Treating Advanced HL in 2019
Sarah Rutherford, MD
Assistant Professor of Medicine
Division of Hematology/Oncology
Weill Cornell Medicine
New York, New York
For many years, a cytotoxic chemotherapy combination was often the sole treatment approach of choice for patients with newly diagnosed, advanced stage classical Hodgkin lymphoma. What are some of the benefits and limitations of that approach?
The standard cytotoxic therapy used for advanced-stage Hodgkin lymphoma in the United States is ABVD, or doxorubicin, bleomycin, vinblastine, and dacarbazine. The cure rates are quite high with this regimen, and it is generally well-tolerated, with predictable side effects that include decrease in blood counts, and particularly, neutrophil count. Despite that, we are generally able to get patients through treatment, particularly the younger patients, without having any significant infectious issues. It does also have some nausea associated with it, but with anti-nausea medication, that is usually tolerated without any significant impact on being able to administer the regimen. Many of our patients are of the age that they may be thinking of having children, so the other really key part of this regimen is that it has a minimal impact on fertility compared to the BEACOPP regimen used more often in Europe. I think that academic and community oncologists have become very comfortable with ABVD. It has been used for many years and generally has been well-tolerated.
On the other hand, ABVD is associated with cardiac toxicity and lung toxicity, which we monitor for very closely. In particular, bleomycin does have a relatively low but real risk of pulmonary toxicity. In the worst cases, patients could die from this—and these are often young, otherwise healthy people who very likely would have been cured by this regimen. Getting bleomycin out of the regimen is key to minimizing pulmonary toxicity. Johnson, et al., recently demonstrated that, after negative interim positron emission tomography (PET) findings, bleomycin could be omitted from the ABVD regimen in advanced-stage HL patients, reducing incidence of pulmonary toxic effects without significantly lowering efficacy.1 Based on those findings, I think many oncologists feel comfortable dropping the bleomycin, and giving AVD, if the PET scan after 2 cycles is negative.
While I have mainly been talking about the younger population, Hodgkin lymphoma certainly is noted to have a bimodal age distribution. For patients in their 60s, 70s, and 80s, ABVD is much less well-tolerated than in the younger population, often because of comorbidities—for example, they may not able to tolerate bleomycin or doxorubicin, the latter of which can cause cardiotoxicity. The older population is also more likely to have infectious complications. We do still use ABVD or modifications of it in some older patients, but that group, in particular, can be tenuous and this can impact our treatment.
The other limitation is that ABVD administration is a lengthy process. For advanced-stage Hodgkin lymphoma, it is typically given every other week for 6 months. Patients may not be able to work regularly during this time, and that can have a financial impact, especially in younger patients who are typically working full-time jobs.
How have treatment options changed with the recent approval of CD30-directed therapy in the setting of newly diagnosed Hodgkin lymphoma?
Brentuximab vedotin is an antibody-drug conjugate targeted to CD30, a protein expressed on the surface of Hodgkin lymphoma cells. Many of us are familiar with this treatment in other settings, as it was originally approved for treatment after autologous stem cell transplant (ASCT) or after two prior chemotherapy treatments.2 There are other data supporting its use as a single agent and in combination with chemotherapy, and recently there was a regimen of brentuximab with bendamustine chemotherapy that had some promising results in a trial published last year.3
Brentuximab vedotin is generally very well-tolerated, particularly when given as a single agent, though one common side effect is neuropathy.4 That is something that we have to be cautious of, particularly in people who have already received chemotherapy before. It can be a dose-limiting side effect. Other potential issues include some gastrointestinal side effects such as diarrhea.
The use of brentuximab vedotin with chemotherapy was studied in patients with previously untreated stage III or IV Hodgkin lymphoma in ECHELON-1, an open-label, multicenter, randomized phase 3 clinical trial.5 A total of 664 patients were assigned to receive brentuximab plus AVD, while 670 received ABVD. A primary endpoint called modified progression-free survival (PFS) was used, which included not only the time to progression or death, but also noncomplete response and subsequent anticancer therapy use.
With median follow-up of 24.6 months, the brentuximab plus AVD arm had superior modified PFS versus ABVD. The 2-year rate of modified PFS was 82.1% for brentuximab plus AVD, and 77.2% for ABVD, with a hazard ratio of progression, death, or modified progression of 0.77 (95% CI, 0.60-0.98; P = .04). Based on this difference, the FDA recently approved brentuximab vedotin for frontline use with AVD chemotherapy.6
Overall survival was a key secondary endpoint of ECHELON-1. It would be wonderful if every trial could have overall survival as the primary endpoint, but unfortunately, it’s not always feasible, particularly in a disease where the overall survival is very high, and it would take a long time to see a significant difference between arms. In this trial, the hazard ratio for interim overall survival was 0.73 (95% CI, 0.45-1.18; P = .20).
While this data is compelling, and I do think there are certain patients who can benefit from brentuximab plus AVD and some reasons why we may use it over ABVD, I think it is important to note there has been some controversy about the modified PFS endpoint, and not all oncologists at this time accept this regimen in newly diagnosed advanced-stage HL patients. There are certainly some reasons why ABVD still may be better for some patients.
I think this is something to follow over time, as more data emerge and we become more familiar with administering this regimen. I also want to note that there is a cooperative group clinical trial in the final stages of planning that will be evaluating brentuximab vedotin plus AVD versus the PD-1 inhibitor nivolumab plus AVD. This study does not even include ABVD as one of the options. I think it will really help to get us more information about the brentuximab plus AVD regimen in addition to the novel combination of nivolumab plus AVD.
Based on these data, how would you choose between ABVD and brentuximab plus AVD?
