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.

scholarly journals BTKCys481Ser Mutation Drives Ibrutinib Resistance through ERK1/2 Hyperactivation, and Can Confer a Protective Effect on Bystander Waldenstrom's Macroglobulinemia and ABC DLBCL Cells through Paracrine Mediated Pro-Survival Signaling

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 803-803
Author(s):  
Jiaji Chen ◽  
Xia Liu ◽  
Manit Munshi ◽  
Lian Xu ◽  
Nickolas Tsakmaklis ◽  
...  
Keyword(s):  
Protective Effect ◽  
Disease Progression ◽  
Tumor Cells ◽  
Research Funding ◽  
Waldenström’S Macroglobulinemia ◽  
Survival Signaling ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Ibrutinib Resistance ◽  
Waldenström's Macroglobulinemia

Abstract Activating mutations in MYD88 promote NF-kB survival signaling in WM and ABC DLBCL cells through BTK and HCK, both targets of ibrutinib (Yang et al, Blood 2013; 2016). These findings likely explain the high rates of response observed in MYD88 mutated WM and ABC DLBCL patients (Treon et al, NEJM 2015; Wilson et al, Nature Med 2015). Resistance to ibrutinib is increasingly being recognized with prolonged therapy in patients with various B-cell malignancies. Mutations at the BTKCys481 site are observed in half of WM patients with disease progression following initial response (Xu et al, Blood 2017), and are also associated with clinical resistance in patients with CLL and MCL. However, in many WM and CLL cases, BTKCys481 mutations are subclonal and their relevance to clinical disease progression remains unclear. Moreover, the signaling mechanisms that promote ibrutinib resistance remain to be clarified. We therefore performed lentiviral transduction studies in MYD88 mutated WM (BCWM.1, MWCL-1) and ABC DLBCL (TMD-8, HBL-1) cells with vector alone, wild-type BTK (BTKWT), and the BTK variant most frequently observed in ibrutinib resistant WM and CLL cases (BTKCys481Ser). BTKCys481Ser but not BTKWT or vector only transduced WM and ABC DLBCL cells uniformly demonstrated persistent BTK and PLCγ2 activation in the presence of ibrutinib (100, 500 nM), along with a 1-3 log fold increase in EC50 to ibrutinib. Western blot analysis showed persistent BTK signaling in BTKCys481Ser expressing cells that was accompanied by ERK1/2 hyperactivation. Use of highly selective and potent ERK1/2 inhibitors (ulixertinib, GDC-0994) induced apoptosis of BTKCys481Ser expressing WM and ABC DLBCL cells, and showed synergistic tumor cell killing with ibrutinib by CellTiter-Glo® Luminescent Cell Viability Assays using Calcasyn, as well as enhanced apoptosis by Annexin V staining. Using a multiplex cytokine assay and confirmed by TaqMan® quantitative RT-PCR assay for cytokine mRNA levels, we identified that ERK1/2 activation in ibrutinib treated BTKCys481Ser WM and ABC DLBCL cells was accompanied by persistent release of pro-inflammatory and growth enhancing cytokines including CXCL13, IL-2R, IL-6, IL-10, IL-12p40, and TNF-a that was blocked by ulixertinib. In contrast, ibrutinib blocked their release in BTKWT WM and ABC DLBCL cells. We next sought to clarify if cytokine release by ibrutinib treated BTKCys481Ser WM and ABC DLBCL could impact survival of bystander tumor cells. We performed experiments using a Transwell system in which BTKCys481Ser or BTKWT transduced WM or ABC DLBCL cells were co-cultured with their native counterpart cells in the presence or absence of ibrutinib (Figures 1A, B). These studies showed that native WM or ABC DLBCL cells were rescued in the presence of ibrutinib when co-cultured with their BTKCys481Ser but not BTKWT transduced counterparts. Finally, use of IL-6 and IL-10 blocking antibodies abolished the protective effect on native tumor cells conferred by co-culture with BTKCys481Ser expressing cells in the presence of ibrutinib (Figures 1C, D). Our findings show that BTKCys481Ser mutation drives ibrutinib resistance through hyperactivation of ERK1/2, and that paracrine mediated ERK1/2 dependent pro-survival signaling by BTKCys481Ser expressing cells can confer a protective effect on bystander Waldenstrom's Macroglobulinemia and ABC DLBCL cells in the presence of ibrutinib. Figure 1 Figure 1. Disclosures Castillo: Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding; Millennium: Research Funding. Treon: Pharmacyclics: Consultancy, Research Funding.

