A phase 2, open-label study of ibrutinib plus rituximab in Japanese patients with Waldenstrom's macroglobulinemia.

Ibrutinib is a first-in-class Bruton kinase inhibitor against B-cell neoplasms including Waldenström macroglobulinemia (WM). This study evaluated the efficacy and safety of ibrutinib-rituximab in Japanese patients with WM. Patients received ibrutinib 420 mg orally once daily plus weekly rituximab 375 mg/m2 IV (8 infusions total). The primary end point was major response rate (MRR; PR or better) by Independent Review Committee assessment. Secondary endpoints were progression-free survival (PFS), safety, pharmacokinetics, and biomarkers. Primary analysis was conducted in 16 patients [baseline, treatment naïve: 8 (50.0%); relapsed/refractory WM: 8 (50.0%)] who received ibrutinib-rituximab, after all patients completed Week 57 or end of treatment. At primary analysis, MRR was 87.5% [14/16 patients; 95% CI: 61.7, 98.4%; p < 0.0001 (null hypothesis: 32% response rate)]. At final analysis (median study intervention duration: 34.4 months, median follow-up: 35.0 months), MRR was unchanged at 87.5%, but VGPR [6/16 (37.5%)] and PR [8/16 (50.0%)] improved. Prior treatment status did not affect response. At final analysis, median PFS was not reached [36-month PFS rate: 86% (95% CI: 55, 96%)]. No critical safety signals were reported. This study demonstrated a positive benefit/risk profile of ibrutinib-rituximab in Japanese patients with WM, consistent with the iNNOVATE study.

Efficacy and safety of therapeutic procedure for Waldenström's macroglobulinemia with hyperviscosity syndrome.

INTRODUCTION: Hyperviscosity syndrome (HVS) is a significant complication in Waldenström's macroglobulinemia (WM), although the significance of plasmapheresis in clinical practice has not been clarified. To confirm the efficacy and safety of plasmapheresis followed by primary therapy for WM with HVS, we retrospectively conducted this study. METHODS: Untreated WM with HVS, or serum immunoglobulin M (IgM) levels ≥4000 mg/dL, were analyzed. The basic therapeutic flow was conducted as follows: (1) performing plasmapheresis, (2) followed by primary therapy without rituximab, and (3) performing the second cycle. The serum IgM reduction rate and adverse events (AEs) were evaluated. RESULTS: Ten patients were enrolled. The median serum IgM levels at diagnosis, post-plasmapheresis, after the first cycle of primary therapy, and after the second cycle were 5174, 2900, 3286, and 2657 mg/dL, respectively. No patients experienced IgM flare or bleeding AEs. CONCLUSION: The therapeutic flow offers sufficient efficacy and safety in WM with HVS.

A Rare Clinical Case of Secondary Central Nervous System Involvement without Transformation in Hairy Cell Leukemia: Case Report and Literature Review.

Introduction Hairy cell leukemia (HCL) is an indolent B-cell lymphoma characterized by a specific genetic mutation, BRAF V600E, which affects the specific morphology and oncogenesis. For HCL, few reports regarding secondary central nervous system involvement (SCNSI) are available. Herein, we present the case of an 80-year-old woman who had a relapse of HCL with SCNSI. Case presentation The diagnosis of HCL was made in June 2015 after identifying BRAF V600E proteins by immunohistochemical analysis, and the disease was then controlled for 6 years by employing chemoimmunotherapy. In February 2021, the patient was admitted with neurological symptoms such as dizziness. Magnetic resonance imaging of the brain showed abnormal enhancement in the cerebrum, and cerebrospinal fluid analysis revealed neoplastic cells without transformation into large cells. Thus, the patient was diagnosed as having SCNSI in HCL. Conclusion We report a case of a rare clinical presentation of SCNSI in HCL with literature review.

Extramedullary hematopoietic pleural effusion in Waldenström's macroglobulinemia.

Extramedullary hematopoietic effusion (EHE) is one of the extremely rare phenomena associated with extramedullary hematopoiesis, which is caused by serous effusions, including pleural effusion, and may be related to hematologic disorders and neoplasms. Herein, we present the case of an 81-year-old man with EHE accompanying Waldenström's macroglobulinemia (WM). The patient complained of anemia and dyspnea. The chest X-ray and computed tomography showed a massive left pleural effusion, and the aspirates revealed infiltration of the immature myeloid cells and megakaryocytes, in addition to the lymphoma cells. To our knowledge, this is the first report of EHE in WM.

