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1. Beat-AML 2024 ELN-refined risk stratification for older adults with newly diagnosed AML given lower-intensity therapy.

Author

Hoff, Fieke, Blum, William, Huang, Ying, Welkie, Rina, Swords, Ronan, Traer, Elie, Stein, Eytan, Lin, Tara, Archer, Kellie, Patel, Prapti, Collins, Robert, Baer, Maria, Duong, Vu, Arellano, Martha, Stock, Wendy, Odenike, Olatoyosi, Redner, Robert, Kovacsovics, Tibor, Deininger, Michael, Zeidner, Joshua, Olin, Rebecca, Smith, Catherine, Foran, James, Schiller, Gary, Curran, Emily, Koenig, Kristin, Heerema, Nyla, Chen, Timothy, Martycz, Molly, Stefanos, Mona, Marcus, Sonja, Rosenberg, Leonard, Druker, Brian, Levine, Ross, Burd, Amy, Yocum, Ashley, Borate, Uma, Mims, Alice, Byrd, John, and Madanat, Yazan

Subjects
Humans, Leukemia, Myeloid, Acute, Aged, Female, Male, Middle Aged, Aged, 80 and over, Prognosis, Risk Assessment, Mutation, Antineoplastic Combined Chemotherapy Protocols
Abstract

Although the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML aged ≥60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-, 11% intermediate-, and 78% had adverse-risk AML. ELN risk was prognostic for overall survival (OS) (P < .001) but did not stratify favorable- from intermediate-risk (P = .71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (n = 316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P < .05). A mutation score was calculated for each combination of these mutations, assigning adverse-risk patients to 2 risk groups: -1 to 0 points (Beat-AML intermediate) vs 1+ points (Beat-AML adverse). In the final refined risk classification, ELN favorable- and intermediate-risk were combined into a newly defined Beat-AML favorable-risk group, in addition to mutation scoring within the ELN adverse-risk group. This approach redefines risk for older patients with ND AML and proposes refined Beat-AML risk groups with improved discrimination for OS (2-year OS, 48% vs 33% vs 11%, respectively; P < .001), providing patients and providers additional information for treatment decision-making.

Published
2024

4. Dose modification dynamics of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) from the PACE and OPTIC trials.

Author

Jabbour, Elias, Apperley, Jane, Cortes, Jorge, Rea, Delphine, Deininger, Michael, Abruzzese, Elisabetta, Chuah, Charles, DeAngelo, Daniel, Hochhaus, Andreas, Lipton, Jeffrey, Mauro, Michael, Nicolini, Franck, Pinilla-Ibarz, Javier, Rosti, Gianantonio, Rousselot, Philippe, Talpaz, Moshe, Vorog, Alexander, Ren, Xiaowei, Kantarjian, Hagop, and Shah, Neil Pravin

Subjects
Humans, Drug Resistance, Neoplasm, Leukemia, Myeloid, Chronic-Phase, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Imidazoles, Pyridazines, Fusion Proteins, bcr-abl, Protein Kinase Inhibitors, Antineoplastic Agents
Abstract

Ponatinib, the only approved all known-BCR::ABL1 inhibitor, is a third-generation tyrosine-kinase inhibitor (TKI) designed to inhibit BCR::ABL1 with or without any single resistance mutation, including T315I, and induced robust and durable responses at 45 mg/day in patients with CP-CML resistant to second-generation TKIs in the PACE trial. However, cardiovascular toxicities, including arterial occlusive events (AOEs), have emerged as treatment-related AEs within this class of TKIs. The OPTIC trial evaluated the efficacy and safety of ponatinib using a novel, response-based, dose-reduction strategy in patients with CP-CML whose disease is resistant to ≥2 TKIs or who harbor T315I. To assess the dose-response relationship and the effect on the safety of ponatinib, we examined the outcomes of patients with CP-CML enrolled in PACE and OPTIC who received 45 mg/day of ponatinib. A propensity score analysis was used to evaluate AOEs across both trials. Survival rates and median time to achieve ≤1% BCR::ABL1IS in OPTIC were similar or better than in PACE. The outcomes of patients with T315I mutations were robust in both trials. Patients in OPTIC had a lower exposure-adjusted incidence of AOEs compared with those in PACE. This analysis demonstrates that response-based dosing for ponatinib improves treatment tolerance and mitigates cardiovascular risk.

