14 results on '"Carly Leventoff"'
Search Results
2. Venetoclax in Previously Treated Waldenström Macroglobulinemia
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Christopher J. Patterson, Lian Xu, Tanya Siddiqi, Maria Luisa Guerrera, Shayna Sarosiek, Zachary R. Hunter, Andrew R. Branagan, Xia Liu, Carly Leventoff, Catherine A Flynn, Ranjana H. Advani, Kirsten Meid, Nicholas Tsakmaklis, Maria Demos, Matthew S. Davids, Guang Yang, Amanda Kofides, Timothy P White, Manit Munshi, Steven P. Treon, Jorge J. Castillo, Richard R. Furman, and John N. Allan
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Adult ,Male ,Cancer Research ,Receptors, CXCR4 ,Time Factors ,Antineoplastic Agents ,chemistry.chemical_compound ,Biomarkers, Tumor ,Medicine ,Humans ,Prospective Studies ,BCL2 ANTAGONIST ,Aged ,Aged, 80 and over ,Sulfonamides ,Venetoclax ,business.industry ,Waldenstrom macroglobulinemia ,Middle Aged ,medicine.disease ,Bridged Bicyclo Compounds, Heterocyclic ,Progression-Free Survival ,United States ,Oncology ,chemistry ,Proto-Oncogene Proteins c-bcl-2 ,Mutation ,Myeloid Differentiation Factor 88 ,Cancer research ,Disease Progression ,Female ,Waldenstrom Macroglobulinemia ,Previously treated ,business - Abstract
PURPOSE BCL2 is overexpressed and confers prosurvival signaling in malignant lymphoplasmacytic cells in Waldenström macroglobulinemia (WM). Venetoclax is a potent BCL2 antagonist and triggers in vitro apoptosis of WM cells. The activity of venetoclax in WM remains to be clarified. PATIENTS AND METHODS We performed a multicenter, prospective phase II study of venetoclax in patients with previously treated WM ( NCT02677324 ). Venetoclax was dose-escalated from 200 mg to a maximum dose of 800 mg daily for up to 2 years. RESULTS Thirty-two patients were evaluable, including 16 previously exposed to Bruton tyrosine kinase inhibitors (BTKis). All patients were MYD88 L265P–mutated, and 17 carried CXCR4 mutations. The median time to minor and major responses was 1.9 and 5.1 months, respectively. Previous exposure to BTKis was associated with a longer time to response (4.5 v 1.4 months; P < .001). The overall, major, and very good partial response rates were 84%, 81%, and 19%, respectively. The major response rate was lower in those with refractory versus relapsed disease (50% v 95%; P = .007). The median follow-up time was 33 months, and the median progression-free survival was 30 months. CXCR4 mutations did not affect treatment response or progression-free survival. The only recurring grade ≥ 3 treatment-related adverse event was neutropenia (n = 14; 45%), including one episode of febrile neutropenia. Laboratory tumor lysis without clinical sequelae occurred in one patient. No deaths have occurred. CONCLUSION Venetoclax is safe and highly active in patients with previously treated WM, including those who previously received BTKis. CXCR4 mutation status did not affect treatment response.
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- 2023
3. A pilot study on dasatinib in patients with Waldenström macroglobulinemia progressing on ibrutinib
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Jorge J. Castillo, Shayna Sarosiek, Catherine A. Flynn, Carly Leventoff, Megan Little, Timothy White, Kirsten Meid, and Steven P. Treon
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General Medicine - Abstract
The hematopoietic cell kinase (HCK) regulates BTK activation and represents a potential therapeutic target in Waldenstrom macroglobulinemia (WM). We investigated dasatinib, a potent HCK inhibitor, in patients with WM progressing on ibrutinib. Study treatment consisted of dasatinib administered at 100 mg by mouth once daily in four-week cycles for up to 24 cycles. This study was registered under ClinicalTrials.Gov ID NCT04115059. Three participants were enrolled and received at least one cycle of dasatinib. The best response was stable disease. Two patients received 5 months and one patient received 1 month of therapy. The dose of dasatinib was decreased in one participant due to volume overload. Based on the lack of responses observed, the study was terminated. Dasatinib might not be effective in patients with WM progressing on ibrutinib.
