Generation of a Large Observational Pan-European Data Platform for Treatment and Outcome Patterns in Patients with Waldenstrom's Macroglobulinemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2096-2096 ◽  
Author(s):  
Christian Buske ◽  
Shalal Sadullah ◽  
Efsthatios Kastritis ◽  
Giulia Benevolo ◽  
Ramon Garcia-Sanz ◽  
...  
Keyword(s):  
Clinical Trials ◽  
United Kingdom ◽  
Czech Republic ◽  
Combination Therapy ◽  
Research Funding ◽  
Chart Review ◽  
Line Treatment ◽  
Front Line ◽  
Waldenström’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Introduction Waldenström's Macroglobulinemia (WM) is a rare indolent lymphoma with a low incidence of ~3 cases per million per year. There are few randomized trials and no well-established treatment standards in WM. Treatment landscapes for treatment-naïve and relapsed WM are heterogeneous and data on treatment choices and their outcome in patients (pts) outside clinical trials are lacking. The goal of this project was to generate data on epidemiologic/treatment patterns and efficacy outcomes for WM over a prolonged period of time (~10 yr) in a large pan-European effort. Methods In this observational chart review, physicians completed a retrospective electronic record for pts who fit the following inclusion criteria: confirmed WM, symptomatic disease at treatment initiation, front line treatment initiated between Jan 2000-Jan 2014, and availability of complete clinical/biologic evaluation at diagnosis/initial therapy. Study endpoints included initial/subsequent lines of treatment, progression-free survival (PFS), and overall survival (OS). The number of pt records per country was prespecified to balance the distribution between European countries. Results Of 454 pt records reviewed, cases were from France (n=92), United Kingdom (UK; n=72), Germany (n=66), Spain (n=60), Italy (n=56), Greece (n=25), Netherlands (n=25), Poland (n=21), Austria (n=19), and Czech Republic (n=16). Data were summarized across 5 lines of treatment for 454, 397, 160, 61, and 26 pts, respectively. Median age at initiation of front-line treatment was 65 yr (range, 29-89); 61% were male. The most common reasons for initiating treatment at diagnosis were constitutional symptoms (58%), cytopenias (72%; anemia [69%]), and IgM-related symptoms (57%). Choice of therapy varied with line of treatment; monotherapy fell from 31% in front-line to 20%/21% in 2nd/3rd-line ( Table 1). Combination therapy with antibody increased from 40% in front-line to 64%/56% in 2nd/3rd-line. Across all lines, rituximab followed by cyclophosphamide, and to a lesser extent, chlorambucil, fludarabine, vincristine, and bendamustine, were the most common agents, excluding steroids, that were used as monotherapy or in any combination with use varying between countries (Table 1). Median PFS decreased with successive lines of treatment (29 vs 23 vs 16 mo), (Figure 1) and varied by country and choice of agents (Table 1). Median OS was 123 mo, but significantly lower in pts ≥75 yr (75 mo) or with high-risk IPSSWM risk score (91 mo) and similar for pts with low/intermediate risk groups. Considerable country-specific OS differences were noted. Other malignancies were reported in 12% after diagnosis of WM. Conclusions The retrospective chart review of WM pts treated in Europe shows that constitutional symptoms and anemia are the most common reasons for initiating therapy. Rituximab was the most commonly used agent across all lines of treatment. Outside clinical trials, monotherapy is widely used even at first relapse with notable differences between countries. This large observational dataset will be an important tool to improve understanding of treatment practice and survival of WM pts in Europe outside of clinical trials, as well as unmet medical needs in the community. Table 1. Use of Monotherapy or Combination Regimens and Median PFS in Front -, 2nd -, and 3rd-Line Settings Overall and by Country Country Number of Cases, n Monotherapy, % Combination Therapy With Antibody†, % Combination Therapy Without Antibody, % Median PFS,Months (95% CI) Front line 2nd line 3rd line Front line 2nd line 3rd line Front line 2nd line 3rd line Front line 2nd line 3rd line Front line 2nd line 3rd line Overall 454 397 160 31 20 21 40 63 56 28 14 21 29.0 (25-31) 23.0 (20-26) 16.0 (10-18) France 92 86 43 62 26 16 24 66 70 14 8 14 28.5 (22-32) 30.0 (20-37) 16.0 (9-32) United Kingdom 72 64 19 18 22 21 19 55 42 63 23 37 31.5 (25-36) 20.0 (11-35) 13.0 (9-33) Germany 66 52 18 9 8 22 61 81 50 30 8 11 36.5 (29-44) 24.0 (16-29) 8.0 (3-16) Spain 60 58 21 43 28 38 38 59 52 18 12 5 18.0 (15-25) 16.0 (12-24) 11.0 (9-24) Italy 56 47 20 20 17 15 57 68 70 23 6 15 30.5 (20-39) 30.0 (18-42) 17.0 (4-21) Eastern European* 37 30 12 8 13 8 32 40 0 60 47 92 33.0 (26-38) 20.0 (16-26) 20.5 (4-38) Smaller European** 71 60 27 35 22 26 56 67 63 7 12 11 23.0 (18-29) 16.0 (13-25) 16.0 (7-26) * Includes Czech Republic and Poland **Includes Austria, Greece, and Netherlands † Antibodies other than rituximab, <1% Figure 1. Figure 1. Kaplan-Meier PFS Estimates by Line of Treatment Disclosures Buske: CELLTRION, Inc.: Consultancy, Honoraria. Sadullah:Roche: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; NAPP: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; TEVA: Consultancy; Boehringer: Other: Travel, Accommodations, Expenses. Kastritis:Janssen: Consultancy, Other: Travel, Accommodations, Expenses. Garcia-Sanz:Janssen: Honoraria, Other: Travel, Accommodations, Expenses; Takeda: Honoraria, Other: Travel, Accommodations, Expenses; Novartis: Research Funding. Leleu:Pierre Fabre: Honoraria; BMS: Honoraria; Novartis: Honoraria; TEVA: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; LeoPharma: Honoraria; Chugai: Honoraria. Willenbacher:Celgene: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; CTI: Consultancy, Other: Travel, Accommodations, Expenses. Hajek:Amgen: Honoraria; Celgene: Consultancy; Janssen: Consultancy. Cheng:Pharmacyclics LLC, an AbbVie Company: Employment. Graef:Pharmacyclics LLC, an AbbVie Company: Employment, Membership on an entity's Board of Directors or advisory committees; AbbVie: Equity Ownership. Dimopoulos:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Genesis Pharma: Research Funding.

