7061 Background: As the first approved Janus kinase inhibitor (JAKi) for pts with symptomatic MF, RUX showed superiority in spleen volume reduction with increased anemia and thrombocytopenia. However, there are few treatment options after RUX intolerance. Jaktinib, an oral novel JAK and ACVR1 inhibitor showed promising efficacy in Jaki-naïve pts with intermediate or high risk MF with mild side effects. Here we present the results of MF pts who were intolerant to RUX and received jaktinib 100 mg bid from a phase 2b study. Methods: Pts who had primary or post-ET/PV MF and were previously treated with RUX for ≥28 days who either required RBC transfusions or required more frequent transfusions on RUX, or had grade 3/4 anemia, thrombocytopenia or hematoma when receiving RUX, and with palpable spleen ≥5 cm were included. The primary endpoint was the proportion of pts with spleen volume reduction of ≥ 35% from baseline (SVR35) at week (wk) 24, assessed centrally 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 pts with ≥ 50% reduction in MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), anemia response, safety, etc. Results: A total of 45 patients received jaktinib 100 mg bid. The full analysis set (FAS) for efficacy included 44 pts who had completed the 24-week treatments and evaluations or terminated prior to wk 24, and excluded one pt because of incorrect diagnosis of MF. The median baseline TSS was 9.5, hemoglobin (Hb) was 79.5 g/L, and platelets was 132.5×10 9 /L. While on RUX, 21 pts (48%) required RBC transfusion and all pts experienced those grade 3 hematological toxicities. In FAS, the SVR35 rate at wk 24 was 43% (19/44). Over the study phase, the best spleen response rate was 55% (24/44). The median time to achieve the first SVR35 was 12 weeks. Response was maintained in 80% pts for at least 24 weeks and median duration was not reached. At wk 24, 62% of the evaluable pts achieved a ≥ 50% improvement in TSS from baseline. Of 31 pts with baseline Hb ≤ 100 g/L, 13 (42%) had a ≥20 g/L Hb increase. Of 19 pts who required RBC transfusion at baseline, 11 (58%) had a 50% decrease in RBC infusion frequency. Of 9 transfusion-dependent pts at baseline, one became transfusion-independent. In the safety set (n = 45), the median jaktinib exposure time was 280 days. The most common grade ≥3 TEAEs were anemia (31%), thrombocytopenia (22%), pneumonia (18%), neutropenia (16%) and leukopenia (16%). Treatment discontinuation due to TEAEs occurred in five pts (11%). A dose reduction or temporary interruption due to TEAEs were reported in 12 pts (27%). Conclusions: Jaktinib demonstrated promising activities in MF pts who was intolerant to RUX by substantially reducing spleen volume, ameliorating MF-related symptom burdens, and elevating Hb levels. Jaktinib could be a viable treatment for MF pts with anemia in this setting. Clinical trial information: NCT04217993 .
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, Myelofibrosis
Ruxolitinib has demonstrated efficacy in patients with myelofibrosis (MF). However, substantial number of patients may not respond after 3-6 months of treatment or develop resistance over time. In this phase 2 trial, patients with a current diagnosis of intermediate or high-risk MF who either had an inadequate splenic response or spleen regrowth after ruxolitinib treatment were enrolled. All patients received jaktinib 100 mg Bid. The primary endpoint was the proportion of patients with ≥35% reduction in spleen volume (SVR 35) at week 24. The secondary endpoints included change of MF-related symptoms, anemic response, and safety profile. From July 6, 2021, to January 24, 2022, 34 ruxolitinib-refractory or relapsed patients were enrolled, 52.9% (18 of 34) were DIPSS intermediate 2 or high risk. SVR 35 at week 24 was 32.4% (11 of 34, 95% CI 19.1%-49.2%) in all patients and 33.3% (6 of 18, 95% CI 16.3%-56.3%) in the intermediate 2 or high-risk group. A total of 50% (8 of 16) transfusion-independent patients with hemoglobin (HGB) <100 g/L at baseline had HGB elevation ≥20 g/L within 24 weeks. Furthermore, 46.4% (13 of 28) of patients had a ≥ 50% decrease in the total symptom score (TSS 50) at week 24. The most common grade ≥3 treatment-emergent adverse events (TEAEs) were thrombocytopenia (32.4%), anemia (32.4%), and leukocytosis (20.6%). In total, 13 (38.2%) of 34 patients had serious adverse events (SAE), of which drug-related SAEs were found in 5 patients (14.7%). These results indicate that jaktinib can be a promising treatment option for patients with MF who have either become refractory to or relapsed after ruxolitinib treatment.
