Expert Discusses Treatment With BV+AVD Regimen in a Classic Hodgkin Lymphoma Case Study

Jonathon B. Cohen, MD, MS

Jonathon B. Cohen, MD, MS

Jonathon B. Cohen, MD, MS, explained to a group of physicians in a recentTargeted Oncologylive case-based peer perspectives presentation the diagnostic workup and treatment considerations and decisions he makes when seeing a patient with Hodgkin lymphoma in the clinic. Cohen, an assistant professor of hematology and medical oncology at Emory University School of Medicine and medical director of infusion services at the Winship Cancer Institute of Emory University, discussed treatment options in relation to a case scenario of a patient with classic Hodgkin lymphoma (cHL).

Case

A 22-year-old women presented with right-sided cervical nodes developing over several months. She was initially evaluated by her obstetrician-gynecologist, who recommended observation. She subsequently developed neck pain while drinking wine. She was referred for lymph node biopsy. Test results confirmed that she had cHL.

She had no medical or surgical history. Her only regular medication was oral contraceptives; she had no known drug allergies. She had no history of tobacco use but had occasionally drank alcoholic beverages. She was a division 1 collegiate swimmer. Her family history of cancer diagnoses included a maternal grandfather with squamous cell cancer, maternal grandmother with melanoma, and an aunt with breast cancer. She had 2 healthy siblings.

Laboratory findings were notable for a white blood cell (WBC) count of 19.8 × 10⁹/L (85%polymorphonuclear cell count); hemoglobin, 12.0 g/dL; platelets, 571,000 mcL; erythrocyte sedimentation rate, 30 mm/hr; creatinine, 0.76 mg/dL; albumin, 4.2 g/dL. She was negative for HIV/hepatitis.

PET/CT staging showed intrathoracic diffuse adenopathy; right-sided cervical nodes, 2.3 × 1.9 (standardized uptake value [SUV], 9.3); left-sided cervical nodes, 2.2 × 1.8 (SUV, 8.8); anterior mediastinum, 4.8 × 2.9 (SUV, 21.3); right-sided axillary, 2.8 × 2.8 (SUV, 12.2); spleen normal size (SUV, 2.9); diffuse uptake in the axial skeleton (SUV, 4.9-5.5); mediastinum, SUV 1.8; liver, SUV 2.4. She received a pathologicdiagnosis of nodular sclerosis cHL.

Per immunohistochemistry (IHC), the Hodgkin cells expressed CD30, CD15, and PAX5 (weak), and were negative for CD3, CD20, and CD45.

What is the prognosis for this patient?

Her labs showed a leukocytosis, an elevated platelet count, and then she had a staging PET/CT that showed some diffuse adenopathy. There was some diffuse uptake in the axial skeleton; not necessarily a lot of local findings but some increased uptake. You can see she had a number of areas, including in the mediastinal, that were highly¹⁸F-FDG [fludeoxyglucose] avid. The pathology review came back as nodule sclerosis cHL with a fairly classic IHC report.

Do you typically calculate a prognostic score for each patient?

Although I often consider what the prognostic score may be, depending on the situation with the patient and how in depth they want to get with their own prognosis, it does not necessarily markedly affect my treatment decision.

There is an international prognostic score for Hodgkin lymphoma that can be used.¹Sometimes I will have patients that have come and have researched it themselves or will have more specific questions about it. Because it does not typically influence the treatment decision that I make, I do not dwell on it when I am talking with the patient.

How do the results of the PET/CT affect treatment selection in this patient? What disease stage is this patient in?

This is someone who presented with advanced-stage cHL. [She is a] young, healthy person, so she can really have any potential therapy that you would think about.

This is an unusual case because you have this bony uptake. It is unclear whether there is marrow involvement versus bone involvement or whether it was anything at all—in this particular case, someone who has not been on growth factor and has not had some other indication for why they have uptake and has other signs of advanced stage disease. You do not want to necessarily do a biopsy in that case because this is a patient who has fairly diffuse adenopathy, so you are treating them as an advanced stage case.

Similarly, at least for me, I do not always get a bone marrow biopsy for patients with Hodgkin lymphoma because it is not commonly involved, and it does not make a big difference in the treatment. When I look at this, I would probably consider this patient as a stage IV. Someone else could look at it and say, “Maybe there is uptake for unclear reasons; maybe it is a stage III,” but I would consider them either a stage III or IVa.

Would you do a bone marrow biopsy based on what was shown on the PET/CT?

This is somebody that could technically be earlier stage, because you really do not think the axial skeleton is involved. I think in a case like this, especially with a young patient in the absence of some other clear indications for why it would be there, I would typically consider them to have bone involvement. But that would be a judgment call, and somebody could look at it and feel otherwise. In this case, it does not look like the patient has had that done. But in that specific scenario where you are thinking, “Is the PET scan showing some marrow involvement?” that [may determine] if I want to treat them as having early stage disease or not.

