Lamanna Details Evolution of CLL Treatment Following Resistance


Nicole Lamanna, MD, discusses treatment options for patients with chronic lymphocytic leukemia who develop resistance to a prior treatment.

Nicole Lamanna, MD

Nicole Lamanna, MD

Following progression, sequencing noncovalent vs covalent BTK inhibitors in the treatment of patients with chronic lymphocytic leukemia (CLL) is key, and data support treating patients with resistant disease who previously received a covalent BTK inhibitor with a venetoclax (Venclexta) platform or noncovalent BTK inhibitor, according to a presentation by Nicole Lamanna, MD, during the 41st Annual CFS® Meeting. She also noted data support treating patients who progressed following post-frontline BCL2 therapy with a covalent BTK inhibitor and a re-challenge with venetoclax-based therapy could be considered for those who experienced a long duration of initial response.1

“The question about double exposure and double refractory [disease] is a challenging one,” Lamanna, an associate clinical professor of medicine and the director of the Chronic Lymphocytic Leukemia Program at the Herbert Irving Comprehensive Cancer Center and New York-Presbyterian/Columbia University Medical Center in New York, New York, said during the presentation.

“Shorter treatment-free remission or progression on [a] prior covalent BTK inhibitor and venetoclax in this double-refractory patient [population means that] changing mechanisms is recommended and use of a noncovalent BTK inhibitor is an option,” Lamanna explained. “[For those with a] longer treatment-free remission—double-exposed, not refractory—venetoclax retreatment is an option. [Additionally], clinical trials with novel mechanisms of action [are] ongoing.”

In the presentation, Lamanna detailed the mutations that develop in BTK, current NCCN guidelines for CLL treatment following progression, and the roles of venetoclax, noncovalent/covalent BTK inhibitors, BTK degraders, and novel agents as therapeutics for patients with CLL.

Development of Resistant Mutations

Resistance mutations to covalent BTK inhibitors have been characterized as mutations in BTK at the C481 binding site position and mutations have been seen in PLCy2 immediately downstream of BTK at multiple hotspots including R665, L845, and S707. BTKC481S mutations are catalytically activating mutations that lead to increased downstream B-cell receptor signaling.1

Lamanna explained that acquired resistance to ibrutinib (Imbruvica) is mediated by mutations in BTK at C481 and most patients receiving ibrutinib have identified mutations in BTKC481 at the time of disease progression.

“As we’ve gotten more mature data and [are] following these patients in different clinical trials, we’re also seeing these different resistant mutations with acalabrutinib [Calquence], zanubrutinib [Brukinsa], as well [as ibrutinib],” Lamanna said.

Data from the phase 3 ELEVATE-RR (NCT02477696) trial evaluating acalabrutinib vs ibrutinib in patients with CLL revealed that among patients who received acalabrutinib (n = 31), 61.29% had a C481S alone mutation and in addition to a C481S mutation, T474I (19.35%), C481F (6.45%), C481Y plus T474I (3.23%), and C481R plus C481Y plus T474I (3.23%) were also seen. In the ibrutinib arm (n = 11), 54.55% of patients had a C481S alone mutation and 18.18% also had a C481F mutation; in addition to a C481S mutation, 9.09% had a C481W mutation and 9.09% had a C481R plus C481Y mutation.2

“We’re also starting to see non-C481 mutations develop, some in gatekeeper areas such as T474I or in kinase-impaired L528W,” Lamanna explained. “There’s some differences between the mutations that are being seen with the different covalent BTK inhibitors, but the majority are still at C481, and we need much more data.”