Objective
To explore the clinical features of chronic myelogenous leukemia (CML) combined with solid malignant neoplasms.
Methods
The clinical data of 8 CML patients with solid malignant neoplasms who were admitted to the Affiliated Tumor Hospital of Zhengzhou University, the Central Hospital of Nanyang City, the First Affiliated Hospital of Science and Technology University of Henan, and the Central Hospital of Xinxiang City from August 2006 to August 2018 were analyzed retrospectively. The clinical features, treatment and prognosis of the patients were summarized with the review of literature.
Results
Among the 8 patients, 3 were male and 5 female, aged 40-76 years, with a median of 50 years old. Seven cases were in CML chronic phase, and 1 was in accelerated phase. Seven patients were treated with tyrosine kinase inhibitor (TKI), and only 1 patient was treated with hydroxyurea. In 8 patients, two cases presented with synchronous multiple primary cancer (SMPC), 6 cases presented with heterochrony multiple primary cancer (HMPC). two patients received the operation, 1 patient received the operation and chemotherapy, 4 patients received chemotherapy, and 1 patient received the isotope treatment. One SMPC patient died and another one was under treatment, and 6 HMPC patients were under treatment.
Conclusions
The relationship between CML and solid malignant neoplasm is under discussion, but patients with CML and solid malignant neoplasm are not unusual. Clinicians should raise awareness to avoid misdiagnosis. The treatment should follow the two main lines that are comprehensive treatment and individualized treatment.
Key words:
Leukemia, myelogenous, chronic; Neoplasms, multiple primary; Treatment; Prognosis
7062 Background: Currently, ruxolitinib is the only marketed Janus kinase inhibitor (JAKi) for pts with MF in China, which demonstrated symptomatic and splenic benefit with increased cytopenias. However, at least 50% of pts develop resistance or intolerance to ruxolitinib in the long-term follow up, for whom life expectancy is largely reduced. There are few therapeutic options after ruxolitinib failure. Jaktinib, an oral novel JAK and AVCR1 inhibitor showed promising activity in Jaki-naïve pts with intermediate or high risk MF with mild side effects. Here we present the results of jaktinib in MF pts who were refractory or relapsed to prior ruxolitinib therapy. Methods: Pts who had primary or post-ET/PV MF and were previously treated with ruxolitinib for at least 3 months and with either inadequate efficacy response (defined as < 10% spleen volume reduction [SVR] by MRI/CT or < 30% decrease in spleen size by palpation from baseline) or spleen regrowth to < 10% SVR or < 30% decrease in spleen size from baseline following an initial response were recruited to receive jaktinib 100 mg twice daily. The primary endpoint was the proportion of pts with SVR ≥ 35% from baseline (SVR35) at week (wk) 24, measured by MRI/CT images and assessed by Independent Review Committee. Secondary endpoints included the best spleen response rate (defined as achieving SVR35 at any time), the proportion of pts with ≥ 50% reduction in MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), improvement of anemia and safety. Results: A total of 34 pts were enrolled. The median duration of previous ruxolitinib treatment was 18.6 months (range 3.4-70.1). The median baseline TSS was 19.5 (range 1-55), hemoglobin (Hb) was 101.5 g/L (range 61-149), and platelets was 159×10 9 /L (range 66-951). 11 pts (32.4%) achieved SVR35 at wk 24. The best spleen response rate was 38.2% (13/34). The median time to achieve the first SVR35 was 8.1 weeks, and the median duration of response was not reached. At wk 24, 13 pts (46.4%) achieved a ≥ 50% improvement in TSS from baseline. Of 16 transfusion-independent pts with Hb ≤ 100 g/L at baseline, 8 (50.0%) had a ≥20 g/L Hb increase by wk 24. Of 6 pts who required RBC transfusion at baseline, 2 had a 50% decrease in RBC infusion by wk 24. The median jaktinib exposure time was 231 days (range 96-371). 23 pts (67.6%) had one or more grade ≥3 treatment emergent adverse events (TEAEs). The most common grade ≥3 TEAEs were anemia (32.4%, n = 11), thrombocytopenia (32.4%, n = 11), leukocytosis (20.6%, n = 7) and leukopenia (11.8%, n = 4). Treatment discontinuation due to TEAEs occurred in 2 pts (5.9%). A dose reduction or temporary interruption due to TEAEs were reported in 9 pts (26.5%). Conclusions: MF pts who were refractory/relapsed to ruxolitinib attained substantial spleen response, and reduction in MF-related symptom burden with jaktinib, which could be a new option for MF pts who have failed ruxolitinib. Clinical trial information: NCT04851535 .
