Phase 2 study of add-on parsaclisib for patients with myelofibrosis and suboptimal response to ruxolitinib: final results.

ABSTRACT: Ruxolitinib reduces spleen volume, improves symptoms, and increases survival in patients with intermediate- or high-risk myelofibrosis. However, suboptimal response may occur, potentially because of signaling via the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway. This phase 2 study evaluated dosing, efficacy, and safety of add-on PI3Kδ inhibitor parsaclisib for patients with primary or secondary myelofibrosis with suboptimal response to ruxolitinib. Eligible patients remained on a stable ruxolitinib dose and received add-on parsaclisib 10 or 20 mg, once daily for 8 weeks, and once weekly thereafter (daily-to-weekly dosing; n = 32); or parsaclisib 5 or 20 mg, once daily for 8 weeks, then 5 mg once daily thereafter (all-daily dosing; n = 42). Proportion of patients achieving a ≥10% decrease in spleen volume at 12 weeks was 28% for daily-to-weekly dosing and 59.5% for all-daily dosing. Proportions of patients achieving ≥50% decrease at week 12 in Myelofibrosis Symptom Assessment Form and Myeloproliferative Neoplasms Symptom Assessment Form symptom scores were 14% and 18% for daily-to-weekly dosing, and 28% and 32% for all-daily dosing, respectively. Most common nonhematologic treatment-emergent adverse events were nausea (23%), diarrhea (22%), abdominal pain and fatigue (each 19%), and cough and dyspnea (each 18%). New-onset grade 3 and 4 thrombocytopenia were observed in 19% of patients, each dosed daily-to-weekly, and in 26% and 7% of patients dosed all-daily, respectively, managed with dose interruptions. Hemoglobin levels remained steady. The addition of parsaclisib to stable-dose ruxolitinib can reduce splenomegaly and improve symptoms, with manageable toxicity in patients with myelofibrosis with suboptimal response to ruxolitinib. This trial was registered at www.clinicaltrials.gov as #NCT02718300.

First Approval of Pacritinib as a Selective Janus Associated Kinase-2 Inhibitor for the Treatment of Patients with Myelofibrosis.

Myelofibrosis is one kind of bone marrow blood cancer that gives mainly bone marrow scarring. JAK families include JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) and they control hematopoiesis and immune cell function. JAK-STAT pathways have the critical roles in the pathogenesis of a variety of autoimmune and inflammatory diseases such as myelofibrosis. The 8 JAK inhibitors are approved by the US FDA for the treatment of various diseases. Abrocitinib, baricitinib, oclacitinib, ruxolitinib, tofacitinib, upadacitinib, fedratinib, and pactrinib with their IC50 values against JAK1, JAK2, JAK3, and TYK2 are included. All approved JAK inhibitors with structural similarities and dissimilarities are summarized. The development story of pacritinib and new design route to overcome intellectual property-related issues by connecting the A ring and C ring to form the macrocyclic compounds like 16 without compromising the binding modes in the hinge region are discussed. By using the powerful ring-closing metathesis (RCM), they designed and synthesized and delivered FDA approved pacritinib. In this short perspective, the chemical structure, physicochemical properties, mechanism of action, drug-interactions, adverse events, and pharmacokinetic profile of pacritinib are summarized. Detailed step by step synthesis of pacritinib is provided. Pacritinib is an orally bioavailable and isoform selective JAK-2 inhibitor for the treatment of patients with myelofibrosis. Detailed metabolism pathway with proper explanation is discussed.

Novel therapeutic agents for myelofibrosis after failure or suboptimal response to JAK2 inhbitors.

PURPOSE OF REVIEW: JAK2 inhibitors have changed the therapeutic strategies for the management of primary and secondary myelofibrosis. Ruxolitinib, the first available agent, improved disease-related symptoms, spleen volume, and overall survival compared to conventional chemotherapy. It has been revealed that after 3 years of treatment, about 50% of patients discontinued ruxolitinib for resistance and/or intolerance and should be candidate to a second line of treatment. RECENT FINDINGS: Second-generation tyrosine kinase inhibitors have been tested in this setting, but all these new drugs do not significantly impact on disease progression. Novel agents are in developments that target on different pathways, alone or in combination with JAK2 inhibitors. SUMMARY: In this review, we summarize all the clinical efficacy and safety data of these drugs providing a vision of the possible future.

