Advancing care in Waldenström macroglobulinemia: Clinical and real-world perspectives

Recent advances have transformed the management of Waldenström macroglobulinemia (WM), particularly with the advent of targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors. These innovations have addressed longstanding challenges including resis­tance, intolerance, and the need for personalized approaches (enabling therapy also for those deemed unfit for chemotherapy).

Bortezomib, ibrutinib, rituximab: Results from ECWM-2

The combination of rituximab and ibrutinib has previously shown remarkable efficacy in both treatment-naïve and relapsed WM patients, as demonstrated in the phase III iNNOVATE trial that revealed significant improvement in progression-free survival (PFS), with a 54-month PFS rate of 68 % for the ibrutinib-rituximab group compared to 25 % for the placebo-rituximab group [1,2]. Additionally, recent findings showed that bortezomib combined with DRC (dexamethasone, rituximab, cyclophosphamide) achieved a major response rate of 85.3 % in WM patients [3].

Building on these findings, the single-arm, open-label ECWM-2 trial, conducted by the European Consortium for Waldenström’s Macroglobulinemia, evaluated the efficacy and safety of a novel frontline combination therapy of bortezomib, ibrutinib, and rituximab (B-IR) in treatment-naïve WM patients. The current analysis was presented by Buske et al. at ASH 2024 [4]. The treatment consisted of an induction phase with 6 cycles (C) of bortezomib, rituximab and ibrutinib followed by 24 months of maintenance with rituximab combined with ibrutinib. Subsequent ibrutinib treatment was administered until progression or non-tolerated toxicity.

The analysis, based on a median follow-up of 43 months, enrolled 53 patients with a median age of 63 years. Most participants were classified as intermediate (39.6 %) or high risk (30.2 %) per ISSWM criteria. Lymphadenopathy was present in 54.7 % of patients, and 22.6 % had splenomegaly. Among 52 patients with available mutational status, 54 % had MYD88 mutations (MYD88^MUT) and CXCR4 wildtype (CXCR4^WT), while 42 % were MYD88^MUT/CXCR4^MUT and 4 % MYD88^WT/CXCR4^WT. TP53 mutations were observed in 6 %.

BI-R rapidly induced deep responses with an overall response rate (ORR) and a major response rate (MRR) of 98 % and 73 %, respectively, after 3 cycles. Median time to major response was 2.8 months, with a one-year probability rate of 81 %. IgM serum levels decreased by a median of 76 %, and hemoglobin levels showed a median increase from 10.5 g/dL to 12.6 g/dL. Very good partial response (VGPR) and complete response (CR) rates progressively increased to a total of 39 % after 2.5 years (Figure 1).

As expected based on previous trials [1,2], the combination with rituximab and bortezomib overcame known shortcomings of ibrutinib monotherapy in MYD88^WT and CXCR4^MUT subgroups, with median time to best response of 6.7 months and a 1-year probability rate of best response of 69 %.

This fast response was paralleled by a rapid reduction in the MYD88^L265P detection rate as measured by droplet digital PCR (ddPCR) of plasma cell-free DNA. The researchers reported reductions by 50 % after three cycles, 73 % after six cycles, and 90.9 % after 2.5 years when patients transitioned to single-agent ibrutinib treatment. The one-year PFS rate was 92 % (p<0.001), and the two-year PFS and overall survival (OS) rates were 88 % each. All events observed were deaths due to COVID-19 reflecting the situation in the early phase of the pandemic. Only one progressive disease was reported after four years which was later reclassified as marginal zone lymphoma (MYD88^WT).

Grade ≥3 adverse events included COVID-19 pneumonia (34.3 %), hypertension (11.4 %), COVID-19 (8.6 %), and neutropenia (8.6 %). Peripheral neuro­pathy grade 1–2 was reported in 17 patients (32.1%). Grade ≥3 events of special interest included infections and infestations in 22 patients (52.4%) and vascular or cardiac disorders in 13 (37.7%) patients.

These data highlight the B-IR combination as a fast-acting, highly effective and well-tolerated frontline therapy in WM. Hence, it might offer a promising new standard of care for treatment-naïve WM patients.

Figure 1: ECWM-2 response rates over time

Zanubrutinib/ixazomib/dexamethasone in newly diagnosed WM

Covalent BTK inhibitors have demonstrated significant efficacy in WM with major response rates of 70 % to 80 %. [5] However, attaining deep remissions remains challenging, and the concept of time-limited therapy with BTK inhibitors has not been extensively studied. At ASH 2024, Wenjie et al. presented results from a phase II study evaluating the combination of zanubrutinib, ixazomib, and dexamethasone in 27 newly diagnosed symptomatic WM patients [6].

