What are the key risk stratification strategies for community oncologists to consider when managing patients with newly diagnosed Hodgkin lymphoma?

Risk stratification is an important step in the management of patients with newly diagnosed Hodgkin lymphoma (HL) because it will guide the selection of appropriate therapy. One of the most important risk stratification factors to consider is if patients have early or advanced disease at presentation. Currently, there is no universal prognostic system for patients with early-stage HL.1 The dose of radiation and number of chemotherapy cycles will vary depending on several factors, including disease bulk, which has varying definitions. Many groups define bulky disease as any mass that is >10 cm in size as the cutoff value, but better results may be possible using a cutoff of ≥7 cm. Patients with bulky masses generally benefit from more cycles of chemotherapy and consolidative radiation. However, the role of radiation in early-stage disease is still being explored due to its long-term associated toxicities.1

For patients with advanced-stage HL, the International Prognostic Score (IPS) can be considered when determining the most appropriate treatment. The IPS considers many factors, including age, sex, disease stage, and laboratory variables. Patients with many risk factors may require more aggressive treatment. Most patients with advanced-stage newly diagnosed HL will be started on a chemotherapy regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), regardless of their number of risk factors. Recently, multiple groups have shown that PET scans after 2 cycles of ABVD is predictive of outcome.2-4 In fact, a PET scan after 2 cycles of ABVD was found to overcome the prognostic significance of the IPS score. Thus, starting treatment with ABVD and then adjusting therapy based upon the PET scan result after 2 cycles of ABVD is a reasonable approach for patients with advanced-stage disease.

What has recent literature shown regarding the efficacy and safety of currently available treatments for newly diagnosed Hodgkin lymphoma?

The RATHL study provides important data for the management of advanced-stage newly diagnosed HL.5 Participants in RATHL underwent a baseline PET-CT scan, received 2 cycles of ABVD, and then underwent an interim PET-CT scan. Those with negative PET findings after 2 ABVD cycles were randomly assigned to continue this chemotherapy regimen or omit bleomycin, thus creating an AVD group, in cycles 3 through 6. Results showed that patients with negative PET scans after 2 cycles of ABVD could safely eliminate bleomycin for cycles 3 through 6. This is desirable given that bleomycin is associated with pulmonary toxicity. Patients in RATHL with positive PET findings after 2 cycles had their treatment escalated to include a chemotherapy regimen of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP). Patients escalating to BEACOPP had slightly more favorable outcomes than what has historically been seen among individuals who were PET-positive after 2 ABVD cycles and then continued with ABVD.5

The findings from RATHL are encouraging, but treatments other than escalated BEACOPP are preferred due to its considerable toxicity. In 2018, the FDA expanded its approval for brentuximab vedotin to treat patients with previously untreated stage III or IV classical HL in combination with AVD.6 Recently, the ECHELON-1 study explored brentuximab vedotin plus AVD in patients with advanced-stage newly diagnosed HL.7 This trial found that progression-free survival was slightly higher in patients treated with brentuximab vedotin plus AVD than for those receiving 6 cycles of ABVD. Toxicity with brentuximab vedotin plus AVD was higher than that of ABVD so there is still room for improvement, but these data demonstrated that this combination represents an advance in the treatment of advanced-stage HL.

In what situations would you consider treatment with brentuximab vedotin plus AVD instead of ABVD for newly diagnosed advanced-stage Hodgkin lymphoma?

I consider using brentuximab vedotin plus AVD as frontline therapy for advanced-stage patients who have several poor prognostic factors. Male patients and those with risk factors, such as stage IV disease and/or B symptoms, appear to benefit more from brentuximab vedotin plus AVD than other patients. Outside a clinical trial, I therefore consider brentuximab vedotin plus AVD for patients with four or more IPS risk factors. This treatment could also be considered if there is a desire to avoid bleomycin due to its associated toxicity, particularly for those with underlying lung disease and those older than 60 years.

With regard to patients older than 60, improved tolerability may be seen with administering brentuximab vedotin sequentially with AVD, as was done in a phase 2 study recently presented at the American Society of Hematology (ASH) 2017 annual meeting.8 Participants were started on brentuximab vedotin monotherapy and then received 6 cycles of AVD chemotherapy, followed by a few additional cycles of brentuximab vedotin monotherapy. Outcomes for these patients were excellent. Considering these data, clinicians could consider using brentuximab vedotin and AVD sequentially rather than concurrently for patients age 60 and older.

