Phase II Trial of Weekly Bortezomib in Combination with Rituximab in Untreated Patients with Waldenstrom's Macroglobulinemia.

Abstract Abstract 3752 Poster Board III-688 INTRODUCTION This study aimed to determine activity and safety of weekly bortezomib and rituximab in patients with untreated Waldenstrom's Macroglobulinemia (WM). Prior studies using twice a week bortezomib in this population showed high responses, but significant neuropathy. METHODS Patients who had symptomatic WM and were not previously treated were eligible. All patients received bortezomib IV weekly at 1.6 mg/m2 on days 1, 8, 15, q 28 days x 6 cycles, and rituximab 375 mg/m2 weekly on cycles 1 and 4. Dexamethasone was not added. Primary endpoint was the percent of patients with at least a minor response. Patients were encouraged to receive herpes zoster prophylaxis but it was not mandated. RESULTS Twenty-six patients were treated. At least minimal response or better was observed, assessed using serum protein electropheresis, in 24/26 cases (92%) with 2 patients (8%) in complete remission (CR)/near CR, 15 (54%) in partial response (PR), and 7(27%) in minimal response (MR). Two patients (8%) had stable disease. By using IgM by nephlometry, all 26 patients (100%) had at least a minor response, with 2 (8%) CR, 15 (58%) in PR and 9 (35%) with minor response. The median time of follow up is 11.2 months (range, 3-18.6). To date, six (23%) patients have developed progressive disease or required a new therapy. A single patient has died due to disease progression. The median progression-free survival and overall survival have not been reached. The most common grade 3 and 4 therapy related adverse events included anemia in 3 patients, lymphopenia in 2 patients; neutropenia, leucopenia, thrombocytopenia, pneumonia, fatigue, allergic reaction and nausea and vomiting in 1 patient for each. Five patients developed grade 2 peripheral neuropathy including 4 did who did not have neuropathy at baseline. It required dose reductions in cycles 4 and 5 and these neuropathies resolved to grade 1 or less with follow up. One case developed grade 1 herpes zoster reactivation in cycle 1. CONCLUSIONS The combination of weekly bortezomib and rituximab showed significant activity and minimal neurological toxicity in patients with untreated WM. Disclosures: Ghobrial: Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Anderson:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Richardson:Keryx Biopharmaceuticals: Honoraria. Treon:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Genentech: Honoraria, Research Funding, Speakers Bureau. Matous:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees.

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Phase II Trial of Weekly Bortezomib in Combination with Rituximab in Relapsed or Relapsed/Refractory Waldenstrom's Macroglobulinemia.

Blood ◽

10.1182/blood.v114.22.2727.2727 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2727-2727

Author(s):

Irene M. Ghobrial ◽

Fangxin Hong ◽

Swaminathan Padmanabhan ◽

Ashraf Z. Badros ◽

Meghan Rourke ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Significant Activity ◽

Waldenström’S Macroglobulinemia ◽

Advisory Committees ◽

Minor Response ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Grade 3 ◽

Waldenström's Macroglobulinemia

Abstract Abstract 2727 Poster Board II-703 INTRODUCTION: This study aimed to determine activity and safety of weekly bortezomib and rituximab in patients with relapsed/refractory Waldenstrom's Macroglobulinemia (WM). METHODS: Patients who had at least one previous therapy were eligible. All patients received bortezomib IV weekly at 1.6 mg/m2 on days 1, 8, 15, q 28 days x 6 cycles, and rituximab 375 mg/m2 weekly on cycles 1 and 4. Primary endpoint was the percent of patients with at least a minor response. RESULTS: Thirty-seven patients were treated. Majority of patients (78%) completed treatment per protocol. At least minimal response (MR) or better was observed in 81% (95% CI: [65,92]) with 2 patients (5%) in complete remission (CR)/near CR, 17 (46%) in partial response (PR), and 11(30%) in MR. The median time to progression was 16.4 months (95% CI, 11.4–21.1). Death occurred in 1 patient due to viral pneumonia. The most common grade 3 and 4 therapy related adverse events included reversible neutropenia in 16%, anemia in 11%, and thrombocytopenia in 14%. Grade-3 peripheral neuropathy occurred in only 2 patients (5%). The median event-free survival (EFS) is 12 months (95% CI, 11–20) with estimated 12 month and 18 month EFS of 49% (95% CI: [31, 67%]) and 38% (95% CI: [20, 56%]). The median overall survival has not been reached. CONCLUSIONS: The combination of weekly bortezomib and rituximab showed significant activity and minimal neurological toxicity in patients with relapsed WM. Disclosures: Ghobrial: Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Anderson:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. 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. Matous:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽

10.1182/blood.v114.22.587.587 ◽

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.

