1,213 results on '"William G. Wierda"'
Search Results
152. Evolving Strategies in First-Line Chronic Lymphocytic Leukemia: Is There a Role for Chemoimmunotherapy?
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Jennifer R. Brown and William G. Wierda
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Oncology ,medicine.medical_specialty ,Standard of care ,business.industry ,Chronic lymphocytic leukemia ,First line ,medicine.disease ,Disease control ,03 medical and health sciences ,0302 clinical medicine ,Chemoimmunotherapy ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,business ,030215 immunology - Abstract
With the enormous progress made in treatment and management, many oncologists have called this the golden age of chronic lymphocytic leukemia (CLL). The past few years alone have seen the approval of multiple agents, including small molecule inhibitors that have led to longer, more durable periods of disease control. However, the introduction of these new drugs into the armamentarium has raised an important question regarding standard of care: is there still a role for chemoimmunotherapy in the first-line setting? At the NCCN 2019 Annual Congress: Hematologic Malignancies, Drs. William G. Wierda and Jennifer R. Brown presented opposing sides of the debate.
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- 2019
153. Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia
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Matthew A. Lunning, Hari P. Miskin, Jonathon B. Cohen, Nathan Fowler, Marshall T. Schreeder, Tanya Siddiqi, Loretta J. Nastoupil, Michael S. Weiss, Jan A. Burger, Christopher R. Flowers, Susan O'Brien, Julie M. Vose, Peter Sportelli, and William G. Wierda
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Adult ,Male ,medicine.medical_specialty ,Lymphoma, B-Cell ,Maximum Tolerated Dose ,Clinical Trials and Observations ,Chronic lymphocytic leukemia ,Immunology ,Heterocyclic Compounds, 4 or More Rings ,Biochemistry ,Gastroenterology ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Adverse effect ,Aged ,Aged, 80 and over ,CD20 ,Dose-Response Relationship, Drug ,biology ,business.industry ,Antibodies, Monoclonal ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Lymphoma ,Leukemia ,Toxicity ,B-Cell Non-Hodgkin Lymphoma ,biology.protein ,Female ,Rituximab ,Neoplasm Recurrence, Local ,business ,medicine.drug - Abstract
Targeting both CD20 and phosphatidylinositol 3-kinase (PI3K), a protein that is critically involved in B-cell maturation, could be an efficacious strategy for treating B-cell malignancies. The safety of the next-generation compounds umbralisib, a PI3K-δ inhibitor, plus ublituximab, an anti-CD20 monoclonal antibody (combination referred to as U2), was evaluated in patients with chronic lymphocytic lymphoma (CLL) or non-Hodgkin lymphoma (NHL) in this phase 1/1b study. Phase 1 dose escalation was performed with a 3 + 3 design to establish the maximum tolerated dose. In this portion, ublituximab was given intravenously (NHL, 900 mg; CLL, 600 or 900 mg) for 12 cycles. Umbralisib was given orally once daily at 800 or 1200 mg (initial formulation) or 400 to 1200 mg (micronized formulation) in the phase 1 dose escalation portion, and at 800 to 1200 mg in the phase 1b portion until progression, toxicity, or study removal. The maximum tolerated dose was not reached in either the CLL or NHL cohort, and only 1 dose-limiting toxicity was observed. U2 had low instances of grade 3 or higher diarrhea (8%), pneumonia (8%), or hepatic toxicity (4%). Treatment discontinuation due to adverse events occurred in 13% of patients, and umbralisib dose reductions occurred in 15% of patients. The overall response rate for all patients was 46% with 17% complete responses. The median duration of response was 20 months (95% confidence interval, 11.3-not reached). U2 was well tolerated, and no new safety signals were observed over single-agent umbralisib. Preliminary efficacy with this combination is promising and warrants further investigation. This study was registered at www.clinicaltrials.gov as #NCT02006485.
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- 2019
154. Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia
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Junyan Lu, Melissa C. Larson, William G. Wierda, Kanti R. Rai, Laura Z. Rassenti, Kari G. Rabe, Lynne V. Abruzzo, Madelyn M. Gerber, James S. Blachly, Thomas J. Kipps, Kerry A. Rogers, Brian Giacopelli, Kevin R. Coombes, Yue Zhong Wu, Akwasi Agyeman, Qiuhong Zhao, Amy S. Ruppert, Thorsten Zenz, Jennifer A. Woyach, Christopher C. Oakes, Michael J. Keating, Christoph Weigel, Tait D. Shanafelt, Jennifer R. Brown, John C. Byrd, Neil E. Kay, University of Zurich, and Oakes, Christopher C
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1303 Biochemistry ,Chronic lymphocytic leukemia ,2720 Hematology ,Immunology ,610 Medicine & health ,Biology ,Biochemistry ,Epigenesis, Genetic ,1307 Cell Biology ,chemistry.chemical_compound ,Chemoimmunotherapy ,hemic and lymphatic diseases ,Biomarkers, Tumor ,medicine ,Humans ,Genetic Testing ,Epigenetics ,2403 Immunology ,Lymphoid Neoplasia ,ZAP70 ,Cancer ,Cell Biology ,Hematology ,DNA Methylation ,Prognosis ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Leukemia ,chemistry ,Genetic Loci ,Ibrutinib ,10032 Clinic for Oncology and Hematology ,DNA methylation ,Disease Progression ,Cancer research - Abstract
Alterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment.
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- 2019
155. Targeting BCL2 in Chronic Lymphocytic Leukemia and Other Hematologic Malignancies
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William G. Wierda and Fevzi Firat Yalniz
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Programmed cell death ,Chronic lymphocytic leukemia ,Antineoplastic Agents ,Apoptosis ,Piperazines ,Nitrophenols ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Pharmacology (medical) ,Molecular Targeted Therapy ,Drug Approval ,Sulfonamides ,Aniline Compounds ,Navitoclax ,United States Food and Drug Administration ,Venetoclax ,business.industry ,Biphenyl Compounds ,Myeloid leukemia ,Bridged Bicyclo Compounds, Heterocyclic ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,United States ,Lymphoma ,Leukemia ,Proto-Oncogene Proteins c-bcl-2 ,chemistry ,Hematologic Neoplasms ,030220 oncology & carcinogenesis ,Cancer research ,business ,030217 neurology & neurosurgery - Abstract
Apoptosis, the process of programmed cell death, occurs normally during development and aging. Members of the B-cell lymphoma 2 (BCL2) family of proteins are central regulators of apoptosis, and resistance to apoptosis is one of the hallmarks of cancer. Targeting the apoptotic pathway via BCL2 inhibitors has been considered a promising treatment strategy in the past decade. Initial efforts with small molecule BH3 mimetics such as ABT-737 and ABT-263 (navitoclax) pioneered the development of the first-in-class Food and Drug Administration (FDA)-approved oral BCL2 inhibitor, venetoclax. Venetoclax was approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, and is now being studied in a number of hematologic malignancies. Several other inhibitors targeting different BCL2 family members are now in early stages of development.
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- 2019
156. Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables
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Stephan Stilgenbauer, Lang Zhou, Su Young Kim, Shuo Ma, Michael Hallek, Kathryn Humphrey, Barbara Eichhorst, Brenda Chyla, Andrew W. Roberts, John C. Byrd, Steven Coutre, John F. Seymour, Thomas J. Kipps, Jalaja Potluri, Matthew S. Davids, William G. Wierda, Maria Verdugo, and Jacqueline Nielsen
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Adult ,Male ,medicine.medical_specialty ,Clinical Trials and Observations ,Chronic lymphocytic leukemia ,Immunology ,Antineoplastic Agents ,Kaplan-Meier Estimate ,Biochemistry ,Gastroenterology ,chemistry.chemical_compound ,Internal medicine ,Humans ,Medicine ,Progression-free survival ,Aged ,Aged, 80 and over ,Sulfonamides ,Hematology ,business.industry ,Venetoclax ,Cell Biology ,Middle Aged ,Bridged Bicyclo Compounds, Heterocyclic ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Minimal residual disease ,Progression-Free Survival ,Lymphoma ,Leukemia ,chemistry ,Female ,Rituximab ,Neoplasm Recurrence, Local ,business ,Biomarkers ,medicine.drug - Abstract
To define the efficacy of venetoclax with extended follow-up and identify clinical or biological treatment effect modifiers, updated data for previously treated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) enrolled in 4 early-phase trials were pooled. Rates of response, complete remission (CR/CRi), and undetectable minimal residual disease (U-MRD) were analyzed for all patients (n = 436) and for those patients who were planned to receive 400 mg/day monotherapy (n = 347). Univariate and multiple regression analyses were performed to identify the pretreatment factors associated with response rates and duration of response (DoR). Objective responses were documented in 75% of all patients, including 22% CR/CRi. Overall, 27% and 16% of the patients achieved U-MRD in blood and marrow, respectively. Estimated median progression-free survival (PFS), DoR, and time to progression were 30.2, 38.4, and 36.9 months, respectively. Similar efficacy outcomes were observed within the 400 mg/day monotherapy subset. For those who achieved CR/CRi, the 3-year PFS estimate was 83%. DoR was superior for patients achieving CR/CRi or U-MRD in landmark analyses. In multiple regression analyses, bulky lymphadenopathy (≥5 cm) and refractoriness to B-cell receptor inhibitor (BCRi) therapy were significantly associated with lower CR rate and shorter DoR. Fewer prior therapies were associated with higher CR rate, but not DoR. Chromosome 17p deletion and/or TP53 mutation and NOTCH1 mutation were consistently associated with shorter DoR, but not probability of response. Thus, both pretreatment factors and depth of response correlated with DoR with venetoclax. Patients without bulky lymphadenopathy, BCRi-refractory CLL, or an adverse mutation profile had the most durable benefit.
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- 2019
157. Association of gene mutations with time‐to‐first treatment in 384 treatment‐naive chronic lymphocytic leukaemia patients
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Alessandra Ferrajoli, Keyur P. Patel, Chi Young Ok, Sanam Loghavi, Prithviraj Bose, Francesco Paolo Tambaro, Boyu Hu, Zhuang Zuo, C. Cameron Yin, William G. Wierda, Xuemei Wang, Hsiang-Chun Chen, Zeev Estrov, Nitin Jain, Jan A. Burger, Mark J. Routbort, Rajyalakshmi Luthra, Guilin Tang, Michael J. Keating, Rashmi Kanagal-Shamanna, L. Jeffrey Medeiros, and Philip A. Thompson
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Gene mutation ,CD38 ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,hemic and lymphatic diseases ,Internal medicine ,Complex Karyotype ,medicine ,Humans ,Aged ,Aged, 80 and over ,business.industry ,ZAP70 ,Karyotype ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Neoplasm Proteins ,Survival Rate ,030220 oncology & carcinogenesis ,Mutation ,Female ,IGHV@ ,business ,Trisomy ,030215 immunology - Abstract
This study correlated somatic mutation results and known prognostic factors with time-to-first treatment (TTFT) in 384 treatment-naive (TN) chronic lymphocytic leukaemia (CLL) patients to help determine disease-specific drivers of early untreated CLL. CLL DNA from either peripheral blood or bone marrow underwent next generation targeted sequencing with a 29-gene panel. Gene mutation data and concurrent clinical characteristics, such as Rai/Binet stage, fluorescence in situ hybridisation (FISH), ZAP70/CD38, karyotype and IGHV mutation, status were analysed in univariable and multivariable analyses to identify associations with TTFT. TTFT was defined as time from diagnosis to initial treatment. In univariable analyses, mutated ATM (P < 0·001), NOTCH1 (P < 0·001) and SF3B1 (P = 0·002) as well as unmutated IGHV (P < 0·001), del(11q) (P < 0·001) and trisomy 12 (P < 0·001) by hierarchal FISH and advanced Rai (P = 0·05) and Binet (P < 0·001) stages were associated with shorter TTFT. Importantly, del(17p), mutated TP53 and complex karyotype were not associated with shorter TTFT. In a reduced multivariable analysis, mutated ATM (P < 0·001) and unmutated IGHV status (P < 0·001) remained significant, showing their importance in early leukaemogenesis. High-risk prognostic markers such as del(17p), mutated TP53 and complex karyotype, were not correlated with TTFT, suggesting that these abnormalities have limited roles in early disease progression but are more important in relapsed CLL.
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- 2019
158. PIM kinase inhibitor, AZD1208, inhibits protein translation and induces autophagy in primary chronic lymphocytic leukemia cells
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Varsha Gandhi, Mary Ayres, Christine M. Stellrecht, Michael J. Keating, Fabiola Cervantes-Gomez, and William G. Wierda
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0301 basic medicine ,Programmed cell death ,autophagy ,Chronic lymphocytic leukemia ,PIM1 ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,PIM kinase ,protein translation ,Kinase ,Chemistry ,Autophagy ,apoptosis ,Cell cycle ,medicine.disease ,3. Good health ,Leukemia ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,chronic lymphocytic leukemia ,Research Paper - Abstract
The PIM1, PIM2, and PIM3 serine/threonine kinases play a role in the proliferation and survival of cancer cells. Mice lacking these three kinases were viable. Further, in human hematological malignancies, these proteins are overexpressed making them suitable targets. Several small molecule inhibitors against this enzyme were synthesized and tested. AZD1208, an orally available small-molecule drug, inhibits all three PIM kinases at a low nanomolar range. AZD1208 has been tested in clinical trials for patients with solid tumors and hematological malignancies, especially acute myelogenous leukemia. The present study evaluated the efficacy and biological actions of AZD1208 in chronic lymphocytic leukemia (CLL) cells. CLL cells had higher levels of PIM2 protein and mRNAs than did normal lymphocytes from healthy donors. Treatment of CLL lymphocytes with AZD1208 resulted in modest cell death, whereas practically no cytotoxicity was observed in healthy lymphocytes. To determine the mechanism by which AZD1208 inhibits PIM kinase function, we evaluated PIM kinase pathway and downstream substrates. Because peripheral blood CLL cells are replicationally quiescent, we analyzed substrates involved in apoptosis, transcription, and translation but not cell cycle targets. AZD1208 inhibited protein translation by decreasing phosphorylation levels of 4E-binding protein 1 (4E-BP1). AZD1208 induced autophagy in replicationally-quiescent CLL cells, which is consistent with protein translation inhibition. These data suggest that AZD1208 may elicit cytotoxicity in CLL cells through inhibiting translation and autophagy induction.