scholarly journals A Meta-Analysis and Meta-Regression of the Efficacy of Front-Line Treatment Combinations with Ponatinib Versus 1st- and 2nd-Generation Tyrosine Kinase Inhibitors for Ph+ Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5189-5189
Author(s):  
Elias J. Jabbour ◽  
Maral DerSarkissian ◽  
Mei Sheng Duh ◽  
Nora McCormick ◽  
Wendy Y. Cheng ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Odds Ratio ◽  
Research Funding ◽  
Second Generation ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Fold Increase ◽  
Line Treatment ◽  
Front Line ◽  
First And Second Generation

Abstract Background: The current standard induction therapy for de novo Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is a tyrosine kinase inhibitor (TKI) in combination with chemotherapy or corticosteroids. Three generations of TKIs are currently available for the treatment of Ph+ ALL. Ponatinib, a third generation multi-targeted TKI, is a more potent inhibitor of BCR/ABL than previous generations. It also is effective in cases where there is a threonine-to-isoleucine substitution at position 315 (T315I mutation), which confers resistance to all first- and second-generation TKIs (i.e., imatinib, dasatinib, and nilotinib). However, evidence on the comparative effectiveness of front-line combination therapy with ponatinib relative to other TKIs in de novo Ph+ ALL has not been well-established. Aims: The purpose of this study is to evaluate the effectiveness, as measured by complete molecular response (CMR) and 2- and 3-year overall survival (OS), of front-line treatment combinations with ponatinib versus first- and second-generation TKIs in de novo Ph+ ALL. Methods: Twenty-six studies of front-line Ph+ ALL treatment with TKI in combination with chemotherapy or corticosteroids (18 studies of imatinib, 5 of dasatinib, 2 of nilotinib, and 1 of ponatinib) were identified from published targeted literature reviews and recently published trials. These consisted of 25 phase 2 through 4 trials and 1 retrospective analysis. Study arms in which patients received chemotherapy or corticosteroids only, a single TKI agent, or in which they received autologous stem cell transplant exclusively were excluded. Data on aggregated patient characteristics were extracted and summarized using the median (range). The proportions of patients achieving CMR (following induction or consolidation therapy) and 2- and 3-year OS were also extracted from all study arms and summarized by TKI group (ponatinib versus all other first and second generation TKIs) using pooled estimates with 95% confidence intervals (CIs) from a random-effects meta-analysis. A binomial distribution was assumed to calculate the 95% CIs for the ponatinib trial. Multivariate logistic meta-regressions were conducted to examine the association between each TKI treatment group and CMR rates, 2-year OS, and 3-year OS, separately, adjusting for age and gender. Results: A total of 32 TKI treatment arms were included in the analysis. The median (range) of age across trial arms was 46 years (36-69 years) and proportion of male patients was 53% (42-67%). The pooled proportion of patients achieving CMR with ponatinib was higher than that with first and second generation TKIs (79% versus 34%). The pooled 2- and 3-year OS with ponatinib were also higher than those with other TKIs (2-year: 83% versus 58%; 3-year: 79% versus 50%). Relative to other TKIs, ponatinib was associated with a statistically significant 6.09-fold increase in the odds of achieving CMR (N=25) [odds ratio=6.09 (95% CI: 1.16-31.90), p=0.034]. While ponatinib was not significantly associated with an increase in the odds of 2-year OS (N=27) [odds ratio=3.70 (95% CI: 0.93-14.73), p=0.062], it was associated with a statistically significant 4.49-fold increase in the odds of 3-year OS (N=19) [odds ratio=4.49 (95% CI: 1.00-20.13), p=0.050] compared to earlier generation TKIs. Conclusion: Frontline treatment with ponatinib in combination with chemotherapy or corticosteroids was associated with significantly