Ruxolitinib In Patients Research Articles

Development and Clinical Validation of Liquid Chromatography-Tandem Mass Spectrometry for Measuring Ruxolitinib in Steroid-Refractory Graft-Versus-Host Disease: A First Step Towards Optimized Treatment.

This non-interventional, prospective, single-center study aimed to develop a technique to measure ruxolitinib (RUX) concentrations and provide preliminary data on the distribution of plasma drug levels in patients with steroid refractory (SR) GvHD. Between April 2023 and May 2024, we analyzed 48 blood samples from 29 patients with SR-GvHD. Median individual plasma concentrations varied across different RUX doses and largely overlapped: 39.2 ng/mL at 10 mg b.i.d (range: 0-73), 13.1 ng/mL at 10-5 mg (range, 6.1-35.6), and 31.6 ng/mL at 5 mg b.i.d (range: 0.7-99.9). Samples taken under non-optimal temperature conditions showed a lower median concentration of 0.77 ng/mL (range: 0-7.4 ng/mL). The four patients who did not respond at days +28 and +180 after RUX initiation (3 with lower gastrointestinal aGvHD, and 1 with ocular, hepatic, and pulmonary cGvHD) showed a median concentration of only (7.4 ng/mL (range, 0-29) ng/mL) with full dosing. The introduction and validation of a liquid chromatography-tandem mass spectrometry method for quantifying plasma RUX concentrations was feasible in our center. Administering predetermined and fixed doses of RUX in patients with SR-GvHD showed highly variable and overlapping plasma drug concentrations. This underscores the potential importance of RUX- pharmacokinetics (PK) monitoring.

Impact of cytopenias and early versus late treatment with ruxolitinib in patients with steroid-refractory acute or chronic graft-versus-host disease.

REACH2 and REACH3 were randomized, multicenter, open-label phase 3 studies comparing the selective Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib versus investigators' choice of best available therapy (BAT) in steroid-refractory (SR) acute (REACH2) or chronic (REACH3) graft-versus-host disease (aGVHD/cGVHD). Moderate-severe aGVHD/cGVHD can progress rapidly; thus, key clinical considerations driving management of patients with SR-aGVHD/SR-cGVHD are prompt treatment initiation and concomitant cytopenias. These posthoc analyses of REACH2/REACH3 describe the impact of timing of treatment initiation after SR-aGVHD/SR-cGVHD diagnosis and development of concomitant cytopenias on treatment outcomes. Ruxolitinib initiation within 3 days from SR-aGVHD diagnosis yielded an extended duration of response and higher Day 28 complete response rates compared with initiation ≥7 days after SR-aGVHD diagnosis (median 178 vs 167 days and 36.6% vs 25.0%, respectively). For patients with SR-cGVHD, Week 24 overall response was not impacted by time to treatment (54.5% vs 42.6% for <14 vs >28 days). Clinically relevant cytopenias were manageable, allowing for maintenance of dose intensity (median 20 mg/d), and did not impact the favorable efficacy outcomes from ruxolitinib treatment. This analysis highlights the practical importance of considering earlier ruxolitinib initiation after SR diagnosis in GVHD and the benefits of ruxolitinib treatment compared with BAT even for patients with cytopenias.

Addition of navitoclax to ruxolitinib in patients with myelofibrosis with progression or suboptimal response

Addition of navitoclax to ruxolitinib in patients with myelofibrosis with progression or suboptimal response

Real-World Use of Ruxolitinib in Patients With Myelofibrosis and Anemia or Thrombocytopenia at Diagnosis.

Ruxolitinib is approved for treatment of myelofibrosis. We evaluated ruxolitinib in patients with anemia (hemoglobin &lt;10 g/dL) or thrombocytopenia (platelet count ≤100×109/L) at diagnosis. This was a retrospective, secondary analysis of a Cardinal Health Oncology Provider Extended Network medical chart review of adults with myelofibrosis diagnosed between 2012-2016 who received first-line ruxolitinib. 176 patients received first-line ruxolitinib and were included in this analysis. At diagnosis, 120 patients had hemoglobin concentrations &lt;10 g/dL and 59 had a platelet count ≤100×109/L. Most patients (95%) with thrombocytopenia also had anemia. Median time of observation after diagnosis was 21.4 months. Among patients with anemia or thrombocytopenia, ruxolitinib dose at end of study was ≥10 mg twice daily (bid) in 88.3% and 83.1%, respectively. Ruxolitinib treatment was ongoing in 76.1% of patients overall and was rarely discontinued for anemia or thrombocytopenia (n=2 total, 1.1%). Per the treating physician, 79.7% of patients had improved symptoms and 62.7% improved spleen size. Most patients with myelofibrosis and anemia or thrombocytopenia at diagnosis tolerated and maintained a ruxolitinib dose ≥10 mg bid for nearly 2 years, resulting in clinical benefit. This real-world evidence supports observations from prospective clinical trials of ruxolitinib in myelofibrosis.