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- 2019
159. Routine sequencing in<scp>CLL</scp>has prognostic implications and provides new insight into pathogenesis and targeted treatments
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Rajyalakshmi Luthra, Cheng C Yin, Alessandra Ferrajoli, Keyur P. Patel, Xuemei Wang, Zhuang Zuo, Hsiang-Chun Chen, Guilin Tang, Prithviraj Bose, Michael J. Keating, Boyu Hu, Zeev Estrov, Mark J. Routbort, Francesco Paolo Tambaro, Chi Young Ok, William G. Wierda, Nitin Jain, L. J. Medeiros, Philip A. Thompson, Rashmi Kanagal-Shamanna, Feng Wang, Jan A. Burger, and Sanam Loghavi
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Adult ,Male ,Gene mutation ,medicine.disease_cause ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Missense mutation ,Gene ,Aged ,Aged, 80 and over ,Mutation ,business.industry ,Genetic heterogeneity ,High-Throughput Nucleotide Sequencing ,Hematology ,Middle Aged ,Prognosis ,Leukemia, Lymphocytic, Chronic, B-Cell ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Bone marrow ,IGHV@ ,business ,030215 immunology - Abstract
Chronic lymphocytic leukaemia (CLL) is a genetically heterogeneous disease characterised by genomic alterations and gene mutations that may portend worse survival or resistance to treatments. A total of 680 blood or bone marrow samples underwent targeted sequencing of 29 genes previously identified as being mutated in CLL, which were correlated to known prognostic clinical characteristics. Overall, 400 (59%) patients were treatment-naive (TN) and 280 (41%) were relapsed/refractory (R/R). Most patients (70%) had ≥1 mutation, with TP53 (22%), SF3B1 (18%), NOTCH1 (13%) and ATM (13%) being the most commonly mutated genes. A higher proportion of R/R patients had mutations in SF3B1 (P = 0·01) and TP53 (P < 0·001). Patients with mutated IGHV CLL more often had mutations in KLHL6 (P = 0·001) and MYD88 (P < 0·001). Pairwise associations showed mutational co-occurrences in the TN group including SF3B1/ATM [false discovery rate (FDR) < 0·05] and NOTCH1/POT1 (FDR < 0·01). Recurrent mutations resulting in premature truncation prior to the ubiquitination domains of NOTCH1 in its PEST domain and BIRC3 in its RING domain can produce proteins that constitutively activate CLL. Frequent missense mutations, such as K700E in SF3B1 and E571K in XPO1, have unknown function but are most likely to be activating mutations. Future directions include using these mutations to identify pathways for therapeutic targeting and rational drug design.
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- 2019
160. Utility of positron emission tomography-computed tomography in patients with chronic lymphocytic leukemia following B-cell receptor pathway inhibitor therapy
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Herbert Eradat, Paul M. Barr, Sharanya M. Ford, Jalaja Potluri, Maria Verdugo, Anthony R. Mato, William G. Wierda, Lang Zhou, Richard R. Furman, Leonard T. Heffner, Michael Y. Choi, John C. Byrd, Bruce D. Cheson, Steven Coutre, Rod A. Humerickhouse, and Matthew S. Davids
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Adult ,Male ,medicine.medical_specialty ,Biopsy ,Chronic lymphocytic leukemia ,Receptors, Antigen, B-Cell ,Phases of clinical research ,Standardized uptake value ,Gastroenterology ,Article ,Young Adult ,chemistry.chemical_compound ,Chemoimmunotherapy ,Positron Emission Tomography Computed Tomography ,Internal medicine ,medicine ,Humans ,Chronic Lymphocytic Leukemia ,Molecular Targeted Therapy ,Aged ,Aged, 80 and over ,medicine.diagnostic_test ,Venetoclax ,business.industry ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Treatment Outcome ,chemistry ,Ibrutinib ,Disease Progression ,Female ,Idelalisib ,business ,Signal Transduction - Abstract
The utility of positron emission tomography-computed tomography (PET-CT) in distinguishing Richter's transformation versus chronic lymphocytic leukemia (CLL) progression after ibrutinib and/or idelalisib was assessed in a post hoc analysis of a phase II study of venetoclax. Patients underwent PET-CT at screening and were not enrolled/treated if Richter's transformation was confirmed pathologically. Of 167 patients screened, 57 met criteria for biopsy after PET-CT. Of 35 patients who underwent biopsy, eight had Richter's transformation, two had another malignancy, and 25 had CLL. A PET-CT maximum standardized uptake value (SUVmax) ≥10 had 71% sensitivity and 50% specificity for detecting Richter's transformation [Odds Ratio (OR): 2.5, 95%CI: 0.4-15; P=0.318]. Response rate to venetoclax was similar for screening SUVmax
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- 2019
161. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia
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Maro Ohanian, Alessandra Ferrajoli, Mariela Sivina, Fong Clow, Zeev Estrov, Graciela M. Nogueras-Gonzalez, Michael J. Keating, Thomas Mathew, Ekaterina Kim, Xuelin Huang, Jeffrey L. Jorgensen, William G. Wierda, Hagop M. Kantarjian, Philip A. Thompson, Nitin Jain, Jianling Li, Tapan M. Kadia, Jan A. Burger, Michael Andreeff, Mei Cheng, and Susan O'Brien
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Male ,Oncology ,Neoplasm, Residual ,Chronic lymphocytic leukemia ,Kaplan-Meier Estimate ,Biochemistry ,law.invention ,chemistry.chemical_compound ,Antineoplastic Agents, Immunological ,Piperidines ,Randomized controlled trial ,immune system diseases ,law ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,Medicine ,Aged, 80 and over ,education.field_of_study ,Remission Induction ,Hematology ,Middle Aged ,Leukemia ,Treatment Outcome ,Ibrutinib ,Disease Progression ,Female ,Rituximab ,BLOOD Commentary ,medicine.drug ,Adult ,medicine.medical_specialty ,Immunology ,Population ,Disease-Free Survival ,Drug Administration Schedule ,Internal medicine ,Humans ,education ,Aged ,business.industry ,Adenine ,Cell Biology ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Clinical trial ,Pyrimidines ,chemistry ,Pyrazoles ,business - Abstract
Ibrutinib, an oral covalent inhibitor of Bruton’s tyrosine kinase, is an effective therapy for patients with chronic lymphocytic leukemia (CLL). To determine whether rituximab provides added benefit to ibrutinib, we conducted a randomized single-center trial of ibrutinib vs ibrutinib plus rituximab. Patients with CLL requiring therapy were randomized to receive 28-day cycles of once-daily ibrutinib 420 mg, either as a single agent (n = 104), or together with rituximab (375 mg/m2; n = 104), given weekly during cycle 1, then once per cycle until cycle 6. The primary end point was progression-free survival (PFS) in the intention-to-treat population. We enrolled 208 patients with CLL, 181 with relapsed CLL and 27 treatment-naive patients with high-risk disease (17p deletion or TP53 mutation). After a median follow-up of 36 months, the Kaplan-Meier estimates of PFS were 86% (95% confidence interval [CI], 76.6-91.9) for patients receiving ibrutinib, and 86.9% (95% CI, 77.3-92.6) for patients receiving ibrutinib plus rituximab. Similarly, response rates were the same in both arms (overall response rate, 92%). However, time to normalization of peripheral blood lymphocyte counts and time to complete remission were shorter, and residual disease levels in the bone marrow were lower, in patients receiving ibrutinib plus rituximab. We conclude that the addition of rituximab to ibrutinib in relapsed and treatment-naive high-risk patients with CLL failed to show improvement in PFS. However, patients treated with ibrutinib plus rituximab reached their remissions faster and achieved significantly lower residual disease levels. Given these results, ibrutinib as single-agent therapy remains current standard-of-care treatment in CLL. This trial was registered at www.clinicaltrials.gov as #NCT02007044.
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- 2019
162. Tolerability and activity of ublituximab, umbralisib, and ibrutinib in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: a phase 1 dose escalation and expansion trial
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Marshall T. Schreeder, Julie M. Vose, Matthew A. Lunning, Susan O'Brien, Hari P. Miskin, Loretta J. Nastoupil, Michael S. Weiss, Christopher R. Flowers, William G. Wierda, Jan A. Burger, Jonathon B. Cohen, M. Purdom, Nathan Fowler, Tanya Siddiqi, and Peter Sportelli
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Male ,medicine.medical_specialty ,Antineoplastic Agents ,Neutropenia ,Heterocyclic Compounds, 4 or More Rings ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,Internal medicine ,medicine ,Humans ,Adverse effect ,Aged ,Pneumonitis ,Dose-Response Relationship, Drug ,Performance status ,business.industry ,Adenine ,Lymphoma, Non-Hodgkin ,Antibodies, Monoclonal ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Rash ,Lymphoma ,Pyrimidines ,Tolerability ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,Pyrazoles ,Female ,Safety ,medicine.symptom ,business ,030215 immunology - Abstract
Summary Background Therapeutic approaches for B-cell malignancies continue to evolve, especially with regard to combination approaches. We assessed the safety and efficacy of the triplet ublituximab, umbralisib, and ibrutinib in patients with advanced B-cell malignancies. Methods We did an open-label, phase 1 study with dose-escalation and dose-expansion phases, at five centres in the USA. Eligible patients were aged 18 years or older with histologically confirmed lymphocytic leukaemia or relapsed or refractory B-cell non-Hodgkin lymphoma, had measurable disease, adequate organ function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Patients with known CNS lymphoma, active hepatitis B or C infection, or HIV were excluded. In the dose-escalation cohort, patients were treated in cycles of 28 days with escalating doses of oral umbralisib (400, 600, or 800 mg) and fixed doses of intravenous ublituximab (900 mg) and oral ibrutinib (420 mg for patients with chronic lymphocytic leukaemia; 560 mg for patients with B-cell non-Hodgkin lymphoma) in a standard 3 × 3 design until disease progression or intolerance. In the dose-expansion phase, patients were given the recommended dose of the drug combination as determined from the dose-escalation phase. The primary endpoints were safety, dose-limiting toxicities, and the maximum tolerated dose of umbralisib, when given in combination with ublituximab and ibrutinib. Safety was assessed in patients who received at least one dose of study drug; activity was assessed in all patients who had at least one post-treatment efficacy measurement. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT02006485. Findings Between Sept 2, 2014, and Nov 6, 2017, we enrolled 46 patients: 24 in the dose-escalation cohort (n=14 chronic lymphocytic leukaemia or small lymphocytic lymphoma; n=10 B-cell non-Hodgkin lymphoma) and 22 in the dose-expansion cohort (n=9 chronic lymphocytic leukaemia or small lymphocytic lymphoma; n=13 B-cell non-Hodgkin lymphoma). 46 patients received at least one dose of study drug. The maximum tolerated dose of umbralisib was not reached. The recommended dose for the dose-expansion phase was umbralisib 800 mg orally once daily plus ibrutinib orally once daily and intravenous ublituximab 900 mg administered on days 1, 8, and 15 of cycle 1, day 1 of cycles 2–6, and on day 1 of cycles 9 and 12. 37 (84%) of 44 patients achieved an overall response (complete or partial response). The most common any-grade adverse events were diarrhoea (n=27 [59%]), fatigue (n=23 [50%]), infusion-related reaction (n=20 [43%]), dizziness (n=17 [37%]), nausea (n=17 [37%]), and cough (n=16 [35%]). Grade 3–4 adverse events were manageable with the most common being neutropenia (n=10 [22%]) and cellulitis (n=6 [13%]). Serious adverse events occurred in 11 (24%) of 46 patients and included rash (n=2 [4%]), pneumonia (n=2 [4%]), atrial fibrillation (n=2 [4%]), sepsis (n=2 [4%]), abdominal pain (n=1 [2%]), syncope (n=1 [2%]), cellulitis (n=1 [2%]), pneumonitis (n=1 [2%]), headache (n=1 [2%]), lung infection (n=1 [2%]), skin infection (n=1 [2%]), pleural effusion (n=1 [2%]), pericardial infusion (n=1 [2%]), upper gastrointestinal bleeding (n=1 [2%]), diarrhoea (n=1 [2%]), and weakness (n=1 [2%]). No deaths related to adverse events occurred. Interpretation The combination of ublituximab, umbralisib, and ibrutinib seems to be tolerable and is associated with encouraging activity in advanced chronic lymphocytic leukaemia and B-cell non-Hodgkin lymphoma. This triplet combination will require further investigation in future studies to improve understanding of this novel, chemotherapy-free triplet combination in the management of these cancers. Funding TG Therapeutics.
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- 2019
163. Creating novel translation inhibitors to target pro-survival proteins in chronic lymphocytic leukemia
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William G. Wierda, Shuxing Zhang, Qun Qin, Mingzhao Zhu, Rong Chen, William Plunkett, Yuling Chen, Wesley Skillern, Kenneth G. Hull, Rajan Chaudhari, Daniel Romo, and Omar Robles
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Male ,Models, Molecular ,0301 basic medicine ,Cancer Research ,Protein Conformation ,Chronic lymphocytic leukemia ,Apoptosis ,Context (language use) ,Plasma protein binding ,Article ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Biomarkers, Tumor ,Tumor Cells, Cultured ,medicine ,Humans ,Initiation factor ,RNA, Messenger ,Aged ,Aged, 80 and over ,Sulfonamides ,Chemistry ,Drug Synergism ,Translation (biology) ,Hematology ,Middle Aged ,Bridged Bicyclo Compounds, Heterocyclic ,Prognosis ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Gene Expression Regulation, Neoplastic ,Thiazoles ,Leukemia ,030104 developmental biology ,Proto-Oncogene Proteins c-bcl-2 ,Oncology ,Protein Biosynthesis ,030220 oncology & carcinogenesis ,eIF4A ,Eukaryotic Initiation Factor-4A ,Cancer research ,Epoxy Compounds ,Myeloid Cell Leukemia Sequence 1 Protein ,Drug Therapy, Combination ,Female ,Macrolides ,Follow-Up Studies - Abstract
The viability of chronic lymphocytic leukemia (CLL) is critically dependent upon staving off death by apoptosis, a hallmark of CLL pathophysiology. The recognition that Mcl-1, a major component of the anti-apoptotic response, is intrinsically short-lived and must be continually resynthesized suggested a novel therapeutic approach. Pateamine A (PatA), a macrolide marine natural product, inhibits cap-dependent translation by binding to the initiation factor eIF4A. In this study, we demonstrated that a synthetic derivative of PatA, des-methyl des-amino PatA (DMDAPatA), blocked mRNA translation, reduced Mcl-1 protein and initiated apoptosis in CLL cells. This action was synergistic with the Bcl-2 antagonist ABT-199. However, avid binding to human plasma proteins limited DMDAPatA potency, precluding further development. To address this, we synthesized a new series of PatA analogs and identified three new leads with potent inhibition of translation. They exhibited less plasma protein binding and increased cytotoxic potency toward CLL cells than DMDAPatA, with greater selectivity towards CLL cells over normal lymphocytes. Computer modeling analysis correlated their structure-activity relationships and suggested that these compounds may act by stabilizing the closed conformation of eIF4A. Thus, these novel PatA analogs hold promise for application to cancers within the appropriate biological context, such as CLL.