Phase I dose-escalation study of milademetan in patients with relapsed or refractory acute myeloid leukemia.

Long-term survival in patients with acute myeloid leukemia (AML) remains low, and current treatment modalities are inadequate. Milademetan (DS-3032, RAIN-32), a small-molecule specific murine double minute 2 inhibitor, has shown a p53 status-dependent antitumor effect in vitro studies. This is the first phase I study report of milademetan monotherapy in relapsed/refractory (R/R) AML patients evaluating the safety, tolerability, pharmacokinetics, and preliminary tumor response for further clinical development. Fourteen patients received 90 (starting dose, n = 4), 120 (n = 6), or 160 mg (n = 4) of oral milademetan once daily in a 14/28 treatment cycle. The median total treatment duration was 1.5 cycles. Dose-limiting toxicity did not occur, and the maximum tolerated dose was not reached. Thus, the recommended dose was defined as 160 mg. The most common adverse events (AEs) were decreased appetite (64.3%), febrile neutropenia (50%), nausea (42.9%), and anemia (35.7%). No deaths or AEs leading to treatment discontinuation occurred. Five serious treatment-emergent AEs occurred in 4 patients. Plasma concentration increased linearly with milademetan dose. However, trends in the safety and efficacy of oral milademetan in patients with R/R AML warrant further clinical investigation. This study can inform future milademetan studies in hematologic malignancies.

Other iatrogenic immunodeficiency lymphoproliferative disorder induced by corticosteroid used for an autoimmune disorder.

Other iatrogenic immunodeficiency lymphoproliferative disorders (oii-LPD) are defined as lymphoid proliferations or lymphomas that occur in patients taking immunosuppressive agents (ISA) for autoimmune disorders (AID). Although methotrexate and tumor necrosis factor-alpha inhibitors cause oii-LPD, the association between corticosteroids and lymphomagenesis remains unknown. Herein, we present the case of a 51-year-old woman with oii-LPD caused by corticosteroid use for autoimmune hemolytic anemia (AIHA). The diagnosis of AIHA was made in May 2016, and AIHA had been well-controlled for 5 years with oral prednisolone (PSL). During a regular follow-up visit in March 2022, an abnormal increase in atypical lymphoid cells in the peripheral blood was found. The bone marrow biopsy specimens showed local aggregations of large cells that were identified as lymphoplasmacytic cells and plasma cells, and that were positive for cluster of differentiation (CD)19 and CD20, with apparent nucleoli among the diffuse infiltration of atypical small lymphocytes. The large cells were partially positive for the Epstein-Barr encoding region in situ hybridization and latent membrane protein 1, which confirmed Epstein-Barr virus (EBV)-affected lymphomagenesis. To our knowledge, this is the first report of an oii-LPD case shown to be induced by corticosteroid use for AID.

Bosutinib in Japanese patients with newly diagnosed chronic-phase chronic myeloid leukemia: final 3-year follow-up results of a phase 2 study.

Bosutinib has been evaluated for treatment of chronic-phase chronic myeloid leukemia (CP-CML) in several clinical studies, including in Japan. This open-label, single-arm, phase 2 study evaluated the efficacy and safety of bosutinib at a starting dose of 400 mg once daily in Japanese patients (n = 60) with newly diagnosed CP-CML. The minimum follow-up period was 3 years and median duration of treatment was 35.9 months. At study completion, 60% of patients were still on treatment. Cumulative rates of major molecular response (MMR), molecular response4 (MR4), and MR4.5 at any time were 70.0%, 53.3%, and 48.3%, respectively. No patient who achieved MMR or MR4 had a confirmed loss of response. No patient experienced on-treatment transformation to accelerated/blast phase or died within 28 days of the last bosutinib dose. Any-grade treatment-emergent adverse events (TEAEs) occurred in 100% (grade ≥ 3: 81.7%) of patients. The most common TEAEs were diarrhea (86.7%), increased alanine aminotransferase (55.0%), and increased aspartate aminotransferase (46.7%). No new safety signals emerged during the follow-up period. Bosutinib continues to demonstrate a favorable benefit/risk profile and is an important treatment option for Japanese patients with newly diagnosed CP-CML. Optimal management of TEAEs during initial treatment with bosutinib should be prioritized.Trial Registration: ClinicalTrials.gov ID: NCT03128411.

