Venugopal Considers BTK and BCL2 Inhibitors in Patient With CLL

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Treatment for a patient with chronic lymphocytic leukemia who has comorbidities including hypertension and atrial fibrillation was the topic of discussion during a Targeted Oncology Case-Based Roundtable event led by Parameswaran Venugopal, MD.

Parameswaran Venugopal, MD

Parameswaran Venugopal, MD

Treatment for a patient with chronic lymphocytic leukemia (CLL) who has comorbidities including hypertension and atrial fibrillation was the topic of discussion during a Targeted Oncology Case-Based Roundtable event led by Parameswaran Venugopal, MD, The Elodia Kehm chair of HematologyProfessor in the Department of Internal MedicineDirector, Section of Hematology at Rush Medical College.

Targeted OncologyTM: Given the patient’s comorbidities, cytogenetics, and disease characteristics, what therapy are you most likely to select?

VENUGOPAL: I would probably [choose] chemoimmuno-therapy because the patient has unmutated IGHV, and patients with unmutated IGHV with deletion 17p [del(17p)] are much better off with a novel agent.

What are the roles of Bruton tyrosine kinase (BTK) and B-cell lymphoma–2 (BCL2) inhibitors? How do you choose among them?

According to the National Comprehensive Cancer Network [NCCN] guidelines, the frontline options for patients without del(17p) are ibrutinib [Imbruvica]; acal-abrutinib [Calquence] with or without obinutuzumab [Gazyva]; and venetoclax [Venclexta] with obinutuzumab.1 First, there is the question between an inhibitor of BTK [acalabrutinib or ibrutinib] and venetoclax, an inhibitor of BCL2—which will you choose? I don’t think we have a randomized study to say one is better than the other. We don’t have any prospectively randomized data to say that a BTK [inhibitor] is better than a BCL2 inhibitor. One could say that the BTK inhibitor has a longer track record, in which case the BTK inhibitor seems to be appropriate.

The next question is which BTK inhibitor: [acalabrutinib or ibrutinib]? One of the points I would consider here is the fact that the patient has atrial fibrillation, even though it is asymptomatic....I would consider acalabrutinib alone, or in combination [with obinutuzumab].

Do you find it curious that the choices are the same whether the patient is younger or older than 65 years?

Age used to be one of the main distinguishing features [by which we would decide] what to offer a patient with CLL, but with the novel agents, the distinction [among age groups] is becoming blurred.

What are recent data on progression-free survival (PFS) following ibrutinib as frontline BTK inhibitor therapy for patients with CLL? Does performance vary with del(11q) or IGHV status?

RESONATE-2 [NCT01722487] was a phase 3, prospective study of frontline ibrutinib in patients who were at least 65 years of age or who had comorbidities that precluded chemoimmunotherapy with fludarabine, cyclophosphamide [Cytoxan], and rituximab [Rituxan] [FCR], which was the standard of care for eligible patients at [the time of the study].2-4 Ibrutinib was given as a single agent, until progression, and patients could get into the extension study and continue. The control arm was chlorambucil [Leukeran]; again, at that time, chlorambucil was considered the standard of care.

After about 18 months’ follow-up, there was a significant difference in favor of ibrutinib in terms of PFS. Median PFS was not reached in the ibrutinib arm and was 18.9 months in the chlorambucil arm [HR, 0.16; 95% CI, 0.09-0.28; P < .001].2 At the 5-year update, remissions were very well maintained. Median PFS for the 2 arms, respectively, was not estimable versus 15 months [HR, 0.146; 95% CI, 0.098-0.218].3

The responses were [also] very well maintained in patients who had del(11q); [perhaps even] a little better than in patients who were without that deletion. Sixtymonth PFS was observed in 79% of ibrutinib patients and in 0% of chlorambucil patients. Respectively, median PFS was not estimable versus 9 months [HR, 0.034; 95% CI, 0.010-0.108]. Regarding IGHV status, whether the patients had mutated IGHV or not, ibrutinib did a good job without significant difference between those groups and clearly superior to chlorambucil-based treatment. At 60 months, PFS with ibrutinib was observed in 67% of patients with unmutated IGHV [HR, 0.105; 95% CI, 0.058-0.190] and in 81% of patients with mutated IGHV [HR, 0.153; 95% CI, 0.067-0.349].3

The E1912 [NCT02048813] study included patients who were eligible for intensive treatment [70 years and younger, with good organ function and performance status, and able to tolerate FCR].5 Patients with del(17p) were excluded. Patients were randomly assigned to receive 6 cycles of FCR, or ibrutinib with rituximab [IR]. Ibrutinib alone was continued after the initial combination treatment until disease progression.

