Page 156 - Haematologica May 2022

J.N. Gustine et al.
(ORR) of 91%, major response rate (MRR) of 79%, and very good partial response rate (VGPR) of 30% with pro- longed follow-up.10,11 Responses to ibrutinib were durable with an estimated 5-year progression-free survival (PFS) and overall survival (OS) of 54% and 87%, respectively. A notable finding was the impact of MYD88 and CXCR4 mutations on ibrutinib outcomes. Patients wild-type (WT) for both MYD88 and CXCR4 had no major responses and a median PFS of 5 months to ibrutinib.10-12 Among patients with mutated MYD88, the concurrent presence of a CXCR4 mutation adversely impacted response rates, response kinetics, and 5-year PFS (38% vs. 70%).10,11 Similar outcomes to ibrutinib monotherapy have been reported in phase II trials of treatment-naïve (n=30) and rituximab-refractory WM patients (n=31), as well as in the recent phase III ASPEN trial (n=199) comparing ibrutinib to zanubrutinib.13-16
Despite the high response rates and durable remissions, acquired ibrutinib resistance is increasingly being observed in WM patients. Approximately half of WM patients who progress on ibrutinib acquire BTK mutations at the binding site of ibrutinib (BTK C481S) or its down- stream mediator PLCg2.17 BTK C481S mutations are high- ly subclonal and confer protection to BTK WT clones via a paracrine mechanism.17,18 Acquired deletions in 6q and 8p that contain regulators of BTK, MYD88/NF-kB, and apoptotic signaling also occur.19 However, data on the clin- ical outcomes of WM patients who progress while on active ibrutinib therapy are limited. Preliminary studies have described an abrupt increase in serum IgM level (i.e., IgM rebound) in some WM patients who discontinue ibrutinib.20,21 We sought to further characterize the clinical presentation, management, and outcomes of WM patients with acquired ibrutinib resistance, as well as the impact of BTK C481S mutations.
Methods
Study design and patient selection
We reviewed a prospectively maintained database of 362 patients seen at our institution between January 2012 and October 2020 who met clinicopathological criteria for WM and received ibrutinib monotherapy.1 Patients who had disease progression on active ibrutinib therapy per consensus guidelines were identified and included in this study.22 A transient increase in serum IgM level associated with a temporary hold of ibrutinib was not con- sidered disease progression. The date a patient discontinued ibru- tinib because of disease progression was defined as time-zero (T0). Pertinent clinical and pathological data were gathered for all patients at the time of T0 until the last follow-up or death. The Dana-Farber/Harvard Cancer Center Institutional Review Board approved this study, and all patients provided written consent.
Response and outcome definitions
We defined an IgM rebound as a ≥25% increase in serum IgM level following T0, with an absolute increase of at least 500 mg/dL, consistent with previous studies.20,21 Response assessment to sal- vage therapy was performed according to consensus guidelines from the 6th International Workshop on WM.22 The ORR was defined as a minor response or better (≥25% reduction in serum IgM level), and the MRR was defined as a partial response or bet- ter (≥50% reduction in serum IgM level). Consensus guidelines were also utilized to assess response to salvage therapy for patients with light chain (AL) amyloidosis and diffuse large B cell
lymphoma (DLBCL).23,24 The ORR and MRR were assessed for each regimen used after T0. Duration of response (DOR) was defined as the length of time between response attainment and progression, death, or last follow-up. Survival after disease pro- gression on ibrutinib was defined as the length of time between T0 and the date of death or last follow-up.
Tumor genotyping
The presence of MYD88, CXCR4, and BTK mutations was detected by allele-specific polymerase chain reaction (AS-PCR) and Sanger sequencing methods, as previously described.6,17,25 A clinically validated next-generation sequencing (NGS) assay was also performed in a subset of patients on unselected bone marrow (BM) aspirate samples to identify TP53 mutations.26
Statistical analyses
Patient characteristics were summarized using descriptive sta- tistics. Continuous variables were dichotomized using standard WM cutoffs to facilitate analysis, and comparisons were made using the c2 test or Fischer exact test depending on the number of observations. Univariate and multivariate logistic regression mod- els were utilized to identify predictive factors for an IgM rebound and response to salvage therapy; the outcome measure was odds ratio (OR) with 95% confidence interval (CI). Time to events was estimated using the Kaplan-Meier method, and comparisons between groups were made using the log-rank test. The Cox-pro- portional hazard regression method was used to fit univariate and multivariate models for OS; the outcome measure was hazard ratio (HR) with 95% CI. P-values were two-sided and considered statistically significant if <0.05. All calculations and graphs were obtained using R (R Foundation for Statistical Computing, Vienna, Austria).
Results
Patient characteristics
We identified 51 WM patients with acquired resistance to ibrutinib monotherapy whose findings are included in this study. The baseline clinical characteristics at T0 are summarized in Table 1. The median duration between WM diagnosis and study entry (T0) was 8.2 years (range, 0.5-24 years). The median treatment duration with ibruti- nib before T0 was 2.0 years (range, 0.4-6.5 years). The median time between disease progression on ibrutinib and T0 was 25 days (range, 0-426 days); seven patients (14%) deriving clinical benefit continued on ibrutinib for >90 days after meeting criteria for disease progression before discontinuing therapy. Forty-three patients (84%) had received ibrutinib in the relapsed or refractory setting, and eight (16%) in the frontline setting. The median num- ber of treatment lines including ibrutinib before T0 was four (range, 1-9). Twenty patients (39%) were previously exposed to the major drug classes during their disease course, including rituximab, proteasome inhibitors, alky- lators, and ibrutinib (i.e., “quadruple-class exposed”). MYD88 and CXCR4 mutations were present in 93% and 58% of genotyped patients, respectively, and the majority (87%) of CXCR4 mutations were nonsense variants. The clinical manifestations at the time of disease progression on ibrutinib showed considerable heterogeneity and are presented in Table 2.
Serum immunoglobulin M rebound
The peak absolute change in serum IgM level following
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