Page 273 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR
progression-free survival to that of patients with NOTCH1 VAF >1%. Instead, the finding suggests the possibility that, in contrast to ibrutinib, zanubrutinib may uniquely suppress the outgrowth of clones with NOTCH1 mutations. Although the numbers of patients with Waldenström macroglobu- linemia, MCL, and marginal zone lymphoma enrolled in our study were small and association analyses could not be performed, mutation profiles of these patients are reported for reference (Figure 1).
At the data cutoff for this analysis, nine patients (12.7%; 9/71) who were intolerant to ibrutinib and/or acalabrutinib and who were subsequently treated with zanubrutinib developed progressive disease. We assessed BTK inhibitor resistance mutations in BTK and PLCG2 in these patients (Table 1). At baseline, BTK C481S mutations were detected in 4.2% (3/71) of patients (Figure 1B). Of these, two patients progressed on zanubrutinib; patients n. 3 and n. 9 progressed at 4.6 months and 17.7 months of zanubrutinib treatment, respectively (Table 1). A third patient (data not shown) with a baseline BTK C481S mutation died from COVID-19 shortly after enrollment before disease assessments could be made. Patient n. 3, with CLL, had a high frequency (VAF=60.9%) of BTK C481S mutations at baseline. This patient had long exposure to ibrutinib treatment (~65 months) prior to enrolling in the study and had disease progression after 4.6 months of zanubrutinib treatment (Table 1). Patient n. 9, with CLL, who also had long prior exposure to
ibrutinib (51.9 months), initially presented with a low frequency BTK C481S mutation (VAF=0.9%) that increased in frequency at the time of disease progression (VAF=20.4%) (Table 1). This patient also had new PLCG2 mutations (L845F and D993H; VAF<1% for both mutations) at disease progression (Table 1). It is worth noting that this patient stayed on zanubrutinib treat- ment for 17.7 months before disease progression, with stable disease as best overall response. This suggests that BTK C481S mutations at low VAF did not prevent zanubrutinib efficacy in this patient. At the time of disease progression, patients n. 1 (CLL) and n. 2 (SLL) had developed new BTK and PLCG2 mu- tations. Patient n. 1 acquired high frequencies of BTK C481S mutations (VAF=19.2%) as well as low frequency mutations in PLCG2 (L845F, N750D, and R665W; VAF<1% for all three PLCG2 mutations) that had not been observed at baseline (Table 1). This patient was on zanubrutinib treatment for 9.2 months before disease progression. Patient n. 2 acquired BTK mutations (C481S: VAF=3.8%; C481Y: VAF=14.0%) and PLCG2 mutations (S707F, L845V, M1141K, and E1139del; VAF <6% for all PLCG2 mutations) at disease progression (Table 1). This patient was on zanubrutinib treatment for 17.9 months prior to disease progression. All BTK mutations detected in this study were located at the BTK-inhibitor binding site (C481S or C481Y). The remaining five patients with disease progression had no BTK or PLCG2 mutations detected at baseline or at dis- ease progression. Patient n. 5, with MCL, had a CCND1-IGH
Table 1. Relapse on zanubrutinib was associated with known Bruton tyrosine kinase inhibitor resistance mutations.
Patient
Disease
Cohort
Duration of prior ibrutinib, months
Duration of prior acalabrutinib, months
Time on zanubrutinib, months
BTK
mutations at baseline (VAF)
BTK mutations at/after PD (VAF)
PLCG2
mutations at baseline
PLCG2 mutations at/after PD (VAF)
1
CLL
2
6.7
10.1
9.2
NDa
C481S, 1442G>C (19.2%) C481S, 14421T>A (1.1%)
ND
L845F, 2535A>C (1.0%) N750D, 2248A>G (0.8%) R665W, 1993C>T (0.3%)
2
SLL
1
17.3
NA
17.9
ND
C481S, 1442G>C (0.3%) C481S, 14421T>A (3.8%) C481Y, 1442G>C (14.0%)
ND
S707F, 2120C>T (5.8%)
L845V, 2533T>G (1.7%) E1139del, 3417_3419del (4.7%) M1141Lys, 3422T>A (0.9%)
3
CLL
1
64.8
NA
4.6
C481S, 1442G>C (60.9%)
C481S, 1442G>C (69.1%)
ND
ND
4
CLL
2
3.1
1.2
13.4
ND
ND
ND
ND
5
MCL
1
6.5
NA
8.7
NDb
ND
NDb
ND
6
CLL
1
4.0
NA
12.8
ND
No sample available
ND
No sample available
7
CLL
1
7.8
NA
7.7
ND
ND
ND
ND
8
CLL
1
1.5
NA
5.5
ND
No sample available
ND
No sample available
9
CLL
1
51.9
NA
17.7
C481S, 1442G>C (0.9%)
C481S, 1442G>C (20.4%)
ND
L845F, 2535A>C (0.4%) D993H, 2977G>C (0.6%)
aInitial sample collected on study day 87. bInitial sample collected on study day 141. BTK: Bruton tyrosine kinase gene; VAF: variant allele fre- quency; PD: progressive disease; PLCG2: phospholipase C gamma 2 gene; CLL: chronic lymphocytic leukemia; MCL: mantle cell lymphoma; SLL: small lymphocytic lymphoma; NA: not applicable; ND: not detected.
Haematologica | 109 July 2024
2287