We have a 52-year-old woman, a longtime smoker, who presented with abdominal pain. Evaluation on physical exam revealed right cervical adenopathy, and a CT [computed tomography] scan, which was done to evaluate the abdominal pain, revealed mediastinal adenopathy and abdominal adenopathy. A PET [positron emission tomography] scan confirmed those findings. She was found, therefore, to have clinical stage IIIa disease. A biopsy of the right cervical node revealed nodular sclerosis, Hodgkin lymphoma, which is classical Hodgkin lymphoma. At the end of staging, she had stage IIIa disease. She had no b symptoms: no weight loss, no fever, and no night sweats. She had a long history of smoking but no significant cardiac disease and no significant pulmonary disease.

She was treated with combination of Adriamycin [doxorubicin], brentuximab vedotin, Velban [vinblastine], and DTIC [dacarbazine], or the ABVVD chemotherapy regimen, as outlined in the recently published ECHELON trial comparing ABVD, which we consider to be a standard treatment approach in Hodgkin lymphoma, with ABVVD, which substitutes brentuximab vedotin for bleomycin in Hodgkin lymphoma.

Now, that trial resulted in an improvement in progression-free survival both internationally and, especially, in the recently evaluated North American cohort. There was improvement in progression-free survival but no benefit up till this point in overall survival.

This patient had a fairly typical treatment course, but that was complicated by a variety of toxicities. She had, after cycle 1, day 1, significant neutropenia with fevers. She was hospitalized for at least a week with febrile neutropenia, which is something we don&rsquo;t really see in the ABVD regimen. In our experience with close to 100 patients at our institution, in data we published several years ago, the incidence of febrile neutropenia with ABVD was 0.4%, so we really see very little of febrile neutropenia.

One of the considerationsone of the concerns&mdash;in the substitution of brentuximab vedotin for bleomycin is that if you&rsquo;re going to use that regimen, you are going to see a higher incidence of febrile neutropenia. I think in that setting, it becomes more important to consider the use of growth factors. Now, one might ask the question, &ldquo;Which patients are most appropriate at initial diagnosis to consider for this regimen versus the standard ABVD regimen? Should it be all patients based on improvement in progression-free survival, or should it be a selected subgroup of patients?&rdquo;

Approaching a Case of Stage IIIa Hodgkin Lymphoma

This patient had an international prognostic score [IPS] of 2. She had risk factors regarding age and a low serum albumin, but her white cell count was normal, her hemoglobin was normal, and her lymphocyte count was normal. She was female, not male, which is a positive prognostic sign. And so, one wonders, is it the international prognostic score that dictates your therapy? We know that in the higher IPS scores, the differences weren&rsquo;t as apparent between the 2 regimens. I think the main driving factor for considering the use of brentuximab vedotin over bleomycin is her age and especially her smoking history.

Our experience has beenand the data suggest&mdash;that patients over the age of 40, especially smokers, have an incidence of anywhere from 30% to 50% of bleomycin lung injury. And in that cohort of patients, mortality is around 20%. Once one develops bleomycin lung injury, the chance of dying from that is 1 in 5. It&rsquo;s a significant toxicity. I think we have been looking for a long time for alternatives to the use of bleomycin in patients who are at higher risk for bleomycin lung injury.

Now, what are some of the risks for that? I&rsquo;ve mentioned age, over 40; smoking history; and also, shown by the Mayo Clinic study published a number of years ago, the use of the growth factor. The use of Neupogen [filgrastim] and Neulasta [pegfilgrastim] stimulates the production of white blood cells. Those white cells release toxic oxygen radicals and other enzymes when they get to the first capillary bed, which is in the lung, and we think that increases the risk of bleomycin lung injury. I think the driving force for the use of this regimen, for a nonbleomycin-containing regimen, was her smoking history and her age.

What are some alternatives? Well, one might have used AVDjust Adriamycin [doxorubicin], Velban [vinblastine], and DTIC [dacarbazine]&mdash;leaving out the bleomycin and not adding brentuximab vedotin. In studies from the German Hodgkin Study Group, leaving out bleomycin and not substituting anything for it results in a slightly worse progression-free survival and overall response rate. Although that is an option, I think that based on the data from the ECHELON study, the addition of brentuximab is a very reasonable option for this patient.

Now, are some of the toxicities this patient had expected? Certainly, the febrile neutropenia was expected. We tend to use a preventive, prophylactic antibiotic in our patients getting ABVD chemotherapy [doxorubicin/bleomycin/vinblastine/dacarbazine], and I would say this also applies to ABVVD [doxorubicin/brentuximab vedotin/vinblastine/dacarbazine] chemotherapy. We&rsquo;ve used Bactrim [sulfamethoxazole/trimethoprim] as prophylaxis, fluconazole, and acyclovir. We don&rsquo;t routinely use antibacterial prophylaxis with drugs such as Levaquin [levofloxacin] or ciprofloxacin. I think the febrile neutropenia in this patient is not unexpected. The lesson there is probably having to use growth factor in patients getting this regimen.