Oral administration of ruxolitinib in psoriasis vulgaris: A case report of plaque psoriasis accompanied by myelofibrosis secondary to polisitemia vera successfully treated with oral ruxolitinib.

Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation and immune cell infiltration. Various therapies have been discovered for psoriasis, including topical treatments, phototherapy, conventional systemic agents such as methotrexate, retinoids and ciclosporine, as well as biologics. Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway inhibitors targeting Tumor Necrosis Factor alpha (TNF-α), interleukin (IL)-23 and IL-17 can be effective in psoriasis. Ruxolitinib is a US Food and Drug Administration-approved first-generation Janus kinase inhibitor for polycythemia vera, myelofibrosis, and acute graft-versus-host disease. Ruxolitinib cream has been investigated in various dermatologic diseases, including atopic dermatitis, vitiligo, psoriasis, and alopecia areata. However, there is limited data on the efficacy of oral ruxolitinib in patients with psoriasis vulgaris. Here, we report a patient diagnosed with myelofibrosis coexisting with psoriasis vulgaris, successfully treated with oral ruxolitinib.

A Multicenter Phase II Trial of Ruxolitinib for Treatment of Corticosteroid Refractory Sclerotic Chronic Graft-Versus-Host Disease.

Sclerotic chronic graft-versus-host disease (cGVHD) represents a highly morbid and refractory form of cGVHD, and novel therapies for sclerotic cGVHD are critically needed. This study aimed to determine the efficacy of ruxolitinib in patients with corticosteroid refractory sclerotic cGVHD. In a single-arm multicenter phase II trial (N = 47), adults with sclerotic cGVHD refractory to corticosteroids and ≥one additional line of systemic therapy for cGVHD received ruxolitinib for ≥six months (ClinicalTrials.gov identifier: NCT03616184). The primary end point was complete or partial response (PR) in skin and/or joint defined according to the 2014 National Institute of Health cGVHD Consensus Criteria. Following the use of ruxolitinib for a median of 11 months, PR in skin and/or joints was noted in 49% (95% CI, 34 to 64) at 6 months, with 45% having joint and fascia response and 19% having skin response. The duration of skin/joint response was 77% (95% CI, 48 to 91) at 12 months. Overall cGVHD PR was noted in 47% (95% CI, 32 to 61). Improvement in Lee Symptom Scale summary and skin subscale scores was noted in 38% of patients. With a cumulative incidence of treatment failure of 20.8% (95% CI, 10.0 to 34.1), nonrelapse mortality (NRM) of 2.2% (95% CI, 0.17 to 10.3), and no recurrent malignancy, failure-free survival (FFS) was 77.1% (95% CI, 61.3 to 87.0) at 12 months. Ruxolitinib was overall well tolerated with no new safety signals. The use of ruxolitinib was associated with relatively high rates of skin/joint responses and overall cGVHD responses, improvement in patient-reported outcomes, low NRM, and high FFS in patients with refractory sclerotic cGVHD. Ruxolitinib offers an effective treatment option for refractory sclerotic cGVHD.

Treatment comparison of hydroxyurea versus ruxolitinib in essential thrombocythaemia: A matched-cohort analysis.

Hydroxyurea is the preferred first-line cytoreductive treatment for high-risk essential thrombocythaemia (ET), but many patients are intolerant or refractory to hydroxyurea. Ruxolitinib has been shown to improve symptoms in patients with ET. This post hoc analysis compared the clinical outcomes of patients with ET who received hydroxyurea only with those who switched from hydroxyurea to ruxolitinib due to intolerance/resistance to hydroxyurea. Patients with ET refractory/intolerant to hydroxyurea treated with ruxolitinib in a completed phase 2 study (HU-RUX) were propensity score matched with patients who received hydroxyurea only in an observational study (HU). Changes in leukocyte and platelet counts were reported at 6-month intervals during the 48-month follow-up. Following propensity score matching, 37 patients were included for analysis in each cohort. Mean (standard deviation [SD]) leukocyte and platelet counts at index were higher for HU-RUX versus HU (leukocyte: 9.3 [5.1] vs. 6.8 [3.1]×109/L; platelet: 1027.4 [497.8] vs. 513.9 [154.7]×109/L), both of which decreased significantly from index to 6 months through to 48 months in HU-RUX (mean [SD] change from index at 6 months-leukocyte: -1.8 [4.6]×109/L; platelet: -391.7 [472.9]×109/L; at 48 months-leukocyte: -3.8 [5.3]×109/L; platelet: -539.0 [521.8]×109/L), but remained relatively stable in HU (mean [SD] change from index at 6 months-leukocyte: 0 [1.8]×109/L; platelet: -5.7 [175.3]×109/L; at 48 months-leukocyte: -0.1 [2.7]×109/L; platelet: -6.9 [105.1]×109/L). In conclusion, these results demonstrate that switching from hydroxyurea to ruxolitinib in patients with ET who are intolerant or refractory to hydroxyurea could improve abnormal haematologic values similar to those who receive first-line hydroxyurea.

