigate the association between treatment with RUX and infectious complications in a large monocentric cohort of MF patients. Methods: We performed a retrospective study including all patients diagnosed with primary, post-polycythemia vera or post-essential thrombocythemia MF in our MPN clinic between January 2011 and April 2020. Patients were considered RUX treated when exposed to treatment for at least two consecutive months. Clinical and biological characteristics at time of MF diagnosis and follow-up were collected from medical charts and electronic medical records. We used logistic regression models to identify specific infection subtypes associated with RUX treatment. Univariate and multivariate analysis assessing the impact of categorical and continuous variables on infectious events cumulative incidence were performed using Cox models. Results: 213 MF patients were included in the study. 114 (51.1%) patients were treated with RUX while 99 didn't receive RUX. Overall 102 patients exhibited a total of 231 infectious episodes. To search for factors associated with occurrence of infectious events, we evaluated the characteristics of MF, potential clinical and biological immune suppression factors (immunosuppressive treatment, prior non-MPN cancer, diabetes, hepatic/renal failure, neutropenia, lymphopenia, hypo-gammaglobulinemia, complement deficiency, prior history of infection), use of infection prophylaxis and RUX treatment using Cox models. In this cohort of MF patients, we found that RUX treatment (HR 5.91, 95%CI[3.48; 10.04], p&amp;lt;0.001) and a performance status &amp;gt; 2 (HR 4.91, 95%CI[2.62; 9.21], p&amp;lt;0.001) were independently associated with infectious complications (Figure A). Infections rates were 74.0% in RUX treated patients versus 28.3% in non-RUX patients. 41 (22.2%) and 16 (34.0%) infections were of grade 3-4, 61 (33.1%) and 19 (40.4%) required hospitalization, while 8 (4.3%) and 2 (4.2%) resulted in patients' death, in RUX treated and RUX naïve patients, respectively (all non-significantly different). Bacterial infections represented 48.0%, viral infections 16.0% and fungal infections 4.8% of the total infectious events. The most frequently infected sites were lungs/respiratory tract (28.1%) and skin/soft tissue (24.2%). RUX treatment was significantly associated with recurrence of HSV-1/2 or VZV (OR 7.57, 95%CI[1.01-57.30], p=0.050), and skin/soft tissue infections including the above herpetic recurrences (OR 3.33, 95%CI[1.13-9.78], p=0.029). 17 (14.9%) patients presented with HSV/VZV recurrence in the RUX treated group compared to 1 (1.0%) in non-treated patients (Figure B). We then thought to evaluate the impact of potential infections risk factors in RUX treated patients at time of treatment initiation in order to inform clinicians' therapeutic decision and follow-up guidance. For this analysis, we evaluated the characteristics of MF, potential clinical and biological immune suppression factors, treatment lines prior to RUX, dose and cumulative exposition to RUX. No clinical or biological factor was significantly associated with the overall risk of infectious events. However, hypo-gammaglobulinemia at time of RUX initiation was independently associated with HSV and/or VZV recurrence (HR 4.57, 95%CI[1.29-16.16], p=0.018). The higher rate of infections in RUX treated patients was associated with a not statistically significant trend towards shorter OS (HR 1.97, 95%CI[0.98; 3.94], p=0.055). Conclusion: This retrospective study shows an association between the occurrence of infectious complications and Ruxolitinib treatment in MF patients, and in particular, a higher incidence of HSV/VZV recurrence and skin/soft tissue infection. Patients with hypo-gammaglobulinemia at time of RUX initiation were at higher risk of HSV/VZV recurrence, suggesting that protein electrophoresis should be performed prior to treatment initiation and primary antiviral prophylaxis proposed to patients with hypo-gammaglobulinemia. Disclosures Rea: BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kiladjian:AbbVie: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Benajiba:Gilead Foundation: Research Funding.