Patients

A total of 21 patients were screened, out of which 16 were enrolled and included in the analysis. All enrolled patients were treated with at least 1 dose of study intervention. At the time of primary analysis data cut-off (24 August 2021), all the treated patients completed the treatment with rituximab and 12 (75.0%) were still on treatment with ibrutinib. At final analysis, 5 (31.3%) discontinued the treatment and 11 (68.8%) patients were on-treatment with ibrutinib and regarded as completed. The reasons for discontinuation of ibrutinib were refusal of patients [3 (18.8%)], progressive disease and other (due to moving) [1 (6.3%)]. Patient disposition is presented in Supplementary Figure 1.

The median (range) age of patients was 68.0 (ranged from 39 to 84) years, and 12 (75.0%) were male. In total, 8 patients (50.0%) were treatment naïve, and 8 (50.0%) were with relapsed/refractory WM (7 had received 1 to 2 prior WM-related therapies). The median (range) time from initial diagnosis to first dose of ibrutinib for treatment naïve patients and those with relapsed/refractory WM was 2.4 (0.5–41.4) months and 95.0 (61.9–221.1) months, respectively. In relapsed/refractory patients, the median (range) time from the last prior treatment to first ibrutinib treatment was 52.4 (15.7–112.7) months. The most common criteria for initiating treatment of WM at screening were symptomatic anemia (62.5%), clinically relevant fatigue (50.0%), and symptomatic hyper-viscosity (18.8%). Majority of patients had median IgM, 36.6 g/L, β2-microglobulin level >3 mg/L (68.8%), hemoglobin ≤110 g/L (75.0%). Median monoclonal protein spike was 22.0 g/L. The baseline demographics, clinical characteristics in Table 1 and symptoms for WM are presented in Supplementary Table 1. Among the patients who received prior WM-related systemic therapies, majority received rituximab [7/8 (87.5%) patients]. Among these, 62.5% used rituximab in combination with other antineoplastic agents (doxorubicin hydrochloride, melphalan hydrochloride, bendamustine hydrochloride, cyclophosphamide hydrate).

Table 1 Summary of demographic and baseline characteristicsEfficacyResponse

At primary analysis, the median duration of study intervention was 16.6 months (range: 4.3; 22.0) and it was 34.3 months (range: 4.3; 39.6) at final analysis. The duration of treatment and responses are presented in Fig. 1. At primary analysis, the MRR per IRC for ibrutinib plus rituximab was 87.5% (14/16 patients; 95% CI: 61.7, 98.4%; p < 0.0001) (Table 2 represents data from final analysis) which was unchanged at 87.5% until final analysis. At final analysis, among the patients who achieved the response, confirmed VGPR was reported in 6/16 (37.5%) and PR in 8/16 (50.0%) patients. Minor response was reported by 1 (6.3%) patient and there was one patient who was not evaluable for the best response per the IRC charter, as evaluable post-treatment images were not available. The MRR reported in previously treated patients with relapsed/refractory WM was the same as that reported in patients who were treatment naïve (87.5% in each) (Table 2). Although it was difficult to evaluate the relationship between IPSS-WM and efficacy because of the small sample size, IPSS-WM in the 2 patients who did not achieve a major response was rated as intermediate (not evaluable patient) and high (minor response patient). At final analysis, in patients who achieved PR or better, the median TTR was 1.87 months (range: 1.0–14.7 months), and the median DOR was not reached.

Fig. 1

Duration of treatment and responses. A swimmer plot that presents the duration of treatment, the first timings of responses, and the timing of progressive disease for each patient

Table 2 Summary of primary efficacy, final analysis (response evaluable analysis set)Progression-free survival

At final analysis, with median follow up of 35.0 months, median PFS based on the Kaplan–Meier estimate was not reached. The PFS rate was 86% (95% CI: 55, 96%) at 36-months (Fig. 2). At primary analysis, among 16 patients, 2 (12.5%) had progressive disease. One patient had progressive disease during the treatment period which led to discontinuation, and the other patient had progressive disease during follow-up period after refused further treatment. At final analysis, there were no additional patients with progressive disease.

Fig. 2

Progression-free survival. Ibr + R ibrutinib + rituximab

Sustained hemoglobin improvement and change of serum immunoglobulin M from baseline

The proportion of patients with sustained hemoglobin improvement was 68.8% at primary analysis which was increased to 75.0% at final analysis. Among the 16 patients, 12 had baseline hemoglobin ≤11 g/dL and out of these 11 (91.7%) achieved sustained hemoglobin improvement, at final analysis. At baseline, the mean (SD) IgM level was noted to be high at 36.9 (±22.3) g/L which reduced to 13.1 (±16.3) g/L at primary analysis and 8.0 (±7.6) g/L at final analysis. At final analysis, for 13 evaluable patients, the mean (±SD) change from baseline over time in IgM level was  −28.2 (±19.2) g/L.

Overall survival and time to next treatment

At final analysis, with median follow-up of 35.0 months, the median OS based on the Kaplan–Meier estimate was not reached; all 16 (100%) patients remained alive at final analysis (Fig. 3A). The median TTNT based on the Kaplan–Meier estimate for all the patients (N = 16) was not reached. At final analysis, 2 (12.5%) patients had received subsequent systematic therapies for WM (1 patient had received rituximab, bendamustine and dexamethasone followed by tirabrutinib hydrochloride, and another 1 had received rituximab, study drug) (Fig. 3B).