Early Access for Medicines in ITALY: The Case of Ruxolitinib for Patients with Graft-Versus-Host Disease.

After European Medicines Agency (EMA) approval, national pricing and reimbursement procedures are necessary to guarantee access to drugs, based on the willingness to pay and the recognition of therapeutic value. These can result in delays in drug availability for patients, even for those with important unfmet needs for whom it may be necessary and ethical to ensure access. The objective of this study was to evaluate the use of ruxolitinib for patients with graft-versus-host disease (GvHD) after EMA approval at the University Hospital of Catania. We analysed data about the use of ruxolitinib in patients with GvHD, describing their basic characteristics, their outcomes and the cost of the treatment. In the reference period, 24 ruxolitinib treatments were started according to the Summary of Product Characteristic. The average treatment duration was 10 months. Twenty patients showed a response, maintained over time, with no adverse reactions. The total expenditure amounts to EUR 963,424. The use of ruxolitinib in a real population confirms its role in an important therapeutic need. The quantification of costs requires a reflection on the sustainability of early access to medicines authorised by the EMA for serious diseases and in the absence of therapeutic alternatives.

Ruxolitinib in treatment-naive or corticosteroid-refractory paediatric patients with chronic graft-versus-host disease (REACH5): interim analysis of a single-arm, multicentre, phase 2 study

Chronic graft-versus-host disease (GVHD) is a debilitating, and sometimes life threatening, complication of allogeneic haematopoietic stem-cell transplantation (HSCT). We aimed to investigate the activity, pharmacokinetics, and safety of ruxolitinib added to corticosteroids in paediatric patients (ie, <18 years) with moderate-to-severe chronic GVHD. In this single-arm, phase 2 study, patients were recruited at 21 hospitals or clinics across 14 countries in Asia, Europe, and Canada. Eligible patients were aged 28 days to younger than 18 years, had undergone allogenic HSCT, and had been diagnosed with treatment-naive or corticosteroid-refractory moderate-to-severe chronic GVHD, per 2014 National Institutes of Health consensus criteria. Patients received oral ruxolitinib dosing on the basis of their age at the start of treatment: those aged 12 years to younger than 18 years received 10 mg twice daily (age ≥12 to <18 years group), those aged 6 years to younger than 12 years (age ≥6 to <12 years group) received 5 mg twice daily, and those aged 2 years to younger than 6 years received 4 mg/m2 twice daily (age ≥2 to <6 years group). Treatment was to be administered in 28-day cycles for approximately 36 months, alongside supportive treatment per institutional guidelines. The primary activity endpoint was overall response rate at cycle 7 day 1. Activity and safety analyses are reported in the full analysis set, which included all patients who received at least one dose of ruxolitinib. Here we report the prespecified interim analysis, scheduled to occur after all patients had completed 1 year of treatment or discontinued treatment, and the results for the primary endpoint evaluation reported here is to be considered final. This study is registered with ClinicalTrials.gov, NCT03774082, enrolment is complete, and the study is ongoing. Between May 20, 2020, and Sept 17, 2021, 48 patients were screened, of whom 45 were enrolled and received at least one dose of study drug (median age was 11·0 years [IQR 7·2-14·3], 16 [36%] were female, 29 [64%] were male, 21 [47%] were White, one [2%] was Black or African American, 23 [51%] were Asian, 17 [38%] were treatment-naive, 28 [62%] were corticosteroid-refractory). As of data cutoff (Oct 19, 2022), after a median ruxolitinib exposure of 55·1 weeks (IQR 13·1-75·3), the overall response rate at cycle 7 day 1 was 40·0% (18 of 45; 90% CI 27·7-53·3), with responses seen in seven (41%) of 17 treatment-naive patients and 11 (39%) of 28 corticosteroid-refractory patients. The most common treatment-related adverse events of grade 3 or worse were neutropenia (eight [18%] of 45) and thrombocytopenia (six [13%]). Seven (16%) patients had grade 3 or worse serious treatment-related adverse events; the most common was hyponatraemia (two [4%] of 45). Three (7%) patients died while on-treatment (within 30 days of treatment discontinuation), one due to Aspergillus infection, one due to septic shock, and one due to acute respiratory distress syndrome; none were considered to be related to study drug. Pending final analysis, this study suggests that ruxolitinib is active and well tolerated in both treatment-naive and corticosteroid-refractory patients aged 2 years to younger than 18 years with chronic GVHD, thereby supporting its use in this patient population. The safety profile of ruxolitinib in this patient population is consistent with that of adults. Final analysis of this study will provide further information on the long-term benefits of ruxolitinib in children with chronic GVHD. Novartis.

