This is a prospective, multicenter, phase II study, in elderly patients affected by Mantle cell lymphoma (MCL) defined as unfit/frail according to Simplified Geriatric Assessment (sGA) and previously untreated.

Patients will receive a treatment with Pirtobrutinib monotherapy until tumor progression, unacceptable adverse event, or patient decision for interruption.

After providing written informed consent, patients will be evaluated for eligibility during a 28-day screening period. Patients will receive pirtobrutinib at a starting dose of 200 mg once daily (2 tablets q.d.). All treatment will be administered orally, and a cycle will be defined as 28 days in length and should be maintained regardless of dose interruptions. Treatment is meant to be administered until tumor progression, unacceptable adverse event, or patient decision for interruption.

Responses shall be assessed at month +3, +6 after start of treatment and then every 6 months using the radiologic method of tumor assessment consistent throughout the study and aligned with the baseline method (CT scan or ultrasound echography are acceptable). Positron Emission Tomography (PET) scan is mandatory at baseline and at month +3 after start of treatment to establish tumor response.

Inclusion Criteria:

1. Histologically documented diagnosis of nodal and extranodal mantle cell lymphoma (MCL) as defined in the 2022 edition of the World Health Organization (WHO) classification

2. Availability of biopsy material for central pathology revision and mutational analysis including TP53 (Tumor Protein p53) mutations

3. Age ≥ 70 years

4. Previously untreated MCL

5. Active disease in need of treatment according to clinical practice (patients with leukemic with symptomatic leukemic non nodal disease may be included)

6. Ineligible to standard full-dose induction therapy (i.e. BR, R-CHOP, VR-CAP, RBAC500)

7. sGA assessment performed before starting treatment

   FRAIL patients defined as follows:

   • Age ≥ 80 years
   • Activities of Daily Living (ADL) <6 residual functions and/or
   • Instrumental Activities of Daily Living (IADL) <8 residual functions and/or
   • Cumulative Illness Rating Scale (CIRS): ≥ 1 comorbidity of grade 3-4 or ≥ 5 comorbidities of grade 2

   UNFIT patients defined as follows:

   • Age ≥ 80 years:
   • ADL 6 residual functions and
   • IADL 8 residual functions and
   • CIRS 0 comorbidities of grade 3-4 and <5 comorbidities of grade 2

   or

   • Age < 80 years:
   • ADL < 5 residual functions and/or
   • IADL < 6 residual functions and/or
   • CIRS ≥ 1 comorbidity of grade 3-4 or >8 comorbidities of grade 2

8. Ann Arbor Stage I - IV

9. At least one bi-dimensionally measurable lesion defined as > 1.5 cm in its largest dimension on CT scan

10. Eastern Cooperative Oncology Group (ECOG) performance status of 0- 2

11. Adequate hematologic function (unless caused by bone marrow infiltrate), defined as follows:

    1. Hemoglobin ≥ 8 g/dL (independent of transfusions within 7 days of screening assessment)
    2. White blood cells (WBC) > 2500/mmc with polymorphonuclear (cells) PMN≥750/ mmc) (independent of growth factor support within 7 days of screening assessment)
    3. Platelets count ≥ 50000/mmc (independent of transfusions within 7 days of screening assessment)

12. Adequate renal function:

    • Creatinine clearance ≥ 30 mL/min or
    • Serum creatinine ≤ 2.5 mg /dL

13. Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x upper limit of normal (ULN)

14. Adequate hepatic function:

    • Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) ≤ 3 x the ULN or ≤ 5 x ULN with documented liver involvement
    • Total bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN with documented liver involvement and/or due to Gilbert's Disease

15. Ability and willingness to comply with the study protocol procedure

16. Life expectancy > 6 months

17. The patient is able to take oral medications

18. The patient must give written informed consent

19. Male subjects must use highly effective contraception during sexual contact with a pregnant female or a female of childbearing potential from the start of study treatment and continuing for at least 3 months after the last dose of pirtobrutinib

Exclusion Criteria:

Patients who meet any of the following criteria are not eligible to enroll:

1. Candidate to watch and wait due to indolent presentation

2. Leukemic non-nodal MCL that has stable asymptomatic disease should not be included in this study

3. Histological diagnosis different from MCL or leukemic non-nodal MCL

4. Fit patients according to sGA eligible to standard full dose therapy

5. Candidate or eligible to full-dose Bendamustine+Rituximab (BR), Rituximab + Cyclophosphamide, Hydroxydaunorubicin (doxorubicin), Oncovin (vincristine) e Prednisone (R-CHOP), bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone (VR-CAP), Rituximab, Bendamustine, Cytarabine (RBAC500) or any other full dose intensive chemotherapy

