Page 161 - Haematologica May 2022

Acquired ibrutinib resistance in WM
salvage therapy, and all were quadruple-class exposed. Patients with a TP53 mutation had a significantly shorter median OS following T0 versus those without (0.5 vs. 21.3 months; P=0.02; Online Supplementary Figure S6).
Discussion
In this study, we sought to describe the natural history of WM patients who acquired resistance to ibrutinib monotherapy. Despite the high response rates and durable remissions, acquired ibrutinib resistance represents an emerging problem in WM patients, and understanding the subsequent disease course may help direct management strategies. Central to our findings was that stopping ibru- tinib in resistant WM patients heralded rapid disease pro- gression, which prompted the need for salvage therapy to achieve disease control. This contrasts the indolent post- treatment course typically observed in WM patients fol- lowing rituximab-based regimens.27-30 Withholding ibruti- nib temporarily for adverse events or procedures can also lead to acute increases in serum IgM level, anemia, and constitutional symptoms, highlighting the capacity of tumoral cells to rapidly disseminate disease following ibrutinib withdrawal.10,13,20,31,32
The exact mechanism driving the rapid disease progres- sion after ibrutinib cessation remains to be clarified. However, the BTK substrate STAT5A regulates IgM secre- tion in WM cells, and its selective reactivation following ibrutinib withdrawal likely contributes to the rapid increase in serum IgM level observed.33,34 In addition, acquired ibrutinib resistance is associated with the clonal expansion of BTK and PLCg2 mutations that trigger pro- survival ERK1/2 signaling and cytokine release, as well as deletions in 6q and 8p that contain regulators of BTK, MYD88/NF-kB, and apoptotic signaling.17-19 It is possible these molecular mechanisms mediating ibrutinib failure contribute to disease acceleration following ibrutinib withdrawal. Indeed, we previously observed a higher risk of rapid disease progression in WM patients discontinuing ibrutinib for acquired resistance versus intolerance, signi- fying differences in underlying disease biology.20 A similar observation has also been described in patients with chronic lymphocytic leukemia (CLL), wherein rapid increases in serum lymphocyte counts were reported after stopping ibrutinib (i.e., “CLL flare”).35,36 Additional investi- gation is needed to elucidate whether the rapid disease progression in WM patients is driven by a hypersecretory state, rapid tumor proliferation, or a combination of both. Evaluating both the BM tumor burden and transcriptional signature in WM cells before and after ibrutinib discontin- uation would provide further mechanistic insights into this phenomenon.
Akin to previous studies, we observed the occurrence of an IgM rebound following discontinuation of ibrutinib.20,21 Rapid increases in serum IgM level can exacerbate WM- related morbidity caused by the IgM paraprotein, includ- ing hyperviscosity, peripheral neuropathy, cold agglutine- mia, and cryoglobulinemia.37 In this study, approximately one in three patients with an IgM rebound acutely devel- oped symptomatic hyperviscosity and required emergent plasmapheresis. These findings indicate that close moni- toring of serum IgM levels is necessary in WM patients immediately after stopping ibrutinib. Hyperviscosity pro- phylaxis with plasmapheresis may also warrant consider-
ation in WM patients stopping ibrutinib with high serum IgM levels, as the risk of symptomatic hyperviscosity increases exponentially when the serum IgM level rises above 3,000 mg/dL.38 A similar approach is recommended in WM patients receiving rituximab-based therapy to mit- igate the risk of hyperviscosity-related injury caused by an IgM flare.39,40
Our data suggest that early initiation of salvage therapy can forestall disease acceleration after stopping ibrutinib. This observation is clinically relevant given the impact of response attainment to salvage therapy on post-ibrutinib survival. Patients who received treatment within 1 week of ibrutinib discontinuation had a significantly lower risk of an IgM rebound, as well as higher response rates to sal- vage therapy. Notably, bridging ibrutinib in combination with the subsequent therapy for 1-2 cycles achieved an objective response in all patients, and may represent a strategy to maintain disease control in select patients. Similar efficacy with bridging has been reported in ibruti- nib-resistant CLL patients who bridged ibrutinib with venetoclax.41 Taken together, these data support the recent consensus guidelines that recommend continuing ibruti- nib until the subsequent therapy, plus consideration of bridging, in ibrutinib-resistant WM patients.42 Clinical tri- als should also consider allowing shorter wash-out periods or overlap of ibrutinib for WM patients in this clinical sce- nario.
The optimal treatment regimen for WM patients after ibrutinib has yet to be established in prospective studies. Our findings demonstrate that standard WM regimens such as Benda-R and BDR are effective as salvage therapy, especially in patients naïve to these agents. Patients with quadruple-class exposed disease, by contrast, had inferior post-ibrutinib outcomes, likely reflecting the presence of a WM clone with little residual sensitivity to available ther- apies. Importantly, the BCL2 inhibitor venetoclax may represent a novel treatment option for WM patients. Preliminary results from a phase II trial evaluating veneto- clax in relapsed or refractory WM patients reported an ORR of 87%, MRR of 81%, and 2-year PFS of 76%. Responses to venetoclax were attained in WM patients previously treated with ibrutinib, akin to studies evaluat- ing venetoclax in ibrutinib-resistant CLL patients.43,44 Combination therapy with IDR or idelalisib plus obinu- tuzumab are alternative novel salvage regimens, but their activity following ibrutinib is currently unknown.45-48 Non-covalent BTK inhibitors, such as LOXO-305 (clinal- trials gov. Identifier: NCT03740529), vecabrutinib (clinal- trials gov. Identifier: NCT03037645), and ARQ-513 (clinal- trials gov. Identifier: NCT03162536), that bind to non- BTK C481S targets are also under investigation in WM patients. Lastly, a clinical trial is underway with the HCK inhibitor dasatinib for WM patients who are progressing on ibrutinib (clinaltrials gov. Identifier: NCT04115059).
Clinical trials have shown CXCR4 mutations confer resistance to ibrutinib monotherapy in WM patients, char- acterized by lower response rates, delayed response attainment, and shorter PFS.10-15,49 Consistent with these findings, our cohort of ibrutinib-resistant WM patients was enriched for CXCR4 mutations relative to the estab- lished incidence (58% vs. 30-40%).3,6,50 Moreover, the majority of CXCR4 mutations were nonsense variants, supporting recent reports that this subtype of CXCR4 mutation shows greater resistance to ibrutinib monother- apy.11,51,52 Combination therapy with ibrutinib plus ritux-
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