Must have transfusion-dependent anemia that meets the following criteria:
Hemoglobin >= 8.5 g/dl (recommended cutoff subject to judgment of medical oncologist), but cannot be transfusion dependent
The patient is oxygen-dependent.
Advanced primary with impeding occlusion, perforation or bleeding, dependent on transfusion
Patients should not have transfusion-dependent thrombocytopenia or bleeding disorders
No hematologic parameters for inclusion; transfusion-dependent patients are eligible and platelet counts should be maintained greater than 10,000/mm^3 throughout cycles 1 and 2
Aplastic anemia with absolute neutrophil count (ANC) < 1,000 and transfusion dependent after failed immunosuppression therapy
Patients with transfusion-dependent anemia.
Platelets >= 100 x 10^9/L (transfusion dependent)
Transfusion dependent anemia with transfusion dependency of ?3 months
Transfusion dependent alpha- or beta-thalassemia
No specific hematologic parameters for study entry are required; transfusion-dependent patients are eligible and platelet counts should be maintained greater than 10,000/mm^3
Subject received HMA for at least 6 cycles and was still transfusion dependent (as defined in 5b below).
Presence of transfusion-dependent thrombocytopenia
Presence of transfusion-dependent thrombocytopenia
Condition (such as transfusion dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that might confound the study results, or interfere with the patient's participation for the full duration of the study treatment.
The patient is oxygen-dependent.
Subject is pacemaker dependent
Presence of transfusion-dependent thrombocytopenia
The patient is oxygen-dependent.
Hemoglobin >= 8 g/dl (can be transfusion dependent)
Patients with transfusion-dependent thrombocytopenia are not eligible
Patient who is growth factor or transfusion dependent
Presence of transfusion-dependent thrombocytopenia
Patients who are platelet or red blood cell transfusion-dependent are eligible
Transfusion dependent at baseline, defined as ? 4 U red blood cell (RBC) transfusion in the 8 weeks prior to first dose of MMB
Presence of transfusion-dependent thrombocytopenia
The patient is oxygen-dependent.
Patient is pacemaker dependent
Aplastic anemia with absolute neutrophil count (ANC) < 1000 and transfusion dependent after they failed immunosuppression therapy
Hemoglobin > 8 g/dl (may be transfusion dependent)
Patients who are oxygen dependent
No specific hematologic parameters for study entry are required; transfusion-dependent patients are eligible and platelet counts should be maintained greater than 10,000/mm^3
Chronic transfusion-dependent anemia with exposure to at least 5 RBCT
Oxygen dependent
Subject is using or is dependent on substances of abuse
For IPSS intermediate-1 or low-risk MDS, participants must be transfusion dependent for red blood cells or platelets (as determined by instructional practices or local standard of care). Participants who are red blood cell transfusion dependent must also have failed erythropoiesis stimulating agents (primary resistance or relapse after a response) or have serum erythropoietin (EPO) levels > 500 U/L.
History of gynecologic malignancy that is estrogen dependent
Subjects must have at least one of the following indications for treatment: \r\n* Symptomatic or progressive splenomegaly\r\n* Symptomatic lymph nodes, nodal clusters, or progressive lymphadenopathy\r\n* Progressive anemia (hemoglobin =< 11 g/dL)\r\n* Progressive thrombocytopenia (platelets =< 100 x 10^9/L)\r\n* Weight loss > 10% body weight over the preceding 6 month period\r\n* Fatigue attributable to CLL\r\n* Fever or night sweats for > 2 weeks without evidence of infection\r\n* Progressive lymphocytosis with an increase of > 50% over a 2-month period or an anticipated doubling time of less than 12 months
Diagnosis of:\r\n* B-CLL monoclonal for Kappa light chain with one or more of the following criteria:\r\n** Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia\r\n** Massive (i.e., at least 6 cm below the left costal margin) or progressive or symptomatic splenomegaly\r\n** Massive nodes (i.e., at least 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy\r\n** Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months\r\n** Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs:\r\n*** Unintentional weight loss of 10% or more within the previous 6 months;\r\n*** Significant fatigue (i.e., Eastern Cooperative Oncology Criteria [ECOG] performance status [PS] 2 or worse; inability to work or perform usual activities);\r\n*** Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without other evidence of infection; or\r\n*** Night sweats for more than 1 month without evidence of infection\r\n*** Patients who have resistant disease after primary treatment\r\n*** Patients who have a short time to progression after the first treatment (< 2 years) OR\r\n* Indolent or aggressive B-cell lymphoma (or other B-cell neoplasm) monoclonal for Kappa-light chain with measurable disease after receiving at least one chemotherapy regimen that includes rituximab or an equivalent monoclonal antibody OR\r\n* Multiple myeloma monoclonal for Kappa-light chain with measurable disease after receiving at least one chemotherapy regimen
Progressive lymphocytosis with > 50% increase over a 2-month period, or anticipated doubling time < 6 months.