Primary Myelofibrosis Occurring during Targeted Therapy for Chronic Lymphocytic Leukemia: A Report of Two Cases.

The disease course of chronic lymphocytic leukemia (CLL) is frequently characterized by the occurrence of various complications, such as second primary cancer, which can impact patients' prognoses. While therapies for CLL have evolved tremendously in the past decades, overlooking the possibility of rare neoplasms that arise along with CLL may hinder the benefit that these therapies grant to patients. Moreover, the ability of newer therapies to alter the landscape of these complications is still largely unknown. Primary myelofibrosis (PMF) is not commonly associated with CLL, with only a few cases reported in the literature, with little information regarding the clinico-biological features and the optimal management for these associated conditions. Here, we report two unusual cases of PMF that occurred a few months after the start of therapy for CLL with targeted agents (ibrutinib and venetoclax). Both cases represented a diagnostic and therapeutic challenge, underscoring the need for clinicians to remain vigilant about the possible co-occurrence of these two hematological malignancies, especially in the era of targeted therapy for CLL.

A prognostic model to predict survival after 6 months of ruxolitinib in patients with myelofibrosis.

Ruxolitinib (RUX) is extensively used in myelofibrosis (MF). Despite its early efficacy, most patients lose response over time and, after discontinuation, have a worse overall survival (OS). Currently, response criteria able to predict OS in RUX-treated patients are lacking, leading to uncertainty regarding the switch to second-line treatments. In this study, we investigated predictors of survival collected after 6 months of RUX in 209 MF patients participating in the real-world ambispective observational RUXOREL-MF study (NCT03959371). Multivariable analysis identified the following risk factors: (1) RUX dose <20 mg twice daily at baseline, months 3 and 6 (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.07-3.00; P = .03), (2) palpable spleen length reduction from baseline ≤30% at months 3 and 6 (HR, 2.26; 95% CI, 1.40-3.65; P = .0009), (3) red blood cell (RBC) transfusion need at months 3 and/or 6 (HR, 1.66; 95% CI, 0.95-2.88; P = .07), and (4) RBC transfusion need at all time points (ie, baseline and months 3 and 6; HR, 2.32; 95% CI, 1.19-4.54; P = .02). Hence, we developed a prognostic model, named Response to Ruxolitinib After 6 Months (RR6), dissecting 3 risk categories: low (median OS, not reached), intermediate (median OS, 61 months; 95% CI, 43-80), and high (median OS, 33 months; 95% CI, 21-50). The RR6 model was validated and confirmed in an external cohort comprised of 40 MF patients. In conclusion, the RR6 prognostic model allows for the early identification of RUX-treated MF patients with impaired survival who might benefit from a prompt treatment shift.

Ruxolitinib-treated polycythemia vera patients and their risk of secondary malignancies.

Recently, there has been increased concern about a risk of secondary malignancies (SM) occurring in myelofibrosis (MF) patients receiving ruxolitinib (RUX). In polycythemia vera (PV), on the other hand, only limited data on the risk of SM under RUX treatment are available. To investigate the association between RUX therapy in PV and SM, we conducted a retrospective, single-center study that included 289 PV patients. RUX was administered to 32.9% (95/289) of patients for a median treatment duration of 48.0 months (range 1.0-101.6). Within a median follow-up of 97 months (1.0-395.0) after PV diagnosis, 24 SM occurred. Comparing the number of PV patients with RUX-associated SM (n = 10, 41.7%) with the 14 (58.3%) patients who developed SM without RUX, no significant difference (p = 0.34, chi square test) was found. No increased incidences of melanoma, lymphoma, or solid "non-skin" malignancies were observed with RUX (p = 0.31, p = 0.60, and p = 0.63, respectively, chi square test). However, significantly more NMSC occurred in association with RUX treatment (p = 0.03, chi-squared test). The "SM-free survival" was not significantly different by log rank test for all 289 patients (p = 0.65), for the patients (n = 208; 72%) receiving cytoreductive therapy (p = 0.48) or for different therapy sequences (p = 0.074). In multivariate analysis, advanced age at PV diagnosis (HR 1.062 [95% CI 1.028, 1.098]) but not administration of RUX (HR 1.068 [95% CI 0.468, 2.463]) was associated with an increased risk for SM (p = 0.005). According to this retrospective analysis, no increased risk of SM due to RUX treatment could be substantiated for PV.