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Enzastaurin in Previously Treated Waldenstrom's Macroglobulinemia: An Open-Label, Multicenter, Phase II Study.

Blood ◽

10.1182/blood.v114.22.3867.3867 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3867-3867

Author(s):

Irene M Ghobrial ◽

Jean-Luc Harousseau ◽

Steven P Treon ◽

Brianna Harris ◽

Courtney E Lin ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Waldenström’S Macroglobulinemia ◽

Two Stage ◽

Advisory Committees ◽

Minor Response ◽

Previously Treated ◽

Grade 3 ◽

A Minor ◽

Waldenström's Macroglobulinemia

Abstract Abstract 3867 Poster Board III-803 Background Enzastaurin is an oral serine/threonine kinase inhibitor that targets the PKC and PI3K/AKT pathways. Enzastaurin has demonstrated activity in preclinical models of multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM), and clinical studies suggest encouraging activity and a well-tolerated safety profile in a variety of hematologic cancers. We are conducting a multicenter, two (parallel) cohort, two-stage, phase II trial to determine whether further study of single-agent enzastaurin is warranted in patients with previously treated WM or MM. The primary objective is to assess the response rate (RR); secondary objectives include assessment of time to progression (TTP), safety, biomarkers, and the impact of adding dexamethasone to enzastaurin in patients with progressive disease (PD). Preliminary results for the WM cohort are reported here. Methods Eligible patients with WM and 1-5 prior therapies were enrolled and treated with 250 mg oral enzastaurin twice daily (1125-mg loading dose on day 1) in 28-day cycles. Patients continued for 8 cycles or until PD or unacceptable toxicity occurred. At the investigator's discretion, dexamethasone (20-40 mg po QD, days 1-4, 9-12, and 17-20 for 4 cycles; days 1-4 of each cycle thereafter) was added to enzastaurin in patients with PD. According to the Simon two-stage design, if 2 of the first 10 patients (in stage 1) experienced a minor response (MR) or better, then the study would be expanded to 29 patients (stage 2). Best response was determined according to the response assessment recommendations of the Third International Workshop on WM (IWWM). Adverse events were graded according to CTCAE version 3.0. Results Twenty-nine patients (7 females, 22 males) with WM were enrolled. The median age was 65.6 years (range: 51.7-82.3 years) and 93% of patients had an Eastern Cooperative Oncology Group performance status of 0. Patients had a median of 2 prior systemic therapies and 26 patients (89.7%) had prior rituximab. Patients completed a median of 4 cycles. Six patients received ≥6 cycles of enzastaurin treatment. Twenty patients remain on study. There were no drug-related discontinuations. None of the patients had a complete response (CR). One patient had a partial response (PR) and 7 patients had a minor response (MR), for a RR (CR+PR+MR) of 27.6%. Immunoglobulin M decreased by ≥25% in 11 patients. Three (10.3%) patients had a PD. One patient had a drug-related grade 3 wound complication; there were no other drug-related grade ≥3 toxicities. One patient died on study due to infection unrelated to enzastaurin. Conclusions Although the results are preliminary, enzastaurin appears to have activity and is well tolerated in patients with previously treated WM. The WM cohort was expanded to allow up to 50 patients to be treated on study. Disclosures: Ghobrial: Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Research Funding, Speakers Bureau. Lin:Eli Lilly and Company: Employment. Yuan:Eli Lilly and Company: Employment. Benhadji:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Leblond:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria.

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Long-lasting responses after four doses of rituximab in Waldenström's macroglobulinemia: Clinical value of minor responses: A follow-up of the Eastern Cooperative Oncology Group E3A98 trial

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.8513 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 8513-8513

Author(s):

M. A. Gertz ◽

R. Abonour ◽

L. T. Heffner ◽

P. R. Greipp ◽

H. Uno ◽

...