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- 2022
4. Phase 1 study of ibrutinib and the CXCR4 antagonist ulocuplumab in CXCR4-mutated Waldenström macroglobulinemia
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Nicholas Tsakmaklis, Aldo M. Roccaro, Timothy P White, Christopher J. Patterson, Guang Yang, Antonio Sacco, Xia Liu, Yang Cao, Zachary R. Hunter, Shayna Sarosiek, Carly Leventoff, Irene M. Ghobrial, Manit Munshi, Jorge J. Castillo, Lian Xu, Steven P. Treon, Catherine A Flynn, Kirsten Meid, Andrew R. Branagan, Amanda Kofides, Maria Luisa Guerrera, and Maria Demos
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Adult ,Receptors, CXCR4 ,medicine.medical_specialty ,Clinical Trials and Observations ,Immunology ,Ulocuplumab ,Antineoplastic Agents ,Antibodies, Monoclonal, Humanized ,Biochemistry ,CXCR4 ,Gastroenterology ,chemistry.chemical_compound ,Piperidines ,Internal medicine ,Humans ,Medicine ,Adverse effect ,Protein Kinase Inhibitors ,Aged ,CXCR4 antagonist ,biology ,business.industry ,Adenine ,Waldenstrom macroglobulinemia ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Rash ,chemistry ,Immunoglobulin M ,Ibrutinib ,Mutation ,biology.protein ,Waldenstrom Macroglobulinemia ,medicine.symptom ,business - Abstract
MYD88 and CXCR4 mutations are common in Waldenström macroglobulinemia (WM). Mutated CXCR4 (CXCR4Mut) impacts BTK-inhibitor response. We conducted a phase 1 trial of the CXCR4-antagonist ulocuplumab with ibrutinib in this first-ever study to target CXCR4Mut in WM. Ibrutinib was initiated at 420 mg/d with cycle 1 and continued until intolerance or progression; ulocuplumab was given cycles 1 to 6, with a 3 + 3 dose-escalation design. Each cycle was 4 weeks. Thirteen symptomatic patients, of whom 9 were treatment-naive patients were enrolled. Twelve were evaluable for response. At best response, their median serum immunoglobulin M declined from 5574 to 1114 mg/dL; bone marrow disease decreased from 65% to 10%, and hemoglobin increased from 10.1 to 14.2 g/dL (P < .001). The major and VGPR response rates were 100% and 33%, respectively, with VGPRs observed at lower ulocuplumab dose cohorts. Median times to minor and major responses were 0.9 and 1.2 months, respectively. With a median follow-up of 22.4 months, the estimated 2-year progression-free survival was 90%. The most frequent recurring grade ≥2 adverse events included reversible thrombocytopenia, rash, and skin infections. Ulocuplumab dose-escalation did not impact adverse events. The study demonstrates the feasibility of combining a CXCR4-antagonist with ibrutinib and provides support for the development of CXCR4-antagonists for CXCR4Mut WM. This trial was registered at www.clinicaltrials.gov as #NCT03225716.
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- 2021
5. Ibrutinib and Venetoclax in Previously Untreated Waldenström Macroglobulinemia
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Jorge J. Castillo, Shayna Sarosiek, Andrew R. Branagan, David J. Sermer, Catherine A. Flynn, Carly Leventoff, Megan Little, Timothy P White, Kirsten Meid, Alexa Canning, Maria Luisa Guerrera, Amanda Kofides, Xia Liu, Manit Munshi, Nicholas Tsakmaklis, Christopher J Patterson, Zachary R Hunter, and Steven P Treon
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
6. Identification of Robust Predictors for Ibrutinib Response By Multi-Omic Genomics in MYD88 Mutated Waldenstrom's Macroglobulinemia
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Kris Richardson, Jorge J. Castillo, Shayna Sarosiek, Andrew R. Branagan, Catherine A. Flynn, Kirsten Meid, Carly Leventoff, Timothy P White, Megan Little, Joshua Gustine, Xia Liu, Amanda Kofides, Shirong Liu, Alexa Canning, Julie Wolf, Katherine Kacena, Christopher J Patterson, Maria Luisa Guerrera, Nickolas Tsakmaklis, Steven P Treon, and Zachary R Hunter
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
7. Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia
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Noopur Raje, Elizabeth O'Donnell, Xia Liu, Kirsten Meid, Carly Leventoff, Zachary R. Hunter, Manit Munshi, Christopher J. Patterson, Amanda Kofides, Shayna Sarosiek, Steven P. Treon, Lian Xu, Andrew R. Branagan, Joshua Gustine, Andrew Yee, Guang Yang, Timothy P White, Maria Demos, Jorge J. Castillo, Maria Luisa Guerrera, Nicholas Tsakmaklis, and Catherine A Flynn
