Brentuximab Vedotin Plus Chemotherapy Works as a Primary Option for Hodgkin Lymphoma

Pierluigi Porcu, MD

Pierluigi Porcu, MD, director, Medical Oncology and Hematopoietic Stem Cell Transplantation and coleader, Immune Cell Regulation and Targeting Program, Sidney Kimmel Cancer Center, at Jefferson Health in Philadelphia, PA, explained how the combination of brentuximab vedotin plus chemotherapy works in in frontline Hodgkin lymphoma.

Targeted Oncology^TM: Following a diagnosis of classical Hodgkin lymphoma, nodular sclerosis type, what additional molecular testing should be ordered?

PORCU: PD-1 and PD-L1; I think most hematopathology labs nowadays run PD-1 and PD-L1 on Hodgkin [lymphoma] cases. Certainly, most hematopathology labs run CD30, although they may not run it on non-Hodgkin lymphoma cases on a routine basis.

Barr virus [EBV]. It’s an in situ hybridization test that’s fairly routine and not very expensive. It identifies cases of Hodgkin lymphoma that are EBV positive. It’s important because there are some pretty good data that [show] EBV identifies a subgroup of Hodgkin lymphoma that has an inferior prognosis in terms of progression-free survival [PFS]. [It’s also important because] there are now treatments for relapsed patients who have EBV-positive lymphoma including Hodgkin.

In some cases, the diagnosis is complex. You may have a gray-zone lymphoma or primary mediastinal B-cell lymphoma, [so it’s important] to have additional markers more in the space of diffuse large B-cell lymphoma to make sure.

In very difficult cases, the other testing would be immunoglobulin heavy chain gene rearrangement. This is routinely negative in Hodgkin lymphoma because the immunoglobulin in genes is aberrantly rearranged and mutated.

Why is PD-1 testing needed for diagnosis?

It doesn’t affect diagnosis. It’s part of the characterization of the Hodgkin lymphoma as a whole. I use it as a routine initial assessment because you never know when patients come back to have a second biopsy how easy it [will be] to get the tissue the second time around.

Can you discuss the International Prognostic Score [IPS]?

The IPS, [also called the Hasenclever index], was published in 1998 and is specifically for advanced-stage serum albumin level of less than 4; a hemoglobin level of less than 10.5; male sex; age equal to or older than 45; stage IV disease; and total WBC count of more than 15,000 or a lymphocyte count of less than 600, less than 8% of the WBC count, or both.1 The patient here has a number of these items. She has a hemoglobin of 9.5, stage IV disease, a WBC count higher than 15,000, and a lymphocyte count less than 600. Her IPS is 4. Based on the data from Hasenclever, her 5-year overall survival [OS] rate is 61%. Interestingly enough, [British Columbia Cancer] looked at their data in terms of the Hasenclever classes and found that for the patients with the highest scores, over time, some of these 5-year survivals were better, but not for the lower ones.

In addition, even though the lymphocyte count is part of the canonical standard, lymphopenia is a common phenomenon in most lymphomas. I follow it closely in T-cell lymphomas, where it’s common for people to have lymphocyte counts less than 500 and certainly less than 250 in AIDS territory, even though they don’t have a history of opportunistic infection. I think the lymphocyte count is clearly an important biological flag marker, although we don’t quite know what the biology of that is.

What are your thoughts on the options provided in the poll and the results?

Essentially here, we’re talking about SWOG S0816 [NCT00822120] or the RATHL [NCT00678327] clinical trial [regimens]. Straight-up escalated BEACOPP [bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, prednisone] German style, brentuximab vedotin [BV; Adcetris] with AVD [doxorubicin, vinblastine, dacarbazine] according to the ECHELON-1 [NCT01712490] trial, or other.

There were 4 votes for PET-adapted therapy with ABVD [doxorubicin, bleomycin, vinblastine, dacarbazine]. We have 7 who voted for BV plus AVD. No votes for escalated BEACOPP, which, even though it’s perfectly appropriate, I’m happy to see [no votes for] because I’m not a fan of escalated BEACOPP, and no [votes for] “other.” The majority would vote for the ECHELON-1 approach for this particular patient.