Keyword(s):

Objective Response ◽

Progression Free Survival ◽

Waldenström’S Macroglobulinemia ◽

Minor Response ◽

Free Survival ◽

Previously Treated ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

A Minor ◽

Waldenström's Macroglobulinemia

8513 Background: Waldenström's macroglobulinemia is a low-grade lymphoplasmacytic lymphoma that is responsive to rituximab. Uniform response criteria define an objective response as a 50% reduction in the IgM level, and a minor response as a 25% reduction in IgM level. No publications in the literature exist that justify the use of the minor response. Clinicians who treat patients that achieve a minor response are left uncertain as to whether the response is adequate and patients should be monitored for progression or whether they should be considered therapy failures and crossover to an alternate chemotherapy regimen in an effort to achieve a deeper response. Methods: 69 patients, 34 previously untreated, and 35 previously treated (but rituximab naive) were included. All patients were treated with a single four-week course of rituximab 375 mg/m2 and were monitored with no further therapy until progression. Results: There were 19 objective and 17 minor responses out of 69 eligible patients (52.2%). Response rate and progression-free survival (26.6 mo) were similar whether patients were previously untreated or previously treated. Previously treated rituximab-naïve and previously untreated patients had, five-year survivals of 48% and 85%, respectively. There was no difference in overall or progression free survival between patients who achieved an objective response when compared to those who achieved a minor response. There was no difference between objective and minor responders by age, time from diagnosis to treatment in the treated group, bone marrow lymphoplasmacytes, hemoglobin level, creatinine, IgM level, or M-spike. The pre-treatment level of IgM did not predict overall survival, progression-free survival, time to progression, or response rate (All p>0.05). This lack of significance was found whether IgM was assessed as a continuous or discrete variable. Conclusions: These results reconfirm rituximab's efficacy as a single-agent for the treatment of Waldenström's macroglobulinemia, and patients who have a 25–50% reduction in their IgM protein derive significant clinical benefits that are durable and appear to not have an impact on overall survival. No significant financial relationships to disclose.

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Azacitidine (AZA) for Patients with Vexas and Myelodysplastic Syndrome (MDS): Data from the French Vexas Registry

Blood ◽

10.1182/blood-2021-152363 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3689-3689

Author(s):

Thibault Comont ◽

Maël Heiblig ◽

Jeremie Dion ◽

Etienne Riviere ◽

Louis Terriou ◽

...

Keyword(s):