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Phases of clinical research ,CXCR4 ,Gastroenterology ,Article ,chemistry.chemical_compound ,Hematoma ,Targeted therapies ,Piperidines ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Adverse effect ,Aged ,Aged, 80 and over ,business.industry ,B-cell lymphoma ,Adenine ,Respiratory infection ,Waldenstrom macroglobulinemia ,Atrial fibrillation ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,Survival Rate ,Oncology ,chemistry ,Ibrutinib ,Female ,Waldenstrom Macroglobulinemia ,business ,Follow-Up Studies - Abstract
Herein, we present the final report of a single-center, prospective phase II study evaluating ibrutinib 420 mg once daily in 30 treatment-naive patients with Waldenstrom macroglobulinemia (WM). The present study is registered with ClinicalTrials.Gov (NCT02604511). With a median follow-up of 50 months, the overall, major, and VGPR response rates were 100%, 87%, and 30%. The VGPR rate was numerically but not significantly lower in patients with than without CXCR4 mutations (14% vs. 44%; p = 0.09). The median time to a minor response was 0.9 months, and to a major response was 1.9 months, though were longer in those with mutated CXCR4 at 1.7 months (p = 0.07) and 7.3 months (p = 0.01). Six patients had disease progression. The median progression-free survival (PFS) was not reached, and the 4-year PFS rate was 76%. There was also a non-significant lower 4-year PFS rate in patients with than without CXCR4 mutations (59% vs. 92%; p = 0.06). The most common treatment-related adverse events were fatigue, upper respiratory infection, and hematoma. Atrial fibrillation occurred in 20% of patients. Ibrutinib monotherapy induced durable responses in treatment-naive patients with WM. CXCR4 mutations impacted VGPR attainment, time to major response, and 4-year PFS rate.
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- 2021
8. Abstract CT550: Phase II study of acalabrutinib and an anti-CD20 monoclonal antibody in patients with anti-MAG mediated neuropathy
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Shayna Sarosiek, Christopher T. Doughty, Andrew Branagan, Catherine A. Flynn, Kirsten Meid, Timothy P. White, Megan Little, Carly Leventoff, Steven P. Treon, and Jorge J. Castillo
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Cancer Research ,Oncology - Abstract
Background: Peripheral neuropathy occurs in 20-25% of patients with an IgM paraprotein and 40-50% of patients with an IgM monoclonal gammopathy have a detectable anti-myelin associated glycoprotein (MAG) antibody. The presence of an anti-MAG antibody is often associated with a chronic, progressive symmetric demyelinating polyneuropathy that can lead to sensory deficits and gait dysfunction, significantly altering a patient’s quality of life. Prior clinical trials have failed to demonstrate an effective long-term therapy for anti-MAG neuropathy. Additionally, the best manner to assess the evolution of this type of neuropathy has not been elucidated. We designed this clinical trial to evaluate a potential therapy for anti-MAG related neuropathy based on previous reports of subjective improvement in patients with anti-MAG neuropathy treated with rituximab or Bruton’s tyrosine kinase inhibitors. We included multiple neurologic outcome measures so their responsiveness and performance could be assessed in a clinical trial setting. Methods: This is a single-arm open-label phase II trial investigating the use of acalabrutinib and an anti-CD20 monoclonal antibody for the treatment of an IgM-associated anti-MAG mediated neuropathy. Eligible patients must have positive anti-MAG antibody titers with an IgM monoclonal gammopathy of undetermined significance (MGUS) or Waldenström macroglobulinemia (WM). Patients must have a predominantly sensory neuropathy characterized by demyelinating features in nerve conduction studies with a modified Rankin score of ≥1 with progressive symptoms or a modified Rankin score of ≥2. The ECOG performance status must be ≤2. Acceptable organ and marrow function are required. Prior exposure to chemotherapy, Bruton Tyrosine Kinase inhibitors, or other therapies for WM are not permitted except for steroids, IVIg, or an anti-CD20 monoclonal antibody given at least 90 days before study drug initiation. Approximately 33 patients will be enrolled in this study. Patients will be