Subsequent toxicities on later cycles included 2 major problems. One is neuropathy. It appears that the neuropathy developed fairly early, after the first day of cycle 2, and then progressed as she went through her course of treatment. The neuropathy can be limiting. Dose reductions do help. And sometimes one has to stop the drug entirely, which I think was done at the end of the course of chemotherapy in this particular patient. The neuropathy might be mild and not limit normal functions, ADLs [activities of daily living], but for this patient, it really had some significant effects on her quality of life.

Hodgkin Lymphoma: Considerations for Frontline Therapy

We&rsquo;re especially concerned about the neurotoxicity of brentuximab vedotin because we&rsquo;re giving it together with Velban [vinblastine], which we know is a potentially neurotoxic agent that can cause peripheral neuropathy, constipation, and muscle cramping. And so, the combination of those 2 is something that is of some concern, and the addition of brentuximab to the entire treatment regimen results in greater neutropenia.

What are alternatives to this? Well, I mentioned that the ECHELON study was recently published, but more recently evenI would say about 3 weeks ago&mdash;we published data from a cooperative study between our institution and a number of other institutions around the country. We did the study with MD Anderson, Memorial Sloan Kettering, Stanford, and several other institutions looking at a population of older patients. In this study, patients had to be older than 60, but I think some patients over the age of 55 were included. This tested the use of brentuximab vedotin, but as a lead-in for 3 cycles, just by itself, followed by AVD [doxorubicin/vinblastine/dacarbazine] chemotherapy.

We were not giving brentuximab together with Adriamycin [doxorubicin], Velban, and DTIC [dacarbazine]. After the end of 4 to 6 cycles of AVD, we gave a consolidation of brentuximab for 3 or 4 cycles. The data were just published in the

this past month and suggest the best outcomes in patients over the age of 60 that are available in the literature today. The toxicity was fairly manageable, especially in patients who didn&rsquo;t have a lot of comorbidities, which is always a concern in older patients.

We were able to mitigate some of the toxicities of brentuximab vedotin when given together with AVD by separating them, using the lead-in brentuximab and then going to AVD. We didn&rsquo;t see severe neutropenia, nor did we see the severe peripheral neuropathy that you see when you give those agents together. I would say that 1 alternative for patients, now that this regimen has been published, would be to use brentuximab as a lead-in and then give a AVD rather than giving them together.

This patient went on and had standard evaluation. She had a PET [positron emission tomography] scan following the second cycle of treatment and was reported as having a Deauville 2 score. We use the Deauville score to evaluate PET scans because it&rsquo;s a fairly subjective evaluation, and no one has come together with a good standard of approach that can be applied across multiple institutions and multiple practices, especially places where people aren&rsquo;t seeing that many cases of [Hodgkin] lymphoma.

This patient had an excellent response. We consider a Deauville 2 to be a complete remission. Some people consider a Deauville 3 to even be complete remission, but Deauville 2 certainly is completely remission. Based on data published many years ago, we know that those patients who achieve a Deauville 2 score or complete remission after 2 cycles of chemotherapy have a much better outcome than those who do not. We know early on that this patient is likely to have a relatively good outcome.

Optimizing Brentuximab Vedotin Use in Hodgkin Lymphoma

Treatment was continued, and the plan was to give 6 cycles, which I think is standard for patients with stage III or IV, or advanced, Hodgkin lymphoma. That treatment was continued, and as it went along, she began to have worsening toxicities. Among them was worsening peripheral neuropathy, which limited her ADLs [activities of daily living]. She also developed what appeared to be cardiac toxicity with a drop in her ejection fraction. Now, in this case, Adriamycin [doxorubicin] was held somewhere around the fifth cycle because the ejection fraction dropped below 50%. I think there&rsquo;s some concern about holding Adriamycin, although there&rsquo;s also concern about cardiac toxicity. It&rsquo;s been very rare that we&rsquo;ve had to hold or stop Adriamycin in patients getting AVD [doxorubicin/vinblastine/dacarbazine], ABVD [AVD + bleomycin], or ABVVD [AVD + brentuximab velcade] chemotherapyany Adriamycin-containing chemotherapy for Hodgkin lymphoma. I think it&rsquo;s an important part of the regimen. I think one has to be certain that there&rsquo;s real cardiac toxicity. [Afterward], the ejection fraction improved, and it was restarted. It&rsquo;s not clear what the course of those events were or why she dropped in ejection fraction.

