Jacqueline Barrientos 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 Hodgkin lymphoma (HL) or any other lymphoproliferative disorder, I start with the basics. I first discuss how this is a condition affecting the blood and as such, the staging criteria and management differ significantly from what the patient may perceive is a more traditional way to deal with common cancers — whereas solid cancers may require surgical intervention, the majority of patients with blood disorders don’t. The hematologist chooses the best treatment based on the patient’s characteristics, which include age, performance status, clinical staging, and laboratory results to determine the optimal therapy. There is no “one-size-fits-all [approach],” as some patients may benefit from more intensive regimens, combined modalities (chemotherapy and radiation). The length of the therapy and the intensity also depend on the patient’s ongoing clinical response and tolerability to the regimen.

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

At present, ctDNA is not a substitute for tissue biopsy for a lymphoma diagnosis, but it can be helpful in situations where accessing the tissue may be difficult. Additionally, our current guidelines recommend determining interim response to therapy with [positron emission tomography/computerized tomography] PET/CT imaging to escalate or deescalate the treatment regimens. PET imaging has limitations, including false-positive and false-negative results that could lead to repeat tissue biopsies, or could miss an early relapse before the onset of radiologically detectable disease. Therefore, novel methods for early detection of relapse and real-time monitoring are needed to improve surveillance strategies, and, in the case of a relapse, to better profile the heterogeneity of the malignant clone.

This is where the technology of ctDNA could help — in patients with a “negative” PET, ctDNA could help interpret whether the result is accurate. More importantly, by genotyping ctDNA through cancer personalized profiling by deep sequencing (CAPP-Seq), we could have the ability to identify biological factors that are mutational drivers of the disease. A recent paper by Davide Rossi and colleagues reported treatment-related clonal evolution in patients with relapsed/refractory classic HL (cHL).1 At present, most of the data we have are from retrospective studies taken periodically from patients as they completed routine treatment, so it is not real-time evaluation. In order to move ctDNA testing from bench research into standard clinical practice, we still need to prove that in doing so, we can change the patient’s outcomes. I do think that in the future, we will incorporate ctDNA testing as a biomarker [to help] determine the patient’s prognosis and change the patient’s outcomes for the better.

Question

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

Answer

Natural killer (NK) cell effector functions are tightly controlled by the balance between inhibitory and activating signals. A potent tumor microenvironment (TME) of immunosuppressive nature in cHL inhibits NK cell proliferation and function, which contributes to various tumor immune-escape mechanisms. Hence, cHL cells induce a quantitative and qualitative NK cell deficiency. NK cell cytotoxicity is significantly diminished at cHL diagnosis, independent of clinical stage. This functional deficiency of NK cells is reversible and can normalize after completion of therapy. This understanding helped to develop the use of PD-1 immunotherapy, as these inhibitors enable the reactivation of dormant and tumor-tolerant immune cells. In addition to PD-1 inhibitors, several other molecules targeting NK cell reactivation are currently under investigation.

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 results with immune checkpoint blockade in cHL have been exciting, with dramatic responses seen in relapsed/refractory disease, but further research is needed into combination strategies. More importantly, we need to evaluate the introduction of this therapeutic strategy into earlier lines of therapy — will this lead to better outcomes? I am excited for an ongoing trial that is currently accruing for newly diagnosed patients with early-stage cHL. This trial incorporates brentuximab vedotin and nivolumab following an initial 2 lead-in cycles of ABVD (ClinicalTrials.gov Identifier: NCT03712202). In addition to testing these agents in combination in the frontline setting, the trial is also evaluating the role of novel biomarkers — it evaluates: 1) if a baseline antitumor immune response, as assessed by a Nanostring gene panel, correlates with progression-free survival (PFS), and 2) if the role of minimal residual disease status, as monitored by CAPP-Seq of ctDNA, can be correlated with PFS.

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

Autoimmune disorders have been associated with an increased risk of malignant lymphomas. This link between autoimmune diseases and lymphomas has been validated by several population-based studies, though the precise mechanism of lymphomagenesis in autoimmune disease is not yet elucidated. Observational studies indicate that lymphoma can develop in individuals with immune dysregulation and/or those taking immunosuppressive drugs for other conditions. At present, it is not known whether the clinical course of lymphomas arising in the setting of autoimmune conditions is different from that of lymphomas occurring in the general population. Moreover, additional research is needed to definitively state whether immunotherapy contributes to lymphoma risk or if it alters the clinical course of malignant lymphomas in patients with an autoimmune diagnosis.

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

I think the field is changing quite rapidly due to the exponential growth in our knowledge of underlying mechanisms of disease. By identifying dysregulated pathways of proliferation and survival of the malignant clone (and with that discovering novel targets), we can treat non-Hodgkin lymphoma and T-cell lymphomas with more precision — meaning, achieving similar outcomes expected from the use of traditional chemoimmunotherapeutic approaches, but without the severity and frequency of toxicities expected from older compounds. We are already seeing that in certain blood disorders such as chronic myeloid leukemia, chronic lymphocytic leukemia, and multiple myeloma, chemotherapy is no longer the standard frontline therapy; rather, the use of targeted/biological agents [is], so I anticipate the same trend to occur in other lymphoproliferative disorders.