treated with acalabrutinib 100 mg orally twice daily on days 1-28 of each cycle and treatment will be administered until disease progression or unacceptable toxicity. Rituximab (or a biosimilar) will be administered on days 1, 8, 15, and 22 of cycles 1 and 4. The primary endpoint of this trial is to evaluate the overall hematologic response rate (defined as ≥25% reduction in serum IgM) associated with the treatment. The key secondary endpoint is to evaluate the proportion of patients that achieve improvement or stability in neuropathic symptoms based on the Inflammatory Rasch-built Overall Disability Scale (I-RODS) patient-reported disability scale. Additional secondary neurologic endpoints include the INCAT disability score, exam-based outcomes (the MRC distal sum score and INCAT-ISS), measures of function (10-meter walk test, 9-hole peg test), a pain scale, a fatigue scale (FSS), and a neuropathy-specific quality of life scale (IN-QOL). Additional secondary endpoints include time to next treatment, overall survival, hematologic response based on MYD88 and CXCR4 mutational status, change in bone marrow disease burden, and proportion of adverse events associated with treatment. This study is currently open and accruing patients. Clinical trial information: NCT05065554 Sponsor: AstraZeneca Citation Format: Shayna Sarosiek, Christopher T. Doughty, Andrew Branagan, Catherine A. Flynn, Kirsten Meid, Timothy P. White, Megan Little, Carly Leventoff, Steven P. Treon, Jorge J. Castillo. Phase II study of acalabrutinib and an anti-CD20 monoclonal antibody in patients with anti-MAG mediated neuropathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT550.
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- 2022
9. Natural history of Waldenström macroglobulinemia following acquired resistance to ibrutinib monotherapy
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Maria Luisa Guerrera, Christopher J. Patterson, Maria Demos, Carly Leventoff, Andrew R. Branagan, Amanda Kofides, Zachary R. Hunter, Joshua Gustine, Jorge J. Castillo, Nicholas Tsakmaklis, Xia Liu, Shayna Sarosiek, Timothy P White, Steven P. Treon, Catherine A Flynn, Manit Munshi, Lian Xu, Guang Yang, and Kirsten Meid
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Oncology ,medicine.medical_specialty ,business.industry ,Adenine ,Waldenstrom macroglobulinemia ,Salvage therapy ,Hematology ,medicine.disease ,Discontinuation ,Natural history ,chemistry.chemical_compound ,Acquired resistance ,Pyrimidines ,chemistry ,Piperidines ,Internal medicine ,Ibrutinib ,Proteasome inhibitor ,medicine ,Humans ,Pyrazoles ,Rituximab ,Waldenstrom Macroglobulinemia ,business ,medicine.drug - Abstract
Ibrutinib is highly active and produces long-term responses in patients with Waldenström macroglobulinemia (WM), but acquired resistance can occur with prolonged treatment. We therefore evaluated the natural history and treatment outcomes in 51 WM patients with acquired resistance to ibrutinib monotherapy. The median time between ibrutinib initiation and discontinuation was 2 years (range, 0.4-6.5 years). Following discontinuation of ibrutinib, a rapid increase in serum immunoglobulin M level was observed in 60% (29/48) of evaluable patients, of whom ten acutely developed symptomatic hyperviscosity. Forty-eight patients (94%) received salvage therapy after ibrutinib. The median time to salvage therapy after ibrutinib cessation was 18 days (95% confidence interval [CI]: 13-27). The overall and major response rates to salvage therapy were 56% and 44%, respectively, and the median duration of response was 48 months (95% CI: 34-not reached). Quadruple-class (rituximab, alkylator, proteasome inhibitor, ibrutinib) exposed disease (odds ratio [OR] 0.20, 95% CI: 0.05-0.73) and salvage therapy ≤7 days after discontinuing ibrutinib (OR 4.12, 95% CI: 1.07- 18.9) were identified as independent predictors of a response to salvage therapy. The 5-year overall survival (OS) following discontinuation of ibrutinib was 44% (95% CI: 26-75). Response to salvage therapy was associated with better OS after ibrutinib (hazard ratio 0.08, 95% CI: 0.02-0.38). TP53 mutations were associated with shorter OS, while acquired BTK C481S mutations had no impact. Our findings reveal that continuation of ibrutinib until subsequent treatment is associated with improved disease control and clinical outcomes.