Published
2024

6. Asciminib monotherapy in patients with chronic-phase chronic myeloid leukemia with the T315I mutation after ≥1 prior tyrosine kinase inhibitor: 2-year follow-up results

Author

Cortes, Jorge E., Sasaki, Koji, Kim, Dong-Wook, Hughes, Timothy P., Etienne, Gabriel, Mauro, Michael J., Hochhaus, Andreas, Lang, Fabian, Heinrich, Michael C., Breccia, Massimo, Deininger, Michael, Goh, Yeow Tee, Janssen, Jeroen J.W.M., Talpaz, Moshe, de Soria, Valle Gomez Garcia, le Coutre, Philipp, DeAngelo, Daniel J., Damon, Andrea, Cacciatore, Silvia, Polydoros, Fotis, Agrawal, Nithya, and Rea, Delphine

Published
2024
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8. Correction: Dose modification dynamics of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) from the PACE and OPTIC trials

Author

Jabbour, Elias, Apperley, Jane, Cortes, Jorge, Rea, Delphine, Deininger, Michael, Abruzzese, Elisabetta, Chuah, Charles, DeAngelo, Daniel J., Hochhaus, Andreas, Lipton, Jeffrey H., Mauro, Michael, Nicolini, Franck, Pinilla-Ibarz, Javier, Rosti, Gianantonio, Rousselot, Philippe, Shah, Neil P., Talpaz, Moshe, Vorog, Alexander, Ren, Xiaowei, and Kantarjian, Hagop

Published
2024
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11. Are oxygen isotope fractionation factors between calcite and water derived from speleothems systematically biased due to prior calcite precipitation (PCP)?

Author

Deininger, Michael, Hansen, Maximilian, Fohlmeister, Jens, Schröder-Ritzrau, Andrea, Burstyn, Yuval, and Scholz, Denis

Subjects
Physics - Geophysics
Abstract

The equilibrium oxygen isotope fractionation factor between calcite and water (18{\alpha}calcite/H2O) is an important quantity in stable isotope geochemistry and allows in principle to infer temperature variations from carbonate {\delta}18O if carbonate formation occurred in thermodynamic equilibrium. For this reason, many studies intended to determine the value of the oxygen isotope fractionation factor between calcite and water (18{\alpha}calcite/H2O) for a wide range of temperatures using modern cave calcite and the corresponding cave drip water or ancient speleothem carbonate and fluid inclusion samples. However, the picture that emerges from all of these studies indicates that speleothem calcite is not formed in thermodynamic equilibrium but under kinetic conditions, provoking a large variability of determined 18{\alpha}calcite/H2O values. Here we present a conceptual framework that can explain the variability of 18{\alpha}calcite/H2O values obtained by cave studies. Prior calcite precipitation (PCP) is calcite precipitation before cave drip water is dripping from the cave ceiling and impinges on the surface of a stalagmite or watch glass. Prior to the karst water dripping from the cave ceiling, PCP can occur in the karst above the cave as well as on the cave ceiling, the cave walls and on the surface of stalactites. We argue that PCP leads to increasing the {\delta}18O value of the dissolved HCO3- ({\delta}18OHCO3-), resulting in an oxygen isotope disequilibrium of the {\delta}18OHCO3- values with respect to the {\delta}18O value of water ({\delta}18OH2O). The oxygen isotope disequilibrium between HCO3- and H2O is re-equilibrated by oxygen isotope exchange between H2O and HCO3. Depending on the temperature, the re-equilibration time varies from hours to days and is usually much longer than the residence time of the drip water on stalactites, but much shorter than the time ...

Published
2021
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15. Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results

Author

Mauro, Michael J., Hughes, Timothy P., Kim, Dong-Wook, Rea, Delphine, Cortes, Jorge E., Hochhaus, Andreas, Sasaki, Koji, Breccia, Massimo, Talpaz, Moshe, Ottmann, Oliver, Minami, Hironobu, Goh, Yeow Tee, DeAngelo, Daniel J., Heinrich, Michael C., Gómez-García de Soria, Valle, le Coutre, Philipp, Mahon, Francois-Xavier, Janssen, Jeroen J. W. M., Deininger, Michael, Shanmuganathan, Naranie, Geyer, Mark B., Cacciatore, Silvia, Polydoros, Fotis, Agrawal, Nithya, Hoch, Matthias, and Lang, Fabian

Published
2023
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17. Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial

Author

Burd, Amy, Levine, Ross L, Ruppert, Amy S, Mims, Alice S, Borate, Uma, Stein, Eytan M, Patel, Prapti, Baer, Maria R, Stock, Wendy, Deininger, Michael, Blum, William, Schiller, Gary, Olin, Rebecca, Litzow, Mark, Foran, James, Lin, Tara L, Ball, Brian, Boyiadzis, Michael, Traer, Elie, Odenike, Olatoyosi, Arellano, Martha, Walker, Alison, Duong, Vu H, Kovacsovics, Tibor, Collins, Robert, Shoben, Abigail B, Heerema, Nyla A, Foster, Matthew C, Vergilio, Jo-Anne, Brennan, Tim, Vietz, Christine, Severson, Eric, Miller, Molly, Rosenberg, Leonard, Marcus, Sonja, Yocum, Ashley, Chen, Timothy, Stefanos, Mona, Druker, Brian, and Byrd, John C

