Lymphoplasmacytic Cells Research Articles

Waldenström macroglobulinemia. Experience in 31 patients

Waldenström macroglobulinemia (WM) is an uncommon indolent B-cell lymphoma, due to the proliferation of lymphoplasmacytic cells, and secretion of a monoclonal IgM protein. To evaluate the clinical characteristics, management and results of treatment of patients with WM at a public hospital in Chile. Review of medical records of 31 patients aged 43 to 85 years (16 males) with WM diagnosed between 2002 and 2017. Clinical features and survival were recorded. All patients had bone marrow compromise, and 31%, extranodal involvement. According to the International Prognostic Score System for WM (IPSSWM) 16, 58 and 26% were at low, intermediate and high risk, respectively. Twenty-five patients (81%) were treated, 32% with plasmapheresis and 36% with rituximab. Four cases (16%) achieved complete remission. Median follow up was 35 months (range 6-159). Estimated overall survival (OS) at 5 and 10 years was 74% and 53%, respectively. According to IPSSWM, the estimated five-year OS was 80, 92 and 39%, for low, intermediate and high-risk patients, respectively. OS was similar to that reported abroad, except for low risk patients, probably due to the low number of cases and short follow up. An improved survival should be expected with the routine use of immunochemotherapy.

AB035. P-03. Explore the mutational landscape and immune profile of EBV-associated lymphoepithelioma-like cholangiocarcinoma

Background: Lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare variant of intrahepatic cholangiocarcinoma, which is highly associated with Epstein-Barr virus (EBV) infection and abundant lymphoplasmacytic cells infiltration. However, the genetic background of LELCC and the immune profiling of their microenvironment remain largely un-elucidated.

Ibrutinib for the treatment of Bing-Neel syndrome, a complication of Waldenström macroglobulinemia: Patient case report

Bing-Neel syndrome is a rare complication of Waldenström macroglobulinemia, characterized by infiltration of lymphoplasmacytic cells to the central nervous system. Multiple treatment modalities exist including purine analogs, bendamustine, high-dose methotrexate, or high-dose cytarabine. Of interest, ibrutinib, a Bruton tyrosine kinase inhibitor has also displayed efficacy in Bing-Neel syndrome. Current literature is limited for the treatment of Bing-Neel syndrome considering its rarity, and while ibrutinib is indicated for the treatment of Waldenström macroglobulinemia, it is utilized off-label for treatment of Bing-Neel syndrome. Additionally, debate exists regarding the recommended dosing strategy for ibrutinib for this indication with disease remission demonstrated at 560 mg and 420 mg. We present a case report that provides additional evidence for this debate with a patient who received 560 mg of ibrutinib initially and maintained disease control despite a dose reduction to 420 mg for tolerability. Ultimately, more data are needed to develop standardized Bing-Neel syndrome treatment strategies with specific consideration to the use of ibrutinib in this condition.

Mutational landscape by targeted next-generation sequencing in EBV-associated lymphoepithelioma-like cholangiocarcinoma.

269 Background: Lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare variant of intrahepatic cholangiocarcinoma, which is highly associated with EBV infection and abundant lymphoplasmacytic cell infiltration. However, there’s limited data of genetic background in LELCC. Therefore, we want to explore the mutation profiles of LELCC, as well as copy number variations. Methods: Five patients’ tumor tissues diagnosed as LELCC, with positive EBER expression were retrospectively collected and microscopically dissected. Of them, two patients’ peripheral blood mononuclear cell served as background of germline mutations. Targeted next-generation sequencing was performed using the ACTOnco Comprehensive Cancer Panel (Ion AmpliSeq Comprehensive Cancer Panel, Life Technologies) to target all coding exons of 409 cancer-related genes for analysis of tumor tissue and blood. PDL1 immunohistochemistry staining with 22C3 antibody pharmDx was applied. Results: All EBV-associated LELCC showed positive expression of PDL1 staining, with combined positive score from 5% to 30%. Both somatic and germline mutations can be detected in LELCC tissue because diffuse infiltration of lymphocytes over tumor. After adjusting for background germline mutation frequency from peripheral blood, only mutations with allele frequency less than or around 10% were considered as somatic mutations. Overall, 10 nonsynonymous somatic mutations were detected in 4 (80%) patients with a range of 1-5 mutations per sample. Mutations were identified including BARD1, EPHA5, MUC16, TNFAIP3, CD19, PTEN, TET1, RECQL4, CD79B, and KDM5A. Copy number changes were rare in this special population. Interesting, one patient who failed to gemcitabine plus cisplatin got partial response after anti-PD1 inhibitor treatment. Conclusions: LELCC is highly correlated with PDL1 expression in tumor and immune cells. It’s necessary to have both tumor tissue and peripheral blood for next-generation sequencing to identify truly somatic mutations in LELCC.

Potential value of apparent diffusion coefficient in the evaluation of hepatic pseudolymphoma.

Hepatic pseudolymphoma, also called reactive lymphoid hyperplasia or nodular lymphoid lesion, is a rare benign non-neoplastic lesion that is histopathologically composed of lymphoid follicles, densely-infiltrated lymphoplasmacytic cells and epithelioid cells (1). The incidence of this disease among females is nine times that of males, which shows a significant gender preference (2). Most hepatic pseudolymphomas are asymptomatic, with an average onset age of 50 years (2).

Natural outbreak of Marek's disease in indigenous chicken and Japanese quail (Coturnix coturnix japonica) in Jos, Plateau State, Nigeria.

Carcasses of an indigenous adult chicken and Japanese quail from different flocks were presented to a veterinary clinic for postmortem (PM) examination in 2014 in Jos, Plateau State, Nigeria. PM observations revealed cutaneous, hepatic, and splenic tumors in the Indigenous chicken. The quail carcass was emaciated with hepatic tumors. Histopathology revealed severe focally extensive non-encapsulated circumscribed large nodules with pleomorphic population of cells mainly composed of lymphoplasmacytic and mixed neutrophilic polymorphonuclear cells in the chicken. The pleomorphic infiltration of lymphohistioplasmacytic cells mixed with neutrophilic polymorphonuclear cells in the quail was consistent with Marek’s disease virus (MDV) infection. Polymerase chain reaction (PCR) was carried out, and the Meq oncogene of the MDV was amplified in the samples collected from the chicken and quail to confirm the presence of the virulent MDV. The samples were also subjected to PCR for detection of MDV Rispens CVI988 vaccine strain which was detected in both chicken and quail samples. The findings in this study represent the first report of confirmatory diagnosis of MD using histopathology in an indigenous chicken and Japanese quail in Nigeria. It is also the first report of the detection of MDV Rispens CVI988 vaccine strain in unvaccinated chicken and quail in Nigeria.

Waldenstrom macroglobulinemia presenting as plasma cell leukemia associated with hyperviscosity syndrome

Objective: Waldenstrom macroglobulinemia (WM) is a rare indolent neoplastic disease characterized by a wide range of clinical presentations related to the direct tumor infiltration. The disease is characterized by monoclonal immunoglobulin M protein in the serum and infiltration of bone marrow with lymphoplasmacytic cells. Case report: We, herein, present an unusual case of WM. A 77-year-old woman admitted to the hospital with fatigue, anorexia, and fever. She had white blood cell elevation and splenomegaly. The patient had no peripheral lymphadenopathy. A large number of plasmablast-like cells were seen in the peripheral blood smear. Laboratory studies revealed a white blood cell count of 54.8 × 103/µl, hemoglobin level of 8.2 g/dl and platelet count was 120 × 103/µl. The diagnosis of WM was established after immunohistochemical analysis of the patient's bone marrow that revealed the presence of a lymphoid/lymphoplasmacytoid-like bone marrow infiltrate along with an elevated serum IgM level. The patient responded to the chemotherapy both clinically and serologically. This case is unusual since numerous plasmablast like cells were seen in peripheral blood smear like plasma cell leukemia at the admission to the hospital. Conclusion : This is the case report of a patient with Waldenstrom macroglobulinemia presenting like plasma cell leukemia in the first admission adding to the spectrum of clinical presentations seen in this disease. This adds to the wide variety of clinical presentations of Waldenstrom macroglobulinemia.

Prognosis of Patients with Waldenström Macroglobulinemia: A Simplified Model

Prognosis of Patients with Waldenström Macroglobulinemia: A Simplified Model

Bing Neel Syndrome: Retrospective Australasian Experience of a Rare Treatable Complication of Waldenström Macroglobulinaemia/ Lymphoplasmacytic Lymphoma

Introduction and aims:Bing Neel syndrome (BNS) is a rare complication of Waldenström Macroglobulinaemia (WM)/ Lymphoplasmacytic Lymphoma (LPL). It is a clinicopathological entity characterised by central nervous system involvement with malignant cells. It presents with diverse symptoms and can be difficult to recognise. However, it is a treatable condition amenable to systemic and intrathecal treatment. We present the Australasian experience of this rare entity.Methods:Inclusion in the study was based on cytologically or histologically confirmed presence of lymphoplasmacytic cells in the CSF or brain biopsy. Ten patients were included from 9 sites in Australia and New Zealand. Relevant retrospective data was extracted after obtaining consent from patients or next of kin.Results: Seven of the 10 patients were males with overall mean age of 63.5 years (range: 49-78 years); 4 patients were < 60 years old. Four patients (40%) did not have a prior diagnosis of WM; the remaining 6 patients were diagnosed ~ 11 years post diagnosis of WM (range: 3 -26 years) and received 1 line of treatment (except for 2 patients who received 2 lines of treatment). Treatment regimens received included R-CVP, chlorambucil-prednisolone, DRC, FCR, oral fludarabine, and RFM.At diagnosis of BNS, IgM and/or PP levels ranged between 3 - 70 g/L with 6 (60%) patients having levels < 10 g/L. One patient had a diagnosis of lymphoplasmacytic lymphoma with IgG paraprotein.Symptoms at presentation of BNS varied from headache, ptosis/ophthalmoplegia, memory loss, subacute hemiplegia, cognitive defects, hearing loss, and sensory or motor neuropathy. None of the patients had B symptoms. Lymphadenopathy was noted in 4 (40%) cases, splenomegaly in 1 (10%) and ECOG performance status ranged from 0-4 with 3 (30%) patients having an ECOG of > 2.Brain +/- spine MRI was done in all cases with 5 (50%) showing leptomeningeal involvement. Orbital infiltration or enhancement of optic or ophthalmic nerves was noted in 3 cases (30%), and 3 patients (30%) had focal signs/masses. 1 had cortical atrophy, and 3 had normal MRI. CSF analysis was abnormal in all cases on cytology with demonstration of abnormal lymphocytes. Where immunophenotyping was performed, it showed presence of CD5, CD10 negative B cells. MYD88 L265P was detected in 3 patients (30%).Treatment of BNS included systemic chemoimmunotherapy in 30%, CNS penetrating intravenous agents in 40%, Ibrutinib in 50%, intrathecal chemotherapy in 30%, and radiotherapy in 10%. More than 1 modality of treatment was used in 40% of patients. Ibrutinib was administered as frontline treatment in combination with high dose MTX or IT chemotherapy in 3 patients, and as single agent monotherapy in 1 patient. Ibrutinib was used as second line treatment in 2 patients with both achieving CR. The number of cycles administered were 2.6 (range 1-9).Response data was available in 9 patients with ORR in 6 (1 CR, 5 PR) and non-response in 3. All patients except the one treated with Ibrutinib monotherapy had at least PR. With a median follow-up time of 20 months, 3 patients have died. The median overall survival of patients was not reached. The 1-year and 3-year OS rates were 80% (95% CI 41-95%) and 60% (16-87%), respectively (Figure 1).Conclusion:BNS should be suspected in WM patients who develop focal or nonspecific neurological symptoms. It can be readily diagnosed on radiological scans i.e. brain and spinal MRI, and/or on CSF analysis. It can be treated with a number of systemic and intrathecal drugs including Ibrutinib, which crosses the blood brain barrier.Fig 1 legend:Kaplan Meir curve demonstrating median overall survival of patients (not reached) and 1-year and 3-year OS rates of 80% (95% CI 41-95%) and 60% (16-87%), respectively. DisclosuresTalaulikar:Takeda: Research Funding; Novartis: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau. Ho:Celgene: Other: Travel to meeting ; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel to meeting; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Simpson:Roche: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta: Research Funding; Merck: Honoraria, Research Funding; BeiGene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MSD: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding. Tam:AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Beigene: Honoraria. Castillo:Pharmacyclics: Consultancy, Research Funding; Millennium: Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy; Beigene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding.

Ibrutinib for the Treatment of Bing-Neel Syndrome

Ibrutinib for the Treatment of Bing-Neel Syndrome

Kidney diseases associated with Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is a rare B-cell lymphoma characterized by lymphoplasmacytic cell infiltration in the bone marrow and other organs and the presence of a monoclonal immunoglobulin M protein in the serum. Although uncommon, several kidney diseases have been associated with WM. In addition to kidney diseases related to lymphoplasmacytic lymphoma infiltration, a variety of glomerular and tubular lesions have been described in patients with WM. Immunoglobulin light chain (AL) amyloidosis and cryoglobulinemic glomerulonephritis are the two predominant glomerular pathologies seen in WM. In this article we review the kidney diseases associated with WM. We also briefly review some nephrotoxicities of novel chemotherapeutic and targeted therapies used for the treatment of WM.

Waldenström macroglobulinemia: 2019 update on diagnosis, risk stratification, and management.

Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in >90% of patients and is found in the majority of IgM monoclonal gammopathy of undetermined significance patients. Age, hemoglobin level, platelet count, β2 microglobulin, and monoclonal IgM concentrations are characteristics that are predictive of outcomes. Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or ibrutinib. Purine nucleoside analogs are active but usage is declining for less toxic alternatives. The preferred Mayo Clinic induction is rituximab and bendamustine. Potential for stem cell transplantation should be considered in selected younger patients. Bortezomib, fludarabine, thalidomide, everolimus, ibrutinib, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in relapsed WM. Given WM's natural history, reduction of therapy toxicity is an important part of treatment selection.

Medial Hypoxia and Adventitial Vasa Vasorum Remodeling in Human Ascending Aortic Aneurysm.

Human ascending aortic aneurysms characteristically exhibit cystic medial degeneration of the aortic wall encompassing elastin degeneration, proteoglycan accumulation and smooth muscle cell loss. Most studies have focused on the aortic media and there is a limited understanding of the importance of the adventitial layer in the setting of human aneurysmal disease. We recently demonstrated that the adventitial ECM contains key angiogenic factors that are downregulated in aneurysmal aortic specimens. In this study, we investigated the adventitial microvascular network (vasa vasorum) of aneurysmal aortic specimens of different etiology and hypothesized that the vasa vasorum is disrupted in patients with ascending aortic aneurysm. Morphometric analyses of hematoxylin and eosin-stained human aortic cross-sections revealed evidence of vasa vasorum remodeling in aneurysmal specimens, including reduced density of vessels, increased lumen area and thickening of smooth muscle actin-positive layers. These alterations were inconsistently observed in specimens of bicuspid aortic valve (BAV)-associated aortopathy, while vasa vasorum remodeling was typically observed in aneurysms arising in patients with the morphologically normal tricuspid aortic valve (TAV). Gene expression of hypoxia-inducible factor 1α and its downstream targets, metallothionein 1A and the pro-angiogenic factor vascular endothelial growth factor, were down-regulated in the adventitia of aneurysmal specimens when compared with non-aneurysmal specimens, while the level of the anti-angiogenic factor thrombospondin-1 was elevated. Immunodetection of glucose transporter 1 (GLUT1), a marker of chronic tissue hypoxia, was minimal in non-aneurysmal medial specimens, and locally accumulated within regions of elastin degeneration, particularly in TAV-associated aneurysms. Quantification of GLUT1 revealed elevated levels in the aortic media of TAV-associated aneurysms when compared to non-aneurysmal counterparts. We detected evidence of chronic inflammation as infiltration of lymphoplasmacytic cells in aneurysmal specimens, with a higher prevalence of lymphoplasmacytic infiltrates in aneurysmal specimens from patients with TAV compared to that of patients with BAV. These data highlight differences in vasa vasorum remodeling and associated medial chronic hypoxia markers between aneurysms of different etiology. These aberrations could contribute to malnourishment of the aortic media and could conceivably participate in the pathogenesis of thoracic aortic aneurysm.

EBV-Negative Lymphoepithelial-Like Carcinoma of the Lower Lip: Immunohistochemical and in Situ Hybridization Analyses

Lymphoepithelial-like carcinoma (LEC), a rare malignant neoplasm, can be associated with the Epstein-Barr virus (EBV). Histologically, it is an undifferentiated carcinoma with an intermixed reactive lymphoplasmacytic infiltrate. LEC appears to be an uncommon type of lip carcinoma. An 82-year-old white woman presented with a lower lip wound, of 1 year's evolution. The lesion presented an ulcerated surface with a flat edge and hardened base, pain, and absence of regional lymphadenopathy. Microscopic analysis evidenced an intense inflammatory infiltrate, composed of lymphoplasmacytic cells, associated with scarce pleomorphic epithelial cells. Immunohistochemistry of the LEC cells highlighted a strong expression of AE1/AE3, EMA, p63, and p53 and a weak expression of CD138. Ki-67 was >85%. In situ hybridization analysis did not show evidence of EBV. A diagnosis of EBV-negative LEC was established. We have described an uncommon type of lip carcinoma, which can present a diagnostic challenge for clinicians and pathologists.

A Case of Bing–Neel Syndrome Successfully Treated with Ibrutinib

Bing–Neel syndrome is a rare manifestation of Waldenström macroglobulinemia characterized by lymphoplasmacytic cells' infiltration into the central nervous system. We present a case of a 74-year-old patient with a known diagnosis of Waldenström macroglobulinemia and newly depressed consciousness. Flow cytology of his cerebral spinal fluid demonstrated a lambda light chain-restricted population of B-cells consistent with a CD5+ CD10+ B-cell lymphoma. Magnetic resonance imaging suggested involvement of the left optic nerve sheath and the bilateral orbital and parietal parenchyma and leptomeninges. He was diagnosed with Bing–Neel syndrome and treated with intrathecal liposomal cytarabine, intravenous high-dose methotrexate, and rituximab without improvement. Subsequently, he started treatment with ibrutinib 560 mg daily and concurrent rituximab. Within three months, he showed clinical and radiologic improvement. The patient has continued on ibrutinib and has now been stable for over 36 months. This represents the longest reported period of successful treatment of Bing–Neel syndrome with ibrutinib.

Elevated vWF Antigen Serum Levels Are Associated With Poor Prognosis, and Decreased Circulating ADAMTS-13 Antigen Levels Are Associated With Increased IgM Levels and Features of WM but not Increased vWF Levels in Patients With Symptomatic WM

BackgroundWaldenström's macroglobulinemia (WM) is a rare malignancy characterized by bone marrow infiltration by lymphoplasmacytic cells and the presence of a monoclonal IgM paraprotein. The interactions of lymphoplasmacytic cells with other cells in their microenvironment, including mast cells and endothelial cells, support their survival and proliferation and can induce resistance to therapy. von Willebrand factor (vWF) plays a key role in primary hemostasis but is also a marker of endothelial “stimulation.” High levels of vWF have been associated with an adverse prognosis in patients with symptomatic WM and might reflect the interactions between lymphoplasmacytic cells and other cells of their microenvironment. Materials and MethodsConsidering vWF and ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) as markers of endothelial dysfunction and activation, we evaluated the prognostic importance of vWF and ADAMTS-13 antigen levels in the serum of patients with previously untreated symptomatic WM to validate vWF as a possible prognostic marker for progression-free and overall survival. We also validated the measurement of vWF in the serum instead of citrated plasma and investigated the possible correlations of ADAMTS-13 antigen levels with disease characteristics. The analysis included 42 patients with symptomatic WM and 19 matched healthy controls. ResultsThe serum levels of vWF antigen provided significant prognostic information, and patients with levels ≥ 200 IU/dL had a very poor prognosis compared with patients with lower levels. The ADAMTS-13 antigen levels were decreased in WM patients and correlated with the IgM levels, β2-microglobulin, and extent of bone marrow infiltration. ConclusionvWF levels measured in the serum could become an important prognostic marker in patients with WM and requires further investigation.

A rare case of xanthogranulomatous mastitis with intraductal papilloma

Xanthogranulomatous inflammation is rare and has been described most commonly in kidney and gallbladder. It is extremely rare in breast. We report here a case of a 42-year-old female who came with firm painless lump in the left breast. Mammography suggested suspicious neoplastic retroareolar lesion. Fine-needle aspiration (FNA) smears suggested a benign cystic lesion and excision of the cyst was advised. Histopathological examination revealed breast tissue infiltrated with polymorphonuclear leukocytes, lymphoplasmacytic inflammatory cells, few giant cells, and sheets of foamy histiocytes (xanthoma cells) with a focus of intraductal papilloma. A diagnosis of xanthogranulomatous mastitis with intraductal papilloma was made. Chronic inflammatory lesions are known to produce firm lesions which may mimic neoplastic lesion. Definitive diagnosis could not be achieved in FNA smears due to the absence of adequate number of xanthoma cells. Final diagnosis was made on histopathology examination. Xanthogranulomatous mastitis is an extremely rare entity. Clinical presentation is quite variable. Imaging modalities and FNA are inadequate for definitive diagnosis.

Cytomorphological Study of Medullary Carcinoma of Breast in Comparison to Infiltrating Ductal Carcinoma.

Introduction:Medullary breast carcinoma (MBC) is one of the rare variants of breast carcinoma, accounting for less than 5% of invasive breast carcinoma. MBCs relatively appear a decade earlier when compared to invasive ductal carcinoma (IDC NOS), which is more prevalent in the elderly age.Subjects and Methods:A retrospective study was conducted in the Department of Pathology from 2009 to 2016. Fine needle aspiration cytology slides of MBCs and IDCs were retrieved, studied microscopically, and reviewed to compare the cytological features.Results:During the study period, MBC cases were 12 and IDC were 319. Random 12 cases of IDC NOS were taken up for comparative cytological evaluation. Various cytological features are assessed and compared using chi square test and independent t test ratio. On comparison of IDC NOS and MBC cases in relation to the parameters like: syncytial clusters and nature of inflammatory infiltrate; the number of positive category was higher in MBC group (83.3%). In contrast, parameters like three-dimensional clusters, acinar pattern, and necrosis; the number of positive category was higher in IDC NOS group with a percentage of 91.7%, 100%, and 67%, respectively. Ratio of lymphoplasmacytic cells to tumor cells between the two showed that the ratio was higher in MBC group. This comparison was statistically significant with a P value of <0.001.Conclusion:Though few variants of breast carcinoma contain lymphoplasmacytic infiltrate, the intensity and pattern of distribution of these lymphocytes and plasma cells in relation to tumor cells helps in distinguishing MBC from other breast carcinomas commonly IDC NOS on cytology. Also MBCs have a better prognosis when compared to IDC NOS.

The role of ibrutinib in Waldenström macroglobulinemia

ABSTRACTIntroduction: Waldenström macroglobulinemia (WM) is an uncommon incurable B-cell lymphoma characterized by the presence lymphoplasmacytic cells in the bone marrow. The recurrent mutation in the MYD88 gene and the deeper understanding of the biology of the MYD88 signaling pathway provided the opportunity to develop targeted drugs.Areas covered: Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor, which has been recently approved by the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for patients with symptomatic Waldenström macroglobulinemia (WM). In this review we aim to present the role of BTK in WM pathophysiology and highlight the role of ibrutinib in the treatment of the disease.Expert opinion: Ibrutinib is an orally administered agent proven to be safe and highly effective which has changed the treatment landscape of the disease. Approximately 90% of the patients will eventually respond to ibrutinib, the responses are deep and durable while only a few discontinue treatment due to treatment related toxicity. Ibrutinib also seems to be extremely effective even in heavily pretreated and rituximab refractory patients in which almost 75% will respond to this treatment regimen. Several studies are ongoing in order to investigate the most appropriate combinations and timepoints of the disease in which ibrutinib should be administered in order to improve response, survival rates and quality of life.

