Hodgkin’s lymphoma: 2023 update on treatment

PD1 antibody

The primary objective for patients diagnosed with advanced disease (stage IIB–IV) is to enhance the proportion of individuals achieving sustained remission while concurrently mitigating the occurrence of long-term adverse effects. Several studies have explored the efficacy and adverse effects of the use of PD1 antibody plus chemotherapy. At the 17th International Conference on Malignant Lymphoma (17-ICML), Herrera et al.³ have reported the results of the SWOG S1826 study, which has demonstrated that, compared with BV-AVD, nivolumab (N)-AVD prolongs PFS and decreases the incidence of toxic reactions in patients diagnosed with advanced stage HL. This breakthrough treatment method is important for patients with advanced HL. However, notably, the study follow-up time was short, and no overall survival (OS) benefit was observed; therefore, longer follow-up is needed. Another investigation has evaluated the effects of pembrolizumab and AVD (doxorubicin, vinblastine, and dacarbazine; APVD) on newly diagnosed cHL. The 2-year PFS and OS were 97% and 100%, respectively, thus indicating favorable safety and efficacy¹⁴. All these studies have demonstrated that anti-PD1 antibodies exhibit notable clinical effectiveness in patients with newly diagnosed HL.

For pediatric and adolescent HL patients, assessing the effectiveness of treatment in relation to the potential long-term consequences is imperative. The Children’s Oncology Group (COG) program has demonstrated a favorable success rate in curing pediatric patients over the past 30 years. However, long-term follow-up studies have revealed that these patients may experience infertility, premature heart failure, and the development of secondary tumors because of the administration of certain alkylating drugs. Therefore, a primary objective of treatment is to achieve a high rate of remission while minimizing the use of radiotherapy and chemotherapy, to mitigate long-term adverse effects. The currently recommended chemotherapy regimen is tailored specifically to children and differs from the regimen used for adults. Recently, at the European Hematology Association 2023 Congress, Vinti et al.⁴ have reported that pembrolizumab and 4 cycles of cyclophosphamide, vincristine, prednisone/prednisolone, and dacarbazine (COPDAC-28) consolidation regimens demonstrate manageable safety and promising antitumor efficacy in the treatment of children and young adults with cHL with a slow early response to first-line chemotherapy (OEPA, vincristine, etoposide, prednisone/prednisolone, and doxorubicin). This study suggests that the pembrolizumab plus COPDAC-28 regimen had the potential to augment the therapeutic response in high-risk cHL populations.

Brentuximab vedotin

eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazide, and prednisone) is a personalized PET2-guided initial therapy for individuals diagnosed with advanced cHL. This treatment approach has achieved remarkable survival outcomes but also caused treatment-associated morbidity. At the 17-ICML, Borchmann et al.⁵ have reported the noninferiority of BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD) to eBEACOPP in the GHSG phase III HD21 trial. Notably, when comparing the eBEACOPP group to the BrECADD group, a reduction in early PFS events was observed in the latter, thus leading to an impressive 3-year PFS rate of 94.9%. These promising PFS outcomes suggest that personalized treatment with PET2-guided BrECADD is currently the optimal therapeutic approach for adult patients with advanced-stage cHL.

The AHOD1331 study was a large phase III randomized trial aimed at assessing the effectiveness and safety of BV-AVEPC, in pediatric patients with newly diagnosed high-risk HL. The experimental group received BV instead of bleomycin to mitigate long-term toxicity and after the fifth cycle of treatment, radiotherapy was performed on the involved sites of slow-responding lesions or large mediastinal adenopathy, in both the BV group and the standard-care group. Incorporating BV into conventional chemotherapy regimens has been found to enhance efficacy while decreasing adverse events or mortality by 59%, without increasing the occurrence of toxic reactions over a 3-year period⁶.

PD-1 plus BV therapy

Multiagent chemotherapy has made substantial advancements in recent years, but as many as 10% of patients with HL do not respond to treatment and have an elevated risk of death. For patients eligible for transplantation, a combination of second-line salvage chemotherapy along with autologous hematopoietic stem cell transplantation is recommended. In the era of new drugs, as treatment advancements continue, the second-line regimen for R/R patients is transitioning from conventional chemotherapy to PD-1 inhibitor treatment, either alone or in conjunction with BV. In a multicenter phase II trial, after undergoing hematopoietic stem cell transplantation, patients initiated treatment with a combination of BV and nivolumab. The PFS rate for 59 patients was 94% (95% CI 84–98), thereby indicating that BV plus nivolumab is highly effective in consolidating patients with R/R cHL⁷. To explore long-term outcomes in patients with R/R cHL who have responded to PD-1 inhibition, 4 phase II trials have been performed in China. A total of 260 patients were included in the analysis. Nearly one-fifth of patients who achieved complete remission with nonrefractory diseases demonstrated the most favorable survival outcome, with a 3-year PFS exceeding 80%. However, the survival outcome of PR patients was poor, and the 3-year PFS was less than 50%⁸. Therefore, additional investigations are imperative to investigate the multimodal treatment approach for patients who attain objective remission after PD-1 monoclonal antibody therapy.

The cure rate for HL in the population of children, adolescents, and young adults (CAYA) is high, exceeding 90%. However, despite this favorable outcome, approximately 10% of patients may experience relapse. Unlike certain non-Hodgkin’s lymphoma subtypes, HL typically exhibits a less aggressive disease progression, thereby offering potential avenues for further therapeutic interventions. For R/R HL in CAYA, the CheckMate 744 study has investigated a risk-stratified, response-adapted system using nivolumab plus BV, followed by BV plus bendamustine. Induction with nivolumab plus BV resulted in a CMR rate of 59% and, any time before consolidation with nivolumab plus BV ± BV plus bendamustine, resulted in a CMR rate of 94%. A high CMR rate with low toxicity was observed in CAYA patients with R/R cHL after use of this response-adapted, risk-stratified salvage treatment⁹.

Bispecific antibody

Because some patients with R/R HL face resistance problems, new therapeutic strategies should be explored. The results of the CD47/PD-L1 bispecific antibody IBI322 in anti-PD-1 or PD-L1 treatment-resistant cHL were orally presented by Yu et al.¹⁰ at the European Hematology Association 2023 Congress. The results showed an objective response rate (ORR) of 47.8% and a disease control rate of 91.3%. IBI322 monotherapy exhibited encouraging antitumor activity and manageable safety profiles in anti-PD-1 or PD-L1 treatment-resistant cHL.

CAR-T therapy

Cellular therapy is considered a highly promising novel therapeutic approach. Previous studies have demonstrated the antitumor efficacy with minimal observable toxicity of CD30-specific chimeric antigen receptor (CAR) T cells in R/R HL. However, the application of readily available allogeneic T-cell therapies is hindered by substantial obstacles, primarily graft-vs.-host disease¹⁵. To address the issue of graft-vs.-host disease, at the 17-ICML, a study was reported promising results for cellular therapies in R/R HL. Epstein-Barr virus-specific T cells (EBVST) were modified by incorporation of a CAR specifically targeting CD30, an antigen upregulated on allo-activated T cells. Consequently, CD30.CAR EBVST cells served as targets for CD30. All 16 patients with R/R HL were assessable for ORR analyses, among whom 12 (75%) had ORRs, thus demonstrating that CD30.CAR EBVST can be considered a safe and effective therapeutic approach for R/R HL¹¹.