A Phase II Study to Evaluate the Efficacy of Bortezomib in Combination with Thalidomide in Treatment-Naïve Waldenstrom Macroglobulinemia Patients.

PURPOSE: Despite the recent success of Bruton's tyrosine kinase (BTK) inhibitors for the treatment of Waldenstrom macroglobulinemia (WM), their indefinite treatment duration ultimately tantamount to substantial financial and emotional burden. On the other hand, fixed duration of proteasome inhibitors (PI) have shown rapid and reasonable response in WM treatment. Despite the well-known synergism between PI and immunomodulatory drugs (IMiD), there is no trials evaluating such combination in WM. MATERIALS AND METHODS: Based on above, we designed this phase II study to investigate the efficacy and safety of 6 cycles of 28-day bortezomib-thalidomide-dexamethasone (VTD) regimen for treatment-naïve WM. RESULTS: A total of 15 patients were enrolled: major response rate was 64.3%, and overall response rate was 78.6%. During the median follow-up of 41 months, median progression-free survival (PFS) was 13 months and overall survival 40 months. For responders, median duration of response was 13 months and median PFS 19 months. The most common adverse event (AE) of any grade was constipation (57.1%). The most common grade ≥ 3 AE was anemia (21.4%). CONCLUSION: All in all, we hereby provide proof-of-concept that PI + IMiD may be an attractive backbone for fixed duration treatment. It should be noted that granting the same level of access to newer drugs globally is virtually impossible. Thus efforts to develop regimens using readily available drugs to yield similar or adequate treatment outcomes should not be disregarded. In this sense, we believe our study holds its place for its novelty and eloquently addresses achieving the daunting societal quest of health equity.

Frontline therapy with bendamustine rituximab (BR) and rituximab cyclophosphamide vincristine prednisone (RCVP) confers similar long-term outcomes in patients with treatment naïve Waldenström macroglobulinemia in a real-world setting: a population-based analysis.

We report on outcomes of 111 patients with treatment naïve Waldenström macroglobulinemia (TN WM) treated with frontline bendamustine-rituximab (BR) (n = 57) or rituximab-cyclophosphamide-vincristine-prednisone (RCVP) (n = 54). Median follow-up was 60.7 months (range 1.9-231.6). Median progression-free survival (PFS) was 60.5 months (95% CI 47.6-73.4) for BR and 79.0 months (95% CI 31.3-126.8) for RCVP (p = .96). Median overall survival (OS) was not reached for BR and 153.4 months (95% CI 114.5-192.4) for RCVP (p = .37). While overall and major response rates did not differ between treatment groups, BR had numerically higher rate of very good partial response or better response (51% vs. 37%, p = .30) and complete response (26% vs. 13%, p = .13). RCVP confers comparable outcomes to BR in a real-world population of TN WM patients and remains an effective regimen, particularly when tolerance or frailty is an issue, or in resource-limited settings.

Cryoglobulinemic glomerulonephritis with underlying occult HBV infection and Waldenström macroglobulinemia: A case report.

INTRODUCTION: Occult hepatitis B virus (HBV) infection, defined as negative hepatitis B surface antigen (HBsAg) but detectable HBV DNA in serum and liver tissue, has very rarely been described in cryoglobulinemia (CG) patients. This case report sheds light on the possible link between occult HBV infection and CG. PATIENT CONCERNS: A 76-year-old man presented with rapidly deteriorating renal function within 1 year. DIAGNOSIS: Cryoglobulinemic glomerulonephritis was diagnosed through renal biopsy. Initially, the patient tested negative for HBsAg, but a low HBV viral load was later discovered, indicating an occult HBV infection. Further studies also revealed Waldenström macroglobulinemia (WM). INTERVENTIONS: We treated the patient as WM using plasma exchange and rituximab-based immunosuppressive therapy. OUTCOMES: After 1 cycle of immunosuppressive treatment, there was no improvement of renal function. Shortly after, treatment was discontinued due to an episode of life-threatening pneumonia. Hemodialysis was ultimately required. CONCLUSION: Future studies are needed to explore the link between occult HBV infection and CG, to investigate the mediating role of lymphomagenesis, and to examine the effectiveness of anti-HBV drugs in treating the group of CG patients with occult HBV infection. We encourage clinicians to incorporate HBV viral load testing into the evaluation panel for CG patients especially in HBV-endemic areas, and to test HBV viral load for essential CG patients in whom CG cannot be attributed to any primary disease.

