Myelofibrosis (MF) is a clonal hematopoietic stem cell neoplasm characterized by constitutional symptoms, splenomegaly, and risks of marrow failure or leukemic transformation and is universally driven by Jak/STAT pathway activation. Despite sharing this pathogenic feature, MF disease behavior can vary widely. MF can generally be categorized into 2 distinct subgroups based on clinical phenotype: proliferative MF and cytopenic (myelodepletive) MF. Compared to proliferative phenotypes, cytopenic MF is characterized by lower blood counts (specifically anemia and thrombocytopenia), more frequent additional somatic mutations outside the Jak/STAT pathway, and a worse prognosis. Cytopenic MF presents unique therapeutic challenges. The first approved Jak inhibitors, ruxolitinib and fedratinib, can both improve constitutional symptoms and splenomegaly but carry on-target risks of worsening anemia and thrombocytopenia, limiting their use in patients with cytopenic MF. Supportive care measures that aim to improve anemia or thrombocytopenia are often ineffective. Fortunately, new treatment strategies for cytopenic MF are on the horizon. Pacritinib, selective Jak2 inhibitor, was approved in 2022 to treat patients with symptomatic MF and a platelet count lower than 50 × 109/L. Several other Jak inhibitors are in development to extend therapeutic benefits to those with either anemia or thrombocytopenia. While many other novel non-Jak inhibitor therapies are in development for MF, most carry a risk of hematologic toxicities and often exclude patients with baseline thrombocytopenia. As a result, significant unmet needs remain for cytopenic MF. Here, we discuss clinical implications of the cytopenic MF phenotype and present existing and future strategies to tackle this challenging disease.

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New approaches to tackle cytopenic myelofibrosis.

Biology and therapeutic targeting of molecular mechanisms in MPNs

Ageing is accompanied by a progressive impairment of cellular function and a systemic deterioration of tissues and organs, resulting in increased vulnerability to multiple diseases. Here, we review the interplay between two hallmarks of ageing, namely, mitochondrial dysfunction and cellular senescence. The targeting of specific mitochondrial features in senescent cells has the potential of delaying or even reverting the ageing process. A deeper and more comprehensive understanding of mitochondrial biology in senescent cells is necessary to effectively face this challenge. Here, we discuss the main alterations in mitochondrial functions and structure in both ageing and cellular senescence, highlighting the differences and similarities between the two processes. Moreover, we describe the treatments available to target these pathways and speculate on possible future directions of anti-ageing and anti-senescence therapies targeting mitochondria.

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Targeting Mitochondria to Control Ageing and Senescence

New Treatments for Myelofibrosis

Development of myelofibrosis (MF) therapeutics has reached fruition as the transformative impact of JAK2 inhibitors in the MPN landscape is complemented/expanded by a profusion of novel monotherapies and rational combinations in the frontline and second line settings. Agents in advanced clinical development span various mechanisms of action (eg, epigenetic or apoptotic regulation), may address urgent unmet clinical needs (cytopenias), increase the depth/duration of spleen and symptom responses elicited by ruxolitinib, improve other aspects of the disease besides splenomegaly/constitutional symptoms (eg, resistance to ruxolitinib, bone marrow fibrosis or disease course), provide personalized strategies, and extend overall survival (OS). Ruxolitinib had a dramatic impact on the quality of life and OS of MF patients. Recently, pacritinib received regulatory approval for severely thrombocytopenic MF patients. Momelotinib is advantageously poised among JAK inhibitors given its differentiated mode of action (suppression of hepcidin expression). Momelotinib demonstrated significant improvements in anemia measures, spleen responses, and MF-associated symptoms in MF patients with anemia; and will likely receive regulatory approval in 2023. An array of other novel agents combined with ruxolitinib, such as pelabresib, navitoclax, parsaclisib, or as monotherapies (navtemadlin) are evaluated in pivotal phase 3 trials. Imetelstat (telomerase inhibitor) is currently evaluated in the second line setting; OS was set as the primary endpoint, marking an unprecedented goal in MF trials, wherein SVR35 and TSS50 at 24 weeks have been typical endpoints heretofore. Transfusion independence may be considered another clinically meaningful endpoint in MF trials given its correlation with OS. Overall, therapeutics are at the cusp of an exponential expansion and advancements that will likely lead to the golden era in treatment of MF. 