Momelotinib vs. ruxolitinib in myelofibrosis patient subgroups by baseline hemoglobin levels in the SIMPLIFY-1 trial

A key hallmark of myelofibrosis is anemia, which ranges from mild to severe based on hemoglobin levels. To more clearly define outcomes with the Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor momelotinib by anemia severity, we performed a descriptive post hoc exploratory analysis of the double-blind, randomized, phase 3 SIMPLIFY-1 study (NCT01969838; N = 432, JAK inhibitor naive, momelotinib vs. ruxolitinib); subgroups were defined by baseline hemoglobin: <10 (moderate/severe), ≥10 to <12 (mild), or ≥12 g/dL (nonanemic). Spleen and symptom results were generally consistent with those previously reported for the intent-to-treat population. In anemic subgroups, momelotinib was associated with higher rates of transfusion independence and reduced/stable transfusion intensity vs. ruxolitinib. No new or unexpected safety signals were identified. Overall, momelotinib provides spleen, symptom, and anemia benefits to JAK inhibitor-naive patients with myelofibrosis regardless of baseline hemoglobin level, and greater anemia-related benefits vs. ruxolitinib in patients with hemoglobin <12 g/dL.

Phase 3 randomized double-blind study evaluating selinexor, an XPO1 inhibitor, plus ruxolitinib in JAKi-naïve myelofibrosis.

TPS6594 Background: Myelofibrosis (MF) is a myeloproliferative neoplasm with common somatic gene driver mutations in JAK2, CALR, and MPL. Selinexor, an investigational oral XPO1 inhibitor, may inhibit MF-relevant JAK/STAT and non-JAK/STAT pathways. Preclinical studies have shown potential synergy with ruxolitinib treatment. In the phase 1 portion of XPORT-MF-034 evaluating selinexor plus ruxolitinib in JAKi-naïve patients with MF, the most common AEs in the 60 mg cohort were nausea (79%), anemia (64%), thrombocytopenia (64%), and fatigue (57%). Nausea was predominantly Grade 1 and transient in nature. Treatment-related AEs leading to treatment discontinuation were thrombocytopenia (n=1) and neuropathy (n=1). SVR35 and TSS50 was achieved by 79% and 58% of the 60 mg cohort intent-to-treat population at Week 24, respectively. Response rates were consistent across subgroups, including sex and regardless of ruxolitinib starting dose. These data provide strong support to further evaluate selinexor (60 mg) and ruxolitinib in patients with JAKi-naïve MF. Methods: The XPORT-MF-034 (NCT04562389) trial includes a global, Phase 3 randomized, double-blind, placebo-controlled study designed to evaluate selinexor and ruxolitinib. JAKi-naïve patients with MF will be randomized 2:1 to receive oral selinexor 60 mg or placebo once weekly (28-day cycle) and twice daily ruxolitinib. Randomization will be stratified by DIPSS risk category (int-1 vs int-2 or high-risk), spleen volume (&lt;1800 cm3 vs &gt;1800 cm3 by MRI/CT scan), and baseline platelet counts (100-200x109/L vs &gt;200x109/L). Dual anti-emetics for nausea prophylaxis will be required for the first two cycles. Select eligibility criteria include ≥18 years of age, spleen volume ≥450 cm3 by MRI or CT, DIPSS intermediate-1, intermediate-2, or high-risk, active symptoms of MF (MFSAF v4.0), currently not eligible for stem cell transplantation, ECOG≤2, and platelet count ≥100 x 109/L. Select exclusion criteria include &gt;10% blasts in peripheral blood or bone marrow; previous treatment with JAKi for MF, or previous treatment with selinexor or other XPO1 inhibitors. The co-primary study endpoints are SVR35 and TSS50 at Week 24 and will be tested hierarchically. The key secondary endpoint is anemia response at Week 24 per the IWG-MRT and ELN criteria. The XPORT-MF-034 Phase 3 trial is currently open for enrollment; a total of 306 JAKi-naïve MF patients will be enrolled and the study was initiated on June 28, 2023. Clinical trial information: NCT04562389 .

A phase Ib, open-label study of add-on therapy with CK0804 in participants with myelofibrosis and suboptimal response to ruxolitinib.