Subjects
Cancer, Clinical Research, Childhood Leukemia, Rare Diseases, Pediatric, Genetics, Hematology, Pediatric Cancer, Clinical Trials and Supportive Activities, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Good Health and Well Being, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Cytarabine, Daunorubicin, Female, Genomics, Humans, Leukemia, Myeloid, Acute, Male, Middle Aged, Mutation, Precision Medicine, Survival Analysis, Treatment Outcome, Medical and Health Sciences, Immunology
Abstract

Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome1,2. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient's leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998 ), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60-92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival.

Published
2020

18. SISALv2: a comprehensive speleothem isotope database with multiple age–depth models

Author

Comas-Bru, Laia, Rehfeld, Kira, Roesch, Carla, Amirnezhad-Mozhdehi, Sahar, Harrison, Sandy P, Atsawawaranunt, Kamolphat, Ahmad, Syed Masood, Brahim, Yassine Ait, Baker, Andy, Bosomworth, Matthew, Breitenbach, Sebastian FM, Burstyn, Yuval, Columbu, Andrea, Deininger, Michael, Demény, Attila, Dixon, Bronwyn, Fohlmeister, Jens, Hatvani, István Gábor, Hu, Jun, Kaushal, Nikita, Kern, Zoltán, Labuhn, Inga, Lechleitner, Franziska A, Lorrey, Andrew, Martrat, Belen, Novello, Valdir Felipe, Oster, Jessica, Pérez-Mejías, Carlos, Scholz, Denis, Scroxton, Nick, Sinha, Nitesh, Ward, Brittany Marie, Warken, Sophie, Zhang, Haiwei, and members, SISAL Working Group

Subjects
Climate Action, Atmospheric Sciences, Geochemistry, Physical Geography and Environmental Geoscience
Abstract

Characterizing the temporal uncertainty in palaeoclimate records is crucial for analysing past climate change, correlating climate events between records, assessing climate periodicities, identifying potential triggers and evaluating climate model simulations. The first global compilation of speleothem isotope records by the SISAL (Speleothem Isotope Synthesis and Analysis) working group showed that age model uncertainties are not systematically reported in the published literature, and these are only available for a limited number of records (ca. 15 %, n = 107/691). To improve the usefulness of the SISAL database, we have (i) improved the database's spatio-temporal coverage and (ii) created new chronologies using seven different approaches for age- depth modelling. We have applied these alternative chronologies to the records from the first version of the SISAL database (SISALv1) and to new records compiled since the release of SISALv1. This paper documents the necessary changes in the structure of the SISAL database to accommodate the inclusion of the new age models and their uncertainties as well as the expansion of the database to include new records and the qualitycontrol measures applied. This paper also documents the age-depth model approaches used to calculate the new chronologies. The updated version of the SISAL database (SISALv2) contains isotopic data from 691 speleothem records from 294 cave sites and new age-depth models, including age-depth temporal uncertainties for 512 speleothems.

Published
2020

21. Phase 1/2 trial of glasdegib in patients with primary or secondary myelofibrosis previously treated with ruxolitinib

Author

Gerds, Aaron T, Tauchi, Tetsuzo, Ritchie, Ellen, Deininger, Michael, Jamieson, Catriona, Mesa, Ruben, Heaney, Mark, Komatsu, Norio, Minami, Hironobu, Su, Yun, Shaik, Naveed, Zhang, Xiaoxi, DiRienzo, Christine, Zeremski, Mirjana, Chan, Geoffrey, and Talpaz, Moshe

Subjects
Brain Disorders, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adolescent, Adult, Aged, Aged, 80 and over, Benzimidazoles, Chemotherapy, Adjuvant, Female, Humans, Male, Middle Aged, Nitriles, Organ Size, Phenylurea Compounds, Primary Myelofibrosis, Pyrazoles, Pyrimidines, Spleen, Treatment Outcome, Young Adult, Glasdegib, Hedgehog inhibitor, Smoothened inhibitor, Myelofibrosis, Clinical Sciences, Immunology
Abstract

