Advanced-stage cHL: Rethinking Our Options in Frontline Therapy
Jonathon B. Cohen, MD, MS
Hematology and Medical Oncology
Emory University School of Medicine
Can you provide a brief description of current therapeutic options for use in the frontline setting to treat patients with advanced-stage cHL?
Patients diagnosed with cHL most frequently present with advanced-stage disease, and most of these individuals are candidates for treatment with combination chemotherapy. In the majority of cases, patients will be cured with currently available therapies, but it’s important to remember a large part of our job is to identify and manage long-term toxicities when developing treatment strategies.
For several years, the standard approach to treating advanced-stage cHL has been to use a four-drug chemotherapy regimen consisting of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) because it has been associated with long-term remission in approximately 75% of patients with advanced-stage disease.1 However, ABVD has both short- and long-term toxicities. The bleomycin component of ABVD is of particular concern because it has been associated with life-altering, lifelong lung toxicity. This can be especially problematic for younger patients because it can impair exercise tolerance and reduce ambulation due to breathing issues. These issues can persist for the remainder of patients’ lives, even if they are cured of their lymphoma.
Over the last few years, efforts have been made to improve outcomes for advanced-stage cHL patients by limiting some of the longer-term toxicities. Two approaches have emerged at the forefront of these efforts. The first approach involves eliminating bleomycin entirely, substituting it with brentuximab vedotin, a CD30-directed antibody-drug conjugate. The other strategy is to use standard ABVD, but also perform PET/CT after 2 cycles. Those with a negative PET/CT can discontinue bleomycin and receive just doxorubicin, vinblastine, and dacarbazine (AVD) for the remaining 4 cycles of treatment. Both of these approaches have benefits and downsides that must be balanced in each patient.
Based on currently available options for upfront advanced-stage cHL treatment, how should community oncologists approach the selection of the right drug for the right patient?
When selecting treatment, community oncologists must take an individualized approach and consider patient preferences so that they choose the best option that fits the patient’s lifestyle. If there are risks for toxicity from frontline ABVD treatment, patients should be considered for brentuximab vedotin. The ECHELON-1 trial showed that brentuximab vedotin plus AVD as a frontline chemotherapy regimen for previously untreated advanced-stage cHL can improve outcomes when compared with standard ABVD.2
It should be noted that there has been some confusion with interpreting data from the ECHELON-1 trial because the primary endpoint was “modified” progression-free survival (PFS) versus a typical PFS endpoint. This is because the study included patients who required additional therapy (e.g., radiation) after chemotherapy due to presumed residual disease. Regardless of the PFS endpoint, the net result is there is a likely modest benefit to using brentuximab vedotin over ABVD, and this is especially true for patients who cannot tolerate frontline ABVD therapy.
When evaluating patients with advanced-stage cHL, it’s also important to determine if there is any underlying lung disease, if patients are active smokers, and if they have high-risk cHL. For patients with these characteristics, brentuximab vedotin plus AVD may be preferred to ABVD. However, for those with lower-risk disease and those at risk for neuropathy, brentuximab vedotin may not be tolerable. These patients may benefit from the approach taken in the RATHL study, which demonstrated that a PET-directed approach could be used to guide treatment. In RATHL, patients with negative PET scans could eliminate the bleomycin component from ABVD to reduce pulmonary toxicity while not sacrificing overall efficacy.3 Patients with positive PET scans after 2 cycles would then be escalated to a bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimen.
Importantly, the response adapted therapy approach used in RATHL relies on having a nuclear medicine physician available to accurately interpret PET scans and assign a Deauville score to guide treatment. If community oncologists plan to embark on a PET-directed approach, they should be prepared to escalate to BEACOPP. It’s also important for community oncologists to be comfortable interpreting data from PET scans and prepared to act upon this information when selecting a specific treatment regimen.
What factors should be considered when community oncologists are managing older advanced-stage cHL patients or those with many comorbidities?
The ECHELON-1 study revealed that brentuximab vedotin plus AVD does not appear to result in a significant improvement over ABVD as treatment for older advanced-stage cHL patients and those with multiple comorbidities. In general, these patients tend to have difficulties with tolerating both regimens, highlighting the need to consider individualized treatment approaches. For those who are not deemed candidates for these regimens, several studies are exploring novel therapies. Options that appear to be particularly encouraging include using brentuximab vedotin alone4 or in combination with bendamustine.5 Other ongoing studies are looking at brentuximab vedotin plus nivolumab for patients who cannot tolerate other combination therapies.6 These options and others are available for various types of patients with advanced-stage cHL in the setting of a clinical trial.