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- 2019
164. Abstract CT028: Fixed-duration (FD) ibrutinib (Ibr) + venetoclax (Ven) for first-line treatment of chronic lymphocytic leukemia (CLL) in patients (pts) with high-risk features: phase 2 CAPTIVATE study
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John N. Allan, Ian W. Flinn, Tanya Siddiqi, Paolo Ghia, Constantine S. Tam, Thomas J. Kipps, Paul M. Barr, Anna Elinder Camburn, Alessandra Tedeschi, Xavier C. Badoux, Ryan Jacobs, Bryone J. Kuss, Livio Trentin, Cathy Zhou, Anita Szoke, Maoko Naganuma, and William G. Wierda
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Cancer Research ,Oncology - Abstract
Background: CAPTIVATE (PCYC-1142; NCT02910583) is an international, multicenter phase 2 study of first-line Ibr + Ven in CLL with 2 cohorts: the Minimal Residual Disease (MRD) and FD cohorts. FD Ibr + Ven provides deep, durable responses (Ghia, ASCO 2021; Wierda, J Clin Oncol 2021). Here, we report efficacy and safety of FD Ibr + Ven in pts with high-risk features. Methods: Pts aged ≤70 y with previously untreated CLL received 3 cycles of Ibr then 12 cycles of Ibr + Ven (Ibr 420 mg/d orally; Ven ramp-up to 400 mg/d orally). Pts in the FD cohort received no further treatment. Pts in the MRD cohort were randomized to subsequent treatment according to MRD status, including a placebo arm for pts who achieved confirmed undetectable MRD (uMRD) with 12 cycles of Ibr + Ven. Data from the FD cohort and MRD cohort placebo arm were pooled for pts with high-risk features (del(17p), TP53 mutated, or unmutated IGHV) treated with FD Ibr + Ven. Results: Of 202 pts treated with FD Ibr + Ven in the FD cohort (n=159) or MRD cohort placebo arm (n=43), 129 pts had high-risk features (Table). Median time on study for these pts was 28.7 mo (range 0.8-45.1). 94% of pts completed planned treatment with Ibr and Ven. Median treatment duration was 13.8 mo (range 0.7-24.9) for Ibr and 11.1 mo (range 9.9-22.1) for Ven. Best response rates of CR and uMRD in peripheral blood and bone marrow were high (Table). The 18-mo landmark estimate for duration of CR was 95%. 24-mo PFS rate was 94%, which was similar to pts without high-risk features (97%). Only 3% of pts discontinued Ibr or Ven due to AEs. The AE profile of Ibr + Ven in pts with high-risk features showed no new safety findings for this FD regimen (Table). Conclusion: First-line Ibr + Ven for a fixed duration provides durable treatment-free remissions and sustained PFS in pts with CLL. These clinical outcomes are maintained in pts with high-risk features, with PFS rates that were similar to pts without high-risk features. Table. Baseline characteristics, efficacy outcomes, and safety Pts with high-risk features (n=129) BASELINE CHARACTERISTICS Median age, y (range) 60 (33-70) Rai stage III/IV, n (%) 36 (28) Bulky disease ≥5 cm, n (%) 47 (36) Genomic risk features, n (%) del(17p) and/or TP53 mutated 29 (22) Unmutated IGHV 119 (92) Complex karyotypea 27 (21) EFFICACY OUTCOMES Overall response rate, n (%) 126 (98) CR, n (%) 76 (59) 18-mo DOCR, % (95% CI) 95 (85-98) uMRD Citation Format: John N. Allan, Ian W. Flinn, Tanya Siddiqi, Paolo Ghia, Constantine S. Tam, Thomas J. Kipps, Paul M. Barr, Anna Elinder Camburn, Alessandra Tedeschi, Xavier C. Badoux, Ryan Jacobs, Bryone J. Kuss, Livio Trentin, Cathy Zhou, Anita Szoke, Maoko Naganuma, William G. Wierda. Fixed-duration (FD) ibrutinib (Ibr) + venetoclax (Ven) for first-line treatment of chronic lymphocytic leukemia (CLL) in patients (pts) with high-risk features: phase 2 CAPTIVATE study [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 CT028.
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- 2022
165. Abstract CT138: Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in combination with venetoclax ± rituximab in relapsed/refractory chronic lymphocytic leukemia: Results from the BRUIN phase 1b study
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Lindsey E. Roeker, Anthony R. Mato, Jennifer R. Brown, Catherine C. Coombs, Nirav N. Shah, William G. Wierda, Manish R. Patel, Katharine L. Lewis, Minna Balbas, Junjie Zhao, Nora C. Ku, Jennifer F. Kherani, Donald E. Tsai, Binoj Nair, and Chan Y. Cheah
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Cancer Research ,Oncology - Abstract
Background: Covalent Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia (CLL), but patients (pts) discontinue these agents due to resistance or intolerance. Pirtobrutinib is an oral, highly selective, non-covalent (reversible) BTKi with promising efficacy and safety in heavily pretreated relapsed/refractory (R/R) CLL pts, regardless of BTK C481 mutation status. Recent clinical studies reported on the safety and efficacy of time-limited venetoclax and covalent BTKi combination regimens. We evaluated the safety and efficacy of pirtobrutinib combined with venetoclax ± rituximab in pts with R/R CLL. Methods: BRUIN is a phase 1/2 global, multicenter study (NCT03740529) of pirtobrutinib in pts with advanced B-cell malignancies. The phase 1b portion evaluated the safety of pirtobrutinib at a continuous dose of 200 mg QD from Cycle 1, Day 1 plus venetoclax starting on Cycle 2, Day 1 with a standard 5-week dose ramp to 400 mg QD (PV) and PV plus rituximab at 375 mg/m2 on Cycle 1, Day 1, then 500 mg/m2 on Day 1 of Cycles 2-6 (PVR). Prior BTKi was allowed; prior venetoclax was not permitted. Objectives included safety and overall response rate (ORR) of each combination. Results: As of 27 SEP 2021, 15 pts received PV and 10 pts received PVR. Median age was 66 years (range, 39-78). Median prior lines of therapy was 2 (range, 1-4). The majority of pts in both cohorts had received prior chemotherapy (56%, n=14), CD20 monoclonal antibody (72%, n=18), and/or covalent BTKi (68%, n=17). No dose-limiting toxicities were reported. Safety profiles were generally similar across both cohorts. The most common treatment-emergent adverse events (TEAE) of any grade, regardless of attribution, were neutrophil count decrease (36%), nausea (32%), fatigue (32%), diarrhea (28%), and constipation (24%). The only Grade ≥3 TEAE to occur in more than 2 pts was neutrophil count decrease (36%, n=9). One pt experienced Grade 4 clinical tumor lysis syndrome with resultant acute kidney injury during venetoclax dose escalation, which resolved with supportive measures. No pts discontinued treatment due to AEs. For the 22 pts with efficacy data available as of 03 NOV 2021, median duration of follow-up was 9 months (range, 3.9-15) and the ORR was 95.5% (95% CI, 77-100). All responding pts except 1 remain on therapy (PVR responder discontinued due to death unrelated to study treatment). As all responses were ongoing and early, and MRD analysis was not yet performed. Conclusions: Pirtobrutinib combined with venetoclax ± rituximab was well tolerated and had a safety profile consistent with known drug class findings and no clear additive toxicities in pts with R/R CLL. Early results demonstrate promising efficacy with combination therapy. Citation Format: Lindsey E. Roeker, Anthony R. Mato, Jennifer R. Brown, Catherine C. Coombs, Nirav N. Shah, William G. Wierda, Manish R. Patel, Katharine L. Lewis, Minna Balbas, Junjie Zhao, Nora C. Ku, Jennifer F. Kherani, Donald E. Tsai, Binoj Nair, Chan Y. Cheah. Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in combination with venetoclax ± rituximab in relapsed/refractory chronic lymphocytic leukemia: Results from the BRUIN phase 1b study [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 CT138.
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- 2022
166. A first-in-human phase 1 trial of NX-2127, a first-in-class oral BTK degrader with IMiD-like activity, in patients with relapsed and refractory B-cell malignancies
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Anthony Mato, Alexey Valeryevich Danilov, Manish R. Patel, Michael Timothy Tees, Ian W. Flinn, Weiyun Z. Ai, Krish Patel, Michael Wang, Susan M. O'Brien, Srinand Nandakumar, May Tan, Erin Meredith, Melissa Gessner, Su Young Kim, Adrian Wiestner, and William G. Wierda
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Cancer Research ,Oncology - Abstract
TPS7581 Background: Bruton’s tyrosine kinase inhibitors (BTKi) have received regulatory approvals and are standard of care for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and WaldenstrÖm macroglobulinemia (WM). However, BTKi-resistant disease remains a clinical challenge with limited options for subsequent therapy. Immunomodulatory drugs (IMiDs, e.g., lenalidomide) are approved as monotherapy for follicular lymphoma (FL), MZL, and MCL, in combination with other therapies for diffuse large B-cell lymphoma (DLBCL) and have shown synergy with BTK-targeted therapy. Dual activity of BTK protein degradation with IMiD-like activity offers a unique approach to overcome known resistance to BTKi. NX-2127 is an oral small molecule that induces BTK degradation via recruitment of cereblon, an adaptor protein of the E3 ubiquitin ligase complex. NX-2127 has shown preclinical activity similar to IMiDs by catalyzing the ubiquitination of Ikaros (IKZF1) and Aiolos (IKZF3), ultimately leading to increased T-cell activation. NX-2127 was shown to degrade both wild-type (WT) and C481-mutated (ibrutinib-resistant) BTK protein in vitro. Robust BTK degradation was also shown in non-human primate studies. Further, NX-2127 demonstrates potent tumor growth inhibition in BTK-dependent mouse xenograft tumor models expressing either WT or ibrutinib-resistant C481S BTK-mutant protein. This dual activity of BTK degradation and IMiD-like activity offers a promising treatment for patients who have failed prior therapy. Methods: NX-2127-001 is a first-in-human, dose escalation (Phase 1a) and cohort expansion (Phase 1b) study designed to evaluate the safety, tolerability, and preliminary efficacy of NX-2127 in adult patients with relapsed/refractory B-cell malignancies with once daily oral dosing. Dose escalation will proceed using a modified Fibonacci design with 1 patient per cohort, proceeding to a standard 3 + 3 design based on protocol specified criteria. There will be up to 5 expansion cohorts in Phase 1b enrolling patients with CLL/SLL, DLBCL, FL, MCL, MZL, and WM. Key eligibility criteria include >2 two prior lines of therapy (>1 prior for WM); measurable disease; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Approximately 130 patients (30 in Phase 1a, 100 in Phase 1b) will be enrolled and treated until disease progression or unacceptable toxicity. The primary objectives are to evaluate safety and tolerability and to determine the maximum tolerated dose (Phase 1a), and to evaluate the early clinical activity of NX-2127 in expansion cohorts (Phase 1b). The Phase 1a part of this study is currently enrolling in the United States. Clinical trial information: NCT04830137.
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- 2022
167. Fixed-duration (FD) ibrutinib (I) + venetoclax (V) for first-line (1L) treatment (tx) of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Three-year follow-up from the FD cohort of the phase 2 CAPTIVATE study
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William G. Wierda, Paul M. Barr, Tanya Siddiqi, John N. Allan, Thomas J. Kipps, Livio Trentin, Ryan Jacobs, Sharon Jackson, Alessandra Tedeschi, Stephen Opat, Rajat Bannerji, Bryone J. Kuss, Carol Moreno, Lisa J. Croner, Edith Szafer-Glusman, Cathy Zhou, Anita Szoke, James P. Dean, Paolo Ghia, and Constantine Si Lun Tam
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Cancer Research ,Oncology - Abstract
7519 Background: CAPTIVATE (PCYC-1142) is a multicenter phase 2 study of 1L I+V in CLL. The primary analysis (PA) evaluating FD tx with I+V was previously presented (Ghia et al., ASCO 2021). Here we present 3-y follow-up results from the FD cohort. Methods: Patients (pts) aged ≤70 y with previously untreated CLL/SLL received 3 cycles of I then 12 cycles of I+V (I 420 mg/d orally; V ramp-up to 400 mg/d orally). Responses were investigator assessed per iwCLL 2008 criteria. Undetectable minimal residual disease (uMRD; -4) was measured by 8-color flow cytometry. Serious AEs (SAEs) deemed related to I reported >30 d after last dose of study drug were collected. Results: 159 pts were enrolled (median age 60 y), including pts with high-risk features of del(17p)/ TP53 mutation (17%), unmutated IGHV (uIGHV; 56%), and complex karyotype (19%). 147 (92%) and 149 (94%) pts completed tx with I and V, respectively. With 1 y of additional follow-up since PA, median time on study was 39 mo (range 1-41). ORR was 96% and was consistent (96%-97%) in pts with high-risk features (Table).The primary endpoint of complete response (CR) including CR with incomplete bone marrow recovery (CRi) rate in pts without del(17p) (n=136) increased nominally from 56% (95% CI, 48-64) to 58% (95% CI 50-66); in all pts, CR rate increased from 55% (95% CI 48-63) to 57% (95% CI 50-65). In pts achieving CR, 93% had durable responses lasting ≥12 mo post-tx. Of pts with uMRD in peripheral blood at 3 mo post-tx, 66/85 (78%) evaluable pts maintained uMRD through 12-mo post-tx. At 36 mo, PFS was 88% (95% CI 82‒92) and OS was 98% (95% CI 94‒99); similar rates were seen in pts with high-risk features (Table). All pts are off tx; no new SAEs of any kind have occurred since the PA. Available data on relevant mutations in BTK, PLCɣ2, or BCL-2 at time of PD will be presented. As of January 2022, 12 pts were retreated with single-agent I after PD (tx duration range 3-29 mo); of evaluated pts, 7/9 had partial responses and 2/9 had stable disease. Conclusions: Fixed duration I+V continues to provide deep, durable responses and clinically meaningful PFS, including in pts with high-risk disease features, representing an all-oral, once-daily, chemotherapy-free FD regimen for previously untreated pts with CLL/SLL. With an additional 1 y of follow-up, no OS events or SAEs occurred. Manageable safety profile is unchanged as previously reported. To date, successful single-agent I retreatment responses are observed. Clinical trial information: NCT02910583. [Table: see text]
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- 2022
168. Updated results from a phase II study of mini-hyper-CVD (mini-HCVD) plus inotuzumab ozogamicin (INO), with or without blinatumomab (Blina), in older adults with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukemia (ALL)
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Walid Macaron, Hagop M. Kantarjian, Nicholas James Short, Farhad Ravandi, Nitin Jain, Tapan M. Kadia, Fadi Haddad, Yesid Alvarado Valero, Naval Guastad Daver, Gautam Borthakur, Courtney Denton Dinardo, Marina Konopleva, William G. Wierda, Jovitta Jacob, Edith Roy, Christopher Loiselle, Anna Milton, Juan Rivera, Rebecca Garris, and Elias Jabbour
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Cancer Research ,Oncology - Abstract
7011 Background: INO and Blina improve overall survival (OS) in patients (pts) with relapsed/refractory B-ALL. The use of these agents in older adults in the frontline setting may allow for use of less chemotherapy and improve remission duration and OS compared to standard therapies. Methods: Pts ≥60 years with newly diagnosed Ph-negative B-cell ALL received mini-HCVD for up to 8 cycles. Initially, INO was given at 1.3-1.8mg/m2 on day 3 of cycle 1 and 0.8-1.3mg/m2 on day 3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. Beginning with pt #50, INO was given in fractionated doses each cycle (0.6 mg/m2 on day 2 and 0.3 mg/m2 on day 8 of cycle 1; 0.3 mg/m2 on day 2 and 8 of cycles 2-4) and 4 cycles of Blina were given following 4 cycles of mini-HCVD plus INO. Maintenance was with 12 cycles of POMP and 4 cycles of Blina (1 cycle of Blina after 3 cycles of POMP). Results: Characteristics of the 80 pts are shown in Table. 6 pts were in complete remission (CR) at enrollment. Among 74 evaluable pts, 73 (99%) responded (CR in 89%). MRD negativity by flow was achieved in 80% of pts after 1 cycle and in 94% overall. The 30-day mortality rate was 0%. Among 79 responders, 11 (14%) relapsed, 4 (5%) underwent SCT, 33 (42%) remain in ongoing continuous remission, and 31 (39%) died in remission. Notably, 6 pts (8%) developed veno-occlusive disease, 1 after subsequent SCT. With a median follow-up of 55 months, the 5-year continuous remission and OS rates were 76% and 47%, respectively. Age ≥70 and poor-risk cytogenetics were associated with worse outcomes. The inferior outcomes in pts ≥70 years was primarily due to higher rates of death in CR. The 5-year OS for pts age 60-69 years without poor-risk cytogenetics (n=37), age 60-69 with poor-risk cytogenetics (n=13), age ≥70 without poor-risk cytogenetics (n=24) and age ≥70 with poor-risk cytogenetics (n=6) were 69%, 39%, 36% and 0%, respectively. Conclusions: The combination of mini-HCVD plus INO, with or without Blina, in older adults with newly diagnosed Ph-negative ALL resulted in an overall response rate of 99% and a 5-year OS rate of 47%. Particularly favorable outcomes were seen in pts age 60-69 years without poor-risk cytogenetics (5-year OS: 69%). Chemotherapy-free regimens may improve outcomes in pts age ≥70 years, and novel agents/regimens are still needed for those with poor-risk cytogenetics. Clinical trial information: NCT01371630. [Table: see text]
