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Spotlight

This roundtable series evaluates the use of combination therapies using immunotherapy and chemotherapy in patients with advanced Hodgkin lymphoma, as discussed by key opinion leaders and participants at virtual live events.

Patients With Advanced Hodgkin Lymphoma Treated Using Frontline Immunotherapy Plus Chemotherapy

Targeted Oncology: When looking at toxicities leading to death reported in the ECHELON-1 trial (NCT01712490), how do we know that pulmonary fibrosis toxicity reported in patients receiving frontline ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for Hodgkin lymphoma isn’t related to receiving bleomycin?

: [The toxicity] happens late. [Older physicians have seen] patients die from bleomycin. It never happens early. It's unusual to die from bleotoxicity in patients who just get ABVD unless they are older, and we don't give bleomycin to patients who are older than 60 years anymore.

But in a younger patient who dies from pulmonary toxicity who received ABVD, a lot of times they have relapsed, and they've also had radiation therapy, and maybe BCNU [carmustine] as part of an [autologous stem cell transplant], so it's hard to tease out. But older patients, in effect, there was a study [North American Intergroup E2496 Trial; NCT00003389] that…compared ABVD with Stanford V [mechlorethamine, doxorubicin hydrochloride, vinblastine, vincristine, bleomycin, etoposide and prednisone], and that was a negative study.

 In that study, the elderly cohort had an 18% death rate, and the majority was from bleomycin. So what we learned from that is that when you're older than 60 years, you probably shouldn't get bleomycin. ­

But in the younger patients, it's very rare. You'd have to probably have some other underlying genetic abnormality to die from bleotoxicity when you're young.

What else stands out concerning the safety and survival outcomes of the ECHELON-1 trial comparing ABVD with BV-AVD (brentuximab vedotin [Adecetris], doxorubicin, vinblastine, and dacarbazine)?

Looking at deaths on treatment in the ECHELON-1 trial, it's hard for me to understand. The most common secondary malignancy in the groups of patients with ABVD was large cell lymphoma,

 which makes me think they already had large cell lymphoma, [but] it was just misdiagnosed, so I don't think anything of [those data], other than the fact that more patients who got ABVD died from Hodgkin lymphoma [or its complications].

I don't think there's a difference in secondary malignancies. I also don't think there is much of a difference with safety. There is more pulmonary toxicity with ABVD and there's more neurotoxicity with BV-AVD, and [for physicians] who don't use a lot of BV, you need to know that if [the patient] can't button their shirt or zip their fly or write a check, you probably need to reduce the dose of brentuximab. I always ask patients, “Can you button this button on your shirt?” If you can't button this button because of neuropathy, it's always grade 2, and [BV] has to be reduced to 0.9 mg/kg. If it's worse than that, you have to drop BV.

How do these therapies impact pregnancy and fertility?

We take care of a lot of young women and a lot of young women are pregnant with Hodgkin lymphoma…. The patients are always undertreated, but there's no difference in the pregnancy rate with BV-AVD and ABVD, which is key.

I don't necessarily know the sperm data with BV-AVD. All the men [used] a sperm bank anyway, but the female pregnancy rate [of partners of men treated for Hodgkin lymphoma] is pretty good.

What dose modifications are required for patients with peripheral neuropathy with BV?

When we see somebody with [peripheral neuropathy related to] BV-AVD, and I think our chief complaint that we get is the patients have bone pain from pegfilgrastim [Neulasta]. The patients are young, and that's their chief complaint. And then when we tell them we can change them to G-CSF [granulocyte-colony stimulating factor]. I usually give G-CSF on day 6 through 10, and if the counts are too high, we can reduce it by a day, and if it's still too high, we can give 3 doses. They don't always say yes, because they don't want to self-inject. But that's by far the biggest complaint that we have, which is much different than, for example, nivolumab [Opdivo]-AVD or pembrolizumab [Keytruda]-AVD.

What immunotherapy agents are being investigated in combination with chemotherapy for Hodgkin lymphoma?

There was a huge national study [SWOG S1826 study; NCT03907488] comparing BV-AVD versus nivolumab-AVD. That study was done, and was powered for nivolumab-AVD to be 5% better than BV-AVD. It's important to think about that in a couple of ways. First, it's a United States study, so it's mandated that the patients who get BV get growth factors.

When patients who receive BV-AVD get growth factors…it's 5% better. It's probably at 84% at 5 years. Those are probably the [most significant] data with BV-AVD.

That means we're asking nivolumab-AVD to be at 89% for advanced stage Hodgkin lymphoma at 5 years. If it's not at 89%, it's going to be a negative study. Now, of course, there are secondary end points with toxicity and whatnot, but the primary end point is efficacy, and efficacy has to be 5% better with that program.

There are many different adverse events [AEs] between these 2 programs. BV-AVD causes neuropathy, and it causes cytopenias.

 Nivolumab-AVD causes immune-related AEs, [and] thyroid dysfunction in about 15% of patients, which I don't [worry] about so much, but it's annoying.