6580 Background: Suboptimal response to JAK2 inhibitor ruxolitinib in patients with myelofibrosis (MF) remains a major unmet medical need. Deregulated inflammatory pathways including CXCR4/CXCR12 axis might limit the therapeutic efficacy of ruxolitinib and contribute to disease progression. In preclinical studies, cord blood-derived, CXCR4 enriched T regulatory cells [CK0804; T-regs] showed ability to suppress inflammatory cytokines playing major role in MF (Huang et al., Cytotherapy, 2023). Methods: This phase Ib study evaluates the safety and activity of up to 6 doses of CK0804 (non-HLA matched, Cryopreserved) T-regs therapy, fixed dose of 100 million cells, added every 28 days to ruxolitinib. Patients with MF on ruxolitinib for ≥12 weeks and stable dose for ≥8 weeks, who have palpable splenomegaly, symptoms, or grade 2 cytopenia are eligible. Primary objective is safety, secondary objective is overall response per IWG-MRT criteria at 24 weeks. Present analysis includes cohort of initial run-in safety phase. Results: Nine patients of median age 68 years (range, 55-84) were enrolled, 44% were males. Median blood counts [range] showed while blood cells 10.6 [3.1-70.4] x10^9/L, hemoglobin 8.8 [7.8-11.5] g/dL, platelets 177 [148-311] x10^9/L. Three patients were transfusion dependent. Median spleen volume was 1449 cubic centimeters (176-5609), 7 patients (78%) had clinically worsening splenomegaly. Median symptoms score (MPN-SAF TSS) was 23 (20-40). Six (67%) had diploid karyotype, 5 (56%) had JAK2 mutation and 8 (89%) had additional no-driver mutations. Median duration of prior ruxolitinib was 35 months (range, 10-132), all patients were on ≥ 10 mg twice daily dose with no dose change throughout the study. Four patients received all six doses of CK0804, three patients have ongoing treatments. One patient experienced infusion reaction to second dose of CK0804 likely due to the excipient dimethylsulfoxide and withdrew consent. One patient died of unrelated cause prior to the infusion 6. There were no nonhematologic or hematologic adverse events. Two transfusion dependent patients who were evaluable for response had decreased monthly need for transfusions by the end of the sixth cycle: 4 to 2.8 units and 1.2 to 0.8 units, respectively. All patients noticed symptoms improvement; median best decline in MPN-SAF TSS was -38% (range, -20% to -71%); with ≥ 50% reduction in 3 patients. One patient achieved ≥ 35% spleen volume reduction at week 12. Longitudinal analysis of markers of inflammation is in progress and will be presented at the conference. Conclusions: This preliminary analysis of run-in phase of study evaluating CXCR4 enriched T regs cell therapy as addition to ruxolitinib shows initial safety with no myelosuppressive adverse events and promising clinical activity. Active enrollment of participants to the expansion cohort is ongoing. Clinical trial information: NCT05423691 .

Efficacy and safety of ruxolitinib in patients with lower risk myelofibrosis: A single-arm, exploratory and prospective study.

Efficacy and safety of ruxolitinib in patients with lower risk myelofibrosis: A single-arm, exploratory and prospective study.

Oral Decitabine/Cedazuridine Is an Effective Ambulatory Therapy for Patients With Myelofibrosis Refractory to JAK2 Inhibitor Therapy

BackgroundOutcomes are dismal for patients with myelofibrosis (MF) who are no longer responsive to JAK2 inhibitors (JAKi) and/or have increasing blast cell numbers. Although prior reports have suggested the benefits of intravenous decitabine (DAC) combined with ruxolitinib for patients with Myeloproliferative Neoplasm (MPN) accelerated/blast phase (AP/BP), decitabine-cedazuridine (DEC-C), an oral fixed-dose combination providing equivalent pharmacokinetic exposure, has not been evaluated in MF. MethodsWe conducted a retrospective analysis of 14 patients with high-risk MF refractory to ruxolitinib or MPN-AP (10-19% blasts) treated with DEC-C +/- JAKi at Mount Sinai Hospital from 2021 to 2024. ResultsThe cohort was elderly (median age,76 years) and almost uniformly possessed high risk mutations with 13 of the 14 patients progressing on JAKi therapy. With a median follow-up of 9.4 months, the median overall survival (OS) was 29 months for the entire cohort. Median OS was 10.8 months for MPN-AP and was not reached for ruxolitinib refractory MF patients. All patients (n = 9) receiving > 4 cycles of DEC-C had clinical benefit exemplified by a reduction in blast cell numbers, spleen size, and lack of progression to MPN-BP (78%). Furthermore, 3/14 patients proceeded to allogeneic stem cell transplant. Myelosuppression was a common adverse event which was managed by reducing the number of days of administration of DEC-C from 5 to 3 per cycle. ConclusionsThis report demonstrates the feasibility, tolerability, and clinical benefit of an exclusively ambulatory regimen for high-risk, elderly patients with advanced MF which warrants further evaluation in a prospective clinical trial.

Ruxolitinib Pharmacokinetics and Pharmacodynamics in Children with Acute and Chronic Graft-versus-Host Disease

IntroductionWe report pharmacokinetics of oral ruxolitinib in children with steroid refractory acute graft versus host disease (GVHD) (<12y) and chronic GVHD (≤18y) using our published pediatric dosing. MethodsPK sampling before and +2 hours after ruxolitinib was performed in patients with established chronic GVHD. More extensive PK analysis was evaluated in patients with newly diagnosed acute or chronic GVHD before, +0.5, 1, 2, 4 and 6 hours after ruxolitinib in patients >10kg, and before, +3 and +6 hours in children <10kg. We measured pSTAT1, 3 and 5 expression on CD4+ and CD8+ T-cells before and 2 hours after ruxolitinib as a pharmacodynamic marker of JAK/STAT inhibition. ResultsThirteen patients were prospectively enrolled (0-≤18y with existing chronic GVHD(n=8), 0-<12y with new onset steroid refractory acute GVHD(n=4) and newly diagnosed steroid-refractory chronic GVHD(n=1). A large variability in PK was seen. Mean oral clearance (CL/F) was 7.76 ± 4.09 L/h (±SD 4.4; range: 3.1-15.3). The average elimination half-life was 2.32 hours (±SD 1.0). Ruxolitinib clearance was higher in children <2 years versus >2 years (12.1 ± 3.0, vs 5.7 ± 2.8 L/h, p=0.005) and was reduced with concurrent azoles and azithromycin. We saw a variable reduction in pSTAT1/3/5 expression on T-cells at time of peak ruxolitinib absorption (2 hours after dose). ConclusionsChildren<10 kg have lower ruxolitinib exposure, possibly due to inherent increased drug clearance or variabilities in dosing methods leading to decreased drug absorption.

