Page 157 - Haematologica May 2022

Acquired ibrutinib resistance in WM
T0 for each patient is shown in Figure 1. An IgM rebound occurred in 29 of 48 (60%) evaluable patients following T0. Three patients who developed symptomatic hypervis- cosity while progressing on ibrutinib received plasma- pheresis immediately before and after T0 and were deemed non-evaluable for an IgM rebound. The median time to an IgM rebound was 27 days (95% CI: 24-33;
Table 1. Baseline characteristics at time of ibrutinib discontinuation (T0).
Figure 2A). The cumulative incidence of an IgM rebound following T0 increased over time: 7 days (9%); 14 days (13%); 21 days (25%); 28 days (46%); and 35 days (65%). Patients with an IgM rebound had a peak median absolute and relative increase in serum IgM level of 1,405 mg/dL (range, 571-7,820 mg/dL) and 79% (range, 27-1,663%), respectively. The degree of BM involvement at T0 signifi- cantly correlated with both the absolute (r=0.44; P=0.047) and relative (r=0.45; P=0.04) changes in serum IgM level. Twenty-one patients (72%) had an increase in serum IgM level back to the pre-ibrutinib baseline or higher. Symptomatic hyperviscosity acutely developed after T0 in ten of 29 patients (34%) with an IgM rebound that prompted emergent plasmapheresis. The median time from T0 to the onset of symptomatic hyperviscosity was 29 days (range, 14-51 days). Serial IgM measurements were available for seven of ten (70%) patients that devel- oped symptomatic hyperviscosity and are shown in Online Supplementary Figure S1. Seven patients (24%) had an IgM rebound present during the first cycle of salvage therapy; none of these patients were receiving rituximab concurrently.
The timing of salvage therapy following T0 impacted the risk of an IgM rebound. Patients who received salvage therapy ≤7 versus >7 days from T0 had significantly lower odds of an IgM rebound (29% vs. 76%; OR 0.15, 95% CI: 0.03-0.67; P=0.005). Bridging ibrutinib with salvage thera- py was also associated with significantly lower odds of an IgM rebound compared to no bridging (17% vs. 69%; OR 0.10, 95% CI: 0.01-0.97; P=0.03). There was a trend for lower odds of an IgM rebound when bridging ibrutinib versus starting salvage therapy within 7 days of T0 (17% vs. 43%; OR 0.11, 95% CI: 0.01-1.19; P=0.11). We were unable to identify any factor at T0 predictive of an IgM rebound. Age, time on ibrutinib, time from WM diagnosis, sex, hemoglobin level, platelet count, serum IgM level, number and type of previous therapies, and MYD88 and CXCR4 mutation status were not associated with higher or lower odds of an IgM rebound (P>0.05 for all compar- isons; Online Supplementary Table S1).
Salvage therapy
Forty-eight patients (94%) received salvage therapy fol- lowing T0. The median time to salvage therapy was 18
Table 2. Clinical manifestations of disease progression on ibrutinib.
Patient characteristic
Median age (range) – yrs WM diagnosis
Ibrutinib initiation Ibrutinib discontinuation
Time from WM diagnosis Median (range) – yrs >10 yrs – no. (%)
Time from ibrutinib initiation Median (range) – yrs
>2 yrs – no. (%)
Time from disease progression on ibrutinib Median (range) – days
>90 days – no. (%)
Male sex – no. (%) Hemoglobin level
Median (range) – g/dL
<10 mg/dL – no. (%) Platelet count
Median (range) – K/uL
<100 K/uL – no. (%) Serum IgM level
Median (range) – mg/dL
>4000 mg/dL – no. (%) Bone marrow involvement
Median (range) - %
>50% – no. (%)
Previous therapy (including ibrutinib)
Median no. of treatment lines (range) Treatment lines – no. (%)
1-2 3-4 5+
Types of therapy – no. (%) IB
All patients (n=51)
59 (40-91) 66 (43-93) 69 (43-93)
8.2 (0.5-24) 20 (39)
2 (0.4-6.5) 25 (49)
25 (0-426) 7 (14) 33 (65)
10.3 (7.3-16.6) 20 (39)
171 (7-463) 16 (31)
1,567 (97-7,935) 9 (18)
70 (5-90) 16 (70)
4 (1-9)
21 (42) 15 (29) 15 (29)
Feature
Progressive cytopenias Lymphadenopathy and/or splenomegaly Malignant pleural effusion
Cardiac AL amyloidosis
Isolated serum IgM increase Symptomatic hyperviscosity
Soft tissue mass
Bing-Neel syndrome
DLBCL transformation
Malignant pericardial effusion
Renal monoclonal IgM deposition
All patients (N=51)
22 (43) 12 (24) 6 (12) 5 (10) 4 (8) 4 (8) 4 (8) 3 (6) 2 (4) 1 (2) 1 (2)
8 (16) IB+R 5(10)
IB+R+PI
IB + R + alkylator IB+R+PI+alkylator
MYD88 mutation – no. (%) CXCR4 mutation – no. (%)
Nonsense Frameshift
10(20)
8 (16)
20(39)
43 (93)
23 (58)
20 (87%)
3 (13%)
Patients may have had more than one manifestation of disease progression on ibruti- nib. Soft tissue masses developed in the palate, orbit, maxilla, and thoracic spine with cord displacement (n=1 for each). None of the patients with histological transforma- tion were previously treated with a nucleoside analogue. AL: light chain amyloidosis; IgM: immunoglobulin M; DLBCL: diffuse large B-cell lymphoma.
Data on bone marrow involvement at the time of ibrutinib relapse was available for 23 patients. MYD88 and CXCR4 mutation status was available for 46 and 40 patients, respectively. IB: ibrutinib; R: rituximab; PI: proteasome inhibitor. WM: Waldenström macroglobulinemia.
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