CLL/SLL patients must have progressive disease with any one of the following characteristics based on standard criteria for treatment as defined by the NCI-Working Group (WG) 1996\r\n* Symptomatic CLL characterized by any one of the following:\r\n** Weight loss >= 10% within the previous 6 months\r\n** Extreme fatigue attributed to CLL\r\n** Fevers >= 100.5 degree Fahrenheit (F) for 2 weeks without evidence of infection\r\n** Drenching night sweats without evidence of infection\r\n* Evidence of progressive bone marrow failure with hemoglobin =< 11 g/dL or platelet count =< 100 x 10^9/L\r\n* Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly\r\n* Note: marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease are not sufficient for protocol therapy OR\r\nbiopsy proven Richter’s transformation or Hodgkin transformation of the CLL; NOTE: both untreated and previously treated patients in this category can be enrolled; they do not need to meet the progressive disease criteria in first bullet as long as measurable disease can be detected by positron emission tomography (PET)/computed tomography (CT) or CT (>= 1.5 cm in diameter)
Subjects must have at least one of the following indications for treatment: \r\n* Symptomatic or progressive splenomegaly\r\n* Symptomatic lymph nodes, nodal clusters, or progressive lymphadenopathy\r\n* Progressive anemia (hemoglobin =< 11 g/dL)\r\n* Progressive thrombocytopenia (platelets =< 100 x 109/L)\r\n* Weight loss > 10% body weight over the preceding 6 month period\r\n* Fatigue attributable to CLL\r\n* Fever or night sweats for > 2 weeks without evidence of infection\r\n* Progressive lymphocytosis with an increase of > 50% over a 2-month period or an anticipated doubling time of less than 12 months
At least one of the following criteria for active disease requiring treatment: progressive splenomegaly and/or lymphadenopathy; anemia or thrombocytopenia due to bone marrow involvement; or progressive lymphocytosis with an increase of >50% over a 2-month period or an unanticipated doubling time of less than 6 months
Active disease meeting at least 1 of the IWCLL 2008 criteria for requiring treatment:\r\n* A minimum of any one of the following constitutional symptoms:\r\n** Unintentional weight loss >10% within the previous 6 months prior to screening\r\n** Extreme fatigue (unable to work or perform usual activities)\r\n** Fevers of greater than 100.5 Fahrenheit for ? 2 weeks without evidence of infection\r\n** Night sweats without evidence of infection\r\n* Evidence of progressive marrow failure as manifested by the development of, or worsening of anemia or thrombocytopenia\r\n* Massive (i.e., > 6 cm below the left costal margin), progressive or symptomatic splenomegaly\r\n* Massive nodes or clusters (i.e., > 10 cm in longest diameter) or progressive lymphadenopathy\r\n* Progressive lymphocytosis with an increase of > 50% over a 2-month period, or an anticipated doubling time of less than 6 months\r\n* Autoimmune anemia or thrombocytopenia that is poorly responsive to corticosteroids
Requires therapy for symptomatic CLL in the opinion of the treating physician as defined by:\r\n* Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or thrombocytopenia)\r\n* Massive (>= 6 cm below the costal margin), progressive or symptomatic splenomegaly\r\n* Massive nodes (>= 10 cm) or progressive or symptomatic lymphadenopathy\r\n* Constitutional symptoms, which include any of the following:\r\n** Unintentional weight loss of 10% or more within 6 months\r\n** Significant fatigue limiting activity\r\n** Fevers >= 100.5 degrees Fahrenheit (F) for 2 weeks or more without evidence of infection\r\n** Night sweats > 1 month without evidence of infection
Patients with CLL/SLL must demonstrate active disease meeting at least 1 of the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for requiring treatment:\r\n* A minimum of any one of the following constitutional symptoms:\r\n** Unintentional weight loss > 10% within the previous 6 months prior to screening\r\n** Extreme fatigue (unable to work or perform usual activities)\r\n** Fevers of greater than 100.5 Fahrenheit (F) for >= 2 weeks without evidence of infection\r\n** Night sweats without evidence of infection\r\n* Evidence of progressive marrow failure as manifested by the development of, or worsening of anemia or thrombocytopenia\r\n* Massive (i.e., > 6 cm below the left costal margin), progressive or symptomatic splenomegaly\r\n* Massive nodes or clusters (i.e., > 10 cm in longest diameter) or progressive lymphadenopathy\r\n* Progressive lymphocytosis with an increase of > 50% over a 2-month period, or an anticipated doubling time of less than 6 months\r\n* Autoimmune anemia or thrombocytopenia that is poorly responsive to corticosteroids
