Efficacy and safety of frontline tislelizumab in patients with de novo Hodgkin lymphoma unsuitable for standard frontline chemotherapy: a phase II, open-label study.

Approximately two-thirds of patients with Hodgkin lymphoma (HL) are cured with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), the standard first-line chemotherapy regimen. 
Most patients are diagnosed in their second or third decade of life, but at least 25% of new cases occur in patients over the age of 65. Outcomes are poorer in elderly HL patients: the disease is inherently more aggressive compared to younger individuals, presents in advanced stage in at least two-thirds of cases, and is associated with multiple risk factors for unfavorable prognosis, according to the International Prognostic Score (IPS) for HL. 

In addition, older patients may present with organ function impairments (particularly of the bone marrow, heart, or lungs), necessitating dose reductions in chemotherapy (especially of anthracyclines), delays in treatment administration, or the discontinuation of bleomycin, a core component of the standard regimen. 
Given the difficulty in delivering full-dose therapy in elderly patients with significant medical comorbidities, there is a need for the development of novel and better-tolerated agents. No monotherapy drug is currently approved for such patients. Even drugs such as gemcitabine or bendamustine, which are relatively well tolerated and active in relapsed/refractory patients, have prescription limitations in this population. 

Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, is the only agent that has shown meaningful results in patients over 60 years old who are ineligible for standard first-line chemotherapy, achieving an overall response rate of 92%, including 73% complete remissions, with a median duration of response of 9.1 months. 

Nivolumab and pembrolizumab, both immune checkpoint inhibitors, have been extensively tested in patients with relapsed/refractory HL following failure of autologous stem cell transplantation and treatment with brentuximab vedotin. Both agents have demonstrated efficacy, with significant and durable objective response rates. Given their acceptable toxicity profiles, both are approved for the treatment of relapsed/refractory HL, offering a valuable option for heavily pretreated patients. 

Tislelizumab (T, BGB-A317) is a humanized IgG4 monoclonal antibody with high affinity and specificity for programmed cell death protein 1 (PD-1). Tislelizumab has demonstrated superior antitumor activity compared to nivolumab in murine models engrafted with human tumor cells and peripheral blood mononuclear cells. In Chinese patients with HL who had failed transplant or were ineligible, high response rates were reported, including 61% complete responses and 24% partial responses. 

It is hypothesized that tislelizumab monotherapy as induction may represent a feasible chemo-free treatment strategy for patients with newly diagnosed HL who are unfit for standard first-line chemotherapy. 

The study will also include baseline biomarker evaluations of the tumor clone and microenvironment, and will explore their potential correlation with treatment response and patient outcomes.