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- 2022
169. Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor–resistant chronic lymphocytic leukemia with disease progression and Richter transformation
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Alessandra Ferrajoli, Rajyalakshmi Luthra, Joseph D. Khoury, Rashmi Kanagal-Shamanna, Zeev Estrov, Michael J. Keating, Mark J. Routbort, Keyur P. Patel, Carlos E. Bueso-Ramos, Jan A. Burger, William G. Wierda, Preetesh Jain, Tahani Alhalouli, L. Jeffrey Medeiros, Nitin Jain, and Hagop M. Kantarjian
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Male ,Cancer Research ,Chronic lymphocytic leukemia ,DNA Mutational Analysis ,Gene mutation ,medicine.disease_cause ,Cohort Studies ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,immune system diseases ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Agammaglobulinaemia Tyrosine Kinase ,Longitudinal Studies ,030212 general & internal medicine ,Aged, 80 and over ,Mutation ,biology ,High-Throughput Nucleotide Sequencing ,Middle Aged ,Prognosis ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,Oncology ,Pyrazines ,030220 oncology & carcinogenesis ,Ibrutinib ,Benzamides ,Disease Progression ,Acalabrutinib ,Female ,Lymphoma, Large B-Cell, Diffuse ,Adult ,Deep sequencing ,03 medical and health sciences ,Biomarkers, Tumor ,medicine ,Humans ,Bruton's tyrosine kinase ,Aged ,business.industry ,Venetoclax ,Adenine ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Pyrimidines ,chemistry ,Drug Resistance, Neoplasm ,Cancer research ,biology.protein ,Pyrazoles ,business ,Follow-Up Studies - Abstract
Background In a proportion of patients with chronic lymphocytic leukemia (CLL), resistance to Bruton tyrosine kinase (BTK) inhibitors (BTKi) is attributed to acquired BTK/phospholipase C gamma 2 (PLCG2) mutations. However, knowledge regarding additional genetic lesions associated with BTK/PLCG2 mutations, and gene mutations in patients lacking BTK/PLCG2 mutations, is limited. Methods Using targeted deep sequencing, mutations in 29 genes associated with CLL and/or the BCR signaling pathway were assessed in patients with CLL who developed resistance to BTK inhibition with ibrutinib/acalabrutinib at a single institution. Results The study group included 29 patients with BTKi-resistant CLL, 23 patients with disease progression, and 6 patients with Richter transformation (RT). The median times to disease progression and RT were 33.3 months and 13.3 months, respectively. In 11 patients, sequencing was possible at both baseline (prior to treatment with BTKi) and at time of disease progression/RT. Of these patients, 4 demonstrated BTK mutations at the time of disease progression/RT; patients without BTK mutations frequently acquired mutations associated with disease progression/RT in TP53, SF3B1, and CARD11, whereas additional mutations were rare in patients with BTK-mutated CLL. Sequencing of all 29 patients at the time of disease progression/RT identified BTK mutations at a frequency of 66%, including a novel V537I mutation. Among patients with disease progression, BTK mutations were observed in 16 patients (70%). The median time to disease progression was shorter in patients without BTK mutations compared with those with BTK-mutated CLL. Among patients with RT, SF3B1 mutations were more frequent than BTK mutations (67% vs 50%). Following BTKi discontinuation, we sequential mutation analysis was performed in 2 patients with RT and 3 patients with disease progression in the setting of persistent disease. Both patients with RT demonstrated disappearance of BTK and expansion of TP53 mutations. All 3 patients with disease progression received venetoclax and demonstrated suppression of BTK mutations. Conclusions Longitudinal, targeted, multigene deep sequencing is informative for the clinical monitoring of mutational evolution in patients with CLL who are receiving BTKi.
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- 2018
170. Venetoclax for chronic lymphocytic leukaemia patients who progress after more than one B‐cell receptor pathway inhibitor
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Paul M. Barr, Richard R. Furman, Maria Verdugo, Herbert Eradat, Matthew S. Davids, John C. Byrd, Lang Zhou, Leonard T. Heffner, Michael Y. Choi, Bruce D. Cheson, Jalaja Potluri, and William G. Wierda
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0301 basic medicine ,B-cell receptor ,Receptors, Antigen, B-Cell ,Antineoplastic Agents ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Refractory ,Correspondence ,Humans ,Medicine ,Aged ,Aged, 80 and over ,Sulfonamides ,Lymphocytic leukaemia ,venetoclax ,business.industry ,Venetoclax ,B‐cell receptor signalling pathway inhibitor ,Hematology ,Middle Aged ,Bridged Bicyclo Compounds, Heterocyclic ,Leukemia, Lymphocytic, Chronic, B-Cell ,relapsed ,refractory ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,business ,chronic lymphocytic leukaemia - Published
- 2018
171. A pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia
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Lisa S. Chen, Varsha Gandhi, Wei Qiao, William G. Wierda, Qi Wu, Prithviraj Bose, Xuelin Huang, Nichole Cruz, Yongying Jiang, Nitin Jain, Philip A. Thompson, Michael J. Keating, Michael H. Kroll, and Shuju Feng
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Male ,Chronic lymphocytic leukemia ,Immunology ,Pilot Projects ,Pharmacology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,Pharmacokinetics ,hemic and lymphatic diseases ,Agammaglobulinaemia Tyrosine Kinase ,medicine ,Humans ,Bruton's tyrosine kinase ,Protein Kinase Inhibitors ,Aged ,Dose-Response Relationship, Drug ,biology ,business.industry ,Adenine ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Leukemia ,Dose–response relationship ,Pyrimidines ,Treatment Outcome ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,Pharmacodynamics ,Toxicity ,biology.protein ,Pyrazoles ,Female ,business ,Signal Transduction ,030215 immunology - Abstract
Ibrutinib is highly efficacious and used at 420 mg/d for treatment of chronic lymphocytic leukemia (CLL). We previously demonstrated a decline in Bruton’s tyrosine kinase (BTK) protein levels in CLL cells after 1 cycle of ibrutinib, suggesting ibrutinib dose could be lowered after the first cycle without loss of biological effect. To test this postulate, a pilot study (NCT02801578) was designed to systematically reduce ibrutinib dosing within the same patient with CLL over the course of three 28-day cycles. After an initial cycle of 420 mg/d, the dose was reduced to 280 mg/d in cycle 2, and then to 140 mg/d in cycle 3. Eleven patients began study treatment, and 9 completed the 3 cycles. Plasma and intracellular pharmacokinetics (PK), BTK occupancy, and pharmacodynamic (PD) response at different doses of ibrutinib were compared. Plasma and intracellular levels of ibrutinib were dose-dependent, and even the lowest dose was sufficient to occupy, on average, more than 95% of BTK protein. In concert, BTK downstream signaling inhibition was maintained with 140 mg/d ibrutinib in cycle 3, and there were comparable reductions in total and phospho-BTK (Tyr223) protein levels across 3 cycles. Reductions of plasma chemokine CCL3 and CCL4 levels, considered to be biomarkers of ibrutinib response, were similar during the 3 cycles. These PK/PD data demonstrate that after 1 cycle of ibrutinib at the standard 420 mg/d dose, the dose can be reduced without losing biological activity. Clinical efficacy of lower doses needs to be systematically evaluated. Such dose reductions would lower drug cost, lessen untoward toxicity, and facilitate rationale-based combinations. This trial was registered at www.clinicaltrials.gov as #NCT02801578.
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- 2018
172. Addition of eltrombopag to immunosuppressive therapy in patients with newly diagnosed aplastic anemia
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Zeev Estrov, Naval Daver, Yesid Alvarado, Rita Assi, Elias Jabbour, Alessandra Ferrajoli, Farhad Ravandi, Tapan M. Kadia, Jan A. Burger, Courtney D. DiNardo, Guillermo Garcia-Manero, Gautam Borthakur, William G. Wierda, Stephany Hendrickson, Hagop M. Kantarjian, and Jorge E. Cortes
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Cancer Research ,medicine.medical_specialty ,business.industry ,Eltrombopag ,medicine.disease ,Gastroenterology ,Pathophysiology ,03 medical and health sciences ,Haematopoiesis ,chemistry.chemical_compound ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,chemistry ,Refractory ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Bone marrow ,Stem cell ,Progenitor cell ,Aplastic anemia ,business ,030215 immunology - Abstract
Background The immune-mediated destruction of hematopoietic stem cells is implicated in the pathophysiology of aplastic anemia (AA). Immunosuppressive therapy (IST) using antithymocyte globulin and cyclosporine is successful in this setting. Eltrombopag is active in patients with refractory AA, presumably by increasing the bone marrow progenitors. Methods This phase 2 trial initially was designed to evaluate standard IST in newly diagnosed patients with severe AA and later was amended to add eltrombopag to simultaneously address immune destruction and stem cell depletion. The primary outcome was the overall response rate (ORR) at 3 months and 6 months. Results A total of 38 patients were enrolled: 17 (45%) received IST alone and 21 (55%) received additional eltrombopag. The ORR was 74%. Patients receiving IST plus eltrombopag had a similar ORR (76% vs 71%; P = .72), complete remission rate (38% vs 29%; P = .73), and median time to response (84 days vs 57 days; P = .30) compared with those receiving IST alone. The 2-year overall survival rate in the IST group was 91% compared with 82% for those patients treated with IST plus eltrombopag (P = .82). No cumulative toxicities were noted after the addition of eltrombopag. Conclusions The addition of eltrombopag to standard IST was well tolerated and resulted in similar responses.
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- 2018
173. Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL
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Tanya Siddiqi, Lin Yang, Jacob D. Soumerai, Jon E. Arnason, Deborah M. Stephens, Lucy Gong, Heidi H. Gillenwater, Peter A. Riedell, Ken Ogasawara, Kathleen A. Dorritie, William G. Wierda, Jerill Thorpe, and Thomas J. Kipps
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Oncology ,medicine.medical_specialty ,Lymphoma, B-Cell ,Immunology ,Antigens, CD19 ,Biochemistry ,Immunotherapy, Adoptive ,chemistry.chemical_compound ,Recurrence ,Internal medicine ,Medicine ,Bruton's tyrosine kinase ,Humans ,biology ,business.industry ,Venetoclax ,Cell Biology ,Hematology ,medicine.disease ,Minimal residual disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Chimeric antigen receptor ,Clinical trial ,Cytokine release syndrome ,chemistry ,Ibrutinib ,biology.protein ,Refractory Chronic Lymphocytic Leukemia ,business ,Cytokine Release Syndrome - Abstract
Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). However, most patients eventually develop resistance to these therapies, underscoring the need for effective new therapies. We report results of the phase 1 dose-escalation portion of the multicenter, open-label, phase 1/2 TRANSCEND CLL 004 (NCT03331198) study of lisocabtagene maraleucel (liso-cel), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory CLL/SLL. Patients with standard- or high-risk features treated with ≥3 or ≥2 prior therapies, respectively, including a BTKi, received liso-cel at 1 of 2 dose levels (50 × 106 or 100 × 106 CAR+ T cells). Primary objectives included safety and determining recommended dose; antitumor activity by 2018 International Workshop on CLL guidelines was exploratory. Minimal residual disease (MRD) was assessed in blood and marrow. Twenty-three of 25 enrolled patients received liso-cel and were evaluable for safety. Patients had a median of 4 (range, 2-11) prior therapies (100% had ibrutinib; 65% had venetoclax) and 83% had high-risk features including mutated TP53 and del(17p). Seventy-four percent of patients had cytokine release syndrome (9% grade 3) and 39% had neurological events (22% grade 3/4). Of 22 efficacy-evaluable patients, 82% and 45% achieved overall and complete responses, respectively. Of 20 MRD-evaluable patients, 75% and 65% achieved undetectable MRD in blood and marrow, respectively. Safety and efficacy were similar between dose levels. The phase 2 portion of the study is ongoing at 100 × 106 CAR+ T cells. This trial was registered at clinicaltrials.gov as NCT03331198.
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- 2021
174. Prognostic factors for progression in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in complete molecular response within 3 months of therapy with tyrosine kinase inhibitors
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Partow Kebriaei, William G. Wierda, Nitin Jain, Naval Daver, Tapan M. Kadia, Farhad Ravandi, Musa Yilmaz, Issa F. Khouri, Philip A. Thompson, Joseph D. Khoury, Courtney D. DiNardo, Marina Konopleva, Rashmi Kanagal Shamanna, Elias Jabbour, Rita Khouri, Hagop M. Kantarjian, Guillermo Garcia-Manero, Bachar Samra, Koji Sasaki, Nicholas J. Short, Cora M. Cheung, Rohtesh S. Mehta, Rebecca Garris, and Richard E. Champlin
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Oncology ,Cancer Research ,medicine.medical_specialty ,Vincristine ,Cyclophosphamide ,Philadelphia chromosome ,Disease-Free Survival ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Philadelphia Chromosome ,030212 general & internal medicine ,Protein Kinase Inhibitors ,business.industry ,Hazard ratio ,Ponatinib ,Hematopoietic Stem Cell Transplantation ,Imatinib ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Prognosis ,Dasatinib ,Transplantation ,chemistry ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
Background The achievement of a 3-month complete molecular response (CMR) is a major prognostic factor for survival in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). However, 25% of patients relapse during therapy with tyrosine kinase inhibitors (TKIs). Methods The authors reviewed 204 patients with Ph-positive ALL who were treated between January 2001 and December 2018 using the combination of hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus a TKI (imatinib, 44 patients [22%]; dasatinib, 88 patients [43%]; or ponatinib, 72 patients [35%]). Progression-free survival (PFS) was defined as the time from the start date of therapy to the date of relapse, death, or last follow-up. Overall survival (OS) was defined as the time from the start date of therapy to the date of death or last follow-up. Results Overall, a 3-month CMR was observed in 57% of patients, including 32% of those who received imatinib, 52% of those who received dasatinib, and 74% of those who received ponatinib. The median follow-up was 74 months (imatinib, 180 months; dasatinib, 106 months; ponatinib, 43 months). Among 84 patients in 3-month CMR, 17 (20%) proceeded to undergo allogeneic stem cell transplantation (ASCT). The 5-year PFS and OS rates were 68% and 72%, respectively. By multivariate analysis, ponatinib therapy was the only significant favorable independent factor predicting for progression (P = .028; hazard ratio, 0.388; 95% CI, 0.166-0.904) and death (P = .042; hazard ratio, 0.379; 95% CI, 0.149-0.966). ASCT was not a prognostic factor for PFS and OS by univariate analysis. Conclusions In patients with Ph-positive ALL, ponatinib is superior to other types of TKIs in inducing and maintaining a CMR, thus preventing disease progression. ASCT does not improve outcome once a 3-month CMR is achieved.
