So today we&rsquo;re discussing the case of a 22-year-old female patient with a recently diagnosed classical Hodgkin lymphoma. This was a young woman who was completing her college coursework and noted some cervical lymphadenopathy over the period of a few weeks to months. She was initially evaluated by her obstetrician-gynecologist who initially observed her, but ultimately, she started developing more symptoms while consuming alcohol. And so as a result, she was referred for a biopsy and ultimately was found to have Hodgkin lymphoma.

As part of her staging evaluation, we completed a PET CT, which identified several areas of enlarged lymph nodes as well as some possible bone lesions. In addition, she had an elevated white blood cell count [and] an elevated platelet count, whereas the rest of her labs were generally within normal limits. She ultimately had her pathology reviewed at Emory where it was confirmed to be a classical Hodgkin lymphoma, nodular sclerosis subtype, and with a fairly typical immunophenotype. As a result, she was diagnosed with a stage IV classical Hodgkin lymphoma.

So this is a case of a fairly typical patient with classical Hodgkin lymphoma. We frequently see this in young people, especially young women, and often patients will feel well up until the point their disease starts to cause more symptoms, and that&rsquo;s when they come to [seek] medical attention.

When I saw this case and completed the staging evaluation, I was somewhat concerned about the fact that she had some uptake on her PET in the bones. This is not entirely uncommon with Hodgkin lymphoma but certainly suggests that this is a more advanced-stage disease.

This is not uncommon to have patients with advanced-stage disease at the time of diagnosis. Certainly, the fact that she is a young woman would support this diagnosis, and interestingly, the fact that she had some symptoms that developed while consuming alcohol has been a classic symptom associated with Hodgkin. Although we don&rsquo;t always see that in real life, it&rsquo;s something that has been described.

Fortunately, most of our patients with classical Hodgkin lymphoma can look forward to responding to therapy and many of them will be cured of their disease. So out of all patients with classical Hodgkin lymphoma that presents at [an] advanced stage, our historical expectation was that roughly 75% would be cured. In recent years, there&rsquo;s been new therapies that have been developed, including one which includes brentuximab vedotin, which appears to be improving that by about 5% to 7%.

So all of my new patients with classical Hodgkin lymphoma will have a PET CT as part of their staging evaluation. I feel that the PET CT is important as it&rsquo;s not entirely uncommon to have extra nodal sites of disease, including the bones like we saw in this patient. And the PET really helps identify those sites. In addition, the PET CT at baseline is important because we frequently rely on an interim PET as well as a posttreatment PET, and it&rsquo;s important to have a baseline. In addition, I typically will have patients complete a battery of laboratory assessments, including assessment for HIV. It is not uncommon for a new diagnosis of HIV to be identified in a patient with a new diagnosis of lymphoma.

One thing that I don&rsquo;t typically require of my patients, unless there&rsquo;s a specific indication, is a bone marrow biopsy. In the past, this was typically done for all new lymphoma patients. But it turns out that it&rsquo;s exceedingly uncommon to have marrow involvement that ultimately impacts treatment. So the only time I really will have a patient obtain a bone marrow biopsy is if they have some sort of hematologic abnormality or something else going on that makes me worry that there might be an additional process going on in the bone marrow.

Case Review: Newly Diagnosed Stage IV Hodgkin Lymphoma

Fortunately, for classical Hodgkin lymphoma, we have a number of effective therapies, and most patients will be cured of their disease. However, it&rsquo;s very important for each individual patient to identify their comorbidities, to take into consideration aspects such as their age and performance status, as well as a number of other things that you may want to consider, like whether or not, for example, they are a smoker and might be at increased risk for pulmonary toxicity or a diabetic that may be at increased risk for neuropathy. And so I often try to take into account a number of factors, both with regards to the disease as well with regards to the patient, when making a decision.

Fortunately, we have a number of effective therapies. Traditionally the treatment for advanced stage Hodgkin Lymphoma was a 4-drug regimen, ABVD [doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine], which was the standard for many years. And this is typically a therapy that&rsquo;s given every other week for 6 months of treatment, or 12 treatments. This is typically well tolerated, but one of the big challenges with this particular therapy is that the bleomycin can certainly increase the risk of pulmonary toxicity, which can be a devastating complication for patients with classical Hodgkin lymphoma.

In recent years, there&rsquo;s now been 2 subsequent studies that have identified alternative options for patients with classical Hodgkin lymphoma. The first is a&hellip; is based on a study called the Raffle Study, which used a PET-adapted approach to manage patients with classical Hodgkin lymphoma. In that particular approach, patients received 4 treatments with ABVD, or 2 cycles. And at the conclusion of those 2 cycles, they have a PET CT. And those that are PET-negative at that point can move to received AVD [Adriamycin, vinblastine, dacarbazine] without the bleomycin, for an additional 4 cycles. Whereas those that are PET-positive would be escalated to BEACOPP [bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine (Oncovin), procarbazine, prednisone], which is a more aggressive therapy that was primarily developed in Europe.