Overall, 24 of 27 enrolled patients underwent up to six 28-day cycles of induction therapy followed by consolidation therapy for up to a total of 24 cycles. One patient (4.2 %) achieved complete remission (CR), 10 patients (41.6 %) achieved very good partial response (VGPR) and 12 (50 %) obtained partial response (PR). The ORR was 100 %, with 45.8 % achieving VGPR or better (primary endpoint). Median time to response was 2 months. Five of 22 patients were CXCR4^MUT; importantly, no significant difference in deep remission rates was observed between CXCR4^MUT and CXCR4^WT (40 % vs. 50 %, p = 0.594).

After a median follow-up of 30.9 months, the median PFS was 40 months, while overall survival (OS) was not evaluable. These results highlight the potential of zanubrutinib, ixazomib, and dexamethasone as an effective, time-limited option for the first-line therapy of patients with WM. The combination had a manageable toxicity profile. Hematological toxicity was the most common adverse event (AE), while serious adverse events included infections (12.5 %) and thrombocytopenia (8.3 %).

BGB-16673: A novel BTK degrader

BTK inhibitors are effective in WM but their use can be limited by toxicities and/or resistance development [7,8]. BGB-16673, a first-in-class bivalent CNS-penetrating BTK degrader, was designed to overcome resistance and intolerance associated with covalent and non-covalent BTK inhibitors (cBTKis, ncBTKis) by binding specifically to BTK and the E3 ligase, which results in BTK degradation via ubiquitination [9,10]. At ASH 2023, BGB-16673 was shown to lead to substantial reductions in BTK protein levels in peripheral blood and tumor tissue [11].

This year, Seymour et al. presented an updated safety and efficacy analysis in the heavily pretreated relapsed/refractory (R/R) WM subgroup of the phase I/II CaDAnCe-101 study [12]. Included WM patients had confirmed R/R WM (≥2 prior therapies); prior treatment with an anti-CD20 antibody as well as exposure to any type of BTKi. BGB-16673 was administered orally once daily in 28-day cycles.

At the time of the data cut-off, the study had enrolled 27 patients with a median age of 73 years and a median of three prior therapies. All patients had received previous cBTKis, and 14.8 % had prior exposure to ncBTKis. Notably, 92.3 % of patients were MYD88^MUT, 44 % harbored BTK^MUT, 48 % carried ­CXCR4^MUT and 52 % had TP53^MUT, as expected in a high-risk, heavily pretreated cohort. Discontinuation of prior BTK inhibitor therapy due to progressive disease (PD) was reported in 77.8 % of patients.

The safety profile was manageable, though treatment-emergent adverse events (TEAEs) were frequent (92.6 %). Grade ≥ 3 AEs were observed in 40.7 % of patients, while treatment-related AEs occurred in 25.9 %. One patient died due to septic shock associated with progressive disease. The most common grade ≥ 3 AEs included neutropenia (25.9 %), anemia (11.1 %), and thrombocytopenia (7.4 %). Importantly, no cases of common BTKi side effects such as atrial fibrillation, hypertension, major hemorrhage, febrile neutropenia or pancreatitis were reported. There were no dose-limiting toxicities or treatment discontinuation due to AEs. Patients who responded to therapy experienced rapid and significant improvement in cytopenias.

At a median follow-up of 5 months, BGB-16673 demonstrated an overall response rate (ORR) of 81.5 %, a disease control rate (DCR) of 93 %, and a major response rate of 74.1 %. Responses were observed across all dose levels, as well as in patients with prior exposure to BTKi therapy. Median time to first response was one month (Figure 2). Already after this short follow-up, VGPR was observed in 25.9 % of patients, and PR occurred in 48.1 %. At the current stage, with only a limited number of cases available, the agent promises to be active regardless of the presence of BTK, MYD, CXCR4 or TP53 mutations, which highlights the broad activity of this degrader. IgM levels decreased in all patients, with rapid declines across all dose levels.

These promising early results position BGB-16673 as a transformative therapy in patients experiencing BTKi failure.

