Targeted Therapies Dominate the Relapsed/Refractory CLL Paradigm

Targeted therapies have helped to improve responses in patients with relapsed chronic lymphocytic leukemia regardless of high-risk disease, although optimal sequencing and toxicity management need to be further explored to strengthen the utilization of these options.

Asher Chanan-Khan, MD

Asher Chanan-Khan, MD

Targeted therapies have helped to improve responses in patients with relapsed chronic lymphocytic leukemia (CLL) regardless of high-risk disease, although optimal sequencing and toxicity management need to be further explored to strengthen the utilization of these options, according to Asher Chanan-Khan, MD.1

“Improved responses with targeted therapies in the relapsed setting is independent of high-risk disease,” Chanan-Khan, a professor of medicine at Mayo Clinic, said during a presentation during the 25th Annual International Congress on Hematologic Malignancies. “We are now in a fortunate time period where even patients with deletion (del)17p have an opportunity to have a longer duration of response.”

Several concepts must be considered when managing patients with relapsed CLL, Chanan-Khan said. First, a diagnosis of CLL must be confirmed. Disease can lead to the complication of Richter’s transformation, which is evidenced by a sharp increase in lactate dehydrogenase levels. Notably, not all patients with relapsed disease will need therapy, according to Chanan-Khan, who added that treatment should be reserved only for patients with active or progressive disease.2 “Second- and subsequent-line treatment decisions should follow the same indications as those used in the frontline setting,” noted Chanan-Khan.

When selecting a treatment strategy for a patient with relapsed disease who previously received treatment with a chemoimmunotherapy, patient characteristics, such as age and comorbidities; disease characteristics, including presence of bulky nodes, fluorescence in situ hybridization score, and IGHV mutational status; and the goal of treatment, should all be considered. The same considerations should be used for patients with relapsed disease who previously received a novel therapy. Here, initial response duration and tolerability of the initial therapy should also be taken into account, according to Chanan-Khan.

BTK Inhibitors Lead the Charge

Several BTK inhibitors are available for use in the relapsed setting, one of which is ibrutinib (Imbruvica). In the phase 3 RESONATE trial (NCT01578707), ibrutinib was compared with ofatumumab (Arzerra) in patients with previously treated CLL or small lymphocytic lymphoma (SLL).3 After a median follow-up of 65.3 months, the median progression-free survival (PFS) continued to be significantly longer in the ibrutinib cohort compared with the ofatumumab cohort, at 44.1 months vs 8.1 months, respectively (HR, 0.148; 95% CI, 0.113-0.196; P <.001).

In patients with high-risk disease, categorized as those with del(17p), a TP53 mutation, del(11q),and/or unmutated IGHV status, ibrutinib continued to demonstrate superiority over the control, at 44.1 months vs 8.0 months, respectively (HR, 0.110; 95% CI, 0.080-0.152). Notably, these patients comprised 82% of the study population.

Moreover, a subgroup analysis of the RESONATE trial examined PFS outcomes across different high-risk patient subgroups.

“Those who had (del)17p showed the most inferiority, [however] patients with del(11q) tended to do very well and their outcome was better,” Chanan-Khan said. “Again, if [a patient has] TP53 or (del)17p, concurrently, [they] tend to do worse than if [they] have 1 or the other. IGHV mutation status, which is another parameter that we tend to monitor in these patients, did not necessarily make a huge difference, [which] is refreshing to see.”

Additionally, ibrutinib has also yielded better outcomes when used in earlier lines of treatment, according to results from an integrated analysis done in patients with CLL who received the BTK inhibitor in either the first-line setting in the phase RESONATE-2 trial (NCT01722487) or the relapsed/refractory setting in the RESONATE trial.4

“These particular data show that…earlier use of a BTK inhibitor, in this case ibrutinib, resulted in a better [5-year] PFS vs if you were to use it later,” Chanan-Khan said. “If you were to use it after 3 prior therapies, the [median] PFS was around 33 months, whereas if you picked it [for use] earlier on in the first-line setting, [median] PFS could be as good as 70 months. This is significantly better in terms of choosing a BTK inhibitor early on.”

Patients in the first-line setting experienced a 5-year overall survival (OS) rate of 83% compared with 58% in patients who received 3 or more prior lines of therapy. The median OS for the overall patient population in the first-line setting had not yet been reached vs 67.4 months in patients who were treated with 3 or more prior lines of therapy.

Another BTK inhibitor, acalabrutinib (Calquence), was approved by the FDA in November 2019 for use in patients with CLL and SLL, based, in part, on the results from the phase 3 ASCEND study (NCT02970318).5,6 Patients with relapsed/refractory CLL who had progressed on at least 1 prior line of therapy were enrolled on the trial. Participants were randomized to receive either 100 mg of oral acalabrutinib or the control regimen of either 150 mg of oral idelalisib (Zydelig) plus rituximab (Rituxan) or 70 mg/m2 of intravenous bendamustine (Bendeka) on days 1 and 2 plus rituximab.