Hepatitis C Viral Infection Is Not Associated with Waldenstrom’s Macroglobulinemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4693-4693
Author(s):  
Xavier Leleu ◽  
Kelly O’Connor ◽  
Allen Ho ◽  
Daniel D. Santos ◽  
Robert Manning ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Hcv Infection ◽  
Antibody Detection ◽  
Low Grade ◽  
Waldenström’S Macroglobulinemia ◽  
Hcv Antibody ◽  
Pcr Assays ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Infection with hepatitis C virus (HCV) has previously been associated with the pathogenesis of low grade B-cell lymphoproliferative diseases including Waldenstrom’s macroglobulinemia (WM). Most of these studies have utilized HCV antibody detection assays, which may not accurately assess HCV presence in patients with impaired humoral responses. In patients with WM, pronounced IgA and IgG hypogammaglobulinemia is present, which remains persistant despite therapy (Blood 104:306b). As such, we investigated the incidence of HCV in 88 randomly selected, and previously untreated patients with the consensus panel diagnosis of WM utilizing both HCV antibody detection and qualitative PCR assays (Quest Diagnostics, Cambridge, MA, USA). The median age for these patients was 61 (38 – 83 years) and the male: female sex ratio was 1.44. No patient had a known history of liver disease, hepatitis B, HCV or HIV infection. Liver function tests obtained at time of serum collection showed normal range SGOT and and SGPT levels for 86/88 patients. In contrast to previous reports, we failed to demonstrate HCV infection by both HCV antibody detection and the PCR assays. These studies therefore show no association of WM with HCV infection.

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.

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

Blood ◽  
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.

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

Blood ◽  
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.

IgA and IgG Hypogammaglobulinemia Is a Constitutive Feature in Most Waldenstrom’s Macroglobulinemia Patients and May Be Related to Mutations Associated with Common Variable Immunodeficiency Disorder (CVID)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3749-3749 ◽  
Author(s):  
Steven Treon ◽  
Zachary Hunter ◽  
Bryan Ciccarelli ◽  
Yangsheng Zhou ◽  
Christina Hanzis ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
Missense Mutation ◽  
Common Variable Immunodeficiency ◽  
Subsequent Treatment ◽  
Waldenström’S Macroglobulinemia ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
The Impact ◽  
Waldenström's Macroglobulinemia ◽  
Common Variable

Abstract Background: Hypogammaglobulinemia of the “uninvolved” immunoglobulins is commonly observed in Waldenstrom’s macroglobulinemia (WM), and has often been attributed to disease-related suppression. However, there is a paucity of information related to the pathogenesis of hypogammaglobulinemia in these disorders. Methods: We evaluated the incidence of IgA and IgG hypogammaglobulinemia in 207 patients with WM, and addressed the impact of therapy and response on IgA and IgG levels for 93 of these patients who required subsequent treatment. We also performed extensive sequence analysis of the promoter, all exonic, and flanking intronic regions from peripheral blood of 19 untreated WM patients who demonstrated IgA and/or IgG hypogammaglobulinemia for 8 genes often observed in common variable immunodeficiency disorders (CVID) and B cell deficiency i.e. AICDA, BTK, CD40, CD154, NEMO(IkBkG), TACI, SH2D1A, UNG. Results: At baseline, 120/207 (58.0%), 131/207 (63.3%), and 102/196 (49.3%) patients had abnormally low levels of serum IgG (<700 mg/dL), IgA (<70 mg/dL), or both, respectively. No correlation between baseline bone marrow disease involvement and immunoglobulin levels was observed. With a median follow-up of 12 months following completion of therapy, IgA and/or IgG levels remained abnormally low for 92.1% and 87.3% of responding patients, respectively, including those who achieved a complete remission. Sequence analysis of the NEMO and CVID gene panel demonstrated intronic variation at position c.1056-6T>C (n=2) and a hemizygous missense mutation at codon 113 for NEMO (n=1), and a heterozygous missense mutation at codon 142 in UNG (n=1). Conclusions: The results of these studies demonstrate that IgA and IgG hypogammaglobulinemia is a constitutive feature of patients with WM, which neither correlates with, nor is impacted by disease burden, despite therapeutic intervention and response. The results also suggest that patients with WM may harbor sequence mutations, which may be a contributor to the pathogenesis and/or morbidity of WM.

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

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3752-3752
Author(s):  
Irene M. Ghobrial ◽  
Swaminathan Padmanabhan ◽  
Ashraf Z. Badros ◽  
Renee Leduc ◽  
Meghan Rourke ◽  
...  
Keyword(s):  
Herpes Zoster ◽  
Board Of Directors ◽  
Research Funding ◽  
Waldenström’S Macroglobulinemia ◽  
Advisory Committees ◽  
Minor Response ◽  
Waldenstrom's Macroglobulinemia ◽  
A Minor ◽  
Waldenström'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.