Lamanna noted there is an emerging heterogeneity in resistance mutations to BTK inhibitors as BTK C481S mutations have also been seen among patients treated with zanubrutinib and BTK mutations outside of the C481 position have been observed. Although BTK resistance testing is not a current standard of care (SOC), she explained it may have clinical implications in the future in addition to implications for BTK inhibitor sequencing regarding covalent vs noncovalent inhibitors.1

SOC Guidelines

When patients become refractory to a covalent BTK inhibitor, the current guidelines recommend noncovalent BTK inhibitors and venetoclax. The preferred regimens in the second- of third-line setting cited by the NCCN Clinical Practice Guidelines include acalabrutinib monotherapy, venetoclax plus rituximab (Rituxan), venetoclax monotherapy, and zanubrutnib. Additionally, pirtobrutinib (Jaypirca) was cited as useful in certain circumstances; Lamanna noted it is not yet approved for CLL but has made the NCCN guidelines for this indication.3

When treating patients with CLL or small lymphocytic lymphoma (SLL) without a del(17p)/TP53 mutation who are BTK inhibitor refractory, the first-line therapy includes continuous treatment with a BTK inhibitor with or without an anti-CD20 monoclonal antibody. Patients continue the same agent until intolerance or progression. In the event of progression, patients will receive venetoclax with or without an anti-CD20 monoclonal antibody in subsequent lines of therapy. In the instance of intolerance, patients may receive an alternative BTK inhibitor or the venetoclax combination in the second line and if intolerance occurs the third-line treatment includes trying the other second-line regimen that was not yet used.

Treatment With Venetoclax

In a phase 2 study (NCT02141282) that enrolled patients with CLL who received a median of 4 prior therapies and were refractory to ibrutinib (n = 91), patients achieved an overall response rate (ORR) of 65% and the estimated 12-month progression-free survival (PFS) rate was 75% (95% CI, 64%-83%). In patients with del(17p) or TP53 mutations (n = 46), the ORR was 61%. Lamanna noted that this study was conducted prior to time limited approaches, and venetoclax was given as chronic continuous monotherapy.4

“Once we saw that venetoclax was giving early induction of complete responses [CRs] and very good responses, particularly in the bone marrow compartment, we combined it with anti-CD20 monoclonal antibody and hence time-limited approaches became the new SOC,” Lamanna explained.

The phase 3 MURANO (NCT02005471) study evaluated venetoclax plus rituximab (n = 194) vs bendamustine plus rituximab (n = 195) as a time-limited approach given as a 2-year duration in patients with relapsed disease; patients achieved a median PFS of 53.6 months (95% CI, 48.4-57.0) vs 17.0 months (95% CI, 15.5-21.7), respectively (HR, 0.19; 95% CI, 0.15-0.26: P < .0001).5

Noncovalent BTK Inhibitors Show Promise

Lamanna noted that noncovalent BTK inhibitors may help fill a gap in CLL when covalent BTK inhibitors are not viable options especially as patients who require treatment following a covalent BTK inhibitor and venetoclax experience poor outcomes. Noncovalent agents include pirtobrutinib and nemtabrutinib (ARQ-531/MK-1026).1

Longer follow-up data from the phase 1/2 BRUIN trial (NCT03740529) confirmed that pirtobrutinib demonstrated efficacy in patients with relapsed/refractory CLL or SLL who previously received a prior covalent BTK inhibitor regardless of C481S mutational status and reason for prior BTK inhibitor discontinuation. The ORR in patients who received a prior BTK inhibitor (n = 247) was 82.2% (95% CI, 76.8%-86.7%) and, at a median follow-up of 19.4 months, the median PFS was 19.6 months (95% CI, 16.9-22.1).6

The ORR in patients who received treatment with prior BTK and BCL2 inhibitors (n = 100) was 79.0% (95% CI, 69.7%-86.5%) and at a median follow-up of 18.2 months, the median PFS was 16.8 months (95% CI, 13.2-18.7). “This was a nice durable response in this heavily pretreated group,” Lamanna noted.

