Jaktinib for the Treatment of Ruxolitinib Intolerance of Myelofibrosis

Inclusion Criteria:

1. Age 18-75 years old (including the threshold value), gender is not limited;
2. Subjects diagnosed with Primary Myelofibrosis according to World Health Organization (WHO) criteria (2016 version), or diagnosed with Post-Polycythemia Vera Myelofibrosisor Post-Essential Thrombocythemia Myelofibrosis according to International WorkingGroup Myeloproliferative Neoplasms Research and Treatment(IWG-MRT) standard. BothJanus Kinase 2(JAK2)mutation and JAK2 wild can be enrolled；
3. According to Dynamic International Prognostic Scoring System(DIPSS) , Subjects withintermediate-risk-2 or high-risk myelofibrosis were assessed, Subjects withintermediate-risk-1 myelofibrosis with hepatosplenomegaly and no response to existingtreatment and requiring treatment can also be enrolled;
4. Subjects who have received or are receiving Ruxolitinib, and：Ruxolitinib treatmenttime is not less than 28 days; Red blood cell transfusion is still needed duringtreatment with Ruxolitinib; or Ruxolitinib dose (including starting dose and adjusteddose)<20mg bid，And must meet at least one of the following：Level 3 or higher plateletcount reduction or Level 3 or higher anemia or Level 3 or higher hematoma/bleeding；
5. Life expectancy > 24 weeks;
6. Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) of 0, 1 or 2；
7. Splenomegaly: palpation of the splenic margin to or above the subcostal at least 5cm；
8. Acceptable laboratory assessments obtained within 14 days prior to enrollment:

• Absolute neutrophil count(ANC)>0.75 x 10^9/L, blood platelet count>100 x 10^9/L;
• Peripheral blood blast count < 10%;
• Aspartate transaminase (AST) and alanine transaminase (ALT)≤3 x the upper limitof the normal range (ULN); Subjects with liver function impairment due to severeextramedullary haematopoiesis or iron removal therapy within 60 days prior toscreening, AST and ALT≤5 x ULN; Direct bilirubin≤2.0 x ULN;
• Calculated creatinine clearance of≥45 mL/min；

9. Meet the requirements of the Ethics Committee, voluntarily sign an informed consentform；
10. Ability to follow research and follow-up procedures.

Exclusion Criteria:

1. Any significant clinical or laboratory abnormalities that the investigator considersto affect safety assessment, such as: a. uncontrolled diabetes (> 250 mg/dL, or 13.9>mmol/L); b. had high blood pressure and antihypertensive drug treatment under twoor unable to descend to the ranges (systolic blood pressure < 160 mmHg, diastolicpressure < 100 mmHg); c. peripheral neuropathy (NCI-CTC AE v5.0 grade 2 or above),etc;
2. Subjects who had a history of congestive heart failure(NCI-CTC AE v5.0 grade 3 orabove), uncontrollable or unstable angina or myocardial infarction, cerebrovascularaccident or pulmonary embolism in the first 6 months;
3. Screening of Subjects who have surgery within the first 4 weeks;
4. Screening for Subjects with arrhythmia requiring treatment or QTc interval (QTcB) >480ms;
5. Screening for bacterial, viral, parasitic or fungal infections that require treatment;
6. Patients which have with a history of congenital or acquired hemorrhagicdiseases;(Note:With the exception of hematoma which caused by Ruxolitinib)
7. Splenectomy Subjects or in the group carried out within three months before the spleenradiation treatment (including internal radiation and external radiation)
8. Screening HIV, HBV DNA positive or higher than the normal reference range, or HCV RNApositive for HCV antibody;
9. Women who are planning to become pregnant or who are pregnant or breast- feeding, aswell as those who were unable to use effective contraceptives throughout thetrial;Male patients who do not use condoms during the administration and within 2 days (approximately 5 half-lives) after the last administration;
10. Subjects who have suffered from malignant tumors (except cured basal cell carcinoma ofthe skin and carcinoma in situ of the cervix) in the past 5 years; Combined with otherserious diseases, the researchers believe that patients' safety or compliance may beaffected;
11. With other serious diseases, the researchers think that may affect patient safety orcompliance;
12. Subjects who had used the Jaktinib;
13. Subjects who have participated in the clinical trials of other new drugs or medicaldevices within the first 1 months;
14. Subjects who used the Hematopoietic growth factors within 14 days before Into thegroup (granulocyte growth factors, or platelet hormone) ；
15. Subjects who cannot cooperate with or cannot perform MRI or CT scans；
16. Subjects with refractory or recurrent myelofibrosis: refractory of myelofibrosis:After at least 28 days of adequate administration of JAKinhibitors, the spleen palpation was less than 15% smaller than beforeadministration.Or at least 3 months later, the spleen volume on MRI/CT decreased by <10% compared with that before the administration. Recurrence of myelofibrosis: after at least 3 months of taking adequate amount of JAKinhibitor, the spleen was enlarged again after shrinking compared with that beforetaking the drug, and compared with the minimum value during taking the drug, thespleen volume increased ≥10% on MRI/CT examination or ≥30% on spleen palpation.
17. Any treatment MF medication (eg hydroxyurea,except ruxolitinib ), any immunomodulationused within 2 weeks prior to enrollment Agent (such as thalidomide), anyimmunosuppressant, glucocorticoids ≥ 10 mg/day of prednisone or equivalent biologicalstrength, or Subjects within 6 half-life of the drug, over time Prevail; Subjects whohad received Ruxolitinib within 1 week prior to enrolling.