scholarly journals Ixazomib, Rituximab and Dexamethasone (IRD) in Patients with Relapsed or Progressive Waldenstrom's Macroblobulinemia: Results of the Prospective Phase I/II HOVON 124/Ecwm-R2 Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 344-344 ◽  
Author(s):  
Marie José Kersten ◽  
Monique C. Minnema ◽  
Josephine M. Vos ◽  
Kazem Nasserinejad ◽  
Marcel Kap ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Research Funding ◽  
Final Analysis ◽  
Waldenström’S Macroglobulinemia ◽  
Oncology Research ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Introduction Since no curative options for Waldenstrom's Macroglobulinemia (WM) are available, novel safe and effective treatments are needed. Several new agents, including BTK inhibitors and proteasome inhibitors (PIs) have shown considerable efficacy. PIs have shown synergy with rituximab in newly diagnosed and relapsed patients, with bortezomib being most extensively used. However, WM patients often have disease-related polyneuropathy (PNP) and there is a considerable risk of bortezomib induced PNP or worsening of existing PNP. Additionally, it requires parenteral administration. In the current study, we aimed to investigate the efficacy and toxicity of the oral and less neurotoxic proteasome inhibitor ixazomib citrate in patients with relapsed WM. Given the fact that WM patients have a tendency to develop rituximab intolerance, we explored the use of subcutaneous rituximab. Methods We conducted a multicenter phase I/II trial of the Ixazomib, Rituximab, Dexamethasone (IRD) combination in patients with relapsed WM. The phase I part of the trial was performed according to a standard '3+3' design with a primary endpoint of dose limiting toxicity, aiming to establish the recommended phase II dose level (RP2D). For the phase II part the primary endpoint was overall response rate (ORR, at least minimal response (MR)) after 8 induction cycles. Treatment consisted of a total of 8 induction cycles q28 days with ixazomib citrate, 4 mg orally on day 1,8,15 and dexamethasone, 20 mg orally on day 1,8,15,22. In cycle 3 rituximab 375 mg/m2 iv on day 1 was added and in cycle 4-8 rituximab was given sc (1400 mg flat dose day 1). Subsequently, patients with at least a PR received 2 years of rituximab maintenance treatment (1400 mg sc q 3 months). Results With 60 patients, enrolment is complete. One patient was ineligible (rituximab refractory). Dose level 1 (ixazomib citrate 4 mg) was feasible and was taken forward as the phase II dose. Of the first 50 eligible patients included in the pre-final analysis and treated at the RP2D, the median age was 69 years (range 46-83) and 72% were male. The median number of prior treatments was 2 (range 1 to 7); 70% had an intermediate or high WM IPSS score. The median hemoglobin level was 10.2 g/dl (range 7.0-15.0) and the median IgM level was 3.4 g/dl (range 1.33-9.1 g/dl). 39/50 patients completed 8 cycles of induction therapy with a median relative dose intensity of 1.0 for all three drugs. Eleven patients went off protocol early (5 progression, 3 toxicity, 2 intercurrent death, 1 insufficient clinical benefit). 74% of patients achieved the primary endpoint (16%≥VGPR, 52%≥PR, 74%≥MR), and best ORR on protocol was 88% (2% CR, 22% VGPR, 44% PR, 20% MR). With a median follow-up of 19.5 months (range 7-49), the median duration of response and median progression free survival were not reached. A rapid and statistically significant decrease in IgM levels was seen already after cycle 2 (before the introduction of rituximab; IgM 3.93 to 2.37 g/dl, p&lt;0.001), accompanied by a rapid increase in Hb levels (Hb 10.5 to 11.5 g/dl, p&lt;0.001), but the depth of response continued to increase until month 12. Two patients had an infusion-related reaction to the first (iv) dose of rituximab; subsequent sc dosing of rituximab was well tolerated in all patients. Grade 3/4 toxicity was seen in 28% and 10% of patients respectively. 21 SAEs were reported in 15 patients, mostly infections. 6 patients died while on the trial (2 progressive disease, 1 progressive multifocal leukencephalopathy (symptoms present already at entry), 2 deaths considered unrelated in elderly patients (&gt;80 years) with multiple pre-existing comorbidities, 1 graft versus host disease after progression and subsequent allogeneic stem cell transplantation. Conclusions Treatment with the combination of ixazomib citrate, sc rituximab and dexamethasone is feasible, easy to administer and shows promising efficacy with manageable toxicity in patients with relapsed or progressive WM. The final analysis for the primary endpoint for all 60 patients will be shown at the conference. Role of the funding source: the study was financially supported by grants from Takeda Oncology, Roche and the Dutch Cancer Society. Acknowledgments: the authors wish to acknowledge the trial coordinators and central datamanagers of HOVON data center and all patients and contributing centers for participation in the trial Figure IgM (A) and Hemoglobin (B) levels during treatment Disclosures Kersten: Gilead: Honoraria; Novartis: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda Oncology: Research Funding; Kite Pharma: Honoraria, Research Funding; Miltenyi: Honoraria; Mundipharma: Honoraria, Research Funding. Minnema:Jansen Cilag: Honoraria; Celgene Corporation: Honoraria, Research Funding; Gilead: Honoraria; Amgen: Honoraria; Servier: Honoraria. Vos:Celgene: Honoraria. Kastritis:Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria. Chamuleau:Genmab: Research Funding. Deeren:Alexion, Amgen, Janssen, Roche, Sunesis, Takeda, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Doorduijn:Roche: Honoraria, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding. OffLabel Disclosure: Ixazomib in Waldenstrom's Macroglobulinemia

