P1021: JAKTINIB IN PATIENTS WITH MYELOFIBROSIS WHO WERE INTOLERANT TO RUXOLITINIB: AN OPEN-LABEL, SINGLE-ARM PHASE 2B STUDY
Yi ZhangHu ZhouZhijian XiaoMinghui DuanSujun GaoGuangsheng HeHongmei JingJunmin LiLiangming MaHuanling ZhuChunkang ChangXin DuMei HongXin LiQingchi LiuWei WangNa XuHaiping YangQingwei ZhaoJie Jin
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Topic: 16. Myeloproliferative neoplasms - Clinical Background: As the first approved Janus kinase inhibitor (JAKi) for patients with symptomatic myelofibrosis (MF), ruxolitinib showed superiority in spleen volume reduction with increased anemia and thrombocytopenia. However, there are few treatment options after ruxolitinib intolerance. Jaktinib, an oral novel JAK and ACVR1 inhibitor showed promising efficacy in JAKi-naïve patients with intermediate or high risk MF with mild side effects. Aims: We conducted a single-arm phase 2b study to evaluate jaktinib in MF patients who were intolerant to ruxolitinib. Here we present the results of the cohort of patients who received jaktinib 100 mg twice a day. Methods: Patients who had primary, post-polycythemia vera or post-essential thrombocythemia MF and were previously treated with ruxolitinib for ≥28 days who either required red blood cell (RBC) transfusions or required more frequent transfusions on ruxolitinib, or had grade 3/4 anemia, thrombocytopenia or hematoma when receiving ruxolitinib, and with palpable spleen ≥5 cm were included. Patients were excluded from the study if they had received ruxolitinib ≥20 mg Bid for at least three months and were refractory or relapsed to ruxolitinib. The primary endpoint was the proportion of patients with spleen volume reduction of ≥35% from baseline (SVR35) at week 24, assessed by Independent Review Committee on the basis of MRI/CT images. Secondary endpoints included the best spleen response rate (defined as achieving SVR35 at any time), the proportion of patients with ≥50% reduction in MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), anemia response, safety, etc. Results: In the full analysis set for efficacy, a total of 44 patients received jaktinib 100 mg twice daily and had completed the 24-week treatments and evaluations or terminated prior to week 24. In addition, one patient was excluded from the efficacy analysis due to incorrect diagnosis of MF but included in the safety analysis. The median baseline TSS was 9.5, hemoglobin was 80 g/L, and platelet count was 132.5×109/L. Patient baseline characteristics are summarized in the Table 1. While on ruxolitinib, 21 patients (47.7%) required RBC transfusion and all patients experienced grade 3/4 anemia, thrombocytopenia or both.The SVR35 rate at week 24 was 43.2% (19/44). Over the study phase, the best spleen response rate was 54.5% (24/44). The median time to achieve the first SVR35 was 12.1 weeks. Spleen response was maintained in 80.4% patients for at least 24 weeks and median duration was not reached. At week 24, 61.8% of the evaluable patients achieved a ≥50% improvement in TSS from baseline. Of 31 transfusion-independent patients with hemoglobin ≤100 g/L at baseline, 13 (41.9%) had an increase of hemoglobin ≥20 g/L by week 24. Of 19 patients who required RBC transfusion at baseline, 11 (57.9%) had a 50% decrease in RBC infusion frequency by week 24. Of nine transfusion-dependent patients at baseline, one became transfusion-independent by week 24. In the safety set (n=45), the median jaktinib exposure time was 280 days. The most common grade ≥3 treatment-related adverse events (TEAEs) were anemia (31.1%, n=14), thrombocytopenia (22.2%, n=10), pneumonia (17.8%, n=8), neutropenia (15.6%, n=7) and leukopenia (15.6%, n=7). Treatment discontinuation due to TEAEs occurred in five patients (11.1%). A dose reduction or temporary interruption due to TEAEs were reported in 12 patients (26.7%). Summary/Conclusion: Jaktinib demonstrated promising therapeutic activities in MF patients intolerant to ruxolitinib. Jaktinib 100 mg bid taken orally, not only substantially reduced splenomegaly, but also ameliorated MF-related symptom burdens and anemia. Jaktinib could be a new treatment for patients with anemia after ruxolitinib. Keywords: Janus Kinase inhibitor, Myeloproliferative disorder, Phase II, MyelofibrosisKeywords:
Ruxolitinib
Myeloproliferative neoplasm
Clinical endpoint
Extramedullary hematopoiesis
Primary myelofibrosis (PMF) is a Ph-negative myeloproliferative neoplasm (MPN), that manifests bone marrow fibrosis, cytopenias, splenomegaly, and constitutional symptoms. The conventional therapeutic options for patients with PMF consist of management of anemia, use of cytoreductive and immunomogulatory agents, and splenectomy or splenic irradiation. Cure is only achievable through allogeneic haematopoietic stem cell transplantation. The discovery of crucial role of JAK2 signaling in pathogenesis of PMF has resulting in new JAK2 inhibitor therapy, such ruxolitinib or other investigated molecules.
Ruxolitinib
Myeloproliferative neoplasm
Constitutional symptoms
Extramedullary hematopoiesis
Pathogenesis
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Extramedullary hematopoiesis
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The development of tumor lysis syndrome (TLS) in association with treatment for myeloproliferative neoplasms (MPNs) is relatively rare. We herein present the case of a post-polycythemia vera (PV) myelofibrosis patient with massive splenomegaly who developed laboratory TLS after treatment with ruxolitinib, a potent JAK1/JAK2 inhibitor. She also exhibited a rapid reduction of spleen volume. Our present case suggests the potential risk of TLS development after ruxolitinib treatment, particularly in patients with massive splenomegaly.
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Myeloproliferative neoplasm
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Myeloproliferative neoplasm
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The translocation t(8;9) produces the fusion gene PCM1-JAK2, resulting in the continuous activation of the JAK2 tyrosine kinase. Myelodysplastic/myeloproliferative neoplasms are the most common disease with t(8;9)/PCM1-JAK2. Individuals with this abnormality have similar features, and JAK2 kinase inhibitor (ruxolitinib) is an effective treatment of the condition. The long-term remission results of ruxolitinib are varied. It is important to determine the response to ruxolitinib. Here, we describe a patient who has been diagnosed with eosinophilia-associated myeloproliferative neoplasm with t(8;9)(p21;p24). This patient has achieved sustained response for >1 year since the administration of ruxolitinib.
Ruxolitinib
Myeloproliferative neoplasm
Janus kinase 2
Myeloproliferative Disorders
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Ruxolitinib, selektivní perorální inhibitor Janus kináz JAK1/JAK2, je kromě terapie primární myelofibrózy schválen do druhé linie terapie pacientů s pravou polycytemií, kteří vykazují intoleranci nebo rezistenci k terapii hydroxyureou. V randomizovaných studiích RESPONSE a RESPONSE-2 byla prokázána jeho superiorita v dosažení hematologické remise i snížení symptomatické zátěže ve srovnání s nejlepší dostupnou terapií. Nejnovějším důležitým poznatkem pro klinickou praxi ze studie MAJIC-PV je benefit ve smyslu prodloužení doby přežití bez trombembolických příhod a také celkové doby přežití.
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"Ruxolitinib for pulmonary extramedullary hematopoiesis in myelofibrosis." Leukemia & Lymphoma, 55(9), pp. 2207–2208
Ruxolitinib
Extramedullary hematopoiesis
Hematologic Neoplasms
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Myeloproliferative neoplasm
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