One alternative to that might have been to add Zinecard [dexrazoxane], which is a cardioprotective agent that chelates iron and diminishes the number of free radicals that are produced and are injurious to the heart. That&rsquo;s probably the mechanism of cardiac toxicity in patients getting Adriamycin, so that would be an option that one would have.

We usually see these patients if they have any cardiac history or drop in injection fraction. We see them together with cardiologists who are especially well versed in oncology and so-called onco-cardiologists, who we get to work with quite a bit. That has really helped our ability to manage these patients. There&rsquo;s also the use of echocardiograms and strain echoes and strain patterns that will help determine cardiotoxicity. It sounds like Adriamycin was resumed in this patient, and she finished the course of treatment minus brentuximab for the last cycle or so of her treatment. An end-of-treatment PET [positron emission tomography] scan showed continued complete remission.

What are some lessons from this case? I think the history of smoking and her age made her a noncandidate for bleomycin, so one is already looking for alternatives. I think this regimen is a reasonable alternative, and I think this regimen is a reasonable alternative for that population of patients. I&rsquo;m not yet ready to make this my standard of care for all patients with [Hodgkin] lymphoma. I think there are trade-offs between the brentuximab and the bleomycin, and one has to weigh the risks and benefit. In this particular patient, I think the benefit would clearly outweigh the risk of using bleomycin because of her smoking history and her age.

The other things to weigh in making these decisions are neuropathies. For example, if she has a history of diabetes or a familial history of peripheral neuropathy, I think one would need to be careful with the use of brentuximab and Velban [vinblastine] together. One might then consider using them separately, where maybe the risk of neurotoxicity would be less. I think one also has to think about what the goal of treatment is in this patient who is age 52 and has stage III disease. The goal is cure it. I think we have to look for the best regimens that will give us the best complete remission rate and the best long-term remission rate, and now we&rsquo;re hoping for cures in any new patient who is seen with Hodgkin lymphoma.

I think the other thing to look at is potential cardiac toxicity. Is there a preexisting history of cardiac disease? Is there a strong family history of cardiac disease? Do we have to consider frequent echocardiograms after every cycle? We&rsquo;ve sometimes done that in patients with significant cardiac disease so that we can make adjustments as we go along.

Balancing Quality of Life and Efficacy in cHL

When making determinations or decisions about chemotherapy in any patientchemotherapy for any disease&mdash;one has to look at the possibility of dose adjustments or dose reductions or dose modifications. Our sense in Hodgkin lymphoma, in a curable malignancy, is that we don&rsquo;t like to make dose adjustments, we don&rsquo;t like to reduce doses, and we don&rsquo;t like to delay treatment. That was the basis in describing our experience of patients with [Hodgkin] lymphoma treated with ABVD [doxorubicin/bleomycin/vinblastine/dacarbazine]&mdash;that we had 0 dose reductions and 0 delays without the use of the growth factor in those patients.

Now, when you&rsquo;re adding drugs such as brentuximab vedotin, one of the issues with it is that you may have to make dose adjustments. We don&rsquo;t have a big database to look at and say that dose adjustments have a negative impact on treatment, but I think if we extrapolate from other cancer chemotherapy, dose intensity is probably still important in this regimen, and I have some concerns about making adjustments in doses for toxicity. At the same time, we have to be cognizant of dose toxicities. That&rsquo;s one of the concerns I have with this particular regimen. By combining brentuximab and Velban [vinblastine], we&rsquo;re going to see more neuropathy, and I do wonder if giving them separately would allow us to give doses of each without having to make adjustments to the dose of the other.

The Adriamycin [doxorubicin] reduction in this patient is a little bit unusual. Stopping it is unusual. I don&rsquo;t think that a dose reduction is warranted. If you see a drop in the injection fraction, you have to make a decision that it&rsquo;s a real reduction, a significant reduction, and consider the use of cognitive protective agents such as Zinecard [dexrazoxane] rather than stopping the drug or adjusting the dosage. Those are the things I would consider if we were in the realm of dose adjustments.

We do have to sometimes deal with neuropathic pain in patients getting brentuximab vedotin and Velban. Our approach has been to treat those symptomatically. Sometimes, we use either gabapentin, pregabalin, or Lyrica [pregabalin], and that is helpful. I will say that I found neuropathic pain a difficult symptom to treat, and I don&rsquo;t find those drugs to be of major benefit, but we certainly do try them. In those patients, sometimes we use muscle relaxants if there&rsquo;s a lot of cramping that you can see with Velban. I think the use of Lyrica in this particular patient is reasonable.