better odds of CMR and 3-year OS in patients newly diagnosed with Ph+ ALL than combination therapy with earlier generations of TKIs. In particular, ponatinib was associated with a 6-fold increase in CMR, the most important factor in predicting long-term survival outcomes. The improved efficacy of ponatinib in Ph+ ALL may be particularly important for patients who are ineligible to undergo stem cell transplantation due to lack of suitably matched donors, advanced age, or significant comorbidities. In such cases, combination therapy with TKI may be a suitable alternative. Though the number of studies included was small and few covariates could be used to adjust for heterogeneity across trials, the results suggest that ponatinib in combination with chemotherapy may represent an effective front-line treatment option for patients with Ph+ ALL. Prospective head-to-head clinical trials are needed to confirm these results. Sponsor: ARIAD Pharmaceuticals, Inc. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. DerSarkissian:ARIAD: Research Funding. Duh:Allergan: Consultancy; Abbvie: Consultancy; Novartis: Research Funding; GSK: Research Funding; Bayer: Research Funding; Janssen: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Medtronic: Research Funding; Takeda: Research Funding; Novo Nordisk: Research Funding; Sanofi: Research Funding; Ariad: Research Funding. McCormick:ARIAD: Research Funding. Cheng:ARIAD: Research Funding. McGarry:ARIAD: Employment, Equity Ownership. Souroutzidis:ARIAD: Research Funding. Huang:ARIAD: Employment, Equity Ownership. Kantarjian:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding.

A Phase II Trial of the Oral mTOR Inhibitor Everolimus (RAD001) in Relapsed or Refractory Waldenstrom's Macroglobulinemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 587-587
Author(s):  
Irene M Ghobrial ◽  
Morie A Gertz ◽  
Betsy LaPlant ◽  
John Camoriano ◽  
Suzanne R. Hayman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Waldenström’S Macroglobulinemia ◽  
Advisory Committees ◽  
Overall Response ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Abstract 587 Background: The phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR) signal transduction pathway controls cell proliferation and survival. Everolimus is an oral agent targeting raptor mTOR (mTORC1). The trial's goal was to determine the anti-tumor activity and safety of single-agent everolimus in patients with relapsed/refractory Waldenstrom's macroglobulinemia (WM). Patients and Methods: Eligible patients had measurable disease (IgM monoclonal protein >1000 mg/dL with >10% marrow involvement or nodal masses >2 cm), a platelet count ≥75,000 × 106/L, a neutrophil count ≥1,000 × 106/L, and a creatinine and bilirubin ≤2x laboratory upper limit of normal. Patients received everolimus 10 mg PO daily and were evaluated monthly. Tumor response was assessed after cycles 2 and 6 and then every 3 cycles until progression. Results: 50 pts were treated. The median age was 63 years (range, 43-85). The overall response rate (CR+PR+MR) was 70% (95% CI: 55-82%), with a PR of 42% and 28% MR. The median duration of response and median progression-free survival (PFS) has not been reached. The estimated PFS at 6 and 12 months is 75% (95%CI: 64-89%) and 62% (95%CI: 48-80%), respectively. Grade 3 or higher related toxicities were observed in 56% of patients. The most common were hematological toxicities with cytopenias. Pulmonary toxicity occurred in 10% of patients. Dose reductions due to toxicity occurred in 52% of patients. Conclusions: Everolimus has high single-agent activity with an overall response rate of 70% and manageable toxicity in patients with relapsed WM, and offers a potential new therapeutic strategy for this patient group. Disclosures: Ghobrial: Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richardson:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Treon:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Genentech: Honoraria, Research Funding, Speakers Bureau. Witzig:Novartis: Research Funding.