A Case of Myelofibrosis and Myelodysplasia Identified Following Exposure to Isotretinoin.

A 15-year-old male individual treated with isotretinoin for acne vulgaris presented with persistent pancytopenia and circulating myeloblasts after discontinuation of the drug. Marrow assessment revealed myelofibrosis (MF) and myeloblasts exhibiting monosomy 7, diagnostic of myelodysplastic syndrome (MDS). Although a popular website seems to associate isotretinoin with MF, no published cases of MF or MDS attributable to this drug were identified. Although we expect that he would eventually have developed MDS and MF, this patient was perhaps identified sooner due to cytopenias accelerated by isotretinoin. This case illustrates that patients exhibiting cytopenias persisting following isotretinoin therapy merit evaluation for underlying hematopoietic disorders.

Developmental low-dose exposure to bisphenol A induces chronic inflammation, bone marrow fibrosis and reduces bone stiffness in female rat offspring only.

BACKGROUND: Developmental exposure to low doses of the endocrine disruptor bisphenol A (BPA) is known to alter bone tissue in young rodents, although how bone tissue is affected in aged animals is not well known. We have recently shown that low-dose developmental exposure to BPA increases procollagen type I N-terminal propeptide (P1NP) levels, a peptide formed during type 1 collagen synthesis, in plasma of 5-week-old female rat offspring while male offspring showed reduced bone size. OBJECTIVE: To analyze offspring bone phenotype at 52 weeks of age and clarify whether the BPA-induced increase in P1NP levels at 5 weeks is an early sign of bone marrow fibrosis development. METHODS: As in our 5-week study, pregnant Fischer 344 rats were exposed to BPA via drinking water corresponding to 0.5 µg/kg BW/day (BPA0.5), which is in the range of human daily exposure, or 50 µg/kg BW/day (BPA50) from gestational day 3.5 until postnatal day 22. Controls were given only vehicle. The offspring were sacrificed at 52 weeks of age. Bone effects were analyzed using peripheral quantitative and micro-computed tomography (microCT), 3-point bending test, plasma markers and histological examination. RESULTS: Compared to a smaller bone size at 5 weeks, at the age of 52 weeks, femur size in male offspring had been normalized in developmentally BPA-exposed rats. The 52-week-old female offspring showed, like the 5-week-old siblings, higher plasma P1NP levels compared to controls but no general increasing bone growth or strength. However, 2 out of 14 BPA-exposed female offspring bones developed extremely thick cortices later in life, discovered by systematic in vivo microCT scanning during the study. This was not observed in male offspring or in female controls. Biomechanical testing revealed that both doses of developmental BPA exposure reduced femur stiffness only in female offspring. In addition, histological analysis showed an increased number of fibrotic lesions only in the bone marrow of female rat offspring developmentally exposed to BPA. In line with this, plasma markers of inflammation, Tnf (in BPA0.5) and Timp1 (in BPA50) were increased exclusively in female offspring. CONCLUSIONS: Developmental BPA exposure at an environmentally relevant concentration resulted in female-specific effects on bone as well as on plasma biomarkers of collagen synthesis and inflammation. Even a dose approximately eight times lower than the current temporary EFSA human tolerable daily intake of 4 µg/kg BW/day, appeared to induce bone stiffness reduction, bone marrow fibrosis and chronic inflammation in female rat offspring later in life.

