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3. Preclinical characterization and clinical trial of CFI-400945, a polo-like kinase 4 inhibitor, in patients with relapsed/refractory acute myeloid leukemia and higher-risk myelodysplastic neoplasms

Author

Murphy, Tracy, Mason, Jacqueline M., Leber, Brian, Bray, Mark R., Chan, Steven M., Gupta, Vikas, Khalaf, Dina, Maze, Dawn, McNamara, Caroline J., Schimmer, Aaron D., Schuh, Andre C., Sibai, Hassan, Trus, Michael, Valiquette, Debbie, Martin, Kylie, Nguyen, Linh, Li, Xuan, Mak, Tak W., Minden, Mark D., and Yee, Karen W. L.

Published
2024
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4. Outcomes in Patients With Poor-risk Cytogenetics With or Without TP53 Mutations Treated With Venetoclax and Azacitidine

Author

Pollyea, Daniel A, Pratz, Keith W, Wei, Andrew H, Pullarkat, Vinod, Jonas, Brian A, Recher, Christian, Babu, Sunil, Schuh, Andre C, Dail, Monique, Sun, Yan, Potluri, Jalaja, Chyla, Brenda, and DiNardo, Courtney D

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Clinical Trials and Supportive Activities, Rare Diseases, Hematology, Clinical Research, 6.1 Pharmaceuticals, Humans, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Bridged Bicyclo Compounds, Heterocyclic, Cytogenetic Analysis, Leukemia, Myeloid, Acute, Mutation, Tumor Suppressor Protein p53, Treatment Outcome, Clinical Trials, Phase III as Topic, Clinical Trials, Phase I as Topic, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposeTo evaluate efficacy and safety of venetoclax + azacitidine in treatment-naïve patients with acute myeloid leukemia harboring poor-risk cytogenetics and TP53mut or TP53wt.Patients and methodsWe analyzed data from a phase III study (NCT02993523) comparing venetoclax (400 mg orally days 1-28) + azacitidine (75 mg/m2 days 1-7) or placebo + azacitidine, and from a phase Ib study (NCT02203773) of venetoclax + azacitidine. Patients were ineligible for intensive therapy. TP53 status was analyzed centrally; cytogenetic studies were performed locally.ResultsPatients (n = 127) with poor-risk cytogenetics receiving venetoclax + azacitidine (TP53wt = 50; TP53mut = 54) were compared with patients with poor-risk cytogenetics (n = 56) receiving azacitidine alone (TP53wt = 22; TP53mut = 18).For poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine versus azacitidine alone resulted in composite remission rates (CRc) of 70% versus 23%, median duration of remission (DoR) of 18.4 versus 8.5 months, and median overall survival (OS) of 23.4 versus 11.3 months, respectively. Outcomes with venetoclax + azacitidine were comparable with similarly treated patients with intermediate-risk cytogenetics and TP53wt.For poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine versus azacitidine alone resulted in CRc of 41% versus 17%, median DoR of 6.5 versus 6.7 months, and median OS of 5.2 versus 4.9 months, respectively.For poor-risk cytogenetics + TP53mut patients, predominant grade ≥3 adverse events (AE) for venetoclax + azacitidine versus azacitidine were febrile neutropenia (55%/39%), thrombocytopenia (28%/28%), neutropenia (26%/17%), anemia (13%/6%), and pneumonia (28%/33%). AEs were comparable between TP53mut and TP53wt patients.ConclusionsIn poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine improved remission rates but not DoR or OS compared with azacitidine alone. However, in poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine resulted in higher remission rates and longer DoR and OS than azacitidine alone, with outcomes comparable with similarly treated patients with intermediate-risk cytogenetics. Toxicities were similar in TP53mut and TP53wt patients. See related commentary by Green and Zeidner, p. 5235.

Published
2022

8. Measurable Residual Disease Response and Prognosis in Treatment-Naïve Acute Myeloid Leukemia With Venetoclax and Azacitidine

Author

Pratz, Keith W, Jonas, Brian A, Pullarkat, Vinod, Recher, Christian, Schuh, Andre C, Thirman, Michael J, Garcia, Jacqueline S, DiNardo, Courtney D, Vorobyev, Vladimir, Fracchiolla, Nicola S, Yeh, Su-Peng, Jang, Jun Ho, Ozcan, Muhit, Yamamoto, Kazuhito, Illes, Arpad, Zhou, Ying, Dail, Monique, Chyla, Brenda, Potluri, Jalaja, and Döhner, Hartmut

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Oncology and Carcinogenesis, Clinical Research, Hematology, Cancer, Rare Diseases, Clinical Trials and Supportive Activities, Good Health and Well Being, Azacitidine, Bridged Bicyclo Compounds, Heterocyclic, Humans, Leukemia, Myeloid, Acute, Neoplasm, Residual, Prognosis, Remission Induction, Sulfonamides, Clinical Sciences, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

