Ruxolitinib for steroid-refractory chronic graft-versus-host disease: Japanese subgroup analysis of REACH3 study.

Ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, has demonstrated safety and efficacy in patients with graft-versus-host disease (GvHD). This phase 3 randomized trial (REACH3) evaluated the efficacy and the safety of ruxolitinib 10 mg twice daily compared with investigator-selected best available therapy (BAT) in a subgroup of Japanese patients (n = 37) with steroid-refractory or dependent (SR/D) chronic GvHD. At data cut-off, treatment was ongoing in 17 patients and discontinued in 20. The overall response rate (complete or partial) at week 24 was greater with ruxolitinib than BAT (50% vs. 20%; odds ratio, 4.13 [95% CI, 0.90-18.9]). The best overall response rate (complete or partial response at any time point up to week 24) was higher with ruxolitinib than BAT (68.2% vs. 46.7%; odds ratio, 2.69 [95% CI, 0.66-10.9]). Ruxolitinib led to longer median failure-free survival than BAT (18.6 months vs. 3.7 months; hazard ratio, 0.34; [95% CI, 0.14-0.85]). The most common grade ≥ 3 adverse events up to week 24 were anemia (ruxolitinib: 22.7%; BAT: 6.7%) and pneumonia (22.7% and 20.0%, respectively). Ruxolitinib showed a higher response rate and improvement in failure-free survival in Japanese patients with SR/D chronic GvHD, with a safety profile consistent with the overall study population.

Post-hoc safety/efficacy analyses from pediatric delgocitinib atopic dermatitis trials.

BACKGROUND: Delgocitinib ointment is usually recommended for use in children at a concentration of 0.25%. However, there are no clear criteria for dosing, except that a 0.5% formulation may also be used, depending on symptom severity. Treatment of atopic dermatitis is based on combinations of topical corticosteroids, tacrolimus ointment, and delgocitinib ointment, but there are no reports on the safety of delgocitinib ointment when used in combination with other drugs. METHODS: This is a post-hoc analysis of data from two delgocitinib ointment trials with pediatric atopic dermatitis patients. The efficacy and safety of the 0.25% and 0.5% formulations were compared. Efficacy and safety were evaluated after up to 4 and 56 weeks of treatment, respectively. The safety of delgocitinib ointment when used in combination with topical corticosteroids and/or tacrolimus ointment was investigated. RESULTS: The dose-response relationship was examined according to baseline disease severity. The proportions of subjects with mild disease who achieved cumulative investigator's global assessment of 0 (clear) or 1 (almost clear) were 46.2% (0.25% ointment), 71.4% (0.5% ointment), and 7.7% (vehicle). For subjects with moderate to severe disease, the corresponding proportions were 19.0%, 20.0%, and 0.0%, respectively. No overall differences were seen in the safety profiles of the 0.25% and 0.5% delgocitinib ointment doses, or in the safety profiles of the two doses relating to disease severity or to concomitant use of topical corticosteroids and/or tacrolimus ointment. CONCLUSIONS: These analyses indicate that after up to 4 weeks of treatment, delgocitinib 0.5% ointment may be more effective than the 0.25% dose for mild atopic dermatitis, and that after up to 56 weeks of treatment, delgocitinib is well tolerated in a pediatric trial population when used as prescribed in combination with topical corticosteroids and/or tacrolimus ointment.

Efficacy and safety of ruxolitinib vs best available therapy for polycythemia vera: An updated systematic review and meta-analysis.

Ruxolitinib, a JAK1/JAK2 inhibitor, has been shown to have lower thromboembolism rates compared to placebo in polycythemia vera (PV) patients. This meta-analysis evaluates ruxolitinib's efficacy and safety against best available therapy (BAT) in patients with PV and in hydroxyurea-resistant/intolerant PV patients. A comprehensive literature search was conducted up to November 2023. We compared ruxolitinib and BAT for efficacy and safety endpoints. Six studies involving 1061 patients were analyzed, with 620 on BAT and 441 on ruxolitinib. Ruxolitinib showed higher hematocrit control (p = 0.015) and treatment response (p = 0.04) compared to BAT. It also significantly improved Myeloproliferative Neoplasms-Symptom Assessment Form scores (MPN-SAF) (p < 0.01). Additionally, patients with PV treated with ruxolitinib had higher rates of nonmelanoma skin cancer (p < 0.01). In subgroup analyses focusing on patients resistant or intolerant to hydroxyurea, ruxolitinib maintained its efficacy, significantly improving treatment response (p < 0.01) and significant improvements in MPN-SAF (p = 0.02) score when compared to BAT. The safety profile was consistent with the overall analyses, showing significantly reduced thromboembolism rates (p = 0.04), increased rates of anemia (p = 0.01), and increased herpes zoster infections (p = 0.02). Ruxolitinib outperforms BAT in PV and patients with PV-resistant or intolerant to hydroxyurea, offering better hematocrit control and reducing symptomatic burden and thromboembolism risk. Yet, it is associated with higher rates of anemia, herpes infection, and skin cancer.