Romiplostim-related myelofibrosis in refractory primary immune thrombocytopenia: A Case report.

RATIONALE: Primary immune thrombocytopenia (ITP) is an immune-mediated disease that is defined as increased platelet destruction and impaired platelet production. Treatment is recommended for highly selected patients, the standard regimen includes glucocorticoid, intravenous immunoglobulin (IVIG). The recombinant thrombopoietin (TPO) receptor agonists, romiplostim, stimulate platelet production and have approved for glucocorticoid or IVIG, splenectomy-refractory chronic ITP patients. PATIENT CONCERNS: A patient has been diagnosed with ITP, reftractory to steroid, IVIG, splenectomy, danazol, and cyclosporine. The patient received romiplostim to normalize his platelet count, however, over the course of the following year, his platelet counts progressively decreased despite increasing the romiplostim dosing. DIAGNOSES: A peripheral blood smear showed a severe leukoerythroblastic reaction and bone marrow biopsy demonstrated myelofibrosis due to romiplostim. OUTCOMES: Since this diagnosis, romiplostim was discontinued for a while, after 3 months, romiplostim was re-administered to improve thrombocytopenia. His platelet count recovered to 70,000/mm after the administration of romiplostim at 2 µg/kg, and he did not experience complications for 6 months. LESSONS: This report represents the first evidence of romiplostim-induced myelofibrosis, which was associated with increased levels of bone marrow reticulin and Masson trichrome staining.

Clinical outcomes under hydroxyurea treatment in polycythemia vera: a systematic review and meta-analysis.

Hydroxyurea is the standard treatment in high-risk patients with polycythemia vera. However, estimates of its effect in terms of clinical outcomes (thrombosis, bleeding, hematologic transformations and mortality) are lacking. We performed a meta-analysis to determine the absolute risk of events in recent cases of patients under hydroxyurea treatment. We searched for relevant articles or abstracts in the following databases: Medline, EMBASE, clinicaltrials.gov, WHO International Clinical Trials Registry, LILACS. Sixteen studies published from 2008 to 2018 reporting number of events using World Health Organization diagnosis for polycythemia vera were selected. Through a random effect logistic model, incidences, study heterogeneity and confounder effects were estimated for each outcome at different follow ups. Overall, 3,236 patients were analyzed. While incidences of thrombosis and acute myeloid leukemia were stable over time, mortality and myelofibrosis varied depending on follow-up duration. Thrombosis rates were 1.9%, 3.6% and 6.8% persons/year at median ages 60, 70 and 80 years, respectively. Higher incidence of arterial events was predicted by previous cardiovascular complication. Leukemic transformation incidence was 0.4% persons/year. Incidence of transformation to myelofibrosis and mortality were significantly dependent on age and follow-up duration. For myelofibrosis, rates were 5.0 at five years and 33.7% at ten years; overall mortality was 12.6% and 56.2% at five and ten years, respectively. In conclusion, we provide reliable risk estimates for the main outcomes in polycythemia vera patients under hydroxyurea treatment. These findings can help design comparative clinical trials with new cytoreductive drugs and prove the feasibility of using critical end points for efficacy, such as major thrombosis.

Bone Marrow Fibrosis and Early Hematological Response as Predictors of Poor Outcome in Azacitidine Treated High Risk-Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia.

