Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2025 Sep 17.
Published in final edited form as: Am J Hematol. 2022 Nov;97(Suppl 2):S19–S25. doi: 10.1002/ajh.26682

Approach to a patient with “double refractory” chronic lymphocytic leukemia: “Double, double toil and trouble” (Shakespeare)

Julia H Aronson 1, Sigrid S Skånland 2,3, Lindsey E Roeker 1, Meghan C Thompson 1, Anthony R Mato 1
PMCID: PMC12439813  NIHMSID: NIHMS1996544  PMID: 36125036

Abstract

As patients continue to live longer with chronic lymphocytic leukemia, it has become evident that there is an unmet treatment need for patients who have progressed on multiple lines of therapy. In this article, we attempt to define the “double refractory” patient as resistant to both Bruton’s tyrosine kinase inhibitors (BTKi) and venetoclax for which prognosis is poor and there remains no standard of care. We further examine the mechanism of resistance to these targeted agents and discuss the current landscape for managing this patient population. Finally, we explore data supporting promising new agents, including non-covalent BTKi, chimeric antigen receptor T cells, and additional classes of agents currently in development.

1 |. CHRONIC LYMPHOCYTIC LEUKEMIA IN 2022: THE ERA OF SEQUENTIAL TARGETED THERAPIES AND UNMET NEEDS

Chemoimmunotherapy (CIT) is no longer the standard of care in the management of chronic lymphocytic leukemia (CLL) in 2022. This seismic shift in the way we manage our patients in the front-line and relapsed/refractory (R/R) settings was brought about due to the approvals of three new classes of targeted agents: Bruton’s tyrosine kinase inhibitors (BTKi; ibrutinib, acalabrutinib), the BCL-2 inhibitor (BCL-2i) venetoclax and phosphatidylinositol-3-kinase inhibitors (PI3Ki; idelalisib, duvelisib).1–6 In the current era, patients who require CLL-directed therapy are likely to be treated with several lines of “chemotherapy-free” targeted therapies as monotherapies or in combinations. In the front-line setting, patients are likely to start with a BTKi-based approach or venetoclax-based approach. In the R/R setting, treatment choice is made based on knowledge of prior lines of therapy, the reasons for discontinuation of prior therapies (completion of a time-limited therapy, progression on continuous therapy, or intolerance to a targeted therapy), and our growing knowledge of mechanisms of resistance to targeted agents.7

Ultimately, as patients are living longer with CLL, we expect most patients to be treated with at least one covalent BTKi and venetoclax across several lines of therapy. We classify BTKi/venetoclax-treated patients with exposure to both novel agents (regardless of the reason for discontinuation) as “double exposed” patients. Patients who are exposed to both a BTKi and venetoclax and who are believed to be resistant to both classes of agents are defined as “double refractory” patients. It is the double refractory patient population that is the focus of this paper, as this ever-growing patient population represents the greatest unmet need in the management of CLL today and in future years.

2 |. DEFINING AND ASSESSING THE PROGNOSIS OF DOUBLE REFRACTORY CLL PATIENT

Unfortunately, the literature on defining prognosis for the double refractory patient population is extremely limited. Most studies that define survival outcomes for patients who have been exposed to both a BTKi and venetoclax do not separate patient groups into those who are double exposed and those who are double refractory. As most of the literature is retrospective in nature, it can be difficult to determine if a patient is clinically resistant to a targeted agent and definitions of clinical resistance are not universally accepted.

In the case of the BTKi, which are administered as continuous therapies, defining clinical resistance is relatively an easier task (vs. venetoclax resistance) as resistant patients are those who progress while on BTKi therapy (vs. stopping for intolerance or other non-progression events). For example, in the RESONATE-2 study, ibrutinib was administered to patients in the front-line setting.2 With 7 years of follow-up now available, the overall discontinuation rate of ibrutinib is 53% and 23% discontinued ibrutinib due to progression (13% while on the drug and 10% after drug discontinuation due to non-progression events).8 Similarly, in the E1912 and A041202 trials, the rates of discontinuation due to disease progression or death were noted to be 10.5% and 19%, respectively. What is not clearly stated in either trial is the percentage of progression events that occurred on therapy as opposed to following therapy discontinuation for a non-progression reason.9,10 Based on these data we conclude the rate of true clinical resistance to ibrutinib in the front-line setting at 7 years is approximately 13%. It is likely that the 10% who progressed after ibrutinib was already discontinued was due to a non-progression event on the study and may be sensitive to treatment with another BTKi and therefore not truly resistant. In the R/R setting, long-term follow-up data from the RESONATE-2 study demonstrates a 27% discontinuation rate of ibrutinib due to clinical progression.8,11,12 Data for acalabrutinib similarly demonstrates 4.5%–7.8% and 31% discontinuation rates due to clinical progression in the front-line and R/R settings, respectively.13,14