Figure 2: Treatment duration and response in the CaDAnCe-101 study

Pirtobrutinib and venetoclax in previously treated WM

BTK inhibitors and BCL-­2 antagonists have demonstrated significant efficacy and tolerability as monotherapies in WM. Notably, ncBTK inhibitors have proven effective in patients whose disease has progressed on covalent BTK inhibitors [13]. However, continuous BTK inhibitor therapy can lead to cumulative toxicity and the emergence of resistance [14]. At ASH 2024, Castillo et al. presented an interim analysis of an investigator-initiated, multicenter, prospective phase II study evaluating a fixed-duration combination of the ncBTK inhibitor pirtobrutinib and venetoclax in patients with previously treated WM [15].

The study therapy was given in 4-week cycles and consisted of pirtobrutinib monotherapy 200 mg/day during cycle one, followed by venetoclax ramp-up during the second cycle. Pirtobrutinib 200 mg/day and venetoclax 400 mg/day were co-administered for cycles 3 – 24. So far, 16 patients with a median age of 67 years and a median of one prior line of therapy have enrolled in this study. Over half of the patients (56 %) had previously received covalent BTK inhibitors, while 69 % had received rituximab-containing regimens and 25 % rituximab-containing regimens and a BTKi. At baseline, MYD88^L265P was detected in 87.5 %, CXCR4^MUT in 37.5 %, and TP53^MUT in 6 %.

After a median follow-up of six months, the VGPR rate was 56 %, with all patients achieving at least a minor response (13 %). In patients with CXCR4^MUT (33 % vs. 70 %; p = 0.35) or previous exposure to cBTK inhibitors (33 % vs. 86 %; p = 0.05), lower VGPR rates were reported. In patients with > 1 line of therapy, the VGPR rate was 71 %, compared to 44 % in patients with only 1 line of prior therapy (p = 0.35; Figure 3). The 6-month progression-free survival rate was 84 %, with two cases of progression in MYD88^WT patients, and the 6-month overall survival rate was 93 % including one COVID-19 death.

Grade 4 adverse events observed included neutropenia (13 %) and thrombocytopenia (13 %). Grade 3 adverse events included anemia (44 %), neutropenia (31 %), hypertension (13 %), headache (6 %), and one case each of myalgia, hypocalcemia, elevated AST levels, upper respiratory infection, glaucoma, and allergic reaction. No cases of tumor lysis syndrome have been detected to date.

Taken together, the combination of pirtobrutinib and venetoclax appears active in symptomatic, previously treated WM patients, and the study continues to enroll an additional 26 patients.

Figure 3: Response to pirtobrutinib and venetoclax in previously treated WM

Loncastuximab tesirine in heavily treated WM

Chemoimmunotherapy (CIT) and covalent BTK inhibitors are standard first- and second-line treatments for WM. Although these therapies are generally well-tolerated and effective, there is no established standard of care for patients who have progressed after both CIT and BTKi treatments [16,17].

At ASH 2024, Sarosiek et al. reported results for loncastuximab tesirine, a CD19-targeted antibody-drug conjugate, from a multicenter, phase II trial of heavily pretreated WM patients who had received at least two lines of therapy (including a rituximab-containing regimen and a BTK inhibitor) [18].

At the time of data cut-off, 10 patients had enrolled in the trial, and eight had received six cycles of loncastuximab tesirine every four weeks. The first 2 cycles were given at a dose of 150 µg/kg, and in cycles 3-6, 75 µg/kg were administered. All patients had MYD88^MUT, 88 % carried CXCR4^MUT, and 63 % carried TP53^MUT. To date, no IgM flare and no tumor lysis syndrome have occurred. Despite the high burden of higher-risk mutations, 88 % responded overall, with very good partial response achieved by 63 % of patients. Responses were rapid, with a median time to minor, major and best response of 13, 54 and 154 days, respectively.

Three out of eight patients required a dose reduction due to hematologic toxicity. Adverse events of interest included skin toxicity (88 %), edema (63 %), cytopenia (100 %) and gamma-glutamyltransferase elevation (63 %). Although skin toxicity and GGT elevation persisted in some patients, cytopenias were transient.

These results position loncastuximab tesirine as a promising third-line option for WM, particularly in patients with high-risk genetic features. Accrual will continue to enroll a total of 36 patients.

Zanubrutinib in Bing-Neel syndrome

Bing-Neel syndrome (BNS), a rare complication of WM characterized by the migration of lymphoplasmacytic lymphocytes to the central nervous system (CNS), remains a therapeutic challenge. According to the NCCN guidelines, the preferred treatment regimens for symptomatic individuals include BTK inhibitors, such as ibrutinib [19,20] and zanubrutinib. However, there are no studies to date evaluating zanubrutinib, a new-generation BTKi, in this specific setting. At ASH 2024, Bermúdez et al. presented results for eleven patients with BNS who received zanubrutinib as treatment for WM across 10 Spanish centers between 2022 to 2024 [21].