Two-year outcomes of tirabrutinib monotherapy in Waldenström's macroglobulinemia.

The phase II study of tirabrutinib monotherapy at a daily dose of 480 mg under fasting conditions for treatment-naïve and relapsed/refractory Waldenström's macroglobulinemia (ONO-4059-05 study) demonstrated a promising efficacy and tolerable safety profile. We conducted an unplanned analysis with a median follow-up of 24.8 months to update the efficacy and safety results and to report patient-reported quality of life. Of 27 enrolled patients, 22 patients continued receiving the study drug. The major response assessed by an independent review committee was observed in 25 patients (93%), including one and five patients who newly achieved complete response and very good partial response, respectively, after the primary analysis. The progression-free and overall survival rates at 24 months were 92.6% and 100%, respectively. Serum IgM levels in all patients except one declined and were maintained at low levels, although transient increases occurred after temporal interruption of the study drug. The disease-related symptoms including recurrent fever and hyperviscosity mostly disappeared. Health-related quality of life, assessed by cancer-specific questionnaires, was mostly maintained. Grade 3-4 neutropenia, lymphopenia, and leukopenia were newly recognized in three, two, and one patient, respectively. Grade 3 treatment-related hypertriglyceridemia was also recognized. Nine patients experienced grade 1-2 bleeding events (33%), one patient experienced grade 2 treatment-related atrial fibrillation, and one patient experienced grade 1 treatment-related hypertension. Treatment-related skin adverse events were observed in 14 patients (52%). Taken together, tirabrutinib has durable efficacy with an acceptable safety profile for treatment-naïve and refractory/relapsed Waldenström's macroglobulinemia.

Quality-of-life analysis of pembrolizumab vs brentuximab vedotin for relapsed/refractory classical Hodgkin lymphoma.

KEYNOTE-204 (NCT02684292) demonstrated a progression-free survival advantage for pembrolizumab over brentuximab vedotin (BV) in patients who had relapsed or refractory classical Hodgkin lymphoma (R/R cHL) following, or who were ineligible for, autologous stem cell transplantation (ASCT). Health-related quality of life (HRQoL), measured by patient-reported outcomes (PROs) from KEYNOTE-204, are reported from patients who received ≥1 dose of study treatment and completed ≥1 PRO assessment. The EORTC QoL Questionnaire Core 30 (QLQ-C30) and EuroQoL EQ-5D were administered at baseline, every 6 weeks until week 24, and every 12 weeks thereafter. Prespecified end points included least squares mean (LSM) changes from baseline to week 24 and time to true deterioration (TTD; ≥10-point decline from baseline). Comparisons were evaluated using 2-sided P values uncontrolled for multiplicity. High compliance at baseline (>90%) and through week 24 (>80%) was demonstrated across treatment groups (PRO analysis set: pembrolizumab, n = 146; BV, n = 150). The EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) score improved from baseline to week 24 on pembrolizumab and worsened on BV and demonstrated significant LSM differences at 24 weeks (GHS/QoL: 8.60 [95% confidence interval, 3.89-13.31]; P = .0004). Significant improvements were observed in each QLQ-C30 domain except emotional and cognitive functioning. Compared with BV, pembrolizumab prolonged TTD for GHS/QoL (hazard ratio, 0.40 [95% CI, 0.22-0.74]; P = .003) and each QLQ-C30 domain except cognitive functioning. In conclusion, pembrolizumab demonstrated overall improvements in PROs of HRQoL measures over BV in the KEYNOTE-204 study. These data and previously reported efficacy results support pembrolizumab as the preferred treatment option for patients with R/R cHL who are ineligible for or experience relapse after ASCT.

Phase 1/2 study evaluating the safety and efficacy of DSP-7888 dosing emulsion in myelodysplastic syndromes.