Clinical resistance to venetoclax is more difficult to define as venetoclax is most commonly administered in combination with an anti-CD20 monoclonal antibody in a time-limited manner (12 months front-line, 24 months R/R).3,4 While we acknowledge there is no universally accepted definition of clinical resistance to venetoclax or any other time-limited targeted therapy combination, it is reasonable to define clinical resistance as any progression event that occurs while on therapy (primary resistance), progression within 24 months following completion of time-limited venetoclax or in any patient for whom venetoclax re-treatment does not result in a durable remission (<12 months). As most patients are likely to respond initially to re-treatment with venetoclax and as this approach is not yet standardized, the authors felt it was critically important to include a definition of resistance to venetoclax re-treatment as part of the proposed definition for the double refractory patient.15 Primary resistance to venetoclax is an extremely rare event (only one event recorded on the front-line CLL14 trial and 10 events recorded in the R/R Murano study), however, a sizable minority of patients do progress within two years of discontinuation of time-limited venetoclax regimens both in the front line and R/R settings.3,4 Data on the durability of response to re-treatment with venetoclax is extremely limited.

Based on this assessment of the literature, to be considered double refractory, a patient should meet the following criteria: (1) Treated with both a BTKi and venetoclax-based therapy in any line of therapy; (2) Experience clinical progression while on a BTKi; (3) Experience clinical progression while on venetoclax, within 24 months after venetoclax discontinuation or being resistant to re-treatment with a venetoclax-based regimen. Double refractory patients are therefore a subset of double-exposed patients with poor prognosis. Figure 1 defines the double refractory patient population and details the most common treatment sequences that can lead to a double refractory CLL patient.

FIGURE 1.

FIGURE 1

Open in a new tab

Defining the double refractory patient population. BTKi, Bruton’s tyrosine kinase inhibitors; CLL, chronic lymphocytic leukemia

In terms of the prognosis of double refractory patients, data are extremely limited and need to be interpreted through the lens of what subsequent therapies were available and offered to double refractory patients. For example, Lew et al. examined survival outcomes for 17 heavily pre-treated patients sequentially treated and resistant to both a BTKi and venetoclax (median 4 prior therapies) and found a median overall survival (OS) of 3.6 months.16 The most common progression event was noted to be Richter’s Syndrome (RS) (vs. CLL) and the most common causes of death in this series were either RS or progression of CLL (11/13 death events, 8 RS, and 3 CLL). Additionally, the data did not suggest that the sequence of targeted agents (BTKi→Ven or Ven→BTKi) impacted survival outcomes once patients were double refractory. Thompson et al. described the outcomes of 125 CLL patients who were treated sequentially with both a BTKi and venetoclax and then treated with a subsequent line of therapy.17 In this series, the most common reason for discontinuing either the BTKi or venetoclax was the progression of disease in 71.1% and 69.6% of patients, however, the percentage of patients who were double refractory was not reported. What is most notable from this series is that progression-free survival (PFS) outcomes differ widely based on the subsequent therapy administered to this patient population with CIT and PI3Ki treated patients demonstrating extremely poor PFS (3 and 5 months, respectively) while those treated with cellular therapies and non-covalent BTKi demonstrated more favorable survival outcomes. Additionally, the study did not report whether treatment for double-exposed patients was administered for CLL or RS.

Mato et al. reported outcomes of 122 patients treated with at least one BTKi and a BCL-2i during the first three lines of therapy.18 In this series, 65 patients were treated with a subsequent line of therapy following a BTKi and a BCL-2i. They report that the median time from the end of the last BTKi/BCL-2i therapy to discontinuation of subsequent therapy or death was 11.4 months (95% confidence interval: 6.5–17.9). Unfortunately, this series did not distinguish whether patients were truly refractory to both a BTKi and venetoclax and did not explore outcomes for individual therapies administered to double refractory patients.