Massive (i.e. > 6 cm below the left costal margin) or progressive/symptomatic splenomegaly OR
Massive lymph nodes or nodal clusters (i.e. > 10 cm in longest diameter), or progressive/symptomatic lymphadenopathy OR
Presence of disease-related constitutional symptoms:\r\n* Weight loss >= 10% over the preceding 6 months\r\n* Significant fatigue (i.e., Eastern Cooperative Oncology Group [ECOG] performance status [PS] 2 or worse; inability to work or perform usual activities)\r\n* Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without other evidence of infection\r\n* Night sweats for more than 1 month without evidence of infection
Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia
Inclusion Criteria:\n\n        Patients with a diagnosis of intermediate or high risk CLL (or variant immunophenotype),\n        SLL, or B-PLL by IWCLL 2008 criteria (48) who have:\n\n          -  Previously received at least one therapy for their disease.\n\n          -  Previously untreated disease and 65 years old OR under 65 years old and or refuse or\n             are ineligible for chemoimmunotherapy\n\n        All patients must satisfy one of the following criteria for active disease requiring\n        therapy:\n\n          -  Evidence of marrow failure as manifested by the development or worsening of anemia or\n             thrombocytopenia\n\n          -  Massive (? 6 cm below the costal margin), progressive or symptomatic splenomegaly\n\n          -  Massive nodes (? 10 cm) or progressive or symptomatic lymphadenopathy\n\n          -  Constitutional symptoms, which include any of the following:\n\n               -  Unintentional weight loss of 10% or more within 6 months\n\n               -  Significant fatigue limiting activity\n\n               -  Fevers ?100.5 degrees F for 2 weeks or more without evidence of infection\n\n               -  Night sweats >1 month without evidence of infection\n\n          -  Patients with a history of Richter's transformation are eligible if they now have\n             evidence of CLL only, with <10% large cells in the bone marrow.\n\n          -  ECOG performance status ? 2\n\n          -  Life expectancy of < 2 years or that would confound assessment of toxicity in this\n             study\n\n          -  Must be ? 18 years of age\n\n        Exclusion Criteria:\n\n          -  Any life-threatening illness, medical condition, or organ dysfunction which, in the\n             investigator's opinion, could compromise the subjects' safety, interfere with the\n             absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.\n\n          -  Subjects with active cardiovascular disease not medically controlled or those who have\n             had myocardial infarction in the past 6 months, or corrected QT interval (QTc) ?480\n             ms.\n\n          -  Malabsorption syndrome, disease significantly affecting GI function, or resection of\n             the stomach or small bowel or gastric bypass, ulcerative colitis, symptomatic\n             inflammatory bowel disease, or partial or complete bowel obstruction.\n\n          -  Grade ?2 toxicity (other than alopecia) continuing from prior anticancer therapy\n             including radiation.\n\n          -  History of a bleeding diathesis (eg, hemophilia, Von Willebrand disease).\n\n          -  Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenia\n             purpura.\n\n          -  History of stroke or intracranial hemorrhage within 6 months before the first dose of\n             study drug.\n\n          -  Requires or receiving anticoagulation with warfarin or equivalent vitamin K\n             antagonists (eg, phenprocoumon) within 28 days of first dose of study drug.\n\n          -  Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole,\n             lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).\n\n          -  Subjects with history of or ongoing drug-induced pneumonitis.\n\n          -  Subjects with human immunodeficiency virus (HIV) or active infection with hepatitis C\n             virus (HCV) or hepatitis B virus (HBV) or any uncontrolled active systemic infection.\n\n          -  Subjects who are known to have hepatitis B infection or who are hepatitis B core\n             antibody or surface antigen positive.
Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma as per IW-CLL 2008 criteria; specifically, patients must also require therapy for that diagnosis, based on meeting at least one of the following criteria:\r\n* Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin < 11.0 g/L) and/or thrombocytopenia (platelets < 100 x 10^9/L)\r\n* Massive (>= 6 cm below the left costal margin), progressive, or symptomatic splenomegaly\r\n* Massive nodes (at least 10 cm longest diameter), progressive, or symptomatic lymphadenopathy\r\n* Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of < 6 months; lymphocyte doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months; in subjects with initial blood lymphocyte counts of < 30 x 10^9/L, LDT should not be used as a single parameter to define indication for treatment; in addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded \r\n* Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy \r\n* Documented constitutional symptoms, defined as 1 or more of the following disease-related symptoms or signs:\r\n** Unintentional weight loss > 10% within 6 months prior to screening\r\n** Significant fatigue (inability to work or perform usual activities)\r\n** Fevers > 100.5° Fahrenheit (F) or 38.0° Celsius (C) for 2 or more weeks prior to screening without evidence of infection\r\n** Night sweats for more than 1 month prior to screening without evidence of infection
Patients must have symptomatic disease requiring therapy; indications for therapy are defined by the iwCLL2008 criteria as follows (one or more are sufficient):\r\n* Clinical manifestations (if believed by the investigator to be caused by CLL):\r\n** Unintentional weight loss > 10% within the previous 6 months\r\n** Significant fatigue\r\n** Fevers of greater than 100.5 degrees Fahrenheit (F) (38 degrees Celsius [C]) for 2 weeks without evidence of infection\r\n** Night sweats without evidence of infection\r\n* Evidence of progressive marrow failure as manifested by the development or worsening of anemia (< 11 g/dl), thrombocytopenia (< 100,000/mm^3) or neutropenia (< 1,500/mm^3)\r\n* Massive (i.e. > 6 cm below left costal margin) or progressive splenomegaly\r\n* Massive nodes/clusters (> 5 cm) or progressive symptomatic adenopathy\r\n* Progressive lymphocytosis with an increase of > 50% over 2 month period, or an anticipated doubling time of less than 6 months\r\n* NOTE: Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease is not sufficient for protocol therapy
Patients with any of the following indications for chemotherapy:\r\n* Evidence of progressive marrow failure as manifested by the development of or worsening anemia (? 11 g/dL) and/or thrombocytopenia (? 100 x 10^9/L) not due to autoimmune disease\r\n* Symptomatic or progressive lymphadenopathy, splenomegaly or hepatomegaly\r\n* One or more of the following disease-related symptoms:\r\n** Weight loss ? 10% within the previous 6 months\r\n** Extreme fatigue attributed to CLL\r\n** Fevers ? 100.4 degree Fahrenheit (F) for 2 weeks without evidence of infection\r\n** Drenching night sweats without evidence of infection
Patients with CLL/SLL demonstrate active disease meeting at least 1 of the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for requiring treatment:\r\n* A minimum of any one of the following constitutional symptoms:\r\n** Unintentional weight loss > 10% within the previous 6 months prior to screening\r\n** Extreme fatigue (unable to work or perform usual activities)\r\n** Fevers of greater than 100.5 F for >= 2 weeks without evidence of infection\r\n** Night sweats without evidence of infection\r\n* Evidence of progressive marrow failure as manifested by the development of, or worsening of anemia or thrombocytopenia\r\n* Massive (i.e., > 6 cm below the left costal margin), progressive or symptomatic splenomegaly\r\n* Massive nodes or clusters (i.e., > 10 cm in longest diameter) or progressive lymphadenopathy\r\n* Progressive lymphocytosis with an increase of > 50% over a 2-month period, or an anticipated doubling time of less than 6 months\r\n* Autoimmune anemia or thrombocytopenia that is poorly responsive to corticosteroids\r\n* Patients with NHL and with B-cell prolymphocytic leukemia must have an indication for treatment in the opinion of the investigator
A minimum of any one of the following constitutional symptoms: Unintentional weight loss >10% within the previous 6 months prior to screening Extreme fatigue (unable to work or perform usual activities) Fevers of greater than 100.5?F for ?2 weeks without evidence of infection Night sweats without evidence of infection.