Board Of Directors ◽

Dose Reduction ◽

Median Time ◽

Research Funding ◽

Autoinflammatory Disease ◽

Advisory Committees ◽

Minor Response ◽

Nationwide Registry ◽

Major Response

Abstract Background MDS are associated in 10% to 25% of the cases with systemic inflammatory or auto-immune diseases (SIAD). The management of SIADs in this context includes glucocorticoids and biologics with variable response rates, but we and others found that hypomethylating agents, especially azacytidine (AZA), can have some efficacy in SIADs associated with lower risk MDS (Fraison, J.-B. et al. Leuk. Res. 43, 13-17 (2016).). The recently described VEXAS syndrome (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome) (Beck et al, NEJM 2020) an autoinflammatory disease characterized by somatic mutation of the UBA1 gene, is often associated with hematological disorders, especially MDS, and its treatment is often unsuccessful Based on a French nationwide registry of patients with VEXAS syndrome, we described the efficacy and safety of AZA in VEXAS syndrome patients with concomitant MDS. Patients A French nationwide registry of 116 patients with VEXAS syndrome was established in Jan 2021. We collected in this registry patient cases with concomitant MDS (according to WHO 2016) who received at least 1 full cycle of AZA (5 to 7 days). Major response of autoinflammatory disease to AZA was defined by at least 50% steroids dose reduction to less than 10 mg/day during at least one month, and minor response by at least 50% steroid dose reduction but to > 10 mg/day, during at least one month. Results Of the 58 patients with concomitant MDS included in the French VEXAS registry, 11 had received at least 1 cycle of AZA. All patients were males and median age was 64 (range 54-73), WHO : MDS MLD (n=6) , MDS SLD (n=1), MDS EB1 (n=4) ) ,R-IPSS low (n=7), intermediate (n=3) high (n=1). Median time from MDS diagnosis to AZA onset was 8 (range 0-88) months. VEXAS phenotype mostly included skin lesions (100%), fever (91%) and constitutional symptoms (91%). All patients, except one, were steroid dependent at AZA onset. In addition to steroids, patients had received a median of 1 immunosuppressive treatment (IST) (range 0-6). The median number of AZA cycles was 11 (range 2-35). Median follow up from AZA onset was 32 months (range 12-75). Five (46%) patients discontinued AZA before the end of follow-up, after 2 to 10 cycles due to failure (n=4) and persistent response after 6 cycles (n=1). Response of autoinflammatory disease to AZA was achieved in 5 patients (45%) including major response in 2 patients, and minor response in 3, while 6 patients had no response. Best response was observed after 4 cycles (n=4) and after 6 cycles (n=1). In responders, prednisone could be discontinued in 1 patient. Duration of response was 6, 8+, 12, 21, 27+ months (Median 16.5). Three of the 5 responders subsequently received another IST. Of 10 anemic and 5 thrombocytopenic patients,3 obtained erythroid and 2 obtained platelet response, respectively (IWG 2006 criteria). Two patients experienced serious adverse events during AZA treatment, including pneumocystis pneumonia (n=1), severe colitis and bacterial pneumonia (n=1). Conclusions Our results, in a limited patient number, suggest that AZA can improve auto inflammatory symptoms in 45% of patients with VEXAS syndrome and underlying MDS, allowing decrease or even discontinuation of steroids, during a median time > 1 year, with concomitant hematological response in about 50% of the cases and limited side effects. A prospective study with more patients will be needed to confirm those results. Disclosures Comont: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau. Riviere: Octapharma: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Terriou: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Terrier: LFB: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees. Georgin-Lavialle: Novartis: Membership on an entity's Board of Directors or advisory committees; Soby: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Fenaux: Syros Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding.

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Global Waldenström's Macroglobulinemia Patient-Derived Data Registry, Whimsical, Highlights Real-World Treatment Outcomes and COVID-19 Data

Blood ◽

10.1182/blood-2021-147720 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1343-1343

Author(s):

Ibrahim Tohidi-Esfahani ◽

Andrew Warden ◽

Elena Malunis ◽

Peter Liburdi deNardis ◽

Michelle Postek ◽

...

Keyword(s):