My personal sense is that for somebody who comes in with a fairly straightforward case, I do not think a bone marrow biopsy is typically required. In this case, if you were to see this situation and think, “I would like to get a marrow just to get a better sense of what is going on in the bones,” I think that would be reasonable here.

I have not traditionally done [an MRI of the spine] to confirm whether or not the patient has marrow involvement. Now, if you did that and you saw some convincing bone lesions, you could potentially then get by without doing the marrow. It is a tough call.

What are the systemic options in frontline therapy for this patient?

One of the big questions here, especially with the recent approval of brentuximab vedotin [Adcetris; BV] in the frontline, is whether you would use BV plus doxorubicin, vinblastine, and dacarbazine [AVD], or would you use ABVD [doxorubicin, bleomycin, vinblastine, and dacarbazine], and how would you do it? If I were seeing this person, I would have these questions. I think that if you did not have a trial or they declined a trial, there are 2 good options. For most patients in this setting, we will try to avoid bleomycin if at all possible, given that she is an athlete and for whom even a subtle change in the respiratory system could significantly affect her quality of life and her activity. 

Case (continued):

The patient was treated with BV + AVD. An interim PET/CT scan showed a Deauville score of 3.

With a young patient such as this one, how do you handle the possible treatment-related impacts on her fertility?

For ABVD, there are pretty good data that would suggest that those patients will not have impaired fertility. There have been some cases of premature ovarian failure in women, so what I typically do is…have a discussion with them. If it is somebody who is in a position where having children in the future is important, I will refer them to a fertility specialist and will typically communicate to the specialist ahead of time that the incidence of infertility is low. It is always helpful for them to have that discussion.

Fortunately, most people treated with ABVD will have no problems and will conceive children naturally. In fact, with young people, I often spend a considerable amount of time in the room talking to them about the fact that you cannot rely on this as birth control. We have had patients that have gotten pregnant on treatment or shortly afterward. Fortunately, it does not happen that often, but it can happen. With ABVD, it is pretty clear that those patients will be fine. With BV + AVD, we do not have that same long-term data, but there is no indication that BV increases the risk of infertility.

If they can wait to see a fertility specialist and have a full evaluation and talk about options, I think that is always ideal. Then everyone feels comfortable with a chance to address that. In situations where people do not have the time or maybe they do not have the financial resources to go down that path, the data that have been pretty reassuring that they will be OK.

Discuss the role of the interim PET/CT results in patients taking BV + AVD.

This patient was treated with BV + AVD, and their interim PET/CT looks good with the Deauville score of 3. They tolerated the therapy well with GCSF support. One thing that is worth at least highlighting here is that initially when the ECHELON-1 study came out²—with ABVD we have a very clear understanding of the role of interim PET and what that means and potentially what you can do with an interim PET that is negative—its [role in BV+AVD] was not clear. We now have had some additional follow-up suggesting that patients that are PET negative at that interim time point are likely to do well. One of the concerns, though, especially with BV, is that there may be a little bit more incidence of false-positives with PET because maybe there is an immune response. And what they saw in the study is that even with those patients that were PET positive, especially those with a Deauville score of 4, many ended up doing well.

The role of interim PET with BV + AVD is a little bit less clear. If you get one and it is negative, you feel pretty good that it is negative. But if you get one and it is positive and it is a Deauville score of 4, but they otherwise seem to be responding, it does not necessarily mean those patients are destined to relapse. One could argue whether or not you should still get it in this setting. I usually still do. I think patients like to get some sort of feedback that things are going in the right direction. But I think if you decided to get one and it is equivocal, there are no data to support then escalating those patients to the BEACOPP [bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone] regimen. That has not really been studied with this regimen.

Discuss the efficacy results of the ECHELON-1 trial that led to the approval of BV + AVD.

I think one of the things that come up often is the question of the progression-free survival [PFS] endpoint. This has been one of the areas of criticism or question about this study. What the investigators were trying to do when they developed this endpoint was identify those patients who had a good response to therapy and did not necessarily progress, but at the end of treatment, you feel like they still had active disease. Those are folks that you may think about treating with radiation therapy or that you feel might need some other sort of treatment. They were trying to identify those patients that did not necessarily have a full response to their induction therapy. In reality, there was a fairly small number of those patients on this study.

What you can see here is that there is an increased rate of modified PFS for patients that received the BV + AVD as opposed to ABVD. The other thing that is important to recall here is that these are patients who received 6 cycles of ABVD. Currently, most people who are going to use it will end up using a PET-adapted approach, where you pull out the bleomycin, so another concern is whether or not this is comparing BV + AVD to what is the current standard. My personal bias is that pulling out the bleomycin of the ABVD is not any better than 6 cycles of ABVD. I still think that this provides a significant improvement an outcome. I think if a patient did not want to get it, they are still likely to do well. But I think this does provide an improvement in PFS.

Which patients on the trial had the best response to therapy?

