Outcomes of patients with CLL that develop dual resistance to BTKi and venetoclax

Patients with chronic lymphocytic leukemia (CLL), especially those with biologically adverse disease, have greatly benefited from the use of targeted therapies, such as covalent Bruton tyrosine kinase (BTK) inhibitors (BTKi) and the BCL2 inhibitor, venetoclax.¹ Patients that develop resistance to their first targeted agent—such as venetoclax, which is a standard of care in CLL²—can be switched to an alternative class. However, relapses with second-line targeted therapy are becoming more of a clinical challenge as double-class-resistant disease is increasingly common.³ Refractory patients with double-class resistance have a poor prognosis. Therefore, Thomas E. Lew et al. published a retrospective analysis in Blood Advances that sought to define the clinicopathological features, management, and outcomes of patients who received targeted therapy for CLL (venetoclax then BTKi vs BTKi then venetoclax) and developed dual resistance.¹

Study design

This study was a retrospective analysis of 165 patients from the Royal Melbourne Hospital and Peter MacCallum Cancer Centre that received a covalent BTKi or venetoclax as CLL treatment between June 2011 and November 2020. Of the 165 patients, 42 had been exposed to both classes of targeted agents, and 19 had progressive disease on both classes; two patients received their second-line targeted agent for Richter transformation (RT), so the total cohort consisted of 17 patients who progressed after receiving both classes.

Baseline characteristics

The study cohort was heavily pre-treated, with a median of four prior lines of therapy. Patients also had adverse disease genetics, including del(17p)/TP53 mutations (present in 88% of patients); 66% of patients had a complex disease karyotype. Patient characteristics at progression are listed in Table 1.

Table 1. Characteristics of the patient population at time of progression*

BTKi, Bruton tyrosine kinase inhibitor; CR, complete remission; MRD, measurable residual disease; PI3Ki, phosphoinositide 3-kinase inhibitor; PD, progressive disease; PR, partial remission; RT, Richter transformation; SD, stable disease; Ven, venetoclax. *Adapted from Lew, et al.1 †Refers to lines of therapy prior to initiation of the second-line targeted agent. ‡No patients with partial remission in this cohort achieved undetectable measurable residual disease.
Characteristic	Ven → BTKi	BTKi → Ven	Whole cohort
n	12	5	17
Median age, years (range)	77 (52–92)	74 (61–87)	76 (52–92)
Median prior therapies†	4.5 (2–8)	4 (3–7)	4 (2–8)
Fludarabine refractory (%)	7 (58)	2 (40)	9 (53)
Prior PI3Ki (%)	0 (0)	1/5 (20)	1/17 (6)
RT prior to second-line targeted agent (%)	3 (25)	0 (0)	3 (18)
del(17p) and/or TP53 mutation (%)	11/12 (92)	4/5 (80)	15/17 (88)
Complex karyotype (≥3 abnormalities)	8/8 (100)	4/4 (100)	12/12 (100)
IGHV unmutated (%)	9/11 (82)	2/2 (100)	11/13 (85)
Concomitant rituximab with Ven (%)	3 (25)	0 (0)	3 (18)
Ven: Best response
PD (%)	0 (0)	0 (0)	0 (0)
SD (%)	1 (8)	2 (40)	3 (18)
PR‡ (%)	7 (58)	3 (60)	10 (59)
CR MRD+ (%)	2 (17)	0 (0)	2 (12)
CR MRD− (%)	2 (17)	0 (0)	2 (12)
Ven: Time to progression, months (range)	24 (9–94)	23 (6–29)	24 (6–94)
BTKi: Best response
PD (%)	0 (0)	0 (0)	0 (0)
SD (%)	2 (17)	1 (20)	3 (18)
PR (%)	8 (67)	4 (80)	12 (71)
CR (%)	2 (17)	0 (0)	2 (12)
BTKi: Time to progression, months (range)	25 (1–55)	24 (4–42)	25 (1–55)

Results

• The median time to progression for patients who received prior venetoclax was 24 months, compared with 25 months for patients who had prior BTKi therapy.
• Disease progression on a second-line targeted agent manifested into progressive CLL in 11 patients and as RT in six patients.
• The median overall survival (OS) after disease progression on a second-line targeted agent was 3.6 months (95% CI, 2–11).