What other studies should community oncologists be aware of regarding emerging treatments for newly diagnosed Hodgkin lymphoma?

Many investigations are currently exploring various treatment combinations for patients with early- and advanced-stage HL in the upfront setting. For early-stage disease, several trials are evaluating upfront chemotherapy using brentuximab vedotin plus AVD with hopes of reducing the need for radiation therapy.9,10 In one such study, patients with bulky disease (defined as masses of ≥7 cm) are receiving either varying amounts of radiation (standard, reduced, or reduced field) or no radiation, depending upon their cohort. Historically, these patients have benefited from radiation, but the hope is to find a way to combine brentuximab vedotin plus AVD in a way that will help eliminate radiation altogether.

Checkpoint inhibitors have already demonstrated efficacy in relapsed and refractory HL, and they are now being explored at in the frontline setting for patients with newly diagnosed HL. Cohort D of the Checkmate-205 study assessed nivolumab plus AVD in the frontline setting. Results from this study were presented at the 2017 ASH annual meeting and showed that this combination was well-tolerated in patients with newly diagnosed, untreated, advanced-stage classical HL.12 At Memorial Sloan Kettering Cancer Center, we are leading a phase 2 trial assessing ABVD and nivolumab in the frontline setting for advanced disease using a PET-adapted approach.11 In this study, patients younger than 60 receive ABVD and those with a positive PET scan after 2 cycles are being switched to AVD plus nivolumab. The primary goal of this study is to determine whether changing treatment to nivolumab plus AVD will improve outcomes for patients who remain PET-positive after 2 cycles of ABVD.

What factors are important to consider when individualizing treatment for patients with newly diagnosed Hodgkin lymphoma?

When designing treatment for patients with early-stage HL, age and sex are important considerations. A chief concern when managing these individuals, particularly women younger than age 35, is the risk for potential secondary problems from radiation. Ideally, we want to avoid radiation to the mediastinum because of concerns for secondary breast cancer. Clinicians must weigh the risks and benefits of radiation therapy for patients with early-stage disease.

For younger patients presenting with early-stage disease, treatment options include full course chemotherapy with 6 cycles of ABVD or a PET-adapted approach. Several studies—including the RAPID trial, the H10 study from the EORTC, and the SWOG study—have looked at PET-adapted approaches that eliminate radiation therapy for patients who are PET-negative during treatment.13-15 These studies observed a slightly lower cure rate with frontline therapy when radiation was eliminated, but overall survival was similar because many patients could be cured with second-line therapy.

Clinicians should discuss the potential need for second-line therapy with patients when using PET-adapted approaches. Doing everything possible to cure the disease with frontline treatment and avoiding second-line therapy may be more valuable to some patients than the potential long-term risks of treatment. Given the lower concern for long-term risks for older patients, radiation therapy should be considered part of their treatment, but clinicians should still discuss its risks and benefits.

What treatment-related adverse events should community oncologists be aware of when managing patients with newly diagnosed Hodgkin lymphoma?

Most oncologists are comfortable with prescribing standard ABVD because there is low concern for treatment-related adverse events, such as fluctuating blood counts and neutropenia. When using brentuximab vedotin plus AVD in the frontline setting, patients will require treatment with growth factor due to higher risk of neutropenic fever observed with this regimen. Escalated BEACOPP comes with several risks for treatment-related adverse events, including higher rates of neutropenic fever, cytopenias, and need for transfusions, as well as increased risks for infertility and secondary malignancies. With checkpoint inhibitors, clinicians should be cognizant of the varying degree of unique immune-mediated toxicities associated with these agents, especially in early-stage disease.

What key takeaways should community oncologists remember when taking steps to individualize treatment for patients with newly diagnosed Hodgkin lymphoma?

Each patient with newly diagnosed HL is unique and will require individualized treatment to optimize outcomes. For early-stage disease, several factors should be considered before proceeding with radiation or using a PET adapted approach, especially age and sex. Radiation therapy may be avoidable in some cases, but clinicians need to discuss the risks and benefits of this approach to ensure that treatment decisions are made collaboratively. For advanced-stage HL, using interim PET scans during treatment can guide therapy and may improve outcomes.