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- 2021
175. Triplet therapy with venetoclax, FLT3 inhibitor and decitabine for FLT3-mutated acute myeloid leukemia
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Marina Konopleva, William G. Wierda, Musa Yilmaz, Farhad Ravandi, Nitin Jain, Ghayas C. Issa, Alessandra Ferrajoli, Abhishek Maiti, Naval Daver, Maro Ohanian, Sanam Loghavi, Philip A. Thompson, Caitlin R. Rausch, Hagop M. Kantarjian, Tapan M. Kadia, Sherry Pierce, Nicholas J. Short, Naveen Pemmaraju, Courtney D. DiNardo, Prithviraj Bose, Koichi Takahashi, Elias Jabbour, Guillermo Montalban-Bravo, Gautam Borthakur, and Kathryn S. Montalbano
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business.industry ,Venetoclax ,Decitabine ,Myeloid leukemia ,Hematology ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Acute myeloid leukaemia ,chemistry.chemical_compound ,Oncology ,chemistry ,Molecularly targeted therapy ,Correspondence ,Cancer research ,Medicine ,business ,FLT3 Inhibitor ,medicine.drug - Published
- 2021
176. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN) : a phase 1/2 study
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Ming Yin, Edward Y. Zhu, Justin Taylor, Michael Wang, Anthony R. Mato, Matthew S. Davids, Nora Ku, Lindsey E. Roeker, Ian W. Flinn, Jennifer A. Woyach, Johan Wallin, Nicole Lamanna, Timothy S. Fenske, Donald E. Tsai, Steven Le Gouill, Suchitra Sundaram, David J. Lewis, John M. Pagel, Toby A. Eyre, Catherine C. Coombs, Stephen J. Schuster, Kevin Ebata, Xuan Ni Tan, Manish R. Patel, Jonathon B. Cohen, Narasimha Marella, Katharine L Lewis, Chan Yoon Cheah, Omar Abdel-Wahab, Bita Fakhri, Binoj Nair, Bryone J. Kuss, M. Lia Palomba, Constantine S. Tam, Alvaro J. Alencar, Wojciech Jurczak, Nirav N. Shah, James N. Gerson, Jennifer R. Brown, Paolo Ghia, Ewa Lech-Marańda, Minal A Barve, Jessica A. Chen, William G. Wierda, Memorial Sloane Kettering Cancer Center [New York], Medical College of Wisconsin [Milwaukee] (MCW), Maria Sklodowska-Curie National Research Institute of Oncology [Krakow, Poland], The University of Western Australia (UWA), Swedish Cancer Institute [Seattle, WA, USA] (SCI), Ohio State University [Columbus] (OSU), University of California [San Francisco] (UC San Francisco), University of California (UC), Oxford University Hospitals NHS Trust, University of Oxford, Columbia University [New York], Sarah Cannon Research Institute [Sarasota, FL, USA] (SCRI), University of Miami Leonard M. Miller School of Medicine (UMMSM), Institute of Hematology and Transfusion Medicine[Warsaw, Poland] (IHTM), MD Anderson Cancer Center [Houston, TX, USA] (MDACC), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), University of Pennsylvania, Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), University Hospitals Plymouth NHS Trust [Plymouth, UK] (UHP), Roswell Park Comprehensive Cancer Center [Buffalo, NY, USA] (RP3C), Emory University [Atlanta, GA], Sarah Cannon Research Institute [Nashville, Tennessee], University of Melbourne, The Royal Melbourne Hospital, Mary Crowley Cancer Research Center [Dallas, TX, USA] (M2CRC), Flinders University Medical Centre [Bedford Park, SA, Australia] (FUMC), Memorial Sloan Kettering Cancer Center [New York, NY, USA] (MSK2C), Dana-Farber Cancer Institute [Boston], Harvard Medical School [Boston] (HMS), Medical College of Wisconsin [Milwaukee, WI, USA] (MCW), Loxo Oncology at Lilly [Stamford, CT, USA] (LO), MD Anderson Cancer Center [Houston], The University of Texas Health Science Center at Houston (UTHealth), Bernardo, Elizabeth, University of California [San Francisco] (UCSF), University of California, University of Oxford [Oxford], University of Pennsylvania [Philadelphia], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Mato, A. R., Shah, N. N., Jurczak, W., Cheah, C. Y., Pagel, J. M., Woyach, J. A., Fakhri, B., Eyre, T. A., Lamanna, N., Patel, M. R., Alencar, A., Lech-Maranda, E., Wierda, W. G., Coombs, C. C., Gerson, J. N., Ghia, P., Le Gouill, S., Lewis, D. J., Sundaram, S., Cohen, J. B., Flinn, I. W., Tam, C. S., Barve, M. A., Kuss, B., Taylor, J., Abdel-Wahab, O., Schuster, S. J., Palomba, M. L., Lewis, K. L., Roeker, L. E., Davids, M. S., Tan, X. N., Fenske, T. S., Wallin, J., Tsai, D. E., Ku, N. C., Zhu, E., Chen, J., Yin, M., Nair, B., Ebata, K., Marella, N., Brown, J. R., and Wang, M.
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Adult ,Male ,medicine.medical_specialty ,Lymphoma, B-Cell ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Lymphoma, Mantle-Cell ,030204 cardiovascular system & hematology ,Neutropenia ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,immune system diseases ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Clinical endpoint ,Bruton's tyrosine kinase ,Humans ,030212 general & internal medicine ,Adverse effect ,Protein Kinase Inhibitors ,Aged ,Aged, 80 and over ,Hematology ,biology ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,3. Good health ,Lymphoma ,Pyrimidines ,Treatment Outcome ,biology.protein ,Pyrazoles ,Mantle cell lymphoma ,Female ,business - Abstract
International audience; Background: Covalent Bruton's tyrosine kinase (BTK) inhibitors are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. We evaluated the safety and efficacy of pirtobrutinib (working name; formerly known as LOXO-305), a highly selective, reversible BTK inhibitor, in these patients.Methods: Patients with previously treated B-cell malignancies were enrolled in a first-in-human, multicentre, open-label, phase 1/2 trial of the BTK inhibitor pirtobrutinib. The primary endpoint was the maximum tolerated dose (phase 1) and overall response rate (ORR; phase 2). This trial is registered with ClinicalTrials.gov, NCT03740529.Findings: 323 patients were treated with pirtobrutinib across seven dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day) with linear dose-proportional exposures. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of 323 patients were fatigue (65 [20%]), diarrhoea (55 [17%]), and contusion (42 [13%]). The most common adverse event of grade 3 or higher was neutropenia (32 [10%]). There was no correlation between pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events. Grade 3 atrial fibrillation or flutter was not observed, and grade 3 haemorrhage was observed in one patient in the setting of mechanical trauma. Five (1%) patients discontinued treatment due to a treatment-related adverse event. In 121 efficacy evaluable patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) treated with a previous covalent BTK inhibitor (median previous lines of treatment 4), the ORR with pirtobrutinib was 62% (95% CI 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (53 [67%] of 79), covalent BTK inhibitor intolerance (22 [52%] of 42), BTK C481-mutant (17 [71%] of 24) and BTK wild-type (43 [66%] of 65) disease. In 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but eight remain progression-free to date.Interpretation: Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients.Funding: Loxo Oncology.
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- 2021
177. Monitoring and Managing BTK Inhibitor Treatment-Related Adverse Events in Clinical Practice
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William G. Wierda, S. M. O'Brien, John C. Byrd, Richard R. Furman, Jeff P. Sharman, Jennifer R. Brown, Paolo Ghia, O'Brien, S. M., Brown, J. R., Byrd, J. C., Furman, R. R., Ghia, P., Sharman, J. P., and Wierda, W. G.
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chronic lymphocytic leukemia ,Neutropenia ,Bruton tyrosine kinase inhibitor ,chemistry.chemical_compound ,immune system diseases ,ibrutinib ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Bruton's tyrosine kinase ,Adverse effect ,RC254-282 ,biology ,business.industry ,acalabrutinib ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Rash ,adverse events ,chemistry ,Ibrutinib ,Perspective ,biology.protein ,Acalabrutinib ,chronic lymphocytic leukemia ,Mantle cell lymphoma ,medicine.symptom ,business - Abstract
Bruton tyrosine kinase (BTK) inhibitors represent an important therapeutic advancement for B cell malignancies. Ibrutinib, the first-in-class BTK inhibitor, is approved by the US FDA to treat patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL; after ≥1 prior therapy); and by the European Medicines Agency (EMA) for adult patients with relapsed/refractory (R/R) MCL and patients with CLL. Ibrutinib treatment can be limited by adverse events (AEs) including atrial fibrillation, arthralgias, rash, diarrhea, and bleeding events, leading to drug discontinuation in 4%–26% of patients. Acalabrutinib, a second-generation BTK inhibitor, is approved by the FDA to treat adult patients with CLL/SLL or MCL (relapsed after 1 prior therapy); and by the EMA to treat adult patients with CLL or R/R MCL. The most common AE associated with acalabrutinib is headache of limited duration, which occurs in 22%–51% of patients, and is mainly grade 1–2 in severity, with only 1% of patients experiencing grade ≥3 headache. Furthermore, acalabrutinib is associated with a low incidence of atrial fibrillation. Zanubrutinib, a selective next-generation covalent BTK inhibitor, is approved by the FDA to treat adult patients with MCL who have received ≥1 prior therapy, and is under investigation for the treatment of patients with CLL. In the phase 3 SEQUOIA trial in patients with CLL, the most common grade ≥3 AEs were neutropenia/neutrophil count decreased and infections. This review provides an overview of BTK inhibitor-related AEs in patients with CLL, and strategies for their management.
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- 2021
178. CLL-039: Pirtobrutinib (LOXO-305), a Next-Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL/SLL: Results from the Phase 1/2 BRUIN Study
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Manish R. Patel, Alvaro J. Alencar, Stephen J. Schuster, Nicole Lamanna, Justin Taylor, Matthew S. Davids, Anthony R. Mato, Paolo Ghia, William G. Wierda, Jennifer A. Woyach, Bita Fakhri, David John Lewis, Minal A. Barve, Omar Abdel-Wahab, Donald E. Tsai, Wojciech Jurczak, Nora C. Ku, Ewa Lech-Marańda, Catherine C. Coombs, John M. Pagel, Nirav N. Shah, Jennifer R. Brown, Toby A. Eyre, James N. Gerson, Chan Yoon Cheah, Binoj Nair, Constantine S. Tam, Jessica Chen, and Lindsey E. Roeker
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Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,Context (language use) ,Hematology ,Discontinuation ,Diarrhea ,Prior Therapy ,Therapeutic index ,hemic and lymphatic diseases ,Internal medicine ,medicine ,biology.protein ,Potency ,Bruton's tyrosine kinase ,medicine.symptom ,business ,Adverse effect - Abstract
Context: Despite the marked efficacy of covalent BTK inhibitors (BTKi) in CLL/SLL, the development of resistance and discontinuation for adverse events can lead to treatment failure. Low oral bioavailability or short half-life of these agents can lead to suboptimal BTK target coverage and ultimately result in acquired resistance in some patients (pts). Pirtobrutinib (LOXO-305) is a highly selective, non-covalent BTKi that inhibits both WT and C481-mutated BTK with equal, low nM potency. Objective: To evaluate pirtobrutinib safety and efficacy in pts with CLL/SLL. Design: BRUIN is an ongoing multi-center phase 1/2 trial (NCT03740529). Enrollment was initiated 21 March 2019. Setting: Global: community hospitals, and academic medical centers. Patients: As of 27 September 2020, 323 previously treated pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, and 66 other B-cell lymphomas) were enrolled. Interventions: Oral pirtobrutinib (7 dose escalation levels: 25–300mg once daily) in 28-day cycles. Main Outcomes Measures: Determining the maximum tolerated dose/recommended phase 2 dose (RP2D), safety profile, and efficacy based on response assessment using disease-specific criteria (iwCLL2018 for CLL/SLL) per protocol. Results: Pirtobrutinib demonstrated high oral exposures, with doses ≥100mg QD exceeding BTK IC90 for the entirety of the dosing interval. No DLTs occurred. The only treatment-emergent adverse events, regardless of attribution or grade seen in ≥10% of pts (n=323), were fatigue (20%), diarrhea (17%), and contusion (13%). An RP2D of 200 mg QD was selected for future studies. The ORR (per iwCLL 2018) was 63%, with 69 PRs, 19 PR-Ls, 45 SDs, 1 PD, and 5 discontinued prior to first response assessment. Responses deepened over time among pts with ≥10 months of follow-up (n=29; 86% ORR). ORR was not influenced by the reason for prior BTKi discontinuation (i.e., progression vs intolerance) or other classes of prior therapy received (including a covalent BTK and a BCL2 inhibitor). The longest followed responding pt continues on treatment for 17.8+ months. Conclusions: Pirtobrutinib showed promising efficacy in pre-treated CLL/SLL pts, was well-tolerated, and exhibited a wide therapeutic index.
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- 2021
179. CLL-139: Acalabrutinib ± Obinutuzumab vs Obinutuzumab + Chlorambucil in Treatment-Naïve Chronic Lymphocytic Leukemia: ELEVATE-TN 4-Year Follow-up
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Patricia F. Walker, Ann Janssens, George A Follows, Ian W. Flinn, Karin Karlsson, Miklos Egyed, Min Hui Wang, Talha Munir, Paolo Ghia, Steven Coutre, Renata Walewska, Laura Fogliatto, Emmanuelle Ferrant, Priti Patel, Florence Cymbalista, Jeff P. Sharman, Veerendra Munugalavadla, Jennifer A. Woyach, William G. Wierda, Versha Banerji, Manali Kamdar, Alan P Skarbnik, Gillian Corbett, Yair Herishanu, Wojciech Jurczak, John M. Pagel, and John C. Byrd
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Cancer Research ,medicine.medical_specialty ,Chlorambucil ,business.industry ,Chronic lymphocytic leukemia ,Phases of clinical research ,Context (language use) ,Hematology ,Interim analysis ,medicine.disease ,Gastroenterology ,Discontinuation ,chemistry.chemical_compound ,Oncology ,chemistry ,Obinutuzumab ,Internal medicine ,medicine ,Acalabrutinib ,business ,medicine.drug - Abstract
Context: Results from ELEVATE-TN (NCT02475681) at a median follow-up of 28.3 months demonstrated superior efficacy of acalabrutinib (A) ± obinutuzumab (O) compared with O + chlorambucil (Clb) in TN CLL (Sharman et al. Lancet 2020;395:1278-91). Objective: To report the results from a 4-year update of ELEVATE-TN. Design: Randomized, multicenter, open-label, 3-arm, Phase 3 study. Patients: TN CLL. Interventions: Patients received A±O or O+Clb. Crossover to A monotherapy was permitted in patients who progressed on O+Clb. Main Outcome Measures: Investigator-assessed (INV) progression-free survival PFS, INV ORR, OS, and safety were evaluated. Results: 535 patients (A+O, n=179; A, n=179; O+Clb, n=177) were randomized with a median age of 70 y; 14% had del(17p) and/or mutated TP53. At a median follow-up of 46.9 months (range, 0.0–59.4; data cutoff: Sept 11, 2020), median PFS was not reached (NR) for A+O and A patients vs 27.8 months for O+Clb patients (both P Conclusions: With a median follow-up of 46.9 months (~4y), the efficacy and safety of A+O and A monotherapy was maintained, with an increase in CR since the interim analysis (from 21% to 27% [A+O] and from 7% to 11% [A]) and low rates of discontinuation.