DSP-7888 is an immunotherapeutic cancer vaccine derived from the Wilms' tumor gene 1 (WT1) protein. This phase 1/2 open-label study evaluated the safety and efficacy of DSP-7888 dosing emulsion in patients with myelodysplastic syndromes (MDS). DSP-7888 was administered intradermally (3.5 or 10.5 mg) every 2 weeks for 6 months and then every 2-4 weeks until lack of benefit. Twelve patients were treated in phase 1 (3.5 mg, n = 6; 10.5 mg, n = 6), with no dose-limiting toxicities reported. Thus, the 10.5 mg dose was selected as the recommended phase 2 dose, and 35 patients were treated in phase 2. Forty-seven patients received ≥1 dose of the study drug and comprised the safety analysis set. The most common adverse drug reaction (ADR) was injection site reactions (ISR; 91.5%). Grade 3 ISR were common (58.8%) in phase 1 but occurred less frequently in 2 (22.9%) following implementation of risk minimization strategies. Other common ADR were pyrexia (10.6%) and febrile neutropenia (8.5%). In the efficacy analysis set, comprising patients with higher-risk MDS after azacitidine failure in phases 1 and 2 (n = 42), the disease control rate was 19.0%, and the median overall survival (OS) was 8.6 (90% confidence interval [CI], 6.8-10.3) months. Median OS was 10.0 (90% CI, 7.6-11.4) months in patients with a WT1-specific immune response (IR; n = 33) versus 4.1 (90% CI, 2.3-8.1) months in those without a WT1-specific IR (n = 9; P = .0034). The acceptable safety and clinical activity findings observed support the continued development of DSP-7888 dosing emulsion.

[Therapeutic algorithm of Waldenström's macroglobulinemia or lymphoplasmacytic lymphoma in Japan].

Waldenström's macroglobulinemia or lymphoplasmacytic lymphoma (WM/LPL) is a rare subtype of indolent B-cell lymphoma with plasmacytic differentiation. Owing to its rarity, the pathogenesis, biology, and standard of care have not been established. In 2012 the MYD88 L265P mutation is proven as the major oncogenesis in WM/LPL; therefore, the pathogenesis and underlying biology of WM/LPL have been drastically explored. Furthermore, treatment options have also been developed, and Bruton's tyrosine kinase (BTK) inhibitor has been recently approved for untreated and relapsed/refractory WM/LPL in August 2020 in Japan. In this article, after a brief review of the clinical and biological characteristics of WM/LPL, we discuss the ideal therapeutic algorithm, including novel BTK inhibitor.

Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicentre, randomised, open-label, phase 3 study.

BACKGROUND: PD-1 blockade via pembrolizumab monotherapy has shown antitumour activity and toxicity in patients with relapsed or refractory classical Hodgkin lymphoma. Here, we present interim analyses from the KEYNOTE-204 study evaluating pembrolizumab versus brentuximab vedotin for relapsed or refractory classical Hodgkin lymphoma. METHODS: In this randomised, open-label, phase 3 study, patients aged 18 years or older with relapsed or refractory classical Hodgkin lymphoma with measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 who were ineligible for or had relapsed after autologous haematopoietic stem-cell transplantation (HSCT) were enrolled at 78 hospitals and cancer centres in 20 countries and territories. Patients were randomly assigned (1:1) with an interactive voice response system to pembrolizumab 200 mg intravenously every 3 weeks or brentuximab vedotin 1·8 mg/kg intravenously every 3 weeks. Randomisation was stratified by previous autologous HSCT and status after front-line therapy. Results from the second interim analysis are presented here, with a database cutoff of Jan 16, 2020. The dual primary endpoints assessed in the intention-to-treat population were progression-free survival as assessed by blinded independent central review, and overall survival (not analysed at this interim analysis). Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT02684292. Recruitment for this trial is closed. FINDINGS: Between July 8, 2016, and July 13, 2018, 151 patients were randomly assigned to pembrolizumab and 153 to brentuximab vedotin. After a median time from randomisation to data cutoff of 25·7 months (IQR 23·4-33·0), median progression-free survival was 13·2 months (95% CI 10·9-19·4) for pembrolizumab versus 8·3 months (5·7-8·8) for brentuximab vedotin (hazard ratio 0·65 [95% CI 0·48-0·88]; p=0·0027). The most common grade 3-5 treatment-related adverse events were pneumonitis (six [4%] of 148 patients in the pembrolizumab group vs one [1%] of 152 patients in the brentuximab vedotin group), neutropenia (three [2%] vs 11 [7%]), decreased neutrophil count (one [1%] vs seven [5%]), and peripheral neuropathy (one [1%] vs five [3%]). Serious treatment-related adverse events occurred in 24 (16%) of 148 patients receiving pembrolizumab and 16 (11%) of 152 patients receiving brentuximab vedotin. One treatment-related death due to pneumonia occurred in the pembrolizumab group. INTERPRETATION: Pembrolizumab showed statistically significant and clinically meaningful improvement in progression-free survival compared with brentuximab vedotin, with safety consistent with previous reports. These data support pembrolizumab as the preferred treatment option for patients with relapsed or refractory classical Hodgkin lymphoma who have relapsed post-autologous HSCT or are ineligible for autologous HSCT. FUNDING: Merck Sharp & Dohme Corp (a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA).