SOHO State of the Art Updates and Next Questions: Novel Therapeutic Strategies in Development for Myelofibrosis.

Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study.

The Combination of Navitoclax and Ruxolitinib in JAK Inhibitor-Naïve Patients with Myelofibrosis Mediates Responses Suggestive of Disease Modification

Background: Navitoclax is an oral, small-molecule inhibitor of anti-apoptotic B-cell lymphoma 2 family proteins (BCL-XL, BCL-2, BCL-W) that is being evaluated in the ongoing, multicenter, multi-cohort, phase 2 trial (REFINE; NCT03222609). Previous results from REFINE Cohort 1a indicated that addition of navitoclax to ruxolitinib resulted in clinically meaningful outcomes with acceptable safety profile in patients with myelofibrosis (MF) with progression or suboptimal response to ruxolitinib monotherapy (Pemmaraju et al. J Clin Oncol. 2022). Aims: To report preliminary safety results of navitoclax monotherapy (Cohort 2) in patients with suboptimal response to prior Janus kinase inhibitors (JAKis). Methods: This phase 2, open-label trial in patients with MF enrolled patients into 4 cohorts according to JAKi experience; all patients provided informed consent. Patients in Cohort 2 had discontinued prior JAKi therapy and received navitoclax monotherapy orally at the starting dose of 100 mg/day (QD) or 200 mg QD if baseline platelet count was 75–150 × 109/L or >150 × 109/L, respectively. Eligible patients had previously received JAKi for ≥12 weeks, or ≥28 days with red blood cell transfusion dependence (≥2 units/month for 2 months) or with ≥ grade 3 adverse event (AE) of thrombocytopenia or anemia, while on JAKi; all patients had splenomegaly. The primary endpoint was spleen volume reduction of ≥35% (SVR35) from baseline (BL) assessed centrally at Week 24. Secondary endpoints included change in grade of bone marrow fibrosis according to the European consensus grading system and anemia response as per International Working Group criteria. Exploratory endpoints included duration of response of SVR35 and overall survival. Safety and AEs were monitored throughout the study. Results: As of Oct 4, 2021, 30 patients were enrolled and received navitoclax. A majority of patients were male (63%), median age was 68 years (range 55–84), with a median prior ruxolitinib exposure of 100 weeks (range 11–496). Fifteen patients (50%) had secondary MF, of which 8 patients (27%) had post–polycythemia vera MF and 7 patients (23%) had post-essential thrombocytopenia MF (Table). Fourteen patients (47%) started navitoclax at a dose of 100 mg QD and 16 patients (53%) started at 200 mg QD. The median follow-up time was 4.2 months (range 0.2–15.5). Median duration of navitoclax exposure was 9.4 weeks (range 0.1–67.1). Twenty-seven patients (90%) experienced ≥1 AE, the most common being: thrombocytopenia (n=16; 53%), diarrhoea (n=9; 30%), and nausea (n=8; 27%). Grade ≥3 AEs were experienced by 63% of patients, with thrombocytopenia (n=11; 37%) and anemia (n=7; 23%) being the most common. Three patients had serious AEs of dyspnea, hypoxia, and pulmonary hypertension. Navitoclax dose reductions and interruptions were experienced by 15 patients (50%) and 16 patients (53%), respectively. Three patients experienced AEs leading to navitoclax discontinuation (pulmonary hypertension, increased bilirubin, and low platelets; n=1 each). Eight patients discontinued navitoclax due to: AE (n=3), consent withdrawal (n=1), physician decision (n=1), disease relapse (n=1), and progressive disease (n=2). Two patients died >30 days after the last dose of navitoclax. Details will be included in the presentation. Image:Summary/Conclusion: Navitoclax monotherapy in patients with MF after prior JAKi had a similar safety profile as previously reported in Cohort 1a. Efficacy analyses are underway to evaluate the activity of navitoclax monotherapy in patients with MF and will be available for the presentation. 