6. Suspect or clinical evidence of central nervous system (CNS) involvement by lymphoma

7. Contraindication to the use Bruton Tyrosine Kinase Inhibitor (BTKi)

8. HBsAg positivity; HBsAg-negative patients with anti-hepatitis B core antigen (HBc) antibody can be enrolled if Hepatitis B Virus (HBV)-DNA are negative and prophylactic antiviral treatment is provided

9. HIV positivity

10. Active herpes zoster infection; previously infected patients is accepted only with concomitant treatment with Valacyclovir

11. Major surgery within 4 weeks prior to investigation treatment

12. Any history of other malignancies unless in remission and with life expectancy > 2 years prior to study entry except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer

13. Patients who experienced grade ≥ 3 arrhythmia.

14. History of severe bleeding diathesis (major bleeding event) Note: Major bleeding is defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2 g per deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome)

15. History of stroke or intracranial hemorrhage within 6 months of investigation treatment

16. History of Chimeric Antigen Receptor T-cell therapy (CAR-T) within 60 days of investigation treatment or presence of any of the following, regardless of prior Stem Cell Transplantation (SCT) and/or CAR-T therapy timing:

    1. active graft versus host disease (GVHD);
    2. cytopenia from incomplete blood cell count recovery post-transplant;
    3. need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity > Grade 1 from CAR-T therapy;
    4. ongoing immunosuppressive therapy (> 20 mg prednisone or equivalent daily)

17. Evidence of any severe active acute or chronic infection

18. Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, HCV-RNA is required. Only patients with HCV-RNA negative are accepted.

19. Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible

20. Clinically significant active malabsorption syndrome or other conditions likely to affect gastrointestinal (GI) absorption of the study drug

21. Evidence of other clinically significant uncontrolled condition(s) including but not limited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the investigator and medical monitor may pose a risk for patient participation. Screening for chronic conditions is not required

22. Active uncontrolled auto-immune cytopenia (e.g., AutoImmune Hemolytic Anemia [AIHA], Idiopathic Thrombocytopenic Purpura [ITP]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts

23. Significant cardiovascular disease defined as:

    1. unstable angina or acute coronary syndrome within the past 2 months prior to study enrollment
    2. history of myocardial infarction within 3 months prior to study enrollment or
    3. documented left ventricular ejection fraction (LVEF) by any method of ≤ 40% in the 12 months prior to study enrollment
    4. ≥ Grade 3 New York Heart Association (NYHA) functional classification system of heart failure
    5. Uncontrolled or symptomatic arrhythmias

24. Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec. QTcF is calculated using Fridericia's Formula (QTcF): QTcF = QT/(RR0.33):

    1. Correction of suspected drug-induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.
    2. Correction for underlying bundle branch block (BBB) allowed. Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker

25. Any other co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent

26. Absence of caregivers in non-autonomous patients

27. Need of anticoagulation with warfarin or another vitamin K antagonist

28. Vaccination with live vaccine within 28 days prior to investigation treatment

29. Have a known hypersensitivity to any of the excipients of Pirtobrutinib or to any intended study medications

No identifiable data, such as name, address, hospital name, date of birth, or any other identifying data, will be shared and should not be requested. For each data sharing request, it is essential that a proforma (available on request) is completed that describes the general purpose, specific aims, data items requested, analysis plan and acknowledgment of the trial management team. Requests will be reviewed based on scientific merit and ethical principles. Requestors who are granted access to the data will be required to complete a data sharing agreement that will be signed by the requester and FIL. In compliance with the national ethics guideline and applicable legislation, individual deidentified patients' data (including study protocol, statistical analysis plan and data coding) can be shared until 5 years after the publication of the study.

In compliance with the domestic ethics guideline and applicable legislation, individual deidentified patients' data underlying the results reported in the publication article (including study protocol, statistical analysis plan and data coding) can be shared until 5 years after the publication of the article.

For each data sharing request, it is essential that a proforma (available on request) is completed that describes the general purpose, specific aims, data items requested, analysis plan and acknowledgment of the trial management team. Requests will be reviewed based on scientific merit and ethical principles. Requestors who are granted access to the data will be required to complete a data sharing agreement that will be signed by the requester and FIL.