What frontline systemic therapy are you most likely to recommend for this patient?

There’s no role for radiation therapy. I think the jury is still out regarding PET-adapted therapy versus non–PET-adapted therapy. When I approach patients with advanced-stage disease, I look at a couple of things. One is, which risk category do they really belong to? The other is that PET-adapted therapy is dependent on the PET [scan]. Good-quality reading of PET scans is far from common; they don’t give you Deauville [score]. It’s unclear how they reach their conclusion because they don’t compare the mediastinal and liver to the hypermetabolic lymph nodes. It’s not that easy to get a good highquality PET interpretation, and if you’re making these big decisions about the escalation—or rather, in my case, deescalation according to the RATHL trial—then not having a goodquality PET is a big problem.

One of the big things about frontline therapy is that now we try to avoid exposure to bleomycin. There are 2 ways of doing that: Pick BV and AVD or treat the patient according to RATHL. That’s if the PET is negative; then you can deescalate and remove the bleomycin from the last 4 cycles of ABVD.²

Which factors do you think are most important?

It looks like everyone is on the same page as far as lung function and lung issues [if] someone is a heavy smoker or has a previous history of lung disease. It’s not common in young people but certainly more common in middleaged or older people. Then, obviously, the selection of the therapy is important. The BV plus AVD had less lung toxicity compared to AVD, but it’s not that they had no lung toxicity. You still have to be worried somewhat and monitor people carefully on this therapy, even if it doesn’t have bleomycin. Then for the PET-adapted ABVD, like RATHL, the first 2 cycles still contain bleomycin. Certainly, that is fundamental.

Here we have lung disease, prognostic score, performance. Age is really, in my practice, an important part of the decision-making because it’s not very common. Patients who are older than 60 or 65 generally represent no more than 20% of the cases of Hodgkin lymphoma. But when you have those patients—I’m sure you all have seen them in your practice—their prognosis is particularly bad, especially for those who are older than 70. Selecting the proper therapy for those patients is difficult and, of course, there are trials currently going on. Some of them have been published. For example, BV and bendamustine is one option. There are also trials with single-agent BV ongoing for patients who are frail on the front line. Besides, of course, all the combinations with checkpoint inhibitors...There’s quite a bit going on. For me, age is a very important component of decision-making.

Can you discuss the findings of the ECHELON-1 trial?

Following the initial phase 1 trial, data from ECHELON-1 showed that you can’t give BV with ABVD because of a high rate of pulmonary toxicity. Finding the right dose of BV [is important] because it has to be given every 2 weeks. There are several dose-escalation records in phase 1, but 1.2 mg/kg was found to be the right tolerable dose for this schedule.

This was a large study of 1334 patients who were randomized 1:1 to receive 6 cycles of ABVD or 6 cycles of BV plus AVD. There was an interim PET scan, mostly to assess the response but not to be acted on, except for Deauville 5. [Those participants] would be given the opportunity to receive alternative therapy, and this was not part of the modified PFS scoring. Then there was an end of therapy CT-PET scan. Standard follow-up inclusion criteria [included] classical Hodgkin lymphoma that was stage III and IV, up to an ECOG performance status of 2, more than 18 years old, measurable disease, and adequate organ function. The primary end point was modified PFS, and a key secondary end point was OS.³

The initial paper was published in the New England Journal of Medicine in early 2018 with 2-year PFS data.3 But follow-up data [presented during the 2020 American Society of Hematology Annual Meeting and Exposition] show a median follow-up of 55.6 months with PFS of 82% [95% CI, 78.7%-84.8%] for BV plus AVD versus 75.2% [95% CI, 71.5%-78.4%] for ABVD. There is an advantage in terms of PFS.4 OS was no different between the 2 cohorts.