In terms of safety, the most common any grade treatment-emergent adverse effects (TEAEs) among patients who received at least 12 months of treatment with pirtobrutinib (n = 326) were fatigue (32.2%), diarrhea (30.7%), neutropenia (29.8%), COVID-19 (28.5%), and contusion (25.8%). Grade 3 of higher neutropenia occurred in 23.9% of patients. AEs of special interest occuring at any grade included bruising (30.7%), arthralgia (21.2%), rash (19.6%), hemorrhage/hematoma (16.6%), hypertension (16.0%), and atrial fibrillation/flutter (2.8%).7

“There seems to be no emerging or new safety issues with pirtobrutinib. [The data] are still immature, but in over 300 patients treated on the original pirtobrutinib study those who have been [on treatment] for greater than 12 months [have shown] no new signals and very few discontinuation or dose reductions with this agent. We’ll need longer time and follow-up, but it appears to be a very clean BTK inhibitor,” Lamanna said.

However, acquired mutations were seen following treatment with pirtobrutinib in patients who previously received covalent BTK inhibitors. Mutations in BTK at the time of disease progression included L528W, V416L, M437R, T474I, and A428D and these mutations cluster within the tyrosine kinase catalytic domain of BTK.1

Further, the noncovalent BTK inhibitor nemtabrutinib has shown signs of efficacy. In the phase 1/2 BELLWAVE-001 (NCT03162536) study, patients with previously treated CLL/SLL (n = 57) experienced an ORR of 56% (95% CI, 42%-69%) and a median PFS of 26.3 months (95% CI, 10.1-not estimable [NE]). Patients with a BTK C481S mutation (n = 36) achieved an ORR of 58% (95% CI, 41%-75%).8

Double-Exposed and Double Refractory Disease

Lamanna stressed the difference of double-exposed vs double-refractory disease regarding patients with relapsed CLL after either exposure or progression to a covalent BTK inhibitor and venetoclax. She highlighted that the optimal treatment-free remission to be considered refractory vs exposed is debatable.1

“The debate has always been about the treatment-free remission [patients] and what could we say is truly refractory vs exposed? We need to have more data to better define this. Most of us say if someone had a venetoclax-based combination and is progressing within a short time, a year or 2 after therapy, we would have expected more given that data from the MURANO study [showing] that patients would have a longer time off treatment. But certainly, we need more data and there’s some clinical trials trying to define double-refractory in this scenario,” Lamanna explained.

Novel strategies for treating these patients that have shown promising activity include CD19-directed CAR T-cell therapies such as lisocabtagene maraleucel (Breyanzi; liso-cel), BTK degraders such as NX-2127 and BGB-16673, and CD20/CD3 bispecific antibodies.1

The phase 1/2 TRANSCEND CLL 004 (NCT03331198) trial evaluated liso-cel, which has a 4-1BB costimulatory domain that enhances the expansion and persistence of the CAR-T cells. Patients enrolled were ineligible for or had failed BTK inhibitor therapy and had high-risk (progressed after least 2 therapies) or standard-risk (progressed after at least 3 therapies) CLL.9

“There are some encouraging response durations that we’re seeing from this trial in this heavily pretreated group. The median [duration of response] has not been reached for the total cohort, but for the patients who had either failed a BTK [inhibitor] and venetoclax, the median response duration is approximately 17 months,” Lamanna explained. “The PFS for the total group was 18 months [and] for patients who] failed BTK [inhibition] and venetoclax, the median PFS was 13 months.

BTK Degraders

When discussing hetero-bifunctional targeted degradation, Lamanna described the DELigase platform which was developed using DNA-encoded libraries to bind E3 ligase and target protein.1

“BTK inhibitors block the enzymatic activity of BTK, so the protein is still there, but it doesn't function. [With] patients who progress on BTK inhibitors the BTK enzyme is no longer functioning, but somehow the protein is still signaling the CLL cells to stay alive and this is believed to be through some scaffolding mechanism,” Lamanna explained. “A different mechanism is targeted protein degradation. The aim of this platform is to eliminate the cancer-causing protein, in this scenario BTK. These therapies are aimed to erase or degrade mutated or unmutated BTK.”