Adding, Reducing, or Discontinuing Agents in cHL Therapy

As we go through decision making about choices of chemotherapy regimens, I think one should try to spend a fair amount of time going over potential short-term and long-term toxicities. We do see late cardiac toxicity sometimes. Using bleomycin, we can see lung toxicity. We can see infertility with all of these regimens, but I&rsquo;m not certain we have a good database when we use brentuximab on the incidence of infertility. We know that with ABVD [doxorubicin/bleomycin/vinblastine/dacarbazine], infertility occurs in younger patients, people in their 20s, maybe 10% to 20% of the time. As patients get older, in their 30s and 40s, that number goes up. We routinely recommend either sperm banking or egg harvesting in men and in women of childbearing age, given the possibility of infertility.

We have a discussion about potential long-term toxicities. We do have a survivorship program at our institution where. I like to call it a long-term follow-up program at our institution, rather than a survivorship program. But I think it&rsquo;s useful because these patients who are going to be 5 to 10 to 15 to 20 years out are going to be followed with their primary care physicians. It&rsquo;s good to have good communication between the oncology group and their primary care physicians, because the primary care physicians may be the ones noticing some of these late toxicities.

We haven&rsquo;t seen second malignancies as a prominent feature in patients getting ABVD. We don&rsquo;t have enough data to say anything about brentuximab. We do know from early Hodgkin lymphoma studies that regimens like MOPP [mechlorethamine/vincristine/procarbazine/prednisone] were associated with a higher risk of secondary malignancies, especially acute leukemia, and so those are concerns. We don&rsquo;t have a lot of information yet on brentuximab because it&rsquo;s brand new in first-line treatment.

First of all, our patients are seen regularly. We usually see patients on a regimen such as this one, which is a day one 1, day 15 regimen, on day 1 of each cycle. We see them once a month. On day 15, they&rsquo;re seen by our nurses, our nurse practitioners, or both. They&rsquo;re encouraged to describe potential toxicities so they&rsquo;re not missed. You can sometimes see mild neuropathy progressing to more severe neuropathy over time. If it&rsquo;s not recognized, you may lose the opportunity to mitigate a dose toxicity.

We really encourage patients to communicate with us about any unexpected symptom. We usually describe and give them a handout regarding what symptoms to expect, and they&rsquo;re encouraged to tell us about anything that deviates from that or anything that is on that list, really.

Hodgkin Lymphoma: Discussing Toxicity With Patients

Our experience with patients who are smokers over the age of 50, in the days when we were still not smart enough to use bleomycin, has been problematic, because these patients really develop significant bleomycin lung injury. Years ago, when we began noticing that and the data on predicting risk for bleomycin lung injury were published and out there, we stopped using bleomycin in that setting. And then we began in our clinical trial, where we gave brentuximab as a lead-in, and we saw basically no lung injury and very little neuropathy. The use of this particular regimen, ABVVD [doxorubicin/brentuximab vedotin/vinblastine/dacarbazine], is relatively new.

We have some experience with it in patients, but because it hasn&rsquo;t become a standard regimen for us, we don&rsquo;t use it in a lot of patients. We recently treated several patients with the regimen and have seen the toxicities that are being described in this particular case: febrile neutropenia, fevers, something we just didn&rsquo;t see before with ABVD. I think there&rsquo;s a learning curve with any new regimen. Everybody who participated in the study now has some experience. But I think as this becomes more routinely used in clinical practice around the country and around the world, we&rsquo;re going to develop a better understanding of the potential risks and toxicities of this regimen.

This patient had what appears to be a complete response measured by a PET [positron emission tomography] scan after the second cycle that would predict for a very high likelihood that she won&rsquo;t recur. I would say she has a 70% or 80% chance of long-term survival without any disease. I think this patient should do quite well.

Are there alternatives if she does recur? There are. We have excellent outcomes in stem cell transplantation in patients who relapse. Just to let you know where we are currently, based on the data published with the use of checkpoint inhibitors in patients with relapsed or refractory [Hodgkin] lymphoma, it looks like response rates in the order of 80% percent, although complete responses are only about 20% to 30% percent. We&rsquo;re beginning a clinical trial looking at the use of pembrolizumab, or Keytruda, which is the checkpoint inhibitor from Merck. We&rsquo;re using that as a lead-in followed by AVD [doxorubicin/vinblastine/dacarbazine] chemotherapy in patients with both early stage and advanced stage Hodgkin lymphoma.

We&rsquo;re going to be presenting some of those data at the ASH [American Society of Hematology] meetings in Cologne with the German Hodgkin Study Group, and there were fairly impressive up-front responses measured by PET scan before any chemotherapy was givenjust with the use of pembrolizumab&mdash;and so we&rsquo;re very excited about those data. We have too few patients to make any major conclusions, but that study is continuing accrual. I think as we look forward to the next phase of treatment of Hodgkin lymphoma, it&rsquo;s going to include the use of checkpoint inhibitors. That&rsquo;s a prediction, but we&rsquo;ll have to wait and see.