Emerging treatments for relapsed/refractory Hodgkin’s lymphoma in China

Dr Qingqing Cai – Sun Yat-Sen University, Guangzhou, China

According to the guidelines of the Chinese Society of Clinical Oncology we have the CSCO guidelines for China. The second line salvage chemotherapy and autologous stem cell transplantation for transplant eligible classical Hodgkin’s lymphoma patients is recommended as the category 1a evidence. Salvage chemotherapy alone is recommended for patients not suitable for transplantation. PD-1 inhibitor monotherapy is also recommended because brentuximab vedotin was available last year so our guidelines haven’t updated.

Can you update us on PD-1 inhibitors and autologous stem cell transplantation?

I can introduce the treatment experience in our centres for the second line treatment before the presence of the PD-1 inhibitors we used the conventional chemotherapy, for example, GVD, ICE or the IGEV following autologous stem cell transplantation consolidation with or without radiotherapy, as the guideline recommendation. However, a low complete response rate and short progression free survival were observed after the conventional chemotherapy which limited the uses of autologous stem cell transplantation and caused a poorer clinical outcome.

In the era of immunotherapy, considering the low complete response rate of PD-1 monotherapy, we have tried giving the PD1 inhibitor combined with the conventional chemotherapy before the autologous stem cell transplantation and with PD-1 inhibitor maintenance after autologous stem cell transplantation. It seems that patients could benefit from the addition of PD-1 inhibitors resulting in a higher complete response rate and more patients eligible for transplantation. Long term outcomes still need to be observed in the future.

Based on this, we also initiated a phase II clinical trial and now we are recruiting classical Hodgkin’s lymphoma patients who failed both lines of therapy to receive the PD-1 inhibitor monotherapy or PD-1 inhibitor plus the GVD regimen to study vinorelbine and liposomal doxorubicin. We hope the final result of this trial can provide evidence for the application of PD-1 in second line therapy.

For subsequent treatment we highly encourage patient participation in clinical trials. If not, we prefer the PD-1 inhibitor or brentuximab vedotin combined with other conventional chemotherapy and seek for the chance of subsequent transplantation. For patients not eligible for transplantation or with relatively low tumour burden, PD-1 inhibitor or brentuximab vedotin monotherapy is also an option and other chemotherapy regimens or novel agents like everolimus or lenalidomide were also used but the outcomes remained poor.

Is there any new data or drugs that are now being used to treat relapsed/refractory Hodgkin’s lymphoma in China?

In China Hodgkin’s lymphoma accounts for about 10% of all lymphomas with an incidence of 2-6 per million. Over 70% of patients can be cured by first line chemotherapy plus or minus radiotherapy. However, 20-30% of patients will progress or relapse within ten years. In the past few years the use of immune checkpoint inhibitors, mainly the PD-1 inhibitors, has greatly changed the treatment strategy of classical Hodgkin’s lymphoma in China and PD-1 inhibitors are now widely used as the salvage therapy for relapsed or refractory disease.

Apart from the pembrolizumab or nivolumab, three other PD-1 inhibitors – sintilimab, tremelimumab and tislelizumab – have been tested in phase II clinical trials in Chinese medical centres and are now available for Chinese classical Hodgkin’s lymphoma patients.

What is coming through and looking promising for the future with regards to ASH 2020?

In the 2020 ASH meeting a new PD-1 inhibitor, GLS-010 was reported and it showed great efficacy for relapsed or refractory classical Hodgkin’s lymphoma in China. Brentuximab vedotin has showed great efficacy in classical Hodgkin’s lymphoma in the last decades, both as salvage therapy and as first line therapy. However, brentuximab vedotin has just become available in China less than one year and its price remains high. The real world efficacy and toxicity of brentuximab vedotin in China needs to be classified in the future. In our centre brentuximab vedotin was mostly used in the first line therapy combined with the ABV regimen for advanced staged patients.

There is no doubt that Hodgkin’s lymphoma has entered the era of immunotherapy and targeted therapy and the outcome of relapsed or refractory Hodgkin’s lymphoma has improved obviously in the past decade owing to the approval of highly active new drugs, brentuximab vedotin and PD-1 inhibitors. For now, several problems need to be illustrated in the future: one, the real world efficacy and toxicity data in China are needed to adjust the use of brentuximab vedotin and PD-1 inhibitors in clinical practice. We can use quite a few real life studies which were reported in the 2020 ASH meeting which can help the decision to understand the drugs better.

The second, several combination therapies in clinical trials were reported such as PD-1 combined with chemotherapy, brentuximab vedotin combined with ICE, brentuximab vedotin combined with PD-1 inhibitor. It is important to explore the combination of active drugs or combinations of new drugs in the future in order to induce deep remissions as well as shorten treatment duration.

The third, novel agents are needed to further improve the outcome of Hodgkin’s lymphoma which fail brentuximab vedotin and PD-1 inhibitors. As covered in the 2020 ASH meeting, novel agents like the JAK inhibitor, STAT inhibitor and anti-CD25 ADC drugs have shown good preliminary efficacy in relapsed or refractory classical Hodgkin’s lymphoma. We need to further investigate it.

What advice do you have for other clinicians?

From the experience in our centre, chemotherapy is now out of date. The rapid development of novel agents doesn’t mean that we have to abandon chemotherapy. So, combining the PD-1 inhibitor with conventional chemotherapy or combining brentuximab vedotin with conventional chemotherapy as second line therapy might be a viable choice for relapsed or refractory Hodgkin’s lymphoma. How to make the best use of chemotherapy and new agents is a new job for oncologists in lymphoma around the world.

Can you explain the efficacy of brentuximab vedotin?

For the patients who are suitable for transplantation, the brentuximab vedotin combined with ICE is the option now for salvage therapy because it produces a higher response rate, complete response rate, and can be a bridge to transplantation for patients. For the elderly patients, if the patient cannot tolerate the chemotherapy then brentuximab vedotin combined with DTIC or combined with PD-1 inhibitor is the better choice for this kind of patient. Also, the brentuximab vedotin combined with PD-1 as a chemo-free treatment is also a better choice for the patients who cannot tolerate chemotherapy.

Also, brentuximab vedotin combined with the PD-1 inhibitor as maintenance after the transplantation is also the one of choice.