Indolent B-cell Lymphoproliferative Disorder Research Articles

BET bromodomain inhibitors PFI-1 and CPI-203 suppress the development of follicular lymphoma via regulating Wnt/β-catenin signaling

ObjectiveFollicular lymphoma (FL) is an indolent B-cell lymphoproliferative disorder, characterized by a lymphoid follicular pattern of growth. PFI-1 or CPI-203 has been known to effectively promote the inhibition of primary effusion lymphoma progression. This study aimed at investigating the anti-tumor properties of PFI-1 and CPI-203 on FL cells and uncover the underlying mechanism of action. MethodsFL cells were treated with PFI-1 and CPI-203, and the treated cells were evaluated for their cell viability, cell cycle and apoptosis using CCK8, flow cytometry, and Western blot assays. A xenograft mouse model was used for assessing the in vivo effects of CPI-203 on tumorigenesis. ResultsPFI-1 or CPI-203 showed potential inhibitory effects on the cell viability of DOHH2 and RL cells in a dose-response-dependent manner. Furthermore, PFI-1 and CPI-203 inhibited cell growth, induced apoptosis of FL cells in vitro, and facilitated the translocation of β-catenin into cytoplasm both in vitro and in vivo. After engrafted with FL cells, CPI-203-treated mice got a longer duration of survival and a smaller tumor size than control mice. Mechanistically, PFI-1 and CPI-203 impede the activity of β-catenin and its downstream molecules by regulating the DVL2/GSK3β axis. ConclusionIn conclusion, PFI-1 and CPI-203 may serve as potential anti-tumor inhibitors for the therapy of FL.

Establishment of the Bcwm.2 Cell Line As a BTK-Inhibitor Resistant, BCL2 Inhibitor Sensitive in Vitro and In Vivo Study Model for Waldenström's Macroglobulinemia

Background: Waldenström's macroglobulinemia (WM) is an indolent B-cell lymphoproliferative disorder characterized by bone marrow (BM) infiltration with lymphoplasmacytic lymphoma and monoclonal immunoglobulin M (IgM) production. Mutations in MYD88 are present in 95-97% of WM patients. Deletions involving chromosome 6q (del6q) are found in up to 50% of WM patients, and include genes that regulate MYD88, BCL2 and apoptotic signaling. Cell lines can play a pivotal role as disease models, contributing to a comprehensive understanding of WM biology and advancing therapeutic strategies. The availability of cell lines for the study of WM remains limited, and none demonstrate del6q. Patient and Methods: We developed and characterized a novel cell line (BCWM.2) from long-term cultures of CD19 + selected BM lymphoplasmacytic cells from a symptomatic, treatment naive WM patient who then received ibrutinib monotherapy on a clinical trial. The patient attained a major response to treatment, and after 2 years progressed. The patient underwent serial bone marrow biopsies, and extensive genomic and transcriptome analysis of his tumor during the study, and the corresponding cell line established at baseline. An in vivo xenograft mouse model of BCWM.2 was also established in NOD SCID mice, and the origin of the xenografted tumor was confirmed by genomic sequencing and immunohistochemistry. Results: BCWM.2 cells exhibited morphologic and immunophenotypic characteristics resembling lymphoplasmacytic cells and demonstrated robust propagation when co-cultured with HS-5 stromal cells in IMDM medium supplemented with 20% FBS. Flow cytometric analysis revealed that BCWM.2 exhibited an immunophenotype consistent with the source WM patient. Whole genome sequencing demonstrated that both BCWM.2 cells and original patient WM cells carried somatic activating mutation in MYD88 (S243N) and shared trisomy in chromosomes 3 and 12, heterozygous deletion of 6q, and amplification of 6p. Notably, a novel mutation in the SRC family member LYN (I297N; T>A), a component of BCR, was identified in BCWM.2 but not the original patient tumor. The I297N mutation found in the regulatory hinge region is predicted to cause activation of LYN. At time of progression on ibrutinib, the dominant clone that emerged in the patient's tumor also carried the I297N mutation. Additionally, mutated genes in BCWM.2 included histone deacetylase HDAC5, tumor suppressor RUNX3, B-cell transcriptional activator SPI1, and AKAP9 (A-Kinase Anchoring Protein 9). Transcriptome analysis showed shared expression patterns between BCWM.2 and patient tumor samples, including diminished gene expression of chromosome 6q. Drug response testing revealed that BCWM.2 cells did not respond to the BTK-inhibitors ibrutinib, zanubrutinib or pirtobrutinib but were sensitive to the BCL2 inhibitor venetoclax. Furthermore, BCWM.2 cells readily engrafted in NOD-SCID mice by direct subcutaneous injection of 2 x 10^6 cells/mouse. Tumor growth (~500 mm^3) was observed in the mice four weeks post-inoculation. Importantly, follow-up evaluations demonstrated serial increases in human IgM levels in the mouse sera post-engraftment. Moreover, BCWM.2 engraftment was confirmed by immunohistochemistry with tumors exhibiting intermediate lymphoid cell morphology with plasmacytoid differentiation, CD20 and MUM1 expression, clonality for lambda light chain and IgM heavy chain, 60% KI67 staining. Whole exome sequencing of engrafted tumors further confirmed the presence of the MYD88 S243N and LYN I297N mutations detected in the cell line and the patient at the time of ibrutinib progression. Conclusions: BCWM.2 represents a novel, BTK-inhibitor resistant, BCL2 inhibitor sensitive WM cell line that demonstrates MYD88 (S243N) and LYN (I297N) somatic activating mutations, and deletions of 6q. BCWM.2 thereby provides an important new disease appropriate cell model for the in vitro and in vivo study of WM, including the development of targeted therapies for this disease.

Ibrutinib in therapy of Waldenstrom’s macroglobulinemia: literature review and clinical observation

Waldenstrom’s macroglobulinemia (WM) is an indolent B-cell lymphoproliferative disorder which despite achieved successes in therapy is characterized by recurrences and refractoriness. Study of molecular biology allowed to use targeted drugs, in particular ibrutinib which acts through suppression of B cell receptor signaling pathway by inhibiting Bruton’s tyrosine kinase. In several large trials, ibrutinib demonstrated its effectiveness and manageable toxicity profile both in patients with newly diagnosed and recurrent/refractory WM. A clinical observation of a patient with WM is presented. Due to minimal response during previous treatment, the patient currently is undergoing monotherapy with ibrutinib with positive antitumor effect, satisfactory tolerability, and absence of significant adverse events. The effect of ibrutinib on humoral immunity during the follow up period was evaluated.

Waldenstrom macroglobulinemia with 11q deletion: A rarely diagnosed entity with review of literature

Waldenstrom macroglobulinemia (WM) is a rare, chronic, and indolent B-cell lymphoproliferative disorder characterized by bone marrow infiltration by small lymphocytes, lymphoplasmacytoid cells, and plasma cells along with the presence of a detectable monoclonal immunoglobulin M. It represents 1%–2% of hematological malignancies with an overall incidence of 3–4 cases/million persons/year. Some deletions are associated with a more aggressive IgM gammopathy and have a high probability of symptomatic transformation. 6q deletion, the most common cytogenetic abnormality, which is present in 42% of cases whereas 11q deletion is rare in WM and is present in only 8% of cases. We are presenting a case of a 70-year-old male patient diagnosed as WM with 11q deletion.

Treatment of Classic Hairy Cell Leukemia: Targeting Minimal Residual Disease beyond Cladribine.

Simple SummaryStandard treatment with purine analogues facilitates a near normal life expectancy in the majority of patients with classic hairy cell leukemia (HCL), a rare chronic B-cell malignancy. However, nearly all patients ultimately relapse and require retreatment, while drug-induced myelotoxicity accumulates predisposing to infectious complications and, possibly, secondary malignancies. Persistence of minimal residual disease (MRD) in a substantial portion of treated patients has become a surrogate for this still limited treatment efficacy. New insights into disease biology initiated design and investigation of several new, chemotherapy-free, targeted drugs with encouraging efficacy in early clinical trials aimed at enhancing eradication of MRD and optimizing drug tolerability. This review provides an update on recent clinical trials investigating treatment strategies beyond purine analogues in HCL and discusses clinically relevant obstacles still to overcome.Classic hairy cell leukemia (HCL) is a rare indolent B-cell lymphoproliferative disorder characterized by profound pancytopenia and frequent infectious complications due to progressive infiltration of the bone marrow and spleen. Lacking effective treatment options, affected patients were confronted with a dismal survival prognosis of less than 5 years when the disease was first described in 1958. Tremendous therapeutic advances were accomplished with the introduction of purine analogues such as cladribine in the 1990s, facilitating a near-normal life expectancy in most HCL patients. Nevertheless, nearly all patients eventually relapse and require successive retreatments, while drug-associated myelotoxicity may accumulate and secondary malignancies may evolve. Detection of minimal residual disease (MRD) in a substantial portion of treated patients has become a surrogate for this still limited treatment efficacy. In the last decade, novel biologic insights such as identification of the driver mutation BRAF V600E have initiated the development and clinical investigation of new, chemotherapy-free, targeted drugs in HCL treatment, with encouraging efficacy in early clinical trials aimed at boosting eradication of MRD while optimizing drug tolerability. This review summarizes current clinical trials investigating treatment strategies beyond purine analogues in HCL and discusses clinically relevant obstacles still to overcome.

Frontline Therapy with Bendamustine-Rituximab (BR) in Patients with Treatment-Naïve Waldenstrom's Macroglobulinemia Confers Similar Long-Term Outcomes to R-CVP in a Real-World Setting: A Population-Based Analysis

Frontline Therapy with Bendamustine-Rituximab (BR) in Patients with Treatment-Naïve Waldenstrom's Macroglobulinemia Confers Similar Long-Term Outcomes to R-CVP in a Real-World Setting: A Population-Based Analysis

Preliminary Clinical Response Data from a Phase 1b Study of Mavorixafor in Combination with Ibrutinib in Patients with Waldenström's Macroglobulinemia with MYD88 and CXCR4 Mutations

Preliminary Clinical Response Data from a Phase 1b Study of Mavorixafor in Combination with Ibrutinib in Patients with Waldenström's Macroglobulinemia with MYD88 and CXCR4 Mutations

IBCL-114: Clinical and Biological Prognostic Factors in Follicular Lymphoma Patients During Treatment

Introduction Follicular lymphoma (FL) is an indolent yet heterogeneous B-cell lymphoproliferative disorder. Most people respond to treatment well. However, a particular group of patients has a poor prognosis, and these patients are difficult to define. Patients and Methods We retrospectively analyzed 143 FL patients treated at the University of Debrecen since 2009. We investigated the prognostic factors that may influence the survival of FL patients. Results We found a standardized uptake value (SUV)max cut-off of 9.85 at the staging PET/CT to significantly separate FL patients’ progression-free survival (PFS) (p=0.0001, HR: 0.2535, 95%CI: 0.1118-0.4878). Lymphocyte/monocyte (Ly/Mo) ratio of 3.41 drawn at diagnosis also significantly predicted PFS (p=0.0027, HR: 2.997, 95% CI: 1.463-6.142). Combining patients with staging SUVmax >9.85 and Ly/Mo 9.85 and interim SUVmax >3.15, a high-risk group of FL patients can be identified (p Discussion Biological prognostic factors, such as the Ly/Mo ratio, may improve the prognostic assessment of staging PET/CT. Nevertheless, PFS difference is translated into OS when using a combination of staging and interim SUVmax. We consider investigating additional biological prognostic factors while currently highlighting PET/CT’s role in FL.

Ascites in A Patient with Hairy Cell Leukaemia and Carcinoma of Breast: A Diagnostic Challenge

Hairy cell leukaemia (HCL) is a rare indolent B-cell lymphoproliferative disorder. We report a diagnostic challenge in detecting the cause of ascites, which is a rare, unique manifestation of HCL. A 72-year-old lady presented with 1-month-history of pain in left upper abdomen and loss of weight. There was hepatomegaly, splenomegaly, bilateral inguinal lymphadenopathy, anaemia, and lymphocytosis. She was diagnosed as HCL, based on morphology, immunophenotyping of peripheral blood and bone marrow biopsy examination. In 2009, she was diagnosed as carcinoma of breast when she presented with a mass in left breast; and she received treatment. For HCL, she received intermittent chemotherapy (Chlorambucil+Prednisolone). Her HCL was stable until 2018 when she presented with recurrent ascites which needed frequent, regular peritoneal paracentesis. Since she had HCL and carcinoma of breast, determining the aetiology of ascites was challenging. Possible causes of her ascites included metastatic carcinoma of breast, HCL, cirrhosis of liver with portal hypertension and peritoneal tuberculosis. Cytology of peritoneal fluid showed mature-looking lymphocytes but no malignant cells. Interestingly, flow cytometry analysis of peritoneal fluid showed the presence of clonal B cell population with lambda light chain restriction. Therefore, it was concluded that her ascites was a manifestation of HCL. A few months later, she succumbed to septicaemia. Impact of ascites on disease course of HCL included rapid disease progression, poor prognosis and shortened survival. We highlight the important role of immunophenotyping in addition to cytomorphology to guide us in confirming the aetiology of ascites in a patient with haematological and solid organ malignancies.

Dabrafenib Is a Safe and Effective Therapy in Relapsed/Refractory Classical Hairy Cell Leukemia

BACKGROUND: Hairy cell leukemia (HCL) is a rare indolent B-cell lymphoproliferative disorder. The BRAF V600E mutation was shown to be the underlying genetic driver for the vast majority of classical HCL (HCLc) cases and treatment with the BRAF inhibitor (BRAFi), vemurafenib, has proven extremely successful. Dabrafenib is an oral BRAFi used in melanoma, often in conjunction with trametinib, a MEK inhibitor. Data exists on the use of dabrafenib combined with trametinib in HCLc but there is no efficacy or safety data on either single agent dabrafenib or dabrafenib combined with rituximab. We present a small series of 7 patients treated with either single agent dabrafenib or combination dabrafenib and rituximab. METHODS: Since 2018 dabrafenib was accessible via a Novartis managed access programme for BRAF V600E mutated HCLc patients who had no alternative treatment options. Six patients received dabrafenib, 2 as single agent due to recent prior ineffective rituximab therapy or severe rituximab infusion reaction and the remaining 4 patients with dabrafenib and rituximab. Dabrafenib was given at 150mg twice daily on a continuous 28 day cycle. Rituximab 375mg/m2 IV was given once every 2 weeks for a total of 8 doses. As there was no availability for re-treatment on cessation of therapy and no other suitable/accessible treatment options, patients with ongoing response and good tolerance were continued on indefinite therapy. One additional patient was treated with frontline dabrafenib and rituximab due to various comorbidities including end stage renal failure limiting other treatment options. RESULTS: Mean age on commencing dabrafenib was 73 (52-87) and in the relapsed patients the median number of prior lines of therapy was 5 (3-13). Four patients had undergone prior splenectomy. Two patients had received prior BRAFi therapy with vemurafenib and 3 had received prior Moxetumomab. Patients received a median of 8 cycles of dabrafenib. 4 patients received all 8 cycles of rituximab with 1 discontinuing rituximab due to adverse drug reaction. Adverse drug reactions to dabrafenib were mostly grade 1-2. The most common reaction was benign keratotic skin lesions occurring in 5/7 patients. Their onset was typically after 4 weeks of treatment, persisting whilst therapy continued. Other notable adverse drug reactions were hair thinning and palmar-plantar erythrodysesthesia both occurring in 3/7 patients. Hair thinning did seem to improve with decreasing the dosage and resolve on cessation of the drug. Palmar-plantar erythrodysesthesia was managed with dose reduction and non-steroidal anti-inflammatory drugs. Response assessment criteria used were from the 2017 hairy cell leukemia foundation consensus guidelines for the diagnosis and management of patients with HCLc. All patients responded to therapy. Hematological response was rapid, most patients achieving hematological CR after 2-3 cycles. Five patients achieved a CR, 2 were MRD+ve, 2 were MRD-ve and 1 was a radiological CR. The remaining 2 patients achieved a hematological response, 1 partial and 1 complete. Six patients had sufficient follow up for assessment with 2/6 having relapsed and 4/6 remaining in remission. Median follow up was 17 months, median DOR and median OS were not reached. The 2 patients in our cohort (patients 1 and 3) receiving prior vemurafenib each received 6 cycles, 1 achieving CR lasting 3 months, the other achieving PR lasting 11 months. Both responded rapidly to dabrafenib, one treated with dabrafenib and rituximab achieved an MRD+ve CR with DOR 21 months. The other received single agent dabrafenib and achieved a hematological response with DOR 15.2 months. Treatment response and survival are shown in table 1 and figure 1. Figures 2-7 show the hematological response at time points within the first year of therapy. DISCUSSION: In this small cohort we have shown that dabrafenib as a single agent or combined with rituximab is a safe and effective therapy in BRAF V600E mutated HCLc, even in those patients with prior time limited duration BRAFi therapy. There was no hematological toxicity noted. The main adverse drug effect was development of skin lesions however none were malignant. The only malignant lesion noted pre dated the commencement of dabrafenib. Dermatological surveillance is therefore recommended. Hematological response was rapid with significant improvement seen as early as 4 weeks from commencing therapy. Disclosures El-Sharkawi: Janssen:Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche:Other: Conference fees. OffLabel Disclosure: Use of BRAF inhibitor Dabrafenib in BRAF V600E mutation positive classical Hairy Cell Leukemia.

Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice

Aberrant NF-κB activation is a hallmark of most B-cell malignancies. Recurrent inactivating somatic mutations in the NFKBIE gene, which encodes IκBε, an inhibitor of NF-κB-inducible activity, are reported in several B-cell malignancies with highest frequencies in chronic lymphocytic leukemia and primary mediastinal B-cell lymphoma, and account for a fraction of NF-κB pathway activation. The impact of NFKBIE deficiency on B-cell development and function remains, however, largely unknown. Here, we show that Nfkbie-deficient mice exhibit an amplification of marginal zone B cells and an expansion of B1 B-cell subsets. In germinal center (GC)-dependent immune response, Nfkbie deficiency triggers expansion of GC B-cells through increasing cell proliferation in a B-cell autonomous manner. We also show that Nfkbie deficiency results in hyperproliferation of a B1 B-cell subset and leads to increased NF-κB activation in these cells upon Toll-like receptor stimulation. Nfkbie deficiency cooperates with mutant MYD88 signaling and enhances B-cell proliferation in vitro. In aged mice, Nfkbie absence drives the development of an oligoclonal indolent B-cell lymphoproliferative disorders, resembling monoclonal B-cell lymphocytosis. Collectively, these findings shed light on an essential role of IκBε in finely tuning B-cell development and function.

Prominent immune signatures of T cells are specifically associated with indolent B-cell lymphoproliferative disorders and predict prognosis.

ObjectivesT cells play an essential role in controlling the development of B‐cell lymphoproliferative disorders (BLPDs), but the dysfunction of T cells in BLPDs largely remains elusive.MethodsUsing multiplexed flow cytometry, we quantified all major subsets of CD4+ helper T cells (Th) and CD8+ cytotoxic T cells (Tc) in 94 BLPD patients and 66 healthy controls. Statistics was utilised to rank T‐cell signatures that distinguished BLPDs from healthy controls and differentially presented between indolent and aggressive categories.ResultsBy comparing with healthy controls, we found that the indolent but not aggressive type of BLPDs demonstrated a high degree of T‐cell activation, showing the increase in type I helper T (Th1) cells and follicular B‐helper T (Tfh) cells, both of which strongly associated with the enhanced differentiation of exhaustion‐like effector cytotoxic CD8+ T cells expressing PD‐1 (Tc exhaustion‐like) in indolent BLPDs. Random forest modelling selected a module of T‐cell immune signatures best performing binary classification of all BLPD patients. This signature module was composed of low naïve Th cells and high Th1, Tfh and Tc exhaustion‐like cells which efficiently identified > 85% indolent cases and was, therefore, assigned as the Indolent Dominant Module of T‐cell immune signature. In indolent BLPD patients, a strong bias towards such signatures was found to associate with clinical characteristics of worse prognosis.ConclusionOur study identified a prominent signature of T‐cell dysregulation specifically for indolent BLPDs, suggesting Th1, Tfh and Tc exhaustion‐like cells represent potential prognostic biomarkers and targets for immunotherapies.

Bilateral Sudden Sensorineural Hearing Loss in Waldenström’s Macroglobulinemia: Case Report and Review of the Literature

Abstract Objective Waldenström’s macroglobulinemia (WM) is a rare indolent B-cell lymphoproliferative disorder, representing 1 to 2% of all hematological malignancies. Involvement of the inner ear is rare with only case reports published over the past six decades. Methods The occurrence of bilateral sudden sensorineural hearing loss is exceeding rare, with limited published data in the literature. We present a case of a 62-year-old man diagnosed with WM who presented with bilateral sequential sudden sensorineural hearing loss. Results A few months following his WM diagnosis, he experienced sudden hearing loss in his left ear. He was treated with a course of oral steroids with no improvement. Three months following this incident, he experienced a similar sudden loss of hearing in his right ear. Treatment for WM was initiated. A repeat hearing test, done 1 week later, did not show any significant improvement in his right hearing. Conclusion The clinical course of WM is highly variable, with relatively infrequent involvement of lymph nodes, spleen, or liver. The inner ear is rarely involved. In this article, otologic clinical presentation is discussed, along with a review of the literature on hearing loss in WM.

Outcome of hairy cell leukemia patients treated with cladribine – a 10-year single-center experience in Pakistan

Introduction and objectiveHairy cell leukemia is an uncommon, indolent B-cell lymphoproliferative disorder. Therapy with cladribine (2-chlorodeoxyadenosine) is able to induce complete remission (CR) in the majority of patients after a single course of treatment. We report the outcomes of patients treated at Aga Khan University Hospital, Karachi, Pakistan. MethodsThis was a retrospective review. Medical records of patients were used to collect data. ResultsA total of 21 patients with hairy cell leukemia were treated with cladribine. All patients achieved an initial CR. Four patients (19%) required hospitalization and therapy for neutropenic fever. Six patients (29%) relapsed at a median of 48 months. All 6 patients were treated for relapse, out of which 4 achieved CR, 1 had partial response and 1 had refractory disease. The overall survival rate was 90.5%, with a median follow-up of 35 months. ConclusionA single course of cladribine is able to induce CR in a vast majority of patients. Unfortunately, relapse is not uncommon. Patients who relapse can be successfully retreated with cladribine. Cladribine has impressive efficacy and a favorable acute and long-term toxicity profile when administered to patients with HCL.

Monoclonal Gammopathy and Hypogammaglobulinemia As Prognostic Factors in Patients with Chronic Lymphocytic Leukemia: A Retrospective Multicentric Experience

Introduction. Chronic Lymphocytic Leukemia (CLL) is an indolent B-cell lymphoproliferative disorder. Several prognostic factors such as IGHV mutation status and chromosomal aberrations as trisomy 12, del11q, del13q or del17p have been detected so far. More recent genetic mutations such as BIRC3, SF3B1, NOTCH1 and TP53 stratifies the prognosis and outcome in CLL patients (pts). However all data above reported, because of expensive techniques and experience typical of big laboratories, are not available to all medical centers. Data concerning the prevalence of hypogammaglobulinemia, IgM or IgG monoclonal gammopathy, and the impact on natural history of CLL pts are controversial and contradictory.The aim of the study is to evaluate the prevalence and the outcome of monoclonal IgM/CLL, IgG/CLL and hypogammaglobulinemia compared with CLL pts with normal immunoglobulin (Ig) levels.Patients and methods. We collected from three different Italian centers 902 pts diagnosed with typical CLL from 1987 to 2017 with a baseline assessment of serum Ig, immunofixation, chromosomal aberrations and clinical features; evaluating their impact on time to progression (TTP), time to treatment (TTT).Results. Once assessment was made, pts included in our study who met eligibility criteria were 902. Fifty-one patients showed IgM monoclonal gammopaty (5,6%); 89 showed IgG (9,9%), 103 patients had hypogammaglobulinemia (11,4%), 659 patients (73%) showed normal gamma level.In the Padova group, the overall prevalence of monoclonal gammopathy is 15.5% of whom 35 pts (10.5%) with IgG/CLL, 17 pts (5%) with IgM/CLL, 45 pts (13.5%) with hypogamma/CLL and 238 pts (71%) with no evidence of paraprotein.Data from the Rome group showed similar results: monoclonal gammopathy is 15.4% of whom 37 pts (9%) with IgG/CLL, 26 pts (6.4%) with IgM/CLL, 42 pts (10.3%) with hypogamma/CLL and 304 pts (74.3%) with no monoclonal gammopathy revealed.In the group from Milano, the prevalence of monoclonal gammopathy is 15.7%; 17 pts (10.7%) with IgG/CLL, 8 pts (5%) with IgM/CLL, 16 pts (10%) with hypogamma/CLL and 118 pts (74.3%) with negativity at immunofixation.Median age was similar in all the groups (66years, range 26-89years) and data gathered from the 3 centers showed an overlapping rate in prevalence of monoclonal gammopathy in CLL and their related subclasses.Median TTP was 75 months (91 months for patients with normal gamma levels and 54 months for patients with abnormal gamma globulin, P<0,0001). TTP comparison among single groups of patients was showed in the table1.Median TTT was 79 months (93 months for patients with normal gamma levels and 54 months for patients with abnormal gamma globulin, P<0,0001). TTT comparison among single groups of patients was showed in the table1.Summary. Our study provided data about incidence and prognosis of monoclonal gammopaty and hypogammaglobulinemia in CLL patients. Twenty-seven percent of patients with CLL showed abnormal gammopaty; these alteration have a negative impact on TTP and TTT in these setting of patients. Finally our data also detected a particular subset of patients with IgM/CLL characterized by a worst TTP and TTT. DisclosuresVisentin:janssen: Consultancy, Honoraria. Reda:ABBVIE: Consultancy; Gilead: Consultancy; Janssen and Cilag: Consultancy; Celgene: Consultancy. Trentin:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Gilead: Research Funding; Janssen: Research Funding.

How we manage patients with Waldenström macroglobulinaemia

Waldenström macroglobulinaemia (WM) is a rare, indolent B-cell lymphoproliferative disorder characterized by cellular involvement in bone marrow and monoclonal IgM production. Symptoms can be related to cytopenias, tumoural involvement, or IgM-related disorders. Somatic mutations in the MYD88 gene have been described in the majority of WM cases. The mutation is responsible for a gain-of-function and induces activation of nuclear factor-κB, for DNA transcription and cell survival. It seems that MYD88 mutation is associated with better prognosis and better response to some treatment. Treatments are started when WM is symptomatic, following systematic biological and morphological assessments. Therapeutic choice depends on age, frailty and urgent efficacy need. In first line, the majority of patients are treated with monoclonal anti-CD20 antibody-based regimens combined with cytotoxic chemotherapy. Rituximab, cyclophosphamide and dexamethasone remain the most commonly used regimen with good safety. Nevertheless, increasing numbers of new drugs are becoming available or are in development. Proteasome inhibitors, such as bortezomib or carfilzmib, showed good and rapid responses. Bruton tyrosine kinase (BTK) inhibitor demonstrated excellent results and is now available for relapse/refractory disease or as first line for some patients. This review highlights the diagnostic procedures and therapeutic approaches in WM.

Idelalisib therapy of indolent B-cell malignancies: chronic lymphocytic leukemia and small lymphocytic or follicular lymphomas.

Chronic lymphocytic leukemia, small lymphocytic lymphoma, and follicular lymphoma are indolent B-cell lymphoproliferative disorders that mainly affect an older population. Although the majority of patients in need of treatment derive significant benefit from conventional chemotherapeutic agents as well as monoclonal antibodies, less toxic and more effective treatments are needed. Novel agents that inhibit the B-cell receptor signaling pathway have shown promising outcomes in these disorders. Idelalisib is a potent selective oral inhibitor of phosphatidylinositol 3-kinase delta and has shown significant clinical activity in B-cell malignancies. In this review, we summarize the clinical trial data using idelalisib as monotherapy or in combination with rituximab for the treatment of relapsed/refractory disease. The adverse effect profile includes autoimmune disorders such as transaminitis, colitis, and pneumonitis. Given the efficacy and manageable toxicity profile of idelalisib, it is being increasingly incorporated into the management of indolent B-cell malignancies.

Recent Advances in Diagnosis and Treatment of Hairy Cell Leukemia

Hairy cell leukemia (HCL) is a rare, indolent B-cell lymphoproliferative disorder that accounts for 2% of all cases of leukemia. Most patients present with pancytopenia and splenomegaly with variable number of ‘hairy’ lymphocytes in blood. BRAF V600E mutation can be detected in virtually 100% of HCL cases and is absent in other B-cell lymphomas. The mutated gene and its responding abnormal protein can be used as specific markers in the diagnosis of HCL. New therapeutic modalities targeting on mutated BRAF and its downstream pathways have shown encouraging results in clinical trials. The objective of this review article is to discuss the recent developments in the diagnosis and management of hairy cell leukemia.

Long term outcomes of hairy cell leukemia patients treated with first and subsequent line with purine analog: The Cleveland Clinic experience.

e18034 Background: Hairy Cell Leukemia (HCL) is an indolent B-cell lymphoproliferative disorder with high initial response rates (RR) and long remissions after treatment with purine nucleoside analogs (PNAS). At the time of relapse, re-challenge with PNAS is routinely offered but there are limited data on outcomes of this approach. To provide guidance to the management of HCL, we examined outcomes after 1stand subsequent line treatment of a large cohort of HCL pts treated at our institution. Methods: We retrospectively analyzed 61 pts ≥ 18 years old diagnosed with HCL at the Cleveland Clinic Taussig Cancer Institute from 1995 to 2013. Baseline demographics, treatment history, RR, progression-free survival (PFS) and overall survival (OS) were calculated from the start of 1st line therapy. OS and PFS were estimated using the Kaplan-Meier method and compared between groups using the log-rank test. Results: Median age was 54 years (range 31-80). 50 were male (82%). Median follow up was 72 months (3-193). 59 p...

Hairy cell leukemia - immunotargets and therapies.

Hairy cell leukemia (HCL) is an indolent low-grade B-cell lymphoproliferative disorder that is reasonably sensitive to standard first-line purine analog therapy. However, in many cases, repeat relapses occur, requiring multiple courses of purine analog therapy, promoting eventual drug resistance. This, coupled with the concerning side effects of repeated purine analog exposure, has prompted the search for alternative targets and therapies that may provide deeper remissions. Novel strategies employing immune-mediated targeting via monoclonal antibody therapies and recombinant immunotoxins appear promising in HCL and are currently under investigation. More recently, the concept of targeted kinase inhibition using small-molecule inhibitors in HCL has emerged as another potentially viable option. As a deeper understanding of the aberrant molecular pathways contributing to the pathogenesis of HCL develops, the landscape of management for HCL, particularly in the relapse setting, may change significantly in the future as a result of these promising immunotargets and therapies.