Ghosh Addresses Brentuximab Vedotin Use in Advanced Hodgkin Lymphoma

Nilanjan Ghosh, MD, PhD, a medical oncologist at Levine Cancer Institute, Atrium Health in Charlotte, NC, discussed the case of a 22-year-old patients with advanced Hodgkin lymphoma.

Targeted Oncology™: What is your assessment of the patient?

GHOSH: The patient’s serum albumin is 4.2 g/dL, so that’s an issue. The fact that she has stage IV disease, and that the white cell count was high, and the lymphocyte count was low are factors leading to an International Prognostic Score [IPS] of 4. The 5-year overall survival for high IPS, based on historical data, is not as good. I don’t know if this would apply as much now, but this is what we have if we use the historical data. That suggests that she is a higher-risk patient. To be honest, the IPS has not affected treatment choice as much, at least in the United States, but we’ll see if some of the newer treatments such as brentuximab vedotin [Adcetris] plus doxorubicin/vinblastine/dacarbazine [A+AVD] have any effect on that subgroup.

What do the National Comprehensive Cancer Network guidelines recommend for stage III or IV disease?

There are 2 treatment pathways that can be followed in patients who have stage III or IV.¹ One focuses on a PET-adaptive pathway, which is ABVD [adriamycin, bleomycin, vinblastine, dacarbazine], followed by AVD [adriamycin, vinblastine, dacarbazine] or BEACOPP [bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone]. The non-PET adaptive therapy is the other pathway and uses brentuximab vedotin and AVD or escalated BEACOPP. Escalated BEACOPP is not usually used in North America.

Which regimen was chosen in this patient?

The patient was treated with brentuximab vedotin and AVD. Interim PET scan shows a Deauville score of 3; the patient tolerated this regimen well with G-CSF support. I think most people are certainly familiar with the Deauville scoring system, so just remembering that if the uptake is less than the liver, that is considered as grade 3 response. If its uptake is moderately above or markedly above, then that’s considered progressive.

What are the key findings of the ECHELON-1 study (NCT01712490)2?

ECHELON-1 evaluated brentuximab and AVD versus ABVD. The standard of care is ABVD. The most important thing to note is the dose of brentuximab, which is 1.2 mg/kg, not 1.8 mg/kg, because this is given every 2 weeks. It’s mirroring when ABVD is administered.

[This was a] large study with [more than] 1200 patients. It examined patients with stage III or IV classical Hodgkin lymphoma who had relatively good performance status. The investigators did allow patients to enroll if they had measurable disease and adequate liver and renal function. There was a PET scan at the end of cycle 2; however, this was not a PET-adaptive therapy. ABVD was given for 6 cycles. There is no decrease to AVD or escalation to BEACOPP

At 3 years, the progression-free survival [PFS] rate was 83% in the treatment arm and 76% in the control arm. This is highly significant, with a P value of .005, a hazard ratio of 0.7.

Overall, subgroup analysis favors brentuximab and AVD. But the confidence intervals do cross over in some categories, especially in the regional subgroup. For some reason, ABVD seems to do better in Asia. The study, though, is not powered to determine if 1 region is better than another. So, you have to take this kind of data with a grain of salt.

Now, remember this patient was young; she’s in her early 20s. In a younger age group, the A+AVD did better than ABVD. She lives in North America, so that’s a region where ABVD did better. And then looking at the IPS, she had a score of 4, and that’s another group in which A+AVD did better.

In general, A+AVD would probably be favored in stage IV disease. Her symptoms are associated with having extranodal sites, and in our case, the patient’s extranodal site was associated with the bones. Her performance status is good.

Looking at the responses in ECHELON-1, the overall response rate was 86% versus 83%, so there are small differences.

Regarding adverse effects [AEs], remember that when we think about brentuximab, we think of peripheral neuropathy. In the study, peripheral neuropathy was 67% for the treatment arm versus 42% in the ABVD arm. For diarrhea, it’s 27% versus 18%, and abdominal pain was slightly higher in ABVD, as well. In terms of any AEs, they’re similar; grade 3 events were more for A+AVD versus ABVD.

I will mention that initially in the protocol there was no mandate for growth factor, so most patients were treated without growth factors. There were increasing incidences of neutropenia and neutropenic fevers in the A+AVD arm. Protocol amendments were performed later and G-CSF support was introduced. It was the middle part of the program. The guidelines recommend that A+AVD should be used with G-CSF support. But the protocol for the most part didn’t initiate G-CSF support except toward the end. So, we see 83 patients who [received] G-CSF support and 579 who didn’t.

In terms of serious AEs, there were more associated with A+AVD. The reason I bring that up is because the majority of that protocol was already carried out without the G-CSF support. The treatment group ended up seeing more AEs and clearly there are more incidences of neuropathy with A+AVD. Drug discontinuation, however, was about the same between the groups. Deaths during treatment [were] very low, and there were more hospitalizations observed with A+AVD.

Did investigators initiate any dose delays?

Most of the dose delays were initiated because of neutropenia and febrile neutropenia. For patients who discontinued more than 1 drug because of AEs, 7% were attributed to peripheral neuropathy, which is an important AE in this treatment.

Regarding pulmonary toxicity, we would expect a bleomycin-containing regimen would have higher pulmonary toxicity. It was seen in 7% of patients with ABVD and 2% with A+AVD,

and grade 3 or more pulmonary toxicity was low in A+AVD but observed in 3% of patients with ABVD.²

How were febrile neutropenia and any neutropenia addressed in the trial?

We see a difference between patients who [received] G-CSF support versus those who didn’t, regarding febrile neutropenia versus any neutropenia. In patients who developed febrile neutropenia during treatment, 11% of those who received G-CSF support experienced the AE, and 21% who did not receive G-CSF support experienced the AE.

For neutropenia any grade, 73% of patients who did not receive GCSF versus 35% of patients who did receive G-CSF support developed it. Similarly, for grade 3 or more neutropenia, 70% who did not receive G-CSF versus 29% of patients who did developed it. To me, that is the most striking observation.

In the ABVD arm, there was neutropenia observed with ABVD, and we all have had patients with ABVD where the absolute neutrophil count is low, and we still go ahead and treat. That is done in standard practice.

In terms of serious AEs, there were more serious AEs with A+AVD compared [with] ABVD, 44% versus 28%. And there were no differences in deaths.

The A+AVD regimen can cause peripheral neuropathy. But if you look at complete resolution of peripheral neuropathy, you can see that 78% of patients treated with A+AVD had complete resolution and 83% of those on ABVD had complete resolution. Patients receiving ABVD also get neuropathy primarily because of vinblastine. Improvement in neuropathy also occurred in both groups; 17% of patients had improvement, not resolution, in the A+AVD arm versus 9% in the ABVD arm. The vast majority had resolution, but many had improvement as well.

However, for ongoing neuropathy that [was] grade 1 or 2, 25% of patients in the A+AVD arm and only 11% in the ABVD group experienced this. We have to be vigilant and monitor them throughout treatment so that it doesn’t get too bad, so appropriate dose reductions can be made.

The bottom line here is most neuropathy is going to go away, but there will be patients where neuropathy can persist, and that can be an annoying thing, especially for a young person. For many in long-term follow-up, they’ll experience improvement in neuropathy over time, which means things are getting better, but that doesn’t mean it’s all resolved.

_References:

_{1. NCCN Clinical Practice Guidelines in Oncology. Hodgkin lymphoma, version 2.2020. Accessed August 26, 2020. http://bit.ly/2YAIYha}

_{2. Connors JM, Jurczak W, Straus DJ, et al. 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}