Advances in Stem Cell Transplantation for Myelofibrosis.

PURPOSE OF REVIEW: Allogeneic hematopoietic cell transplantation is the only potentially curative treatment for myelofibrosis. This review discusses issues not well-covered by existing guidelines: timing of transplant, pre-transplant spleen management and alternative donors; providing our approach to these situations. RECENT FINDINGS: Research continues to allow better identification, by better risk stratification and advances in understanding likelihood of durable JAKi response, which patients are likely to derive benefit from upfront transplant versus those for whom delayed transplant may be more appropriate. Several options of JAKi therapy provide a non-surgical option for pre-HCT splenomegaly management, allowing some patients to avoid risks associated with splenectomy. Recent years have also seen a sharp spike in haploidentical donor transplants, along with narrowing of the gap in outcomes between donor types. Continuous enrollment in prospective studies or well-designed registries is required to generate the high-quality data needed to develop better decision tools for these scenarios.

[JAK inhibitors for myelofibrosis: ruxolitinib and momelotinib].

Myelofibrosis should be diagnosed according to the WHO classification (2022, 5th Ed.) and International Consensus Conference 2022 criteria. Testing for driver mutations in the three genes JAK2, CALR, and MPL is recommended to ensure a definitive diagnosis. Ruxolitinib is the only JAK inhibitor currently approved in Japan, but momelotinib is under regulatory review. The MOMENTUM study showed similar spleen volume reduction at 24 weeks and MFSAF-TSS reduction as the COMFORT study of ruxolitinib. Momelotinib acts on ACVR1 and, therefore, improves anemia through suppression of hepcidin. Anemia and/or transfusion dependency are known to be associated with overall survival duration. Consequently, supportive care measures such as ESA and danazol in lieu of transfusion should be considered in addition to JAK inhibitor selection. Mean survival after discontinuation of JAK inhibitors is 11 to 14 months. Pacritinib (not approved in Japan) is suitable for MF patients with thrombocytopenia. JAK inhibitor selection and supportive care by ESA or danazol in lieu of transfusion should be considered. Many classes of drugs other than JAK inhibitors for myelofibrosis are under investigation.

Successful treatment of rheumatoid arthritis-associated interstitial lung disease with filgotinib: A case report on janus kinase 1 inhibition.

Filgotinib, a janus kinase 1 (JAK1) inhibitor, is used in the treatment of rheumatoid arthritis (RA). RA-associated interstitial lung disease (RA-ILD) is a severe RA complication with no established effective treatment. We report the case of a patient with RA-ILD successfully treated with filgotinib. A 46-year-old woman with RA and RA-ILD, presenting with a non-specific interstitial pneumonia pattern, was refractory to abatacept and prednisolone but responded to filgotinib. Both arthritis and RA-ILD improved significantly, and the patient remained in remission for over 12 months. Basic research indicates that JAK1 plays a role in the cytokine signal transduction in ILD; however, there are no clinical reports on the efficacy of filgotinib in RA-ILD. This case suggests filgotinib as a potential treatment for patients with RA-ILD, particularly in the early stages of this disease.

Impact of Previous Alopecia Areata Treatment on Efficacy Responses up to Week 48 Following Ritlecitinib Treatment: A Post Hoc Analysis.