This is particularly attractive because it allows patients to receive a lower dose of bleomycin. The challenge, however, is that if a patient is PET-positive, escalating to BEACOPP can be a very aggressive intervention and can sometimes be challenging.

In addition to that approach, we also now have a novel combination, which includes the antibody-drug conjugate, brentuximab vedotin, which targets CD30, in combination with AVD. And this regimen is now FDA approved based on the ECHELON-1 study, which was presented at ASH [American society of Hematology] in 2017 and subsequently published in the

. And this was a comparison of BVAVD [brentuximab vedotin + Adriamycin, vinblastine, dacarbazine] versus ABVD for 6 cycles. And this also provides an opportunity to avoid bleomycin. What we found was that, in [the] study, there was an improvement in the modified progression-free survival. The modified progression-free survival includes those patients that progress or that die from other reasons and also includes a small number of patients that may not have progressed but had an inadequate therapy and ultimately went on to receive additional treatment. And the idea behind including that endpoint was that these were patients that had not necessarily been successfully treated with the induction regimen. So it was a goal to really be more realistic with the assessment. So these are 2 very reasonable options. At this point, I typically do not recommend ABVD for a full 6 cycles and go with one of these 2 treatment options.

Effective Therapies in Classical Hodgkin Lymphoma

Fortunately, we have now 2 very good options for patients with classical Hodgkin lymphoma [cHL], and it really comes down to the individual patient to decide which option is most appropriate. So for any patient that I see where I&rsquo;m concerned at all about the possibility of lung toxicityso this would include patients with a history of asthma, patients that have a smoking history, or some other pulmonary condition&mdash;I almost always try to avoid bleomycin. And similarly, for patients that have an increased risk for neuropathy or potentially an increased risk for infection, I might be hesitant to use brentuximab vedotin.

In patients, though, that have neither of these comorbidities and where I really feel that they&rsquo;re a good candidate for both approaches, I often talk about, with patients, about the fact that the brentuximab vedotin does appear to have an improved modified progression-free survival. In addition, at this year&rsquo;s ASH [American Society of Hematology] meeting, we saw some longer-term follow-up from the ECHELON-1 study, including looking at the more standard progression-free survival endpoint. And based on this improvement, although modest, I feel that it&rsquo;s reasonable in many patients to offer them brentuximab vedotin plus AVD [doxorubicin (Adriamycin), vinblastine (Oncovin), and dacarbazine] [BVAVD].

In addition, those patients that have some particularly higher-risk features, like more advanced stage or extra nodal disease, might be a little bit more likely to benefit from the BVAVD as opposed to standard therapy. And for those reasons, I opted to pursue that with this particular patient.

So it&rsquo;s very important for any patient on treatment to be monitored closely for the development of toxicity. Although these are outpatient regimens and generally well tolerated, there have been a number of complications identified. With BVAVD, one of the biggest challenges that we&rsquo;ve seen has been actually infection related to low blood counts. So neutropenia is a well-described toxicity of brentuximab vedotin, as well as a combination chemotherapy. And in the ECHELON-1 study, they did identify several instances of neutropenia, as well as febrile neutropenia, for patients receiving this regimen. I typically do require all of these patients to receive growth factor support as a result of this risk if they&rsquo;re going to receive BV plus AVD. And so that&rsquo;s one of the things that I do to try to avoid those risks.

In addition, I screen all of my patients for neuropathy during the time that they&rsquo;re on treatment, and then it&rsquo;s also important to recognize that there are other sort of more standard chemotherapy-associated toxicities, including nausea and vomiting; anthracycline-associated mucocytes; and cardiomyopathy and so forth that need to be monitored.

Patient Selection Based on the ECHELON-1 Study in cHL

Brentuximab vedotin [BV] is an antibody-drug conjugate that targets CD30 and was really a remarkable achievement when it was initially developed several years ago. Up until this time, we had had combination chemotherapy and could consider an autologous transplant for patients with relapsed disease. But for those who progressed after an autologous transplant or for whom transplant was not an option, we had very limited options and often relied on chemotherapy-based combinations, including gemcitabine and such.

Brentuximab vedotin has a very high overall response rate as a single agent in the relapsed setting. And so for several years now, we&rsquo;ve been using it and it&rsquo;s markedly changed the outlook for patients with relapsed disease.

I was excited to see it being evaluated in a number of other settings, including in the postauto transplant setting as consolidation. This is particularly effective for patients [who] have high-risk disease, including those [who] relapse early or may have extra nodal sites of disease. I often will offer brentuximab vedotin to those patients as soon as they finish their autologous transplants. And now we obviously have the opportunity to use brentuximab vedotin in the frontline setting in combination with AVD [doxorubicin (Adriamycin), vinblastine (Oncovin), and dacarbazine]. So it really has revolutionized the management of patients with classical Hodgkin lymphoma.

