Potential strategies to overcome relapsed and refractory Waldenström’s macroglobulinemia

Although covalent BTK inhibitors are increasingly important in the management of patients with Waldenström’s macroglobulinemia (WM), progression and intolerance frequently necessitate treatment discontinuation. In the relapsed/refractory setting, the therapeutic options following chemoimmunotherapy and covalent BTK inhibitor therapy are limited, with no accepted standard of care [1, 2].

Non-covalent BTK inhibition with pirtobrutinib

According to the results of the phase I/II BRUIN study presented by Palomba et al. at ASH 2022, the highly selective, non-covalent (reversible) BTK inhibitor pirtobrutinib has demonstrated promising efficacy in heavily pretreated patients with relapsed/refractory WM including those who had previously received chemoimmunotherapy and covalent BTK (cBTK) inhibitors [3]. In the dose-escalation and dose-expansion phase I part of BRUIN, pirtobrutinib 25 mg to 300 mg QD was tested in a population harboring various B-cell malignancies. Eighty patients with WM received pirtobrutinib 200 mg QD in the phase II part. Among these, 63 were cBTK-inhibitor–pretreated, with a median number of prior lines of 3; almost 80 % had received both chemoimmunotherapy and BTK inhibition. Progressive disease was the reason for cBTK inhibitor discontinuation in two thirds of cases.

Pirtobrutinib demonstrated promising efficacy. Major response rates were 66.7 % and 88.2 % in the cBTK-inhibitor–pretreated and –naïve cohorts, respectively (Table). Notably, very good partial remission was obtained in 23.8 % and 29.4 %, respectively, which emphasized the depth of response achieved with pirtobrutinib even in the pretreated group. No substantial differences in major responses were observed according to patient and disease characteristics; this included prior therapy and reason for discontinuation of any prior cBTK inhibitor. At the time of the data cutoff, 55.6 % of patients after cBTK inhibitor therapy remained on pirtobrutinib therapy. Median overall survival (OS) had not been reached yet in this group, while median progression-free survival (PFS) was 19.4 months. At 18 months, the OS and PFS rates were 81.7 % and 57.1 %, respectively.

Pirtobrutinib continued to be well tolerated, with low rates of treatment-related grade ≥ 3 adverse events (AEs) that were highest for neutropenia (11.5 %). Among AEs of special interest (i.e., bruising, rash, arthralgia, hemorrhage, hypertension, atrial fibrillation/flutter), grade ≥ 3 treatment-related AEs ranged from 0.0 % to 0.6 %. Discontinuations and dose reductions due to treatment-related AEs occurred in 2.6 % and 4.5 %, respectively.

Table Remission rates with pirtobrutinib in the response-evaluable patient population according to pretreatment with covalent BTK inhibitors

Pembrolizumab plus rituximab

The first clinical trial to investigate checkpoint inhibition in WM is the phase II, non-randomized, single-arm, open-label PEMBROWM study. Patients with relapsed/refractory WM who had received at least one prior line of treatment and were not refractory to rituximab were treated with rituximab weekly for the first 28 days and then every 3 months for up to one year, while pembrolizumab was administered Q3W for a maximum of 18 cycles. After a median of 3 previous treatment lines, more than half of patients were refractory to BTK inhibitor therapy. The rationale for the trial resulted from the observation that PD-1 and PD-L1 is widely expressed in the bone marrow of WM patients, with soluble PD-1 ligands regulating T-cell function [4].

EMBROWM closed early due to slow accrual, with a final total of 17 patients 5 of whom completed the full 18 cycles of treatment [5]. Nine responders at 24 weeks were required for the study to meet the primary endpoint, which was the overall response rate (ORR) at 24 weeks; however, at this timepoint, only 8 patients responded. Nevertheless, the results indicated encouraging efficacy in this heavily pretreated population. The best ORR was 56 %. After a median follow-up of 16 months, median PFS was 13 months and median OS had not been reached yet. The 1-year PFS and OS rates were 55 % and 92 %, respectively. Median time to next treatment (TTNT) was 18 months; at 1 year, the TTNT rate amounted to 71 %.

The majority of AEs were grade 1 and 2 and most commonly included anemia (29 %), fever (29 %), infusion-related reactions (35 %) and creatinine elevation (29 %). Among grade ≥ 3 AEs, low blood counts and infection were observed most frequently. Only one grade 3 immune-related AE occurred. The quality-of-life scores according to the QLQ-30 questionnaire showed no significant differences between baseline and week 24. In their conclusion, the authors emphasized that a randomized study would be required to evaluate the added benefit of the PD-1 blockade to rituximab monotherapy in a highly relapsed/refractory WM patient population.


  1. Gustine JN et al., Ibrutinib discontinuation in Waldenström macroglobulinemia: Etiologies, outcomes, and IgM rebound. Am J Hematol 2018; 93: 511-517
  2. Gertz MA, Waldenström macroglobulinemia: 2021 update on diagnosis, risk stratification, and management. Am J Hematol 2021; 96(2): 258-269
  3. Palomba ML et al., Efficacy of pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in relapsed/refractory Waldenström Macroglobulinemia: Results from the phase 1/2 BRUIN study. ASH 2022, 229
  4. Jalali S et al., Soluble PD-1 ligands regulate T-cell function in Waldenström macroglobulinemia. Blood Adv 2018; 2(15): 1985-1997
  5. Kothari J et al., PembroWM: results of a phase II trial investigating the safety and efficacy of rituximab and pembrolizumab in relapsed/refractory Waldenström’s macroglobulinemia. ASH 2022, abstract 1574

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