The goal of this clinical trial is to test the effect of tislelizumab treatment in patients with Hodgkin lymphoma. The main question it aims to answer is whether including a drug called tislelizumab in first-line treatment of Hodgkin lymphoma for patients age 60 years and older is effective and well-tolerated.

Participants will initially receive tislelizumab infusion every 21 days for 3 doses. After this a PET scan will be performed to assess the response. The subsequent treatment patients receive will depend on the following factors:

1. The lymphoma stage (early stage or advanced stage)
2. The presence or absence of specific high-risk features at the time of diagnosis
3. How well the lymphoma responds to the initial 3 doses of tislelizumab

Trial patients who are deemed eligible for the trial will receive 3 cycles of tislelizumab which will be administered at a dose of 200 mg (IV) on day 1 of each 21-day cycle. Patients will then undergo a PET-CT scan (PET1). Subsequent treatment is determined by the patient's stage and response to tislelizumab (as determined by PET1).

Patients with early stage lymphoma and no high-risk features who respond very well to the initial 3 doses of tislelizumab will receive a further 2 doses of tislelizumab, followed by radiotherapy, followed by tislelizumab once every 21 days for up to 2 years.

All other patients will receive a combination of tislelizumab with chemotherapy for between 2 and 6 cycles. Each cycle will last 28 days. Tislelizumab will be given on day 1 and chemotherapy (doxorubicin (also known as Adriamycin), vinblastine and dacarbazine, or AVD) will be given on days 1 and 15, as injections or infusions into a vein. Following this some patients may require radiotherapy depending on their response to treatment.

Patients who are in complete metabolic response (CMR) at PET1 will receive 2 fewer cycles of tislelizumab and AVD therapy than those not in CMR.

A further 1 or 2 PET scans will be performed to assess how well the lymphoma has responded to the trial treatment, depending on the results of previous scans. After completing the treatment patients will then be followed-up for at least 2 years from the start of their participation in the trial.

Note: Initial patients will be recruited to a safety run in. Once 6 evaluable patients have completed 2 cycles of tislelizumab and AVD after PET1 the independent data monitoring committee (IDMC) will review the data, and if considered tolerable, recruitment will continue to the full sample size (80 patients).

Inclusion Criteria:

1. Newly diagnosed untreated classic Hodgkin lymphoma (Stage I-IV)
2. Age 60 years or over
3. In the view of the investigator, fit for combination chemotherapy (includes those who would require planned dose reduction although no lower than 50% doxorubicin)
4. Written informed consent
5. Measurable disease on contrast enhanced CT as defined by Cheson et al., 2014 1 (Nodal lesion of longest diameter 1.5 cm or extranodal lesion of longest diameter 1.0 cm).
6. ECOG performance status 0-2
7. Adequate bone marrow function (Platelets ≥ 75 x 109/L without platelet transfusion for 72 hours, Neutrophils ≥ 1.0 x 109/L without G-CSF for 7 days)
8. Adequate liver function tests (ALT / AST ≤ 2.5 x ULN, total serum bilirubin ≤ 1.5 x ULN)
9. Creatinine Clearance ≥ 30 ml/min as defined by the Cockroft-Gault equation
10. Adequate cardiac function as determined by a transthoracic echocardiogram demonstrating left ventricular ejection fraction is ≥ 50% and confirming the absence of severe valvular heart disease
11. Willing to comply with the contraceptive requirements of the trial
12. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures

Exclusion Criteria:

1. Nodular lymphocyte predominant Hodgkin lymphoma

2. History of autoimmune disorders (with the exception of hypothyroidism, type 1 diabetes, vitiligo, alopecia)

3. History of solid organ transplant

4. Grade 2 or higher peripheral neuropathy

5. Presentation with disease causing symptomatic compression of vital structures (e.g. stridor due to tracheal compression). Other cases of radiological compression of vital structures require discussion with TMG prior to registration

6. Women who are pregnant or breastfeeding

7. Active hepatitis B or C infection defined by

   1. Hepatitis B surface antigen positivity OR
   2. Anti-hepatitis B core antibody positivity with detectable circulating HBV DNA (hepatitis B core antibody patients with undetectable circulating HBV DNA are eligible but must take suitable prophylaxis for reactivation)
   3. Anti-Hepatitis C antibody positivity unless patient has been treated for hepatitis C and has undetectable HCV RNA

8. Known HIV infection

9. Positive PCR for SAR-CoV-2 RNA within the 2 weeks prior to registration. Patients with a history of SARS-CoV-2 are required to have a documented negative PCR swab since documented SARS-CoV-2 infection

10. Immunosuppressive therapy within the 2 months prior to registration apart from inhaled, intranasal or topical corticosteroids. Systemic corticosteroids are permitted prior to study entry but must be weaned to 10 mg prednisolone / day for a minimum of 7 days prior to cycle 1 day 1

11. Live vaccine given within 30 days prior to registration

12. Active infection requiring systemic therapy with ongoing symptoms at registration or where the planned duration of therapy would continue beyond cycle 1 day 1

13. Major surgery within 4 weeks prior to registration (excisional biopsy is not considered major surgery)

14. Myocardial infarction, unstable angina, coronary artery bypass graft, cerebrovascular accident or transient ischaemic attack within 6 months prior to registration

15. Previously treated haematological malignancy

16. Solid-organ malignancy active within the last 3 years, except where the natural history or treatment does not have the potential to interfere with assessment of safety or efficacy of trial treatment, for example:

    1. Adequately treated non-melanoma skin cancer considered to be in remission
    2. Melanoma in situ following resection
    3. Carcinoma in situ of the breast or cervix
    4. Carcinoma of the prostate of Gleason grade 6 or less with stable prostate-specific antigen levels
    5. Cancer considered cured by surgical resection or unlikely to impact survival in the next 3 years, for example local transitional carcinoma of the bladder or benign tumours of the adrenal gland or pancreas

17. A history of other malignancies should be discussed with the trial management group prior to registration

18. Patient not fit for AVD chemotherapy in the opinion of the investigator