Lymphoplasmacytic lymphoma in a patient with Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disease characterized by benign skin hamartomas, pulmonary cysts leading to spontaneous pneumothorax, and an increased risk of renal cancer. BHD syndrome is caused by germline mutations in the folliculin (FLCN) gene, a putative tumor suppressor, which result in loss of function of the folliculin protein and may cause cancer predisposition. In a 45-year-old woman with anemia, lymphadenopathy, and a history of recurrent spontaneous pneumothorax, 18F-FDG PET/CT detected diffuse and slight 18F-FDG accumulation in the bone marrow, enlarged spleen, and systemic multiple enlarged lymph nodes. Genetic examination identified a germline nonsense mutation [c.998C > G (p.Ser333*)] on exon 9 of FLCN. Pathological examination of the lymph node revealed a diffuse neoplastic proliferation of plasmacytoid lymphocytes. The neoplastic lymphoid cells were positive for CD20, CD138, and light chain kappa as per immunohistochemistry and mRNA in situ hybridization, and a MYD88 gene mutation [c.755T > C (p.L252P)] was identified. Accordingly, she was diagnosed with lymphoplasmacytic lymphoma concomitant with BHD syndrome. To the best of our knowledge, this is the first report describing the development of hematological malignancy in a patient with BHD syndrome. The FLCN mutation might contribute lymphomagenesis as an additional mutation cooperating with the MYD88 mutation.

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).

Occurrence of lymphoplasmacytic lymphoma in a chronic myeloid leukemia patient following long-term treatment with tyrosine kinase inhibitors: A case report.

INTRODUCTION: After tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 were introduced for the treatment of chronic myeloid leukemia, clinical outcomes have improved dramatically. However, together with the increase in the survival rate, a more frequent occurrence of secondary malignancies has been observed as well. TKIs have been demonstrated to be a risk factor of malignancies such as non-Hodgkin lymphoma, prostate cancer, and skin cancer. However, lymphoplasmacytic lymphoma (LPL) has never been reported as a secondary malignancy after TKI treatment in chronic myeloid leukemia (CML). PATIENT CONCERNS: An 81-year-old male patient diagnosed with CML and treated with TKIs for a long period (15 years) was admitted due to a chief complaint of abdominal pain. A large abdominal mass was detected by imaging that included computed tomography. DIAGNOSIS: LPL was confirmed from biopsies after ultrasonography and sigmoidoscopy. Serum IgM level was increased and M protein and monoclonal gammopathy, IgM_kappa light chain type were detected. INTERVENTIONS: The patient received six cycles of R-CHOP chemotherapy. OUTCOMES: After chemotherapy, he showed response. The sizes of the abdominal mass and lymph nodes decreased; moreover, serum M protein and IgM levels decreased, as well. CONCLUSION: Herein, for the first time, we describe a patient who developed LPL as a secondary malignancy after administration of TKIs for the treatment of CML. Our observations indicate the importance of awareness of this secondary malignancy that can develop in CML patients treated with TKIs.

Human MYD88L265P is insufficient by itself to drive neoplastic transformation in mature mouse B cells.

MYD88 L265P is the most common mutation in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and one of the most frequent in poor-prognosis subtypes of diffuse large B-cell lymphoma (DLBCL). Although inhibition of the mutated MYD88 pathway has an adverse impact on LPL/WM and DLBCL cell survival, its role in lymphoma initiation remains to be clarified. We show that in mice, human MYD88L265P promotes development of a non-clonal, low-grade B-cell lymphoproliferative disorder with several clinicopathologic features that resemble human LPL/WM, including expansion of lymphoplasmacytoid cells, increased serum immunoglobulin M (IgM) concentration, rouleaux formation, increased number of mast cells in the bone marrow, and proinflammatory signaling that progresses sporadically to clonal, high-grade DLBCL. Murine findings regarding differences in the pattern of MYD88 staining and immune infiltrates in the bone marrows of MYD88 wild-type (MYD88WT) and MYD88L265P mice are recapitulated in the human setting, which provides insight into LPL/WM pathogenesis. Furthermore, histologic transformation to DLBCL is associated with acquisition of secondary genetic lesions frequently seen in de novo human DLBCL as well as LPL/WM-transformed cases. These findings indicate that, although the MYD88L265P mutation might be indispensable for the LPL/WM phenotype, it is insufficient by itself to drive malignant transformation in B cells and relies on other, potentially targetable cooperating genetic events for full development of lymphoma.

A risk-stratification model based on the initial concentration of the serum monoclonal protein and MYD88 mutation status identifies a subset of patients with IgM monoclonal gammopathy of undetermined significance at high risk of progression to Waldenström macroglobulinaemia or other lymphoproliferative disorders.