On the study, they had an independent central review and investigator-assessed review, and you can see they were generally very similar. In the forest-plot analysis…the main thing that you can see is that, in pretty much all cases, there is evidence that the BV + AVD is favored over ABVD. The 1 area that I would point out is the group [of patients that are] a little bit older. The people that were >65 years did not seem to have an improvement. For patients that are >60 years, this can be a fairly challenging regimen to tolerate due to some of the cytopenias. It is not that I would not give it to someone >60 years, but I would typically look at those patients a little bit closer before I start them on therapy. Unfortunately, those patients also do not do as well with ABVD, both due to toxicity issues and because they often they do not respond quite as well. In most other settings, the BV + AVD was favored.

Looking at the responses in the intent-to-treat analysis, you could see that most patients—regardless of what regimen they were given—had a good response to therapy, maybe with a slight improvement with the BV + AVD, although I would not say it is markedly different. You can look at the Deauville scores and see that there was a small increase in the number of patients with a score of 2 or better. You can see the Deauville scores in both arm, and, fortunately, most patients had a Deauville score of 1 or 2 at the completion of cycle 2 of therapy.

Is it worth the risk of increased adverse events to administer BV + AVD?

There is an increased risk of peripheral neuropathy in patients who receive BV. Up to two-thirds of patients had peripheral neuropathy, and you can also see that there was an increased risk of more significant neutropenia. One of the issues that developed from the study was that initially, they did not require growth factor for all their patients. An amendment that was implemented required the use of growth factor. After that, a lot of these severe cases of severe neutropenia were significantly decreased. Most patients, especially with growth factor support, will tolerate the BV + AVD.

What is your approach toward toxicity-monitoring management for patients receiving first-line BV + AVD? Do you tend to use growth factor if you are going to administer it?

I have had some challenges getting growth factor support for this regimen. At least for the first couple of patients that I treated, I was able to get it, but I had to go through a phone call to insurance first. It did not just go through.

I am pretty comfortable treating patients with Neulasta Onpro [pegfilgrastim] on the day that they get treated. Technically, it gets administered 13 days prior to the next cycle. I tend to be OK with that. We have had a handful of people with WBC counts of 18 to 20 [× 10⁹/L] when they are ready for their next treatment, but in those cases, I am typically pretty comfortable proceeding. I know others have used Neupogen [filgrastim] for a short course in between cycles, although that can be challenging for the patient.

I think either way is reasonable; I just think it is good to have low thresholds. For ABVD, we used to have this sense that you would treat those patients on schedule regardless of neutrophil count. You do not give them pegfilgrastim because of the bleomycin toxicity, but there are definitely higher incidences of neutropenic fever with [BV + AVD] than there are with ABVD.

Is the recovery from neuropathy from BV + AVD relatively prolonged, like it was with ABVD?

With BV in general, I find that people who develop neuropathy often can take several months to recover. I have had some really bad experiences with people who were getting single-agent BV for relapsed Hodgkin lymphoma and ended up having nearly disabling neuropathy. I will often counsel patients that it will take several months. One of the challenges is that people will not want to come off therapy or they do not want a dose reduction. They keep it from [their physician] until they cannot drive or put on their shirt. By that point, it can take a really long time for them to get better.

Case (continued):

The patient tolerated treatment well with granulocyte colony-stimulating factor (GCSF).

What regimen would you use in a patient who is transplant eligible?

If I have somebody that is going to go to transplant— which is, fortunately, many of these young people—I will often still use ICE [ifosfamide, carboplatin, and etoposide]. There is another regimen called GVD [gemcitabine, vinorelbine, and doxorubicin hydrochloride liposome injection (Doxil)] that you can give as an outpatient, which is nice. But it is not clear whether any of them are necessarily better than the others. BV has been safely given in the first salvage setting prior to transplant. It can be administered in that setting, but it is not usually my first choice. If they have not gotten it before and they are high risk, I will think about giving it in the maintenance setting. You can give it, but right now most of our patients will get ICE. If anybody does have a patient [who is eligible for transplant], we do have a pembrolizumab [Keytruda]/ICE study that is open [NCT03077828]. That is a pretransplant study. Outside of that setting, I would usually just do ICE.

Would you offer this patient involved-site radiation therapy [ISRT], and when would you make that decision?

I have often referred folks for ISRT. To me, it is an opportunity to have a chance, in somebody who has had a good response and has a little bit of smoldering disease, to give them a course of radiation and not have to take them to transplant. Then it is worth trying to do that unless there is some concern about the toxicity from the radiation. For advanced stage disease, 1 of the main times that I will refer someone to ISRT is if they still have a little bit of smoldering disease at the end.

References:

1. The international prognostic scoring system. Leukemia & Lymphoma Society website. lls.org/disease-information/myelodysplastic-syndromes/diagnosis/the-international-prognostic-scoring-system. Accessed March 18, 2019.
2. 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(4):331-344. doi: 10.1056/NEJMoa1708984.