The primary end point was PFS. At the 4-year followup, 3-year PFS was 89% in the IR group and 71% in the FCR group [HR, 0.39; 95% CI, 0.26-0.57; P < .0001] indicating superiority of IR.6 Please note that there was no single-agent ibrutinib arm in this study. Among patients with mutated IGHV, there was no significant 3-year PFS difference between the IR and FCR groups [88% versus 82% respectively; HR, 0.42; 95% CI, 0.16-1.16; P = .086]. [However], among patients with unmutated IGHV there was a significant difference [favoring IR][89% vs 65%; HR, 0.28; 95% CI, 0.17-0.48; P < .0001]. Three-year overall survival [OS] was 98.8% in the IR arm and 91.5% in the FCR arm [HR, 0.17; 95% CI, 0.05-0.54; P < .001].5 This was the basis of the approval of the ibrutinib-plus- rituximab combination.7

What data are there showing efficacy of frontline acalabrutinib? Is it consistently effective across various patient subpopulations?

The ELEVATE CLL TN trial [NCT02475681] looking at the second BTK inhibitor approved for CLL, acalabrutinib, was in older patients [65 years or older] or younger patients with comorbidities.8,9 Also, this [study] had a single-agent arm. The comparison arm was chlorambucil plus obinutuzumab [CO]; [this was compared with] acalabrutinib as a single agent and with acalabrutinib in combination with obinutuzumab [AO]. The final end point was PFS.8

Median follow-up was about 28 months. Acalabrutinib, whether given alone or in combination with obinutuzumab, was far superior to CO. Patients who received acalabrutinib alone demonstrated a median PFS that was not reached during follow-up [95% CI, 34.2-not evaluable]; patients who received AO likewise demonstrated a median PFS that was not reached [95% CI, not evaluable (NE)-NE]. Median PFS for the CO group was 22.6 months [95% CI, 20.2-27.6]. A reduced relative risk of progression or death was observed in the group that received acalabrutinib alone [HR, 0.20; 95% CI, 0.13-0.30; P < .0001] and in the AO group [HR, 0.10; 95% CI, 0.06-0.17; P < .0001].10

The best overall response rate [ORR] was 94% for the AO group [95% CI, 89%-97%] and 79% [95% CI, 72%-84%] for the CO group [P < .0001]. For the acalabrutinib monotherapy group, the best ORR was 86% [95% CI, 80%-90%; P = .80]. There [was a higher rate] of complete response in the AO group [13%], compared with acalabrutinib alone [1%], or the chemotherapy combination [5%], and the rate of stable disease was 2%, 5%, and 9%, respectively. The difference in OS between the AO arm and the chemotherapy arm was very close to being significant [HR, 0.47; 95% CI, 0.21-1.06; P = .0577]. We need to remember that patients [who progressed on CO] did cross over to the acalabrutinib arm.8

In all the subgroups, defined by age, Rai stage, performance status, bulky disease, or the presence or absence of del(11)(q22.3), mutated IGHV, [or del(17)(p13.1) with or without mutated TP53], patients who received acalabrutinib alone or in combination with obinutuzumab did better than [those who received] chemotherapy.10

Do BCL2 inhibitors appear to be a viable alternative to BTK inhibitors as frontline CLL therapy? How do they perform with respect to IGHV mutation status?

The phase 3 CLL14 trial [NCT02242942] compared the combination of venetoclax plus obinutuzumab [VO] with the combination of chlorambucil plus obinutuzumab [CO] in first-line CLL.11

The PFS was clearly superior at the 4-year mark, 74.0% for patients receiving VO versus 35.4% for patients receiving CO [HR, 0.33; 95% CI, 0.25-0.45; P < .0001]. The 4-year time-to-next-treatment rate is also clearly superior, 81.08% versus 59.9%, respectively [HR, 0.46; 95% CI, 0.32-0.65; P < .0001].11,12

This [study also looked at] PFS by IGHV mutation. Whether they had IGHV mutation or not, patients did very well with the venetoclax combination [HR, 1.96; 95% CI, 0.92-4.17; P = .08].