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- 2021
180. CLL-348: STAT3 Induces the Expression of GLI1 in Chronic Lymphocytic Leukemia Cells
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Zhiming Liu, Ping Li, William G. Wierda, Phillip Thompson, Zeev Estrov, Michael J. Keating, Nitin Jain, Srdan Verstovsek, Jan A. Burger, Alessandra Ferrajoli, David Harris, Preetesh Jain, Taghi Manshouri, Prithviraj Bose, Ivo Veletic, and Uri Rozovski
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Cancer Research ,integumentary system ,medicine.diagnostic_test ,biology ,business.industry ,Chronic lymphocytic leukemia ,Hematology ,Transfection ,medicine.disease ,Molecular biology ,Hedgehog signaling pathway ,CD19 ,Flow cytometry ,Oncology ,immune system diseases ,hemic and lymphatic diseases ,STAT protein ,medicine ,biology.protein ,CD5 ,business ,STAT3 ,neoplasms - Abstract
The glioma associated oncogene-1 (GLI1), a downstream effector of the embryonic Hedgehog pathway, was detected in chronic lymphocytic leukemia (CLL), but not normal adult cells. GLI1-activating mutations were identified in 10% of patients with CLL. However, what induces GLI1 expression in GLI1-unmutated CLL cells is unknown. Because signal transducer and activator of transcription 3 (STAT3) is constitutively activated in CLL cells, and sequence analysis detected putative STAT3-binding sites in the GLI1 gene promoter, we hypothesized that STAT3 induces the expression of GLI1. Western immunoblotting detected GLI1 in CLL cells from 7 of 7 patients, flow cytometry analysis confirmed that CD19+/CD5+ CLL cells co-express GLI1, and confocal microscopy showed co-localization of GLI1 and phosphorylated STAT3. Chromatin immunoprecipitation showed that STAT3 protein co-immunoprecipitated GLI1, as well as other STAT3-regulated genes. Transfection of CLL cells with STAT3-shRNA induced a mark decrease in GLI1 levels, suggesting that STAT3 binds to and induces the expression of GLI1 in CLL cells. An electromobility shift assay confirmed that STAT3 binds, and a luciferase assay showed that STAT3 activates the GLI1 gene. Transfection with GLI1-siRNA significantly increased the spontaneous apoptosis rate of CLL cells, suggesting that GLI1 inhibitors might provide therapeutic benefit to patients with CLL.
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- 2021
181. Expression of BCL2 alternative proteins and association with outcome in CLL patients treated with venetoclax
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Fateeha Furqan, Ignacio I. Wistuba, Francisco Vega, Paolo Strati, Luisa M. Solis Soto, Joseph D. Khoury, William G. Wierda, Marina Konopleva, Ellen J. Schlette, Mario L. Marques-Piubelli, and Alessandra Ferrajoli
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Cancer Research ,Chronic lymphocytic leukemia ,Antineoplastic Agents ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Sulfonamides ,Venetoclax ,business.industry ,Bcl-2 family ,Hematology ,medicine.disease ,Bridged Bicyclo Compounds, Heterocyclic ,Leukemia, Lymphocytic, Chronic, B-Cell ,Oncology ,chemistry ,Proto-Oncogene Proteins c-bcl-2 ,Apoptosis ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,business ,030215 immunology - Abstract
Venetoclax, a BCL-2 inhibitor, is highly effective for the treatment of patients with chronic lymphocytic leukemia (CLL) and dependence on alternative proteins may result in resistance to BCL-2 inhibition. Patients with CLL treated with venetoclax as monotherapy at MD Anderson Cancer Center between 05/2012 and 01/2016 were included and pretreatment bone marrow was analyzed by immunohistochemistry (IHC) for BCL-W, BCL-XL, BCL2-A1 and MCL-1. Twenty-seven patients were included. BCL-W + and BCL-2A1+ was found in 15% and 7% of the patients, respectively. Both BCL-XL and MCL-1 were negative in all samples. A higher CR and longer PFS rates were observed in patients with BCL-W+ (
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- 2020
182. The LEukemia Artificial Intelligence Program (LEAP) in chronic myeloid leukemia in chronic phase: A model to improve patient outcomes
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William G. Wierda, Jorge E. Cortes, Guillermo Garcia-Manero, Sherry Pierce, Junya Sato, Gautam Borthakur, Guillermo Montalban-Bravo, Ghayas C. Issa, Mary Beth Rios, Farhad Ravandi, Kelly A. Soltysiak, Kiran Naqvi, Courtney D. DiNardo, Rashmi Kanagal-Shamanna, Koji Sasaki, Preetesh Jain, Elias Jabbour, Marina Konopleva, Koichi Takahashi, Jeffrey Skinner, and Naval Daver
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Adult ,Male ,Multivariate analysis ,Adolescent ,Decision tree ,Models, Biological ,Article ,Disease-Free Survival ,law.invention ,Randomized controlled trial ,law ,Artificial Intelligence ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,Survival rate ,Protein Kinase Inhibitors ,Aged ,business.industry ,Myeloid leukemia ,Cancer ,Hematology ,Middle Aged ,medicine.disease ,Survival Rate ,Leukemia ,Cohort ,Female ,Artificial intelligence ,business - Abstract
Extreme gradient boosting methods outperform conventional machine-learning models. Here, we have developed the LEukemia Artificial intelligence Program (LEAP) with the extreme gradient boosting decision tree method for the optimal treatment recommendation of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia in chronic phase (CML-CP). A cohort of CML-CP patients was randomly divided into training/validation (N = 504) and test cohorts (N = 126). The training/validation cohort was used for 3-fold cross validation to develop the LEAP CML-CP model using 101 variables at diagnosis. The test cohort was then applied to the LEAP CML-CP model and an optimum TKI treatment was suggested for each patient. The area under the curve in the test cohort was 0.81899.Backward multivariate analysis identified age at diagnosis, the degree of comorbidities, and TKI recommended therapy by the LEAP CML-CP model as independent prognostic factors for overall survival. The bootstrapping method internally validated the association of the LEAP CML-CP recommendation with overall survival as an independent prognostic for overall survival. Selecting treatment according to the LEAP CML-CP personalized recommendations, in this model, is associated with better survival probability compared to treatment with a LEAP CML-CP non-recommended therapy. This approach may pave a way of new era of personalized treatment recommendations for patients with cancer.
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- 2020
183. Clinical Outcomes of Patients With Chronic Myeloid Leukemia With Concurrent Core Binding Factor Rearrangement and Philadelphia Chromosome
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Carlos E. Bueso-Ramos, Farhad Ravandi, Naval Daver, Ghayas C. Issa, Naveen Pemmaraju, William G. Wierda, Joseph D. Khoury, Guillermo Garcia-Manero, Shimin Hu, Kiyomi Morita, Kelly A. Soltysiak, Elias Jabbour, Koji Sasaki, Guillermo Montalban-Bravo, Sherry Pierce, Gautam Borthakur, and Jorge E. Cortes
- Subjects
Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Chromosomal translocation ,Philadelphia chromosome ,Core binding factor ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,Philadelphia Chromosome ,Retrospective Studies ,Chemotherapy ,business.industry ,Core Binding Factors ,Myeloid leukemia ,Hematology ,Middle Aged ,medicine.disease ,Transplantation ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,Stem cell ,business ,030215 immunology - Abstract
Background Acquisition of additional cytogenetic abnormalities (ACAs) in addition to Philadelphia chromosome is frequently observed in patients with chronic myeloid leukemia (CML) in advanced phase. The presence of core binding factor (CBF) translocations determines the diagnosis of acute myeloid leukemia regardless of blast percentage, and CBF rearrangements are rarely identified as ACAs. Patients and Methods A retrospective chart review of patients with CML who had CBF rearrangement, t(8;21) or inv(16), in Philadelphia chromosome-positive clones was conducted. Additional cases of CML with CBF rearrangements were identified through literature review. Results Between August 1997 and December 2014, we identified 11 patients who had Philadelphia chromosome and CBF rearrangement in the same clones: 1 (9%) with t(8;21) and 10 (91%) with inv(16). Nine (82%) patients were in blast phase, and 2 (18%) in second chronic phase. Four (36%) patients received tyrosine kinase inhibitor monotherapy, 2 (18%) received tyrosine kinase inhibitor and chemotherapy, and 5 (45%) received chemotherapy only. Three (27%) patients achieved complete remission with incomplete count recovery, and 4 (36%) had no response after the initial therapy. Three (27%) patients underwent allogeneic stem cell transplantation. The median event-free survival and overall survival for the 11 patients were 2 months and 6 months, respectively. Literature review identified 14 patients with CML with CBF rearrangement with a median overall survival of 14 months. Conclusion Acquisition of CBF rearrangement in addition to Philadelphia chromosome is a rare phenomenon associated with poor prognosis. CBF rearrangements as ACAs in patients with CML can be considered high-risk features.
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- 2020
184. KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results
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Daniel J. DeAngelo, William G. Wierda, Remus Vezan, Michael R. Bishop, Lovely Goyal, Gary J. Schiller, Olalekan O. Oluwole, Rajul K. Jain, John M. Rossi, Adriana K. Malone, Martha Arellano, Armin Ghobadi, Maria R. Baer, Ryan D. Cassaday, John M. Pagel, Houston Holmes, Tong Shen, William B. Donnellan, Adrian Bot, Yi Lin, Raya Mawad, Mehrdad Abedi, Aaron C Logan, Kristen M. O'Dwyer, Bijal D. Shah, Januario E. Castro, and Jae H. Park
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Neoplasm, Residual ,Adolescent ,Clinical Trials and Observations ,Immunology ,Antigens, CD19 ,Biochemistry ,Gastroenterology ,Immunotherapy, Adoptive ,Disease-Free Survival ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Tocilizumab ,Refractory ,Internal medicine ,medicine ,Clinical endpoint ,Biomarkers, Tumor ,Humans ,Young adult ,Adverse effect ,Aged ,Cell Proliferation ,Receptors, Chimeric Antigen ,Dose-Response Relationship, Drug ,business.industry ,Cell Biology ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Minimal residual disease ,Confidence interval ,Cytokine release syndrome ,030104 developmental biology ,Treatment Outcome ,chemistry ,030220 oncology & carcinogenesis ,Female ,Inflammation Mediators ,business ,Cytokine Release Syndrome - Abstract
ZUMA-3 is a phase 1/2 study evaluating KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We report the phase 1 results. After fludarabine-cyclophosphamide lymphodepletion, patients received a single infusion of KTE-X19 at 2 × 106, 1 × 106, or 0.5 × 106 cells per kg. The rate of dose-limiting toxicities (DLTs) within 28 days after KTE-X19 infusion was the primary end point. KTE-X19 was manufactured for 54 enrolled patients and administered to 45 (median age, 46 years; range, 18-77 years). No DLTs occurred in the DLT-evaluable cohort. Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 31% and 38% of patients, respectively. To optimize the risk-benefit ratio, revised adverse event (AE) management for CRS and NEs (earlier steroid use for NEs and tocilizumab only for CRS) was evaluated at 1 × 106 cells per kg KTE-X19. In the 9 patients treated under revised AE management, 33% had grade 3 CRS and 11% had grade 3 NEs, with no grade 4 or 5 NEs. The overall complete remission rate correlated with CAR T-cell expansion and was 83% in patients treated with 1 × 106 cells per kg and 69% in all patients. Minimal residual disease was undetectable in all responding patients. At a median follow-up of 22.1 months (range, 7.1-36.1 months), the median duration of remission was 17.6 months (95% confidence interval [CI], 5.8-17.6 months) in patients treated with 1 × 106 cells per kg and 14.5 months (95% CI, 5.8-18.1 months) in all patients. KTE-X19 treatment provided a high response rate and tolerable safety in adults with R/R B-ALL. Phase 2 is ongoing at 1 × 106 cells per kg with revised AE management. This trial is registered at www.clinicaltrials.gov as #NCT02614066.
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- 2020
185. STAT3 induces the expression of GLI1 in chronic lymphocytic leukemia cells
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Srdan Verstovsek, David Harris, Ping Li, Preetesh Jain, Michael J. Keating, Prithviraj Bose, Phillip Thompson, William G. Wierda, Nitin Jain, Zeev Estrov, Zhiming Liu, Ivo Veletic, Uri Rozovski, Alessandra Ferrajoli, and Taghi Manshouri
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0301 basic medicine ,GLI1 ,Chronic lymphocytic leukemia ,CD19 ,Flow cytometry ,STAT3 ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,medicine ,neoplasms ,integumentary system ,biology ,medicine.diagnostic_test ,Chemistry ,apoptosis ,Transfection ,medicine.disease ,Molecular biology ,Hedgehog signaling pathway ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,STAT protein ,CD5 ,transcription ,CLL ,Research Paper - Abstract
The glioma associated oncogene-1 (GLI1), a downstream effector of the embryonic Hedgehog pathway, was detected in chronic lymphocytic leukemia (CLL), but not normal adult cells. GLI1 activating mutations were identified in 10% of patients with CLL. However, what induces GLI1 expression in GLI1-unmutated CLL cells is unknown. Because signal transducer and activator of transcription 3 (STAT3) is constitutively activated in CLL cells and sequence analysis detected putative STAT3-binding sites in the GLI1 gene promoter, we hypothesized that STAT3 induces the expression of GLI1. Western immunoblotting detected GLI1 in CLL cells from 7 of 7 patients, flow cytometry analysis confirmed that CD19+/CD5+ CLL cells co-express GLI1 and confocal microscopy showed co-localization of GLI1 and phosphorylated STAT3. Chromatin immunoprecipitation showed that STAT3 protein co-immunoprecipitated GLI1 as well as other STAT3-regulated genes. Transfection of CLL cells with STAT3-shRNA induced a mark decrease in GLI1 levels, suggesting that STAT3 binds to and induces the expression of GLI1 in CLL cells. An electromobility shift assay confirmed that STAT3 binds, and a luciferase assay showed that STAT3 activates the GLI1 gene. Transfection with GLI1-siRNA significantly increased the spontaneous apoptosis rate of CLL cells, suggesting that GLI1 inhibitors might provide therapeutic benefit to patients with CLL.
