Tuscano Reviews Treatment and Toxicity Management for a Patient With Classic Hodgkin Lymphoma

Joseph Michael Tuscano, MD, professor of Medicine ay UC Davis Comprehensive Cancer Center in Sacramento, CA, discussed the case of a 22-year-old patient with classic Hodgkin lymphoma during a Targeted Oncology Case-Based Roundtable event held virtually.

Targeted Oncology^TM: Please discuss some factors that stick out to you when reviewing this patient’s case.

TUSCANO: The International Prognostic Score [IPS] is made up of [multiple] factors: low albumin level [<4 g/dL], hemoglobin level under 10.5 g/dL, male sex, age 45 years or more, stage IV [Ann Arbor classification], white cell count 15,000/mm³ or more, lymphocyte count under 600/mm³, under 8% of the WBC, or both.¹

The IPS is predictive. This patient had a few “dings”: He had a low albumin level, he’s male, and he [had] stage IV disease, with an IPS of 4 and 5-year overall survival [OS] of 61%. Normally, I don’t calculate IPS…because it hasn’t been shown to change treatment outcomes. There are few prospective studies that use the IPS that have defined outcomes or treatment approaches based on it. But there are some data that suggest certain treatments, especially modern treatments, may be better, and there may be better outcomes in a patient with a high-hrisk IPS score.

Assessing prognosis is important. Some patients want to know it; others do not. It is good for accurate charting and communication with our patients and our colleagues and, potentially, referral for clinical trial.

How do you decide between PET-adapted therapy and brentuximab vedotin (Adcetris) plus AVD (doxorubicin, vinblastine, dacarbazine)?

Bleomycin-mediated lung toxicity is unpredictable and is not necessarily related to dose, so some people can get it early. It can be independent of dose, and some people can get it late. It can be severe and occasionally lethal. Elderly patients get it much more commonly [than younger patients]…and in elderly patients, the mortality is like 20%.

What are your thoughts on this poll? What do you think is most important?

These are all very important. I’m assuming that for lung disease and smoking history, those are patients for whom you would potentially consider brentuximab vedotin/AVD and completely omit bleomycin.

Some of the factors [you consider in treatment selection]… are history of lung disease and smoking history…because those are the patients for whom you would definitely go with brentuximab vedotin/AVD and eliminate bleomycin. The NCCN [National Comprehensive Cancer Network] guidelines… state that you can give, for primary treatment, modified response-adapted therapy for advanced Hodgkin lymphoma. The other options are the ECHELON-1 [NCT01712490] regimen and the German Hodgkin Study Group HD15 regimen. NCCN prefers that you restage after 2 cycles for patients with a Deauville criteria score of 1 to 3. You use 2 cycles of ABVD [doxorubicin, bleomycin, vinblastine, dacarbazine] for patients with Deauville 4 [or 5]. You can also escalate to BEACOPP [bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone]. You can do 2 more [of either regimen] and restage again. For patients with Deauville score of 4 or 5, NCCN recommends escalated BEACOPP. Brentuximab vedotin/AVD is a category 2B recommendation [and a 2A in select patients with no neuropathy, IPS of 4 or greater, or bleomycin contraindication].²

Which trial looked at the regimen that this patient received?

The ECHELON-1 trial was a randomized trial that compared ABVD for 6 cycles versus brentuximab vedotin/AVD for 6 cycles. [Patients] were able to get an end-of-cycle-2 PET scan, and if [they] had a Deauville score of 5, [they] could get alternate therapy and then an end-of-treatment PET scan. The primary end point was modified progression-free survival [mPFS]. PFS is usually defined as [the interval of time until] progression or death; mPFS is additional therapy, progression, or death.³ The reason that becomes important is some patients won’t meet the criteria [for clinical trial] for progression and their disease is not responding or their disease will be a bit worse. In practice, we usually wouldn’t continue treatment for patients in whom disease is getting worse or who have persistent or refractory disease. The patients [described] could get additional therapy or maybe radiation therapy, and then they would meet the end point for mPFS. This analysis was for mPFS.³

What are the efficacy data in the ECHELON-1 trial?

The [investigator] PFS rate at 3 years, a median follow-up of 37 months, for brentuximab vedotin/AVD was 83% versus 76% for ABVD, which was statistically significant, with a P value of .005. There wasn’t an OS benefit; the PFS benefit was 7 [percentage points].⁴

In patients on brentuximab vedotin/AVD versus ABVD, for the younger patients [< 45 years (HR, 0.686; 95% CI, 0.494-0.954) versus ≥ 45 years (HR, 0.741; 95% CI, 0.511- 1.076)] and the North American patients [HR, 0.49; 95% CI, 0.315-0.764] compared with [those from] other regions, you see better mPFS, although it’s not clear why brentuximab vedotin/AVD was more significant in the North American population. In patients on brentuximab vedotin/AVD versus ABVD with IPS of 4 to 7, mPFS was a little better [HR, 0.588; 95% CI, 0.386-0.894]…versus IPS 2 or 3 [HR, 0.804; 95% CI, 0.558-1.158] and IPS 0 or 1 [HR, 0.666; 95% CI, 0.381-1.163]; the statistical significance was more favorable for IPS 4 to 7.⁴