Limited information exists regarding the impact of preoperative serum creatinine changes on cardiac surgery-associated acute kidney injury (CSA-AKI). This study aimed to investigate the development of AKI in patients with a baseline estimated glomerular filtration rate (eGFR) of ≥60 mL/min/1.73 m2 who present with an elevation in preoperative serum creatinine.
Fungal communities are diverse and abundant in coastal waters, yet, their ecological roles and adaptations remain largely unknown. To address these gaps, ITS2 metabarcoding and metatranscriptomic analyses were used to capture the whole suite of fungal diversity and their metabolic potential in water column and sediments in the Yellow Sea during August and October 2019. ITS2 metabarcoding described successfully the abundance of Dikarya during August and October at the different examined habitats, but strongly underrepresented or failed to identify other fungal taxa, including zoosporic and early-diverging lineages, that were abundant in the mycobiome as uncovered by metatranscriptomes. Metatranscriptomics also revealed enriched expression of genes annotated to zoosporic fungi (e.g., chytrids) mainly in the surface water column in October. This enriched expression was correlated with the two-fold increase in chlorophyll-a intensity attributed to phytoplanktonic species which are known to be parasitized by chytrids. The concurrent high expression of genes related to calcium signalling and GTPase activity suggested that these metabolic traits facilitate the parasitic lifestyle of chytrids. Similarly, elevated expression of phagosome genes annotated to Rozellomycota, an early-diverging fungal phylum not fully detected with ITS2 metabarcoding, suggested that this taxon utilizes a suite of feeding modes, including phagotrophy in this coastal setting. Our data highlight the necessity of using combined approaches to accurately describe the community structure of coastal mycobiome. We also provide in-depth insights into the fungal ecological roles in coastal waters, and report potential metabolic mechanisms utilized by fungi to cope with environmental stresses that occur during distinct seasonal months in coastal ecosystems.
The aim of the present study was to analyse the incidence of mutations in the BCR-ABL1 kinase region in patients with newly diagnosed or treated chronic myeloid leukaemia (CML), and the association between mutations clinicopathological characteristics. Samples were collected for mutation analysis from patients who exhibited tyrosine kinase inhibitor resistance following treatment or were in the accelerated or blast phase at diagnosis. The mutations in the breakpoint cluster region (BCR)-ABL proto-oncogene 1 (ABL1) kinase domain were evaluated using conventional sequencing or ultra-deep sequencing (UDS) of peripheral blood samples. Sanger sequencing and UDS of the cDNA region corresponding to the BCR-ABL1 kinase domain was performed. χ2 test was used to assess the association of categorical variables between the mutated and non-mutated groups. In addition, the Kaplan-Meier method was applied to generate the survival curves. Sequencing detected 28 different mutations in 54 of the 175 (30.86%) patients with CML. A total of 14 (8.0%) patients presented with the T315I mutation, accounting for the largest proportion in the mutated group. Eight patients (4.6%) presented with more than one mutation, three (37.5%) of whom harboured T315I coexisting with other mutations, and for nine (5.1%) patients, the results differed between conventional sequencing and UDS, with the mutations being missed by conventional sequencing. The results form this study suggested that programing mutation analysis in patients with chronic myeloid leukaemia timely may guide the choice of TKIs.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)