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- 2021
10. Cell‐free <scp>DNA</scp> analysis for detection of <scp> MYD88 L265P </scp> and <scp> CXCR4 S338X </scp> mutations in <scp>W</scp> aldenström macroglobulinemia
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Lian Xu, Catherine A Flynn, Maria Luisa Guerrera, Christopher J. Patterson, Jorge J. Castillo, Zachary R. Hunter, Guang Yang, Amanda Kofides, Timothy P White, Nicholas Tsakmaklis, Kirsten Meid, Steven P. Treon, Xia Liu, Shayna Sarosiek, Maria Demos, Carly Leventoff, Joshua Gustine, Andrew R. Branagan, and Manit Munshi
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Oncology ,medicine.medical_specialty ,business.industry ,Macroglobulinemia ,Waldenstrom macroglobulinemia ,Hematology ,Gold standard (test) ,medicine.disease ,CXCR4 ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Cell-free fetal DNA ,law ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Bone marrow ,business ,Genotyping ,Polymerase chain reaction ,030215 immunology - Abstract
MYD88L265P and CXCR4S338X variants are highly prevalent and impact disease presentation, prognosis, and/or treatment outcome in Waldenstrom's Macroglobulinemia (WM). The use of bone marrow (BM) aspirate represents the current "gold standard" for molecular testing in WM. Although these variants are identified in peripheral blood (PB), the diagnostic yield in PB is inferior to BM, particularly for previously treated patients. Tumor enrichment can significantly improve testing sensitivity, but is not feasible in most clinical laboratories. Recent studies have demonstrated the feasibility of identifying MYD88 and CXCR4 mutations using cell-free DNA (cfDNA) from the plasma of WM patients. We therefore prospectively collected matched BM and PB samples from 28 consecutive WM patients. Overall, five different tissue fractions were isolated for analysis: CD19-selected BM, unselected BM, CD19-selected PB, unselected PB, and cfDNA. Quantitative allele-specific polymerase chain reaction assays for MYD88L265P and CXCR4S338X mutations were performed for each tissue fraction, and findings benchmarked against CD19-selected BM. Both MYD88L265P and CXCR4S338X were identified with high sensitivity and specificity in cfDNA derived from the plasma of WM patients, including previously treated patients. The use of cfDNA represents a non-invasive, convenient, and potentially cost-effective method for genotyping patients with WM. This article is protected by copyright. All rights reserved.
- Published
- 2021
11. Multicenter phase 2 study of daratumumab monotherapy in patients with previously treated Waldenström macroglobulinemia
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Jorge J, Castillo, Edward N, Libby, Stephen M, Ansell, M Lia, Palomba, Kirsten, Meid, Catherine A, Flynn, Carly, Leventoff, Christopher B, Hergott, Tomasz, Sewastianik, Elizabeth A, Morgan, Ruben, Carrasco, Jonathan R, Fromm, Guang, Yang, Zachary, Hunter, and Steven P, Treon
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Receptors, CXCR4 ,Antibodies, Monoclonal ,Humans ,Waldenstrom Macroglobulinemia ,Stimulus Report - Abstract
Daratumumab was associated with an overall response of 23% and a median PFS of 2 months in previously treated patients with WM. The 2 patients who attained a partial response to daratumumab exhibited higher baseline CD38 median fluorescent intensity in plasma cells.
