Current and novel BTK inhibitors in Waldenström’s macroglobulinemia

Abstract

The current therapeutic approach in Waldenström’s macroglobulinemia (WM) is being driven by insights in disease biology and genomic landscape. Bruton’s tyrosine kinase (BTK) plays a key role in signaling pathways for the survival of WM clone. BTK inhibition has changed the treatment landscape of the disease. Ibrutinib has resulted in deep and durable responses both as an upfront and salvage treatment with a manageable toxicity profile. However, the need for fewer off-target effects and deeper responses has resulted in the clinical development of second-generation BTK inhibitors. Zanubrutinib has resulted in clinically meaningful antitumor activity, including deep and durable responses, with a low discontinuation rate due to treatment-related toxicities. Cardiovascular adverse events seem to be milder compared with ibrutinib. Interestingly, the efficacy of zanubrutinib in WM is significant both for MYD88L265P and MYD88WT patients. Although the randomized, phase III ASPEN clinical trial did not meet its primary endpoint in terms of showing a superiority of zanubrutinib in deep responses compared with ibrutinib, secondary efficacy and safety endpoints underscore the potential clinical role of zanubrutinib in the treatment algorithm of WM independent of the MYD88 mutational status. Combination regimens and non-covalent BTK inhibitors are emerging as promising treatment strategies. Long-term data will determine whether next-generation BTK inhibitors are more potent and safer compared with ibrutinib, and whether they are able to overcome resistance to ibrutinib, either alone or in combination with inhibitors of other interrelated molecular pathways.

Rare central nervous system lymphomas

“…[99][100][101][102] In one study, 2-year event-free survival (measured from the time of treatment initiation to disease progression, treatment toxicity or death from any cause) was 80%. 92 Although secondgeneration BTKi have shown promise in treating systemic LPL, 103 we found no reported data on these agents in the context of BNS.…”

Two‐year outcomes of tirabrutinib monotherapy in Waldenström’s macroglobulinemia

“…Ibrutinib is often accompanied by AEs including atrial fibrillation, bleeding events, and hypertension, leading to discontinuation of the treatment in 5%–10% of patients with WM 5,7–9 . Systematic reviews of ibrutinib studies using eight randomized controlled trials for B‐cell malignancies revealed a relative risk for atrial fibrillation and hypertension of 4.69 and 2.82, whereas patients suffering life‐threatening arrhythmias have also been reported 27–29 . In the ASPEN clinical trial, patients receiving zanubrutinib had a lower incidence of atrial fibrillation, bleeding AEs, and hypertension compared with those taking ibrutinib, leading to lower treatment discontinuation rate in patients on zanubrutinib treatment 20 …”

“… 5 , 7 , 8 , 9 Systematic reviews of ibrutinib studies using eight randomized controlled trials for B‐cell malignancies revealed a relative risk for atrial fibrillation and hypertension of 4.69 and 2.82, whereas patients suffering life‐threatening arrhythmias have also been reported. 27 , 28 , 29 In the ASPEN clinical trial, patients receiving zanubrutinib had a lower incidence of atrial fibrillation, bleeding AEs, and hypertension compared with those taking ibrutinib, leading to lower treatment discontinuation rate in patients on zanubrutinib treatment. 20 These results supported the idea that the second‐generation BTK inhibitor could minimize off‐target effects such as HER2 and TEC kinases and reduce toxicities related to BTK inhibitors.…”

“…5,[7][8][9] Systematic reviews of ibrutinib studies using eight randomized controlled trials for B-cell malignancies revealed a relative risk for atrial fibrillation and hypertension of 4.69 and 2.82, whereas patients suffering life-threatening arrhythmias have also been reported. [27][28][29] In the ASPEN clinical trial, patients receiving zanubrutinib had a lower incidence of atrial fibrillation, bleeding AEs, and hypertension compared with those taking Other notable TRAEs were skin TRAEs including rash and erythema. A recent review reported that both acalabrutinib and zanubrutinib are associated with a range of dermatological AEs not different from those in ibrutinib treatment.…”

Bing-Neel Syndrome: An Initial Manifestation of Waldenstrom Macroglobulinemia

“…This suggests that it is reasonable to switch to another regimen in the case of nonresponse or relapse. Second-generation BTK inhibitors have demonstrated safety and efficacy for WM patients [ 13 - 14 ] and may prove useful in treating BNS as well. Finally, autologous stem cell transplant has achieved remarkable results in a small case series, where 11/14 patients with BNS showed disease response and 10/14 remained in remission at three years [ 15 ].…”