All patients with untreated advanced-stage cHL should be considered for enrollment in a clinical trial, a recommendation that is endorsed in current guidelines.7 In particular, elderly patients and those with many comorbidities should be seen as clinical trial candidates because there is no current accepted standard of care for these individuals. Historically, these patients have had inferior results with treatment and are at higher risk for toxicity. Any patient older than 60 years of age should be viewed as an ideal candidate for clinical trials looking at new or tailored approaches to treatment. Beyond finding a cure, another big challenge in advanced-stage cHL is determining if patients are being exposed to unnecessary long-term toxicities from the amount of therapy they received. Investigators are actively seeking ways to limit the amount of chemotherapy, especially in newly diagnosed patients.
Which emerging frontline therapies are being investigated as treatment for advanced-stage cHL, and what caveats should be considered when using these treatments?
An interesting area of development for managing advanced-stage cHL is the potential utility of programmed cell death protein 1 (PD-1) antibodies, such as nivolumab and pembrolizumab. These agents are already FDA-approved for relapsed/refractory cHL, but they are also being evaluated as frontline treatment in combination with chemotherapy or brentuximab vedotin. There’s hope that brentuximab vedotin plus a PD-1 antibody-based treatment can be used as induction therapy in the future, and these combinations are already being investigated in the frontline setting for elderly patients.8
What strategies can help community oncologists address common concerns from patients who are newly diagnosed with advanced-stage cHL?
Many patients with advanced-stage cHL are younger individuals who may be college students or just starting their careers or families. A chief concern among these patients is future fertility, but this topic often falls to the backburner because these individuals may focus on starting treatment quickly or feel apprehension about freely discussing the issue, even though it weighs on their minds. Community oncologists should proactively discuss fertility concerns with patients and be prepared to address how treatment may affect future fertility. We have a long track record showing that ABVD recipients can still conceive children naturally after receiving this therapy, and the same appears to be true with brentuximab vedotin plus AVD. However, since there are no guarantees of future fertility, community oncologists should refer interested patients to speak with fertility specialists.
Patients who are newly diagnosed with advanced-stage cHL are often educated on their treatment options, but they may struggle with deciding on the approach that will work best for them. In most cases, patients want to play a role in decision making, but they will still rely on their healthcare provider when making treatment choices. This places the onus on community oncologists to discuss treatment options thoroughly and address concerns about any potential side effect. Clinicians need to be confident with their therapy recommendations and should be prepared to describe what patients can expect throughout their treatment. The good news is most patients who do achieve remission will be able to tolerate therapy, but the key is to ask questions on what they care about most and address all concerns prior to initiating treatment.
- Shanbhag S, Ambinder RF. Hodgkin lymphoma: A review and update on recent progress.CA Cancer J Clin. 2018;68:116‐132. Available at: https://onlinelibrary.wiley.com/doi/full/10.3322/caac.21438. Accessed September 26, 2018.
- Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378:331-344. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819601/. Accessed September 26, 2018.
- Johnson P, Federico M, Kirkwood A, et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med. 2016; 374:2419-2429. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa1510093. Accessed September 26, 2018.
- Forero-Torres A, Holkova B, Goldschmidt J, et al. Phase 2 study of frontline brentuximab vedotin monotherapy in Hodgkin lymphoma patients aged 60 years and older. Blood. 2015;126:2798-2804. Available at: http://www.bloodjournal.org/content/126/26/2798. Accessed September 26, 2018.
- LaCasce A, Bociek G, Matous J, et al. Brentuximab vedotin in combination with bendamustine for patients with Hodgkin lymphoma who are relapsed or refractory after frontline therapy. Blood. 2014;124:293. Available at: http://www.bloodjournal.org/content/124/21/293. Accessed September 26, 2018.
- Herrera AF, Moskowitz AJ, Bartlett NL, et al. Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2018;131:1183-1194. Available at: http://www.bloodjournal.org/content/bloodjournal/early/2017/12/07/blood-2017-10-811224.full.pdf. Accessed September 26, 2018.
- National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Hodgkin Lymphoma. Version 3.2018. April 16, 2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed September 26, 2018.
- Wang Y, Nowakowski1 GS, Wang ML, Ansell SM. Advances in CD30- and PD-1-targeted therapies for classical Hodgkin lymphoma. J Hematol Oncol. 2018;11:57. Available at: https://jhoonline.biomedcentral.com/track/pdf/10.1186/s13045-018-0601-9. Accessed September 26, 2018.