Azacitidine (AZA) treatment is effective treatment for patients with myeloid disorders, and factors predictive of treatment outcome are under investigation. Little is known about the effect of bone marrow fibrosis on response to AZA therapy. We, retrospectively, evaluated clinical predictors of overall survival (OS) and overall response rate (ORR) for patients treated with AZA in a real-life cohort. We evaluated 94 consecutive patients treated with AZA outside of clinical trials (75mg/m2/day for 7 days every 28 days; 5 + 2 + 2 schedule), from June 2009 to February 2016. Ninety-three patients were evaluated for response. After a median of 6 cycles, ORR-complete response (CR; including marrow CR) + partial response (PR) + hematological improvement (HI)-was 41.9% (CR = 18.3%; PR = 11.8%; HI = 11.8%). Stable disease was observed in 21.5%, and failure in 36.5%. Pre-AZA bone marrow blast percentage, International Prognostic Scoring System (IPSS) or IPSS-R category, and time from diagnosis to AZA had no effect on response. Median OS from start of therapy was 18.5 months, and was significantly related to higher IPSS category (P = .01), poor cytogenetics according to the IPSS (P = .01), poor and very poor cytogenetics according to the IPSS-R (P = .02), and lower ORR (P = .006). Patients with MF-0 pre-AZA demonstrated significantly higher ORR, (CR + PR + HI) and stable disease, and lower failure rates than those with any grade of fibrosis. Indeed, cases with pre-AZA fibrosis > MF-1 had shorter OS (P = .005). Achievement of HI before 4 cycles of treatment negatively impacted OS (P = .009).

ß-Arrestin2 mediates progression of murine primary myelofibrosis.

Primary myelofibrosis is a myeloproliferative neoplasm associated with significant morbidity and mortality, for which effective therapies are lacking. ß-Arrestins are multifunctional adaptor proteins involved in developmental signaling pathways. One isoform, ß-arrestin2 (ßarr2), has been implicated in initiation and progression of chronic myeloid leukemia, another myeloproliferative neoplasm closely related to primary myelofibrosis. Accordingly, we investigated the relationship between ßarr2 and primary myelofibrosis. In a murine model of MPLW515L-mutant primary myelofibrosis, mice transplanted with donor ßarr2-knockout (ßarr2-/-) hematopoietic stem cells infected with MPL-mutant retrovirus did not develop myelofibrosis, whereas controls uniformly succumbed to disease. Although transplanted ßarr2-/- cells homed properly to marrow, they did not repopulate long-term due to increased apoptosis and decreased self-renewal of ßarr2-/- cells. In order to assess the effect of acute loss of ßarr2 in established primary myelofibrosis in vivo, we utilized a tamoxifen-induced Cre-conditional ßarr2-knockout mouse. Mice that received Cre (+) donor cells and developed myelofibrosis had significantly improved survival compared with controls. These data indicate that lack of antiapoptotic ßarr2 mediates marrow failure of murine hematopoietic stem cells overexpressing MPLW515L. They also indicate that ßarr2 is necessary for progression of primary myelofibrosis, suggesting that it may serve as a novel therapeutic target in this disease.

[Progression of bone marrow fibrosis with reticulin and collagen hyperplasia during treatment with the thrombopoietin receptor agonist romiplostim in a patient with immune thrombocytopenia].

Romiplostim is a thrombopoietin (TPO) receptor agonist that has attracted attention as a novel drug for the treatment of refractory immune thrombocytopenia (ITP). However, bone marrow reticulin and collagen fibrosis during the long-term use of romiplostim has recently become a concern. Here, we present a patient with ITP who exhibited bone marrow fibrosis after the completion of a Japanese phase III clinical trial and long-term extension study of romiplostim. The patient was a 64-year-old woman. She was diagnosed with refractory ITP and participated in a clinical trial of romiplostim. Myeloblasts were found in her peripheral blood in Week 116 of treatment with romiplostim in the long-term extension study, and romiplostim was discontinued. In Week 118, teardrop cells appeared and she underwent a bone marrow biopsy. Results showed reticulin and collagen fiber hyperplasia and her platelet count decreased markedly to 0.4×10(4)/µl with macroscopic hematuria. Thereafter, a reduced dose of romiplostim was resumed. Approximately one year after the resumption of romiplostim, a bone marrow biopsy revealed a decrease in reticulin and collagen fibrosis. Although few patients exhibited bone marrow fibrosis with TPO and the event may be reversible, our observations indicate that careful monitoring is required for general clinical use.