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- 2020
186. CN4 Patient-Reported Outcomes from the Phase 3, Randomized Study of Acalabrutinib with or without Obinutuzumab Versus Chlorambucil PLUS Obinutuzumab for Treatment-Naïve Chronic Lymphocytic Leukemia (ELEVATE-TN)
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J. Woyach, Jeffrey P. Sharman, S. Coutre, Priti Patel, Talha Munir, Wojciech Jurczak, V. Banerji, J.C. Byrd, U. Emeribe, M.H. Wang, P. Walker, William G. Wierda, E. Flood, P. Ghia, and G. Salles
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Oncology ,medicine.medical_specialty ,Chlorambucil ,business.industry ,Health Policy ,Chronic lymphocytic leukemia ,Public Health, Environmental and Occupational Health ,medicine.disease ,law.invention ,Therapy naive ,chemistry.chemical_compound ,Randomized controlled trial ,chemistry ,law ,Obinutuzumab ,Internal medicine ,medicine ,Acalabrutinib ,business ,medicine.drug - Published
- 2021
187. Translocation t(1;19)(q23;p13) in adult acute lymphoblastic leukemia - a distinct subtype with favorable prognosis
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Gokce Altay Toruner, Marina Konopleva, Farhad Ravandi, Zeev Estrov, Guillermo Garcia-Manero, Tapan M. Kadia, William G. Wierda, Rashmi Kanagal-Shamanna, Elias Jabbour, C. Cameron Yin, Hagop M. Kantarjian, Musa Yilmaz, Nitin Jain, Jorge E. Cortes, Nicholas J. Short, Ghayyas Issa, Susan O'Brien, Koji Sasaki, Joseph D. Khoury, and Sherry Pierce
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Oncology ,Adult ,congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,medicine.medical_specialty ,Oncogene Proteins, Fusion ,Chromosomal translocation ,Intensive chemotherapy ,Favorable prognosis ,Translocation, Genetic ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,medicine ,Overall survival ,Humans ,Cumulative incidence ,Adult patients ,business.industry ,Complete remission ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Chromosomes, Human, Pair 1 ,030220 oncology & carcinogenesis ,Adult Acute Lymphoblastic Leukemia ,business ,Chromosomes, Human, Pair 19 ,030215 immunology - Abstract
The recurring translocation t(1;19) (q23;p13) with TCF3-PBX1 rearrangements are uncommon in adult acute lymphoblastic leukemia (ALL), and their prognostic impact remains to be described in the era of modern chemotherapies. We investigated 427 adult patients with newly diagnosed pre-B ALL, 16 (4%) had t(1;19)(q23;p13) at diagnosis. All 16 patients achieved complete remission after induction with intensive chemotherapy, and with a median of 7-year follow-up, 2 relapsed. The 5-year cumulative incidence of relapse and overall survival rates were 14% and 82%, respectively. Our analysis showed that adult patients with t(1;19)(q23;p13) positive ALL had favorable prognosis with intensive chemotherapy regimens.
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- 2020
188. Survivorship in AML - a landmark analysis on the outcomes of acute myelogenous leukemia patients after maintaining complete remission for at least 3 years
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Tapan M. Kadia, Naval Daver, Michael Andreeff, William G. Wierda, Richard E. Champlin, Sherry Pierce, Hagop M. Kantarjian, Jorge E. Cortes, Koji Sasaki, Elias Jabbour, Steven M. Kornblau, Courtney D. DiNardo, Marina Konopleva, Nicholas J. Short, Gautam Borthakur, Naveen Pemmaraju, Catherine Kendall Major, Farhad Ravandi, and Guillermo Garcia-Manero
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Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Survivorship ,03 medical and health sciences ,Myelogenous ,0302 clinical medicine ,hemic and lymphatic diseases ,Survivorship curve ,Internal medicine ,medicine ,Humans ,neoplasms ,Retrospective Studies ,Chemotherapy ,business.industry ,Remission Induction ,Complete remission ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Hematology ,medicine.disease ,humanities ,Leukemia ,Leukemia, Myeloid, Acute ,030220 oncology & carcinogenesis ,Landmark analysis ,business ,High recurrence rate ,030215 immunology - Abstract
Acute myeloid leukemia (AML) carries poor survival and high recurrence rate. We conducted a retrospective analysis of AML patients (N = 453) treated with chemotherapy only or chemotherapy + hematop...
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- 2020
189. A phase I/II study of the combination of quizartinib with azacitidine or low-dose cytarabine for the treatment of patients with acute myeloid leukemia and myelodysplastic syndrome
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Michael Andreeff, Zeev Estrov, Maria Rhona Pinsoy, Naval Daver, Yesid Alvarado, Naveen Pemmaraju, Marina Konopleva, Lianchun Xiao, Tapan M. Kadia, Farhad Ravandi, Hagop M. Kantarjian, Sherry Pierce, Alessandra Ferrajoli, Jorge E. Cortes, Guillermo Garcia-Manero, Gautam Borthakur, Mahesh Swaminathan, Mark J. Levis, Courtney D. DiNardo, Maro Ohanian, Veronica A Guerra, Elias Jabbour, William G. Wierda, and Nitin Jain
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Oncology ,medicine.medical_specialty ,Azacitidine ,Low dose cytarabine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,In patient ,Benzothiazoles ,neoplasms ,Quizartinib ,business.industry ,Phenylurea Compounds ,Cytarabine ,Editorials ,Myeloid leukemia ,Hematology ,Middle Aged ,Leukemia, Myeloid, Acute ,Phase i ii ,chemistry ,fms-Like Tyrosine Kinase 3 ,Myelodysplastic Syndromes ,Cohort ,Mutation ,business ,030215 immunology ,medicine.drug - Abstract
FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with poor prognosis. We hypothesized that quizartinib, a selective and potent FLT3 inhibitor, with azacitidine (AZA) or low-dose cytarabine (LDAC) might improve the outcomes in patients with FLT3-ITD-mutated AML. In this open-label phase I/II trial, patients of any age receiving first-salvage treatment for FLT3-ITD AML or age >60 years with untreated myelodysplastic syndrome or AML were treated with quizartinib plus AZA or LDAC. Seventy-three patients were treated (34 frontline, 39 first-salvage). Among previously untreated patients, composite response (CRc) was achieved in 13/15 (87%, 8 CR, 4 Cri, 1 CRp) treated with quizartinib/AZA and 14/19 (74%, 1 CR, 8 CRi, 5 CRp) in quizartinib/LDAC. The median OS was 19.2 months for quizartinib/AZA and 8.5 months for quizartinib/LDAC cohort; RFS was 10.5 and 6.4 months, respectively. Among previously treated patients, 16 (64%) achieved CRc in quizartinib/AZA and 4 (29%) in quizartinib/LDAC. The median OS for patients treated with quizartinib/AZA and quizartinib/LDAC was 12.8 vs. 4 months, respectively. QTc prolongation grade 3 occurred in only 1 patient in each cohort. Quizartinib-based combinations, particularly with AZA, appear effective in both frontline and first-salvage for patients with FLT3-ITD-mutated AML and are well tolerated.
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- 2020
190. Incidence and characterization of fungal infections in chronic lymphocytic leukemia patients receiving ibrutinib
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Philip A. Thompson, Michael Frei, Samuel L. Aitken, Adam J. DiPippo, William G. Wierda, Nitin Jain, and Dimitrios P. Kontoyiannis
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chronic lymphocytic leukemia ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Medicine ,Bruton's tyrosine kinase ,Humans ,biology ,business.industry ,Incidence (epidemiology) ,Adenine ,Incidence ,Hematology ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Clinical trial ,chemistry ,Mycoses ,030220 oncology & carcinogenesis ,Ibrutinib ,biology.protein ,Pyrazoles ,business ,Tyrosine kinase ,030215 immunology - Abstract
Ibrutinib, a first-generation inhibitor of Bruton’s tyrosine kinase (BTK), is an important therapeutic option in chronic lymphocytic leukemia (CLL) [1]. In clinical trials, invasive fungal infectio...
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- 2020
191. Incidental Richter transformation in chronic lymphocytic leukemia patients during temporary interruption of ibrutinib
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Paul J. Hampel, Pei Lin, Hussein Abdul-Hassan Tawbi, Alessandra Ferrajoli, William G. Wierda, Timothy G. Call, Nitin Jain, Roberto N. Miranda, Ellen D. McPhail, Sameer A. Parikh, Mahsa Khanlari, Hua Jay J. Cherng, and Wei Ding
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Oncology ,medicine.medical_specialty ,Chronic lymphocytic leukemia ,chemistry.chemical_compound ,Piperidines ,immune system diseases ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,In patient ,neoplasms ,Richter transformation ,business.industry ,Adenine ,Clinical course ,Hematology ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Stimulus Report ,Lymphoma ,Leukemia ,Pyrimidines ,chemistry ,Ibrutinib ,Pyrazoles ,Lymphoma, Large B-Cell, Diffuse ,business - Abstract
Key Points An incidental histologic diagnosis of DLBCL was identified during temporary interruption of ibrutinib treatment in patients with CLL. In contrast to an aggressive clinical course typical of Richter transformation, these patients responded to reinitiation of ibrutinib alone.
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- 2020
192. Treating Leukemia in the Time of COVID-19
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Srdan Verstovsek, Philip A. Thompson, Naval Daver, William G. Wierda, Tapan M. Kadia, Nitin Jain, Bouthaina S. Dabaja, Naveen Pemmaraju, Marina Konopleva, Courtney D. DiNardo, Farhad Ravandi, Hagop M. Kantarjian, Guillermo Garcia-Manero, Elias Jabbour, Caitlin R. Rausch, Mary Alma Welch, Guillermo Montalban Bravo, and Shilpa Paul
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medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Review ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,Pandemic ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,In patient ,Intensive care medicine ,Pandemics ,Acute leukemia ,Leukemia ,Myeloproliferative Disorders ,business.industry ,Venetoclax ,SARS-CoV-2 ,Cancer ,COVID-19 ,Hematology ,General Medicine ,medicine.disease ,Chronic leukemia ,chemistry ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Acute Disease ,Chronic Disease ,business ,Myelodysplastic syndrome ,030215 immunology - Abstract
The coronavirus disease 2019 (COVID-19) pandemic poses several challenges to the management of patients with leukemia. The biology of each leukemia and its corresponding treatment with conventional intensive chemotherapy, with or without targeted therapies (venetoclax, FLT3 inhibitors, IDH1/2 inhibitors, Bruton’s tyrosine kinase inhibitors), introduce additional layers of complexity during COVID-19 high-risk periods. The knowledge about COVID-19 is accumulating rapidly. An important distinction is the prevalence of “exposure” versus “clinical infectivity,” which determine the risk versus benefit of modifying potentially highly curative therapies in leukemia. At present, the rate of clinical infection is 30% in patients with cancer, careful consideration should be given to the risk of COVID-19 in leukemia. Instead of reducing patient access to specialized cancer centers and modifying therapies to ones with unproven curative benefit, there is more rationale for less intensive, yet effective therapies that may require fewer clinic visits or hospitalizations. Here, we offer recommendations on the optimization of leukemia management during high-risk COVID-19 periods.
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- 2020
193. CXCL13 plasma levels function as a biomarker for disease activity in patients with chronic lymphocytic leukemia
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Jan A. Burger, Zeev Estrov, Nicholas Chiorazzi, Shih-Shih Chen, Lianchun Xiao, Alicia Vaca, Michael J. Keating, Nitin Jain, Mariela Sivina, Alessandra Ferrajoli, William G. Wierda, Ekaterina Kim, and Xuelin Huang
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Chronic lymphocytic leukemia ,Severity of Illness Index ,CXCR5 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,Piperidines ,immune system diseases ,In vivo ,hemic and lymphatic diseases ,medicine ,Biomarkers, Tumor ,Humans ,CXCL13 ,Receptor ,Aged ,Retrospective Studies ,business.industry ,Adenine ,Germinal center ,Hematology ,medicine.disease ,Prognosis ,Chemokine CXCL13 ,Leukemia, Lymphocytic, Chronic, B-Cell ,Survival Rate ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,Cancer research ,Female ,business ,Follow-Up Studies - Abstract
The chemoattractant CXCL13 organizes the cellular architecture of B-cell follicles and germinal centers. During adaptive immune responses, CXCL13 plasma concentrations transiently increase and function as a biomarker for normal germinal center activity. Chronic lymphocytic leukemia (CLL) cells express high levels of CXCR5, the receptor for CXCL13, and proliferate in pseudofollicles within secondary lymphoid organs (SLO). Given the morphologic and functional similarities between normal and CLL B-cell expansion in SLO, we hypothesized that CXCL13 plasma concentrations would correlate with CLL disease activity and progression. We analyzed CXCL13 plasma concentrations in 400 CLL patients and correlated the findings with other prognostic markers, time to treatment (TTT), CCL3 and CCL4 plasma concentrations, and in vivo CLL cell proliferation. We found that CXCL13 plasma concentrations were higher in CLL patients with active and advanced stage disease, resulting in a significantly shorter TTT. Accordingly, high CXCL13 levels correlated with other markers of disease activity and CCL3 levels. Higher CLL cell birth rates in vivo also associated with higher CXCL13 plasma concentrations. Interestingly, elevated CXCL13 plasma levels normalized during ibrutinib therapy, and increased in ibrutinib resistance patients. Collectively, these studies emphasize the importance of CXCL13 in crosstalk between CLL cells and the SLO microenvironment.
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- 2020
194. Integrated Mechanistic Model of Minimal Residual Disease Kinetics With Venetoclax Therapy in Chronic Lymphocytic Leukemia
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Ahmed Salem, Walid M. Awni, Rod A. Humerickhouse, Dale Miles, Sathej Gopalakrishnan, Kevin J. Freise, William G. Wierda, Brenda Chyla, Sven Mensing, and Rajeev M. Menon
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Oncology ,medicine.medical_specialty ,Neoplasm, Residual ,Combination therapy ,Chronic lymphocytic leukemia ,Antineoplastic Agents ,030226 pharmacology & pharmacy ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacokinetics ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Pharmacology (medical) ,Pharmacology ,Sulfonamides ,business.industry ,Venetoclax ,medicine.disease ,Bridged Bicyclo Compounds, Heterocyclic ,Minimal residual disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Confidence interval ,Kinetics ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Rituximab ,Bone marrow ,business ,medicine.drug - Abstract
Minimal residual disease (MRD) is an important emerging clinical end point in chronic lymphocytic leukemia (CLL). The objective of this research was to develop an integrated mechanistic model to evaluate the impact of venetoclax-rituximab combination therapy on MRD kinetics. Using data from 435 patients with relapsed or refractory CLL, an integrated model was developed and validated that accounted for venetoclax dosing and pharmacokinetics, rituximab treatment, absolute lymphocyte count, and blood and bone marrow (BM) MRD data. Simulations of venetoclax-rituximab (six cycles) combination predicted the proportion (90% confidence interval) of patients with BM MRD below 10-4 to be 57% (54-61%) and 63% (59-67%) at 12 and 24 months of treatment, respectively. Continued venetoclax treatment to 48 months only increased the predicted rate of negative BM MRD to 66% (63-70%). These results indicate that treatment with venetoclax-rituximab combination for a finite 2-year period would nearly maximize the rate of negative BM MRD (< 10-4 ). Preliminary clinical data agree with these predictions and more long-term follow-up data are awaited to confirm the same.
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- 2020
195. Achieving complete remission in CLL patients treated with ibrutinib: clinical significance and predictive factors
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Zeev Estrov, William G. Wierda, Daniela Dueñas, Mariela Sivina, Philip A. Thompson, Nitin Jain, Luisa M. Solis Soto, Ignacio I. Wistuba, Jan A. Burger, Michael J. Keating, Alessandra Ferrajoli, Hagop M. Kantarjian, Ellen J. Schlette, Paolo Strati, and Ekaterina Kim
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Oncology ,medicine.medical_specialty ,business.industry ,Chronic lymphocytic leukemia ,Immunology ,MEDLINE ,Complete remission ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Internal medicine ,Ibrutinib ,medicine ,Clinical significance ,Predictor variable ,business ,Letter to Blood ,030215 immunology - Abstract
In this Letter to Blood, Strati and colleagues report that depth of response is associated with durability of benefit in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib. Patients who achieve a complete remission have longer durations of response than those with partial response. The authors provide preliminary evidence associating tumor-associated macrophages with depth of treatment response.
