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Acalabrutinib in ibrutinib-intolerant R/R CLL patients
recurrence, switching to another drug class such as vene- toclax should be considered.28 The safety profile and effi- cacy of different therapeutic agents and combination strategies has been evaluated in head-to-head trials. One such trial is ASCEND, a phase III study of acalabrutinib monotherapy versus rituximab plus idelalisib (I-R) or rit- uximab plus bendamustine (B-R), which demonstrated improved PFS for acalabrutinib compared with either rit- uximab combination; there were fewer serious adverse events and fewer adverse events leading to discontinua- tion with acalabrutinib monotherapy compared with I- R.29 In that study, fatal adverse events occurred in 6/154 (4%), 5/118 (4%), and 2/35 (6%) patients receiving acal- abrutinib monotherapy, I-R, and B-R, respectively.
This study was not designed to test whether acalabru-
tinib is effective in patients with therapeutic resistance to ibrutinib and the analysis of mutations associated with resistance to ibrutinib was exploratory. Among patients with evaluable samples at baseline (92%), most (95%) had no mutation in BTK/PLCG2, as determined by deep sequencing of sorted B cells. One patient harboring a PLCG2 D993N mutation at baseline achieved a response to acalabrutinib. This is an uncommon PLCG2 potentially gain-of-function mutation and may not confer resistance to acalabrutinib or ibrutinib. However, acalabrutinib may not be effective in patients who develop progression on ibrutinib with typical resistance mutations.
Of the five patients with paired baseline and progres- sion samples, only one acquired mutations in BTK and PLCG2 after a best overall response of PR and a DOR of
Table 2. Adverse events occurring in ≥10% of patients (all grades) or ≥5% of patients (grade ≥3 in severity).
Adverse event
Diarrhea
Headache
Contusion
Dizziness
Upper respiratory tract infection Cough
Nausea
Neutropeniaa
Arthralgia
Fatigue
Pneumonia
Pyrexia
Lymphocyte count increasedb Thrombocytopeniac
Backpain
Constipation
Dyspnea
Rash
Sinusitis
Anemia
Upper-airway cough syndrome Fall
Hematuria Hypertension Nightsweats Peripheral edema Urinary tract infection Weight increased Abdominalpain Influenza-like illness Chills
Depression
Hyperhidrosis
Insomnia
Nasal congestion
All grades
32 (53) 25 (42) 24 (40) 20 (33) 20 (33) 18(30) 15(25) 15 (25) 14 (23) 14(23) 13 (22) 12(20) 10 (17) 10 (17) 10(17) 10 (17) 10(17) 10(17) 10 (17) 9(15) 9 (15) 8(13) 8(13) 8 (13) 8(13) 8 (13) 8 (13) 8 (13) 7(12) 7 (12) 6(10) 6(10) 6 (10) 6(10)
6 (10)
Grade 1
18 (30) 20 (33) 20 (33) 18 (30) 3 (5)
All treated patients (N=60)
Grade 2
11 (18)
4 (7)
4(7) 0
1 (2) 1 (2)
Grade 3
Grade 4
0
0
0
0
0
0
0
5 (8) 0
0
0
0
0
2 (3) 0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Grade 5
0
0
0
0
0
0
0
0
0
0
2 (3) 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3 (5) 1 (2)
17 (28) 0 9(15) 9(15) 0 10(17) 5(8) 0
0 3(5) 7(12)
8 (13) 6(10) 0 7(12) 0
3 (5) 4(7) 9 (15) 7(12) 6(10) 0 3(5) 6 (10) 4(7) 5(8) 2 (3) 4(7) 6 (10) 0
3 (5) 2(3) 4 (7) 6(10) 3(5) 6 (10) 4(7)
3 (5)
5 (8) 1 (2) 7(12) 1(2) 4 (7) 7 (12)
5(8) 0
2 (3)
2 (3)
5(8)
0
3(5) 0 4(7) 0
10 (17)
3(5)
3 (5)
2(3)
2(3)
4 (7)
4(7) 0
8 (13) 3 (5) 1(2) 1 (2)
0 3(5) 0 2(3) 1(2) 2 (3)
2 (3)
7 (12)
5 (8)
4(7)
2 (3)
0
3(5)
0
2(3)
3 (5)
0
1 (2)
0
1(2)
1 (2)
0
0
0
0
0
All data presented as n (%). aIncludes neutropenia and decreased neutrophil count. bIncludes lymphocytosis and increased lymphocyte count. cIncludes decreased platelet count and thrombocytopenia.
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