Glasdegib is a potent and selective oral inhibitor of the Hedgehog pathway. We report data from the single-arm, lead-in cohort of an open-label phase 1b/2 trial of glasdegib in patients with primary/secondary myelofibrosis (MF) previously treated with at least one Janus kinase inhibitor (JAKi). Patients received glasdegib 100 mg orally once daily until there was no further clinical benefit. Primary endpoints included adverse events (AEs). Secondary endpoints included patients with spleen volume reduction (SVR) ≥35% at week 24, patients with ≥50% total symptom score (TSS) reduction, and pharmacokinetics. All 21 treated patients had one or more AE and five (23.8%) had serious AEs. Most common (>30%) AEs were dysgeusia (61.9%), muscle spasms (57.1%), alopecia (38.1%), fatigue (33.3%), and decreased appetite (33.3%). Although no patient had ≥35% SVR at week 24, one patient previously treated with ruxolitinib had an SVR of 32.9%. At week 12, two (9.5%) patients had ≥50% reduction in TSS from baseline and ˜40% had ≥20% reduction. One patient had an anaemia response. Following administration of glasdegib 100 mg once daily, the median time to peak plasma concentrations at steady-state generally occurred at 1 h post-dose. The safety profile of glasdegib monotherapy was manageable in patients with primary/secondary MF. Further study of glasdegib in combination with JAKi in a MF population may be warranted.

Published
2019

24. Bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia: final results from the BFORE trial

Author

Brümmendorf, Tim H., Cortes, Jorge E., Milojkovic, Dragana, Gambacorti-Passerini, Carlo, Clark, Richard E., le Coutre, Philipp, Garcia-Gutierrez, Valentin, Chuah, Charles, Kota, Vamsi, Lipton, Jeffrey H., Rousselot, Philippe, Mauro, Michael J., Hochhaus, Andreas, Hurtado Monroy, Rafael, Leip, Eric, Purcell, Simon, Yver, Anne, Viqueira, Andrea, and Deininger, Michael W.

Published
2022
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25. Integrative analysis of drug response and clinical outcome in acute myeloid leukemia

Author

Bottomly, Daniel, Long, Nicola, Schultz, Anna Reister, Kurtz, Stephen E., Tognon, Cristina E., Johnson, Kara, Abel, Melissa, Agarwal, Anupriya, Avaylon, Sammantha, Benton, Erik, Blucher, Aurora, Borate, Uma, Braun, Theodore P., Brown, Jordana, Bryant, Jade, Burke, Russell, Carlos, Amy, Chang, Bill H., Cho, Hyun Jun, Christy, Stephen, Coblentz, Cody, Cohen, Aaron M., d’Almeida, Amanda, Cook, Rachel, Danilov, Alexey, Dao, Kim-Hien T., Degnin, Michie, Dibb, James, Eide, Christopher A., English, Isabel, Hagler, Stuart, Harrelson, Heath, Henson, Rachel, Ho, Hibery, Joshi, Sunil K., Junio, Brian, Kaempf, Andy, Kosaka, Yoko, Laderas, Ted, Lawhead, Matt, Lee, Hyunjung, Leonard, Jessica T., Lin, Chenwei, Lind, Evan F., Liu, Selina Qiuying, Lo, Pierrette, Loriaux, Marc M., Luty, Samuel, Maxson, Julia E., Macey, Tara, Martinez, Jacqueline, Minnier, Jessica, Monteblanco, Andrea, Mori, Motomi, Morrow, Quinlan, Nelson, Dylan, Ramsdill, Justin, Rofelty, Angela, Rogers, Alexandra, Romine, Kyle A., Ryabinin, Peter, Saultz, Jennifer N., Sampson, David A., Savage, Samantha L., Schuff, Robert, Searles, Robert, Smith, Rebecca L., Spurgeon, Stephen E., Sweeney, Tyler, Swords, Ronan T., Thapa, Aashis, Thiel-Klare, Karina, Traer, Elie, Wagner, Jake, Wilmot, Beth, Wolf, Joelle, Wu, Guanming, Yates, Amy, Zhang, Haijiao, Cogle, Christopher R., Collins, Robert H., Deininger, Michael W., Hourigan, Christopher S., Jordan, Craig T., Lin, Tara L., Martinez, Micaela E., Pallapati, Rachel R., Pollyea, Daniel A., Pomicter, Anthony D., Watts, Justin M., Weir, Scott J., Druker, Brian J., McWeeney, Shannon K., and Tyner, Jeffrey W.