Does frontline therapy with venetoclax help to achieve undetectable MRD? They also looked at minimal residual disease [MRD] in peripheral blood and bone marrow. [In all subgroups], there was significant response in favor of the venetoclax combination. With VO, 75.5% of patients achieved undetectable MRD, and 55.8% of these achieved complete response [CR]. With CO, 35.2% of patients achieved undetectable MRD, and 40.8% of these achieved CR [P < .001 for MRD and CR assessments]. Results were similar when MRD was assayed in the bone marrow. So, VO induces deeper remission.

What is the significance of achieving this? There are some indications that people who achieve CR with undetectable [MRD] can have longer PFS than can patients who do not achieve that. At 24 months, in the VO arm, the percentage of patients with PFS was 89.1% among patients with undetectable MRD and 61.9% among patients with detectable MRD.14

What, if anything, can we conclude from a comparison of these trials?

These are different studies, and it doesn’t make sense to compare without a prospective trial. I depend more on the tolerance and the patient characteristics for choosing which BTK and BCL2 inhibitor.

The data show that one [can] monitor the peripheral blood [to assay MRD]. We don’t have data to say that the peripheral blood finding will [be a definite] surrogate; it looks [like] it may be.14 But routinely, outside clinical trials, will you do that? I routinely do flow cytometry at the end of treatment, and in most of the patients we do bone marrow biopsy before we tell the patient that they are in complete remission, so the flow cytometry, not PCR, [assays] MRD. PCR probably would be useful if you have a marker up front, like a cytogenetic marker that disappears and can be [interpreted] as MRD negativity. But the question is what is the significance? Currently, we don’t know.


1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 4.2021. Accessed June 8, 2021.

2. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. doi:10.1056/NEJMoa1509388

3. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798. doi:10.1038/s41375-019-0602-x

4. Eichhorst BF, Busch R, Stilgenbauer S, et al; German CLL Study Group (GCLLSG). First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood. 2009;114(16):3382-3391. doi:10.1182/blood-2009-02-206185

5. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmuno-therapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443. doi:10.1056/NEJMoa1817073

6. Shanafelt TD, Wang V, Kay NE, et al. Ibrutinib and rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia (CLL): extended follow-up from the E1912 trial. Blood. 2019;134(suppl 1):33. doi:10.1182/blood-2019-126824

7. FDA approves ibrutinib plus rituximab for chronic lymphocytic leukemia. News release. FDA. April 21, 2020. Accessed June 9, 2021.

8. Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients (pts) with treatment-naive chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl 1):31. doi:10.1182/blood-2019-128404

9. Project Orbis: FDA approves acalabrutinib for CLL and SLL. News release. FDA. November 21, 2019. Accessed June 9, 2021.

10. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinu-tuzumab versus chlorambucil and obinutuzumab for treatment-naïve 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

11. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225‐2236. doi:10.1056/NEJMoa1815281

12. Al-Sawaf O, Zhang C, Robrecht S, et al. Clonal dynamics after venetoclax-obinutuzumab therapy: novel insights from the randomized, phase 3 CLL14 trial. Blood. 2020;136(suppl 1):22-23. doi:10.1182/blood-2020-136977

13. Al-Sawaf O, Zhang C, Tandon M, et al. Fixed-duration venetoclax-obinutu-zumab for previously untreated patients with chronic lymphocytic leukemia: follow-up of efficacy and safety results from the multicenter, open-label, randomized, phase III CLL14 trial. Presented at: 56th Annual Meeting of the American Society of Clinical Oncology; May 29-June 2, 2020; virtual. Accessed June 11, 2021.

14. Fischer K, Ritgen M, Al-Sawaf O, et al. Quantitative analysis of minimal residual disease (MRD) shows high rates of undetectable MRD after fixed-dura-tion chemotherapy-free treatment and serves as surrogate marker for progres-sion-free survival: a prospective analysis of the randomized CLL14 trial. Blood. 2019;134(suppl 1):36. doi:10.1182/blood-2019-125825

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