- Published
- 2020
12. Pirtobrutinib (LOXO-305) Is Active and Overcomes ERK Related Pro-Survival Signaling in Ibrutinib Resistant, BTK Cys481 Mutant Expressing WM and ABC DLBCL Lymphoma Cells Driven By Activating MYD88 Mutations
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Michael J. Poitras, Shayna Sarosiek, Xia Liu, Manit Munshi, Timothy P White, Kirsten Meid, Andrew R. Branagan, Christopher J. Patterson, Guang Yang, Prafulla C. Gokhale, Steven P. Treon, Jorge J. Castillo, Joshua Gustine, Carly Leventoff, Nickolas Tsakmaklis, Amanda Kofides, Maria Luisa Guerrera, Catherine A Flynn, and Zachary R. Hunter
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MAPK/ERK pathway ,biology ,Immunology ,Mutant ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Lymphoma ,chemistry.chemical_compound ,chemistry ,immune system diseases ,hemic and lymphatic diseases ,Ibrutinib ,medicine ,biology.protein ,Cancer research ,Bruton's tyrosine kinase ,Abc dlbcl ,Survival signaling - Abstract
MYD88 mutations are common in B-cell malignancies including Waldenstrom Macroglobulinemia (WM) and ABC subtype of Diffuse Large B-cell Lymphoma (ABC DLBCL). Mutated MYD88 activates BTK, and triggers downstream pro-survival signaling that includes NF-kB and ERK (Yang et al, Blood 2013; Blood 2016). ERK related signaling triggers inflammatory cytokine production including IL-6 and IL-10 (Chen et al, Blood 2016). Ibrutinib covalently binds to BTK Cys481 and inactivates BTK and downstream NF-kB and ERK signaling. Ibrutinib is approved for the treatment of WM and is associated with high overall response rates (>90%) and long term progression free survival in WM though intolerance to therapy, as well as resistance related to acquired BTK Cys481 mutations frequently leads to treatment discontinuation. We therefore investigated a novel, non-covalent BTK-inhibitor, pirtobrutinib that binds to BTK at non-Cys481 amino acids (G473-K483). Pirtobrutinib showed highly selective anti-proliferative activity against MYD88 mutated WM (BCWM.1, MWCL-1) and ABC DLBCL (TMD-8 and HBL-1) versus MYD88 wild-type (OCI-Ly7, OCI-Ly19, Ramos, and RPMI-8226) cells, with marked apoptotic effect exhibited against primary MYD88 mutated WM cells at pharmacologically achievable levels (100-500 nM). Importantly, pirtobrutinib blocked BTK activity and overcame ibrutinib resistance in BCWM.1 WM and TMD-8 ABC DLBCL cells transduced to express both wild-type and mutated BTK (BTK Cys481Ser) with similar efficacy. The downstream signaling consequences of pirtobrutinib in vector only, wild-type and mutant BTK Cys481 expressing BCWM.1, MWCL-1, TMD-8 and HBL-1 cells was also examined. Treatment of vector only and wild-type BTK Cys481 expressing WM and ABC DLBCL cells with ibrutinib or pirtobrutinib abrogated both p-BTK and p-ERK signaling. In contrast, only pirtobrutinib blocked p-BTK and p-ERK signaling in mutant BTK Cys481 expressing WM and ABC DLBCL cells. In previous studies, we showed that inflammatory cytokine production that included IL-6 and IL-10 driven by ERK triggered ibrutinib resistance in wild-type BTK Cys481 MYD88 mutated lymphoma cells co-cultured with their mutated BTK expressing counterparts (Chen et al, BLOOD 2018). ERK-driven cytokine resistance to ibrutinib was postulated to explain how disease progression occurs in patients with modest variant expression of mutated BTK Cys481 (Woyach et al, JCO 2017; Xu et al, Blood 2017). Co-culture of BTK Cys481 mutated expressing TMD-8 cells with wild-type BTK expressing TMD-8 cells triggered resistance of the latter to ibrutinib. Treatment with pirtobrutinib blocked IL-6 and IL-10 production and overcame the protective effects conferred by BTK Cys481 mutated TMD-8 cells in these experiments. Lastly, oral administration of pirtobrutinib blocked p-BTK and p-ERK in BTK Cys481 mutated TMD-8 tumors xenografted in mice. Our findings therefore show that pirtobrutinib inhibits growth of MYD88 mutated lymphoma cells in a highly selective manner and can trigger apoptosis of primary WM patient BM lymphoplasmacytic cells at levels comparable to ibrutinib. Moreover, pirtobrutinib effectively blocked mutated BTK Cys481 driven BTK and ERK1/2 activation and produced similar cellular efficacy in both BTK wild-type and BTK Cys481 mutated cells. Pirtobrutinib also blocked the protective effect conferred to BTK wild-type cells through paracrine cytokines released by BTK Cys481Ser expressing cells. Lastly, pirtobrutinib blocked BTK and ERK1/2 activation in TMD8-BTK Cys481Ser xenografted mice. The findings support the development of pirtobrutinib in MYD88 driven lymphomas, including those resistant to ibrutinib on the bases of BTK Cys481 mutations. Disclosures Branagan: Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; CSL Behring: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Consultancy; Sanofi Genzyme: Consultancy. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding. Yang: Blueprint Medicines Corporations: Current Employment, Current holder of individual stocks in a privately-held company. Treon: BeiGene: Consultancy, Research Funding; Eli Lily: Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding.