P1070: navitoclax monotherapy in patients with myelofibrosis previously treated with jak-2 inhibitors: safety and tolerability

Background: Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, is the current standard of care for patients with myelofibrosis (MF) that improves disease symptoms in approximately 40% of patients with limited impact on disease biology. Many patients lose response over time, highlighting an unmet need for novel therapies. Navitoclax is a first-in-class, oral, small molecule that binds with high affinity to BCL-XL and BCL-2, key pro-survival proteins in the apoptotic pathway, and has a synergistic effect when used in combination with JAK inhibitors to enhance malignant cell death in MF. This ongoing, open-label, multicenter, phase II trial (NCT03222609) is evaluating the efficacy and safety of navitoclax with or without ruxolitinib in patients with MF and previously published data suggest clinically meaningful activity of the combination in patients with prior ruxolitinib failure (Pemmaraju et al., ASH 2020). Here, we report results from patients who were JAK inhibitor-naïve and treated with navitoclax and ruxolitinib combination therapy. Aims: N/A Methods: Enrolled patients had primary or secondary MF with splenomegaly (DIPSS ≥ Intermediate-1) and did not receive prior therapy with JAK-2 or bromodomain and extraterminal motif (BET) inhibitors. Patients initiated navitoclax at 100 mg once per day (QD) or 200 mg QD if baseline platelet count was ≤150 × 109/L or >150 × 109/L, respectively. Ruxolitinib was orally administered twice daily at a starting dose based on baseline platelet count as per the local ruxolitinib label. The primary endpoint was spleen volume reduction of ≥35% (SVR35) from baseline at week 24. SVR35 was assessed at weeks 12, 24, and once every 24 weeks thereafter. Key secondary endpoints were ≥50% reduction in total symptom score (TSS50), bone marrow fibrosis reduction, and anemia response (per International Working Group criteria). Adverse events (AEs) were monitored throughout the study. Results: As of Oct 04, 2021, 32 patients received navitoclax plus ruxolitinib. The median duration of follow-up was 6.1 (range, 1.9 to 18.6) months. Twenty-eight (88%) patients received a navitoclax dose of 200 mg, and 4 (13%) received 100 mg OD. The median age was 69 years (range, 44 to 83), median spleen volume was 1889.08 cm3 (range, 645.6 to 7339.6), and 38% had at least 1 prior line of therapy. The median navitoclax and ruxolitinib exposures were 24.1 (range, 5.1 to 80.9) and 24.1 (5.1 to 80.9) weeks, respectively. Thirty-one (97%) patients experienced ≥1 AE, 25 (78%) had Grade ≥3 AEs, and 6 (19%) had serious AEs. The most frequent Grade ≥3 AEs were anemia (34%), thrombocytopenia (31%), and neutropenia (19%). Three (9%) and 2 (6%) patients experienced an AE that led to navitoclax and ruxolitinib discontinuation, respectively, and 2 (6%; 1 progressive disease, 1 cardiac disorder unrelated to navitoclax) AEs led to death ≤30 days after the last dose of navitoclax. SVR35 was achieved by 52% of evaluable patients at week 24 (SVR35 in DIPSS Intermediate-2, 50%; High-risk, 33%) and by 76% at any time on the study (Table). The median time to first SVR35 was 12.1 (range, 11 to 47) weeks. Image:Summary/Conclusion: The combination of navitoclax and ruxolitinib was well tolerated and demonstrated early and robust reductions in spleen volume, anemia, and BM fibrosis in patients without prior JAK-2 inhibitor exposure. SVR35, anemia, and bone marrow fibrosis improved over time. 

S197: navitoclax plus ruxolitinib in jak inhibitor-naïve patients with myelofibrosis: preliminary safety and efficacy in a multicenter, open-label phase 2 study

Q. Qin

Papers

Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study.

The Combination of Navitoclax and Ruxolitinib in JAK Inhibitor-Naïve Patients with Myelofibrosis Mediates Responses Suggestive of Disease Modification

P1070: navitoclax monotherapy in patients with myelofibrosis previously treated with jak-2 inhibitors: safety and tolerability

S197: navitoclax plus ruxolitinib in jak inhibitor-naïve patients with myelofibrosis: preliminary safety and efficacy in a multicenter, open-label phase 2 study

Addition of Navitoclax to Ongoing Ruxolitinib for Patients with Myelofibrosis: Subgroup Analysis of Molecular Biomarkers in the Phase 2 Study (REFINE)