Real World ◽

Research Funding ◽

Waldenström’S Macroglobulinemia ◽

First Line ◽

Advisory Committees ◽

Eortc Qlq C30 ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Eortc Qlq ◽

Waldenström's Macroglobulinemia

Abstract Introduction: WhiMSICAL (Waldenström's Macroglobulinemia Study Involving CArt-wheeL) is the first global Waldenström's Macroglobulinemia (WM) registry capturing patient-derived data to complement scarce clinical trials data in this rare cancer (Tohidi-Esfahani et al, Am J Hematol 2021). The registry was interrogated to identify real-world first line treatment outcomes, quality of life (QoL) and coronavirus disease 2019 (COVID-19) data. Methods: The registry captures data through www.cart-wheel.org, an online rare cancer database, utilizing a tailored questionnaire developed by clinician and patient investigators. WM patients complete consent online, then enter symptom, pathology, treatment, QoL (EORTC QLQ-C30) and COVID-19 data, and can return to update their data on an ongoing basis. Recruitment is driven by social media messaging by the International Waldenström's Macroglobulinemia Foundation investigators. Time to next treatment (TTNT) was assessed from start of first therapy to start of second therapy. Patients without a documented second therapy were censored at the time of last edit to their account. COVID-19 questions included testing, disease severity, vaccination and impact on WM management. Results: As of July 2021, 558 patients from 20 countries have participated in the registry, predominantly from USA (50%), Australia (22%) and the UK (9%). Median age at diagnosis was 61 years (range 24-83) with male predominance (61%). 371 patients documented first-line therapies, with a total of 54 unique therapeutic combinations listed. The seven most common therapies were: bendamustine rituximab (BR, n=94), rituximab monotherapy (Rit., n=52), dexamethasone rituximab cyclophosphamide (DRC, n=33), ibrutinib (n=25), bortezomib dexamethasone rituximab (n=15), rituximab cyclophosphamide vincristine prednisolone (n=14) and chlorambucil (n=10). Comparison of TTNT was limited to the four most common first-line therapies: BR, Rit., DRC, with zanubrutinib (n=5) and ibrutinib plus rituximab (n=2) adding to the first line Bruton tyrosine Kinase inhibitor (BTKi) cohort (n=32). Median ages for the BR, BTKi, DRC and Rit. cohorts were 65, 66, 61 & 65 years, respectively. More patients in the BR cohort listed comorbidities (37%), with BTKi-treated patients reporting the least (19%). Pre-treatment disease burden (median IgM and hemoglobin) trended to being higher in the BR and DRC cohorts (figure 1B-D, IgM p=0.24, Hb p=0.27). At median follow up ranging from 31 to 39 months, BR had superior TTNT to DRC (median: not reached and 104 months, p=0.007, figure 1C) and Rit. (median 26 months, p < 0.0001, figure 1D), and trended to superiority compared to BTKi (median not reached, p=0.08, figure 1B). Median TTNT for the entire cohort (n=371) was 108 months (median follow up 55 months, figure 1A). Assessment of QoL was conducted in all patients (any line of treatment) and compared between patients currently on BTKi therapy (n=64) and patients not exposed to BTKi and treated within the last 12 months (n=84). The expanded BTKi cohort reported better QoL, with mean EORTC QLQ-C30 global scale of 82 ± 14.4 compared to the BTKi-naïve cohort mean 73.4 ± 20.9, p=0.005. This was despite more prior lines of treatment (median 2 [IQR 1-4] compared to 1 [IQR 1-1]; p<0.0001). 324 (58%) patients responded to the COVID-19 questions. 144/324 (44%) had undergone testing for COVID-19, with 11 (8%) returning a positive result; none after vaccination. Median length of symptoms was seven days (range 2-30), with two hospitalized, one requiring intensive care. Both hospitalized patients were on second line ibrutinib. Of 211 responses regarding vaccination status, 15 (7%) were not vaccinated, eight due to availability, five due to personal choice and two due to clinician advice. Regarding impact of the pandemic on their WM management, 5% had treatment schedule disruption and 53% reported reduced face-to-face consultations. Conclusion: The WhiMSICAL registry provides a scientifically robust and ethically approved portal for the patients' voice. The data highlight the real-world efficacy of combination chemoimmunotherapy, particularly first-line BR, and suggest a better QoL with BTKi than other therapies. As this global data platform grows, the breadth of data allows for new insights into WM with patient reported outcomes advancing knowledge and facilitating treatment decisions for clinicians and patients. Figure 1 Figure 1. Disclosures D'Sa: Sanofi: Honoraria; BeiGene: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding. Kersten: Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support; Novartis: Consultancy, Honoraria, Other: Travel support; BMS/Celgene: Consultancy, Honoraria; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Research Funding. Thomas: Acerta Pharma: Research Funding; Ascentage Pharma: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; X4 Pharma: Research Funding; Genentech: Research Funding. Palomba: Ceramedix: Honoraria; Rheos: Honoraria; Nektar: Honoraria; Priothera: Honoraria; Lygenesis: Honoraria; WindMIL: Honoraria; Wolters Kluwer: Patents & Royalties; Juno: Patents & Royalties; BeiGene: Consultancy; Kite: Consultancy; Magenta: Honoraria; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; PCYC: Consultancy; Notch: Honoraria, Other: Stock; Novartis: Consultancy; Pluto: Honoraria. Olszewski: Acrotech Pharma: Research Funding; Celldex Therapeutics: Research Funding; TG Therapeutics: Research Funding; PrecisionBio: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding. Trotman: PCYC: Research Funding; roche: Research Funding; BMS: Research Funding; TAKEDA: Research Funding; JANSSEN: Research Funding; beigene: Research Funding.