Rash is not easy. Rash is a real [issue] with pembrolizumab and nivolumab when combined with chemotherapy. They also get this gastrointestinal discomfort syndrome, which is hard to explain. It's not benign, even though it's outpatient treatment, but we'll see what happens when the study is reported. [I have heard] that there will be some toxicity data that's going to be reported [later this year at the International Conference on Malignant Lymphoma] out in Lugano, [Switzerland].

This study is the [SWOG S1826 study]. We [at the University of Miami] put 18 patients on, and all our patients have done well. The first 12 patients all got BV-AVD; although it's supposed to be random. I think there is 1 patient who [responded] and that patient got BV-AVD.

Merck is doing an industry-sponsored study…comparing pembrolizumab-AVD versus ABVD, and I don't know if that's being done in the United States all that much, but it’s being done quite a bit in Europe.

The phase 2 data with pembrolizumab-AVD look quite good.

 The phase 2 data with nivolumab-AVD last had been updated in 2019.

 At that point, the results were decent. Now, we have been championed a program called pembrolizumab-GVD [gemcitabine, vinorelbine, and liposomal doxorubicin], which is a study that Alison J. Moskowitz, MD, and I wrote before I left Memorial Sloan Kettering Cancer Center, and we brought that [to the University of Miami], in patients with relapsed Hodgkin lymphoma. That's one of the best treatments we've ever given, and it's phenomenal. It has a litany of AEs, but it's outpatient and it's pretty well tolerated.

1. Advani RH, Hong F, Fisher RI, et al. Randomized phase III trial comparing ABVD plus radiotherapy with the Stanford V regimen in patients with stages I or II locally extensive, bulky mediastinal Hodgkin lymphoma: a subset analysis of the North American Intergroup E2496 trial. 

. 2015;33(17):1936-1942. doi:10.1200/JCO.2014.57.8138

2. Ansell SM, Radford J, Connors JM, et al. Overall Survival with brentuximab vedotin in stage III or IV hodgkin's lymphoma. 

. 2022;387(4):310-320. doi:10.1056/NEJMoa2206125

3. Straus D, Collins G, Walewski J, et al. Primary prophylaxis with G-CSF may improve outcomes in patients with newly diagnosed stage III/IV Hodgkin lymphoma treated with brentuximab vedotin plus chemotherapy. 

. 2020;61(12):2931-2938. doi:10.1080/10428194.2020.1791846

4. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV hodgkin's lymphoma. 

. 2018;378(4):331-344. doi:10.1056/NEJMoa1708984

5. Advani RH, Moskowitz AJ, Bartlett NL, et al. Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results. 

. 2021;138(6):427-438. doi:10.1182/blood.2020009178

6. Allen PB, Savas H, Evens AM, et al. Pembrolizumab followed by AVD in untreated early unfavorable and advanced-stage classical Hodgkin lymphoma. 

. 2021;137(10):1318-1326. doi:10.1182/blood.2020007400

7. Ramchandren R, Domingo-Domènech E, Rueda A, et al. Nivolumab for newly diagnosed advanced-stage classic hodgkin lymphoma: safety and efficacy in the phase II CheckMate 205 study. 

. 2019;37(23):1997-2007. doi:10.1200/JCO.19.00315

8. Moskowitz AJ, Shah G, Schöder H, et al. Phase II trial of pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin as second-line therapy for relapsed or refractory classical Hodgkin lymphoma. 

. 2021;39(28):3109-3117. doi:10.1200/JCO.21.01056

During a Targeted Oncology™ Case-Based Roundtable™ event, Craig Moskowitz, MD, discussed the use of brentuximab vedotin in patients with Hodgkin lymphoma. This is the second of 2 articles based on this event. 

Tolerability With Brentuximab Vedotin Treatment in Hodgkin Lymphoma

: What studies led to the use of brentuximab vedotin (Adecetris) for patients with advanced Hodgkin lymphoma?

 The ECHELON-1 [NCT01712490] study which compared ABVD [doxorubicin, bleomycin, vinblastine, and dacarbazine] with BV-AVD [brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine] was published a number of years ago in the 

 It has a [complicated] history to it. Whether it was the best study to do is unclear, but it was a large, randomized industry-sponsored study for patients with stage III and IV disease, which is important, because a lot of the random assignment trials that are cooperative group-based, or from the German group, included patients with stage IIB disease as well.

In fact, there's a study called the RATHL study [NCT00678327], where you give ABVD for 2 cycles, and if the PET scan is negative, then you de-escalate, drop bleomycin, and give AVD [doxorubicin, vinblastine, and dacarbazine] for 4 months. [Over] 40% of patients in that study had stage II disease [including stage IIA with adverse features].

 That's not a study of patients with advanced-stage Hodgkin lymphoma.

One of the things I like about the ECHELON-1 trial is that it is truly for patients with advanced stage disease. It has been published multiple times now in various formats, and shockingly, the last time the data was reassessed, there was an overall survival [OS] advantage to the BV-AVD arm.

