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  J.N. Gustine et al.
 imab is also adversely impacted by CXCR4 mutations, with a shorter 36-month PFS in CXCR4 mutated versus CXCR4 WT WM patients (64% vs. 84%, respectively).53-55 Given the importance of CXCR4 mutations, clinical trials evaluating the CXCR4 inhibitors ulocuplumab (clinaltrials gov. Identifier: NCT03225716) and mavorixafor (clinaltri- als gov. Identifier: NCT04274738) in combination with ibrutinib are currently ongoing in CXCR4-mutated WM patients.
A notable finding was the similar disease course between BTK C481S and BTK WT ibrutinib-resistant WM patients. It is possible a shared ERK1/2 signature underlies this clinical observation. In WM patients with BTK WT, PLCg2 mutations and DOK2 deletions were identified as possible molecular mechanisms driving acquired ibrutinib resistance.17,19 Both are predicted to trigger ERK1/2 signal- ing similar to the effect of BTK C481S mutations,18,56 although studies are needed to confirm the functional sig- nificance of PLCg2 and DOK2 in WM. These studies may also inform the utility of ERK1/2 inhibitors as a strategy to overcome acquired ibrutinib resistance in WM patients with BTK WT. The use of an ERK1/2 inhibitor has previ- ously been shown to abrogate the effects of BTK C481S in WM cells and restore sensitivity to ibrutinib.18 We also observed TP53 mutations were associated with refractory disease and shorter survival after acquiring resistance to ibrutinib. Although both preclinical and clinical data sug- gest ibrutinib has activity in TP53-mutated WM patients, additional work is needed to identify novel treatments for this high-risk group.57,58 A phase II trial evaluating ibrutinib in previously untreated WM patients with serial whole- exome sequencing is now complete and will provide addi- tional insights into mechanisms of ibrutinib resistance, as well as the impact of ibrutinib on clonal evolution (clini- caltrials gov. Identifier: NCT02604511).
Limitations of this study include the inherent selection bias associated with a retrospective study from a single tertiary referral center. Nevertheless, this study constitutes the largest clinical experience of WM patients with acquired ibrutinib resistance, and the patients included are
representative of those who participate in clinical trials. This study can therefore serve as a “real-world” bench- mark for assessing new drugs in WM patients with acquired ibrutinib resistance.
In conclusion, our findings show that discontinuation of ibrutinib can herald rapid disease progression in WM patients with acquired ibrutinib resistance. A rapid rebound in serum IgM level frequently occurs and can cause symptomatic hyperviscosity. Continuing ibrutinib until the subsequent treatment, with consideration of bridging, may represent a reasonable strategy to maintain disease control. Prospective studies are needed to clarify the optimal management of WM patients with acquired ibrutinib resistance.
Disclosures
SPT, JJC, GY, and ZRH have received research funding and/or consulting fees from Pharmacyclics and Janssen Pharmaceuticals; SPT has received research funding from Bristol Myers Squibb, X4 Pharmaceuticals, and Beigene; JJC received research funding and/or consulting fees from Abbvie, Beigene, Roche, and TG Therapeutics.
Contributions
JNG, SS, SPT, and JJC designed the study and performed the data analysis; MLG, LX, AK, NT, MM, MD, XL, GY, and ZRH performed molecular testing on patient samples; SS, CAF, KM, CL, TW, CJP, ARB, SPT and JJC took care of the patients and collected the samples; JNG, SPT, and JJC drafted the man- uscript. All authors critically reviewed and approved the manu- script.
Funding
JJC would like to thank the support of the WMR Fund. The authors would also like to thank the Siegel Research Fund for WM, the Orszag Family Fund for WM Research, the D’Amato Family Fund for WM Research, the International Waldenström’s Macroglobulinemia Foundation, and the Kerry Robertson Fund for WM. SPT, ZRH and GY are supported by an NIH SPORE in Multiple Myeloma (grant: 2P50CA100707-16A1).
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