METHODS OF TREATING B-CELL PROLIFERATIVE DISORDER

1 . A method of mitigating the diarrhea of a patient having chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), the method comprising orally administering to the patient zanubrutinib or a pharmaceutically acceptable salt thereof at a dose of 160 mg of zanubrutinib twice a day or 320 mg of zanubrutinib once a day, wherein the administration mitigates the diarrhea of the patient as compared to the diarrhea of a comparable patient orally administered with ibrutinib at a dose of 420 mg once daily.

2 . The method of claim 1 , wherein the patient meets the following criteria prior to the administration:

(iii) an age greater than or equal to 18;

(iv) relapsed or refractory to at least 1 prior therapy for CLL or SLL; and

(v) measurable disease by computerized tomography (CT) or magnetic resonance imaging (MM).

3 . The method of claim 2 , wherein the patient further meets the following criteria prior to the administration:

(i) requiring treatment of CLL or SLL as manifested by at least 1 of the following criteria:

(A) evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia or thrombocytopenia;

(B) massive, progressive, or symptomatic splenomegaly;

(C) massive nodes, or progressive or symptomatic lymphadenopathy;

(D) progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte-doubling time of less than 6 months;

(E) autoimmune anemia or thrombocytopenia that was poorly responsive to corticosteroids or other standard therapy;

(F) constitutional symptoms, as manifested any one or more of the following disease-related symptoms:

(a) unintentional weight loss of at least 10% within the previous 6 months;

(b) significant fatigue;

(c) fever of more than 100.5° F. or 38° C. for at least 2 weeks without other evidence of infection; and

(d) night sweats for more than 1 month without evidence of infection;

(ii) Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2;

(iii) life expectancy of at least 6 months;

(iv) adequate bone marrow function as manifested by:

(A) absolute neutrophil count (ANC) of at least 1000/mm 3 , or at least 750/mm 3 if the patient has bone marrow involvement; and

(B) platelet count of at least 75,000/mm 3 , or at least 50,000/mm 3 if the patient has bone marrow involvement by CLL;

(v) Adequate organ function as manifested by:

(A) creatinine clearance of at least 30 mL/min;

(B) aspartate aminotransferase/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase no more than 2.5 times of upper limit of the normal range unless due to CLL/SLL; and

(C) serum total bilirubin of more than 2.0 times of upper limit of the normal range unless the patient has Gilbert's syndrome; and

(vi) practicing contraception during the administration, and for at least 90 days after the administration.

4 . The method of claim 2 , wherein the patient does not have any one of the following conditions:

(iv) prior treatment with a BTK inhibitor;

(v) prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix or breast;

(vi) history of severe bleeding disorder;

(vii) history of stroke or intracranial hemorrhage within 180 days;

(viii) active fungal, bacterial, or viral infection requiring systemic therapy; and

(ix) major surgery within 4 weeks of the first dose of study drug.

5 . The method of claim 4 , wherein the patient further does not have any one of the following conditions:

(i) known prolymphocytic leukemia or history of, or currently suspected, Richter's transformation;

(ii) clinically significant cardiovascular disease as manifested by any one of the following:

A. myocardial infarction within 6 months prior to the administration;

B. unstable angina within 3 months prior to the administration;

C. New York Heart Association class III or IV congestive heart failure;

D. history of clinically significant arrhythmias;

E. QTcF of more than 480 milliseconds based on Fridericia's formula;

F. history of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place; and

G. uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure of more than 170 mmHg and diastolic blood pressure of more than 105 mmHg;

(iii) history of stroke or intracranial hemorrhage within 180 days before the administration;

(iv) severe or debilitating pulmonary disease;

(v) disease significantly affecting gastrointestinal function, comprising malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction;

(vi) active fungal, bacterial, or viral infection requiring systemic therapy;

(vii) known central nervous system involvement by leukemia or lymphoma;

(viii) known infection with HIV or serologic status reflecting active viral hepatitis B or C infection as manifested by any one of the following:

A. presence of hepatitis B surface antibody (HBsAb) or hepatitis B core antibody (HBcAb); and

B. Presence of hepatitis C virus (HCV) antibody;

(ix) moderate or severe hepatic impairment, comprising Child-Pugh class B or C;

(x) one of the following prior treatments:

A. treatment with monoclonal antibody-based therapy within 28 days prior to the administration;

B. treatment with chimeric antigen receptor T-cell therapy within 180 days prior to the administration;

C. treatment with Chinese herbal medicine with anticancer intent within 28 days prior to the administration;

D. chemotherapy or radiation treatment within 21 days prior to the administration; and

E. hematopoietic stem cell transplantation within 90 days prior to the administration;

(xi) corticosteroid use of no more than 10 mg/day prior to the administration or corticosteroid use of more than 10 mg/day within 4 weeks prior to the administration;

(xii) toxicity from prior anticancer therapy that has not recovered to Grade 1 or lower, except for alopecia, ANC, and platelet count;

(xiii) pregnancy or lactation;

(xiv) vaccination with a live vaccine within 35 days prior to the administration;

(xv) alcohol or drug addiction;

(xvi) treatment with warfarin or other vitamin K antagonists; and

(xvii) treatment with a strong CYP3A inhibitor or inducer.

6 . The method of claim 4 , wherein the patient has relapsed or refractory CLL or relapsed or refractory SLL.

7 . The method of claim 4 , wherein the patient has a 17p deletion (del(17p)) or a TP53 mutation.

8 . The method of claim 4 , wherein the zanubrutinib or the pharmaceutically acceptable salt thereof is administered at a dose of 160 mg of zanubrutinib twice a day.

9 . The method of claim 4 , wherein the zanubrutinib or the pharmaceutically acceptable salt thereof is administered at a dose of 320 mg of zanubrutinib once a day.

10 . The method of claim 4 , further comprising assessing baseline risk of tumor lysis syndrome (TLS) in the patient, monitoring TLS during the PFS time, and treating TLS when it occurs.

11 . A method of prolonging progression-free survival (PFS) time compared to administering ibrutinib at a dose of 420 mg once daily comprising orally administering to a patient having chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in need thereof zanubrutinib or a pharmaceutically acceptable salt thereof at a dose of 160 mg of zanubrutinib twice a day or 320 mg of zanubrutinib once a day.

12 . The method of claim 11 , wherein the patient meets the following criteria prior to the administration:

(i) an age greater than or equal to 18;

(ii) relapsed or refractory to at least 1 prior therapy for CLL or SLL; and

(iii) measurable disease by computerized tomography (CT) or magnetic resonance imaging (MM).

13 . The method of claim 12 , wherein the patient further meets the following criteria prior to the administration:

(i) requiring treatment of CLL or SLL as manifested by at least 1 of the following criteria:

(A) evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia or thrombocytopenia;

(B) massive, progressive, or symptomatic splenomegaly;

(C) massive nodes, or progressive or symptomatic lymphadenopathy;

(D) progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte-doubling time of less than 6 months;

(E) autoimmune anemia or thrombocytopenia that was poorly responsive to corticosteroids or other standard therapy;

(F) constitutional symptoms, as manifested any one or more of the following disease-related symptoms:

(a) unintentional weight loss of at least 10% within the previous 6 months;

(b) significant fatigue;

(c) fever of more than 100.5° F. or 38° C. for at least 2 weeks without other evidence of infection; and

(d) night sweats for more than 1 month without evidence of infection;

(ii) Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2;

(iii) life expectancy of at least 6 months;

(iv) adequate bone marrow function as manifested by:

(A) absolute neutrophil count (ANC) of at least 1000/mm 3 , or at least 750/mm 3 if the patient has bone marrow involvement; and

(B) platelet count of at least 75,000/mm 3 , or at least 50,000/mm 3 if the patient has bone marrow involvement by CLL;

(v) Adequate organ function as manifested by:

(A) creatinine clearance of at least 30 mL/min;

(B) aspartate aminotransferase/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase no more than 2.5 times of upper limit of the normal range unless due to CLL/SLL; and

(C) serum total bilirubin of more than 2.0 times of upper limit of the normal range unless the patient has Gilbert's syndrome; and

(vi) practicing contraception during the administration, and for at least 90 days after the administration.

14 . The method of claim 12 , wherein the patient does not have any one of the following conditions:

(i) prior treatment with a BTK inhibitor;

(ii) prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix or breast;

(iii) history of severe bleeding disorder;

(iv) history of stroke or intracranial hemorrhage within 180 days;

(v) active fungal, bacterial, or viral infection requiring systemic therapy; and

(vi) major surgery within 4 weeks of the first dose of study drug.

