Ruxolitinib Exposure Research Articles

Ruxolitinib for pediatric patients with treatment-naïve and steroid-refractory acute graft-versus-host disease: the REACH4 study

AbstractIn REACH4, a phase 1/2, open-label, single-arm, multicenter study, the pharmacokinetics (PK), efficacy, and safety of ruxolitinib were evaluated in treatment-naïve and steroid-refractory pediatric patients with grade 2 to 4 acute graft-versus-host disease (aGVHD; n = 45). Ruxolitinib dosing was based on age and targeted the exposure in adults receiving 10 mg twice daily; group 1 (aged ≥12 to <18 years) received 10 mg twice daily and preliminary starting doses for groups 2 (aged ≥6 to <12 years) and 3 (aged ≥2 to <6 years) were 5 mg twice daily and 4 mg/m2 twice daily, respectively. The phase 1 primary objective was to assess ruxolitinib PK parameters and define an age-appropriate recommended phase 2 dose (RP2D) for patients aged <12 years. The phase 2 primary objective was to measure the activity of ruxolitinib as assessed by overall response rate (ORR) at day 28; the key secondary objective was to assess the durable ORR at day 56. Ruxolitinib exposure was comparable across age groups; starting doses were confirmed as the RP2D. The median duration of ruxolitinib exposure was 3.8 months (range, 0.3-11.2). ORR in all patients was 84.4% (90% confidence interval [CI], 72.8-92.5) at day 28, with a durable ORR at day 56 of 66.7% (90% CI, 53.4-78.2); high response rates were observed across age groups and in both treatment-naïve and steroid-refractory subgroups. Adverse events were consistent with those expected in patients with aGVHD (anemia, decreased neutrophil and leukocyte count) treated with ruxolitinib. In pediatric patients with aGVHD, ruxolitinib showed clinically meaningful efficacy with no new safety signals. This trial was registered at www.ClinicalTrials.gov as #NCT03491215.

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.

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.

Perioperative Outcomes and Management in Patients with Myeloproliferative Neoplasms: A Multicentric Retrospective Analysis of 354 Surgical Interventions

Background: Classic myeloproliferative neoplasms (MPN) polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), are characterized by concurrent risk of thrombotic and hemorrhagic complications. These risks are reported to be further compounded perioperatively ( Blood, 2008), though scarce contemporary data exist. Further, the lack of evidence-based guidelines leads to heterogeneous management. The objective of this study was to comparatively assess perioperative complication rates (thrombotic, hemorrhagic, and survival) and management practices in a large MPN population. Methods: Consecutive surgical interventions in patients with WHO-defined PV, ET and MF recruited from the Quebec MPN Research Group Registry (6 centers; between 1986-2023) were analyzed. Endpoints (90 days post-surgery) and surgical definitions were per convention. Standard statistics were used (JMP® Pro 14.1.0 software; SAS Institute, Cary, NC, USA). Results: A total of 354 procedures were captured in 184 patients: PV, n=87 (47%); ET, n=66 (36%); MF, n=31 (17%). Cardiovascular risks were balanced; previous venous thrombosis was enriched in PV (p=0.04; Table 1A). Major surgeries were performed in 45 cases (30%), primarily PV (p=0.004); most being general (69%) (Table 1B). Interventions were urgent in 41 cases (28%); 49 (42%) of 195 evaluable were under general anesthesia. The majority of PV/ET subjects continued antiplatelet and cytoreductive agents peri-intervention, though cytoreduction was stopped in 12-22%. Thromboprophylaxis was administered in n=42 (23%). Surgical bleeding occurred in n=8 (2%). At 90-day follow-up, arterial/venous thrombosis occurred each in n=3 (1%), hemorrhage in n=25 (8%), and death in n=4 (1%). Overall complication rate was 12% (n=40). PV patients displayed significantly higher rates of surgical bleeding (6%; p=0.0006) and perioperative hemorrhage (13%; p=0.04). Factors impacting 90-day surgical outcomes: Hemorrhage-free survival (HFS): PV: General anaesthesia (p=0.04) and antithrombotic prophylaxis (p=0.05) negatively impacted HFS on multivariate testing (Table 2). ET: Driver mutation status CALR vs JAK2 (HR 24.6; 95% CI 1.2-504; p=0.05) and urgent interventions (HR 11.5; 95% CI 0.93-144; p=0.03) emerged as independent predictors for HFS. MF: Discontinuation of antiplatelet agents perioperatively was the sole factor impacting HFS (p=0.01). Perioperative complication-free survival (CFS; composite endpoint): PV: While several factors were significant on univariate testing (procedure, leukocytosis, ruxolitinib exposure, cytoreduction modification, thromboprophylaxis), multivariate testing disclosed only lower hematocrit (&amp;lt; 35%; p=0.05) to impact complication rates. ET: Urgent (p&amp;lt;0.0001) and major procedures (p=0.009), thromboprophylaxis use (p=0.001), platelet count &amp;gt; 450 x 10 9/L (p=0.02), and absence of antiplatelet (p=0.02) were significant independent predictors of CFS. MF: Antiplatelet discontinuation (HR 6.5; 95% CI 0.8-50.4; p=0.02), nature of cytoreduction (ruxolitinib vs hydrea; p=0.04) and cytoreduction discontinuation pre-operatively (p=0.006) negatively impacted CFS on multivariate analysis. Limited informative events for thrombosis/survival precluded analyses. Conclusions: This is, to our knowledge, the largest and most contemporary analysis of surgical procedures in patients with MPN. Firstly, it confirms prevalent bleeding perioperatively, though balanced by fewer thrombotic events, calling for further study of thromboprophylaxis/antiplatelet practices in this setting. Second, it discloses key management patterns, notably routine discontinuation of cytoreduction, which had a detrimental impact on outcomes. Third, correlation of uncontrolled platelets and overzealous hematocrit control with higher complication rates in ET and PV, respectively, underscores importance of judicious target control. Further, CALR driver mutation status associated with bleeding risk in ET, independent of platelet count, suggesting additional contributing mechanisms. Finally, ruxolitinib use was an independent predictor of perioperative complications in MF, though this may reflect skewing towards higher-risk populations. Further studies will be required to validate findings, with this data serving as a preliminary signal for awareness of risk and reappraisal of management strategies.