Evidence of progressive marrow failure as manifested by the development of, or worsening of anemia or thrombocytopenia
Massive (i.e., >6 cm below the left costal margin), progressive or symptomatic splenomegaly
Massive nodes or clusters (i.e., >10 cm in longest diameter) or progressive lymphadenopathy
Progressive lymphocytosis with an increase of >50% over a 2-month period, or an anticipated doubling time of less than 6 months
Active disease per International Workshop on Chronic Lymphocytic (IWCLL) 2008 criteria, as defined as one of the following:\r\n* Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia\r\n* Massive (i.e., at least 6 cm below the left costal margin) or progressive or symptomatic splenomegaly\r\n* Massive nodes (i.e., at least 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy\r\n* Progressive lymphocytosis with an increase of more than 50 percent over a two-month period or lymphocyte doubling time (LDT) of less than six months; LDT can be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of two weeks over an observation period of two to three months; in patients with initial blood lymphocyte counts of less than 30 x 10^9/L (30,000/L), LDT should not be used as a single parameter to define a treatment indication; in addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infection) should be excluded\r\n* Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy\r\n* Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs: \r\n** Unintentional weight loss of 10 percent or more within the previous six months\r\n** Significant fatigue (i.e., ECOG performance scale [PS] 2 or worse; inability to work or perform usual activities) \r\n** Fevers higher than 100.5 degrees Fahrenheit (F) or 38.0 degrees Celsius (C) for two or more weeks without other evidence of infection\r\n** Night sweats for more than one month without evidence of infection
Patients must have histologically confirmed B-cell CLL/SLL according to World Health Organization (WHO) criteria with at least one of the following indications for treatment:\r\n* Progressive disease or marked splenomegaly or hepatomegaly\r\n* Anemia (hemoglobin [Hgb] < 11 mg/dL) or thrombocytopenia (platelets < 100,000 /mm^3)\r\n* Unexplained weight loss exceeding 10% of body weight over the preceding 6 months\r\n* Fevers > 100.5 degrees F or night sweats for greater than 2 weeks without evidence of infection\r\n* Progressive lymphocytosis, with an increase exceeding 50% over a 2 month period or a doubling time of less than 6 months\r\n* Significant fatigue (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v] 4.03 grade 2 or higher)
Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia.
Massive or progressive or symptomatic splenomegaly.
Massive nodes or progressive or symptomatic lymphadenopathy.
Patients meeting any of the following consensus criteria for initiating treatment for their CLL:\r\n* Progressive symptomatic splenomegaly and/or lymphadenopathy identified by physical examination\r\n* Anemia ( < 11g/dL) or thrombocytopenia ( < 100,000/uL) due to bone marrow involvement\r\n* Presence of unintentional weight loss > 10% over the preceding 6 months\r\n* National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >= 3 fatigue\r\n* Fevers > 100.5°F or night sweats for > 2 weeks without evidence of infection
Patients must meet criteria for treatment as defined by IWCLL 2008 guidelines which includes at least one of the following criteria:\r\n* Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or thrombocytopenia)\r\n* Massive (>= 6 cm below the costal margin), progressive or symptomatic splenomegaly\r\n* Massive nodes (>= 10 cm) or progressive or symptomatic lymphadenopathy\r\n* Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy\r\n* Constitutional symptoms, which include any of the following:\r\n** Unintentional weight loss of 10% or more within 6 months\r\n** Significant fatigue\r\n** Fevers > 100.5 degrees F for 2 weeks or more without evidence of infection\r\n** Night sweats > 1 month without evidence of infection
All patients must have a diagnosis of chronic lymphocytic leukemia (CLL) by immunophenotyping and flow cytometry analysis of blood or bone marrow\r\n* Patients must meet criteria for treatment based on the criteria proposed by National Cancer Institute (NCI)-sponsored CLL Working Group to include at least one of the following:\r\n** Weight loss of more than 10% over the preceding 6 months; or\r\n** Extreme fatigue attributable to progressive disease; or\r\n** Fever or night sweats without evidence of infection; or\r\n** Worsening anemia (Rai stage Ill) or thrombocytopenia (Rai stage IV); or\r\n** Massive lymphadenopathy (> 10 cm) or rapidly progressive lymphocytosis (lymphocyte doubling time < 6 months); or \r\n** Prolymphocytic or Richter's transformation; or\r\n* Patients with CLL who have received at least one prior line of therapy; or\r\n* Patients with CLL who have frequent infections and/or recurrent secondary cancers