Ruxolitinib in patients with graft versus host disease (GvHD): findings from a compassionate use program

The ruxolitinib compassionate use (CU) program offered ruxolitinib to patients ≥2 years of age with confirmed steroid-resistant acute or chronic graft-versus-host disease (aGvHD and cGvHD, respectively). Data from 1180 patients (n = 775, 370 and 35 with cGvHD, aGvHD, and non-specified GvHD, respectively) were analyzed. Most patients had severe cGvHD (56%) or stage III/IV aGvHD (70%) disease and had previously received corticosteroids ( > 80%); ruxolitinib was requested primarily as a second-/third-line option. Patients <12 and ≥12 years old most often received the recommended ruxolitinib doses (5 mg twice daily [BID] and 10 mg BID, respectively); however, 23% and 30% of ≥12 year olds with cGvHD and aGvHD, respectively, received the lower dose of 5 mg BID. Notably, corticosteroid usage decreased with ruxolitinib treatment; at the initial ruxolitinib request, 81% and 91% of patients with cGvHD and aGvHD, respectively, were receiving corticosteroids whereas at resupply, 62% and 64%, respectively, were receiving corticosteroids. Eighty two percent of evaluable patients with cGvHD had a complete or partial response to treatment and 56% of evaluable patients with aGvHD had a best response of grade 0/I. These findings demonstrate the rapid and positive effects of ruxolitinib in patients with GvHD in a real-world setting.

Metabolic and nutritional effects of ruxolitinib in patients with myelofibrosis: Preliminary results

Metabolic and nutritional effects of ruxolitinib in patients with myelofibrosis: Preliminary results

SHP2 Inhibition Enhances JAK2 Inhibitor Therapy in Preclinical Models of Myeloproliferative Neoplasms

The classic myeloproliferative neoplasms (MPNs) polycythemia vera, essential thrombocythemia, and primary myelofibrosis are driven by aberrant activation of the JAK2 kinase, primarily by mutations in 3 different genes, JAK2, MPL, and CALR. JAK2 inhibitor therapy is generally effective at reducing MPN patient constitutional symptoms and thus can improve quality of life but has minimal effect on reducing mutant driver allele burden and does not readily alter the course of disease, reflecting the ability of MPN-driving cells to persist during therapy. Thus, the ability of current anti-JAK2 therapies to significantly modify underlying disease biology is limited. Long-term studies of the JAK2 inhibitor ruxolitinib in myelofibrosis patients have, however, identified survival benefits, yet this may be due to anti-inflammatory and spleen reducing impacts. Ultimately, the inability of ruxolitinib and other approved JAK2 inhibitors to effectively antagonize allele burden indicates alternative therapeutic approaches are needed to overcome the persistent survival of MPN-driving cells during JAK2 inhibitor therapy. Efforts to identify mechanisms that can thwart the effects of JAK2 inhibition in MPN cells have highlighted activation of the RAS-ERK pathway, including mechanisms of RAS-ERK signaling that are independent of JAK2. ERK or MEK inhibition have been shown to enhance the activity of ruxolitinib in MPN mouse models, but monotherapeutic inhibition of these kinases displayed limited efficacy. The SHP2 (Src homology region 2 domain-containing phosphatase-2) tyrosine phosphatase mediates RAS activation and subsequent MEK/ERK signaling downstream of cytokine and growth factor receptors. SHP2 plays a role in oncogenic signaling and in resistance to kinase targeted therapies, exemplified in both solid tumor and leukemia models. Given the evidence that activation of RAS-ERK signaling can antagonize the effects of JAK2 inhibition and the fact that SHP2 mediates RAS activation via multiple mechanisms downstream of numerous growth factor and cytokine receptors, we hypothesized that SHP2 may contribute to the survival of MPN cells during JAK2 inhibitor treatment and may provide a therapeutic target to improve current anti-JAK2 therapies. Using preclinical MPN models, we aimed to block RAS activation by inhibiting SHP2 to assess the potential SHP2 inhibition may have as a monotherapy or in combination with JAK2 inhibition. We found that the SHP2 inhibitors RMC-4550 and SHP099 enhanced growth inhibition of MPN model cell lines (e.g., SET2 and UKE1) in combination with ruxolitinib, effectively preventing ruxolitinib persistent growth. Concomitant treatment with both inhibitors led to enhanced inhibition of RAS-GTP levels and ERK activation and increased apoptosis compared to single agents. SHP2 inhibition antagonized the neoplastic growth of primary hematopoietic progenitor cells from MPN patients and synergized with ruxolitinib in all patient samples assessed. In an MPN mouse model driven by MPL-W515L, RMC-4550 antagonized MPN phenotypes, including leukocytosis, hepatosplenomegaly, and allele burden. RMC-4550 treatment diminished levels of a subset of pro-inflammatory cytokines, including IL-1β, CXCL9, and TNFα, among others. The combination of RMC-4550 with ruxolitinib not only suppressed advancing leukocytosis but led to white blood cell levels lower than at treatment initiation (Panel A) and suppressed thrombocytosis compared to ruxolitinib alone. The combination also led to enhanced inhibition of hepatomegaly, extramedullary hyperplasia, megakaryocyte hyperplasia, and allele burden, and a trend toward improved fibrosis. The SHP2 inhibitor RMC-4550 enhanced the survival of mice (following termination of treatment analyses) as both a monotherapy (p &amp;lt; 0.0001 compared to vehicle) and in combination with ruxolitinib (p &amp;lt; 0.01 compared to ruxolitinib monotherapy). Importantly, the combination of SHP2 inhibition using RMC-4550 with JAK2 inhibition using ruxolitinib for 4 weeks in wildtype mice was well tolerated with respect to hematologic parameters and exemplified by no effect on body weight (Panel B). Given SHP2 inhibitors are already undergoing clinical evaluation in patients with solid tumors, our findings suggest that SHP2 is a therapeutic target with potential to be rapidly translated to clinical assessment for MPN patients.