 It's [nearly] unheard of in the management of aggressive lymphoma. There is almost no aggressive lymphoma study out there, [whether] in large cell lymphoma, Hodgkin lymphoma, Burkitt lymphoma, mantle cell lymphoma, [or other types], where 1 arm shows an OS advantage.

They almost always show a progression-free survival advantage, or what the German [researchers] call freedom from treatment failure, and you can decide what treatment failure is. When I was at Memorial Sloan Kettering Cancer Center, we used to use event-free survival [EFS].

In lymphoma management in general, it's almost shocking for there to be an OS advantage. So, when this study came out, nobody ever thought that this particular treatment program, BV-AVD, would have a survival advantage over ABVD. The results are what they are. I started studying brentuximab vedotin in 2009. We participated in the phase 2 single-agent [frontline] brentuximab vedotin study [NCT01716806], and then I wrote the AETHERA study [NCT01100502] [for patients with high-risk Hodgkin lymphoma following autologous stem cell transplant] and published that in 2015. That is how brentuximab got approved in those settings.

Then we started studying nivolumab [Opdivo] and pembrolizumab [Keytruda], and those drugs got approved. Eventually, these drugs have both moved earlier [in the treatment paradigm, as has] brentuximab. Brentuximab is approved, the other 2 have not been approved [in the first line].

 Pembrolizumab has been shown to be superior to BV in the palliative setting.

How are patients with stage III or IV Hodgkin lymphoma evaluated after receiving frontline BV-AVD or ABVD therapy for Hodgkin lymphoma?

Hodgkin lymphoma is an aggressive lymphoma. It’s not as aggressive as diffuse large B-cell lymphoma, but patients die from it. In reality, what you want to do is [separate] patients with primary refractory disease. It’s divided into 2 different groups. Years ago, we defined in large cell lymphoma, as well as later in Hodgkin lymphoma, that not all patients with primary refractory disease are the same. There are 2 possibilities. The first possibility is that the patient gets a complete course of treatment. At the end of the treatment, the imaging is abnormal, you do a biopsy, and the patient has disease. That means they have received a complete course of therapy, but it didn't work. That, by definition, is primary refractory disease.

The other possibility is [the physician] gave the patient 3 different treatments, and now they have a new node in their neck. And then [the physician] biopsies the patient, and they have lymphoma. That's also primary refractory disease. Some physicians would argue that those things are different. Some would argue that the second group of patients have [what is] maybe called primary progressive lymphoma. That means a patient had an incomplete course of primary treatment, and progressed on that.

But the world has combined those 2 things together. In reality, we've published and shown that the first group of patients do exactly the same as relapsed patients. And the primary progressive patients almost never catch up.

What I think has happened is that the patients who have primary progression have not been helped by either one of these treatments. The patients who have had primary refractory disease but had an incomplete response to full-course therapy probably don't exist [if they receive frontline] BV-AVD. BV-AVD is curing those patients, and that's why the [Kaplan-Meier] curves [in the ECHELON-1 trial] start splaying after they have completed their treatment.

Because if the first thing was true, the [Kaplan-Meier] curves would splay early. Remember, if there were no one progressing on treatment, then the BV-AVD arm would be flat at the top. But that's not the case. It drops. So I think that there is still a small group of patient with Hodgkin lymphoma…5% to 8% of patients who progress on primary treatment. Those patients are not being helped by BV. It's the other group of patients who are.

So if you were giving somebody BV-AVD and they were on cycle 3, and you did a PET scan, you would have 2 possibilities. No. 1, the disease was shrinking down [but] there was still mild activity. And possibility No. 2 was that the disease was shrinking down, but they had a new lesion in the spleen. Those patients need to have therapy changed. They will not go into remission [with BV-AVD].

The first group of patients where everything is shrinking down and there's still slight abnormality, they probably will go into remission. I've been doing this for a long time, so I've seen these things, but to me, that's the most important take-home point from these things.

1. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV hodgkin's lymphoma. 

2018;378(4):331-344. doi:10.1056/NEJMoa1708984

2. Johnson P, Federico M, Kirkwood A, et al. Adapted treatment guided by interim PET-CT Scan in advanced Hodgkin's lymphoma. 

 2016;374(25):2419-2429. doi:10.1056/NEJMoa1510093

3. Ansell SM, Radford J, Connors JM, et al. Overall survival with brentuximab vedotin in stage III or IV Hodgkin's lymphoma. 

4. FDA expands approval of Adcetris for first-line treatment of stage III or IV classical Hodgkin lymphoma in combination with chemotherapy. News release. FDA. March 20, 2018. Accessed March 29, 2023. https://bit.ly/42MBFT0

5. Kuruvilla J, Ramchandren R, Santoro A, et al. Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicentre, randomised, open-label, phase 3 study. 

. 2021;22(4):512-524. doi:10.1016/S1470-2045(21)00005-X

During a Targeted Oncology™ Case-Based Roundtable™ event, Craig Moskowitz, MD, discussed the history of the use of brentuximab vedotin in Hodgkin lymphoma and how to evaluate patients after primary therapy. 