Published
2022
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27. Design and rationale for the life after stopping tyrosine kinase inhibitors (LAST) study, a prospective, single-group longitudinal study in patients with chronic myeloid leukemia

Author

Atallah, Ehab, Schiffer, Charles A, Weinfurt, Kevin P, Zhang, Mei-Jie, Radich, Jerald P, Oehler, Vivian G, Pinilla-Ibarz, Javier, Deininger, Michael WN, Lin, Li, Larson, Richard A, Mauro, Michael J, Moore, Joseph O, Ritchie, Ellen K, Shah, Neil P, Silver, Richard T, Wadleigh, Martha, Cortes, Jorge, Thompson, James, Guhl, Jessica, Horowitz, Mary M, and Flynn, Kathryn E

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Clinical Trials and Supportive Activities, Hematology, Clinical Research, Cancer, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Good Health and Well Being, Antineoplastic Agents, Clinical Protocols, Fusion Proteins, bcr-abl, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Longitudinal Studies, Molecular Targeted Therapy, Patient Reported Outcome Measures, Protein Kinase Inhibitors, Quality of Life, Recurrence, Research Design, Watchful Waiting, Chronic myeloid leukemia, Oncology, Targeted therapy, Tyrosine kinase inhibitor, Discontinuation, Clinical trial, Study design, Patient-reported outcome, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis, Epidemiology
Abstract

BACKGROUND:Treatment of chronic myeloid leukemia with a tyrosine kinase inhibitor (TKI) offers significant improvements over previous treatments in terms of survival and toxicity yet nevertheless is associated with reduced health-related quality of life and very high cost. Several small studies from Europe and Australia suggested that discontinuing TKIs with regular monitoring was safe. METHODS:The Life After Stopping TKIs (LAST) study is a large, U.S.-based study that aims to improve the evidence for clinical decision making regarding TKI discontinuation with monitoring in patients with chronic myeloid leukemia who have a deep molecular response to TKI therapy. The LAST study is a non-randomized, prospective, single-group longitudinal study of 173 patients. The co-primary objectives are to determine the proportion of patients who develop molecular recurrence (> 0.1% BCR-ABLIS) after discontinuing one of four TKIs (imatinib, dasatinib, nilotinib, or bosutinib) and to compare the patient-reported health status of patients before and after stopping TKIs. Outcomes are assessed at baseline and throughout the 36-month study follow-up period with a central laboratory used for blood samples. All samples with undetectable BCR-ABL are also examined using digital polymerase chain reaction, which is a more sensitive nanofluidic polymerase chain reaction system. DISCUSSION:Because of their high cost and side effects, discontinuation of TKIs for patients with chronic myeloid leukemia who have a deep molecular response to TKI therapy is a promising approach to treatment. The LAST study is the largest U.S.-based TKI discontinuation study. It is the first to allow participation from patients on any of 4 first- and second-generation TKIs, includes a robust approach to measurement of clinical and patient-reported outcomes, and is using digital polymerase chain reaction to explore better prediction of safe discontinuation. TRIAL REGISTRATION:This study was registered prospectively on October 21, 2014 and assigned trial number NCT02269267 .

Published
2018

28. Identification and prioritization of myeloid malignancy germline variants in a large cohort of adult patients with AML

Author

Yang, Fei, Long, Nicola, Anekpuritanang, Tauangtham, Bottomly, Daniel, Savage, Jonathan C., Lee, Tiffany, Solis-Ruiz, Jose, Borate, Uma, Wilmot, Beth, Tognon, Cristina, Bock, Allison M., Pollyea, Daniel A., Radhakrishnan, Saikripa, Radhakrishnan, Srinidhi, Patel, Prapti, Collins, Robert H., Tantravahi, Srinivas, Deininger, Michael W., Fan, Guang, Druker, Brian, Shinde, Ujwal, Tyner, Jeffrey W., Press, Richard D., McWeeney, Shannon, and Agarwal, Anupriya

Published
2022
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29. MS4A3 promotes differentiation in chronic myeloid leukemia by enhancing common β-chain cytokine receptor endocytosis

Author

Zhao, Helong, Pomicter, Anthony D., Eiring, Anna M., Franzini, Anca, Ahmann, Jonathan, Hwang, Jae-Yeon, Senina, Anna, Helton, Bret, Iyer, Siddharth, Yan, Dongqing, Khorashad, Jamshid S., Zabriskie, Matthew S., Agarwal, Anupriya, Redwine, Hannah M., Bowler, Amber D., Clair, Phillip M., McWeeney, Shannon K., Druker, Brian J., Tyner, Jeffrey W., Stirewalt, Derek L., Oehler, Vivian G., Varambally, Sooryanarayana, Berrett, Kristofer C., Vahrenkamp, Jeffery M., Gertz, Jason, Varley, Katherine E., Radich, Jerald P., and Deininger, Michael W.