Platelet Response in Pacritinib-Treated Patients with Cytopenic Myelofibrosis: A Retrospective Analysis of PERSIST-2 and PAC203 Studies

Background: Myelofibrosis (MF) is a myeloid malignancy characterized by clonal hematopoisis, bone marrow fibrosis (BMF) and ineffective extramedullary hematopoiesis, resulting in progressive cytopenias. Thrombocytopenia is both prognostic of poor outcomes and predictive of treatment intolerance with the JAK1/2 inhibitor ruxolitinib, which exacerbates cytopenias. Pacritinib is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that can be administered at full dose to patients regardless of baseline platelet count (PLT). While prior studies have shown that pacritinib is associated with PLT stability in most patients, PLT improvement has not been described outside of a recently published case report ( Yacoub A, et al. JCO Precis Oncol. 2023;7:e2200523). Here, we report rates of hematologic improvement in PLTs (HI-P) with pacritinib across two clinical trials. Methods: Patients with baseline PLT ≤100x10 9/L on the pacritinib 200 mg BID arms of the phase 3 PERSIST-2 study (randomized ≥12 weeks prior to study termination) or the phase 2 dose-finding PAC203 study were included. HI-P was defined per International Working Group (IWG) criteria (baseline PLT &amp;lt;20x10 9/L: increase to &amp;gt;20x10 9/L and by at least 100%; baseline PLT 20-100 x 10 9/L: absolute increase of ≥30x10 9/L) in the absence of PLT transfusions, sustained over any 8 weeks while on treatment. Efficacy outcomes (reduction in spleen volume, symptom score, and BMF) were compared between HI-P responders vs non-responders (those who did not meet IWG criteria). Rates of PLT improvement were also analyzed on the best available therapy (BAT) arm of the PERSIST-2 study over the treatment period (end of study treatment). Results: Of 117 patients randomized to pacritinib (75 from PERSIST-2, 42 from PAC203), 16% (n=19) experienced HI-P on study (as defined in methods). Additionally, 14 of the 19 HI-P patients had sustained platelet improvement over ≥12 weeks). By contrast, only 5% (4/77) of patients on BAT achieved HI-P response prior to end of study treatment. HI-P responders on pacritinib compared to non-responders, had numerically higher median baseline PLT count (63 vs 45x10 9/L) and hemoglobin (Hb; 10.3 vs 8.8 g/dL). A similar percentage had prior (&amp;lt;30 days) JAK2 inhibitor exposure (68.4% vs 66.3%) and JAK2V617F mutation (78.9 vs 74.5%); median JAK2 allele burden was low in both responders and non-responders (26.7% vs 36.9%). Among HI-P responders with prior ruxolitinib exposure, most (85%, 11/13) had recent exposure within the prior 30 days, with median dose of 10 mg BID. PLT improvement was noted within the first 12 weeks in most HI-P responders, whereas PLT count remained stable, on average, among non-responders ( Figure 1a). To evaluate if recent ruxolitinib exposure and washout of drug was responsible for HI-P, we analyzed the subset of patients with ruxolitinib exposure in previous 30 days (11/19). The mean platelet count increased from 56 to 141x10 9/L at week 12. In the remaining 8/19 patients without recent ruxolitinib exposure (n=6 were treatment naïve), platelets increased from 59 to 102 x 10 9/L at week 12. While there was no difference in the magnitude of spleen volume or symptom score reduction in HI-P responders vs non-responders, a correlation with change in BMF was noted. Among the 36 patients with available bone marrow data from baseline and week 24, HI-P responders were numerically more likely to have BMF reduction (67%, n=4/6) compared to non-responders (23%, n=7/30, P=0.057, Figure 1b). There was no difference in the rate of hemorrhagic events (by standardized MedDRA queries) in PLT responders vs non-responders (47% vs 46%), though grade ≥3 bleeding was observed at lower frequency in responders compared to non-responders (10.5% vs 16%). Other commonly reported adverse events with pacritinib occurred at similar frequency between responders and non-responders. Discussion: PLT improvement meeting IWG criteria occurs in a subset of MF patients treated with pacritinib and does not seem to be explained by changes in spleen volume. Further studies are warranted to assess the correlation between hematologic improvement and BMF reduction with pacritinib. It is possible that pacritinib's unique mechanism of action as an IRAK1 inhibitor could result in modulation of the bone marrow microenvironment and thrombopoiesis. Study funded by CTI BioPharma Corp., a Sobi company.

A Physiologically-Based Pharmacokinetic Model of Ruxolitinib and Posaconazole to Predict CYP3A4-Mediated Drug-Drug Interaction Frequently Observed in Graft versus Host Disease Patients.

Ruxolitinib (RUX) is approved for the treatment of steroid-refractory acute and chronic graft versus host disease (GvHD). It is predominantly metabolized via cytochrome P450 (CYP) 3A4. As patients with GvHD have an increased risk of invasive fungal infections, RUX is frequently combined with posaconazole (POS), a strong CYP3A4 inhibitor. Knowledge of RUX exposure under concomitant POS treatment is scarce and recommendations on dose modifications are inconsistent. A physiologically based pharmacokinetic (PBPK) model was developed to investigate the drug-drug interaction (DDI) between POS and RUX. The predicted RUX exposure was compared to observed concentrations in patients with GvHD in the clinical routine. PBPK models for RUX and POS were independently set up using PK-Sim® Version 11. Plasma concentration-time profiles were described successfully and all predicted area under the curve (AUC) values were within 2-fold of the observed values. The increase in RUX exposure was predicted with a DDI ratio of 1.21 (Cmax) and 1.59 (AUC). Standard dosing in patients with GvHD led to higher RUX exposure than expected, suggesting further dose reduction if combined with POS. The developed model can serve as a starting point for further simulations of the implemented DDI and can be extended to further perpetrators of CYP-mediated PK-DDIs or disease-specific physiological changes.