Not all the subgroups had a clear advantage, but younger patients, less than 45, and patients with the highest IPS did. There was an odd distinction: The North American cases appeared to have a stronger benefit compared with the European cases. I don’t think anyone has a good explanation for that at this point. In addition, male sex and good performance status seem to be falling on the side of the fence that has a greater gain from BV plus AVD.⁵

In terms of adverse events [AEs], peripheral neuropathy was more common in the BV plus AVD group compared with the ABVD group [67% vs 43%, respectively]. There were also some gastrointestinal AEs, [including diarrhea (27% vs 18%, respectively) and abdominal pain (21% vs 10%)]. Overall, the 2 cohorts were fairly comparable in terms of overall AEs, except for...a greater number of hospitalizations and infections in the BV plus AVD cohort, which then led to the amendment toward the end of enrollment.³

Key toxicities are pulmonary toxicity and infections and neutropenia. Pulmonary toxicity was seen in both the BV plus AVD and ABVD cohorts, but ABVD had a significantly greater rate of pulmonary toxicity. In terms of on-study death, there were 9 deaths on the BV plus AVD cohort, and of those, 7 were from neutropenia or neutropenic infection. On the other hand, there were 13 deaths on the ABVD cohort, and the majority of them were because of pulmonary toxicity.³

Was the peripheral neuropathy reversible?

Eighty-four percent in the BV plus AVD cohort and 86% in the AVBD cohort reported complete resolution of peripheral neuropathy at almost 5 years. The median to improvement was 30 weeks for BV plus AVD and 16 weeks for AVBD, and then there was a subset that had ongoing neuropathy, mostly grades 1 and grade 2.⁴

In terms of survivorship, what guidance do you offer patients?

We still don’t know much about safety from the standpoint of fertility. In this study, there were a good number of pregnancies and deliveries with healthy babies in women who participated.

Historically, there is a large body of data showing that the impact of ABVD, particularly 6 cycles of ABVD, is trivial to minimal in terms of fertility. Therefore, for patients treated with ABVD, I only [recommend] fertility consultation if the patient or the spouse has a significant degree of anxiousness about it. The other thing I always tell patients about fertility—and this is true for any disease—is that it’s impossible to figure out what your fertility is if you never had kids. If someone had children already, then you know that their baseline fertility is standard or average. It’s there. If they never did, then it’s impossible to say what it will be following treatment with anything.

We also don’t know what the impact is going to be on second-line efficacy. BV is not going to be a weapon in your toolbox when people progress after BV plus AVD. I think that these are the big questions that we have that require long-term followup. I’m selective with the patients that I treat with BV plus AVD. Certainly, for the younger patients, less than age 45, and patients who have advanced stage or high IPS scores, I tend to use this frontline approach. For the others, I’m less enthusiastic about using it. I think the financial cost is worth it in those subgroups, including the risk to some degree, but it may not be in the others.

Is progressive multifocal leukoencephalopathy [PML] a concern?

Yes, there is some concern. I’m very familiar with the PML cases that were diagnosed in patients who were treated with BV as a single agent with T-cell lymphoma. This is something that I mention to patients as a possible long-term, very severe risk, just like you have the same [risk] when you give Rituxan [rituximab]. I think there should be a concern, but it’s a minimal concern for this population based on the data that we have.

_REFERENCES:

_{1. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on advanced Hodgkin’s disease. N Engl J Med. 1998;339(21):1506-1514. doi:10.1056/NEJM199811193392104}

_{2. NCCN. Clinical Practice Guidelines in Oncology. Hodgkin lymphoma, version 2.2021. Accessed February 1, 2021. https://bit.ly/3oDAEZ4}

_{3. 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}

_{4. Straus DJ, Długosz-Danecka M, Connors J, et al. Brentuximab vedotin with chemotherapy for patients with previously untreated, stage III/IV classical Hodgkin lymphoma: 5-year update of the ECHELON-1 study. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Accessed February 4, 2021. https://bit.ly/3pKKnx7}

_{5. Straus DJ, Długosz-Danecka M, Alekseev S, et al. Brentuximab vedotin with chemotherapy for stage III/IV classical Hodgkin lymphoma: 3-year update of the ECHELON-1 study. Blood. 2020;135(10):735-742. doi:10.1182/ blood.2019003127}