Interleukin-17 and TH17 Pathway Supports Waldenstrom's Macroglobulinemia Cell-Growth: Potential Therapeutic Implications

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 446-446
Author(s):  
Rao H Prabhala ◽  
Dheeraj Pelluru ◽  
Mariateresa Fulciniti ◽  
Puru Nanjappa ◽  
Christine Pai ◽  
...  
Keyword(s):  
Cell Growth ◽  
Cell Population ◽  
Inflammatory Cytokines ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Research Funding ◽  
Immune Dysfunction ◽  
Waldenström’S Macroglobulinemia ◽  
Cytokines And Chemokines ◽  
Waldenström's Macroglobulinemia

Abstract Abstract 446 Waldenstrom's macroglobulinemia (WM), similar to multiple myeloma (MM), is associated with immune dysfunction. Both T and B cell dysfunctions are reported with suppressed uninvolved immunoglobulin, and inadequate vaccine and T cell responses. Although some mechanisms mediating immune dysregulation in WM have been studied, its molecular and cellular basis remains ill defined. Similarly, number of inflammatory cytokines and chemokines has been implicated in this process, but their effect on WM cell growth and immune function has not been well characterized. Recently, TH17 cells, a new CD4 cell population, has been identified by the presence of IL-17. TH17 cells play an important role in auto-immunity and in the development of anti-tumor immunity. As TH17 cells support MM cell growth and induce immune dysfunction in MM, we have evaluated the the role of TH17 cells and associated pro-inflammatory cytokines in WM. We first analyzed T helper cell subsets (TH1, TH2, and TH17) in freshly isolated PBMC from WM, and observed that all three cell types were decreased in WM compared with normal donors. Particularly, the IFN-γ producing TH1 cells from patients with WM were significantly reduced compared to normal donors (11±2% vs 30±3% respectively, P<0.01). However, unlike MM, IL-17 producing TH17 cell numbers were reduced in PBMC from WM patients (n=8) compared to PBMC from normal donors (n=8) and patients with MM (n=11), (1.5±0.5 vs 2.5±0.5% vs 4.50±0.8% respectively; p<0.05). Furthermore, when we polarized isolated naïve CD4 cells from WM patients using TH17 polarizing cocktail consisting of IL-6, IL-1β, IL-23 and TGF-β to induce TH17 cells differentiation, WM patients, unlike MM patients, showed significantly lower induction of TH17 cells in CD4 population compared to normal donor TH17 cells (0.3±0.1% WM; 11.9±2 % MM and 3.6±0.7% ND). Next, we evaluated the serum levels of cytokines and chemokines in sera from patients with WM in comparison with normal donors. The sera from WM patients showed significantly elevated levels of IL-2 (5 folds), IL-15 (2 folds) and GM-CSF (2 folds) among 19 cytokines, compared with sera from normal donors. When we evaluated TH17 cell-associated cytokines, both IL-1-beta (3 folds) and IL-17 (2 folds) were significantly elevated in sera from WM patients compared with sera from normal donors. In addition, we observed modulation of chemokines including, MCP-1, MIP-1, Eotaxin and RANTES in sera from WM patients. Finally, when we cultured WM cell-line in the presence or absence of IL-17 with or without stromal cells, we observed significant induction of WM cell proliferation by IL-17 and its inhibition by anti-IL17 antibody. These data shows that although similar to MM, there is immune dysfunction in WM, the mechanisms driving these effects especially cytokine milieu, and TH17 cell population are different between MM and WM. Disclosures: Treon: Millennium Pharmaceuticals, Genentech BiOncology, Biogen IDEC, Celgene, Novartis, Cephalon: Consultancy, Honoraria, Research Funding; Celgene Corporation: Research Funding; Novartis Corporation: Research Funding; Genentech: Consultancy, Research Funding. Munshi:Millennium Pharmaceuticals: Honoraria, Speakers Bureau.

