During a <em>Targeted Oncology</em> live case-based peer perspectives presentation, Jonathon B. Cohen, MD, MS, recently discussed the treatment considerations and decisions he makes when treating patients with classical Hodgkin Lymphoma
Jonathon B. Cohen, MD, MS
During aTargeted Oncologylive case-based peer perspectives presentation, Jonathon B. Cohen, MD, MS, recently discussed the treatment considerations and decisions he makes when treating patients with classical Hodgkin Lymphoma (cHL). Cohen, an assistant professor and medical director of infusion services at Emory University School of Medicine, revealed his treatment decisions to the group based on a case scenario of a patient with stage IV cHL.
A 22-year-old collegiate swimmer presented with right cervical nodes developing over several months was initially evaluated by her OB/GYN who recommended observation. She subsequently developed neck pain while drinking wine.
The patient was referred for lymph node biopsy and was diagnosed with cHL. She had no past medical or surgical history and her only medication was oral contraception; she had no known drug allergies. Her social history included no tobacco use and only occasional ethyl alcohol. Her maternal grandfather had a history of squamous cell cancer and her maternal grandmother had a history of melanoma. Her aunt had breast cancer. Otherwise, she had 2 healthy siblings.
Laboratory findings were notable for the following: white blood count (WBC), 19.8 (85% polymorphonuclears); hemoglobin (Hb), 12.0 g/L; platelets, 571; erythrocyte sedimentation rate, 30; creatinine, 0.76 mg/dL; albumin, 4.2 g/dL; HIV/hepatitis, negative. Staging PET/CT also revealed the following: intrathoracic adenopathy; right cervical, 2.3 x 1.9 (standardized uptake value [SUV], 9.3); left cervical, 2.2 x 1.8 (SUV 8.8); anterior mediastinum, 4.8 x 2.9 (SUV 21.3); right axillary, 2.8 x 2.8 (SUV 12.2); spleen SUV, 2.9 with normal size; diffuse uptake in the axial skeleton (SUVs 4.9-5.5); mediastinum SUV, 1.8; liver SUV, 2.4.
The patient was pathologically diagnosed with nodular sclerosis cHL. Per immunohistochemistry (IHC), the Hodgkin cells express CD30, CD15, and PAX5 (weak) and are negative for CD3, CD20, and CD45.
What is the prognosis of this patient? How often do you calculate a prognostic score for a patient?
There is an international prognostic score, or the Hasenclever index, for advantaged-stage Hodgkin lymphoma that includes factors such as Hb, age, stage, gender, WBC, among others. If I have a patient that asks for their prognosis, I will often think about it. But I would be lying if I said that for every single patient with advanced-stage Hodgkin lymphoma, I pull out a calculator and calculate it. That is because in the past you could provide such counseling for patients, but it didn't necessarily play a role in the treatment that I was going to offer.
In general, one of the challenges that we face with lymphoma is that we have many prognostic scorings, but we don't necessarily have some sort of action to take in reaction to that. It is a little bit more of a patient-directed discussion. For patients who ask, I often will go through the scoring. With some of the newer therapies available, however, the scoring may be more beneficial particularly for the higher-risk patients. It is worth considering.
What are the systemic options for frontline therapy for this patient?
For a long time, ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) has been the standard of care within the United States. However, there are other therapies that are out there. There was the Stanford V (mechlorethamine, doxorubicin, vincristine, bleomycin, vinblastine, etoposide, and prednisone), which was compared head to head with ABVD and didn't necessarily look worse than the standard of care, however, it has typically not been adopted.
There is also the elevated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), which has been used primary in Europe. In Germany, they will often use this for higher-risk patients. In the United States, we have been hesitant to use it because there tends to an increase in infection risk, infertility, and secondary malignancies. The German Hodgkin study group will say the risk isn't quite as high as people think. But, in general, we have been using ABVD in the United States.
I remember being a fellow and asking my mentor if there is ever a situation where you wouldn't use ABVD as your frontline treatment choice. She said the only reason would be if she had a patient who she didn't think could tolerate it. Typically, it's what we've been using.
The patient was treated with A(BV)VD (doxorubicin,brentuximab vedotin [Adcetris], vinblastine, and dacarbazine). Interim PET/CT scan imaging revealed Deauville 3. She tolerated treatment well with granulocyte-colony stimulating factor support (G-CSF).
What is your approach toward toxicity monitoring and management for patients receiving first-line ABVD?
There have been 2 studies that have come out in the last couple of years that have changed the landscape of management for patients. One is the RATHL study which used standard ABVD for 2 cycles followed by a PET scan.1Patients with a negative scan could discontinue bleomycin and receive only AVD for the final 6 cycles. The opposite of that is if they were positive on PET scan. Then they would have to escalate to BEACOPP. That is something that I would say hasn't always been adopted. Often patients are comfortable doing ABVD and after a negative PET stopping the bleomycin. However, from what I have seen, there is not a lot of people being escalated to BEACOPP just for having a positive PET.
