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Clinical relevance of MYD88 mutations in B-NHL
survival.117,118 With regards to CLL, Improgo et al.39 stated that MYD88(L265P) occurs mainly in patients with mutated IGHV or chromosome 13q deletions and both alterations are associated with a superior survival. Furthermore, WM patients with wildtype MYD88 had an increased risk of disease transformation, ibrutinib resist- ance and shorter overall survival.9,117, 118
Targeted therapies
The oncogenic activity of MYD88(L265P), as well as its high frequency in several B-NHL subtypes, ensure that MYD88 and its affiliated signaling pathways are very interesting for targeted therapeutic strategies. As reviewed by Yu et al.18 and Weber et al.,119 several targets are conceivable for direct or indirect inhibition, such as IRAK1 and IRAK4 in the myddosome-complex, TAK1 in downstream signaling, BTK in the BCR pathway, TLR9 in the My-T-BCR supercomplex, and components of the concurrently activated PI3K/AKT/mTOR and HCK path- ways (Figure 2).
Of these targets, inhibition of BTK has been the most extensively studied, regardless of the fact that BTK is not a MYD88(L265P)-specific target and is not directly involved with the myddosome complex. The BTK inhibitor ibrutinib is approved as treatment for CLL, man- tle cell lymphoma, relapsed/refractory marginal zone lymphoma, and WM by the United States Food and Drug Administration (FDA). Additionally, the FDA permitted the combined use of ibrutinib and rituximab as the first non-chemotherapeutic regimen for WM patients. In early clinical trials in patients with relapsed/refractory DLBCL
and primary DLBCL of the central nervous system, ibru- tinib elicited an overall response rate of 80-85% in those with MYD88(L265P) alone or in combination with mutat- ed CD79B.19,120 Furthermore, in a randomized phase III trial, ibrutinib plus R-CHOP improved the overall survival of DLBCL patients younger than 60 years regardless of the cell-of-origin.121 Nonetheless, ibrutinib tends to pro- duce many off-target effects and acquisition of resistance to the drug is common. For instance, ibrutinib resistance can be caused by the C481S mutation in BTK (NM_000061), which hampers the interaction between ibrutinib and BTK,122 but also by mutations in PLCg2,123 CARD11,120 and CXCR4.124 Given these drawbacks of ibrutinib, next-generation BTK inhibitors, such as acal- abrutinib and zanubrutinib, are being developed and used for research. Studies demonstrated that acalabrutinib achieved an overall response rate of 95% in relapsed CLL125 and 81% in relapsed mantle cell lymphoma,126 and this medicine is now approved as treatment for mantle cell lymphoma by the United States FDA. Zanubrutinib achieved an overall response rate of 90% in WM, and was also shown to be well tolerated and to overcome the ibru- tinib resistance mechanism induced by CXCR4 muta- tions.127
In addition to studies on BTK inhibition, several phase I/II clinical trials have investigated the response of novel therapeutic targets (in)directly involved with MYD88 in patients with B-NHL. In relapsed/refractory WM, mTOR inhibition with everolimus produced an overall response rate of 50%.128 In several subtypes of relapsed/refractory B-NHL, PI3K inhibition with parsaclisib produced overall response rates ranging between 20% and 78%, with a low risk of adverse events and improved long-term out-
Figure 2. Signaling cascades in mutated MYD88 B-cell non-Hodgkin lymphoma can be inhibited by several targeted therapeutic strategies. A combination of several therapies might increase efficacy and reduce the risk of relapse, depending on the molecular profile of the B-cell non-Hodgkin lymphoma.
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