Continuous or fixed-duration BTK inhibitor treatment for WM

In this issue of Blood Advances, Owen et al¹ report long-term results of acalabrutinib monotherapy in treatment-naive (TN, n = 14) or relapsed/refractory (R/R, n = 92) Waldenström macroglobulinemia (WM) in the phase 2 ACE-WM-001 trial. After a median follow-up of 63.7 months, the median progression-free survival (PFS) was not estimable and 67.5 months in the TN and R/R cohorts, with estimated 66-month PFS rates of 83.6% and 52.0%, respectively. This study provides the longest follow-up for Bruton tyrosine kinas inhibitor (BTKi) therapy in WM and demonstrated excellent long-term control of this disease.

For this rare indolent B-cell lymphoma, rituximab-based regimens, such as RCD (rituximab, cyclophosphamide and dexamethasone) and BR (bendamustine and rituximab), have yielded high efficacy and long-term disease control in first-line therapy^2,3 (see table). Six cycles of RCD provided a median PFS of 3 to 4 years, whereas BR prolonged this to 5 to 6 years.⁴ After the identification of MYD88 L265P as the driver genetic event in WM, BTK inhibitors have emerged as another highly effective and more convenient oral treatment option for patients with WM. Ibrutinib, the first-generation BTKi, yielded a 4-year PFS of 76% after a 50 months follow-up in 30 patients with TN.⁵ In this study by Owen et al, acalabrutinib monotherapy achieved an estimated 66-month PFS of 83.6% in 14 patients with TN. Although the sample sizes in both studies were small, the consistently long PFS achieved with both ibrutinib and acalabrutinib appears comparable to that of BR or RCD in front-line therapy. Therefore, 2 major frontline treatment options are currently available for symptomatic WM: fixed-duration regimens (BR, RCD) and continuous BTKi therapy, like the treatment paradigm in chronic lymphocytic leukemia (CLL).

The long-term follow-up results of different treatments in WM

Regimens	N	Median follow-up (months)	Overall response rate	≥VGPR rate	PFS	OS
RCD2	100 TN	68.8	87.7%	10%	Median: 50.1 months	91% at 5 years
BR3	69 TN	76.1	97%	19% CR/37% VGPR	66.6% at 5 years	80% at 5 years
Acalabrutinib1	14 TN/92 R/R	63.7	92.9%/94.6%	7.1%/41.3%	Median: NR/67.5 months 83.6%/52.0% at 66 months	90.9%/71.2% at 66 months
Ibrutinib5	30 TN	50	100%	30%	76% at 4 years	100% at 4 years
Ibrutinib6	31 (rituximab refractory)	58	87%	29%	Median: 39 months 40% at 5 years	73% at 5 years
Ibrutinib7	99 R/R /18 TN	44.4	93.9%	25.3%	69.7% at 42 months	85.2% at 42 months
Zanubrutinib7	102 R/R /19 TN	44.4	95.1%	36.3%	78.3% at 42 months	87.5% at 42 months
Venetoclax8	32 R/R /16 BTKi exposed	81	84/75%	19%	Median: 36/28 months 24% at 5 years	95% at 5 years

OS, overall survival; NR, not reached.

The advantages and disadvantages of fixed-duration immunochemotherapy or continuous BTKi therapy have been widely discussed in CLL. In this study, the most common serious treatment-emergent adverse events were infections, including pneumonia (10.4%), lower respiratory tract infection (9.4%), and COVID-19 infection. Atrial fibrillation/flutter (11.3%), bleeding events (62.3%) and hypertension (6.6%) were the clinical interest events. Although most adverse events (AEs) occurred during the first 6 to 9 months, the incidence of atrial fibrillation/flutter accumulated with long-term acalabrutinib administration, increasing from 4.7% to 11.3%. The combination of BTKi with other agents to develop time-limited regimens may represent an approach to reduce cumulative BTKi-associated AEs. Our group previously combined zanubrutinib with ixazomib and dexamethasone for up to 24 months to treat 27 patients with TN WM and achieved a very good partial response or complete response (VGPR/CR) rate of 45.8%, with arrhythmia reported in 1 patient (4.2%),⁹ which is lower than that reported with continuous zanubrutinib therapy in ASPAN study (7.9%).⁷ Optimizing the use of BTK inhibitors with other agents to develop time-limited treatment strategies was encouraged by the 11th international workshop on Waldenström macroglobulinemia) consensus.¹⁰ Our group and Adam Suleman’s group from Canada are conducting clinical trials evaluating the efficacy and safety of 1 year of zanubrutinib or acalabrutinib combined with 6 cycles of BR as fixed-duration first-line therapy for WM (ClinicalTrials.gov identifiers: NCT05914662 and NCT04624906). The preliminary results showed VGPR/CR rate of more than 60% without arrhythmia reported. Based on these encouraging results and the ongoing controversy regarding the necessity of 6 courses of BR, our group and Andrew Branagan’s group at Massachusetts General Hospital have initiated clinical trials investigating 4 cycles of BR with combined with 12 to 15 cycles of zanubrutinib, with the aim of maintaining efficacy while reducing treatment-related toxicity (ClinicalTrials.gov identifiers: NCT07259122 and NCT06561347).

For patients with R/R WM, BTKi therapy is the preferred choice according to the National Comprehensive Cancer Network guidelines. In this study, acalabrutinib produced a median PFS of 67.5 months, with an estimated 66-month PFS rate of 52.0%, which appears comparable to the 42-month PFS rates reported with zanubrutinib and ibrutinib in the ASPEN study (78.3% and 69.7%, respectively).⁷ A fixed 2-year course of the B cell lymphoma 2 inhibitor (venetoclax) monotherapy also yielded a median PFS of 36 months in 32 patients with R/R WM,⁸ which was numerically shorter than that of continuous BTKi therapy (see table).

In summary, this study by Owen et al showed that acalabrutinib monotherapy produced durable responses in both TN and R/R patients with WM, making it a preferred choice in both settings. However, the cumulative toxicity associated with continuous BTKi use highlights the unmet need for time-limited BTKi combination treatment in the future.

Conflict-of-interest disclosure: The authors declare no competing financial interests.