Venetoclax → BTKi

• In patients who received venetoclax as their first-line targeted agent (n = 12), best responses were stable disease (SD), partial remission (PR), and complete remission (CR) in 8%, 58%, and 34% of patients, respectively.
• Three patients developed RT; these patients then received salvage chemotherapy followed by consolidative autologous stem cell transplant (SCT; n = 2) or involved-field radiotherapy (IFRT; n = 1), followed by BTKi treatment (ibrutinib, n = 1; zanubrutinib, n = 2).
• The remaining nine patients who progressed after receiving venetoclax commenced BTKi treatment directly (ibrutinib, n = 8; zanubrutinib n = 1).
• The overall response rate to second-line BTKi was 84%.
  • The PR was 67% and the CR was 17%.
  • The median time to progression was 25 months.
  • At disease progression following second-line BTKi, four patients developed RT (one due to relapse and three due to new development of RT), and eight patients developed progressive CLL.

BTKi → Venetoclax

• In patients who received a BTKi as their first targeted agent (n = 5), the overall response rate was 80%, all of which were PRs.
• In all five patients who were treated with a BTKi, disease progression was to CLL, with no cases of RT, and all patients were administered 400 mg of daily venetoclax monotherapy as their next treatment.
• Three patients had a PR to second-line venetoclax, with a median time to progression of 23 months.
• During progression on second-line treatment with venetoclax, two patients developed RT (with synchronous diagnosis of treatment-associated myelodysplasia, n = 1) and three developed progressive CLL.

Whole cohort

• The median OS for the whole cohort following disease progression on second-line targeted therapy was 3.6 months.
• There was no significant survival benefit between patients who developed RT or progressive CLL on second-line targeted therapy (median OS, 3.3 vs 8 months, respectively; p = 0.341).
• First-line treatment choice did not significantly impact the OS between patients treated with venetoclax or a BTKi (median OS, 2.9 vs 5.3, respectively; p = 0.756).
• Significant correlations between OS and baseline clinicopathological variables were not identified by univariate analyses; however, this analysis was limited by a small sample size.
• A total of 76% of patients have died, mainly due to disease progression:
  • RT (n= 8)
  • CLL (n = 3)
  • cardiac arrest (n = 1)
  • pneumonia (n = 1)
• Four patients with progressive disease on second-line targeted therapy remained alive at last follow-up:
  • Three patients survived and received the following:
    • One received pirtobrutinib and was alive <2 months post progression
    • One received ibrutinib re-treatment and was alive <2 months post progression
    • One received R-mini-CHOP/IFRT and was alive 10 months post progression
  • One patient received idelalisib–rituximab then allogeneic SCT (allo-SCT) and was alive 39 months post progression.
• Two patients had stable double-class-resistant CLL with ibrutinib–venetoclax combination therapy for 10 months and 15 months, respectively; one of these patients had detectable BCL2, BTK, and PLCG2 mutations.

Conclusion

Overall, the data indicate that patients with CLL have an increased likelihood of developing resistance to BTKi and venetoclax therapy, and these patients have a poor prognosis and high frequency of RT. Although current therapeutic options—including PI3K inhibitors and chemoimmunotherapy—are available, these have limitations regarding efficacy and tolerability. As disease progression following second-line targeted agent therapy has a dismal prognosis, allo-SCT should be considered for eligible patients at the time of stable remission on second-line targeted therapy, particularly if high-risk features, such as TP53 abnormalities and complex karyotype, are present.

The patient population in this study was heavily pre-treated with chemoimmunotherapy; therefore, it becomes difficult to generalize the findings to patients who are chemotherapy naïve and received targeted agents as frontline therapy or in combination. Preliminary data are ongoing to determine the best therapies for those who relapse after a BTKi or venetoclax in CLL. Although studies for non-covalent BTKi and chimeric antigen receptor T-cell therapy are promising, regulatory approval and longer-term follow-up are required before they are used routinely in clinical practice, and other treatment options are needed for this patient population.