Protection Against Breakthrough Delta/Omicron Variants in Vaccinated Patients with Myeloproliferative Neoplasms (MPN)

Background Information on breakthrough SARS-CoV-2 infections in MPN vaccinated patients (pts) is very limited. In these diseases, effectiveness of coronavirus disease 2019 (Covid-19) vaccines may be influenced not only by the MPN phenotype and the intrinsic reduced immunological competence, but also by the prior Covid-19 infection that can elicit a natural immunity against reinfections. Patients In the European LeukemiaNet (ELN) observational registry, 863 MPN pts with Covid-19 have been enrolled since February 2020 and in 649 of them, information on the vaccination status is now available. To ensure that well characterized reinfections were considered, diagnosis of breakthrough Covid-19 included a positive naso-pharyngeal swab and symptoms highly suggestive for SARS CoV-2 infection. ResultsBreakthrough infections in vaccinated patients with previous Covid-19 infection The effectiveness of previous Covid-19 infection in preventing reinfections was tested in a group of 131 and 287 unvaccinated and vaccinated MPN pts, respectively. Prior Covid-19 occurred during the first and second wave in 74% and 98% pts, respectively and the interval between Covid-19 and the breakthrough infection in unvaccinated and in vaccinated was similar (8.5 months). Administered vaccine doses (Pfizer in 71%) were 1-2 and 3-4 in 77% and 23% of vaccinated cases, respectively. The proportion of PV, ET, pre-PMF was similar in the two groups while the number of MF pts was lower (19%) than in the unvaccinated group (28%) (p=0.024). Reinfections occurred during delta (n=4) or omicron variants period (n=14) in 8 (6.1%) and 10 (3.5%) unvaccinated and vaccinated pts (p=ns) and hospitalization was required in 0 and 2 pts, respectively. Severity of the acute infection was variable and 1 death was registered.Breakthrough infections in vaccinated patients without previous Covid-19 infection Breakthrough infections were reported in 231 vaccinated cases (ET=89, PV=75, MF=54 and pre-PMF=13) without prior Covid-19. In 51% of pts the administered vaccine doses were 1-2 and 3-4 in 49%. No relevant vaccine related side effects were registered. Time interval from vaccination to Covid-19 was 8.1 months. Twenty-six pts (11%) required hospitalization and 205 (89%) were managed at home. Hospitalized pts were older (median age 76), males (69%) with MF (39%), and prior exposure to ruxolitinib (42%, 7 MF and 4 PV). Of note, values of C-reactive protein (CRP) and neutrophil/lymphocyte ratio (NLR) were significantly more elevated in hospitalized cases (CRP=33.1 vs. 2.0 and NLR=5.9 vs. 3.3, p<0.001). Although some infections occurred in the second wave, corresponding to alpha/beta/gamma coronavirus infection (6%), the majority of breakthrough episodes occurred in delta and omicron variant periods (41% and 53%). Three deaths were registered in hospitalized pts. We explored the risk of hospitalization and evaluated the marginal effect of gender, age and ruxolitinib exposure in a logistic model fitted to predict this event. We found that the risk of hospitalization was substantially higher only in males on ruxolitinib and increased with age (Figure). We also found that the inflammatory status measured with NLR could explain these results (data not shown). Conclusion The effectiveness of previous Covid-19 in preventing reinfection occurring during the delta and omicron variants of SARS-CoV-2 was robust (94% and 97% in unvaccinated and vaccinated pts, respectively). This is good news for MPN patients who recovered from Covid-19 and the hope is that this effectiveness can work against any future SARS-CoV-2 variant. In the cohort of vaccinated pts without prior Covid-19, we identified a subgroup of patients with more severe delta and omicron disease, at high risk of hospitalization, consisting of males who were on ruxolitinib and had elevated inflammatory biomarkers. Subsequent studies are needed to interpret these latest results. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Population-Based Study on Survival of Higher Risks Myelofibrosis Patients Treated with Ruxolitinib in the Italian Lombardy Region

