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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
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.
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*
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) |
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. |
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.
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