Effect of New or Worsening Anemia on Clinical Outcomes in 2233 Patients with Myelofibrosis Treated with Ruxolitinib in the Expanded-Access Jump Study

Introduction: Transient dose-dependent anemia is a known consequence of ruxolitinib treatment and can influence decisions regarding initiation, dosing, and discontinuation of therapy. Whether new or worsening anemia following ruxolitinib initiation has an impact on efficacy is unknown. A recent analysis of pooled COMFORT-I/II data indicated that new or worsening anemia did not impact the clinical outcomes of spleen volume response or symptom control (Al-Ali et al., Abstract PB2185, Presented at EHA 2023). The analysis presented here sought to validate this result using data from JUMP, the largest trial of ruxolitinib in patients with myelofibrosis (MF) to date. Methods: JUMP was a large (N=2233) single-arm, phase 3b, expanded-access trial that enrolled and provided ruxolitinib treatment for patients with MF in a setting similar to routine clinical practice. The study evaluated the safety and efficacy of ruxolitinib in patients aged ≥18 years with diagnosed primary or secondary intermediate (Int)-1, Int-2, or high-risk MF (International Prognostic Scoring System criteria) with baseline platelets ≥50×10 9 /L. All patients received ruxolitinib twice daily at a starting dose of 5-20 mg based on baseline platelet count. In this post hoc analysis, patients were stratified at baseline based on anemia due to MF (anemia defined as hemoglobin [Hb] &amp;lt;100 g/L) and transfusion status among patients with anemia (transfusion-requiring anemia [TRA; received ≥2 units of red blood cells over 8 weeks before first ruxolitinib dose] or non-transfusion-requiring anemia [NTRA]). Outcomes were stratified by presence or absence of new or worsening anemia following ruxolitinib initiation (defined as a decrease in Hb of ≥15 g/L or new transfusion requirement at Week 4, 8, or 12). Outcomes evaluated included spleen length response (SLR; defined as ≥50% reduction at Week 24 or 48 from baseline assessed with manual palpation), ≥6.5-point increase in Functional Assessment of Cancer Therapy-Lymphoma total score (FACT-Lym TS response) from baseline at Weeks 24 and 48, and overall survival (OS) measured by Kaplan-Meier method. Results: 2233 patients were included (baseline status: nonanemic, n=1386 [62.1%]; NTRA, n=521 [23.3]; TRA, n=326 [14.6]). Median (range) age of all patients was 67.0 (18-89) years, and 54.5% were men. Baseline characteristics were comparable between patients with vs without new or worsening anemia. Rates of SLR at Week 24 among patients with vs without new or worsening anemia were 31.5% vs 31.2%, respectively, (nonanemic; P=0.93), 24.4% vs 27.9% (NTRA; P=0.49), and 25.0% vs 29.8% (TRA; P=0.48; Table). FACT-Lym TS response at Week 24 for patients with vs without new or worsening anemia was 34.5% vs 34.0% (nonanemic; P=0.86), 32.7% vs 29.6% (NTRA; P=0.52), and 41.7% vs 32.1% (TRA; P=0.13). Similar trends were observed at Week 48 among patients with vs without new or worsening anemia for both SLR (35.6% vs 26.1%; P=0.02 [nonanemic], 29.6% vs 27.2%; P=0.71 [NTRA], and 19.0% vs 33.3%; P=0.10 [TRA]) and FACT-Lym (30.4% vs 23.3%; P=0.02 [nonanemic], 26.4% vs 27.6%; P=0.84 [NTRA], and 34.2% vs 33.3%; P=0.91 [TRA]). For nonanemic patients at baseline, time to median OS was not reached in either cohort; however, better OS was seen in those without vs with new/worsening anemia (hazard ratio: 0.559, [95% CI: 0.357-0.876]; P=0.01; Figure). For patients with baseline anemia (NTRA and TRA), no difference in OS was observed in those with or without new/worsening anemia ( P=0.24) Conclusions: Analysis of 2233 patients in the JUMP trial indicates that onset of new or worsening anemia following ruxolitinib initiation did not diminish clinical benefit of treatment. Ruxolitinib was associated with improvements in spleen size and symptom burden irrespective of baseline anemia and transfusion status. These results are consistent with a recent analysis of pooled COMFORT-I/II data (n=277), which reported similar findings for spleen volume and symptom responses. In contrast to the controlled clinical trial setting of COMFORT-I/II, JUMP reflects a real-world setting and enrolled a broader MF population, including those with platelet count &amp;lt;100×10 9/L and lower-risk MF. Taken together, these results support real-world use of ruxolitinib in patients with MF, regardless of baseline anemia or development of treatment-related anemia.

