Catherine S Diefenbach MD

Question

What is your strategy for communicating with patients about the general efficacy of drugs that exist to treat classical Hodgkin lymphoma?

Answer

For patients with classical Hodgkin lymphoma (HL), it is vitally important to communicate with newly diagnosed patients about the curability of this [type of] lymphoma for many patients. For patients with early-stage disease, I communicate that our goal is to maximize cure while minimizing potential long-term toxicities from chemotherapy. The integration of newer drugs into first-line or initial therapy has only been approved for advanced-stage patients. For these patients, we discuss the benefits and risks of standard chemotherapy using a risk-adapted approach versus integration of brentuximab into first-line chemotherapy. For patients with relapsed disease, I discuss the new drugs that have been approved for relapsed HL, the role of autologous stem cell transplant, and innovative clinical trials that offer access to therapies or novel combinations.

Question

Please explain how cell-free DNA (cfDNA) and/or circulating tumor (ctDNA) can be used to detect mutations in classical Hodgkin lymphoma. From your perspective, how far along is the science in this field for lymphoma, and is further research needed?

Answer

While cfDNA and ctDNA have prognostic value in diffuse large B-cell lymphoma (DLBCL), where levels correlate with advanced stage and higher [international prognostic index] risk factors, investigation of cfDNA is at an early stage in classical HL. While some lymphomas such as DLBCL and primary mediastinal lymphoma have high levels of cfDNA, in HL, there are small numbers of tumor cells compared with the number of surrounding inflammatory cells in the tumor microenvironment. For this reason, tumor genotyping has been challenging in HL, and detection of cfDNA has been challenging as well. Recently, one study using CAPP-Seq was used to assess ctDNA, and in a small subset of these patients with serial assessments, a 2-log decrease in ctDNA was predictive of a favorable outcome.1 But this is one small retrospective study; significantly more research is needed with large prospective clinical trials before this approach can be integrated into clinical practice or inform treatment decisions for HL patients.

Question

What is the role of natural killer cells in classical Hodgkin lymphoma, and how can treatment strategies incorporate them?

Answer

The specific role of natural killer (NK) cells in the tumor microenvironment of HL is unclear, but they form a component of the abundant peritumoral tumor microenvironment in which the Hodgkin Reid Sternberg (HRS) cells grow and thrive. It has been hypothesized that recruiting NK cells to the tumor might enhance tumor-directed apoptosis. There are no US Food and Drug Administration (FDA)-approved agents for the treatment of HL that target NK cell activation, but there is 1 agent that is currently in clinical trials. A tetravalent bispecific antibody targeting CD16A on NK cells and the CD30 antigen expressed on the surface of HRS cells showed modest activity in relapsed HL as a single agent, but was much more active when combined with the checkpoint inhibitor pembrolizumab, suggesting that combining NK cell engagement with immune activation is a promising strategy for relapsed HL.² This approach continues to be investigated in HL in ongoing clinical trials.

Question

What are the most promising trials in classical Hodgkin lymphoma that are under way? Are there areas in which you feel more research should be directed?

Answer

The most promising trials in HL include: E4412 (ClinicalTrials.gov Identifier: NCT01896999), a randomized phase 2 study comparing the doublet of brentuximab vedotin and nivolumab to the triplet of brentuximab vedotin, nivolumab, and ipilimumab for patients with relapsed HL, which demonstrated an extremely high complete response rate in phase 1 studies; trials of CD30-directed chimeric antigen (CAR) T cells, including CD19-directed CAR T cells for checkpoint inhibitor refractory patients; trials of other antibody-drug conjugates, such as ADCT-301, a CD25 targeting ADC (ClinicalTrials.gov Identifier: NCT02432235); AFM13, a bispecific antibody targeting NK-cell activation and CD30 combined with pembrolizumab (ClinicalTrials.gov Identifier: NCT02665650); trials of nivolumab and pembrolizumab in combination with chemotherapy;3 and other phase 1 trials of novel targets, such as macrophages (CD47) and other tumor antigens that incorporate HL patients into their eligible population.

Combinations of brentuximab vedotin with chemotherapy have been described: brentuximab vedotin and bendamustine, or brentuximab vedotin in combination with ICE [ifosfamide, carboplatin, and etoposide] chemotherapy either in combination or sequentially, and in combination with DHAP [dexamethasone, cytarabine, and cisplatin].In the first-line setting, the ECHELON-1 trial combined brentuximab vedotin with standard AVD [doxorubicin, vinblastine, and dacarbazine] chemotherapy and demonstrated an approximately 5% improvement in PFS for the experimental BV [bleomycin and vinblastine]-containing arm.4 Subset analysis suggested a greater benefit for patients with the highest risk disease. Current trials include approaches combining the checkpoint inhibitor nivolumab with standard first-line ABVD [doxorubicin, bleomycin, vinblastine, and dacarbazine] chemotherapy.

Question

Autoimmunity-associated lymphoma: What are the trends in this space, and do you expect to see a rise in the incidence of this cancer subgroup? Could immunotherapies for other diseases/cancers affect incidence levels?

Answer

Both autoimmune disease and the immune-modifying drugs used to treat autoimmune disease increase the risk of developing lymphoma; however, this risk remains very small, as most people with autoimmune disease will never develop lymphoma. However, as the incidence of autoimmune disease increases, the incidence of autoimmune disease–associated lymphoma will likely increase as well.

Question

Where is the field going for non-Hodgkin lymphoma (NHL) and T-cell lymphomas? What are exiting new and/or emerging therapies? Do you think chemotherapy will remain the standard frontline therapy in the near future?

Answer

For DLBCL we have seen the most recent phase 3 trial integrating lenalidomide with R-CHOP, which was negative.5 The ongoing phase 3 integrating the anti-CD79 antibody-drug conjugate polatuzumab is ongoing;6 if this is a positive trial, it may change the standard of care for relapsed DLBCL. However, to date, all trials in the first-line therapy space for DLBCL have been negative.

For relapsed DLBCL, the approval of CAR T-cell therapies (CAR-T) has been a major advance in the field, with a cure now possible for patient with refractory disease.7 This is the first therapeutic modality that cures patients with lymphoma who are unable to achieve a complete remission or good disease control. Also for relapsed DLBCL, the CD79b-directed antibody-drug conjugate polatuzumab vedotin in combination with bendamustine and rituximab is now approved for relapsed DLBCL.

For [follicular lymphoma], the recent approval of rituximab and lenalidomide (R2) gives a new chemotherapy-free therapeutic option for relapsed patients.

For all lymphomas, the field is moving toward rational combinations, which are derived from the understanding of lymphoma biology. Ideally, integration of targeted therapy and immunotherapy will lessen the toxicity of chemotherapy platforms. Personally, I do not believe that we will move away from chemotherapy, as it has a vital role in reducing tumor bulk and releasing tumor antigen to further stimulate immune activation. However, as CAR-T becomes safer and easier to administer, it may move forward to earlier lines of treatment.