15 . The method of claim 14 , wherein the patient further does not have any one of the following conditions:

(i) known prolymphocytic leukemia or history of, or currently suspected, Richter's transformation;

(ii) clinically significant cardiovascular disease as manifested by any one of the following:

A. myocardial infarction within 6 months prior to the administration;

B. unstable angina within 3 months prior to the administration;

C. New York Heart Association class III or IV congestive heart failure;

D. history of clinically significant arrhythmias;

E. QTcF of more than 480 milliseconds based on Fridericia's formula;

F. history of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place; and

G. uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure of more than 170 mmHg and diastolic blood pressure of more than 105 mmHg;

(iii) history of stroke or intracranial hemorrhage within 180 days before the administration;

(iv) severe or debilitating pulmonary disease;

(v) disease significantly affecting gastrointestinal function, comprising malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction;

(vi) active fungal, bacterial, or viral infection requiring systemic therapy;

(vii) known central nervous system involvement by leukemia or lymphoma;

(viii) known infection with HIV or serologic status reflecting active viral hepatitis B or C infection as manifested by any one of the following:

A. presence of hepatitis B surface antibody (HBsAb) or hepatitis B core antibody (HBcAb); and

B. Presence of hepatitis C virus (HCV) antibody;

(ix) moderate or severe hepatic impairment, comprising Child-Pugh class B or C;

(x) one of the following prior treatments:

A. treatment with monoclonal antibody-based therapy within 28 days prior to the administration;

B. treatment with chimeric antigen receptor T-cell therapy within 180 days prior to the administration;

C. treatment with Chinese herbal medicine with anticancer intent within 28 days prior to the administration;

D. chemotherapy or radiation treatment within 21 days prior to the administration; and

E. hematopoietic stem cell transplantation within 90 days prior to the administration;

(xi) corticosteroid use of no more than 10 mg/day prior to the administration or corticosteroid use of more than 10 mg/day within 4 weeks prior to the administration;

(xii) toxicity from prior anticancer therapy that has not recovered to Grade 1 or lower, except for alopecia, ANC, and platelet count;

(xiii) pregnancy or lactation;

(xiv) vaccination with a live vaccine within 35 days prior to the administration;

(xv) alcohol or drug addiction;

(xvi) treatment with warfarin or other vitamin K antagonists; and

(xvii) treatment with a strong CYP3A inhibitor or inducer.

16 . The method of claim 14 , wherein the patient has relapsed or refractory CLL or relapsed or refractory SLL.

17 . The method of claim 14 , wherein the patient has a 17p deletion (del(17p)) or a TP53 mutation.

18 . The method of claim 14 , wherein the zanubrutinib or the pharmaceutically acceptable salt thereof is administered at a dose of 160 mg of zanubrutinib twice a day.

19 . The method of claim 14 , wherein the zanubrutinib or the pharmaceutically acceptable salt thereof is administered at a dose of 320 mg of zanubrutinib once a day.

20 . The method of claim 14 , further comprising assessing baseline risk of tumor lysis syndrome (TLS) in the patient, monitoring TLS during the PFS time, and treating TLS when it occurs.

21 . A method of reducing the risk of atrial fibrillation or flutter of a patient having chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), the method comprising orally administering to the patient zanubrutinib or a pharmaceutically acceptable salt thereof at a dose of 160 mg of zanubrutinib twice a day or 320 mg of zanubrutinib once a day, wherein the administration reduces the risk of the atrial fibrillation or flutter of the patient as compared to the atrial fibrillation or flutter of a comparable patient orally administered with ibrutinib at a dose of 420 mg once daily.

22 . The method of claim 21 , wherein the patient meets the following criteria prior to the administration:

(i) an age greater than or equal to 18;

(ii) relapsed or refractory to at least 1 prior therapy for CLL or SLL; and

(iii) measurable disease by computerized tomography (CT) or magnetic resonance imaging (MM).

23 . The method of claim 22 , wherein the patient further meets the following criteria prior to the administration:

(i) requiring treatment of CLL or SLL as manifested by at least 1 of the following criteria:

(A) evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia or thrombocytopenia;

(B) massive, progressive, or symptomatic splenomegaly;

(C) massive nodes, or progressive or symptomatic lymphadenopathy;

(D) progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte-doubling time of less than 6 months;

(E) autoimmune anemia or thrombocytopenia that was poorly responsive to corticosteroids or other standard therapy;

(F) constitutional symptoms, as manifested any one or more of the following disease-related symptoms:

(a) unintentional weight loss of at least 10% within the previous 6 months;

(b) significant fatigue;