“If you look at the PFS for this particular study, you will see that the median PFS had not yet been reached at the time these data were presented [in those who received] acalabrutinib vs 16.5 months in those who received either a PI3K inhibitor or a chemoimmunotherapy,” Chanan-Khan reported. “Again, [this is] in favor of a BTK inhibitor in the relapsed setting.”

BCL-2 Inhibitors Serve as an Additional Option

Although several BCL-2 inhibitors are in development for patients with relapsed CLL, the only agent currently FDA-approved is venetoclax (Venclexta). In the phase 3 MURANO trial (NCT02005471), venetoclax was evaluated in combination with rituximab compared with bendamustine/rituximab in patients with relapsed/refractory CLL.7,8

Data from the 4-year survival analysis of the trial showed that the combination of venetoclax and rituximab resulted in a median 4-year PFS of 57.3 months (95% CI, 49.4-65.2) compared with 4.6 months (95 CI, 0.1-9.2) with bendamustine/rituximab.

“You can easily see the that the venetoclax/rituximab arm had a significant 4-year PFS benefit,” Chanan-Khan said. “If you compare the OS [rates], [we see] a significant advantage in patients who were on venetoclax and rituximab at 85.3% vs 66.8% [HR, 0.41; 95% CI, 0.26-0.65 with bendamustine/rituximab].”

Notably, patients who were treated with the experimental combination and had undetectable minimal residual disease (MRD) at the end of their therapy had a superior PFS compared with those who had low MRD positivity (HR, 0.50) and high MRD positivity (HR, 0.15).

“Those who had undetectable MRD tended to have significantly better outcomes in terms of 24-month PFS vs high MRD–positive patients. If you look at the data that are available at 1.5 years, 90% of patients who [had undetectable MRD] were progression free vs 8%,” Chanan-Khan said. “MRD becomes an important area in terms of [patients with] relapsed/refractory [disease]. Therefore, there’s an increased desire to combine or achieve MRD as an end point, even in this particular patient population.”

Strategies for Progression on Targeted Regimens

Patients who have progressed on a targeted therapy is becoming increasingly common as novel agents such as PI3K inhibitors, BTK inhibitors, and BCL-2 inhibitors are used more often.

One possible approach for patients who progress after treatment with ibrutinib and/or idelalisib is venetoclax, a concept that was examined in a phase 2 study (NCT02141282).9 Patients enrolled on the study had a median of 4 prior lines of therapy (range, 1-15). Those who were treated with venetoclax monotherapy experienced a median PFS of 24.7 months. The median duration of response (DOR) and OS had not been reached at 24 months of follow-up.9-11

Chanan-Khan also reviewed strategies for patients who had progressed after being treated with venetoclax.

“If [a patient who] previously received venetoclax were to now receive a BTK inhibitor, the outcome is the best in terms of [the fact that] over 80% of these patients will respond. However, if [a patient is] BTK resistant, then the ORR tends to be less,” Chanan-Khan concluded. “Patients who are BTK intolerant, when given treatment, tend to have even better responses of around 70%. As I noted earlier, CD20 antibodies tend to [yield…the least] responses in terms of sequencing.”


  1. Chanan-Khan A. Treatment of relapsed CLL. Presented at: 25th Annual International Congress on Hematologic Malignancies; February 25-28, 2021; Virtual. Accessed February 26, 2021.
  2. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760. doi:10.1182/blood-2017-09-806398
  3. 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:10.1002/ajh.25638
  4. Barr PM, Tedeschi A, Munir T, et al. Using ibrutinib in earlier lines of treatment results in better outcomes for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Blood. 2019;134(suppl 1):3054. doi:10.1182/blood-2019-123327
  5. FDA takes second action under international collaboration, approves new treatment option for patients with chronic lymphocytic leukemia. News release. FDA. November 21, 2020. Accessed February 26, 2021.
  6. 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:10.1200/JCO.19.03355.
  7. Seymour JF, Kipps TJ, Eichhorst BF, et al. Four-year analysis of Murano study confirms sustained benefit of time-limited venetoclax-rituximab (VenR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl 1):355. doi:10.1182/blood-2019-123930
  8. Kater AP, Wu JQ, Kipps T, et al. Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study. J Clin Oncol. 2020;38(34):4042-4054. doi: 10.1200/JCO.20.00948
  9. Bryrd JC, Wierda WG, Davids MS, et al. Durability of response to venetoclax (VEN) in patients with CLL relapsed/refractory to ibrutinib and/or idelalisib. J Clin Oncol. 2018;36(suppl 15):7512-7512. doi:10.1200/JCO.2018.36.15_suppl.7512
  10. 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
  11. Coutre S, Choi M, Furman RR, et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018;12(131):1704-1711. doi:10.1182/blood-2017-06-788133
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