In this retrospective study, patients had a median age of 72 years at BNS diagnosis. Symptoms included sensory and motor deficits (45 %), language disorders (27 %), visual disturbances (18 %), and confusion (18 %). Six patients presented with BNS as the initial manifestation of WM; one of them also had hyperviscosity syndrome at the time of diagnosis, while the remaining five exhibited constitutional symptoms. The other patients developed BNS later in their disease course. According to the ISSWM risk stratification, 36.5 % of patients were classified as low risk, 36.5 % as intermediate risk, and 27 % as high risk. CSF analysis revealed a median clonal B-cell infiltration of 33 %, and imaging abnormalities were noted in five cases. These included diffuse leptomeningeal enhancement in three patients and localized tumors in two patients.

Nine patients received zanubrutinib as first-line treatment for BNS, one as second-line therapy after rituximab, high-dose methotrexate, and procarbazine, and another following ibrutinib. Zanubrutinib was administered at 160 mg BID in seven patients and 320 mg daily in four. Clinical responses, defined as symptomatic neurological improvement, were achieved in 73 % of patients, including two complete responses. Median time of exposure to zanubrutinib was seven months. Toxicities were limited to grade 1–3 neutropenia in two patients, that did not require dose reductions. One patient discontinued treatment due to lack of efficacy. Two patients died within one month of treatment: one due to disease progression and the other due to neutropenic septic shock and CMV disease.

At a median follow-up of 7 months, the overall survival rate was 82 %. These findings provide evidence that zanubrutinib is an effective and safe option for managing BNS both in first-line and salvage settings.

Long-term outcomes of zanubrutinib: ASPEN extension study

The phase III ASPEN study (NCT03053440) compared zanubrutinib with ibrutinib in patients with MYD88^MUT WM (cohort 1) and assessed zanubrutinib in MYD88^WT WM (cohort 2) [22,23]. BGB-3111-LTE1 (NCT04170283) is a zanubrutinib long-term extension study that enrolled ­74 zanubrutinib-treated patients from ­ASPEN.

At ASH 2024, D’Sa et al. reported extended safety and efficacy outcomes of the ad-hoc analysis of the LTE1 trial [24]. Among the 129 patients treated with zanubrutinib in the ASPEN trial, 75 were enrolled in the LTE1 study and 72 of them continued zanubrutinib treatment. The median age at ASPEN study entry was 67 years, with 81.3 % showing relapsed/refractory WM and a median of one prior line of therapy. AT LTE1 entry, the median age was 71 years, with a median time since zanubrutinib treatment initiation of 50.6 months. As of April 17^th, 2024, 52 patients were still on study treatment, and the median treatment duration was 23.8 months.

Grade ≥3 and serious treatment-emergent adverse events (TEAEs) occurred in 29.2 % and 23.6 % of patients, respectively. No discontinuations due to adverse events were reported, and only 4.2 % of patients experienced TEAEs leading to dose reductions. However, fatal TEAEs including cardiac failure, fall/subdural hematoma, and colorectal cancer were reported in 4.2 % of patients. No grade ≥ 3 or serious TEAEs occurred in ≥ 5 % of patients. Overall, a decline in the prevalence of TEAEs was reported over time, particularly in those associated with BTK inhibition, such as atrial fibrillation and hypertension (Figure 4).

Patients from ASPEN cohort 1 (MYD88^MUT) had an ORR of 96.1 %, with 40.2 % achieving VGPR or better. Median duration of response was not yet reached, and the 60-month event-free rate for PFS was 74.8 %. For cohort 2 (MYD88^WT), the ORR was 84.6 %, and the VGPR+ rate was 30.8 %, with a 60-month event-free rate for PFS of 39.3 % and a median duration of response of 41.1 months. Sixty-month event-free rates for overall survival were 82.8 % and 79.0 % for cohorts 1 and 2, respectively. Of note, durable responses were also demonstrated in patients with CXCR4^MUT and TP53^MUT.

With a median follow-up of 5.8 years, these findings confirm the long-term efficacy and tolerability of zanubrutinib, reinforcing its status as standard of care for WM.