(c) fever of more than 100.5° F. or 38° C. for at least 2 weeks without other evidence of infection; and

(d) night sweats for more than 1 month without evidence of infection;

(ii) Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2;

(iii) life expectancy of at least 6 months;

(iv) adequate bone marrow function as manifested by:

(A) absolute neutrophil count (ANC) of at least 1000/mm 3 , or at least 750/mm 3 if the patient has bone marrow involvement; and

(B) platelet count of at least 75,000/mm 3 , or at least 50,000/mm 3 if the patient has bone marrow involvement by CLL;

(v) Adequate organ function as manifested by:

(A) creatinine clearance of at least 30 mL/min;

(B) aspartate aminotransferase/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase no more than 2.5 times of upper limit of the normal range unless due to CLL/SLL; and

(C) serum total bilirubin of more than 2.0 times of upper limit of the normal range unless the patient has Gilbert's syndrome; and

(vi) practicing contraception during the administration, and for at least 90 days after the administration.

24 . The method of claim 22 , wherein the patient does not have any one of the following conditions:

(i) prior treatment with a BTK inhibitor;

(ii) prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix or breast;

(iii) history of severe bleeding disorder;

(iv) history of stroke or intracranial hemorrhage within 180 days;

(v) active fungal, bacterial, or viral infection requiring systemic therapy; and

(vi) major surgery within 4 weeks of the first dose of study drug.

25 . The method of claim 24 , wherein the patient further does not have any one of the following conditions:

(i) known prolymphocytic leukemia or history of, or currently suspected, Richter's transformation;

(ii) clinically significant cardiovascular disease as manifested by any one of the following:

A. myocardial infarction within 6 months prior to the administration;

B. unstable angina within 3 months prior to the administration;

C. New York Heart Association class III or IV congestive heart failure;

D. history of clinically significant arrhythmias;

E. QTcF of more than 480 milliseconds based on Fridericia's formula;

F. history of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place; and

G. uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure of more than 170 mmHg and diastolic blood pressure of more than 105 mmHg;

(iii) history of stroke or intracranial hemorrhage within 180 days before the administration;

(iv) severe or debilitating pulmonary disease;

(v) disease significantly affecting gastrointestinal function, comprising malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction;

(vi) active fungal, bacterial, or viral infection requiring systemic therapy;

(vii) known central nervous system involvement by leukemia or lymphoma;

(viii) known infection with HIV or serologic status reflecting active viral hepatitis B or C infection as manifested by any one of the following:

A. presence of hepatitis B surface antibody (HBsAb) or hepatitis B core antibody (HBcAb); and

B. Presence of hepatitis C virus (HCV) antibody;

(ix) moderate or severe hepatic impairment, comprising Child-Pugh class B or C;

(x) one of the following prior treatments:

A. treatment with monoclonal antibody-based therapy within 28 days prior to the administration;

B. treatment with chimeric antigen receptor T-cell therapy within 180 days prior to the administration;

C. treatment with Chinese herbal medicine with anticancer intent within 28 days prior to the administration;

D. chemotherapy or radiation treatment within 21 days prior to the administration; and

E. hematopoietic stem cell transplantation within 90 days prior to the administration;

(xi) corticosteroid use of no more than 10 mg/day prior to the administration or corticosteroid use of more than 10 mg/day within 4 weeks prior to the administration;

(xii) toxicity from prior anticancer therapy that has not recovered to Grade 1 or lower, except for alopecia, ANC, and platelet count;

(xiii) pregnancy or lactation;

(xiv) vaccination with a live vaccine within 35 days prior to the administration;

(xv) alcohol or drug addiction;

(xvi) treatment with warfarin or other vitamin K antagonists; and

(xvii) treatment with a strong CYP3A inhibitor or inducer.

26 . The method of claim 24 , wherein the patient has relapsed or refractory CLL or relapsed or refractory SLL.

27 . The method of claim 24 , wherein the patient has a 17p deletion (del(17p)) or a TP53 mutation.

28 . The method of claim 24 , wherein the zanubrutinib or the pharmaceutically acceptable salt thereof is administered at a dose of 160 mg of zanubrutinib twice a day.

29 . The method of claim 24 , wherein the zanubrutinib or the pharmaceutically acceptable salt thereof is administered at a dose of 320 mg of zanubrutinib once a day.

30 . The method of claim 24 , further comprising assessing baseline risk of tumor lysis syndrome (TLS) in the patient, monitoring TLS during the PFS time, and treating TLS when it occurs.