Introduction Myelofibrosis (MF) is a severe disease, and patients in the higher prognostic risk categories have a median overall survival (OS) between two and four years after diagnosis. Ruxolitinib (RUX) is the first approved drug for MF, with efficacy in terms of reduction of spleen and symptoms. An improvement of OS with RUX has been reported in different studies, such as a post-hoc analysis of the registration trials (Verstovsek et al, 2017) and in the real-world setting (Guglielmelli et al, 2022). In Italy, RUX is available since October 2014 for intermediate-2 (INT-2) and high risk (HR) and since January 2018 for intermediate-1 MF cases. High-cost drugs are delivered and monitored by each regional health authority. In this study, we analyzed the outcome of INT-2 and HR MF patients treated with RUX in Lombardy, a region of roughly 10 million individuals. Methods This is a population-based retrospective cohort study based on healthcare utilization databases of Lombardy region, including data on hospital admissions, drug prescriptions, outpatient's health services and demographics. The study cohort included all beneficiaries of the Regional Health Service who started RUX between October 2014 and December 2017 (to include only INT-2 and HR MF patients) and followed-up until 31st July 2021 (minimum observation period of the study: 3.5 years). The primary outcome of the study was OS, defined as the time between RUX start and death for any cause or censoring due to migration or to end of data availability. The secondary outcome was time-to-treatment failure (TTF), defined as the time between RUX start and interruption for any reason, including allogenic stem cells transplant (allo-SCT) or death, or censoring. OS and TTF were estimated by the Kaplan-Meier method and 95% confidence interval (95%CI) was calculated. The incidence of adverse events (AEs) and secondary malignancies (included blast phase, BP, or post MF-myelodysplastic syndromes, MDS) that required hospital admission and occurring during follow-up was assessed and expressed as incidence rate (IR) x100 person-years (p-y). Infections, bleedings, and major thrombotic events were considered if they occurred within 90 days from the last RUX prescription and before evolution into BP/MDS. Results During study period, 315 MF patients started RUX. Median age at first administration was 70 years (range, 24-92) and 57% were females. Within the three months preceding RUX start (from now on, referred to as "baseline"), 76 (24%) subjects received at least one red blood cells (RBC) transfusion unit and, among those, 18 (24%) could be classified as RBC transfusion-dependent (TD- Gale et al, 2011). RUX initial dose was <20 mg bid in 216 (69%) subjects and, within this subgroup, 93 (43%) started with only 5 mg bid. As for the 284 (90%) patients with at least six months of RUX exposure, modification of RBC transfusions needs compared to baseline is reported in Table 1. Median study follow-up was 40.5 months (range, 1-82). Overall, 173 (55%) deaths were observed. Median OS was 46.3 months (95%CI: 41.6-56.0), as reported in Figure 1. Treatment failure was observed in 144 (46%) patients, and the median TTF was 25.3 months (95%CI: 19.6-33.9). Among those subjects, median treatment duration was 12 months (range, 0.9-75.5). Allo-SCT was performed in 36 (11.4%) subjects at a median time of 8.7 months (range, 1.4-66.7) after RUX start. The most frequent AEs were infections (IR: 13.5 x100 p-y), bleeding events (4.2 x100 p-y) and thrombosis (1.8 x100 p-y). Secondary solid tumours had an IR of 4.5 x100 p-y, while the latter was 1.2 x100 p-y for lymphoproliferative disorders. Evolution into BP/MDS was reported in 58 (18%) of the cohort, with an IR of 5.8 x100 p-y. Conclusions This study provided a real-world description of RUX treatment outcomes in an unselected population-based cohort of patients with higher risks MF, reflecting the daily clinical practice in Lombardy, the most populated Italian region. In this cohort of 315 long observed INT-2 and HR MF patients, RUX demonstrated to have a robust effect on survival. Among patients without baseline transfusions needs, 21% started receiving RBC units during the first six months of exposure to RUX. In the same period, 77% of subjects that transfused at baseline continued receiving RBC units. MF progression rate into BP/MDS after RUX start was comparable to data of the pre-RUX era, confirming this still remains an unmet clinical need in the field. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prospective Follow-up of Patients with Myelofibrosis (MF) and Treated with Ruxolitinib in France: The Rumycup Study

Introduction MF is a clonal blood disease affecting 1.5 per 100,000 people worldwide. MF is characterized by megakaryocytic proliferation and atypia, usually accompanied by reticulin and/or collagen fibrosis, splenomegaly, anemia, and constitutional symptoms. Current treatments for MF are palliative, aiming to alleviate symptoms and restore quality of life. Ruxolitinib (Jakavi®) is an oral JAK1/JAK2 inhibitor, first in its class, and currently approved in >90 countries for the treatment of splenomegaly or disease-related symptoms in patients with MF. This study aimed to evaluate the use and outcome of ruxolitinib therapy during the first year after initiation in clinical practice. Methods RUMYCUP was a French, multicenter, non-interventional, prospective study. Adult patients with MF primary or secondary to polycythemia vera (PV) or essential thrombocythemia (ET) and for whom a decision was taken to initiate treatment with ruxolitinib, were included in the study. Primary data were collected at inclusion and at 3, 6, 9 and 12 months. The primary objective of this study was to assess ruxolitinib exposure during 11.5 months after treatment initiation. The secondary objectives were to describe patients' characteristics and treatment with ruxolitinib. Results Between Oct-2018 and Sep-2021, 152 patients were enrolled in the study in 49 French centers. Of them, 146 were included in the analysis population and 150 were included in the safety population. Overall, 50.7% of patients (95% CI: 42.3; 59.0) received ruxolitinib for at least 11.5 months, with a higher proportion in patients with splenomegaly at initiation than in those with no or unknown splenomegaly (53.8% vs 37.9%). At inclusion, 58.9% of patients were male, and the mean age was 70.9 years. Half of the patients were diagnosed with primary MF, 33.6% had a post-ET and 15.8% had a post-PV MF. The driver mutations were JAK2V617F in 69.2% of patients, CALR in 11.6%, and MPL in 4.8%. Among patients with available prognostic scores, 30.9% had a high-risk disease, 36.8% and 26.5% had an intermediate 2 or 1 risk disease, respectively, and 5.9% had a low risk disease, based on the International Prognosis Scoring System. At inclusion, 27.4% of patients had hepatomegaly, 32.9% had night sweats, 21.2% had weight loss, and 5.5% had fever. Within the 3 months prior to ruxolitinib initiation, 72.3% of patients did not receive any transfusion of Red Blood Cell (RBC) concentrates, 17.0% had >2 and 10.6% had 1 or 2 RBC transfusions. The median length of the spleen measured by palpation was 8.0 cm below costal margin and the median decrease was of 2.5 cm at Month 12. At inclusion, 58.2% of patients had had at least one previous treatment line and 19.9% two or more lines. As first line, 55.8% of patients received hydroxyurea. During follow-up, <43% of patients received RBC units and <10% of patients received platelet transfusions. Ruxolitinib was initiated at a median dose of 25 mg/day, and the main reasons for starting treatment were splenomegaly (78.1% of patients) and symptoms (58.9%). During follow-up, the dose was increased in 26.7% of patients (mostly for optimization of efficacy), decreased in 14.4% (mostly due to the occurrence of an adverse event [AE], including lack of efficacy) and both increased and decreased in 21.2% of patients. The treatment was temporarily stopped for 20% of patients, for a median 0.5 months. For 27.6% of them, the treatment interruption lasted >21 days. A total of 513 AEs were described in 89.3% of patients. AEs suspected to be related to ruxolitinib were reported in 57.3% of patients, and 58.0% reported 251 serious AEs (SAEs). Overall, 42 SAEs reported in 24 (16.0%) patients led to death. One SAE suspected to be related to ruxolitinib treatment (hemorrhage), led to the death of one patient. The 23 other deaths were not suspected to be related to ruxolitinib treatment and the most frequent SAEs leading to death, were disease progression (5/150 patients) or myelofibrosis and malignant neoplasm progression (3/150), COVID-19 (3/150) and other infections (5/150). Conclusion This 1-year follow-up conducted in France gives a first overview on the exposure to treatment and disease characteristics in patients with MF treated with ruxolitinib in clinical practice. The evaluation in real life conditions showed that half of the patients included in this study maintained ruxolitinib treatment for at least 11.5 months after initiation.