Published
2022
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30. Correction: Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee

Author

Januzzi, James L., Garasic, Joseph M., Kasner, Scott E., McDonald, Vickie, Petrie, Mark C., Seltzer, Jonathan, Mauro, Michael, Croce, Kevin, Berman, Ellin, Deininger, Michael, Hochhaus, Andreas, Pinilla-Ibarz, Javier, Nicolini, Franck, Kim, Dong-Wook, DeAngelo, Daniel J., Kantarjian, Hagop, Xu, Jing, Hall, Tracey, Srivastava, Shouryadeep, Naranjo, Daniel, and Cortes, Jorge

Published
2022
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31. Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee

Author

Januzzi, James L., Garasic, Joseph M., Kasner, Scott E., McDonald, Vickie, Petrie, Mark C., Seltzer, Jonathan, Mauro, Michael, Croce, Kevin, Berman, Ellin, Deininger, Michael, Hochhaus, Andreas, Pinilla-Ibarz, Javier, Nicolini, Franck, Kim, Dong-Wook, DeAngelo, Daniel J., Kantarjian, Hagop, Xu, Jing, Hall, Tracey, Srivastava, Shouryadeep, Naranjo, Daniel, and Cortes, Jorge

Published
2022
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32. Ponatinib (PON) in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) and the T315I mutation (mut): 4-year results from OPTIC.

Author

Deininger, Michael, primary, Apperley, Jane, additional, Arthur, Christopher Kevin, additional, Chuah, Charles, additional, Hochhaus, Andreas, additional, de Lavallade, Hugues, additional, Lipton, Jeffrey Howard, additional, Lomaia, Elza, additional, McCloskey, James K., additional, Maness, Lori J., additional, Mauro, Michael J., additional, Moiraghi, Beatriz, additional, Pavlovsky, Carolina, additional, Rosti, Gianantonio, additional, Rousselot, Philippe, additional, Undurraga Sutton, Maria, additional, Ren, Xiaowei, additional, Vorog, Alexander, additional, Kantarjian, Hagop M., additional, and Cortes, Jorge E., additional

Published
2024
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33. Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial

Author

Gotlib, Jason, Reiter, Andreas, Radia, Deepti H., Deininger, Michael W., George, Tracy I., Panse, Jens, and Vannucchi, Alessandro M.

Subjects
Diagnosis, Testing, Care and treatment, Risk factors, Methods, Mastocytosis -- Diagnosis -- Care and treatment -- Risk factors, Event history analysis -- Methods, Avapritinib -- Testing, Mast cell disease -- Diagnosis -- Care and treatment -- Risk factors
Abstract

Author(s): Jason Gotlib [sup.1] , Andreas Reiter [sup.2] , Deepti H. Radia [sup.3] , Michael W. Deininger [sup.4] , Tracy I. George [sup.5] , Jens Panse [sup.6] , Alessandro M. [...], Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200 mg in patients with AdvSM (n = 62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM-Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes in measures of disease burden and safety. The primary endpoint was successfully met (P = 1.6 × 10.sup.-9), with an ORR of 75% (95% confidence interval 57-89) in 32 response-evaluable patients with AdvSM who had sufficient follow-up for response assessment, including 19% with complete remission with full or partial hematologic recovery. Reductions of [greater than or equal to]50% from baseline in serum tryptase (93%), bone marrow mast cells (88%) and KIT D816V variant allele fraction (60%) were observed. The most frequent grade [greater than or equal to]3 adverse events were neutropenia (24%), thrombocytopenia (16%) and anemia (16%). Avapritinib demonstrated a high rate of clinical, morphological and molecular responses and was generally well tolerated in patients with AdvSM. In a prespecified interim analysis of a pivotal phase 2 trial, avapritinib, a selective KIT inhibitor, elicited robust clinical and molecular responses, was generally well tolerated and led to improved patient-reported outcomes in patients with advanced systemic mastocytosis.

Published
2021
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35. Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial

Author

Cortes, Jorge, Apperley, Jane, Lomaia, Elza, Moiraghi, Beatriz, Undurraga Sutton, Maria, Pavlovsky, Carolina, Chuah, Charles, Sacha, Tomasz, Lipton, Jeffrey H., Schiffer, Charles A., McCloskey, James, Hochhaus, Andreas, Rousselot, Philippe, Rosti, Gianantonio, de Lavallade, Hugues, Turkina, Anna, Rojas, Christine, Arthur, Christopher Kevin, Maness, Lori, Talpaz, Moshe, Mauro, Michael, Hall, Tracey, Lu, Vickie, Srivastava, Shouryadeep, and Deininger, Michael

Published
2021
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37. Proceedings from the Inaugural American Initiative in Mast Cell Diseases (AIM) Investigator Conference

