Inclusion Criteria:
* Histologically confirmed diagnosis of mantle cell lymphoma, with review of the diagnostic pathology specimen at one of the participating institutions. Whenever possible, the Ki67 fraction should be reported or evaluated, cytogenetics should be performed, and TP53 status should be assessed (preferably by next-generation sequencing; immunohistochemical staining would be next-preferred).
* No prior anti-lymphoma therapy, with the following exceptions:
* Prior radiotherapy for localized disease is permitted.
* A course of radiotherapy for urgent symptomatic disease is also permitted. Short-course systemic corticosteroids is permissible for disease control (must be \< 7 days and ≤ 100mg/day of prednisone or ≤ 20mg/day of dexamethasone, or equivalent). Steroids must be discontinued prior to study treatment.
* Measurable disease, defined as ≥1 measurable nodal lesion (long axis \>1.5 cm or short axis \>1.0 cm) or ≥1 measurable extra-nodal lesion (long axis \>1.0 cm) on PET, CT, or magnetic resonance imaging (MRI). Disease should be FDG-avid based on PET.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. (Appendix A)
* Age ≥18 years and considered a candidate for high-dose cytarabine by the treating physician.
* Adequate hematologic and organ function defined as:
* Absolute neutrophil count ≥ 1.0 x109/L, or ≥ 0.5 x109/L if bone marrow involvement (use of growth factor support allowed).
* Hemoglobin ≥ 8 g/dL and independent of transfusion within 7 days of screening.
* Platelets ≥ 100 x109/L, or ≥ 50 x109/L if bone marrow involvement, and independent of transfusion within 7 days of screening.
* Estimated CrCl ≥ 30mL/min (by Cockcroft-Gault formula or by 24-hour urine collection).
* AST/ALT \< 2.5 X institutional upper limit of normal (ULN), or \< 5.0 X institutional ULN if documented liver involvement of lymphoma.
* Total bilirubin \< 2.0 X ULN (unless active hemolysis); for subjects with Gilbert's Syndrome, direct bilirubin \< 1.5 X ULN.
* Patients with known infection with human immunodeficiency virus (HIV) are eligible, provided all 3 of the following are true: 1) presence of controlled disease, defined as CD4 count ≥ 200/uL and an undetectable viral load, 2) disease control has been stable on anti-retroviral therapy for at least 6 months prior to study enrollment, and 3) there are no prohibitive drug-drug interactions between study drugs and the necessary anti- retroviral therapies.
* Willingness to provide a pre-treatment tumor sample by core needle or excisional surgical biopsy. A fresh biopsy is strongly encouraged, but an archival sample is acceptable if it is collected within 90 days and without intervening treatment and the following provisions are met: 1) availability of a tumor-containing formalin-fixed, paraffin-embedded (FFPE) tissue block, 2) if the tumor containing FFPE tissue block cannot be provided in total, sections from this block should be provided that are freshly cut and mounted on positively-charged glass slides. Preferably, 25 slides should be provided; if not possible, a minimum of 15 slides is required. Exceptions to this criterion may be made with approval of the Sponsor-Investigator.
* Willingness to remain abstinent or to use two effective contraceptive methods that result in a failure rate of \<1% per year from screening until at least:
* 6 months after the last dose of bendamustine,
* 6 months after the last dose of cytarabine,
* 90 days after the last dose of zanubrutinib,
* 90 days after the last dose of sonrotoclax, and/or
* 12 months after the last dose of rituximab, whichever of the above is longest. Examples of contraceptive methods with a failure rate of \<1% per year include:
* Tubal ligation, male sterilization, hormonal implants, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
* Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of \<1% per year. Barrier methods must always be supplemented with the use of a spermicide.
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. In contrast, periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
* Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
* Known central nervous system involvement.
* Known active infection requiring systemic antimicrobial therapy at trial enrollment.
* Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia).
* Participants who require warfarin or other vitamin K antagonists for anticoagulation. Other anticoagulants including direct oral anticoagulants (i.e. apixaban, rivaroxaban) and low-molecular weight heparin are allowed.
* History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusions or other medical interventions.
* History of stroke or intracranial hemorrhage within 6 months of first dose of zanubrutinib.
* History of significant or life-threatening hemorrhage within 3 months of first dose of zanubrutinib.
* History of uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia, unless these conditions are related to the underlying malignancy.
* Active hepatitis C infection. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable (NOTE: the limit of detection for HCV RNA must have a sensitivity of \< 15 IU/mL). Subjects who received treatment for HCV that was intended to eradicate the virus and who have an undetectable HCV RNA may participate without serial HCV RNA screening. Other patients may participate if they are willing to undergo every 3- month monitoring for HCV reactivation.
* Active hepatitis B infection. Patients with positive hepatitis B serologies with undetectable HBV DNA (NOTE: the limit of detection for HBV DNA must have a sensitivity of \< 20 IU/mL) are permitted in the trial but should receive prophylactic antiviral therapy (i.e. entecavir) and undergo every 3 month HBV DNA monitoring.
* Prior history of another malignancy unless treated with curative intent and disease-free for at least 3 years at time of screening with expected low risk of recurrence during expected timeframe of study participation. Such patients should first be discussed with the Sponsor-Investigator. Additional exceptions: non-melanoma skin cancer, in situ cervical or breast cancer, or Gleason 6 prostate cancer managed with observation.
* Patients with the following cardiac conditions will be excluded:
* New York Heart Association Class III or IV heart failure.
* Myocardial infarction within 6 months of screening.
* Unstable angina within 3 months prior to screening.
* Active uncontrolled arrhythmia.
* History of clinically significant ventricular arrhythmias within 6 months of screening (eg sustained Vtach, Vfib, torsades de pointes).
* History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place.
* Uncontrolled hypertension as indicated by ≥ 2 consecutive blood pressure measurements showing systolic blood pressure \> 170 mm Hg and diastolic blood pressure \> 105 mm Hg at screening.
* Screening 12-lead EKG showing a baseline QTcF (Fridericia's correction) \> 480 msec.
* Unable to swallow capsules or disease significantly affecting gastrointestinal function, such as malabsorption syndrome.
* Participants receiving any medications or substances that are strong CYP3A inducers.
Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.
* Patients who are pregnant, breast-feeding, or intending to become pregnant during the study.
* Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study or limit adherence to study requirements.
* Inability to comply with protocol mandated restrictions.