PurposeThere is limited evidence on the clinical utility of monitoring measurable residual disease (MRD) in patients with acute myeloid leukemia treated with lower-intensity therapy. Herein, we explored the outcomes of patients treated with venetoclax and azacitidine who achieved composite complete remission (CRc; complete remission + complete remission with incomplete hematologic recovery) and MRD < 10-3 in the VIALE-A trial.MethodsThe patients included in this report were treated with venetoclax and azacitidine. Bone marrow aspirate samples for multiparametric flow cytometry assessments were collected for central analysis at baseline, end of cycle 1, and every three cycles thereafter. MRD-negative response was defined as < 1 residual blast per 1,000 leukocytes (< 10-3 or 0.1%) with an estimated analytic sensitivity of 0.0037%-0.0027%. CRc, duration of remission (DoR), event-free survival (EFS), and overall survival (OS) were assessed. A multivariate Cox regression analysis identified prognostic factors associated with OS.ResultsOne hundred sixty-four of one hundred ninety (86%) patients with CRc were evaluable for MRD. MRD < 10-3 was achieved by 67 of 164 (41%), and 97 of 164 (59%) had MRD ≥ 10-3. The median DoR, EFS, and OS were not reached in patients with CRc and MRD < 10-3, and the 12-month estimates for DoR, EFS, and OS in this group were 81.2%, 83.2%, and 94.0%. Among patients with CRc and MRD ≥ 10-3, the median DoR, EFS, and OS were 9.7, 10.6, and 18.7 months. Multivariate analysis showed that CRc with MRD < 10-3 was a strong predictor of OS (adjusted hazard ratio = 0.285; 95% CI, 0.159 to 0.510; P < .001).ConclusionPatients who achieved CRc and MRD < 10-3 with venetoclax and azacitidine had longer DoR, EFS, and OS, than responding patients with MRD ≥ 10-3.

Published
2022

9. Venetoclax combinations delay the time to deterioration of HRQoL in unfit patients with acute myeloid leukemia

Author

Pratz, Keith W, Panayiotidis, Panayiotis, Recher, Christian, Wei, Xudong, Jonas, Brian A, Montesinos, Pau, Ivanov, Vladimir, Schuh, Andre C, DiNardo, Courtney D, Novak, Jan, Pejsa, Vlatko, Stevens, Don, Yeh, Su-Peng, Kim, Inho, Turgut, Mehmet, Fracchiolla, Nicola, Yamamoto, Kazuhito, Ofran, Yishai, Wei, Andrew H, Bui, Cat N, Benjamin, Katy, Kamalakar, Rajesh, Potluri, Jalaja, Mendes, Wellington, Devine, Jacob, and Fiedler, Walter

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Oncology and Carcinogenesis, Clinical Research, Rare Diseases, Cancer, Antineoplastic Combined Chemotherapy Protocols, Bridged Bicyclo Compounds, Heterocyclic, Cytarabine, Fatigue, Humans, Leukemia, Myeloid, Acute, Quality of Life, Sulfonamides, Cardiorespiratory Medicine and Haematology, Cardiovascular medicine and haematology, Oncology and carcinogenesis
Abstract

Phase 3 trials Viale-A and Viale-C evaluated health-related quality of life (HRQoL) in patients with AML unfit for intensive chemotherapy who received venetoclax (VEN) + (AZA) (Viale-A) or low-dose cytarabine (LDAC) (Viale-C) or placebo (PBO) + AZA or LDAC. Patient-reported outcomes included: EORTC QLQ-C30 global health status (GHS/QoL) and physical functioning (PF), PROMIS Cancer Fatigue Short Form 7a (Fatigue), and EQ-5D-5L health status visual analog scale (HS-VAS). Time to deterioration (TTD), defined as worsening from baseline in meaningful change thresholds (MCT) of ≥10, 5, or 7 points for GHS/QoL or PF, fatigue, and HS-VAS, respectively, was assessed; differences between groups were analyzed using Kaplan-Meier and unadjusted log-rank analyses. VEN + AZA vs PBO + AZA patients had longer TTD in GHS/QoL (P = 0.066) and fatigue (P = 0.189), and significantly longer TTD in PF (P = 0.028) and HS-VAS (P MCT in GHS/QoL. Overall, VEN may positively impact HRQoL in patients with AML ineligible for intensive chemotherapy, leading to longer preservation of functioning and overall health status.

Published
2022

10. Asparaginase completion among adults including older patients with acute lymphoblastic leukemia treated with a modified DFCI protocol

Author

Perusini, Maria Agustina, Andrews, Claire, Eshetu, Atenafu G., Gupta, Vikas, Maze, Dawn, Yee, Karen W. L., Bankar, Aniket, Davidson, Marta B., Richard-Carpentier, Guillaume, Chan, Steven M., Schimmer, Aaron D., Sibai, Jad, Alharbi, Salman, Lucero, Josephine A., Linn, Swe Mar, Minden, Mark D., Schuh, Andre C., and Sibai, Hassan

Published
2024
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14. Standardising acute myeloid leukaemia classification systems: a perspective from a panel of international experts

Author

Shallis, Rory M, Daver, Naval, Altman, Jessica K, Komrokji, Rami S, Pollyea, Daniel A, Badar, Talha, Bewersdorf, Jan P, Bhatt, Vijaya R, de Botton, Stéphane, de la Fuente Burguera, Adolfo, Carraway, Hetty E, Desai, Pinkal, Dillon, Richard, Duployez, Nicolas, El Chaer, Firas, Fathi, Amir T, Freeman, Sylvie D, Gojo, Ivana, Grunwald, Michael R, Jonas, Brian A, Konopleva, Marina, Lin, Tara L, Mannis, Gabriel N, Mascarenhas, John, Michaelis, Laura C, Mims, Alice S, Montesinos, Pau, Pozdnyakova, Olga, Pratz, Keith W, Schuh, Andre C, Sekeres, Mikkael A, Smith, Catherine C, Stahl, Maximilian, Subklewe, Marion, Uy, Geoffrey L, Voso, Maria Teresa, Walter, Roland B, Wang, Eunice S, Zeidner, Joshua F, Žučenka, Andrius, and Zeidan, Amer M

Published
2023
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15. Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial

Author

de Botton, Stéphane, Montesinos, Pau, Schuh, Andre C., Papayannidis, Cristina, Vyas, Paresh, Wei, Andrew H., Ommen, