Outcomes with Interferon in Essential Thrombocythemia: A Systematic Review and Meta-Analysis

Introduction Essential thrombocythemia (ET) is a BCR-ABL negative myeloproliferative disorder characterized by high burden of symptoms, thrombocytosis, increased risk of thrombosis and bleeding, and risk of progression to Myelofibrosis. Interferon alpha (IFN-α) is a potent immunomodulation agent proposed to be capable of inducing complete hematological remission in patients with myeloproliferative disorders. Many INF- α have been studied for treatment of patients with ET. We present a systematic review and meta-analysis assessing the efficacy of IFN-α therapy in patients with ET. Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on PubMed, Cochrane, and Clinical trials.gov using MeSH terms and keywords for " Thrombocythemia, Essential " AND " Interferons " in April 2021. We did not place any time constraints. Our search produced a total of 825 records and duplicates were removed. After screening and removing irrelevant and review articles, we included 21 original articles reporting IFN-α as the only treatment for ET in adult patients. The data were collected for baseline characteristics of the participants and efficacy and safety of the intervention. Quality evaluation was done using the NIH quality assessment tool. The inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with 95% Confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.16-2). Results A total of 388 patients from 21 articles were evaluated. The median age of participants was 54 (35-62) years and 31% (n=64/205) were males. The type of IFN used were Interferon-alpha in 4 studies, pegylated (PEG)IFN-α-2a in 2 studies, IFN-α-2b in 6 studies, recombinant IFN-α-2C in 3 studies, recombinant IFN-y in 1 study, PEG-IFN-2b in 1 study, recombinant IFN-2b in 2 studies, and PEG-IFN in 1 study. The pooled overall hematological response (OHR) was 86.4% (95% Cl 0.67-0.98, I 2= 65%, p=0.02, n=73) with complete hematological response (CHR) of 70.6% (95% Cl 0.54-0.84, I 2=34%, p=0.21, n=65) and partial hematological response (PHR) of 13% (95% Cl 0.02-0.27, I 2=42%, p=0.16, n=65). The pooled overall molecular response (OMR) was 84% (95% Cl 0.72-0.93, I 2=13%, p=<0.01, n=81) with complete molecular response (CMR) of 64.2% (95% Cl 0.41-0.84, I 2=68%, p=<0.01, n=81) and partial molecular response (PMR) of 35% (95% Cl 0.16-0.56, I 2=33%, p=0.01, n=43). Side effects reported were nausea, allergic reactions, liver dysfunction, dose dependent mild myalgia, fever, malaise, itching, persistent fever, headache, and flu like symptoms. Conclusion Interferon alpha, in different formulations shows consistent and high activity in patients with essential thrombocythemia. It resulted in clinical responses, as well as molecular responses. Side effect profiles were consistent among different reports and were reasonable tolerated. There is a large body of evidence supporting actively and safety of this approach in a diverse ET patient population. Figure 1 Figure 1. Disclosures McGuirk: Gamida Cell: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Astelllas Pharma: Research Funding; Novartis: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Bellicum Pharmaceuticals: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; EcoR1 Capital: Consultancy; Pluristem Therapeutics: Research Funding. Yacoub: Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company.

Outcomes with Interferon in Polycythemia Vera: A Systematic Review and Meta-Analysis

Introduction Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm that presents with increase proliferation of red cells as well as variable presence of thrombocytosis & leukocytosis. Currently treatment options for PV are phlebotomy, low-dose aspirin or cytoreductive therapy. Interferon (IFN) is a biological response modifier that exerts myelosuppressive action on excessively proliferative cell lineages and is also a non-leukemogenic drug. We conducted a systematic review and meta-analysis on the efficacy of Interferon for the treatment of PV. Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on PubMed, Cochrane, and Clinical trials.gov using MeSH terms and keywords for " Polycythemia Vera " AND " Interferons ". A total of 577 records were discovered using database searching. All search results were imported into the Endnote X9.0 reference manager, and duplicates were removed. After screening and excluding review and irrelevant articles, 22 original articles reporting IFN as treatment for PV in adult patients were included. The data were collected for baseline characteristics of the participants and efficacy and safety of the intervention. Quality evaluation was done using the NIH quality assessment tool. The inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with 95% Confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.16-2). Results A total of 1123 patients were evaluated from 22 studies. The median age was 54.5 (47.5-67) years and median follow-up time was 24 (9-146) months. The median prior number of phlebotomies was 4.55 (2-18). The type of IFN used were recombinant IFN-alpha-2a in 2 studies, IFN-a2b in 5 studies, recombinant IFN-a in 6 studies, and Pegylated-recombinant IFN-α2a in 7 studies. The pooled overall hematological response (OHR) was 86% (95% Cl 0.76-0.93, I 2= 84%, p=<0.01, n=460) with pooled complete hematological response (CHR) of 63% (95% Cl 0.50-0.76, I 2=85%, p=<0.01, n=409) and pooled partial hematological response (PHR) of 22% (95% Cl 0.12-0.34, I 2=81%, p=<0.01, n=361). Pooled overall molecular response (OMR) was 64% (95% Cl 0.56-0.71, I 2=0%, p=0.6, n=190) with pooled complete molecular response (CMR) of 24% (95% Cl 0.14-0.35, I 2=75%, p=<0.01, n=276) and pooled partial molecular response (PMR) of 38% (95% Cl 0.31-0.45, I 2=0%, p=0.5, n=191). Side effects reported were nausea, allergic reactions, liver dysfunction, dose dependent mild myalgia, fever, malaise, itching, persistent fever, headache, and flu like symptoms [Table 1]. Conclusion Interferon shows promising results when used for the treatment of polycythemia vera with a durable hematologic and molecular response and has an acceptable side effects profile. However, large randomized clinical trials are needed to confirm these findings and to explore the dose and combination of interferon with other drugs.. Figure 1 Figure 1. Disclosures Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Bellicum Pharmaceuticals: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Novartis: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Fresenius Biotech: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Astelllas Pharma: Research Funding; Gamida Cell: Research Funding. Yacoub: Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company.

A Phase II Study of the Efficacy and Tolerance of Azacytidine (AZA) in Steroid Dependent/Refractory Systemic Autoimmune and Inflammatory Disorders (SAID) Associated with MDS or CMML (GFM- AZA-SAID -trial)

Background: Systemic autoimmune and inflammatory diseases (SAIDs) occur in 10-15% of MDS or CMML patients. They are often severe, difficult to treat and steroid resistant/dependent disorders. In a retrospective report of 22 patients with steroid-dependent MDS/CMML associated SAID, we observed promising results with azacytidine (AZA) on the SAID component (Fraison et al, Leuk Res, 2016). In this prospective French nationwide trial, we aimed at confirming this effect prospectively. Patients and Methods: This open-label, single-arm multicenter, phase II study included MDS/CMML patients with IPSS/CPSS int 2 or high, or lower IPSS/CPSS but with significant cytopenias, especially ESA resistant anemia (or, for CMML, proliferative features) and SAID with steroid dependence and/or resistance. The primary endpoint was response rate (RR, including CR and PR) of SAID after 6 cycles of AZA. Secondary endpoints included RRof SAID after 3 cycles of AZA, response of MDS, time to MDS progression (including to AML), overall survival (OS) and safety. AZA was used at 75 mg/m²/d x 7 days, every 4 weeks for a minimum of 6 cycles (unless overt disease progression occurred before). At the onset of AZA, prednisone (PRED) was administered at 1 mg/kg during 1 month and then decreased progressively over 6 months. Results: 30 patients were included between July 2017 and June 2020 , 29 of whom received AZA and were considered evaluable: median age 72 [range 68-78], 69% males; WHO: MDS ML (n=11; 41%), CMML (n=11, 41%), MDS-RS (n=2, 7%), EB-1 (n=1) and EB-2 (n=1), unclassified (n=3); IPSS-R : good (n=15, 54%), very good (n=3; 11%, each), intermediate (n=7; 25%) and very poor profile (n=3; 11%) (all CMML had WBC <13G/l and could be classified by IPSS-R). SAIDs features included non-infectious fever (n=5; 17%), skin lesions (n=14; 48%), joint involvement (n=18; 68%), chondritis (n=6; 21%) and peripheral nervous system impairment (n=3; 10%). 11 (38%) /28 tested patients had UBA1 mutation (VEXAS syndrome), while inin the remaining cases SAID was vasculitis (n=5), rheumatic disease (n=6), neutrophilic dermatosis (n=2) and others (n=5). 19 patients (65.5%, IC95% [45.7.82.1]) obtained a SAID response after 6 cycles (including 8 CR and 11 PR), while 17 (58.6% (IC95% [38.9; 76.5]) patients achieved an IWG 2006 hematological response (7 CR, 9 SD with HI and 1 marrow CR). All the 13 patients who received 12 cycles of AZA achieved SAID CR or PR at 12 months, and 10 of them had a hematological response (6 CR, 1PR, 2 HI, 1 marrow CR). The SAID response rate at 12 month was at 72.4% (IC95% : [51.3;85.6]). SAIDs complete/partial response occurred in 3/9 (33%) UBAI-positive versus 8/19 (42%) non-mutated cases. No significant prognostic factor of SAID response after 6 cycles, including sex, age, WHO classification, IPSS-R, UBA1 and TET-2 mutation status was found. With a median follow-up of 18.5 months [11.8; 24.3], 9 (31%) patients had died, with a 1-year OS of 82.3% (IC95% [69.4; 97.7]. At least one SAE occurred in 23 patients, with a median of 2 events/patient [1.5; 5.5]. Death was due to infection (n=5, two of them in patients with good IPSS-R, but severe steroid dependent SAID), MDS progression (n=2), or unrelated causes (n=2). Conclusion We confirmed prospectively an effect of AZA on the autoimmune/inflammatory component in two thirds of MDS/CMML patients with steroid dependent / refractory concomitant systemic autoimmune/inflammatory disease. No significant difference in AZA response was noted between UBA1 mutated and unmutated MDS patients. The adverse events and mortality rates, often from infectious origin, appear to be those expected in such an MDS population, potentially worsened by the associated SAID and background of immunosuppressive treatment (especially steroids) Disclosures Terriou: Alexion, AstraZeneca Rare Disease: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Ades: ABBVIE: Honoraria; TAKEDA: Honoraria; CELGENE/BMS: Honoraria; NOVARTIS: Honoraria; JAZZ: Honoraria, Research Funding; CELGENE: Research Funding. Fenaux: Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria.

Prognostic Relevance of Cytogenetic Chromosomal Abnormalities on Outcome Among AL Amyloidosis Patients in the Netherlands

Introduction Systemic light chain (AL) amyloidosis is a clonal plasma cell neoplasm, that carries a poor prognosis. Treatment is adapted from protocols as used in MM, and include bortezomib-based (PI) regimens with or without stem cell transplantation (SCT). PI-based regimens have improved treatment responses and outcomes. Cytogenetic analysis has become an important tool in the diagnostic process of plasma cell disorders, and evidence for prognostic significance of specific genetic abnormalities in relation to therapy efficacy is recognized in systemic AL amyloidosis. Thus far, this prognostic significance has been evaluated in single center institutions. Aim This nationwide, population-based study aimed to assess the impact of cytogenetic abnormalities on hematological response and survival among patients with systemic AL amyloidosis treated with PI-based regimens. Methods We identified 349 patients ≥18 years with systemic AL amyloidosis diagnosed between 2017 and 2019 in the Netherlands Cancer Registry, with survival follow-up until February 1, 2021. Data on therapeutic strategy was known for all individual patients. The cytogenetic aberrations studied include gain(1q), hyperdiploidy, del(17p), and IGH rearrangements, i.e. t(11;14), t(4;14), t(14;16), and t(v;14q32) (non-specified IGH rearrangement). Hematological response and overall survival (OS) were evaluated in relation to cytogenetic aberrations. OS was defined as death by any cause post-diagnosis. Uni- and multivariable analysis for establishing independent predictors of OS, i.e. age, sex, cytogenetic assessment and SCT, was performed using Cox regression. Patients diagnosed at autopsy (n=4), patients who did not start first-line therapy (n=64) or received other therapies (n=37), and patients with systemic AL amyloidosis related to Waldenström Macroglobulinemia (n=10) were excluded. Results In our analytic cohort, 234 patients (median age 67 years; 62% males) were treated with PI-based regimens. Of these patients, 153 (65%) were ≤70 years at diagnosis. SCT was performed in 70 (30%) patients following PI-based regimens. For 170 (73%) patients, cytogenetic assessment was performed. IGH rearrangements were observed in 76 patients (45%), comprised of t(11;14) in 27 patients, t(4;14) in 3 patients, t(14;16) in 2 patients and non-specified IGH rearrangements in 44 patients. Furthermore, 26 patients carried a gain(1q), 4 patients a del(17p), and 33 patients were hyperdiploid. Due to the limited patient number with del(17p), response and OS was not evaluated for this subgroup. A complete remission (CR; n=53), very good partial response (VGPR; n=66), or partial remission (PR; n=55) was accomplished for 74% of the patients, ≥VGPR for 51% of the patients. The reached hematological response was irrespective of the detected cytogenetic abnormalities. In detail, ≥VGPR was 56% for patients with a t(11;14), 62% for patients with a gain(1q), 55% for patients with hyperdiploidy, and 50% for patients with an IGH rearrangement and this was not statistical significant different from patients without these cytogenetic abnormalities. The 3-year OS was 61% for patients treated with PI-based regimens. For patients with a cytogenetic assessment (n=170), there was no significant difference in 3-year OS between patients with or without a t(11;14) (69% vs. 66%, respectively; p=0.70), with or without gain(1q) (57% vs. 68%, respectively; p=0.58), with or without hyperdiploidy (72% vs. 65%, respectively; p=0.63), or with or without an IGH rearrangement (59% vs. 72%; p=0.21). Only SCT was an independent predictor for reduced risk of mortality in uni- and multivariable analyses, overall as well as for the specific cytogenetic subgroups. Conclusion In this Dutch 'real world' population of AL amyloidosis patients treated with PI-based regimens, 74% had a ≥PR and 51% had ≥VGPR. The 3-year OS was 61%. We evaluated the cytogenetic data of 170 patients, but could not confirm a relation between PI-based regimens and outcome, overall as well as in specific cytogenetic subgroups. Patient numbers of the cytogenetic subgroups were low and we could not determine the partner gene in 44 patients with an IGH rearrangement. To the best of our knowledge, this is the first population-based study to evaluate the prognostic relevance of cytogenetic abnormalities in relation to hematological response and OS among systemic AL amyloidosis patients. Disclosures Minnema: Alnylam: Consultancy; Kite/Gilead: Consultancy; Jansen-Cilag: Consultancy; BMS: Honoraria; Celgene: Other: Hospitality.

Case Report: Lenalidomide as a Second-Line Treatment for Bortezomib-Ineffective Nephrotic Syndrome Caused by LCDD: 2 Case Reports and a Literature Review

Background: Light-chain deposition disease (LCDD) is a rare systemic disorder characterized by the deposition of monoclonal light chains in organs. The kidney is a prominent target of light-chain deposition, with a median time to end-stage renal disease (ESRD) of 2.7 years and 5-year ESRD-free survival of 37%. The therapeutic management of LCDD remains ill-defined. In addition to bortezomib-based therapy as first-line therapy, the effect of lenalidomide on LCDD is rarely reported.Case Presentation: This study describes two male LCDD patients in their 60s with nephrotic syndrome and moderately impaired renal function. One patient had monoclonal IgGλ with underlying MGRS, and another had monoclonal IgGκ with underlying monoclonal gammopathy that developed into symptomatic MM during follow-up. The hallmarks of this disease were consistent with previous reports. Both patients initially received BCD therapy, but no hematological response was observed. Consequently, the nephrotic syndrome was refractory. Sequential Rd therapy was initiated, and partial hematological response and nephrotic remission were observed in the IgGλ patient but absent in the IgGκ patient.Conclusion: Limited reports have demonstrated the effect of lenalidomide in LCDD. We report the outcome of lenalidomide in two cases of bortezomib-resistant LCDD. This treatment might be a beneficial supplement for those unresponsive or intolerant to bortezomib in LCDD, but the effect should be prospectively investigated.

Clinicopathological characteristics and long-term prognosis of monoclonal immunoglobulin light chain associated Fanconi syndrome

Background and aims: Monoclonal immunoglobulin light chain associated Fanconi syndrome (LC-FS) is a rare disease that involves proximal tubules. As most of the reported cases came from western countries, we aimed to analyze the clinicopathological characteristics of Asian LC-FS and its treatment responses to chemotherapy. Methods: A total of 26 LC-FS patients in a single-center were retrospectively studied. Results: At diagnosis, the mean age of the 26 Asian LC-FS patients was 54.7 ± 14.7 years, with females accounting for 57.7%. They presented with different degrees of proximal tubular dysfunctions with normoglycemic glycosuria (88.0%), hyperphosphaturia (84.2%) and aminoaciduria (84.0%) as the most common features. The mean estimated glomerular filtration rate (eGFR) was (68.0 ± 26.4) ml/min per 1.73 m2. After chemotherapy, renal response was achieved in 58.3% cases, which was accompanied by hematological response, and tubular response was acquired in 66.7% cases. During 3 years of follow-up, the eGFR levels significantly decreased in the monoclonal gammopathy of renal significance patients, few of whom (21.4%) had received chemotherapy. Conclusion: Asian LC-FS patients had mild renal function disorder. The chemotherapy could improve both renal and tubular functions, which may be related to the hematological response.

A Retrospective Study of 67 Inflammatory Waldenström's Macroglobulinemia

Introduction Waldenström's macroglobulinemia (WM) is an indolent lymphoma with medullary infiltration by a lymphoplasmacytic clone associated with an immunoglobulin M paraprotein. Some patients diagnosed with WM present a concomitant inflammatory syndrome: increased C-reactive protein (CRP) levels, fever, recurrent night sweats, anorexia. These patients were usually referred as inflammatory WM despite no definition has been established. Here, we describe clinical and biological characteristics of inflammatory WM patients, response to treatment, survival and discuss pathogenesis hypotheses. Methods In this descriptive retrospective study, we included WM patients followed at Saint-Louis hospital between 2007 and 2019 with WM diagnosis fulfilling the World Health Organization's criteria, with medullary infiltration proven by bone marrow biopsy or aspiration examination and monoclonal M paraprotein, associated with a biological inflammatory syndrome with or without clinical inflammatory signs. Inflammatory WM diagnosis was retained in the absence of differential diagnoses for the inflammatory syndrome such as cancer, infection, autoimmune or inflammatory diseases, using complete blood workup, PET and body scanner. Results Two-hundred and forty-two patients were included: 67 of inflammatory phenotype (28%), 166 non-inflammatory (68%) and 9 with inflammatory syndrome of unknown origin (4%). Describing inflammatory WM, diagnoses were made between 1985 and 2018, 50% after 2007. At treatment initiation, median age was 69 years (range 45-94), monoclonal IgM median value was 24.9 g/L (4.8-77.3) (Table 1). Median CRP was 40.5mg/L (IQR 23.8-64.8). CRP was correlated with fibrinogen (r =0.53, 95% confidence interval (CI) 0.18-0.76, p=0.006) and inversely correlated with albuminemia (r=-0.65, CI -0.82- -0.39, p < 0.001). Mean medullary infiltration was 50%. Three of 35 patients with avalaible karyotype had 6q deletion. Only 12 patients had medullary molecular analysis: 9 of them harboured MyD88 L265P mutation, 2 p53 mutations and none CXCR4 WHIM mutation. Five cryoglobulin tests were positive, Coombs test positive for 3 patients and anti-MAG antibodies positive for 2. Indications for front-line therapy were cytopenias in 44 patients (88%), inflammatory syndrome for 20 (40%), systemic symptoms in 15 (30%), tumoral syndrome in 10 (20%) and hyperviscosity syndrome in 3 (6%). Sixty-two patients were treated, at front-line 60% received rituximab-based therapy and 39% monotherapy. Overall response rate was 84%. Inflammatory and hematological response were statistically correlated (OR 13.8, CI 2.07-74.6, p = 0.005). Median follow-up was 12.6 years (IQR 7.0-22.8). Median progression-free survival (PFS) after front-line therapy was 32 months and estimated PFS was 68% (CI 55-78) at 10 months, 59% (CI 46-70) at 20 months and 30% (CI 19-42) at 5 years. Overall survival (OS) for inflammatory and non-inflammatory WM patients were not significantly different (median OS 14.0 and 16.4 years, respectively, c2 0,14, p=0,71, Figure 1). At 5 years, estimated OS was 85% (CI 71-93) inflammatory patients and 84% (CI 75-90) for non-inflammatory, at 10 years 66% (CI 48-79) and 70% (CI 58-79). Three patients were secondarily diagnosed with diffuse large B-cell lymphoma (DLBCL). Conclusions We reported 67 WM patients with inflammatory phenotypes, representing a third of WM patients in our cohort. Compared with literature, their clinical and biological characteristics do not differ from non-inflammatory WM patients, as well as response to treatment and PFS. There is no excess of transformation into DLBCL. Our inflammatory and non-inflammatory cohorts show no difference in terms of OS. Inflammatory response is strongly correlated with hematological response. Non-decrease of CRP level during treatment and increase of CRP during follow-up in inflammatory WM patients should be a warning sign for refractory disease or relapse. Further studies are needed to better delineate this sub-group of patients and explore its pathogenesis. Studying medullary cytokinic environment, WM cells, tumoral microenvironment and M paraprotein contributions could elucidate the underlying pathophysiological mechanisms involved. Disclosures Thieblemont: Roche, Hospita: Research Funding; Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Cellectis: Speakers Bureau.