Fig. 3

A Overall survival and B Time to next treatment. Ibr + R ibrutinib + rituximab

Safety

At final analysis, all 16 patients experienced at least 1 TEAE. TEAEs considered to be related to study intervention were reported in 13 (81.3%) patients. In total, 12 (75.0%) patients reported ibrutinib-related TEAEs and 9 (56.3%) reported rituximab-related TEAEs. There were no TEAEs leading to discontinuation or death. Safety summary is presented in Table 3.

Table 3 Summary of safety, final analysis (safety analysis set)

The most frequently (>15%) reported TEAEs were rash reported in 6 (37.5%) patients; neutrophil count decreased, pyrexia and hypertension in 5 (31.3%) patients each; contusion in 4 (25.0%) patients; and platelet count decreased, white blood cell count decreased, nasopharyngitis, erythema, pruritus, abdominal pain upper, and diarrhea in 3 (18.8%) patients each (Table 4). The most frequently reported (>15%) TEAEs related to ibrutinib were atrial fibrillation and hypertension reported in 4 (25.0%) each; neutrophil count decreased reported in 5 (31.3%), and platelet count decreased reported in 3 (18.8%) patients each.

Table 4 TEAEs occurring with ≥10% frequency, final analysis (safety analysis set)

The incidence of TEAEs from day 1 to Week 16 were reported in 15 (93.8%) patients, from Week 16 to Week 32 in 12 (75.0%) patients and after Week 32 in 12 (80.0%) patients. TEAEs reported by onset of timing (occurrence period) are presented in Table 5.

Table 5 TEAEs by occurrence period (in ≥10% patients), final analysis (safety analysis set)

Grade ≥3 TEAEs were reported in 12 (75.0%) patients and the most frequently reported Grade ≥3 TEAEs were hypertension [4 (25.0%)], neutrophil count decreased and dehydration [2 (12.5%) in each]. Serious TEAEs were reported in 4 (25.0%) patients; serious TEAEs reported after primary analysis were arthritis bacterial, COVID-19, Escherichia bacteremia, pneumonia bacterial, hypophagia, and cystitis hemorrhagic [1 (6.3%) patient each]. All serious TEAEs were Grade ≥3 in severity except arthritis bacterial. For majority of serious TEAEs, the relationship with study intervention was considered as doubtful by the investigator except for pneumonia bacterial, COVID-19, dehydration and hypophagia which were considered not related with ibrutinib. The serious TEAE of cellulitis was considered as probably related to ibrutinib.

TEAEs leading to dose reduction of ibrutinib, and interruption of ibrutinib were reported in 2 (12.5%), and 11 (68.8%) patients, respectively (Table 3). IgM rebound due to interruption was observed in 5 patients. All these patients did not have withdrawal symptom, and serum IgM level of all patients were reduced after restart of the ibrutinib administration. A total of 6 (37.5%) patients had 1 or more TEAEs leading to dose interruption of rituximab during the study. Treatment with ibrutinib was interrupted due to all serious TEAEs except Escherichia bacteremia, arthritis bacterial and hypophagia. All the serious TEAEs were reported as resolved at the time of final analysis except cellulitis which was reported as recovering/resolving.

Among the TEAEs, rash was reported as related to ibrutinib and rituximab in 2 (12.5%) patients each. In total, 7 (43.8%) patients had  ≥1 rash events. The rash events reported were rash [6 (37.5%)], rash maculo-papular and genital rash [1 (6.3%) patients each]. There were no patients who reported Grade ≥3 TEAEs of rash.

Infusion related reactions were reported in 7 (43.8%) patients. The infusion related reaction reported were erythema [3 (18.8%) patients]; pruritus, rash, and pyrexia [2 (12.5%) patients]; headache, neuropathy peripheral, presyncope, supraventricular extrasystoles and eyelid oedema [1 (6.3%) patients]. Infusion-related reactions TEAEs of Grade  ≥3 were reported in 2 (12.5%) patients which were presyncope and pyrexia [1 (6.3%) patients each].

There were no patients with liver function abnormalities as per the Hy’s Law laboratory criteria, and IgM flare.

Pharmacokinetics

For ibrutinib (PK evaluable set, n = 15); at Week 4/Day 1; the mean (SD) Cmax (n = 15) was 122 (149) ng/mL, AUC24h (n = 12) was 763 (834), AUClast (n = 15) was 836 (1115) ng*h/mL, and median Tmax (n = 15) after first dose was 3.6 h (range: 0.8–4.2 h) (Supplementary Table 2). For PCI-45227 (PK evaluable set, n = 15); at Week 4/Day 1; the mean (SD) Cmax (n = 15) was 87.2 (57.3) ng/mL, AUC24h (n = 11) was 1152 (808) ng*h/mL, AUClast (n = 15) was 1075 (768) ng*h/mL, and median Tmax (n = 15) after first dose was 3.75 h (range: 1.75–5.03 h) (Supplementary Table 2).

The metabolite/parent ratio [mean (SD)] based on the Cmax (n = 15), AUC24h (n = 11), AUClast (N = 15), were 1.22 (0.946), 1.78 (0.862), 3.01 (3.07), respectively.

Biomarker analysis

Among the bone marrow samples from 10 of the 16 participants, 7 samples provided assay results, and 3 samples were not evaluable. MYD88L265P mutations were present in 6/7 (85.7%). CXCR4WHIM mutations were present in 2/7 (28.6%). The major response rates for each of the subgroups MYD88L265P/CXCR4WT, MYD88L265P/CXCR4WHIM, and MYD88WT/CXCR4WT using the bone marrow samples were 4/4 (100.0%) 2/2 (100.0%) and 0/1 (0%), respectively.