• Participants must meet the following criteria on screening examination to be eligible to participate in the study:

• Participants must have histologically determined mantle cell lymphoma with pathologic review at the participating institutions, that has either:

‣ Relapsed or primary refractory after at least one line of therapy including anti-CD20 monoclonal antibody treatment (part A) or; Had no previous anti-lymphoma therapy other than corticosteroids or radiotherapy (parts B and C).

⁃ Participants in part A, relapsed or refractory following prior therapy, may have had a prior autologous or allogeneic stem cell transplant and may have been treated with chimeric antigen receptor T-cells (CAR T-cells).

• Participants in parts B and C, without prior anti-lymphoma therapy, must require treatment as defined by any of the following criteria:

‣ Symptomatic adenopathy or splenomegaly

⁃ Local symptoms due to extranodal disease

⁃ Organ function impairment due to disease involvement, including cytopenias due to marrow involvement (WBC \<1.5x109/L; absolute neutrophil count \[ANC\] \<1.0x109/L, Hgb \<10g/dL; platelets \<100x109/L)

⁃ Presence of systemic B symptoms (fever, drenching night sweats, or unintentional weight loss ≥ 10% body weight over previous 6 months) or functionally significant fatigue

• Participants in part B without prior anti-lymphoma therapy should be deemed to be ineligible for autologous stem cell transplant by the treating physician and/or have a TP53 mutation detected by next generation sequencing at a variant (mutant) allele fraction above the validated threshold for calling a new variant or high TP53 expression on immunohistochemistry (\>50% positive lymphoma cells)

• Participants in part C without prior anti-lymphoma therapy should be deemed to be eligible for autologous stem cell transplant by the treatment physician and have no evidence of TP53 mutation (TP53 wild type) detected by next generation sequencing and no evidence of high TP53 expression on immunohistochemisty

• Participants in parts B and C must have an archived formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen from the original diagnostic biopsy and peripheral blood available for submission to Adaptive Biotechnologies for ClonoSEQ®ID molecular marker identification of a unique clonal immunoglobulin DNA sequence. Only those participants in parts B and C who have a molecular marker identified from the peripheral blood will be eligible for minimal residual disease (MRD) driven treatment interruptions.

• Participants in parts B and C who do not have a molecular marker identified by ClonoSEQ from the peripheral blood will be deemed to be MRD indeterminate and are not eligible for peripheral blood MRD driven treatment interruptions. These participants will be able to enroll in the study assuming all other eligibility criteria are met but will receive 7 cycles of AVO combination therapy followed by 17 cycles of acalabrutinib and venetoclax therapy (24 total cycles of AV) and 2 years of maintenance obinutuzumab for a total of 31 cycles of therapy.

• Measurable disease with a lymph node or tumor mass ≥ 1.5 cm in at least one dimension by CT, PET/CT, or MRI. Patients without measurable disease will be eligible if they have marrow involvement and cytopenias related to their lymphoma (hemoglobin \<10 g/dL, absolute neutrophil count \< 1.0 x 109/L, or platelets \< 100 x 109/L) OR symptomatic splenomegaly \> 15cm in craniocaudal diameter.

• Age ≥ 18 years.

• ECOG performance status ≤2 (Karnofsky ≥60%)

• Participants must have adequate organ and marrow function as defined below:

‣ Absolute neutrophil count ≥ 750 cells/mm3 (0.75 x109/L) unless due to marrow involvement by lymphoma in which case ANC must be ≥ 500 cells/mm3 (0.5x109/L)

⁃ Platelet count without transfusional support must be ≥ 75,000 cells/mm3 (75 x109/L), unless due to marrow involvement by lymphoma, in which case platelets must be ≥ 50,000 cells/mm3 (50 x109/L)

⁃ Hemoglobin without transfusional support must be ≥ 8.0 g/dL (80 g/L) unless due to marrow involvement by lymphoma, in which case hemoglobin must be ≥ 7.0 g/dL (70 g/L)

⁃ Creatinine clearance (CrCl) ≥ 50 ml/min using 24-hour urine collection for creatinine clearance or calculated CrCl or calculated glomerular filtration rate (GFR) ≥ 50 ml/min/1.73 m2 using the CKD-EPI equation

⁃ Total bilirubin ≤ 2 times the upper limit of normal, unless there is disease involvement of the liver, hemolysis, or a known history of Gilbert's disease, in which case direct bilirubin must be ≤ 3 times the upper limit of normal

⁃ AST and ALT ≤ 2.5 times the upper limit of normal, unless documented liver involvement by lymphoma, in which case AST and ALT must be ≤ 5 times the upper limit of normal

⁃ PT/INR ≤ 2 times the upper limit of normal and PTT ≤ 2 times the upper limit of normal

• Willingness to provide pre-treatment bone marrow (or recent archival w/o intervening therapy) and on-treatment bone marrow and peripheral blood samples

• The effects of the study drugs on the developing human fetus are unknown. Women of child-bearing potential must agree to remain abstinent or use highly effective contraception (defined as contraceptive measures that result in a failure rate of \<1% per year) during the treatment period and for at least 2 days after the last dose of acalabrutinib, 90 days after the last dose of venetoclax or 18 months after the last dose of obinutuzumab, whichever is longer. Men with female sexual partners of childbearing potential should agree to remain abstinent or use contraceptive measures which include a condom plus an additional contraceptive method that together result in a failure rate of \<1% per year during the treatment period and for at least 90 days after the last dose of venetoclax or 6 months after the last dose of obinutuzumab, whichever is longer. Men should refrain from donating sperm during the same period. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

• Ability to understand and the willingness to sign a written informed consent document.