Efficacy and Safety of Ruxolitinib in Polycythemia Vera

To evaluate the efficacy and safety of ruxolitinib in patients with polycythemia vera (PV). The clinical data of patients with PV treated with ruxolitinib in Peking Union Medical College Hospital from January 1, 2013 to December 31, 2019 were retrospectively analyzed. The starting dose of oral ruxolitinib was 10 mg twice daily and could be increased after 3 months of treatment if hematocrit (HCT) control was not achieved. HCT control was defined as HCT<45% in the absence of phlebotomy. Thirty-three patients (17 males and 16 females) were treated with ruxolitinib at a median age of 50 (21-72) years. JAK2V617F and JAK2exon12 alleles were detected in 31 and 2 patients, respectively. Before treatment, median hemoglobin level was 187 (166-208) g/L, median white blood cell and platelet level was 10.4 (5.0-15.8)×109/L and 457(237-677)×109/L, respectively. Totally 17 patients (51.5%) who were resistant to or intolerant of hydroxyurea were treated with ruxolitinib as second-line therapy, and 16 patients (48.5%) were treated with ruxolitinib as first-line therapy voluntarily. The median time since PV diagnosis to treatment of ruxolitinib was 47 (3-188) months. By December 31, 2019, all the patients continued to receive ruxolitinib. The median duration of ruxolitinib exposure was 19 (2-91) months. Both in the first-line therapy group and second-line therapy group, 15 cases (accounting for 93.8% and 88.2%, respecitvely) achieved HCT control. The median time from start of therapy to HCT control was 2.2 (0.8-11.6) months. One patient (3.0%) had disease progression after HCT control. The most common hematologic adverse events included anemia and thrombocytopenia, according to CTCAE classification, including 1 case of grade 1 anemia (3.0%) and 1 case of grade 2 thrombocytopenia (3.0%). There was no thromboembolic event occurred during the therapy of ruxolitinib. The remission rate of HCT in PV patients treated with ruxolitinib is high, and adverse reactions are rare. Ruxolitinib is effective in HCT control and generally well tolerated in patients with PV.

P1009: PREDICTORS OF HOSPITALIZATION AND SEVERE OUTCOMES IN PATIENTS WITH MPN AND COVID-19

Background: Risk factors for severe COVID-19 in myeloproliferative neoplasms (MPN) have been extensively explored. However, no information is available on risk factors to hospitalization at COVID-19 diagnosis. Aims: To provide an evidence-based triage and inform for a timely and antiviral therapy prescription in early phases of viral replication. Methods: The MPN-COVID study is still enrolling consecutive adult MPN patients with COVID-19 infection since February 15, 2020. Among 479 patients (ET n=175, PV n=158, MF n=91, and pre-PMF n=55) with COVID-19 from Feb 2020 to Jun 2021, 248 (52%) were managed at home and 231 (48%) were hospitalized. Results: Univariate analysis Compared to outpatients, those admitted to hospital were more likely to be men (58.9% vs. 45.2%, p=0.003), older than 70 years (61.3% vs. 29.0%, p<.001), with at least one comorbidity (79.7% vs. 55.5%, p<.001) and a history of thrombosis (26.5% vs. 16.6%, p=0.008). Overt myelofibrosis (MF) cases were more frequent in hospital (38.5% vs. 18.1%, p<.001) than PV, ET or pre-PMF. Ruxolitinib was more frequently used in patients who underwent to hospital than managed at home. (25.7% vs. 12.1%, p<.001). In comparison with outpatients, hospitalized cases had a significantly lower median values of hemoglobin (12.1 vs. 13.3 g/dL, p<.001), platelets (250 vs. 390 x109/L, p<.001), absolute lymphocytes (0.8 vs. 1.4 x109/L, p<.001) and higher neutrophil counts (5.1 vs. 4.5 x109/L, p=0.022), leading to a significant increase of neutrophil to lymphocyte ratio (NLR) (6.6 vs. 3.2, p<.001). Compared to lymphocytopenia, the best sensitivity and specificity was found for NLR, whose AUC was 77.28% by ROC analysis. Multivariate analysis By adjusting for sex, comorbidity, fever, systemic symptoms, O2 saturation, previous thrombosis, MPN type, ruxolitinib exposure, and first vs. subsequent waves and vaccination period, three factors emerged as independent predictors of hospitalization: age over 70 years, (OR=3.02, p=0.038), dyspnea (OR=7.23, p<.001) and NLR ≥4, (OR=6.94, p<.001). Interaction model of risk factors In a model fitted to test the interaction terms of the three significant variables, we evaluated the marginal effect of NLR and dyspnea across different age classes (Figure) and found that in younger patients (i.e., from 50 to 70 years) dyspnea was the stronger predictor than increased NLR; conversely, both dyspnea and NLR showed a high and comparable marginal effect in age >80 years. Remarkably, the probability of hospitalization consistently exceeded 90% for any age group when dyspnea and NLR were concomitantly present, and their combination was more prevalent in MF (42%) than in the other phenotypes (24%, 25% and 29% in pre-PMF, PV and ET patients, respectively). In addition to predict hospitalization, dyspnea and NLR≥4 were also associated with severity of COVID-19 illness in terms of respiratory support at hospitalization (OR=2.44, p=0.023). Of note, only age >70 years and NLR higher than 6 were predictors of survival in hospitalized patients (OR=3.24, p=0.007 and OR=5.41, p=0.041, respectively). Image:Summary/Conclusion: For triage purposes of MPN patients tested positive for COVID-19, dyspnea, age and NLR are powerful predictors of hospitalization and identify patients at higher probability of invasive or non-invasive respiratory support and survival, particularly in overt MF. This MPN subgroup at high risk for progression to severe COVID-19 disease should be prioritized for antiviral therapy, even in the ambulatory setting.

