Company supplying drug/funding ceased support.

This study evaluates the effectiveness of acalabrutinib treatment in patients with chronic lymphocytic leukemia (CLL) deemed at high risk for Richter's Transformation (RT). This is a single arm study. Enrolled patients will initiate therapy with acalabrutinib and will dose continuously. While on study, subjects will be monitored monthly for the first 3 months, then every three months thereafter until disease progression, discontinuation due to toxicity, death, or study completion.

This is a multi-center, single arm, Phase II clinical trial to investigate the effectiveness of acalabrutinib treatment within 6 months of chronic lymphocytic leukemia (CLL) diagnosis for patients with CLL deemed at high risk for Richter's Transformation (RT).

Inclusion Criteria:

• Subject must be able to voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures.

• The time from diagnosis to consent should be ≤6 months.

• Subject must be ≥ 18 years of age.

• Subject must have diagnosis of CLL/SLL based upon 2018 iwCLL Guidelines.

• Rai stage 0-2 disease without indication for treatment as defined by the 2018 iwCLL guidelines

• Subject must have high risk CLL as defined by any one of the following:

  • NOTCH1 mutated (classic frameshift mutation only)
  • Unmutated V4-39 B cell receptor usage
  • Pathogenic c-MYC mutations
  • Complex karyotype, (by CpG/oligodeoxynucleotide stimulation)
  • Deletion 17p, or presence of TP53 mutation

• Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.

• PT/PTT/INR within 1.5 x the ULN

• Adequate renal function defined by serum creatinine less than 2 x ULN

• Adequate hepatic function:

  • ALT/AST less than 2x ULN
  • Tbili less than 1.5 X ULN unless bilirubin elevation is due to Gilbert's syndrome (total bilirubin <3)

• Subject must have adequate bone marrow function.

  • Absolute neutrophil count ≥1.0 x103/μL
  • Hemoglobin ≥ 11.0 g/dL
  • Platelets ≥ 100 x 103/μL

Exclusion Criteria:

• Previous exposure to any systemic anti-cancer therapy as a treatment for CLL, including but not limited to chemotherapy, immunotherapy, radiotherapy, or investigational therapy. Note, patients treated with chemotherapy for a prior non-hematologic malignancy if more than 5 years earlier are eligible.

• Subject with a history of malignancy except for non-melanoma skin cancers. Subjects treated with curative intent via methods of local resection and or locally targeted anticancer treatment and are free of malignancy for at least 5 years from treatment end will be allowed to enroll.

• Subject requires chronic immunosuppressive therapy for any reason or was treated with immunosuppressive therapy within 6 months of study entry.

• Subjects with a history of autoimmune hemolytic anemia or immune thrombocytopenia purpura.

• Subject has prolymphocytic leukemia.

• Active bleeding, or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease)

• Subject requires warfarin or equivalent vitamin K antagonist

• Uncontrolled or active significant infection,

• History of or suspected or confirmed PML

• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study.

• Patients with stroke or CNS hemorrhage within 6 months

• Pregnant or breastfeeding

  • Women of childbearing potential (WCBP) who are sexually active with heterosexual partners must agree to use highly effective methods of contraception during treatment and for 2 days after the last dose of acalabrutinib.

• Major surgical procedure within 28 days of first dose of study drug. If a subject had surgery, they must have recovered adequately from any toxicity or complications before the first dose of study drug.

• Has difficulty with or is unable to swallow oral medication or has significant gastrointestinal disease that would limit absorption of oral medication.

• Subject is known to be positive for human immunodeficiency virus (HIV)

• Active hepatitis C, as confirmed by being positive for Hep C RNA by PCR

• Active hepatitis B infection documented by a positive PCR for Hep B DNA. If hepatitis B serology is positive for hepatitis B core antibody, but Hep B DNA PCR is negative, patient is eligible to enroll.

• Subject requires strong CYP 3A4/5 inhibitors or inducers (Appendix B).

• Subject requires proton pump inhibitors. (Subjects that can transition to an H2 antagonist are allowed to enroll.)