3 |. DEFINING MECHANISMS OF RESISTANCE TO COVALENT BTK INHIBITORS AND VENETOCLAX: IMPLICATIONS FOR SELECTING SUBSEQUENT THERAPIES IN DOUBLE REFRACTORY CLL PATIENTS

The best characterized and most common resistance mechanisms to covalent BTKi (cBTKi) in CLL are mutations of the C481 residue in BTK, located at the drug binding site, and of the BTK effector PLCG2.19–21 In a series of 29 BTKi-resistant CLL patients (23 with disease progression, 6 with RS), mutations in BTK were detected in 19 patients (65.5%).22 Two of the patients with RS and three of the patients with progressive disease were studied also after BTKi discontinuation. The RS patients received several subsequent lines of therapy, including venetoclax, resulting in the disappearance of the BTK mutated CLL clone over time. The three patients with progressive disease all received venetoclax as the next line of therapy, which similarly suppressed the BTK mutated clones.22 This finding provided a rationale for studying the addition of venetoclax to ibrutinib in CLL patients who progress on ibrutinib monotherapy (NCT03943342).23 Unfortunately, the observation portion of the study proved not feasible and was withdrawn due to competing studies during the COVID-19 pandemic (Kerry Rogers, personal communication). A similar single-center phase 2 trial adding venetoclax to ibrutinib-resistant patients has fully accrued but has not yet been reported (NCT03513562).

Resistance to venetoclax is largely mediated by acquired mutations in the BH3-binding domain of BCL2, the target of venetoclax.24–26 In a seminal study, 7 of 15 patients (46.7%) who progressed on venetoclax developed G101V mutated BCL2.24 None of these patients had received previous treatment with ibrutinib. Resistance to venetoclax can also be mediated by overexpression of the pro-survival proteins BCL-XL and MCL-1.27 These proteins are also upregulated in response to CD40 activation by T cells in the CLL microenvironment, and this resistance mechanism can be overcome by combination treatments ex vivo.28,29

In a study of 24 ibrutinib-refractory CLL patients who progressed on subsequent venetoclax treatment, BTK and/or PLCG2 mutations were detected in all patients prior to venetoclax.30 Five of 8 patients (63%) who progressed on venetoclax had C481S BTK mutations at similar frequency pre and post-venetoclax, and several novel mutations in BTK and PLCG2 persisted or increased during treatment with venetoclax. In three patients with RS, however, venetoclax treatment led to a decrease in BTK and PLCG2 mutant clones. In contrast to what was observed in venetoclax-resistant CLL that had not been exposed to ibrutinib, G101V BCL-2 mutations were rare in double refractory patients.24,30 Instead, previously unreported BCL2 mutations were detected at CLL progression in 5 of 11 patients (45.5%). The reported mechanisms of resistance to cBTKi and venetoclax provide a rationale for combination therapies. Such combinations are studied in several clinical trials, but they are not yet approved.31

4 |. CLINICAL PRACTICE IN 2022: MANAGEMENT OF THE DOUBLE REFRACTORY PATIENT WITH CURRENTLY APPROVED AGENTS

Unfortunately, the data are extremely unpromising or unavailable to support the use of currently approved agents for the management of double refractory patients. Available options include CIT combinations, anti-CD20 monoclonal antibodies, PI3Ki, and allogeneic stem cell transplantation. While some case reports and preclinical data suggest that patients may be “re-sensitized” to agents they were previously resistant to (i.e., BTKi), the limited clinical data available do not support this practice and it is not recommended in double refractory patients.32 For example, in a small series of 16 patients who were treated with the sequence of a covalent BTKi (discontinued for clinical resistance) → venetoclax (progression) → alternate covalent BTKi, the median PFS to the second BTKi was only 4 months.33