The other approach is substituting brentuximab vedotin for bleomycin based on the ECHELON-1 study, which looked at A(BV)VD versus ABVD for 6 cycles.2One of the challenges is that the RATHL study, which is the ABVD and the drop of bleomycin for some patients, came out after this study had already been designed and was underway. Therefore, we do not have a head-to-head comparison of those 2 approaches. In general, that is the challenge when deciding what to do for your patient. On 1 side, I think everyone agrees that 6 cycles of bleomycin is not ideal. There is a lot of lung toxicity and if you have to radiate some of these patients down the road, it is a big problem. Both studies were designed to see if we could improve on ABVD.
What is the rationale for substituting brentuximab vedotin for bleomycin for a patient such as this?
The primary endpoint for the ECHELON-1 study was modified progression-free survival (PFS). They included the standard PFS, in other words patients who progresses or die from another cause. But in addition to that, patients who completed therapy but had a partial response or some sort of residual disease that was felt to have demonstrated a failure and additional treatment was needed, was considered an event. They were trying to capture those patients that may not have necessarily progressed but had not had an adequate response. Those were considered a treatment failure, and that is where the modified PFS came into play. In order to meet that endpoint, it had to be centrally reviewed for an inadequate response.
The hazard ratio was 0.77 and it ended up being a modest but real difference in outcome. I think the other thing to keep in mind is that the ABVD group, which historically has about a 75% PFS rate, overperformed in this study. There was necessarily a marked difference in the complete response rate, but when you look at the duration of response there was also benefit.
Depending on who you ask, there are strong opinions on either side. There are definitely some positives to including brentuximab vedotin. There are also reasonable arguments against doing that. I have found it to be a pretty well-tolerated regimen. I feel that although it might be a relatively small difference in PFS, even a difference of 5% to 8%, to me, it is worth it. If someone comes to me and says they would rather do ABVD, I don't think it is inappropriate to do that either.
What factors would you consider when selecting a treatment for this patient?
If they have a particularly high prognostic scoring, you may be more inclined to use brentuximab vedotin. For folks that are high risk, it probably does add some benefit. In the ECHELON-1 study, the lower-risk patients seemed to benefit from A(BV)VD, but there was significant benefit for the higher-risk patients with multiple risk factors. These patients are typically over the age of 45, male patients, and advanced stage. Those are the ones that benefited the most from this regimen.
Additionally, the patients who were treated in North American compared to other regions tended to have a marked improvement with A(BV)VD as opposed to ABVD. It is unclear why that is. One of the possibilities is that in North America we tend to be more comfortable treating patients on schedule, even if they are having adverse events, where potentially in other parts of the world they might not be so accustomed to doing that. But, that is something that hasn't fully been understood.
If you look at age, those patients over the age of 60 tended to not have the same benefit as the younger patients. For patients over the age of 60, those are patients where you want to be careful about making sure they are a fit patient before you treat them with this regimen.
What is your approach toward toxicity monitoring and management for patients receiving first-line A(BV)VD?
In the study, there was a higher rate of febrile neutropenia in those patients who received brentuximab vedotin as opposed to the ABVD regimen. The only thing that I would point out is that after some of these toxicities started being identified, they started instituting G-CSF as a standard for patients who were getting A(BV)VD. With that, the rate tends to go down quite a bit. Especially for older patients, the rate of neutropenia is higher. But with G-CSF it is typically something that you can manage.
If you are going to use ABVD, I would typically recommend against using GCSF because there is an increased risk of lung toxicity. That has been one of the challenges, especially for older patients. For a 22-year-old, such as this patient, if you are treating them with ABVD and their absolute neutrophil count is 480 on day 15 and you're ready to give them the dose, I tend to be comfortable proceeding with the regimen.
The other toxicity that you have to be aware of here is neuropathy. You can get neuropathy with brentuximab vedotin. That is something that we will typically monitor in our patients. In the patients that I've treated so far, I honestly haven't had a lot of neuropathy.
How do you counsel patients about potential/actual toxicities of this regimen at decision-making, during therapy, and into survivorship?
Fortunately, for ABVD there is pretty good literature on fertility preservation. With A(BV)VD, we don't have the best track record because it is a new regimen. But with single-agent brentuximab vedotin, typically there is preserved fertility. If I see a patient, and they are a young female or male, I will have a discussion about fertility and their thoughts. A single, 22-year-old may not be necessarily be thinking about fertility, but their parents probably have. In most cases, I tell them that they will most likely be able to conceive naturally, but I still feel that everyone at least merits a discussion with a fertility expert regarding what would be involved with that process. In many cases with Hodgkin lymphoma, although it is an aggressive lymphoma, it is 1 where you have a few weeks if you needed to make those arrangements.