scholarly journals Real-World Practice Patterns in a Nationwide Cohort of Veterans with Waldenström's Macroglobulinemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5270-5270
Author(s):  
Kelli M Rasmussen ◽  
Vikas Patil ◽  
Hsu-Chih Chien ◽  
Deborah Kay Morreall ◽  
Catherine Li ◽  
...  
Keyword(s):  
United States ◽  
Real World ◽  
Research Funding ◽  
Treatment Options ◽  
The United States ◽  
Waldenström’S Macroglobulinemia ◽  
The Real ◽  
Treatment Practices ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Background Waldenström's macroglobulinemia (WM) is a rare indolent cancer. Because of its low incidence, the treatment practices for WM primarily rely on data from phase 2 trials, which often have no consensus as to how to best treat this uncommon disease. The heterogeneity of treatments available can be observed in clinical practice guidelines, which recommend traditional chemotherapies, second-generation proteasome inhibitors, multiagent immunotherapies, and the novel Bruton's tyrosine kinase inhibitor, ibrutinib (IBR). Yet, despite clinical evidence and treatment guidelines recommending multiagent chemoimmunotherapy in first-line (1L) patients with WM, a majority of patients still receive monotherapy, namely chlorambucil in Europe and monotherapy rituximab (R) in the United States. To date, there have been no reports on the real-world treatment practices in 1L of WM since the introduction of IBR. The primary objective of this study is to understand the 1L treatment practices for WM in a nationwide cohort of Veterans treated in the largest integrated healthcare system in the United States, the Veterans Health Administration (VA). Methods Using the VA Cancer Registry System and electronic healthcare records, we identified Veterans diagnosed with WM between January 1, 2006, to December 31, 2018. Treatment regimens were classified in accordance with the National Comprehensive Cancer Network (NCCN) guidelines for WM (versions 1.2006, 2.2013, and 2.2019). Eligible patients were followed until loss to follow-up, death or the end of the study observation period (June 30, 2019). The 1L of treatment was examined; with the start date for 1L being the index date. Patients with a cancer diagnosis other than WM and patients who did not receive 1L treatment were excluded from the study. Results We identified 340 patients who were diagnosed with WM and received a 1L treatment regimen between 2006-2019 in the VA. Median age at diagnosis was 68 years (range: 37-92); 334 (98%) of patients were male. Demographics are further described in Table 1. At diagnosis, the median serum IgM was 3083 mg/dl (range: 10-11500), the median hemoglobin was 11 g/dl (range: 5-17), and the platelet count was 204 k/dl (range: 5-732). A noticeable shift in the adoption of treatments can be observed when comparing treatment practices in patients treated between 2006-2009, 2010-2014, and those treated between 2015-2019. From 2006-2009 the majority of 1L patients received monotherapy with R (23, 37%) or chlorambucil (14, 22%). Between 2010-2014, the majority of patients received monotherapy R (43, 34%), with increasing adoption of bendamustine + R (8, 6%) and bortezomib (27, 21%). Between 2015-2019, IBR became the leading 1L treatment (38, 25%), followed by bendamustine + R (33, 22%), monotherapy R (33, 22%), and bortezomib + R (28, 19%). The estimated survival rate of WM patients treated with 1L was 79% at three-years, 68% at 5-years, and 55% at 7-years. Conclusions Our study is one of the first to examine the real-world treatment practices of WM patients treated with 1L after the approval of novel agent IBR. Our results highlight the heterogeneity of treatment options available for WM patients. We also describe the evolution of treatment choices in 1L over the last decade: from chlorambucil and rituximab monotherapy, to ibrutinib, bendamustine, and bortezomib. Retrospective and/or observational studies examining treatments and outcomes in WM patients should take these shifts in treatment practices into consideration. Given the persistent utilization of monotherapy R as a treatment in 1L, despite the superior efficacy of other treatment options such as ibrutinib, bendamustine and bortezomib regimens, our results indicate the need for continued efforts to educate clinicians about the appropriate treatment options available for this rare disease. Acknowledgments: The study was sponsored by Pharmacyclics Disclosures Sauer: University of Utah and SLC VA Medical Center: Employment. Halwani:Genentech, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Amgen: Research Funding; Kyowa Hakko Kirin: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Miragen: Research Funding.

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