Second-Generation BTK Inhibitor With Anti-CD20 Antibody Improves Survival and Responses in Treatment-Naive CLL

Justin Kline, MD

Director, Lymphoma Program

Professor of Medicine

University of Chicago

Chicago, IL

CASE SUMMARY

• A female patient aged 61 years reported symptoms of unintentional weight loss and increasing fatigue.

Physical Examination

• Chronically ill appearing and continues only limited daily activity
• ECOG performance status: 1
• Axillary lymphadenopathy, spleen palpable approximately 6 cm below costal margin

Laboratory Results

• White blood cell count: 47,000/mL (upper limit of normal, 11,000)
• 76% lymphocytes
• Hemoglobulin: 8.7 g/dL (lower limit of normal, 12.0 g/dL)
• Platelet count: 115,000/μL (lower limit of normal, 150,000/μL)
• Absolute neutrophil count: 3,600/μL (within normal limits)
• Lactate dehydrogenase: 250 U/L (within normal limits)
• β₂-Microglobulin: 4.3 μg/L (upper limit of normal, 1.8 mg/L)
• Comprehensive chemistry panel: within normal limits
• Flow cytometry: CD5+, CD20+, CD23+
• Fluorescence in situ hybridization: del(11q)
• Molecular analysis: IGHV unmutated
• CT scan showed diffuse 1- to 3-cm adenopathy and confirmed splenomegaly.

Targeted Oncology: What treatment would you consider for a patient like this?

KLINE: Acalabrutinib [Calquence], in comparison with ibrutinib [Imbruvica], is well tolerated....¹ I think the main decision point for me, [in treating a patient without] a TP53 deletion mutation, is does the patient have a preference for time-limited therapy...or are they OK with being on a pill once or twice a day indefinitely? Some patients have preferences, and others don’t, but initially I leaned more toward giving a Bruton tyrosine kinase [BTK] inhibitor [to these patients]. Once I became more comfortable with venetoclax [Venclexta], it’s a bit more painful to initiate as...in the first few weeks with the dose ramp-up [it] is a little bit cumbersome, particularly for patients [who] have a moderate or high risk for tumor lysis syndrome. After that [period it’s]...well tolerated. So, I think any [choice between] acalabrutinib, acalabrutinib plus an anti-CD20 therapy, venetoclax plus anti-CD20 therapy, and zanubrutinib [Brukinsa] is reasonable. Ibrutinib, although it’s a major breakthrough drug, probably from a safety perspective, and maybe even an efficacy perspective too, is not the best first choice [in a patient like this]. Still, I think we all have patients who are on ibrutinib and have been tolerating it well.... I have patients who are still on ibrutinib going on 8 to 9 years now, and I don’t switch that if they’re tolerating it. However, do I prescribe ibrutinib newly? No.

What were the results of the phase 3 ELEVATE-TN study (NCT02475681) that would make you choose acalabrutinib for a patient like this?

The progression-free survival [PFS] of these patients at 5 years was 84% in [those who] received acalabrutinib plus obinutuzumab, 72% [in patients who] received acalabrutinib alone, and only 20% in patients [who] received obinutuzumab plus chlorambucil [HR, 0.21; 95% CI, 0.15-0.30; P < .0001].² Again, acalabrutinib is remarkably effective in untreated chronic lymphocytic leukemia [CLL], but these results are not a big surprise.... Adding a good anti-CD20 antibody to acalabrutinib led to an improved PFS in these patients; [still], it was relatively small, but it’s not nothing. [Further], we know patients with unmutated IGVH have a poor prognosis, as it’s a more aggressive disease [in those cases], and patients with mutated IGVH do well.

For patients with unmutated IGVH, obinutuzumab plus chlorambucil was terrible [with a 4% PFS rate at 5 years], but patients with mutated IGVH do well no matter what [with an 86% PFS rate for those on acalabrutinib and obinutuzumab and 77% for those on acalabrutinib monotherapy]. So, it’s a little bit harder to see a major difference [between patients with unmutated IGVH in either arm], although there was a difference.²

How did patients respond to and tolerate treatment with acalabrutinib?

BTK inhibitors typically do not induce complete remissions in patients with CLL. The vast majority of the responses are partial responses, but when adding obinutuzumab to acalabrutinib you do start to see some complete responses as well [Figure³]. So, perhaps not surprisingly, most people respond to these agents [with an objective response rate of 96.1% in the acalabrutinib and obinutuzumab arm compared with 83.1% in the obinutuzumab plus chlorambucil arm (P < .0001)]. Moreover, acalabrutinib with or without obinutuzumab favored all subgroups of patients [on this study].³ With acalabrutinib, you see some of the same adverse events [AEs] of any grade that we were seeing with ibrutinib. Namely atrial fibrillation [7.3%], bleeding [43.6%], although major bleeding was relatively rare [3.4%], and hypertension [8.9%].³ In my experience with acalabrutinib, the more common AEs are usually headache, cough, and myalgia. Although, I think in general, acalabrutinib is better tolerated than ibrutinib overall.

How does the addition of an anti-CD20 antibody therapy compare with other agents added to BTK inhibition?

The addition of rituximab [Rituxan] to ibrutinib did not improve outcomes.⁴ Based on that, a lot of people have in their heads that adding an anti-CD20 therapy to a BTK inhibitor does not make a difference. But it turns out that obinutuzumab seems to be a more potent anti-CD20 antibody, at least in CLL. The results with obinutuzumab did not really pan out [in other diseases]…but it was more toxic, so I don’t think that’s really made its way into practice, as obinutuzumab causes more neutropenia and more infections. Also, when rituximab is given [to patients with] lymphoma or CLL, it’s given on day 1 of each cycle, and in CLL that dose goes up to 500 mg/m² on subsequent cycles. Obinutuzumab is given on day 1, day 8, day 15, day 22, and then on day 1 of subsequent cycles up to a 6-month period. So, people are simply getting more anti-CD20 antibody in CLL, so I don’t know if it’s just that [treatment] design or simply a better anti-CD20 antibody. That all being said, I have not incorporated obinutuzumab into treatment with acalabrutinib. But again, looking at the objective response rate, it is definitely a bit higher with acalabrutinib plus obinutuzumab vs obinutuzumab plus chlorambucil.³ Also, 41% of patients who were [randomly assigned] to obinutuzumab plus chlorambucil crossed over, and it’s hard to assess OS with that kind of crossover.³

REFERENCES:

1. Roeker LE, DerSarkissian M, Ryan KJ, et al. Comparing acalabrutinib and ibrutinib in the real world: a study of 2,509 patients with chronic lymphocytic leukemia. Blood. 2022;140(suppl 1);4156-4158. doi:10.1182/blood-2022-167213

2. Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia. Leukemia. 2022;36(4):1171-1175. doi:10.1038/s41375-021-01485-x

3. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2

4. Burger JA, Sivina M, Jain N, et al. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019;133(10): 1011-1019. doi:10.1182/blood-2018-10-879429