Patients on brentuximab vedotin/AVD versus ABVD with stage IV disease had a better mPFS versus patients with stage III disease [HR, 0.723; 95% CI, 0.537-0.973, versus HR, 0.643; 95% CI, 0.412-1.004, respectively]. mPFS for B symptoms versus no B symptoms was better for patients on brentuximab vedotin/AVD [(HR, 0.760; 95% CI, 0.558- 1.035) versus ABVD (HR, 0.572; 95% CI, 0.378-0.866)]. The mPFS for number of extranodal sites for each arm was pretty much the same. All categories favored brentuximab vedotin/AVD in terms of the hazard ratio.⁴

In terms of overall response, it was 86% versus 83% for patients on brentuximab vedotin/AVD versus ABVD, respectively [difference, 3.2; 95% CI, –2.2 to 8.6]; complete response was 73% versus 70% [difference 3.0; 95% CI, –2.3 to 8.4], not a huge difference.³

How did these patients react to treatment in terms of toxicity?

The adverse events [AEs] were about the same for both arms. Grade 3 AEs were a little higher for brentuximab vedotin/AVD, and the serious AEs were also a little higher. It’s important to understand that the first part of this trial was done without G-CSF.³ Another important point is that for ABVD, sometimes it’s hard to keep people on that every-2-weeks schedule. In previous trials, they didn’t allow G-CSF because it increases bleomycin-mediated lung toxicity. There are data, mostly in younger patients, [showing] that you can treat at day 15 or the next cycle despite counts and the outcomes are good; patients don’t develop much febrile neutropenia. But it makes me nervous not to use growth factors in some of those patients, especially elderly patients. This trial started off with no G-CSF, but that was later amended because they saw a lot more neutropenia in the brentuximab vedotin/AVD arm, so G-CSF was mandated.³

Dose delays of 1 or more drugs in over 5% of patients on brentuximab vedotin/AVD due to AEs were 21% for neutropenia and 8% for febrile neutropenia. Discontinuation of more than 1 drug due to AEs was 13% for patients on brentuximab vedotin/AVD.⁵ Pulmonary toxicity was quite a bit less: [For] all grades, [it] was 2% with brentuximab vedotin/ AVD versus 7% with ABVD, but about half of that was grade 3 or 4. Grade 3 or 4 is serious pulmonary toxicity, requiring oxygen, and some of those cases can be lethal. If you look at on-study deaths, there were 7 neutropenia-related deaths in the brentuximab vedotin/AVD arm, but that went down after institution of G-CSF; if you look at pulmonary toxicity–related deaths, there were 11 in the ABVD arm.³

Febrile neutropenia during treatment with brentuximab vedotin/AVD was 21% before G-CSF and went down to 11% with growth factor; it was relatively low in the ABVD arm, at 8% [before decreasing to 7%]. Any neutropenia was cut in half [brentuximab vedotin/AVD, 73% before G-CSF versus 35% after; ABVD, 57% before versus 21% after], and grade 3 neutropenia was cut in half [brentuximab vedotin/AVD, 70% before G-CSF versus 29% after; ABVD, 50% before versus 19% after], all by adding G-CSF.³ I think [adding it] is kind of a no-brainer for those who are using brentuximab vedotin/AVD because there’s a lot more neutropenia with it.

There was more peripheral neuropathy in patients receiving brentuximab vedotin/AVD, but the important part was: Did it get better? If you look at brentuximab vedotin/ AVD–induced neuropathy, 78% had complete resolution… for ABVD-induced neuropathy, 83% had complete resolution. The median time to complete resolution was longer for brentuximab vedotin/AVD versus ABVD, 28 versus 14 weeks, respectively; improvement was 17% versus 9%, respectively; median time to improvement was 40 versus 32 weeks, respectively; and ongoing peripheral neuropathy was 25% versus 11%, respectively.4 The vast majority of the ongoing cases are grade 1 and 2.

Secondary malignancies are a big issue, especially in our younger patients, and rates can be anywhere from 7% to 10%, 10 to 15 years after receiving ABVD; it’s not insignificant. The incidence was lower with brentuximab vedotin/AVD than with ABVD [14% versus 20%] in ECHELON-1, but we don’t yet know whether that is statistically significant.⁴

_REFERENCES:

_{1. Hasenclever D, Diehl V, Armitage JO, et al; International Prognostic Factors Project on Advanced Hodgkin’s Disease. A prognostic score for 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, version2.2021. Accessed February 22, 2021. https://bit.ly/3oDAEZ4}

_{3. Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximabvedotin 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, Alekseev S, et al. Brentuximab vedotin withchemotherapy for stage III/IV classical Hodgkin lymphoma: 3-year update of theECHELON-1 study. Blood. 2020;135(10):735-742. doi:10.1182/blood.2019003127}

_{5. Adcetris. Prescribing information. Seagen Inc; 2019. Accessed February 22,2021. https://seagendocs.com/Adcetris_Full_Ltr_Master.pdf}