Impact of Individual Comorbidities on Survival of Patients with Myelofibrosis.

Simple SummaryThe coexistence of cancer with other chronic conditions has substantial implications for treatment decisions and outcomes for both neoplasms and chronic disease. Reports have demonstrated the impact of comorbidities on survival in different hematologic disorders. Myelofibrosis (MF) guidelines do not consider the complex interrelations between MF and comorbidity. Several works have shown how MF patients have a wide variety and high burden of comorbidities and demonstrated that the comorbidity burden was significantly associated with an unfavorable impact on survival. These previous studies about comorbidity on MF are retrospective and consider the cumulative rather than individual comorbidity burden. The influence of individual comorbidities on outcome in MF patients has not been studied. We sought to identify the comorbidities in MF patients at diagnosis and to assess the influence of those different comorbidities on survival. Considering them individually may contribute to the personalization of MF management and optimizing outcomes.The comorbidity burden is an important risk factor for overall survival (OS) in several hematological malignancies. This observational prospective study was conducted to evaluate the impact of individual comorbidities on survival in a multicenter series of 668 patients with primary myelofibrosis (PMF) or MF secondary to polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). Hypertension (hazard ratio (HR) = 4.96, p < 0.001), smoking (HR = 5.08, p < 0.001), dyslipidemia (HR = 4.65, p < 0.001) and hepatitis C virus (HCV) (HR = 4.26, p = 0.015) were most adversely associated with OS. Diabetes (HR = 3.01, p < 0.001), pulmonary disease (HR = 3.13, p < 0.001) and renal dysfunction (HR = 1.82, p = 0.037) were also associated with an increased risk of death. Multivariate analysis showed that pulmonary disease (HR = 2.69, p = 0.001), smoking (HR = 3.34, p < 0.001), renal dysfunction (HR = 2.08, p = 0.043) and HCV (HR = 11.49, p = 0.001) had a negative impact on OS. When ruxolitinib exposure was included in the model, the effect of each comorbidity on survival was modified. Therefore, individual comorbidities should be taken into account in determining the survival prognosis for patients with MF.

Real-world analysis of main clinical outcomes in patients with polycythemia vera treated with ruxolitinib or best available therapy after developing resistance/intolerance to hydroxyurea.

BackgroundRuxolitinib is approved for patients with polycythemia vera (PV) who are resistant/intolerant to hydroxyurea, but its impact on preventing thrombosis or disease‐progression is unknown.MethodsA retrospective, real‐world analysis was performed on the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to subsequent treatment with ruxolitinib (n = 105) or the best available therapy (BAT; n = 272). Survival probabilities and rates of thrombosis, hemorrhage, acute myeloid leukemia, myelofibrosis, and second primary cancers were calculated according to treatment. To minimize biases in treatment allocation, all results were adjusted by a propensity score for receiving ruxolitinib or BAT.ResultsPatients receiving ruxolitinib had a significantly lower rate of arterial thrombosis than those on BAT (0.4% vs 2.3% per year; P = .03), and this persisted as a trend after adjustment for the propensity to have received the drug (incidence rate ratio, 0.18; 95% confidence interval, 0.02‐1.3; P = .09). There were no significant differences in the rates of venous thrombosis (0.8% and 1.1% for ruxolitinib and BAT, respectively; P = .7) and major bleeding (0.8% and 0.9%, respectively; P = .9). Ruxolitinib exposure was not associated with a higher rate of second primary cancers, including all types of neoplasia, noncutaneous cancers, and nonmelanoma skin cancers. After a median follow‐up of 3.5 years, there were no differences in survival or progression to acute leukemia or myelofibrosis between the 2 groups.ConclusionsThe results suggest that ruxolitinib treatment for PV patients with resistance/intolerance to hydroxyurea may reduce the incidence of arterial thrombosis.Lay Summary Ruxolitinib is better than other available therapies in achieving hematocrit control and symptom relief in patients with polycythemia vera who are resistant/intolerant to hydroxyurea, but we still do not know whether ruxolitinib provides an additional benefit in preventing thrombosis or disease progression.We retrospectively studied the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to whether they subsequently received ruxolitinib (n = 105) or the best available therapy (n = 272).Our findings suggest that ruxolitinib could reduce the incidence of arterial thrombosis, but a disease‐modifying effect could not be demonstrated for ruxolitinib in this patient population.

The MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study

Idasanutlin, an MDM2 antagonist, showed clinical activity and a rapid reduction in JAK2 V617F allele burden in patients with polycythemia vera (PV) in a phase 1 study. This open-label phase 2 study evaluated idasanutlin in patients with hydroxyurea (HU)-resistant/-intolerant PV, per the European LeukemiaNet criteria, and phlebotomy dependence; prior ruxolitinib exposure was permitted. Idasanutlin was administered once daily on days 1 through 5 of each 28-day cycle. The primary end point was composite response (hematocrit control and spleen volume reduction > 35%) in patients with splenomegaly and hematocrit control in patients without splenomegaly at week 32. Key secondary end points included safety, complete hematologic response (CHR), patient-reported outcomes, and molecular responses. All patients (n = 27) received idasanutlin; 16 had response assessment (week 32). Among responders with baseline splenomegaly (n = 13), 9 (69%) attained any spleen volume reduction, and 1 achieved composite response. Nine patients (56%) achieved hematocrit control, and 8 patients (50%) achieved CHR. Overall, 43% of evaluable patients (6/14) showed a ≥50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (week 32). Nausea (93%), diarrhea (78%), and vomiting (41%) were the most common adverse events, with grade ≥ 3 nausea or vomiting experienced by 3 patients (11%) and 1 patient (4%), respectively. Reduced JAK2 V617F allele burden occurred early (after 3 cycles), with a median reduction of 76%, and was associated with achieving CHR and hematocrit control. Overall, the idasanutlin dosing regimen showed clinical activity and rapidly reduced JAK2 allele burden in patients with HU-resistant/- intolerant PV but was associated with low-grade gastrointestinal toxicity, leading to poor long-term tolerability. This trial was registered at www.clinincaltrials.gov as #NCT03287245.

Peripheral Blasts Are Associated with Response to Ruxolitinib and Outcome in Patients with Chronic-Phase Myelofibrosis

Peripheral Blasts Are Associated with Response to Ruxolitinib and Outcome in Patients with Chronic-Phase Myelofibrosis

Clinical Features Associated with Long-Term Ruxolitinib Exposure in Myelofibrosis and Predictive Role of Neutrophils

Clinical Features Associated with Long-Term Ruxolitinib Exposure in Myelofibrosis and Predictive Role of Neutrophils

Comparative Effectiveness of Fedratinib and Pacritinib for the Treatment of Myelofibrosis in Patients with Low Platelet Counts: A Simulated Treatment Comparison Study

Introduction: Myelofibrosis (MF) is a Philadelphia chromosome-negative myeloproliferative neoplasm with an estimated prevalence of 4-6/100,000 persons in the USA. Patients with MF experience aberrant hematopoiesis, bone marrow fibrosis, splenomegaly, and cytopenias, including thrombocytopenia, as well as diminished survival ranging from months to years, depending on risk status. Symptoms progressively worsen, underscoring the need for effective treatments across heterogeneous risk statuses and patient dispositions. Among intermediate- to high-risk patients, Janus kinase 2 (JAK2) inhibitors are the primary treatment for MF. Fedratinib was approved by the US Food and Drug Administration (FDA) based on the results of the JAKARTA trials (NCT01437787; NCT01523171), and a new drug application for pacritinib has been submitted to the FDA for the treatment of MF in patients with severe thrombocytopenia. A head-to-head trial of fedratinib and pacritinib for the treatment of MF has not been conducted. Moreover, there is a paucity of evidence evaluating these agents in patients with MF and thrombocytopenia (platelets < 100 × 10 9/L). Therefore, indirect treatment comparisons (ITCs) are required to assess the comparative efficacy of fedratinib and pacritinib in this population.Methods: A systematic literature review (SLR) was conducted to identify all clinical evidence in patients with MF and thrombocytopenia. Based on the SLR results, the JAKARTA, JAKARTA-2, and PERSIST-2 (NCT01773187) trials were identified as the studies to form the basis of the ITC. A pooled analysis data set was developed based on individual patient-level data from the fedratinib 400-mg arms of the JAKARTA and JAKARTA-2 trials including patients with platelets < 100 × 10 9/L. Published summary data from the pacritinib 200-mg arm of the PERSIST-2 trial served as the comparator. Simulated treatment comparisons (STCs) were used to compare spleen volume reduction (SVR) ≥ 35% while adjusting for mutually reported baseline patient characteristics such as age, sex, Dynamic International Prognostic Scoring System, Eastern Cooperative Oncology Group (ECOG) performance status (PS), JAK2 V617F mutation status, prior ruxolitinib exposure, and laboratory tests. Final adjustment models were selected based on fit statistics and the literature review. Indirect relative risk (RR) was estimated with 95% confidence intervals (CIs) using unanchored naive ITC (unadjusted) and STC (adjusted) methodologies.The PERSIST-2 trial included patients with baseline platelets < 50 × 10 9/L, but did not report median baseline counts. Therefore, a sensitivity analysis was conducted to evaluate the impact of differential median baseline platelet counts. In the sensitivity analysis, an outcome model was generated in the full pooled JAKARTA trial population irrespective of platelet count, and platelet count was forced into the multivariable adjustment model. Outcomes were simulated at 3 median baseline platelet counts (25, 50, and 75 × 10 9/L) and compared using similar methodology to the main analysis.Results: The main analysis suggests that fedratinib is associated with a greater proportion of SVR ≥ 35% than pacritinib (Table, A). According to the naive ITC, fedratinib was numerically favored over pacritinib in terms of SVR ≥ 35% (RR, 1.67 [95% CI, 0.94-2.97]). After adjustment for ECOG PS, JAK2 V6127F mutation status, and prior ruxolitinib exposure, fedratinib was statistically favored relative to pacritinib for SVR ≥ 35% (RR, 1.76 [95% CI, 1.00-3.10]).Results of the platelet-count-adjusted sensitivity analysis showed that a significant difference was observed in favor of fedratinib with respect to SVR ≥ 35% (Table, B). The resulting indirect RRs were similar regardless of simulated median baseline platelet count, which suggest that differential baseline platelet count has a minimal impact on the ITC results.Conclusion: This analysis used a population-adjusted ITC to assess the comparative efficacy of pacritinib and fedratinib in patients with MF and thrombocytopenia. Following population adjustment, fedratinib was associated with a greater proportion of patients achieving SVR ≥ 35% than pacritinib. In lieu of a head-to-head clinical trial, further real-world evidence studies should be conducted to assess the effectiveness of these treatments in the clinical setting. [Display omitted] DisclosuresDaniele: BMS/Celgene: Consultancy; Purple Squirrel Economics: Current Employment. Abraham: Bristol Myers Squibb: Current Employment. Kee: Bristol Myers Squibb: Current Employment. Tremblay: Cytel: Consultancy; Purple Squirrel Economics: Current Employment. Rose: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. McBride: BMS: Current Employment.