A multicenter, open-label, phase II study of tirabrutinib (ONO/GS-4059) in patients with Waldenström's macroglobulinemia.

Tirabrutinib is a second-generation Bruton's tyrosine kinase inhibitor with greater selectivity than ibrutinib. Here, we conducted a multicenter, phase II study of tirabrutinib in patients with treatment-naïve (Cohort A) or with relapsed/refractory (Cohort B) Waldenström's macroglobulinemia (WM). Patients were treated with tirabrutinib 480 mg once daily. The primary endpoint was major response rate (MRR; ≥ partial response). Secondary endpoints included overall response rate (ORR; ≥ minor response), time to major response (TTMR), progression-free survival (PFS), overall survival (OS), and safety. In total, 27 patients (18 in Cohort A; 9 in Cohort B) were enrolled. The median age was 71 y, and the median serum immunoglobulin M level was 3600 mg/dL. Among the patients, 96.2% had the MYD88L265P mutation. MRR and ORR were 88.9% and 96.3%, respectively (Cohort A: MRR, 88.9%; ORR, 94.4%; Cohort B: MRR, 88.9%; ORR, 100%). Median TTMR was 1.87 mo. PFS and OS were not reached with a median follow-up of 6.5 and 8.3 mo for Cohorts A and B, respectively. The most common adverse events (AEs) were rash (44.4%), neutropenia (25.9%), and leukopenia (22.2%), with most AEs classified as grade 1 or 2. Grade ≥ 3 AEs included neutropenia (11.1%), lymphopenia (11.1%), and leukopenia (7.4%). No grade 5 AEs were noted. All bleeding events were grade 1; none were associated with drug-related atrial fibrillation or hypertension. Although the follow-up duration was relatively short, the study met the primary endpoint. Therefore, tirabrutinib monotherapy is considered to be highly effective for both untreated and relapsed/refractory WM with a manageable safety profile. (JapicCTI-173646).

Phase 2 study of bosutinib in Japanese patients with newly diagnosed chronic phase chronic myeloid leukemia.

This open-label, single-arm, phase 2 study (ClinicalTrials.gov, NCT03128411) evaluated the efficacy, safety, and pharmacokinetics of bosutinib at a starting dose of 400 mg once daily (QD) in Japanese patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML). The primary endpoint was major molecular response (MMR) at Month 12 in the modified as-treated population (Philadelphia chromosome-positive [Ph+] patients with e13a2/e14a2 transcripts). Sixty Japanese patients with CP CML were treated with bosutinib; median age was 55 years (range 20-83), 60.0% were males, and all were Ph+ and had e13a2/e14a2 transcripts. After median follow-up of 16.6 months (range 11.1-21.9), 41 (68.3%) patients remained on bosutinib. The MMR rate at Month 12 was 55.0% (2-sided 90% confidence interval: 44.4-65.6). There were no on-treatment transformations to accelerated/blast phase, and no patient died on treatment or within 28 days of the last bosutinib dose. The most common treatment-emergent adverse events were diarrhea (86.7%), increased alanine aminotransferase (55.0%), and increased aspartate aminotransferase (46.7%). The primary objective of this phase 2 study was met, and there were no new safety signals for bosutinib. These data suggest bosutinib is an effective first-line treatment option for Japanese patients with newly diagnosed CP CML.