IgM monoclonal gammopathies of undetermined significance (IgM MGUS) are associated with a risk of progression to Waldenström macroglobulinaemia (WM) or other lymphoproliferative disorders (LPD) of 1-2% per year. We analysed 176 consecutive patients with IgM MGUS to evaluate risk factors for progression. With a median follow-up of 83 months (1214 person-years), 15 patients (8·5%) progressed to WM (n = 14) or marginal zone lymphoma (n = 1). The rate of progression was 1·32% per year (95% confidence interval [CI] 0·80-2·20). The serum monoclonal protein concentration and the MYD88 mutation were independent risk factors for progression (Hazard ratio [HR] 23·3, 95% CI 2·0-273·3, P = 0·012 and HR 24·4, 95% CI 2·2-275·3, P = 0·010, respectively). The cumulative incidence of progression, while considering death as a competing event, was 11·6% at 5 years and 38·0% at 10 years in MYD88-mutated patients with a serum monoclonal protein of 10 g/l or higher, as compared with 0% at 5 years and 1·1% at 10 years for patients with none or one risk factor. This risk-stratification model is able to identify a subset of patients with IgM MGUS at high risk of progression to WM or LPD who deserve a lifelong follow-up.

Carfilzomib-based combination regimens are highly effective frontline therapies for multiple myeloma and Waldenström's macroglobulinemia.

Multiple myeloma (MM) and Waldenström's macroglobulinemia (WM) are plasma cell disorders often treated with proteasome inhibitors. Recently, several studies evaluated carfilzomib as an initial treatment for these diseases and reported outstanding clinical outcomes. We conducted a retrospective study to report the efficacy and safety of frontline carfilzomib-based combinations in a standard of care setting. From 2014 until 2016 we identified newly diagnosed MM (n = 54) and WM (n = 6) patients treated with carfilzomib as initial therapy who met study inclusion criteria. The response rate for myeloma patients was 98% with 77% of patients undergoing upfront autologous stem cell transplant. The clinical benefit for WM was 100% with all patients having a resolution of B symptoms and anemia after treatment. Carfilzomib-based regimens are well tolerated and offer a neuropathy sparing approach with excellent responses both in newly diagnosed MM and WM making them a good choice for the frontline treatment of these diseases.

Multiple cystic lung lesions and autoimmune thrombocytopaenia developing after chemotherapy for pulmonary indolent B-cell lymphoma with plasmacytic differentiation.

Among lung malignancies, primary pulmonary lymphoma is rare and many of them are indolent B-cell lymphomas. We describe a case of primary pulmonary indolent B-cell lymphoma with plasmacytic differentiation, which exacerbated with the manifestation of macroglobulinaemia and was successfully treated using chemotherapy. The patient subsequently developed pulmonary cysts and thrombocytopaenia due to autoimmune pathology and was successfully treated using prednisolone. This case suggests that in indolent B-cell lymphoma with plasmacytic differentiation, immunoglobulin M level should be carefully followed even if it is within the normal range at lymphoma onset. Additionally, new cystic pulmonary infiltrates that develop during the post-treatment follow-up of an indolent pulmonary B-cell lymphoma may indicate pulmonary lymphoma recurrence, but there is also a possibility of an immunological complication.

Targeting Myddosome Signaling in Waldenström's Macroglobulinemia with the Interleukin-1 Receptor-Associated Kinase 1/4 Inhibitor R191.

PURPOSE: Waldenström's macroglobulinemia is an incurable lymphoproliferative disorder driven by an L265P mutation in the myeloid differentiation primary response gene 88 (MYD88), which activates downstream NF-κB signaling through the Myddosome. As this pathway depends in part on activity of interleukin-1 receptor-associated kinases (IRAKs)-1 and -4, we sought to evaluate the potential of the IRAK1/4 inhibitor R191 in preclinical models. EXPERIMENTAL DESIGN: Patient-derived cell lines and primary samples were used in both in vitro and in vivo experiments to model Waldenström's macroglobulinemia and its response to IRAK1/4 inhibitors. RESULTS: R191 induced a dose- and time-dependent reduction in viability of BCWM.1 and MWCL-1 Waldenström's cell lines, and suppressed activation of IRAK1/4. This was associated with cell-cycle arrest at G0-G1, reduced levels of cyclin-dependent kinases 4 and 6, and induction of apoptosis in cell lines and primary patient samples. Further downstream, R191 exposure led to reduced activation of NF-κB, and of protein kinase B/Akt/mammalian target of rapamycin signaling, whereas expression of a constitutively active Akt mutant induced R191 resistance. Gene expression profiling and gene set enrichment analysis revealed a signature consistent with inhibition of c-Myc and activation of the endoplasmic reticulum stress response. In both subcutaneous and systemic murine models of Waldenström's, R191 showed antitumor activity. Finally, the activity of R191 was enhanced when it was combined with novel chemotherapeutics such as bortezomib, afuresertib, and ibrutinib. CONCLUSIONS: Taken together, these data support the translation of R191 as an approach to target IRAK1/4 to the clinic for patients with Waldenström's macroglobulinemia.

Czech Registry of Monoclonal Gammopathies - Technical Solution, Data Collection and Visualisation.

BACKGROUND: The Registry of Monoclonal Gammopathies (RMG) was established by the Czech Myeloma Group in 2007. RMG is a registry designed for the collection of clinical data concerning diagnosis, treatment, treatment results and survival of patients with monoclonal gammopathies. Data on patients with monoclonal gammopathy of undetermined significance (MGUS), Waldenström macroglobulinaemia (WM), multiple myeloma (MM) or primary AL ("amyloid light-chain") amyloidosis are collected in the registry. DATA: Nineteen Czech centres and four Slovak centres currently contribute to the registry. The registry currently contains records on more than 5,000 patients with MM, almost 3,000 patients with MGUS, 170 patients with WM and 26 patients with primary AL amyloidosis, i.e. more than 8,000 records on patients with monoclonal gammopathies altogether. RESULTS: This paper describes technology employed for the collection, storage and subsequent online visualisation of data. The CLADE-IS platform is introduced as a new system for the collection and storage of data from the registry. The form structure and functions of the new system are described for all diagnoses in general; these functions facilitate data entry to the registry and minimise the error rate in data. Publicly available online visualisations of data on patients with MGUS, WM, MM or primary AL amyloidosis from all Czech or Slovak centres are introduced, together with authenticated visualisations of data on patients with MM from selected centres. CONCLUSION: The RMG represents a data basis that makes it possible to monitor the disease course in patients with monoclonal gammopathies on the population level.Key words: Registry of Monoclonal Gammopathies - RMG - registries - monoclonal gammopathies - CLADE-IS - data visualisation - database.

Waldenström's macroglobulinemia: Two malignant clones in a monoclonal disease? Molecular background and clinical reflection.

Waldenström's macroglobulinemia (WM) is a complex disease characterized by apparent morphological heterogeneity within the malignant clonal cells representing a continuum of small lymphocytes, plasmacytoid lymphocytes, and plasma cells. At the molecular level, the neoplastic B cell-derived clone has undergone somatic hypermutation, but not isotype switching, and retains the capability of plasmacytic differentiation. Although by classical definition, WM is formed by monoclonal expansion, long-lived clonal B lymphocytes are of heterogeneous origin. Even more, according to current opinion, plasma cells also conform certain population with pathogenic and clinical significance. In this article, we review the recent advances in the WM clonal architecture, briefly describe B-cell development during which the molecular changes lead to the malignant transformation and mainly focus on differences between two principal B-lineage clones, including analysis of their genome and transcriptome profiles, as well as immunophenotype features. We assume that the correct identification of a number of specific immunophenotypic molecular and expression alterations leading to proper aberrant clone detection can help to guide patient monitoring throughout treatment and successfully implement therapy strategies directed against both B- and plasma cell tumor WM clones.

Guideline for the diagnosis, treatment and response criteria for Bing-Neel syndrome.

Bing Neel syndrome is a rare disease manifestation of Waldenström's macroglobulinemia that results from infiltration of the central nervous system by malignant lymphoplasmacytic cells. In this guideline we describe the clinical symptoms, as well as the appropriate laboratory and radiological studies, that can aid in the diagnosis. The presentation of Bing Neel syndrome may be very diverse, and includes headaches, cognitive deficits, paresis, and psychiatric symptoms. The syndrome can present in patients with known Waldenström's macroglobulinemia, even in the absence of systemic progression, but also in previously undiagnosed patients. Diagnostic work-up should include cerebral spinal fluid analysis with multiparameter flow cytometry to establish B-cell clonality, protein electrophoresis and immunofixation for the detection and classification of a monoclonal protein as well as molecular diagnostic testing for immunoglobulin gene rearrangement and mutated MYD88. MRI of the brain and spinal cord is also essential. The second challenge is to expand our knowledge of prognosis and treatment outcome. Prospective clinical trials on Bing Neel syndrome patients that employ uniform treatment along with appropriate laboratory cerebral spinal fluid assessments and standardized MRI protocols will be invaluable, constituting a significant step forward in delineating treatment outcome for this intriguing disease manifestation.