Two PI3Ki are approved for the treatment of R/R CLL (idelalisib and duvelisib).5,6 A deep look at the pivotal studies that led to the approvals of these agents reveals that they were conducted in patients naïve to both BTKi and venetoclax. While not yet approved for CLL, the PI3Ki, umbralisib, has essentially only been studied in novel agent naïve patients in the pivotal Unity CLL trial (NCT02612311). To summarize, we have no prospective data available to define the safety and confirm the activity of PI3Ki in BTKi and/or venetoclax-resistant CLL patients. However, real-world retrospective data strongly suggest that PI3Ki are not at all effective in double refractory patients (possibly due to cross-resistance or intolerance) and should not be considered a standard of care in this patient population, especially if a clinical trial option is available. In a small series of 17 double refractory patients who were subsequently treated with a PI3Ki, Mato et al. estimated the median PFS to be 5 months for PI3Ki (overall response rate [ORR] 46.9%).33 Similarly, in a larger series of double exposed patients (proportion of double refractory not defined), Thompson et al. estimated the median PFS to PI3Ki following both a BTKi and venetoclax to be only 5 months (ORR 41%).17 While outside of the scope of this review, we also note that currently approved PI3Ki are not well tolerated in the R/R setting, which may also contribute to their poor clinical efficacy in double refractory patients. For example, in the ASCEND R/R study of idelalisib and rituximab (vs. acalabrutinib), 65% of patients discontinued idelalisib due to adverse events at 3 years.34 A recent U.S. Food and Drug Administration briefing heavily commented on the toxicity profile of PI3Ki as a class, including the recommendations for box warnings and limitations of use.35 While several ongoing R/R randomized studies in BTKi and/or venetoclax pre-exposed CLL patients utilize PI3Ki as the standard of care control arm, there remains an open question as to whether this class of agents is appropriate at all as a standard of care for comparison in this patient population.

CIT is no longer frequently prescribed in the first several lines of CLL-directed therapy. Unfortunately, no prospective studies have been conducted evaluating CIT in either double-exposed or double-refractory patients. Real-world data for CIT efficacy are not available in double refractory patients who are CIT naïve. CIT was not effective (median PFS 3 months) in one small real-world series of 23 heavily pretreated patients who received CIT following venetoclax.33 Whether the mechanisms of resistance to targeted therapies and clonal evolution of CLL render CIT to be an ineffective approach in non-transformed, CLL progression following a BTKi/venetoclax remains an unknown gap in the literature. Regarding anti-CD20 monoclonal antibodies, poor PFS results were found for anti-CD20 monoclonal antibodies administered to heavily pre-treated patients (median PFS 2 months).33 Given that venetoclax is administered with an anti-CD20 monoclonal antibody, this class is likely to be less effective in general when administered in a later line of therapy.

For the small subset of patients who have been exposed to a BTKi and venetoclax, there is limited data to suggest a role for allogeneic stem cell transplantation in a highly selected patient population. However, in the two series of allogeneic stem cell transplantation published by Roeker et al. and Thompson et al., a distinction is not made between double exposed and double refractory patients.17,36 With this limitation in mind, the median PFS following allogeneic stem cell transplantation in double-exposed patients was not reached and was 11 months, respectively. We speculate that for patients who are truly refractory to either a BTKi or venetoclax immediately prior to allogeneic stem cell transplantation that PFS and OS will be inferior as compared to the current series of double-exposed patients. A detailed analysis of predictors of long-term disease-free survival following allogeneic stem cell transplantation can be found in the series reported by Roeker et al.36

5 |. FROM BENCH TO BEDSIDE: PROMISING AGENTS IN DEVELOPMENT TO ADDRESS THE UNMET NEEDS OF DOUBLE REFRACTORY PATIENTS

The two most promising classes of agents in development to address the unmet needs of double refractory patients are the noncovalent BTKi (ncBTKi) and chimeric antigen receptor T cells (CAR-T). While cBTKi has transformed the management of CLL, both resistance and intolerance limit their long-term effectiveness. Discontinuation rates for this class are estimated to be ~50% between 5–7 years after initiation. Half of all discontinuations are due to predictable intolerance events (cardiovascular, infection, dermatologic, musculoskeletal, and bleeding).8,37 Furthermore, the most common mechanism of resistance to cBTKi in CLL is the development of C481S mutations rendering the binding of cBTKi to be ineffective.19 Venetoclax and cBTKi are thought to have little overlap in terms of hypothesized mechanisms of resistance. Therefore, ncBTKi were developed as inhibitors of BTK with equal potency against wild-type BTK and C481 mutated CLL and potentially an effective approach for BTKi resistant or double refractory patients.