Figure 4: Prevalence of recurrent TEAEs (all grades) of special interest over time

Long-term impact of BTK inhibitor dose interruptions in WM

Most WM patients receive continuous oral BTKi monotherapy for several years [25,26]. However, the impact of dose interruptions of BTK inhibitors on disease control remains limited, although up to 20 % of patients may experience withdrawal symptoms [27,28]. To address this, Trotman et al. presented findings at ASH 2024 from a pooled analysis of WM patients across three key studies—ASPEN, BGB-3111-AU-003, and BGB-3111-LTE1—that evaluated zanubrutinib in various clinical settings [29].

This analysis contained data from the phase 1/2 BGB-3111-AU-003 study (NCT02343120) evaluating zanubrutinib monotherapy in patients with B-cell malignancies [30,31], the phase III ASPEN study (NCT03053440) comparing zanubrutinib with ibrutinib in patients with MYD88^MUT WM and assessing zanubrutinib in MYD88^WT WM [22,23], as well as the respective extension study BGB-3111-LTE1 (NCT04170283).

Data from 301 patients were included in the analysis (ASPEN, n=227 [zanubrutinib, n=129; ibrutinib, n=98]; AU-003, n=74 treated with zanubrutinib). At data cutoff, 225 patients (75 %) experienced a total of 806 dose interruptions (DIs), most commonly due to adverse events (73 %) or surgical procedures (64 %). The median duration of DIs was seven days, and 56 DIs were longer than 28 days. In terms of adverse events that led to DIs, the most common was neutropenia with 8 %. For DIs ≥28 days, the most common event was pneumonia (33 %; Table 1).

During DIs for less than 14 days, the median change in hemoglobin was -0.2 g/dL, whereas for DIs ≥28 days, the median change was -0.5 g/dL. The proportion of DI events with hemoglobin decline of > 2 g/dL was 5 % with DIs < 14 days, and 25 % with DIs ≥ 28 days. Hemoglobin recovery occurred after 33 % of DIs associated with hemoglobin decreases of > 2 g/dL. The authors noted that in patients with hemoglobin decreases of > 2 g/dL following DI, no increase in PD rate was observed compared to the overall study population. The median time from treatment reinitiation to hemoglobin recovery was 84 days. Patients with longer interruptions (≥ 28 days), as compared to those with DIs <14 days, had higher rates of IgM flare (41 % vs. 5 %) and a higher median change in IgM levels (0.43 g/dL vs. 0.003 g/dL). However, most patients (74 % vs. 82 %) regained disease control upon treatment resumption, with a median time to IgM recovery of 154 days.

The median treatment duration was 49 months, and the overall progressive disease (PD) rate was 24 %, whereas patients with dose interruptions in the first 12 months of treatment had a higher rate of PD (29 %) than those with dose interruptions after 1 year (13 %; p = 0.017).

This underscores the importance of careful management of BTKi interruptions, particularly early in therapy, to minimize the risk of progression.

Table 1

Real-World outcomes from the WhiMSICAL registry

WM has traditionally been treated with chemoimmunotherapy including regimens like bendamustine-rituximab (BR) and dexamethasone-rituximab-cyclophosphamide, which provide high response rates and prolonged PFS. More recently, the treatment landscape has shifted towards targeted therapies such as BTK inhibitors and the BCL-2 antagonist venetoclax, which offers additional options for WM management [13]. However, the rarity of WM limits the availability of large clinical trials, especially those that capture diverse disease manifestations, treatment responses, and quality of life (QoL) outcomes [32].

To address these gaps, the WhiMSICAL registry provides patient-entered efficacy and QoL data of first-line treatments on a global level, featuring 704 patients from 23 countries. At ASH 2024, Low et al. presented an updated analysis of this real-world study comparing BR and BTK inhibitors in the frontline setting [33]. There was a male predominance (63 %), with a median age at diagnosis of 59 years. 453 patients underwent first-line treatment, with BR being the most common first-line therapy (n = 133). This group was compared with patients receiving BTKis as first-line therapy (n = 63). At a median follow-up of 79 months since diagnosis, there was no significant difference in time to next treatment between those two groups, with the median not reached vs. 107 months (p = 0.31; Figure 5). However, patients on BTKis reported significantly better QoL scores within 12 months of commencing first-line therapy (79.3 vs. 68.6, p = 0.02), although these differences equalized 12–24 months post-treatment initiation (79.4 vs. 78.0, p = 0.81).

While BR demonstrated robust long-term efficacy, BTKi treatment was associated with improved QoL, especially early during therapy. Overall, this real-world analysis highlights the value of both regimens, emphasizing the importance of individualized treatment selection based on patient preferences and clinical profiles.

Figure 5: Time to next treatment comparison between BTK inhibitors vs. BR

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