[Recurrence of Waldenström macroglobulinemia accompanied by factor X deficiency].

A medical check-up revealed severe anemia in an 85-year-old man who had been diagnosed with Waldenström macroglobulinemia 11 years previously. On the other hand, prolonged PT and aPTT were demonstrated on admission, and were attributed to a significant decrease in factor X activity. These abnormalities were all considered to be have been caused by an exacerbation of the underlying disease and, thus, chemotherapy with the RCD regimen (rituximab, cyclophosphamide, dexamethasone) was started. No significant improvement was obtained and the patient died suddenly on day 154. AL amyloidosis was diagnosed by histopathological examinations and also confirmed by a sequence analysis of amyloid protein. This case with Waldenström macroglobulinemia complicated by AL amyloidosis and recurrent factor X deficiency is quite rare.

[Diffuse large B-cell lymphoma occurring in a Waldenström macroglobulinemia patient with central nervous system infiltration].

The rare central nervous system (CNS) infiltration of Waldenström macroglobulinemia (WM) is known as Bing-Neel syndrome (BNS). Furthermore, the transformation of WM into diffuse large B-cell lymphoma (DLBCL) is also unusual. Herein, we report a 69-year-old male with DLBCL transformed from BNS. In November 2008, the patient visited a prior hospital because of anemia and was diagnosed with WM. After receiving chemotherapy (R-CHOP), his serum immunoglobulin M (IgM) level decreased and then remained at approximately 2000 mg/dl for 3 years. In November 2011, he complained of visual impairment and photophobia in his left eye. Magnetic resonance imaging showed enlargement of the left optic nerve and cerebrospinal fluid examination indicated CNS infiltration of WM cells. Consequently, he was diagnosed with BNS. He thus received CNS targeted chemotherapy (R-MPV) and achieved a partial response. In May 2014, IgM was elevated and swelling of systemic lymph nodes was detected. Inguinal lymph node biopsy yielded a pathological diagnosis of DLBCL and the clonality of tumor cells between WM and DLBCL was confirmed by the allele-specific oligonucleotide polymerase chain reaction (ASO-PCR).

Biology, prognosis, and therapy of Waldenström Macroglobulinemia.

Waldenström Macroglobulinemia (WM) is a rare B-cell lymphoma characterized by the uncontrolled accumulation of malignant lymphoplasmacytic cells, mainly in the bone marrow, and monoclonal IgM production. Despite its rarity, our understanding of the biology of this disease has improved significantly in recent years with the identification of recurrent mutations in the MYD88 and CXCR4 genes. Based on the diversity of clinical features observed in WM patients, therapy should be highly personalized having into account several factors such as age, co-morbidities, IgM levels, and presence of hyperviscosity, coagulopathy, cryoglobulinemia, or cold agglutinin disease. In this chapter, we review the recent advances in the biology of WM and the current therapeutic options for untreated and relapsed WM patients. Finally, we discuss the role of prognostic factors and current evidence supporting an improvement in the survival of WM patients in the last decade.

Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is an indolent low-grade lymphoma characterized by bone marrow infiltration with lymphoplasmacytic cells associated with a monoclonal immunoglobulin M protein. It is considered incurable. The 5-year survival rate for patients with symptomatic WM is 87% for those with low-risk disease, 68% for those with intermediate-risk disease, and 36% for those with high-risk disease. Owing to recent advances in therapy with new targeted treatment options, relative survival has improved. Insights into mutations in MYD88 L265P and the WHIM-like CXCR4 have been shown to be significant not just in terms of their diagnostic and prognostic value, but also as potential targets for therapy. For patients with symptomatic WM, the different classes of agents used to treat WM include alkylating agents (eg, cyclophosphamide and chlorambucil), nucleoside analogues (eg, cladribine and fludarabine) and monoclonal antibodies (eg, rituximab and alemtuzumab). With an increasing number of novel treatment options available including everolimus, bendamustine, bortezomib, ibrutinib, carfilzomib, lenalidomide, and panobinostat, the optimal timing and introduction of these options in the absence of phase 3 trials remains controversial. A treatment algorithm based on Mayo Stratification for Macroglobulinemia and Risk-Adapted Therapy (mSMART) and a comparison of important clinical trials in WM is provided.