NX-2127 is a targeted BTK and IKZF3 degrader that demonstrated a mean 86% BTK degradation in patients with CLL (n = 17). The ORR was 33% but Lamanna noted this is increasing with more follow-up. Responses were also seen in patients with BTK/BCL-2 double refractory disease and among patients who progressed on a noncovalent BTK inhibitor.10

A Potential Role for Bispecific Antibodies

“[Bispecific antibodies] are associated with cytokine release syndrome, so you do have to monitor patients closely and some will need steroids or tocilizumab to mitigate [that] AE,” Lamanna explained regarding bispecific antibodies. “But we’re seeing phenomenal responses.”

In the phase 1/2 EPCORE CLL-1 (NCT04623541) trial, patients (n = 10) treated with epcoritamab-bysp (Epkinly) experienced an ORR of 60% and the CR rate was 50%. The median time to response was 1.3 months (range, 1.1-2.4).11

Editor’s Note: Dr Lamanna cites receiving SAB/Consultant/Honoraria from AbbVie, Adaptive Biosciences, Allogene Therapeutics, AstraZeneca, BeiGene, Genentech, Janssen, LOXO/Eli Lilly, Pharmacyclics; Honoraria from Aptitude Health, BioAscend, Clinical Care Options, Curio, DAVA Oncology, OncLive, PER, Peerview, and Targeted Oncology; and Institutional Research funding from AbbVie, AstraZeneca, BeiGene, Genentech, Genmab, LOXO/Eli Lilly, MingSight, Octapharma, Oncternal, and TG Therapeutics.


  1. Lamanna N. Addressing resistance: new agents in development. Presented at: 41st Annual CFS®; November 8-10, 2023; New York, NY.
  2. Woyach et al. Level up with personalized care for CLL/SLL achieving better total care with targeted agents & innovative combinations. Presented at 17th International Conference on Malignant Lymphoma; June 13-17, 2023; Lugano, Switzerland.
  3. NCCN. Clinical Practice Guidelines in Oncology. Chronic Lymphocytic leukemia/small lymphocytic lymphoma, version 3.2023. Accessed November 8, 2023.
  4. Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018;19(1):65-75. doi:10.1016/S1470-2045(17)30909-9
  5. Seymour JF, Kipps TJ, Eichhorst BF, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022;140(8):839-850. doi:10.1182/blood.2021015014
  6. Mato AR, Woyach JA, Brown JR, et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med. 2023;389(1):33-44. doi:10.1056/NEJMoa2300696
  7. Coombs CC, Shah NN, Jurczak W, et al. Long-term safety with ≥12 months of pirtobrutinib in relapsed/refractory (R/R) B-cell malignancies. J Clin Oncol. 2023;41(suppl 16):7513. doi:10.1200/JCO.2023.41.16_suppl.7513
  8. Woyach J, Flinn IW, Eradat H, et al. Nemtabrutinib (MK-1026), a non-covalent inhibitor of wild-type and C481S mutated bruton tyrosine kinase for B-cell malignancies: efficacy and safety of the phase 2 dose-expansion BELLWAVE-001 study. HemaSphere. 2022;(6):578-579. doi:10.1097/01.HS9.0000845612.25766.0c
  9. Siddiqi T, Soumerai JD, Dorritie KA, et al. Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL. Blood. 2022;139(12):1794-1806. doi:10.1182/blood.2021011895
  10. Mato AR, Wierda WG, Ai WZ, et al. NX-2127-001, a first-in-human trial of NX-2127, a bruton's tyrosine kinase-targeted protein degrader, in patients with relapsed or refractory chronic lymphocytic leukemia and B-cell malignancies. Blood. 2022;140(Suppl 1):2329–2332. doi:10.1182/blood-2022-164772
  11. Kater AP, Ye CJ, Sandoval-Sus J, et al. Subcutaneous epcoritamab in patients with richter's syndrome: early results from phase 1b/2 trial (EPCORE CLL-1). Blood. 2022;140(suppl 1):850–851. doi:10.1182/blood-2022-158298
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