So we fortunately now have an FDA approval for patients to receive brentuximab vedotin in the frontline setting in combination with AVD. And this was based on the ECHELON-1 study that was published earlier this year in the [

]. And what they found in this study was that there was a statistically significant improvement in the modified progression-free survival when compared to ABVD [doxorubicin, bleomycin, vinblastine, dacarbazine] for 6 cycles. Over the last 12 to 18 months, we&rsquo;ve now had additional data published or presented, which has identified some longer-term follow-up, and we continue to see this benefit for patients. In addition, we&rsquo;ve now had a chance to look at additional endpoints, such as this more standard progression-free survival, and we continue to see a benefit for patients over ABVD for 6 cycles.

So the case that we described today was a 22-year-old healthy female with no significant past medical history who had advance-stage Hodgkin lymphoma. And I think BVAVD [brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine] is a very reasonable option for a patient in that situation. I think you could certainly consider other options, including a PET-adapted approach. I think both are very reasonable. But I often will choose BVAVD based on the improvement in modified, and now standard, progression-free survival.

I often think about frontline BV in most of my patients with advanced-stage Hodgkin lymphoma. I think it is especially important to consider in patients that have an underlying lung toxicity or some other pulmonary condition that would put them at risk to receive bleomycin. I think that&rsquo;s probably the group that I feel the strongest about receiving BV as opposed to ABVD. In addition, though, those patients that have high-risk featuresagain, including extra nodal disease, anemia, low albumin and other features that make up the international prognostic score&mdash;those patients I think may especially benefit from intensification to receive BVAVD.

Frontline BVAVD in Classical Hodgkin Lymphoma

: This patient went on to brentuximab vedotin plus AVD [doxorubicin (Adriamycin), vinblastine (Oncovin), and dacarbazine] [BVAVD], and after 2 cycles of therapy, we did obtain an interim PET CT. It&rsquo;s important to recognize that this is not designed to be a PET-directed therapy in that at least at the time the study was initially reported, we really didn&rsquo;t understand the importance of interim PET. Subsequently, it has been reported out that interim PET is predictive of outcome in patients with BVAVD, and fortunately, this patient did have an interim PET with a Deauville [score]of 3, which supported continuing treatment through the full 6 cycles. This patient has now completed therapy and has achieved a complete remission.

Patients [who] complete induction therapy for classical Hodgkin lymphoma [cHL] [who] achieve a complete remission can expect to have a prolonged progression-free survival, and many of those patients will actually be cured. We know from a number of studies that have been conducted that having a negative interim PET is particularly important, and then again, having that end-of-treatment PET show no evidence of disease is important. So I would say that this patient has a very high likelihood of being cured of their disease. And, in fact, when we look at long-term follow-up of patients treated for Hodgkin lymphoma, we find that after the first year to 18 months that the most common cause of death for those patients is actually complications of treatment or other causes and not necessarily the Hodgkin lymphoma itself.

For patients [who] complete induction therapy for classical Hodgkin lymphoma, most of them will ultimately be cured of their disease and will not require any additional treatment. However, if a patient were to relapse several years down the road, or even several months down the road, we typically would consider evaluating that patient for an autologous stem cell transplant. This is typically accomplished first by completing aggressive salvage therapy, which is designed to re-induce the remission, and then moving forward with high-dose therapy and stem cell rescue. This can be a curative approach in up to 50% of patients, although that number can vary widely based on a number of factors, including the time to relapse.

For a patient with advanced-stage classical Hodgkin lymphoma, we now have a number of very good options for patients to receive. We have BVAVD, which now has an FDA label in the frontline setting. And then we also have a very reasonable approach with PET-adapted therapy using ABVD [doxorubicin, bleomycin, vinblastine, dacarbazine], with the possibility of de-escalating to AVD for a patient [who&rsquo;s] PET-negative.

I think it&rsquo;s very important for anyone [who&rsquo;s] treating a patient with classical Hodgkin lymphoma to truly take into consideration the patient and their particular comorbidities when making a treatment decision. I think it&rsquo;s also important to recognize that should you decide to proceed with a PET-adapted approach, that you be prepared to escalate to BEACOPP [bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone] should you find that the interim PET is positive. That&rsquo;s how we feel that that strategy is most appropriately applied. In general, however, patients can be expected to do well, but it&rsquo;s very important to remember that there can be toxicities identified and that many of these patients are young people and sometimes complications that are encountered during therapy can last for many years and can significantly alter the lifestyle for these patients. So it&rsquo;s very important to monitor them while they&rsquo;re on therapy and then in the months and years afterwards.

Classical Hodgkin Lymphoma: Is There a Cure?

Case Review: Newly Diagnosed Stage IV Hodgkin Lymphoma

Effective Therapies in Classical Hodgkin Lymphoma

Patient Selection Based on the ECHELON-1 Study in cHL

Frontline BVAVD in Classical Hodgkin Lymphoma

Potential to Cure Advanced Stage cHL