Participants must satisfy one of the criteria for treatment initiation, as outlined in the iwCLL NCI-WG guidelines. The criteria include: (a) Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia, (b) Massive (i.e., greater than or equal to [>=] 6 centimeters [cm] below the left costal margin) or progressive or symptomatic splenomegaly, (c) Massive nodes (i.e., >= 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy, (d) Progressive lymphocytosis with an increase of greater than (>) 50 percent (%) over a 2-month period or lymphocyte doubling time (LDT) of less than (<) 6 months, (e) Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy, (f) Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs: unintentional weight loss of >=10% within the previous 6 months, significant fatigue (i.e., Eastern Cooperative Oncology Group Performance Status [ECOG PS] of 2 or worse or the inability to work or perform usual activities), fevers higher than 100.5 degrees Fahrenheit (°F)/38.0 degrees Celsius (°C) for >= 2 weeks without other evidence of infection, or night sweats for >1 month without evidence of infection
Inclusion Criteria:\n\n        Disease Related:\n\n          1. Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria.\n\n          2. Age 65 yrs and older OR if less than 65 years, must have at least one of the following\n             criteria:\n\n               -  Cumulative Illness Rating Score (CIRS) >6\n\n               -  Creatinine clearance estimated <70 mL/min using Cockcroft-Gault equation.\n\n               -  Del 17p by FISH or TP53 mutation by PCR or Next Generation Sequencing\n\n          3. Active disease meeting at least 1 of the following IWCLL criteria for requiring\n             treatment:\n\n               -  Evidence of progressive marrow failure as manifested by the development of, or\n                  worsening of, anemia and thrombocytopenia\n\n               -  Massive, progressive, or symptomatic splenomegaly\n\n               -  Massive nodes (at least 10 cm longest diameter), or progressive or symptomatic\n                  lymphadenopathy.\n\n               -  Progressive lymphocytosis with an increase of more than 50 percent over a 2-month\n                  period or a lymphocyte doubling time (LDT) of <6 months. LDT may be obtained by\n                  linear regression extrapolation of absolute lymphocyte counts obtained at\n                  intervals of 2 weeks over an observation period of 2 to 3 months. In patients\n                  with initial blood lymphocyte counts of <3,000/µL, LDT should not be used as a\n                  single parameter to define indication for treatment. In addition, factors\n                  contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections)\n                  should be excluded.\n\n               -  Autoimmune hemolytic anemia and/or immune thrombocytopenia that is poorly\n                  responsive to corticosteroids or other standard therapy.\n\n               -  Autoimmune hemolytic anemia is defined by at least one marker of hemolysis\n                  (indirect bilirubin above the upper limit of normal (ULN) not due to liver\n                  disease, increased lactate dehydrogenase (above ULN) without alternative\n                  etiology, or increased absolute reticulocytosis (above ULN) or bone marrow\n                  erythropoiesis in the absence of bleeding AND at least one marker direct or\n                  indirect autoimmune mechanism (positive direct antiglobulin for IgG or C3d, cold\n                  agglutinins).\n\n               -  Immune thrombocytopenia is defined by platelets ?100,000/µL and increased\n                  megakaryocytes on the bone marrow exam.\n\n               -  Constitutional symptoms, defined as one or more of the following disease-related\n                  symptoms or signs, documented in the patient's record prior to randomization:\n\n               -  unintentional weight loss >10 percent within 6 months prior to screening.\n\n               -  significant fatigue (inability to work or perform usual activities).\n\n               -  fevers >100.5°F or 38.0°C for 2 or more weeks prior to screening without evidence\n                  of infection.\n\n               -  night sweats for more than 1 month prior to screening without evidence of\n                  infection.\n\n          4. Measurable nodal disease by computed tomography (CT), defined as at least 1 lymph node\n             >1.5 cm in the longest diameter in a site that has not been previously irradiated. An\n             irradiated lesion may be assessed for measurable disease only if there has been\n             documented progression in that lesion since radiotherapy has ended.\n\n             Laboratory\n\n          5. Adequate hematologic function independent of transfusion and growth factor support for\n             at least 7 days prior to screening and randomization.\n\n          6. Adequate hepatic and renal function\n\n          7. Men and women ? 18 years of age.\n\n          8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.