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- 2021
13. Dose Reductions Related to Adverse Effects in Patients with Waldenström Macroglobulinemia Treated with the BTK-Inhibitor Ibrutinib
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Jorge J. Castillo, Joshua Gustine, Kirsten Meid, Timothy P White, Carly Leventoff, Shayna Sarosiek, Catherine A Flynn, and Steven P. Treon
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Oncology ,medicine.medical_specialty ,biology ,business.industry ,Immunology ,Waldenstrom macroglobulinemia ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Ibrutinib ,biology.protein ,medicine ,Bruton's tyrosine kinase ,In patient ,Adverse effect ,business - Abstract
The BTK-inhibitor ibrutinib is the first FDA approved therapy for Waldenström macroglobulinemia (WM) and produces overall response rates >90% and long-term disease control in both treatment naïve and previously treated patients. Despite the remarkable efficacy of ibrutinib, dose reduction is often required for intolerance. In this study, we analyzed those patients requiring a dose reduction and evaluated the time to dose reduction, the symptoms leading to dose reduction, the rate of improvement in symptoms after dose reduction, and the hematologic response at 12 months after dose reduction. 385 patients received treatment with ibrutinib in our clinic from May 2012 through October 2020. Their baseline characteristics are shown in Table 1. Starting dose for these patients was 560 mg (n=11); 420 mg (n=358); 280 (n=15); 140 mg (n=1). Approximately 1/3 of all patients were treatment naïve at the time ibrutinib was initiated. Anemia, constitutional symptoms, and symptomatic hyperviscosity (or risk of hyperviscosity) were the most common reasons for treatment initiation. Reasons for dose reduction are shown in Table 2. Ninety-five patients (25%) required at least one dose reduction of ibrutinib. Twenty-three patients (6%) required a second dose reduction. Of the patients requiring dose reductions, 1 patient started at 280 mg and reduced to 140 mg, 91 patients started ibrutinib at 420 mg (1 patient ultimately had dose reduction to 70 mg, 22 patients to 140 mg, and 68 patients to 280 mg), and three patients started ibrutinib at 560 mg in the setting of Bing-Neel syndrome (2 patients had dose reduction to 420 mg and 1 patient to 280 mg). Patients requiring a dose reduction had a median age of 71 years (range, 46-96) at the time of ibrutinib initiation versus 66 years (range, 40-93) for those not requiring a dose reduction (p Median time to first dose reduction was 7.3 months (range, 0.5-75) and median time to second dose reduction from initiation of ibrutinib was 23 months (range, 3-75). Of the 95 patients requiring a dose reduction, 40 patients (42% of all patients with dose reductions) had improvement in at least 1 of the medication side effects after the initial dose reduction. Twenty-two patients (23%) had complete resolution of adverse effects. Twenty-six patients (27%) had no change in symptoms and 10 of these patients required an additional dose reduction. After the second dose reduction, 5 patients had improvement or resolution in symptoms. Two patients had no adverse effects prior to dose reduction and medication was reduced simply due to drug interaction. Of the 48 patients with 1-year hematologic follow-up data available, 10 patients (21%) had improvement in hematologic response and 35 patients (73%) maintained their hematologic response despite dose reduction. Three patients (6%) had worsening of hematologic response after dose reduction. In conclusion, one quarter of WM patients in this series on ibrutinib required a dose reduction due to development of intolerable medication side effects. In the majority of these patients, adverse effects improved or resolved with dose reduction. Importantly, hematologic response remained stable or improved in most patients despite dose reduction. Figure 1 Figure 1. Disclosures Treon: BeiGene: Consultancy, Research Funding; Eli Lily: Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding.
- Published
- 2021
14. Diagnostic Next-generation Sequencing Frequently Fails to Detect MYD88L265P in Waldenström Macroglobulinemia
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Amanda Kofides, Kirsten Meid, Catherine A Flynn, Manit Munshi, Jorge J. Castillo, Joshua Gustine, Carly Leventoff, Guang Yang, Maria Luisa Guerrera, Xia Liu, Lian Xu, Nicholas Tsakmaklis, Timothy P White, Andrew R. Branagan, Maria Demos, Christopher J. Patterson, Steven P. Treon, Shayna Sarosiek, and Zachary R. Hunter
- Subjects
Letter ,business.industry ,medicine ,Waldenstrom macroglobulinemia ,Diseases of the blood and blood-forming organs ,Hematology ,Computational biology ,RC633-647.5 ,medicine.disease ,business ,DNA sequencing - Published
- 2021
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