Promise: Investigation into the Combination of a Potent Beti with Ruxolitinib in Patients with High or Intermediate-2 Risk Myelofibrosis Not Receiving an Adequate Response with Ruxolitinib Alone

ISRCTN: 12451433 Background: Myelofibrosis (MF), a chronic myeloproliferative neoplasm (MPN), often results in progressive splenomegaly and cytopenia (1). Acute myeloid leukaemia develops in 10-20% of patients, and median survival with intermediate-2 disease is four years (2). Stem cell transplant can be curative, but is only suitable for younger, comorbidity-free patients (median MF diagnosis is 73.6 years) (3). Janus Kinase 2 (JAK2) mutation is common in MPN, and the JAK1/2 inhibitor ruxolitinib was approved in 2011 (4). However, patients still experience high disease burden, with a clear need for further treatments. Research has now focused on bromodomain and extra terminal (BET) inhibitors (5), in particular the role these have in disease associated inflammation (6). Preclinical data suggests BETi disrupts this inflammation leading to anti-fibrotic activity within MPN models. BETi with ruxolitinib eliminates fibrosis in MF mouse models thus overcoming a limitation of ruxolitinib monotherapy (7). OPN-2853 (previously PLX2853) is potent against isolated bromodomains from multiple BET proteins with rapid drug absorption, high Cmax, and short half-life differentiating it from other BETi. Preclinical efficacy has been demonstrated across a range of hematologic malignancies. PROMise is evaluating OPN-2853 in combination with ruxolitinib to identify the recommended phase 2 dose (RP2D). Methods: Primary Objectives: To assess the RP2D of OPN-2853 in combination with ruxolitinib that is safe and tolerableTo assess the efficacy of the combination of OPN-2853 and ruxolitinib for reduction in spleen size PROMise is a single country (UK) multicentre study, recruiting up to 60 patients with high or intermediate-2 risk MF who are not receiving an adequate response on ruxolitinib alone. Patients must have been treated with ruxolitinib for at least 24 weeks, on a stable dose for at least 4 weeks, and have ongoing splenomegaly. PROMise is split into three ruxolitinib dose categories based on platelet count which are assessed independently, Low Dose (5mg-20mg daily), Mid Dose (25mg-45mg daily) and High Dose (≥50mg daily). These are evaluated in combination with three OPN-2853 dose levels, Level 1 (20mg OD Decreased Dose), Level 2 (40mg OD Starting Dose) and Level 3 (80mg OD Increased Dose). Cohorts of patients (n=2-4) receive up to eight 21-day cycles of OPN-2853 and ruxolitinib. Patients are closely monitored for Dose Limiting Toxicities in cycle 1. The Trial Safety Committee (TSC) meets following cycle 1 to establish the dose recommendations of OPN-2853 for each dose category using the continual reassessment method (CRM). The CRM is utilised independently for each dose category, as such it is possible for the low, mid and high doses to be allocated to different OPN-2853 doses. Following cycle 8, patients may continue to receive OPN-2853 if experiencing clinical benefit and are followed up annually. Peripheral blood, bone marrow aspirate and bone marrow trephine samples are taken from all patients to measure the proportion who achieve a molecular response, and to determine the on target transcriptional response in myeloid cells. Additionally, pharmacokinetic samples are taken at specified timepoints pre and post dose to establish PK properties of OPN-2853 in combination with ruxolitinib. Current Status: To date PROMise has recruited 14 patients across all dose categories, and two TSC meetings have taken place.