INTRODUCTION: Patients with alopecia areata (AA) may have received several therapies for management of AA during their lives. In the ALLEGRO phase 2b/3 (NCT03732807) study, the oral JAK3/TEC family kinase inhibitor ritlecitinib demonstrated efficacy and an acceptable safety profile in patients aged ≥ 12 years with AA and ≥ 50% scalp hair loss. This post hoc analysis investigated associations between prior use of AA therapies and Severity of Alopecia Tool (SALT) responses in patients receiving ritlecitinib for AA. METHODS: Patients receiving ritlecitinib 30 mg or 50 mg once daily with or without an initial 4-week 200-mg daily loading dose were grouped by previous exposure to AA treatments, including topicals, intralesional corticosteroids (ILCS), topical immunotherapy, and systemic immunosuppressants or any prior AA treatment. Multivariable logistic regression analyses evaluated the association between response based on a SALT score of ≤ 20 and any prior treatment for AA at weeks 24 and 48. RESULTS: Of 522 patients, 360 (69.0%) had previous exposure to any AA treatment. At Week 24, SALT ≤ 20 response was positively associated with prior use of ILCS (odds ratio [OR], 2.12; 95% confidence interval [CI], 1.23-3.65; P < 0.05) and negatively associated with prior use of systemic immunosuppressants (OR 0.50; 95% CI 0.28-0.88; P < 0.05). Prior use of topicals or topical immunotherapy was not associated with SALT ≤ 20 response at Week 24. By Week 48, no association was identified between SALT ≤ 20 response and prior use of topicals, ILCS, topical immunosuppressants, or systemic immunosuppressants (all P > 0.05). Previous exposure to any AA therapy was not associated with SALT ≤ 20 response at weeks 24 or 48 (all P > 0.05). CONCLUSIONS: Prior AA treatment history had no effect on longer-term treatment response to ritlecitinib. TRIAL REGISTRATION NUMBER: NCT03732807.

Comparative efficacy and hematologic safety of different dosages of JAK inhibitors in the treatment of myelofibrosis: a network meta-analysis.

Background: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis associated with substantial morbidity and mortality. The therapeutic landscape for MF has advanced with the development of Janus kinase inhibitors (JAKis) like ruxolitinib (RUX), fedratinib (FED), pacritinib (PAC), and momelotinib (MMB), aiming to alleviate symptoms and enhance patient comfort. Methods: A network meta-analysis was conducted to assess the efficacy and safety of eleven JAKi treatment regimens across nine randomized controlled trials (RCTs) with a total of 2340 participants. Outcomes were evaluated in terms of spleen volume reduction (SVR), total symptom score reduction (TSSR), hematological safety profiles, and overall survival (OS). Results: RUX and MMB were superior in achieving SVR and TSSR, with significant dose-response relationships observed. PAC and MMB were associated with a decreased risk of grade 3/4 anemia and thrombocytopenia compared to other JAKis. However, no substantial benefits in OS were observed with newer JAKis compared to RUX. The poorer OS outcomes with certain PAC dosages were likely influenced by baseline patient characteristics, particularly severe cytopenias. Conclusion: The introduction of JAKis significantly changed the treatment of MF. This meta-analysis reaffirms the core role of RUX and positions MMB as a potentially powerful alternative for treating symptoms and reducing spleen size. Meanwhile, MMB and PAC have a positive effect on anemia in MF while FED is more tolerable for patients with thrombocytopenia. However, it should be noted that these results are influenced by baseline patient characteristics, particularly cytopenias, which affects both management and overall survival. Therefore, there is an urgent need for personalized dosing strategies to optimize the balance between efficacy and safety, with careful consideration of patient-specific factors. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023424179.

Efficacy and safety of ritlecitinib in vitiligo patients across Fitzpatrick skin types with biomarker analyses.

Efficacy and safety of ritlecitinib (an oral JAK3/TEC family kinase inhibitor) were evaluated in patients with nonsegmental vitiligo (NSV) across Fitzpatrick skin types (FSTs). Patients with FST I-III ('light skin'; n = 247) and FST IV-VI ('dark skin'; n = 117) received once-daily ritlecitinib 50 mg (with/without 4-week loading dose), low-dose ritlecitinib or placebo for 24 weeks. At baseline, patients with light skin displayed higher CLM-1 and NCR1 serum levels than patients with dark skin (p < 0.05). At 24 weeks, ritlecitinib 50 mg improved the extent of depigmentation measured by percent change from baseline in facial-vitiligo area scoring index (placebo-adjusted mean difference [90% CI]) in patients with light (-15.2 [-24.7, -5.8]; p = 0.004) and dark (-37.4 [-50.3, -24.4]; p < 0.0001) skin, with continuous re-pigmentation through week 48. Treatment-emergent adverse events were similar across FSTs. At weeks 4 and 24, ritlecitinib 50 mg reduced CXCL11 serum levels (p < 0.001) in patients with light skin, whereas patients with dark skin had increased levels at week 4 (p = 0.05) and no significant change at week 24. Ritlecitinib 50 mg decreased IL-9 and IL-22 expression levels in dark skin compared with light skin (qPCR; p < 0.05). These differences in immune dysregulations may explain why NSV patients with dark skin respond to therapy earlier than patients with light skin.

Real-world study comparing the efficacy of Janus kinase inhibitors in patients with difficult-to-treat rheumatoid arthritis.