Meta Analysis of Grade 3 and/or 4 Toxicities in Low-Grade Non-Hodgkin Lymphoma (LG-NHL) Patients Receiving Maintenance Rituximab (MR) Therapy: Impact of Schedule on Toxicity

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2704-2704
Author(s):  
Chadi Nabhan ◽  
Dana Villines ◽  
Tina V. Valdez ◽  
Michele Ghielmini ◽  
Shu-Fang Hsu Schmitz ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Research Funding ◽  
Meta Analysis ◽  
Statistical Significance ◽  
Comparative Trial ◽  
Progression Free Survival ◽  
Low Grade ◽  
Front Line ◽  
Grade 3 ◽  
The Impact

Abstract Abstract 2704 Background: MR has improved the outcome and progression-free survival (PFS) in patients with follicular lymphoma (FL) in front-line and relapsed settings. However, maintenance schedules have been empirically designed based on either B-cell depletion kinetics or rituximab levels, with no consensus on the optimal regimen. Overall, toxicities have been predictable and tolerable but the impact of MR schedule on toxicities has not been previously reported and could influence selection of maintenance regimens. Methods: Using PubMed, prospective clinical trials employing MR were identified. Data presented in abstract form or at meetings were deemed incomplete and thus excluded. Data were analyzed from published manuscripts as percentages of subjects experiencing an adverse event (AE). Percentages were considered as the unit of analysis as this adjusted for the uneven sample sizes. Data were collected for overall Grade 3 and/or Grade 4 toxicity (AE reported at any phase of treatment) and was further categorized as AE occurring during initial treatment or during MR. Grade 1 and 2 toxicities were excluded from meta-analysis, given lack of consistent reporting. No grade 5 toxicities were reported. The incidence, severity, and type of toxicity was analyzed by type of induction (Rituximab (R) vs. R plus chemotherapy), histology (FL vs. FL plus other LG-NHL), setting (front-line vs. relapsed), and MR schedule (one dose every 2 months vs. one dose every 3 months vs. 4 doses every 6 months). Results: Nine clinical trials involving 1,928 patients were included in this Meta analysis (4 of which were randomized controlled in the MR phase). Of those, 1,004 patients received MR. The mean percentage of Grade 3/4 toxicities during any phase of treatment was 26% (95% CI = 0.12–51.88) but when restricted to the MR phase; it was 12.88% (95% CI = 6.50–19.26). Toxicities were numerically higher in patients receiving R induction plus chemotherapy versus R induction alone and in patients receiving MR for relapsed disease versus newly diagnosed patients, but did not reach statistical significance (P = 0.661 and 0.517, respectively). However, patients receiving MR every 2 months were significantly more likely to develop grade 3 and 4 toxicities compared to patients receiving MR every 6 months (P = 0.005). No statistical differences were demonstrated between the 2 vs. 3 months schedules or when comparing the 3 vs. 6 months schedules (P = 0.342 and 0.267, respectively) (Table 1). Statistically significant differences were also found in studies restricted to FL versus others allowing non-FL histologies (P = 0.025) with the FL patients experiencing more toxicity than others. The most frequently reported toxicities were neutropenia and infections. There were no treatment-related deaths in any of the arms. Conclusions: Approximately 13% of patients receiving MR experience grade 3 and/or 4 toxicities, mainly consisting of neutropenia and infections. MR given every 6 months appears to provide the least grade 3 and 4 toxicities. There is a suggestion of increased toxicity in FL histologies. It is important to note that this meta-analysis did not address efficacy and only a true comparative trial can definitively establish the relative risk/benefit ratios amongst MR schedules. Disclosures: Nabhan: Genentech: Research Funding, Speakers Bureau. Ghielmini:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Smith:Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Overview on clinical trials in Waldenstrom's macroglobulinemia

2014 ◽  
Vol 4 (12) ◽  
pp. 1139-1154
Author(s):  
Alessandra Tedeschi ◽  
Anna Maria Frustaci ◽  
Paola Picardi ◽  
Enrica Morra
Keyword(s):  
Clinical Trials ◽  
Waldenström’S Macroglobulinemia ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

A Retrospective Study of 67 Inflammatory Waldenström's Macroglobulinemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-15
Author(s):  
Dikelele Elessa ◽  
Stephanie Harel ◽  
Alexis Talbot ◽  
Marion Malphettes ◽  
Catherine Thieblemont ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Biological Characteristics ◽  
Response To Treatment ◽  
Front Line ◽  
Waldenström’S Macroglobulinemia ◽  
Line Therapy ◽  
Hematological Response ◽  
Inflammatory Syndrome ◽  
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 &lt; 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.