What I take away from ECHELON-1 is that the subgroups that benefited the most from this regimen were North American patients, and those with particularly high-risk features, such as those with one or more extranodal sites, an International Prognostic Score (IPS) of 4 to 7, and stage IV disease.5 Male patients also did seem to do better with this regimen, as did those patients who were less than 60 years old. So I think, certainly, a patient that meets several of these criteria is someone who I would consider for the brentuximab vedotin plus AVD regimen.
The rate of pulmonary toxicity in ECHELON-1 was clearly lower in the group that did not get bleomycin. Those receiving ABVD had a 3% rate of grade 3 or higher pulmonary toxicity, versus just 1% in the brentuximab plus AVD group. I think if you had a patient with baseline problems with lung disease, and I actually had a patient that fit this category recently, then it would be appropriate to minimize the risk of having problems related to bleomycin by simply withdrawing it from the regimen and substituting it with BV.
As I noted before, peripheral neuropathy is one of the most common side effects associated with brentuximab vedotin, though many of these cases will resolve over time after the drug has stopped. In ECHELON-1, peripheral neuropathy occurred more often in the brentuximab plus AVD arm versus the ABVD arm. That is something else to keep in mind: If someone has a lot of peripheral neuropathy going into the regimen, you may prefer to treat them with ABVD rather than put them on this newer regimen.
Let’s switch gears and talk about relapsed or refractory Hodgkin lymphoma. What are the current challenges associated with patients beyond first-line therapy?
Although cure rates are high in Hodgkin lymphoma, about 5% to 10% of patients are refractory to first-line therapy, and 10% to 30% of patients will relapse after achieving a complete response.7 The big-picture approach would be that the patient gets a second-line therapy, and then once they get into a complete response, we would follow-up with an ASCT. This has significant toxicity associated with it due to the additional high-dose chemotherapy, and can significantly impact fertility, so I strongly advocate for patients to see a fertility specialist, even before they get an ABVD or brentuximab-AVD regimen, because I know that it is possible that they may need to get a transplant later.
Another big challenge with relapsed or refractory Hodgkin lymphoma is that there is not really a standard second-line regimen. This is a good thing, as it means that you can really tailor the treatment to your patient, but it also can be overwhelming to know that there are so many regimens out there.
The most standard treatment would be ICE, or ifosfamide, carboplatin and etoposide, which can have substantial toxicities, and another potential regimen is DHAP (dexamethasone, cytarabine, and cisplatin) that has similar side effects. In recent years, there have been attempts to develop outpatient chemotherapy regimens for these patients that may be less toxic, and there is brentuximab vedotin, as I mentioned before.
The complete response rate for brentuximab vedotin is around 30% when it is used as a single agent, so some institutions would use a regimen with a higher complete response rate from the beginning in relapsed/refractory patients, while others may give that drug first to see if they are able to get the patient into a complete response without needing additional therapy, and as I mentioned, there is data to support some chemotherapy regimens that include brentuximab vedotin.
What results do you anticipate from clinical trials in the near future with the potential to change clinical practice?
An interesting trial was recently published on brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma.8 The interim results that were reported were promising, and we anticipate additional final results in the future. In general, it has been really exciting to see the data emerging in the last few years on checkpoint inhibitors, nivolumab and pembrolizumab, that have been approved in Hodgkin lymphoma, because it really has enabled patients to be exposed to a completely novel therapy that is not chemotherapy related at all.9,10
There are so many options now available now for these patients, and there will be more that will be developed. The next 10-15 years will be a very interesting time for the treatment of Hodgkin lymphoma, as it has been over the last 10 years. With all these new therapies, hopefully, we are going to be able to take out some of the chemotherapy agents altogether that we worry about, such as bleomycin, and ideally, the cure rates will be higher with novel therapies, so that we have less people in the relapsed and refractory setting.
- 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(25):2419-2429. doi: 10.1056/NEJMoa1510093.
- American Society of Hematology. FDA Grants Accelerated Approval to Brentuximab Vedotin for Two Indications. Published August 19, 2011. https://www.hematology.org/Clinicians/Drugs/FDA/766.aspx. Accessed May 16, 2019.
- LaCasce AS, Bociek RG, Sawas A, et al. Brentuximab vedotin plus bendamustine: A highly active first salvage regimen for relapsed or refractory Hodgkin lymphoma. Blood. 2018;132(1):40-48. doi: 10.1182/blood-2017-11-815183.
- Ansell SM. Brentuximab vedotin. Blood. 2014;124(22):3197-3200. doi: 10.1182/blood-2014-06-537514.
- Connors JM, Jurczak W, Straus DJ, et al. Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma. N Engl J Med. 2018;378(4):331-344. doi: 10.1056/NEJMoa1708984.
- U.S. Food and Drug Administration. FDA expands approval of Adcetris for first-line treatment of Stage III or IV classical Hodgkin lymphoma in combination with chemotherapy. https://www.fda.gov/news-events/press-announcements/fda-expands-approval-adcetris-first-line-treatment-stage-iii-or-iv-classical-hodgkin-lymphoma. Accessed May 22, 2019.
- Cavalli FG. Hodgkin’s disease: Treatment of relapsed disease. Ann Oncol. 2002;13(suppl 4):159-162. doi:10.1093/annonc/mdf654
- 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(11):1183-1194. doi:10.1182/blood-2017-10-811224.
- U.S. Food and Drug Administration. Nivolumab (Opdivo) for Hodgkin Lymphoma. https://www.fda.gov/drugs/resources-information-approved-drugs/nivolumab-opdivo-hodgkin-lymphoma. Accessed May 22, 2019.
- U.S. Food and Drug Administration. Pembrolizumab (KEYTRUDA) for classical Hodgkin lymphoma. https://www.fda.gov/drugs/resources-information-approved-drugs/pembrolizumab-keytruda-classical-hodgkin-lymphoma. Accessed May 22, 2019.