Phase II study of dose-adjusted gemcitabine, dexamethasone, cisplatin, and rituximab in elderly relapsed diffuse large B-cell lymphoma patients.

High-dose chemotherapy and autologous stem cell transplantation (ASCT) are too toxic for elderly patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Therefore, effective and tolerable regimens for elderly patients are urgently needed. The present phase II study assessed the efficacy and safety of dose-adjusted therapy with gemcitabine, dexamethasone, cisplatin, and rituximab (GDP-R) in this population. ASCT-ineligible elderly patients with relapsed or refractory DLBCL received dose-adjusted GDP-R in each 28-day cycle for up to six cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints were complete response (CR) rate, progression-free survival (PFS), and safety. Thirty-three patients were enrolled and received dose-adjusted GDP-R. The median age was 75 years (range: 68-87 years). The ORR was 82.8% (90% confidence interval [CI], 67.1-93.0%), with a CR rate of 58.6% (90% CI, 41.7-74.1%). At a median follow-up of 20.9 months, the 2-year PFS rate was 46.8% (90% CI, 30.7-61.5%) and the 2-year overall survival rate was 63.2% (90% CI, 45.8-76.3%). The most frequently observed grade 4 adverse events were neutropenia (63.6%), thrombocytopenia (57.6%), and lymphocytopenia (39.4%). Dose-adjusted GDP-R is a promising salvage regimen for ASCT-ineligible elderly patients with relapsed DLBCL after rituximab-containing chemotherapy and warrants further investigation.

Phase I study of ibrutinib in Japanese patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma.

This phase I study evaluated the safety and efficacy of single-agent ibrutinib in Japanese patients with treatment-naïve chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (aged 20-69 years and ineligible for chemotherapy using fludarabine or cyclophosphamide, or aged ≥70 years). Eight patients received oral ibrutinib 420 mg once daily until progressive disease or unacceptable toxicity. The primary endpoint was safety; secondary endpoints included the overall response rate (ORR). At the time of final analysis (August 22, 2018), eight patients (all with CLL; median age, 68.5 years) had received ibrutinib for a median of 32.2 months (range, 10.4-35.9); all patients had discontinued study treatment, with 50.0% of patients switching to marketing-approved ibrutinib as subsequent anticancer therapy. All patients had ≥1 adverse event (AE); the most common AEs included a decreased platelet count, upper respiratory tract infection, increased lymphocyte count, diarrhea, nasopharyngitis, peripheral edema and rash. Four patients (50.0%) had a total of eight grade ≥3 AEs, most commonly lung infection and decreased neutrophil count. Eight serious AEs were reported in four patients (50.0%); these included a case of muscle hemorrhage (grade 3), decreased neutrophil count (grade 4) that led to dose reduction and one case of fatal cardiac arrest. The ORR was 87.5% (7/8 patients [exact 95% confidence interval 47.3-99.7]). One patient had a complete response, six had a partial response and one had a partial response with lymphocytosis. Ibrutinib had an acceptable safety profile and high ORR in Japanese patients with treatment-naïve CLL.

[Waldenström macroglobulinemia: Japanese perception].

Waldenström macroglobulinemia (WM) is a rare low-grade B-cell lymphoma. This report focuses on WM in Japan. Regarding epidemiology, per the 2016 registry data by the Japanese Society of Hematology, WM and lymphoplasmacytic lymphoma (LPL) cases were 229 and 125, respectively (1.97% of 17,957 mature lymphoid malignancies), with the annual incidence of WM/LPL in Japan 2.8 per million. In addition, 6q deletion (6q del) is the leading aberration and one of the poor prognostic factors in WM. Our findings suggested that the serum IgM level was higher in WM with 6q del compared with those without, and the B-cell receptor signaling pathway and IL-21 receptor expression were activated in WM with 6q del. Hence, these findings might be attributed to the aggressiveness of the WM with 6q del. Regarding treatment, recent studies investigating the epidemiological treatment pattern for WM have reported rituximab (R) monotherapy and alkylating regimen (±R) as the leading initial treatment. Nevertheless, ideal treatment algorithm in Japan warrants further investigation.