Author

Gotlib, Jason, George, Tracy I., Carter, Melody C., Austen, K. Frank, Bochner, Bruce, Dwyer, Daniel F., Lyons, Jonathan J., Hamilton, Matthew J., Butterfield, Joseph, Bonadonna, Patrizia, Weiler, Catherine, Galli, Stephen J., Schwartz, Lawrence B., Elberink, Hanneke Oude, Maitland, Anne, Theoharides, Theoharis, Ustun, Celalettin, Horny, Hans-Peter, Orfao, Alberto, Deininger, Michael, Radia, Deepti, Jawhar, Mohamad, Kluin-Nelemans, Hanneke, Metcalfe, Dean D., Arock, Michel, Sperr, Wolfgang R., Valent, Peter, Castells, Mariana, and Akin, Cem

Published
2021
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38. miR-155 promotes FLT3-ITD-induced myeloproliferative disease through inhibition of the interferon response.

Author

Wallace, Jared A, Kagele, Dominique A, Eiring, Anna M, Kim, Carissa N, Hu, Ruozhen, Runtsch, Marah C, Alexander, Margaret, Huffaker, Thomas B, Lee, Soh-Hyun, Patel, Ami B, Mosbruger, Timothy L, Voth, Warren P, Rao, Dinesh S, Miles, Rodney R, Round, June L, Deininger, Michael W, and O'Connell, Ryan M

Subjects
Pediatric Research Initiative, Cancer, Hematology, Stem Cell Research, Childhood Leukemia, Genetics, Rare Diseases, Pediatric Cancer, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Animals, CRISPR-Cas Systems, Cell Line, Tumor, Disease Models, Animal, Female, Humans, Interferons, Leukemia, Myeloid, Acute, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, MicroRNAs, Mutation, Myeloid Progenitor Cells, Myelopoiesis, Myeloproliferative Disorders, Tumor Stem Cell Assay, fms-Like Tyrosine Kinase 3, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Paediatrics and Reproductive Medicine, Immunology
Abstract

FLT3-ITD+ acute myeloid leukemia (AML) accounts for ∼25% of all AML cases and is a subtype that carries a poor prognosis. microRNA-155 (miR-155) is specifically overexpressed in FLT3-ITD+ AML compared with FLT3 wild-type (FLT3-WT) AML and is critical for the growth of FLT3-ITD+ AML cells in vitro. However, miR-155's role in regulating FLT3-ITD-mediated disease in vivo remains unclear. In this study, we used a genetic mouse model to determine whether miR-155 influences the development of FLT3-ITD-induced myeloproliferative disease. Results indicate that miR-155 promotes FLT3-ITD-induced myeloid expansion in the bone marrow, spleen, and peripheral blood. Mechanistically, miR-155 increases proliferation of the hematopoietic stem and progenitor cell compartments by reducing the growth-inhibitory effects of the interferon (IFN) response, and this involves targeting of Cebpb. Consistent with our observations in mice, primary FLT3-ITD+ AML clinical samples have significantly higher miR-155 levels and a lower IFN response compared with FLT3-WT AML samples. Further, inhibition of miR-155 in FLT3-ITD+ AML cell lines using CRISPR/Cas9, or primary FLT3-ITD+ AML samples using locked nucleic acid antisense inhibitors, results in an elevated IFN response and reduces colony formation. Altogether, our data reveal that miR-155 collaborates with FLT3-ITD to promote myeloid cell expansion in vivo and that this involves a multitarget mechanism that includes repression of IFN signaling.

Published
2017

41. Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts

Author

Zeidan, Amer M, Boddu, Prajwal C, Patnaik, Mrinal M, Bewersdorf, Jan Philipp, Stahl, Maximilian, Rampal, Raajit K, Shallis, Rory, Steensma, David P, Savona, Michael R, Sekeres, Mikkael A, Roboz, Gail J, DeAngelo, Daniel J, Schuh, Andre C, Padron, Eric, Zeidner, Joshua F, Walter, Roland B, Onida, Francesco, Fathi, Amir, DeZern, Amy, Hobbs, Gabriela, Stein, Eytan M, Vyas, Paresh, Wei, Andrew H, Bowen, David T, Montesinos, Pau, Griffiths, Elizabeth A, Verma, Amit K, Keyzner, Alla, Bar-Natan, Michal, Navada, Shyamala C, Kremyanskaya, Marina, Goldberg, Aaron D, Al-Kali, Aref, Heaney, Mark L, Nazha, Aziz, Salman, Huda, Luger, Selina, Pratz, Keith W, Konig, Heiko, Komrokji, Rami, Deininger, Michael, Cirici, Blanca Xicoy, Bhatt, Vijaya Raj, Silverman, Lewis R, Erba, Harry P, Fenaux, Pierre, Platzbecker, Uwe, Santini, Valeria, Wang, Eunice S, Tallman, Martin S, Stone, Richard M, and Mascarenhas, John