A 10-year retrospective cohort study of ruxolitinib and association with nonmelanoma skin cancer in patients with polycythemia vera and myelofibrosis

Clinical trials report occurrence of nonmelanoma skin cancers (NMSCs) with ruxolitinib in patients with polycythemia vera (PV) or myelofibrosis (MF); however, the level of risk and effect of covariates are not known in the real-world setting. To systematically assess the risk of developing NMSC after ruxolitinib exposure in patients with PV or MF. A 10-year retrospective cohort of patients with PV or MF at Stanford Medical Center was identified and matched according to age, gender, race, Charlson Comorbidity Index, disease diagnosis, and follow-up time. The main outcome measure was hazard ratio (HR) for NMSC (comprised of basal cell carcinoma and squamous cell carcinoma [SCC]) after ruxolitinib exposure, adjusted for covariates. The study cohort consisted of 564 patients (188 exposed to ruxolitinib for at least 4weeks, 376 unexposed). Ruxolitinib-exposed patients with PV or MF had an adjusted NMSC HR of 2.69 (95% CI, 1.03-7.02). In particular, ruxolitinib exposure was associated with SCC (HR, 3.24; 95% CI, 1.45-7.22), with non-Janus kinase 2-mutated patients showing even higher SCC risk (HR, 7.40; 95% CI, 2.54-21.63). Retrospective design. Our real-world results indicate that SCC risk is increased in patients with PV or MF taking ruxolitinib and support consideration of skin cancer monitoring.

Real-world survival of US patients with intermediate- to high-risk myelofibrosis: impact of ruxolitinib approval

The Janus kinase inhibitor ruxolitinib is approved for the treatment of myelofibrosis (MF) and improved overall survival (OS) versus control therapy in the phase 3 COMFORT trials. The aim of this retrospective analysis was to examine the real-world impact of ruxolitinib on OS in patients with MF. The US Medicare Fee-for-Service claims database (parts A/B/D) was used to identify patients with ≥ 1 inpatient or ≥ 2 outpatient claims with an MF diagnosis (January 2010–December 2017). Eligible patients with MF were ≥ 65 years old (intermediate-1 or higher risk based on age). Patients were divided into 3 groups based on ruxolitinib approval status at diagnosis and ruxolitinib exposure: (1) preapproval, ruxolitinib-unexposed; (2) post-approval, ruxolitinib-unexposed; and (3) post-approval, ruxolitinib-exposed. In total, 1677 patients with MF were included (preapproval [all ruxolitinib-unexposed], n = 278; post-approval, n = 1399 [ruxolitinib-unexposed, n = 1127; ruxolitinib-exposed, n = 272]). Overall, median age was 78 years, and 39.8% were male. Among patients with valid death dates (preapproval, n = 119 [42.8%]; post-approval, ruxolitinib-unexposed, n = 382 [33.9%]; post-approval ruxolitinib-exposed, n = 54 [19.9%]), 1-year survival rates were 55.6%, 72.5%, and 82.3%, and median OS was 13.2 months, 44.4 months, and not reached, respectively. Risk of mortality was significantly lower post- versus preapproval regardless of exposure to ruxolitinib (ruxolitinib-unexposed: adjusted hazard ratio [HR], 0.67; ruxolitinib-exposed: adjusted HR, 0.36; P < 0.001 for both); post-approval, mortality risk was significantly lower in ruxolitinib-exposed versus ruxolitinib-unexposed patients (adjusted HR, 0.61; P = 0.002). Findings from this study complement clinical data of ruxolitinib in MF by demonstrating a survival benefit in a real-world setting.

Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice\u2014a prospective single-center trial

PurposeKnowledge on Ruxolitinib exposure in patients with graft versus host disease (GvHD) is scarce. The purpose of this prospective study was to analyze Ruxolitinib concentrations of GvHD patients and to investigate effects of CYP3A4 and CYP2C9 inhibitors and other covariates as well as concentration-dependent effects.Methods262 blood samples of 29 patients with acute or chronic GvHD who were administered Ruxolitinib during clinical routine were analyzed. A population pharmacokinetic model obtained from myelofibrosis patients was adapted to our population and was used to identify relevant pharmacokinetic properties and covariates on drug exposure. Relationships between Ruxolitinib exposure and adverse events were assessed.ResultsMedian of individual mean trough serum concentrations was 39.9 ng/mL at 10 mg twice daily (IQR 27.1 ng/mL, range 5.6–99.8 ng/mL). Applying a population pharmacokinetic model revealed that concentrations in our cohort were significantly higher compared to myelofibrosis patients receiving the same daily dose (p < 0.001). Increased Ruxolitinib exposure was caused by a significant reduction in Ruxolitinib clearance by approximately 50%. Additional comedication with at least one strong CYP3A4 or CYP2C9 inhibitor led to a further reduction by 15% (p < 0.05). No other covariate affected pharmacokinetics significantly. Mean trough concentrations of patients requiring dose reduction related to adverse events were significantly elevated (p < 0.05).ConclusionRuxolitinib exposure is increased in GvHD patients in comparison to myelofibrosis patients due to reduced clearance and comedication with CYP3A4 or CYP2C9 inhibitors. Elevated Ruxolitinib trough concentrations might be a surrogate for toxicity.