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ASH 2023: Lymphomas and CLL

CE / CME

Key Studies in Lymphomas and CLL: Independent Coverage of ASH 2023

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Nurses: 1.00 Nursing contact hour

Physicians: maximum of 1.00 AMA PRA Category 1 Credit™

Pharmacists: 1.00 contact hour (0.1 CEUs)

Released: March 06, 2024

Expiration: March 05, 2025

Ian Flinn
Ian Flinn, MD, PhD
CME/CE Information

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SWOG S1826: Nivolumab-AVD vs BV-AVD in Older Patients (Aged ≥60 Yr) With Advanced-Stage cHL

The phase III SWOG S1826 trial is an important study comparing nivolumab vs BV both added to combination chemotherapy consisting of AVD in patients with newly diagnosed advanced cHL (NCT03907488). Presented at ASH 2023 was a subgroup analysis from SWOG S1826 in older patients (≥60 years of age).31

Generally, older patients with cHL have worse outcomes with inferior survival compared to younger patients.32 When doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was the standard of care regimen, we wondered whether worse outcomes were due to bleomycin toxicity. However, even with the BV-AVD regimen, the outcomes in older patients are not as good as we would like and are not nearly as good as those in the younger population. So, the goal here was to see if the benefit of nivolumab-AVD was maintained in this older population.31

Of note, G-CSF was required in those treated with BV-AVD and optional for those who received nivolumab-AVD. This was due to the higher incidence of neutropenia with BV. There was also an option for radiotherapy at the end of treatment, if residual FDG-avid lesions were present.

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SWOG S1826 (Older Patient Subset): Baseline Characteristics

The baseline characteristics among those included in this subgroup analysis were relatively well-balanced.31 The median age was 66.4 years and 67.1 years in those who received nivolumab-AVD and BV-AVD, respectively. There were a few patients aged 80 years or older in each arm, but the majority were between 60 and 69 years (65% and 74%, respectively). Many of these patients had a high IPI score of 4 to 7 (50% and 45%, respectively). A small percentage had bulky disease (15% and 10%), but approximately half had B symptoms upon entering the trial (52% and 55% of those receiving nivolumab-AVD and BV-AVD, respectively).

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SWOG S1826 (Older Patient Subset): Efficacy

Looking at the time to event analysis, PFS was dramatically improved with nivolumab-AVD vs BV-AVD (HR: 0.35; 95% CI: 0.12-1.02; P = .022), with 1-year PFS estimates of 93% vs 64%, respectively. EFS was also improved with nivolumab-AVD vs BV-AVD, with 1-year estimates of 93% and 57%, respectively (HR: 0.19; 95% CI: 0.06-0.61; P = .0011). No OS benefit was observed at the time of this analysis.

Some critics of the overall SWOG S1826 parent study,33 where a PFS benefit but not an OS benefit was observed, argue that the median follow-up of 12.1 months is too short and thus these data will not change their practice. However, I think the difference in efficacy between nivolumab-AVD vs BV-AVD in this subgroup analysis in older patients is difficult to ignore. Whether you look at PFS or EFS, the improvements between those who received nivolumab-AVD vs BV-AVD are huge.31 Although an OS benefit may not have been demonstrated overall, you still may be able to save a large group from needing to get a second therapy (ie, chemotherapy followed by an autologous stem cell transplant), so I have adopted this regimen in my clinical practice.

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SWOG S1826 (Older Patient Subset): Safety

In terms of safety, more neutropenia (53% vs 32%), including grade 3 or higher (49% vs 30%), was observed in those receiving nivolumab-AVD compared to BV-AVD.31 I believe this difference is due to all patients receiving BV-AVD being required to receive G-CSF. Other hematopoietic AEs were worse with BV-AVD vs nivolumab-AVD.

Furthermore, the rate of infections, including grade 3 or higher, and neuropathy were higher with BV-AVD compared to nivolumab-AVD, which is not unexpected.

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SWOG S1826 (Older Patient Subset): Safety (cont’d)

The incidence of hypothyroidism was higher in the nivolumab-AVD arm compared to the BV-AVD arm, consistent with what we see with nivolumab monotherapy. There was also an increase in the incidence of rash in the nivolumab-AVD arm. However, these are manageable toxicities.

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SWOG S1826 (Older Patient Subset): Patient Disposition

Looking at patient disposition, we see that patients receiving BV-AVD had a higher early treatment discontinuation rate than those receiving nivolumab-AVD. Again, I think that testifies to the better tolerability of nivolumab-AVD compared to BV-AVD.

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SWOG S1826: Clinical Implications

In my clinical practice, I have adopted the nivolumab-AVD regimen as frontline therapy for all patients with advanced cHL, unless a patient has a contraindication to immune checkpoint inhibitor therapy. With this recent subgroup analysis, it is more evident how important this regimen is, particularly in an older population, where the differences between nivolumab-AVD and BV-AVD are even more stark. Again, some may argue that without evidence of an OS benefit, they are not going to change to nivolumab-AVD. However, I think it is likely, especially in this older population, that an OS difference will eventually emerge. With cHL, it will just take some time to see. For example, this was true with BV + AVD, where a difference in survival eventually became apparent.

The phase III SWOG S1826 trial is comparing nivolumab vs brentuximab vedotin (BV) both added to combination chemotherapy consisting of doxorubicin, vinblastine, and dacarbazine (AVD) in patients with newly diagnosed advanced classical Hodgkin lymphoma (cHL). In talking with an older patient about treatment options, which of the following findings would you tell them was reported at ASH 2023 for nivolumab-AVD vs BV-AVD in a subgroup analysis of patients 60 years of age or older?

AN + AD in Early-Stage cHL

For our final ASH 2023 study, I will move into the setting of early-stage cHL. Part C of the phase II SGN35-027 trial evaluated BV plus nivolumab with doxorubicin and dacarbazine (AN + AD) in patients with untreated, early-stage cHL.34 In this regimen, bleomycin and vinblastine are removed from the chemotherapy backbone. Patients were treated with 4 cycles of AN + AD before undergoing the second assessment for response (the first was done at Cycle 2).

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AN + AD in Early-Stage cHL: Baseline Characteristics

The median age of patients in this study was 31 years, which is representative of cHL. Approximately half (55%) of the patients were women. Patients predominantly had stage II disease (89%), with the majority being stage IIa. Approximately one fourth (23%) had B symptoms.

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AN + AD in Early-Stage cHL: Antitumor Activity

The ORR with AN + AD was similar in both the overall and efficacy evaluable populations, 95% and 98%, respectively. The CR rate was comparable as well, 91% and 93%. A few patients (5%) in each population achieved a partial response. Almost all patients (99%) achieved a CR at some point, either during treatment or in long-term follow-up. The DoR >12 months and duration of CR >12 months was very high at 99% and 98%, respectively. So this regimen was highly efficacious, though with a short follow-up (16.5 months).34

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AN + AD: Clinical Implications

Although this is very encouraging data looking at deintensifying therapy for patients with early-stage HL, I do feel it is difficult to apply a single-arm study in HL, particularly in the early-stage setting. Hopefully this regimen will be evaluated in a randomized trial. That said, I think BV is an important drug in this disease and am hopeful for regimens combining it with immune checkpoint inhibition.

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