OBJECTIVE: This study aimed to analyze the clinical efficacy of JAK inhibitors in difficult-to-treat rheumatoid arthritis (D2TRA) and non-D2TRA patients and evaluate the factors influencing their efficacy using real-world data. METHOD: Here, 159 JAK inhibitor-treated patients with rheumatoid arthritis were categorized into D2TRA and non-D2TRA groups. Data including the Clinical Disease Activity Index (CDAI) at initiation and 6 months after drug administration, drug retention months, and reason for discontinuation due to toxic adverse events were collected. RESULTS: The retention rates at 6 months were 64.0% (D2TRA) and 78.4% (non-D2TRA) and were significantly different between the two groups (p = 0.030). The discontinuation rate owing to toxic adverse events significantly differed between the two groups (p = 0.030). The CDAI-low disease activity (LDA) rates differed significantly between the two groups (non-D2TRA, 62.3%; D2TRA, 34%; p < 0.001). CDAI-LDA achievement at 6 months after drug introduction was significantly associated with the number of times that biologic and/or targeted synthetic disease-modifying anti-rheumatic drugs were previously used and the CDAI at baseline in all patients treated with JAK inhibitors. However, no predictive factors were identified for D2TRA patients treated with JAK inhibitors. CONCLUSION: Compared to non-D2TRA patients, D2TRA patients demonstrated significantly lower drug retention rates, CDAI-LDA achievement rates, and safety of JAK inhibitors. No significant predictive factor for CDAI-LDA achievement 6 months after drug introduction was detected in D2TRA patients. Key Points • The retention of JAK inhibitors were significantly lower for the treatment of D2TRA patients in comparison with non-D2TRA patients. • The efficacy and safety of JAK inhibitors were significantly lower for the treatment of D2TRA patients. • Number of previous uses of b/tsDMARDs and CDAI at baseline were identified as the predictive factors for resistance to CDAI-LDA achievement to JAK inhibitor treatment. • No significant predictive factor for CDAI-LDA achievement 6 months after drug introduction was detected in D2TRA patients.

Drug-Induced Alopecia Areata From Upadacitinib.

This case report describes an unexpected occurrence of alopecia areata (AA) in a 55-year-old woman undergoing treatment with upadacitinib for atopic dermatitis. This patient developed AA approximately one year into her upadacitinib treatment for atopic dermatitis. This case highlights possible upadacitinib-induced AA, which has not been reported in the literature. Not only does this case demonstrate the typical timeline for drug-induced alopecia, but it also raises questions about whether upadacitinib can cause drug-induced alopecia.

Successful Treatment of Refractory Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis (SAPHO) Syndrome With Tofacitinib: A Case Report.

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is primarily manifested by persistent inflammation affecting the musculoskeletal system and the skin. The treatment of SAPHO syndrome remains a challenge. Tofacitinib is a Janus kinase (JAK) inhibitor that inhibits a range of cytokines. Here, we report a patient who had been diagnosed with SAPHO syndrome refractory to initial treatment and responded well to tofacitinib. An 18-year-old male was presented to our center with polyarthritis, associated with sternal and clavicular pain. There was a nine-month history of skin lesions affecting his chest and back and was diagnosed with a case of SAPHO syndrome. Nonsteroidal anti-inflammatory drugs, conventional disease-modifying antirheumatic agents, and biological drugs were unhelpful. After five weeks of starting tofacitinib at 5mg twice daily in combination with methotrexate, the patient reported significant improvement in dermatological and osteoarticular symptoms. JAK inhibitors, especially tofacitinib, can be a good choice for the treatment of SAPHO refractory to disease-modifying antirheumatic drugs (DMARDs) and tumor necrosis factor (TNF) inhibitors.

Development of a Formulation and In Vitro Evaluation of a Pulmonary Drug Delivery System for a Novel Janus Kinase (JAK) Inhibitor, CPL409116.

The pursuit of targeted therapies for cytokine-dependent diseases has led to the discovery of Janus kinase (JAK) inhibitors, a promising class of drugs. Among them, CPL409116, a selective dual JAK and rho-associated protein kinase inhibitor (ROCK), has demonstrated potential for treating conditions such as pulmonary fibrosis exacerbated by the COVID-19 pandemic. This study investigated the feasibility of delivering CPL409116 via inhalation, with the aim of minimizing the systemic adverse effects associated with oral administration. Two micronization methods, jet milling and spray drying, were assessed for CPL409116, with spray drying chosen for its ability to produce an amorphous form of the compound. Moreover, parameters such as the mixing energy, drug load, and force control agent significantly influenced the fine particle fraction (FPF), a critical parameter for pulmonary drug delivery. This study provides insights into optimizing the formulation parameters to enhance the delivery efficiency of CPL409116 to the lungs, offering potential for improved therapeutic outcomes in cytokine-dependent pulmonary diseases.