\n\n        Exclusion Criteria:\n\n          1. Any prior treatment of CLL or SLL\n\n          2. Evidence of central nervous system (CNS) involvement with primary disease of CLL/SLL\n\n          3. History of other malignancies, except:\n\n               -  Malignancy treated with curative intent and with no known active disease present\n                  for ?3 years before the first dose of study drug and felt to be at low risk for\n                  recurrence by treating physician.\n\n          4. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura\n\n          5. Known or suspected history of Richter's transformation.\n\n          6. Concurrent administration of >20mg/day of prednisone within 7 days of randomization\n             unless indicated for prophylaxis or management of allergic reactions (eg, contrast)\n\n          7. Known hypersensitivity to one or more study drugs\n\n          8. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.\n\n          9. Any uncontrolled active systemic infection or an infection requiring systemic\n             treatment that was completed ? 7 days before randomization.\n\n         10. Known bleeding disorders or hemophilia.\n\n         11. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.\n\n         12. Known history of human immunodeficiency virus (HIV) or active with hepatitis B virus\n             (HBV) or hepatitis C virus (HCV).\n\n         13. Major surgery within 4 weeks of randomization.\n\n         14. Any life-threatening illness, medical condition, or organ system dysfunction that, in\n             the investigator's opinion, could compromise the subject's safety or put the study\n             outcomes at undue risk.\n\n         15. Currently active, clinically significant cardiovascular disease, such as uncontrolled\n             arrhythmia or Class 3 or 4 congestive heart failure or a history of myocardial\n             infarction, unstable angina, or acute coronary syndrome within 6 months prior to\n             randomization.\n\n         16. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting\n             gastrointestinal function, or resection of the stomach or small bowel, symptomatic\n             inflammatory bowel disease or ulcerative colitis, or partial or complete bowel\n             obstruction.\n\n         17. Concomitant use of warfarin or other vitamin K antagonists.\n\n         18. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.\n\n         19. Lactating or pregnant\n\n         20. Unwilling or unable to participate in all required study evaluations and procedures.\n\n         21. Unable to understand the purpose and risks of the study and to provide a signed and\n             dated informed consent form (ICF) and authorization to use protected health\n             information (in accordance with national and local subject privacy regulations).
Indication for treatment as defined by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines:\r\n* Massive (i.e. > 6 cm below the left costal margin) or progressive/symptomatic splenomegaly OR\r\n* Massive lymph nodes or nodal clusters (i.e. > 10 cm in longest diameter), or progressive/symptomatic lymphadenopathy OR\r\n* Presence of disease-related constitutional symptoms\r\n** Weight loss >= 10% over the preceding 6 months\r\n** Significant fatigue (i.e., Eastern Cooperative Oncology Group [ECOG] performance status [PS] 2 or worse; inability to work or perform usual activities)\r\n** Fevers higher than 100.5° Fahrenheit (F) or 38.0° Celsius (C) for 2 or more weeks without other evidence of infection\r\n** Night sweats for more than 1 month without evidence of infection\r\n* Progressive lymphocytes with an increase of >= 50% over a 2-month period or an anticipated doubling time of less than 6 months; OR\r\n* Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia\r\n* Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroids or other standard therapy
Subjects must not have received any prior systemic therapy for CLL and currently have an indication for treatment as defined by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 guidelines:\r\n* Massive or progressive splenomegaly; OR\r\n* Massive lymph nodes, nodal clusters, or progressive lymphadenopathy; OR\r\n* Grade 2 or 3 fatigue; OR\r\n* Fever >= 100.5 degrees Fahrenheit or night sweats for greater than 2 weeks without documented infection; OR\r\n* Presence of weight loss >= 10% over the preceding 6 months; OR\r\n* Progressive lymphocytosis with an increase of >= 50% over a 2-month period or an anticipated doubling time of less than 6 months; OR\r\n* Evidence of progressive marrow failure as manifested by the development of or worsening of anemia and or thrombocytopenia
Has met at least one of the following indications for treatment:\r\n* Evidence of progressive marrow failure as manifested by the development of worsening anemia (hemoglobin [Hg] < 11 g/dl) and/or thrombocytopenia (platelets < 100 x 10^9/L)\r\n* Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly\r\n* One or more of the following disease-related symptoms:\r\n** Weight loss >= 10% within the previous 6 months\r\n** Grade 2 or 3 fatigue attributed to CLL\r\n** Fevers > 100.5 Fahrenheit (F) for 2 weeks without evidence of infection\r\n** Clinically significant night sweats without evidence of infection\r\n* Progressive lymphocytosis (not due to the effects of corticosteroids) with an increase of > 50% over a two-month period or an anticipated doubling time of less than six months