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International Phase III Study of Chlorambucil Versus Fludarabine As Initial Therapy for Waldenstrom's Macroglobulinemia and Related Disorders: Results in 414 Patients on Behalf of FCG CLL/ WM, GOELAMS, GELA, NCRI, ALLG

Blood ◽

10.1182/blood.v118.21.776.776 ◽

2011 ◽

Vol 118 (21) ◽

pp. 776-776 ◽

Cited By ~ 1

Author(s):

Veronique Leblond ◽

Julie Lejeune ◽

Olivier Tournilhac ◽

Pierre Morel ◽

marie Sarah Dilhuydy ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Second Malignancies ◽

Waldenström’S Macroglobulinemia ◽

Advisory Committees ◽

Free Survival ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Waldenström's Macroglobulinemia ◽

Grade Iii

Abstract Abstract 776 Background: Waldenstrom's macroglobulinemia (WM) and related-disorders (Marginal Zone Lymphoma: MZL, and non immunoglobulin IgM lymphoplasmacytic lymphoma: LPL) are rare diseases Very few randomized trials were reported in this setting. Most commonly patients with WM are initially treated with an alkylating agent, such as chlorambucil (CBL) or with a nucleoside analogue such as fludarabine (F) or 2CdA, alone or in association with monoclonal antibody. Methods: WM1 study was a prospective international randomized open-label study that included patients with previously untreated WM MZL and LPL. At registration, patients were stratified as having WM, SLVL, or LPL, and were randomized in the two arms. The aim of the study was to compare the efficacy of oral CBL at a dose of 8 mg/m2 for 10 days every 28 days to a maximum of 12 cycles with oral F at a dose of 40 mg/m2 orally for 5 days every 28 days to a maximum of 6 cycles. 418 patients were enrolled into the study from 07/01 to12/09. 414 patients were included and 405 received at least one course of chemotherapy. There were 339 WM, 37 MZL and 38 LPL with a median age of 68 years (40-89). 207 patients were randomized in the F arm and 207 patients in the CBL arm. At inclusion, the median of haemoglobin (g/l), platelets (Giga/l), albumin (g/l) and beta 2 microglobulin (mg/l) were 9.9, 218, 37.1 and 3.47 respectively. Results: In intention to treat basis, the overall response rate (CR+PR) was 47.8 % in the F arm versus 38.6% in the CBL arm (p=0.06). With a median follow-up time of 35.9 months, the median of progression free survival time (PFS) and disease free survival (DFS) were statistically longer in the F arm: PFS 36.3m vs 27.1 m ( p=0.01) and DFS 38.3m vs 19. 9m (p= 0.0006). In WM group, factors influencing negatively PFS were CBL arm, albumin< 35g/l, platelets<100 G/l and age> 70 years. Main toxicity was haematological with 17/203 (8.3%) vs 18/203 (9%) of grade III- IV thrombocytopenia and 50/203 (24.6%) vs 39/202 (19.3%) of grade III-IV anemia in F and CBL arms respectively. Overall survival rate at 5 years was 61.4% [52.9;71.3] in CBL arm and 70.3% [62.7-78.8] in F arm (p=0.04) (Fig 1). Cumulative Incidence of second malignancies (solid tumors and haematological malignancies except Richter syndrome (RS)) was statistically higher in the chlorambucil arm (25 versus 8, p= 0.004) (Fig 2). The number of RS was 8 in F arm and 9 in CBL arm. Conclusion: F by oral route is a safe and effective ambulatory treatment in WM and close related disorders patients, even in the elderly and more effective than CBL with a duration of response over 3 years. An unexpected finding was a statistically higher number of second malignancies in the C arm and we cannot rule out an oncogenic role of CBL in this setting. Of note, we stress that it is the first time that a front- line treatment has a significant impact on overall survival in WM patients. Disclosures: Leblond: mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tournilhac:Amgen: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees.

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FGF/FGFR Axis-Blockade Leads to Anti-Tumor Activity in Waldenstrom's Macroglobulinemia By Silencing MYD88

Blood ◽

10.1182/blood-2020-136523 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 43-44

Author(s):

Antonio Sacco ◽

Cinzia Federico ◽

Arianna Giacomini ◽

Cinzia Caprio ◽

Federica Maccarinelli ◽

...