Molecular Basis of Ibrutinib Resistance in Waldenstrom's Macroglobulinemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 756-756 ◽  
Author(s):  
Lian Xu ◽  
Nicholas Tsakmaklis ◽  
Guang Yang ◽  
Jiaji G Chen ◽  
Xia Liu ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Deep Sequencing ◽  
Molecular Basis ◽  
Research Funding ◽  
Waldenström’S Macroglobulinemia ◽  
Targeted Deep Sequencing ◽  
Pcr Assays ◽  
Waldenstrom's Macroglobulinemia ◽  
Ibrutinib Resistance ◽  
Waldenström's Macroglobulinemia

Abstract Ibrutinib is a small molecule that is approved by the U.S. FDA for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström's Macroglobulinemia (WM). In WM, mutated MYD88 supports the growth and survival of malignant lymphoplasmacytic cells (LPC) through BTK, while CXCR4WHIM mutations promote ibrutinib resistance (Yang et al, Blood 2013; Cao et al, Leukemia 2013). Ibrutinib irreversibly binds to Cys481 on BTK, and blocks its kinase activity. Despite high response rates and durable remissions in WM (Treon et al, NEJM 2015; Dimopoulos et al, ASH 2015), disease progression can occur in WM patients on active ibrutinib therapy. To investigate the molecular basis of ibrutinib resistance in WM, we first focused on BTK mutations at Cys481 that have been associated with ibrutinib resistance in CLL and MCL using Sanger sequencing and nested AS-PCR. To capture the known variants at BTK Cys481, three AS-PCR assays for Cys481SerG>C, Cys481SerT>A, and Cys481ArgT>C were developed with a sensitivity of detecting 0.1% of mutant alleles. Using these assays, we evaluated 8 WM patients who progressed on ibrutinib. Among these 8 patients, 5 had BTK Cys481 mutations: 3 were positive for Cys481SerG>C, and2 were positive for all the three (Cys481SerG>C, Cys481SerT>A, and Cys481ArgT>C) mutations. Cloning/sequencing analysis confirmed co-occurrence of multiple Cys481 mutations within individual WM patients and the presence of mutations at different alleles. Furthermore, targeted deep sequencing (>300X coverage) confirmed all BTK Cys481 mutations, and identified an additional mutation at Cys481 (Cys481TyrG>A) in both patients who were positive for Cys481SerG>C, Cys481SerT>A and Cys481ArgT>C. The estimated allele frequencies by targeted deep sequencing for individual BTK mutations ranged from 1-34%. In contrast, no BTK Cys481 mutations were identified in 100 ibrutinib naive WM patients using the nested AS-PCR assays. Among the 8 WM patients included in this study, all had activating MYD88 mutations, and 4 had CXCR4WHIM mutations. All 4 patients with CXCR4WHIM mutations had BTK Cys481 mutations. We next utilized targeted deep sequencing to expand the mutation analysis to the entire coding regions of the BTK, as well as select genes relevant to BCR and MYD88 signaling. A missense mutation in CARD11 (L878F) was identified in one patient who lacked any BTK Cys481 mutations, while a missense mutation in PLCG2 (Y495H) was found in another patient with a Cys481SerG>C mutation. The findings provide the first reported insights into the molecular mechanisms associated with ibrutinib resistance in WM, and highlight the emergence of multiple BTK mutated clones within individual patients who progress on ibrutinib. Disclosures Castillo: Biogen: Consultancy; Abbvie: Research Funding; Pharmacyclics: Honoraria; Millennium: Research Funding; Otsuka: Consultancy; Janssen: Honoraria. Palomba:Pharmacyclics: Consultancy. Furman:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Treon:Janssen: Consultancy; Pharmacyclics: Consultancy, Research Funding.

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