Patients are eligible if they have stage III or IV disease; patients with stage 0, I or II disease will be eligible if they have evidence of active disease defined as one or more of the following signs/symptoms:\r\n* Documented weight loss of >= 10% over a six month period \r\n* Febrile episodes of 38 degrees Celsius (100.5 degrees F) or greater for greater than 2 weeks without evidence of infection \r\n* Massive or progressive splenomegaly defined as > 6 cm below the left costal margin \r\n* Massive (> 10 cm in longest diameter) or progressive lymphadenopathy
Constitutional symptoms related to CLL/SLL: \r\n* Fever > 100.5 degrees Fahrenheit (F) for >= 2 weeks or night sweats for > 1 month, both without evidence of infection\r\n* Unintentional weight loss of >= 10% body weight in previous 6 months\r\n* Extreme fatigue (ECOG PS > 2; inability to work or perform usual activities)\r\n* Lymphocyte doubling time of =< 6 months or 50% increase in absolute lymphocyte count within 2 months\r\n* Progressive anemia (Rai stage III) or thrombocytopenia (Rai stage IV)\r\n* Recurrent infections unrelated to hypogammaglobulinemia\r\n* Autoimmune phenomenon poorly responsive to corticosteroids or other standard therapy\r\n* Massive, progressive or symptomatic lymphadenopathy (> 10 cm in longest diameter) or splenomegaly (> 6 cm below left costal margin)
Indication for treatment as defined by the National Cancer Institute (NCI) Working Group & International Workshop in CLL Guidelines (2, 3):\r\n* Massive (i.e. > 6 cm below the left costal margin) or progressive / symptomatic splenomegaly OR\r\n* Massive lymph nodes or nodal clusters (i.e. > 10 cm in longest diameter), or progressive / symptomatic lymphadenopathy OR\r\n* Presence of disease-related constitutional symptoms:\r\n** Weight loss >= 10% over the preceding 6 months \r\n** Significant fatigue (i.e., Eastern Cooperative Oncology Group [ECOG] performance status [PS] 2 or worse; inability to work or perform usual activities)\r\n** Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without other evidence of infection\r\n** Night sweats for more than 1 month without evidence of infection OR\r\n* Progressive lymphocytosis with an increase of >= 50% over a 2-month period or an anticipated doubling time of less than 6 months OR\r\n* Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and / or thrombocytopenia OR\r\n* Autoimmune anemia and / or thrombocytopenia poorly responsive to corticosteroids or other standard therapy
Progressive lymphocytosis, with an increase exceeding 50% over a 2 month period or a doubling time of less than 6 months.
Active disease and indication for treatment based on the IWCLL updated NCI-WG guidelines, defined by presence of at least any one of the following conditions: Evidence of progressive marrow failure as manifested by development or worsening of anaemia and/or thrombocytopenia; Massive (i.e. at least 6 cm below the left costal margin) or progressive or symptomatic splenomegaly; Massive nodes (i.e. at least 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy; Progressive lymphocytosis with an increase of more than 50% over a two-month period or a lymphocyte doubling time of less than 6 months.
Progressive or massive lymphadenopathy OR
Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma as per International Workshop on Chronic Lymphocytic Leukemia (IW-CLL) 2008 criteria; specifically, patients must also require therapy for that diagnosis, based on meeting at least one of the following criteria:\r\n* Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin < 11.0 g/L) and/or thrombocytopenia (platelets < 100 x 10^9/L)\r\n* Massive (>= 6 cm below the left costal margin), progressive, or symptomatic splenomegaly\r\n* Massive nodes (at least 10 cm longest diameter), progressive, or symptomatic lymphadenopathy\r\n* Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of < 6 months; lymphocyte doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months; in subjects with initial blood lymphocyte counts of < 30 x 10^9/L, LDT should not be used as a single parameter to define indication for treatment; in addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded\r\n* Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy\r\n* Documented constitutional symptoms, defined as 1 or more of the following disease-related symptoms or signs:\r\n** Unintentional weight loss > 10% within 6 months prior to screening\r\n** Significant fatigue (inability to work or perform usual activities) fevers > 100.5 degrees Fahrenheit (F) or 38.0 degrees Celsius (C) for 2 or more weeks prior to screening without evidence of infection\r\n** Night sweats for more than 1 month prior to screening without evidence of infection