Keyword(s):

Bone Marrow ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Board Of Directors ◽

Protein Level ◽

Research Funding ◽

Fibroblast Growth ◽

Waldenström’S Macroglobulinemia ◽

Advisory Committees ◽

Waldenström's Macroglobulinemia

The human fibroblast growth factor/fibroblast growth factor-receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenstrom's Macroglobulinemia (WM). Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We investigated the role of FGF/FGFR system blockade in WM by using a pan-FGF trap molecule, NSC12, a small molecule identified using pharmacophore modeling of the interaction of a minimal PTX3-derived FGF-binding pentapeptide with FGF2. By interrogating the transcriptome signature of patients' BM-derived CD19-positive cells (GEO9656, GEO6691), we found a significant enrichment of FGF/FGFR-driven signaling cascades, including PI3K-AKT, MAPK and STAT3 pathways (FDR<0.25; P<0.05); coupled with higher expression of FGFs (FGF2, FGF7, FGF12, FGF18; P<0.05) in WM cells as compared to their normal cellular counterpart. FGFRs are also shown to be overexpressed in WM. We performed transcriptome profiling of NSC12-treated WM cells, confirming the blockade of the FGFR-signaling blockade; and, importantly, we discovered the efficacious silencing of MYD88 and MYD88-dopwnstream target HCK in WM cells. These findings were confirmed at protein level, showing inhibition of MYD88-driven pathways, such as BTK-, and SYK-phosphorylation. As a further demonstration of the functional impact of NSC12-dependent targeting of MYD88, we could confirm the inhibition of both canonical and non-canonical NF-kB in NSC12-treated WM cells, as assessed at nuclear protein level by WB and by using the NFkB activity assay. In addition, the NSC12-dependent inhibition of MYD88 resulted in silencing of the MAPK-ERK signaling cascade, thus leading to NSC12-induced Myc-silencing in WM cells. We next confirmed the efficacy of NSC12 in silencing bone marrow stromal cell (BMSC)-induced FGFR3 phosphorylation; paralleled by inhibition of of pro-survival pathways, including pAKT, the AKT-downstream pGSK3β; p-ERK; and p-STAT3. Functional sequelae of the FGF/FGFR blockade in WM cells were studied, demonstrating inhibition of WM cell growth, induction of apoptosis, enhanced ER stress and initiation of UPR. Of note, anti-WM activity of NSC12 was also documented using primary bone marrow-derived CD19+ cells isolated from patients with WM. In contrast, NSC12 did not show cytotoxicity on PBMC-derived CD19+ cells isolated from healthy donors. The anti-WM activity exerted by NSC12 was confirmed also within the context of the supportive bone marrow milieu, as shown both in vitro and in vivo. BCWM.1, MWCL1 cells were cultured with NSC12 in the presence or absence of primary WM BMSCs: adherence of WM cells to BMSCs triggered a significant increase in the proliferation, which was inhibited by NSC12in a dose-dependent manner (P<0.05). Using a disseminated humanized WM model, BCWM.1 M-Cherry-Luc tumor-bearing mice were treated with either NSC12 or vehicle control. NSC12-treated mice presented with a significant inhibition of WM tumor growth as demonstrated by bioluminescence imaging analysis. NSC12-dependent reduction of WM tumor cell BM infiltration was confirmed by IHC performed on harvested femurs, in comparison to vehicle-treated mice. Importantly, we assessed MYD88-mRNA expression using harvested bone marrow femurs; and found a significant reduction of MYD88- and MYD88-downstream target HCK in NSC12-treated mice was confirmed ex vivo (P<0.05). Overall, our studies are reporting on the use of NSC12, as a novel potential therapeutic strategy to specifically halt the FGF/FGFR axis in WM; and demonstrate how the observed anti-WM activity exerted by NSC12 may be driven, at least in part, by inhibition of MYD88. Disclosures Motta: Roche: Honoraria; Janssen: Honoraria. Rossi:Alexion: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Roccaro:Amgen: Other; AstraZeneca: Research Funding; Celgene: Other; Janssen: Other; Italian Association for Cancer Research (AIRC): Research Funding; Transcan2-ERANET: Research Funding; European Hematology Association: Research Funding.

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Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Blood ◽

10.1182/blood-2019-130419 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4619-4619

Author(s):

Jee Yon Shin ◽

Sung-Soo Park ◽

Gi June Min ◽

Silvia Park ◽

Sung-Eun Lee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Advisory Committees ◽

Sibling Donor ◽

Alternative Donor ◽

Matched Sibling ◽

Grade Ii

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽

10.1182/blood-2019-128053 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4112-4112

Author(s):

Charline Moulin ◽

Romain Morizot ◽

Thomas Remen ◽

Hélène Augé ◽

Florian Bouclet ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Intermediate Risk ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Long Term Survivors ◽

First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

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