A Novel, Highly Selective IRAK1 Inhibitor Jh-X-119-01 Shows Synergistic Tumor Cell Killing with Ibrutinib in MYD88 Mutated B-Cell Lymphoma Cells

▪Activating mutations in MYD88 are present in many B-cell lymphoproliferative disorders including WM (95%), ABC DLBCL (39%), Primary CNS Lymphoma (80-90%), Marginal Zone Lymphoma (6-10%) and Chronic Lymphocytic Leukemia (4-8%). In MYD88 mutated WM and ABC DLBCL cells, MYD88 triggers NF-kB pro-growth and survival signaling through divergent pathways driven by BTK and IRAK4/IRAK1 (Ngo et al, Nature 2011; Yang et al, Blood 2013). Ibrutinib targets BTK, and has shown high levels of activity in MYD88 mutated WM, ABC DLBCL and PCNSL. Responses however are partial, and complete remissions are lacking. We therefore sought to clarify if persistent IRAK4/IRAK1 signaling was responsible for survival of malignant lymphoplasmacytic cells (LPC) in WM patients on ibrutinib. We observed by flow cytometric analysis that while BTK activation was suppressed in WM patients on ibrutinib for >6 months, both IRAK4 and IRAK 1 remained hyperactivated. Treatment of LPC from patients on ibrutinib with a toolbox IRAK4/IRAK1 inhibitor resulted in marked reduction of NF-kB and induction of apoptosis. Subsequently, we performed lentiviral transduction studies in MYD88 mutated BCWM.1 cells, and observed in an inducible model system that knockdown of IRAK1 produced more robust apoptotic effects versus IRAK4 (Figure 1A). Given these findings, we have pursued a medical chemistry campaign to develop a potent and highly selective inhibitor of IRAK1 kinase activity, JH-X-119-01. JH-X-119-01 inhibited IRAK1 biochemically with an IC50 of 9.3 nM while exhibiting no inhibition of IRAK4 at concentrations up to 10 µM, and showed exceptional Kinome selectivity with off-target inhibition of only two kinases, YSK4 and MEK3 (Figure 1B). Mass spec labelling studies were used to confirm that JH-X-119-01 irreversibly labelled IRAK1 at cysteine 302. JH-X-119-01 showed antiproliferative effects on MYD88 mutated WM and ABC DLBCL cells. Importantly, the combination of JH-X-119-01 with Ibrutinib led to synergistic tumor cell killing in MYD88 mutated WM and ABC-DLBCL cells, and suppression of NF-ĸB activation (Figure 1C). In vivo PK studies revealed a favorable profile for JH-X-119-01 with a moderate half-life of 1.61 hours, a Cmax of 9.95 µM, and a low clearance of 18.84 mL/min/kg when dosed IV. Our findings evidence the development of a novel, highly selective IRAK1 kinase inhibitor, JH-X-119-01, that shows specific inhibition of IRAK1 kinase activity and a reduction of tumor cell survival in MYD88 mutated WM. Importantly, JH-X-119-01 shows synergistic tumor cell killing with ibrutinib in MYD88 mutated WM and ABC-DLBCL cells. This study provides a framework for the development of highly selective IRAK1 inhibitors for use alone, and in combination with ibrutinib in MYD88 mutated B-cell lymphomas. [Display omitted] DisclosuresCastillo:Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Millennium: Research Funding; Pharmacyclics: Consultancy, Research Funding. Treon:Pharmacyclics: Consultancy, Research Funding.