Two ncBTKi have demonstrated promising activity in heavily pre-treated CLL patients. In the BRUIN study, 146 cBTKi pretreated patients and 57 venetoclax pretreated patients received the ncBTKi pirtobrutinib (formerly LOXO 305).38 While 67% of cBTKi pretreated patients discontinued cBTKi due to clinical resistance, we do not have a breakdown of reasons for venetoclax discontinuation (i.e., resistance vs. intolerance). The publication states that 54 patients were previously treated with at least a cBTKi and venetoclax (all double exposed, double refractory status unknown). The ORR to pirtobrutinib was noted to be 60% (49%–78%) in cBTKi/BCL-2i double-exposed patients. We conclude that the median PFS was not reached given the small number of progression events recorded for the entire CLL cohort. The publication also defines and describes a new population of CLL patients treated with pirtobrutinib who were previously treated with the 5 major classes of approved CLL-directed therapies (cBTKi, venetoclax, PI3Ki, chemotherapy, CD20 antibodies). In these “pentavalent exposed,” the ORR to pirtobrutinib was 58%. Pirtobrutinib was extremely well tolerated with a discontinuation rate due to an adverse event of only 1.5%. Nemtabrutinib (formerly ARQ 531) is a ncBTKi also being studied in 68 heavily pretreated CLL patients of whom 84% previously received a cBTKi (ORR 57.9%).39 Unfortunately, the publication does not provide data on the number of patients who were also previously treated with venetoclax and therefore estimates of activity in the BTKi/BCL-2i pretreated patients are not available. The discontinuation rate of nemtabrutinib due to an adverse event was 8%. Recently, mechanisms of resistance to ncBTKi have been described in the R/R setting by the development of unique mutations in BTK, which render both cBTKI and ncBTKi ineffective.40 While no prospective data is yet available describing successful treatment options for “triple refractory” patients who are resistant to cBTKi, ncBTKi, and venetoclax, understanding the mechanisms of resistance and testing new classes of molecules in these patients will be of the utmost importance for the development of the optimal sequence of CLL directed therapies for our highest risk patients.

While a comprehensive review on CAR-T and other cellular therapies for the management of CLL is outside of the scope of this review, data for lisocabtagene maraleucel (liso-cel) from the phase I TRANSCEND CLL 004 are important to highlight as they include a small subset of patients who were defined as double exposed.41 Liso-cel is a CD19-directed CAR-T cell and was administered as a monotherapy to 25 patients (four median prior therapies, 100% cBTKi exposed, 65% venetoclax exposed). In this population, the ORR to liso-cel was 82% (45% CR, 75% uMRD in peripheral blood, 65% uMRD in bone marrow). Wierda et al. treated 19 patients (four median prior therapies, 100% R/R to ibrutinib, 53% had prior venetoclax) with the combination of liso-cel and ibrutinib (to enhance T cell activity).42 The combination of liso-cel and ibrutinib resulted in an ORR of 95% (89% uMRD in the peripheral blood) and a complete remission rate of 47%. PFS was not reported but 15 of 17 responders maintained their response at 3 months.42 Figure 2 includes an updated sequencing algorithm that hypothesizes how we plan to incorporate ncBTKi (not yet approved) into clinical practice, if available, and highlights a diminished role for PI3Ki in the 3rd line setting.

FIGURE 2.

FIGURE 2

Open in a new tab

Updated sequencing algorithm incorporating noncovalent Bruton’s tyrosine kinase inhibitors (ncBTKi). CAR-T, chimeric antigen receptor T cells; SCT, stem cell transplantation

There are also several additional classes of agents in development for which either pre-clinical data or very early clinical data suggest possible activity in heavily pretreated CLL patients, including those resistant to all modern targeted therapies. There are many emerging new drug targets that are being or should be studied in double refractory CLL patients, such as agents that induce selective protein degradation, bispecific antibodies, and novel cellular therapies. While one can easily conclude that double refractory patients are likely to be enrolled in these studies, it is not clear from the inclusion/exclusion criteria whether they will be studied as a unique cohort or if any of these studies define and distinguish double exposed from double refractory patients. If this is not carefully done a priori, data for the emerging classes of CLL-directed therapies in double refractory patients will likely be limited and somewhat difficult to interpret and apply to clinical practice.