Published
2020
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42. A concept for improving fluid balance monitoring during hospitalisation

Author

Rasmussen, Anna Villebro, Nissen, Kathrine Jerichau, Konradsen, Hanne, Deininger, Michael, Rasmussen, Anna Villebro, Nissen, Kathrine Jerichau, Konradsen, Hanne, and Deininger, Michael

Abstract

Background: During hospitalisation, maintaining fluid balance in patients is an essential nursing goal, but also a challenging task. Most often printed fluid balance charts (FBCs) placed at a patient’s bedside to record fluid intake throughout the day are used, and they often result in incorrect registration and contribute to nurses spending much time on documentation. A more accurate and less time-consuming method for fluid balance monitoring (FBM) is therefore needed. Aim: To develop a new way of FBM. Method: We describe a multidisciplinary design process during which we leveraged engineering methods and tools to develop a solution that potentially supports patient care and safety, reduces staff workload, improves accuracy of fluid assessment, integrates with current nursing practise, supports an easy adoption in the healthcare system, and allows patients to be involved in the process. Conclusion: The Tablet System has the potential to offer a more accurate and less time-consuming method for fluid balance monitoring that addresses two megatrends in healthcare: digitisation of manual tasks and empowering patients.

Published
2024

46. Novel insights into the biology and treatment of chronic myeloproliferative neoplasms*

Author

Mughal, Tariq I, Barbui, Tiziano, Abdel-Wahab, Omar, Kralovics, Robert, Jamieson, Catriona, Kvasnicka, Hans-Michael, Mullaly, Ann, Rampal, Raajit, Mesa, Ruben, Kiladjian, Jean-Jacques, Deininger, Michael, Prchal, Josef, Hehlmann, Rüdiger, Saglio, Giuseppe, and Van Etten, Richard A

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Oncology and Carcinogenesis, Rare Diseases, Hematology, Genetics, Cancer, Orphan Drug, Chronic Disease, Humans, Myeloproliferative Disorders, Prognosis, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Myeloid leukemias and dysplasias, molecular genetics, signaling therapies, prognostication, myeloproliferative disorders, Clinical Sciences, Immunology, Cardiovascular medicine and haematology
Abstract

Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoiesis characterized by a high frequency of genetic alterations, and include chronic myeloid leukemia (CML) and the BCR-ABL1-negative MPNs. Herein we summarize recent advances and controversies in our understanding of the biology and therapy of these disorders, as discussed at the 8th post-American Society of Hematology CML-MPN workshop. The principal areas addressed include the breakthrough discovery of CALR mutations in patients with JAK2/MPL wild type MPN, candidate therapies based on novel genetic findings in leukemic transformation and new therapeutic targets in MPNs, and an appraisal of bone marrow histopathology in MPNs with a focus on the potential new clinical entity of "masked" polycythemia vera. An update on clinical trials of Janus kinase (JAK) inhibitors is presented as well as current understanding regarding the definitions and mechanisms of resistance to JAK inhibitors, and updated information on the safety and efficacy of discontinuation of tyrosine kinase inhibitors in patients with CML.

Published
2015

48. JAK2ex13InDel drives oncogenic transformation and is associated with chronic eosinophilic leukemia and polycythemia vera

Author

Patel, Ami B., Franzini, Anca, Leroy, Emilie, Kim, Soo Jin, Pomicter, Anthony D., Genet, Lidvine, Xiao, Michael, Yan, Dongqing, Ahmann, Jonathan M., Agarwal, Archana M., Clair, Phillip, Addada, Juanah, Lambert, Jonathan, Salmon, Matthew, Gleich, Gerald J., Cross, Nicholas C.P., Constantinescu, Stefan N., O'Hare, Thomas, Prchal, Josef T., and Deininger, Michael W.

Published
2019
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49. CDK4/CDK6 inhibition as a novel strategy to suppress the growth and survival of BCR-ABL1T315I+ clones in TKI-resistant CML

Author

Schneeweiss-Gleixner, Mathias, Byrgazov, Konstantin, Stefanzl, Gabriele, Berger, Daniela, Eisenwort, Gregor, Lucini, Chantal Blanche, Herndlhofer, Susanne, Preuner, Sandra, Obrova, Klara, Pusic, Petra, Witzeneder, Nadine, Greiner, Georg, Hoermann, Gregor, Sperr, Wolfgang R., Lion, Thomas, Deininger, Michael, Valent, Peter, and Gleixner, Karoline V.

Published
2019
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