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- 2020
196. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors
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Pinaki P. Banerjee, David Marin, Mecit Kaplan, William G. Wierda, Partow Kebriaei, Rafet Basar, Rohtesh S. Mehta, Katayoun Rezvani, Sattva S. Neelapu, Michael J. Keating, Enli Liu, Peter F. Thall, Lucila Nassif Kerbauy, May Daher, Kai Cao, Evan N. Cohen, Homer A. Macapinlac, Ana Karen Nunez Cortes, Philip A. Thompson, Bethany J Overman, Yago Nieto, Elizabeth J. Shpall, Richard E. Champlin, Michael Wang, Chitra Hosing, Vandana Nandivada, and Indresh Kaur
- Subjects
Male ,Transplantation Conditioning ,Antigens, CD19 ,Genetic Vectors ,Receptors, Antigen, T-Cell ,Cell- and Tissue-Based Therapy ,030204 cardiovascular system & hematology ,Immunotherapy, Adoptive ,CD19 ,Article ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,hemic and lymphatic diseases ,medicine ,Humans ,030212 general & internal medicine ,Clinical efficacy ,Receptor ,Aged ,Receptors, Chimeric Antigen ,biology ,business.industry ,Lymphoma, Non-Hodgkin ,Remission Induction ,General Medicine ,Middle Aged ,medicine.disease ,Allografts ,Fetal Blood ,Leukemia, Lymphocytic, Chronic, B-Cell ,Chimeric antigen receptor ,Lymphoma ,Killer Cells, Natural ,Leukemia ,Retroviridae ,biology.protein ,Cancer research ,Cytokines ,Female ,Car t cells ,business ,human activities - Abstract
BACKGROUND: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations. METHODS: In this phase 1 and 2 trial, we administered HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood to 11 patients with relapsed or refractory CD19-positive cancers (non-Hodgkin’s lymphoma or chronic lymphocytic leukemia [CLL]). NK cells were transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch. The cells were expanded ex vivo and administered in a single infusion at one of three doses (1×10(5), 1×10(6), or 1×10(7) CAR-NK cells per kilogram of body weight) after lymphodepleting chemotherapy. RESULTS: The administration of CAR-NK cells was not associated with the development of cytokine release syndrome, neurotoxicity, or graft-versus-host disease, and there was no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. The maximum tolerated dose was not reached. Of the 11 patients who were treated, 8 (73%) had a response; of these patients, 7 (4 with lymphoma and 3 with CLL) had a complete remission, and 1 had remission of the Richter’s transformation component but had persistent CLL. Responses were rapid and seen within 30 days after infusion at all dose levels. The infused CAR-NK cells expanded and persisted at low levels for at least 12 months. CONCLUSIONS: Among 11 patients with relapsed or refractory CD19-positive cancers, a majority had a response to treatment with CAR-NK cells without the development of major toxic effects. (Funded by the M.D. Anderson Cancer Center CLL and Lymphoma Moonshot and the National Institutes of Health; ClinicalTrials.gov number, NCT03056339.)
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- 2020
197. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 4.2020, NCCN Clinical Practice Guidelines in Oncology
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William G, Wierda, John C, Byrd, Jeremy S, Abramson, Syed F, Bilgrami, Greg, Bociek, Danielle, Brander, Jennifer, Brown, Asher A, Chanan-Khan, Julio C, Chavez, Steve E, Coutre, Randall S, Davis, Christopher D, Fletcher, Brian, Hill, Brad S, Kahl, Manali, Kamdar, Lawrence D, Kaplan, Nadia, Khan, Thomas J, Kipps, Megan S, Lim, Shuo, Ma, Sami, Malek, Anthony, Mato, Claudio, Mosse, Mazyar, Shadman, Tanya, Siddiqi, Deborah, Stephens, Suchitra, Sundaram, Nina, Wagner, Mary, Dwyer, and Hema, Sundar
- Subjects
Organizations, Nonprofit ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Medical Oncology ,Prognosis ,Leukemia, Lymphocytic, Chronic, B-Cell ,Disease-Free Survival ,United States ,Immunophenotyping ,Bone Marrow ,Drug Resistance, Neoplasm ,Antineoplastic Combined Chemotherapy Protocols ,Mutation ,Biomarkers, Tumor ,Humans ,Transplantation, Homologous ,Lymph Nodes ,Lymphocytes ,Neoplasm Recurrence, Local ,Neoplasm Staging - Abstract
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are characterized by a progressive accumulation of leukemic cells in the peripheral blood, bone marrow, and lymphoid tissues. Treatment of CLL/SLL has evolved significantly in recent years because of the improved understanding of the disease biology and the development of novel targeted therapies. In patients with indications for initiating treatment, the selection of treatment should be based on the disease stage, patient's age and overall fitness (performance status and comorbid conditions), and cytogenetic abnormalities. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.
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- 2020
198. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results
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Farrukh T. Awan, Melanie M. Frigault, Raquel Izumi, Ahmed Hamdy, Wayne Rothbaum, Kathleen A. Burke, Todd Covey, Priti Patel, Paolo Ghia, Min Hui Wang, Susan O'Brien, Jennifer R. Brown, John M. Pagel, Richard R. Furman, Deborah M. Stephens, Stephen Devereux, William G. Wierda, Jennifer A. Woyach, Anna Schuh, Jorge M. Chaves, Peter Martin, John C. Byrd, Michael Gulrajani, Jacqueline C. Barrientos, Peter Hillmen, Byrd, J. C., Wierda, W. G., Schuh, A., Devereux, S., Chaves, J. M., Brown, J. R., Hillmen, P., Martin, P., Awan, F. T., Stephens, D. M., Ghia, P., Barrientos, J., Pagel, J. M., Woyach, J. A., Burke, K., Covey, T., Gulrajani, M., Hamdy, A., Izumi, R., Frigault, M. M., Patel, P., Rothbaum, W., Wang, M. H., O'Brien, S., and Furman, R. R.
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Adult ,Male ,medicine.medical_specialty ,Cyclophosphamide ,Anemia ,Clinical Trials and Observations ,Chronic lymphocytic leukemia ,Immunology ,Antineoplastic Agents ,Neutropenia ,Biochemistry ,Gastroenterology ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Agammaglobulinaemia Tyrosine Kinase ,Humans ,Protein Kinase Inhibitors ,Aged ,Aged, 80 and over ,Hematology ,business.industry ,Cell Biology ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Fludarabine ,Treatment Outcome ,Pyrazines ,Benzamides ,Acalabrutinib ,Female ,Neoplasm Recurrence, Local ,business ,Progressive disease ,medicine.drug - Abstract
Therapeutic targeting of Bruton tyrosine kinase (BTK) has dramatically improved survival outcomes for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Acalabrutinib is an oral, highly selective BTK inhibitor that allows for twice-daily dosing due to its selectivity. In this phase 1b/2 study, 134 patients with relapsed/refractory CLL or SLL (median age, 66 years [range, 42-85 years]; median prior therapies, 2 [range, 1-13]) received acalabrutinib 100 mg twice daily for a median of 41 months (range, 0.2-58 months). Median trough BTK occupancy at steady state was 97%. Most adverse events (AEs) were mild or moderate, and were most commonly diarrhea (52%) and headache (51%). Grade ≥3 AEs (occurring in ≥5% of patients) were neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%), and diarrhea (5%). Atrial fibrillation and major bleeding AEs (all grades) occurred in 7% and 5% of patients, respectively. Most patients (56%) remain on treatment; the primary reasons for discontinuation were progressive disease (21%) and AEs (11%). The overall response rate, including partial response with lymphocytosis, with acalabrutinib was 94%; responses were similar regardless of genomic features (presence of del(11)(q22.3), del(17)(p13.1), complex karyotype, or immunoglobulin variable region heavy chain mutation status). Median duration of response and progression-free survival (PFS) have not been reached; the estimated 45-month PFS was 62% (95% confidence interval, 51% to 71%). BTK mutation was detected in 6 of 9 patients (67%) at relapse. This updated and expanded study confirms the efficacy, durability of response, and long-term safety of acalabrutinib, justifying its further investigation in previously untreated and treated patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443.
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- 2020
199. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial
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William G. Wierda, Veerendra Munugalavadla, Renata Walewska, Raquel Izumi, Patricia F. Walker, Alan P Skarbnik, Gillian Corbett, Florence Cymbalista, Yair Herishanu, Wojciech Jurczak, Miklos Egyed, Steven Coutre, Jennifer A. Woyach, John M. Pagel, Manali Kamdar, Ian W. Flinn, Ann Janssens, Laura Fogliatto, George A Follows, Priti Patel, John C. Byrd, Gilles Salles, Min Hui Wang, Sofia Wong, Versha Banerji, Talha Munir, Paolo Ghia, Jeff P. Sharman, Karin Karlsson, Sharman, J. P., Egyed, M., Jurczak, W., Skarbnik, A., Pagel, J. M., Flinn, I. W., Kamdar, M., Munir, T., Walewska, R., Corbett, G., Fogliatto, L. M., Herishanu, Y., Banerji, V., Coutre, S., Follows, G., Walker, P., Karlsson, K., Ghia, P., Janssens, A., Cymbalista, F., Woyach, J. A., Salles, G., Wierda, W. G., Izumi, R., Munugalavadla, V., Patel, P., Wang, M. H., Wong, S., and Byrd, J. C.
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Male ,medicine.medical_specialty ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,Article ,law.invention ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Randomized controlled trial ,Obinutuzumab ,law ,Chemoimmunotherapy ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Clinical endpoint ,Agammaglobulinaemia Tyrosine Kinase ,Humans ,030212 general & internal medicine ,Progression-free survival ,Aged ,Aged, 80 and over ,Chlorambucil ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Progression-Free Survival ,chemistry ,Concomitant ,Pyrazines ,Benzamides ,Female ,business ,Progressive disease ,medicine.drug - Abstract
Background: Acalabrutinib is a selective, covalent Bruton tyrosine-kinase inhibitor with activity in chronic lymphocytic leukaemia. We compare the efficacy of acalabrutinib with or without obinutuzumab against chlorambucil with obinutuzumab in patients with treatment-naive chronic lymphocytic leukaemia. Methods: ELEVATE TN is a global, phase 3, multicentre, open-label study in patients with treatment-naive chronic lymphocytic leukaemia done at 142 academic and community hospitals in 18 countries. Eligible patients had untreated chronic lymphocytic leukaemia and were aged 65 years or older, or older than 18 years and younger than 65 years with creatinine clearance of 30–69 mL/min (calculated by use of the Cockcroft-Gault equation) or Cumulative Illness Rating Scale for Geriatrics score greater than 6. Additional criteria included an Eastern Cooperative Oncology Group performance status score of 2 or less and adequate haematologic, hepatic, and renal function. Patients with significant cardiovascular disease were excluded, and concomitant treatment with warfarin or equivalent vitamin K antagonists was prohibited. Patients were randomly assigned (1:1:1) centrally via an interactive voice or web response system to receive acalabrutinib and obinutuzumab, acalabrutinib monotherapy, or obinutuzumab and oral chlorambucil. Treatments were administered in 28-day cycles. To reduce infusion-related reactions, acalabrutinib was administered for one cycle before obinutuzumab administration. Oral acalabrutinib was administered (100 mg) twice a day until progressive disease or unacceptable toxic effects occurred. In the acalabrutinib-obinutuzumab group, intravenous obinutuzumab was given on days 1 (100 mg), 2 (900 mg), 8 (1000 mg), and 15 (1000 mg) of cycle 2 and on day 1 (1000 mg) of cycles 3–7. In the obinutuzumab-chlorambucil group, intravenous obinutuzumab was given on days 1 (100 mg), 2 (900 mg), 8 (1000 mg), and 15 (1000 mg) of cycle 1 and on day 1 (1000 mg) of cycles 2–6. Oral chlorambucil was given (0·5 mg/kg) on days 1 and 15 of each cycle, for six cycles. The primary endpoint was progression-free survival between the two combination-therapy groups, assessed by independent review committee. Crossover to acalabrutinib was allowed in patients who progressed on obinutuzumab-chlorambucil. Safety was assessed in all patients who received at least one dose of treatment. Enrolment for this trial is complete, and the study is registered at ClinicalTrials.gov, NCT02475681. Findings: Between Sept 14, 2015, and Feb 8, 2017, we recruited 675 patients for assessment. 140 patients did not meet eligibility criteria, and 535 patients were randomly assigned to treatment. 179 patients were assigned to receive acalabrutinib-obinutuzumab, 179 patients were assigned to receive acalabrutinib monotherapy, and 177 patients were assigned to receive obinutuzumab-chlorambucil. At median follow-up of 28·3 months (IQR 25·6–33·1), median progression-free survival was longer with acalabrutinib-obinutuzumab and acalabrutinib monotherapy, compared with obinutuzumab-chlorambucil (median not reached with acalabrutinib and obinutuzumab vs 22·6 months with obinutuzumab, hazard ratio [HR] 0·1; 95% CI 0·06–0·17, p
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- 2020
200. International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia
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Francesca Romana Mauro, Manuela Hoechstetter, Emanuele Zucca, Gianluca Gaidano, Giorgia Chiodin, Julio Delgado, Richard Rosenquist, Bernhard Gerber, Giovanna Cutrona, Šárka Pospíšilová, Massimo Gentile, Antonino Neri, Mark A. Hess, Petra Langerbeins, Valeria Spina, Hartmut Döhner, Wei Wu, Lorenzo De Paoli, Sameer A. Parikh, Michele Ghielmini, Kari G. Rabe, Mattias Mattsson, Clara Deambrogi, Fortunato Morabito, Georg Stussi, Silke Gillessen, Elena Bianchi, Adalgisa Condoluci, Carmen D. Herling, Davide Rossi, Michael Hallek, Tycho Baumann, Michael Doubek, Robin Foà, Franco Cavalli, Stephan Stilgenbauer, Riccardo Moia, Manlio Ferrarini, Emili Montserrat, Francesco Forconi, Jana Kotašková, Alessio Bruscaggin, Lodovico Terzi di Bergamo, William G. Wierda, Karin E. Smedby, and Jasmin Bahlo
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Male ,Oncology ,medicine.medical_specialty ,Chronic lymphocytic leukemia ,Immunology ,Biochemistry ,Asymptomatic ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Stage (cooking) ,Survival rate ,Aged ,Retrospective Studies ,030304 developmental biology ,Clinical Trials as Topic ,0303 health sciences ,business.industry ,a b c ,Retrospective cohort study ,Cell Biology ,Hematology ,Nomogram ,Prognosis ,medicine.disease ,Combined Modality Therapy ,Leukemia, Lymphocytic, Chronic, B-Cell ,3. Good health ,Survival Rate ,Nomograms ,030220 oncology & carcinogenesis ,Mutation ,Cohort ,Disease Progression ,Female ,medicine.symptom ,IGHV@ ,business ,Follow-Up Studies - Abstract
Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.
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- 2020
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