6 |. CONCLUSIONS

Several therapeutic agents, including BTKi and BCL-2i, have transformed the way in which we treat patients with CLL, yet as more patients continue to demonstrate clinical progression after multiple lines of therapy, the need to address this newly defined patient population, the “double refractory” population, has become evident. Through an attempt to define clinical resistance to both BTKi and venetoclax, we can build a time-specific framework for considering treatment with additional lines of therapy. Given that the most common mechanisms of resistance are through acquired mutations of both BTK, BCL2, and up-regulation of key parallel pathways, management of these patients has more recently focused on other molecular targets. As we have reviewed, noncovalent BTKi and CAR-T therapy have both shown promising treatment abilities in these heavily pretreated patients; however, there is a great need for further investigation.

ACKNOWLEDGMENTS

S.S.S. is supported by the Research Council of Norway under the frames of ERA PerMed (Project Number 322898) and Digital Life Norway (Project Number 294916).

Funding information

Digital Life Norway, Grant/Award Number: 294916; Research Council of Norway, Grant/Award Number: 322898

CONFLICT OF INTEREST

S.S.S. has received honoraria from AbbVie and AstraZeneca, and research support from BeiGene and TG Therapeutics. L.E.R. has served as a consultant/advisor for AbbVie, AstraZeneca, Beigene, Janssen, Lockwood Group, Loxo Oncology, MJH, OncLive, Pharmacyclics, Pfizer, and TG Therapeutics, travel support from Loxo Oncology, holds minority ownership interest in Abbott Laboratories and has received research funding (paid to the institution) from Pfizer, Loxo Oncology, and Aptose Biosciences. M.C.T. has received an honorarium from MJH Life Sciences, Curio Science, VJHemOnc, Brazilian Association of Hematology and Hemotherapy (ABHH), and Massachusetts Medical Society. A.R.M. has served as a consultant advisory board/steering committee for Abbvie, AstraZeneca, BeiGene, Bristol Myers Squibb, Celgene, Genentech, Laboratorios Pfizer Ltda., LOXO Oncology, Octopharma, Pharmacyclics LLC, Nurix, Genmab, TG Therapeutics; DSMB for Celgene, TG Therapeutics, member of Medical Advisory Board for CLL Society, CME speaker for Curio, consultant for DAVA, Medscape, and an ad hoc scientific advisor for the Lymphoma Research Foundation.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable for this article.