Janus kinase inhibitor monotherapy and combination therapies for myelofibrosis: what's the current standard of care?

INTRODUCTION: JAK inhibitors (JAKi) have changed the treatment paradigm of myelofibrosis (MF). Currently, 4 JAKis are approved in the US as monotherapy (mono) to treat patients with MF. JAKis are also being studied in combination (combo) with novel agents. Herein, we review some of the key studies that evaluated JAKi as mono and combo in MF. AREAS COVERED: We performed a Pubmed search for 'JAK inhibitors' and 'myelofibrosis' from 1/2010 to 12/2023. For mono, we included only the unique phase II/III studies of the approved JAKi. Selective studies that evaluated JAKi in combo with the novel agents were also included. EXPERT OPINION: JAKis aim to provide clinical benefit to patients via spleen size reduction and MPN symptom improvement. In order to potentially increase clinical benefit for patients with MF, several novel agents are being partnered with ruxolitinib (RUX) with the ongoing hypothesis to augment greater measures of MF disease modification. The novel agents are either 'added-on' to RUX or as a combo in JAKi naïve patients. Also, the mutant-targeting era of therapies is now beginning with novel CALR-mutated, novel JAK2 V617F mutation-specific and type II JAK2i in the initial stages of drug development, representing a new approach to treatment.

JAK-inhibitor Tofacitinib in Severe Laryngeal Sarcoidosis: A Case Report.

Sarcoidosis is an inflammatory, non-caseating granulomatous multisystem disease associated with JAK-STAT (Janus kinases-signal transducer and activator of transcription proteins) pathway activation. We present a patient with severe multi-systemic sarcoidosis who showed marked improvement with tofacitinib with regards to pulmonary, cutaneous, nasal and laryngeal disease. Tofacitinib prevented critical laryngeal stenosis from progressing to tracheostomy, induced regression of cutaneous lesions and improved pulmonary function in this steroid-resistant and immunosuppressive intolerant case. This case report supports further the role of JAK-inhibitors in the treatment of systemic sarcoidosis. Laryngoscope, 2024.

An Open-Label, Investigator-Initiated, Single-Centre Pilot Study to Determine the Safety and Efficacy of Tofacitinib in Resistant Chronic Spontaneous Urticaria.

Background: Chronic spontaneous urticaria (CSU) is a distressing skin condition characterized by the recurrent appearance of itchy hives. A subset of CSU patients remains resistant to conventional treatment with high-dose antihistamines. Tofacitinib, a Janus kinase inhibitor, has shown promise in various inflammatory skin diseases. We aimed to evaluate the efficacy of oral tofacitinib in patients with CSU resistant to antihistamines. Methods: This study examined data retrospectively from seven patients who were diagnosed with CSU and were treated with tofacitinib for at least six months. These patients initially exhibited resistance to treatment with four-fold up-dosed antihistamines. One of the patients was already on omalizumab, and another was tried on cyclosporine. The patients were administered oral tofacitinib at a dosage of 5 mg twice daily for six months. Patients were followed up monthly for disease control and side effects. The response to treatment was evaluated using the urticaria activity score over 7 days (UAS7) and urticaria control test (UCT). Paired t-tests were conducted to determine the statistical significance of the results using SPSS version 25 software. Results: Six out of the seven patients demonstrated a significant improvement in both UAS7 and UCT scores after six months of treatment with oral tofacitinib. The mean UAS7 score decreased from 24.86 at baseline to 3.83 at the study endpoint (P < 0.0001). Similarly, the mean UCT score increased from 0.57 at baseline to 14 at the study endpoint (P < 0.0001). The standard deviations for both measures were 4.85 and 0.98 at baseline and 3.1 and 3.1 at the study endpoint for UAS7 and UCT, respectively. Conclusion: In this six-month follow-up study, oral tofacitinib demonstrated significant efficacy in treating CSU patients' resistant to high-dose antihistamines. Most patients experienced a remarkable reduction in urticaria activity and an improvement in disease control. These findings suggest that tofacitinib holds promise as a potential therapeutic option for this challenging subset of CSU patients. However, larger, randomized controlled trials are warranted to further investigate the long-term safety and effectiveness of tofacitinib in this population.