REFERENCES

  • 1.Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213–223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425–2437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107–1120. [DOI] [PubMed] [Google Scholar]
  • 4.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] [PubMed] [Google Scholar]
  • 5.Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997–1007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Crombie JL, Tyekucheva S, Savell A, et al. A phase I study of duvelisib and venetoclax in patients with relapsed or refractory CLL/SLL. Blood. 2019;134:1763. [Google Scholar]
  • 7.Roeker LE, Mato AR. Approaches for relapsed CLL after chemotherapy-free frontline regimens. Hematology Am Soc Hematol Educ Program. 2020;2020(1):10–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Barr PM, Owen C, Robak T, et al. Up to Seven Years of Follow-Up in the RESONATE-2 Study of First-Line Ibrutinib Treatment for Patients with Chronic Lymphocytic Leukemia. Wolters Kluwer Health; 2021. [Google Scholar]
  • 9.Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib–rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432–443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379:2517–2528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Munir T, Brown JR, O’Brien S, et al. Final analysis from RESONATE: up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019;94(12):1353–1363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.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] [PMC free article] [PubMed] [Google Scholar]
  • 13.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] [PMC free article] [PubMed] [Google Scholar]
  • 14.Byrd JC, Hillmen P, Ghia P, et al. First Results of a Head-to-Head Trial of Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia. Wolters Kluwer Health; 2021. [Google Scholar]
  • 15.Thompson MC, Allan JN, Sail K, et al. Venetoclax re-treatment of chronic lymphocytic leukemia (CLL) patients after a previous venetoclax-based regimen. Blood. 2020;136:39–41. [Google Scholar]
  • 16.Lew TE, Lin VS, Cliff ER, et al. Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition. Blood Adv. 2021;5(20):4054–4058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Thompson MC, Roeker LE, Coombs CC, et al. Addressing a new challenge in chronic lymphocytic leukemia: outcomes of therapies after exposure to both a covalent Bruton’s tyrosine kinase inhibitor and venetoclax. Blood. 2021;138:2628. [Google Scholar]
  • 18.Mato AR, Chen Y, Girvan AC, et al. Outcomes for Patients with Chronic Lymphocytic Leukemia Previously Treated with a Covalent BTK Inhibitor and BCL2 Inhibitor in the United States: a Real-World Database Study. American Society of Hematology; 2021:639. [Google Scholar]
  • 19.Woyach JA, Furman RR, Liu T-M, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370(24):2286–2294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Woyach J, Huang Y, Rogers K, et al. Resistance to acalabrutinib in CLL is mediated primarily by BTK mutations. Blood. 2019;134:504. [Google Scholar]
  • 21.Quinquenel A, Fornecker L, Letestu R, et al. Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study. 134:641–644. [Google Scholar]
  • 22.Kanagal-Shamanna R, Jain P, Patel KP, et al. Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor–resistant chronic lymphocytic leukemia with disease progression and Richter transformation. Cancer. 2019;125(4):559–574. [DOI] [PubMed] [Google Scholar]
  • 23.Rogers KA, Wei L, Bhat SA, et al. A multicenter study of ibrutinib resistance development and intervention with venetoclax in patients with chronic lymphocytic leukemia. Blood. 2019;134:3049. [Google Scholar]
  • 24.Blombery P, Anderson MA, Gong J-N, et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov. 2019;9(3):342–353. [DOI] [PubMed] [Google Scholar]
  • 25.Blombery P, Thompson ER, Nguyen T, et al. Multiple BCL2 mutations cooccurring with Gly101Val emerge in chronic lymphocytic leukemia progression on venetoclax. Blood. 2020;135(10):773–777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Tausch E, Close W, Dolnik A, et al. Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia. Haematologica. 2019;104(9):e434–e437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Guieze R, Liu V, Rosebrock D, et al. Mitochondrial reprogramming underlies resistance to BCL-2 inhibition in lymphoid malignancies. Cancer Cell. 2019;36:369–384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Thijssen R, Slinger E, Weller K, et al. Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors. Haematologica. 2015;100(8):e302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Haselager M, Thijssen R, West C, et al. Regulation of Bcl-XL by non-canonical NF-κB in the context of CD40-induced drug resistance in CLL. Cell Death Differ. 2021;28(5):1658–1668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Lucas F, Larkin K, Gregory CT, et al. Novel BCL2 mutations in venetoclax-resistant, ibrutinib-resistant CLL patients with BTK/PLCG2 mutations. Blood. 2020;135(24):2192–2195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Skånland SS, Mato AR. Overcoming resistance to targeted therapies in chronic lymphocytic leukemia. Blood Adv. 2021;5(1):334–343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.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] [PMC free article] [PubMed] [Google Scholar]
  • 33.Mato AR, Roeker LE, Jacobs R, et al. Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res. 2020;26(14):3589–3596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849–2861. [DOI] [PubMed] [Google Scholar]
  • 35.Richardson NC, Kasamon Y, Pazdur R, Gormley N. The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint. Lancet Oncol. 2022;23(5):563–566. [DOI] [PubMed] [Google Scholar]
  • 36.Roeker LE, Dreger P, Brown JR, et al. Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents. Blood Adv. 2020;4(16):3977–3989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Mato AR, Nabhan C, Thompson MC, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103(5):874–879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892–901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Woyach JA, Flinn IW, Awan FT, et al. Preliminary efficacy and safety of MK-1026, a non-covalent inhibitor of wild-type and C481S mutated Bruton tyrosine kinase, in B-cell malignancies: a phase 2 dose expansion study. Blood. 2021;138:392. [Google Scholar]
  • 40.Wang E, Mi X, Thompson MC, et al. Mechanisms of resistance to noncovalent Bruton’s tyrosine kinase inhibitors. N Engl J Med. 2022;386(8):735–743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.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] [PMC free article] [PubMed] [Google Scholar]
  • 42.Wierda WG, Dorritie KA, Munoz J, et al. Transcend CLL 004: phase 1 cohort of lisocabtagene maraleucel (liso-cel) in combination with ibrutinib for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Blood. 2020;136:39–40. [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data sharing is not applicable for this article.

RESOURCES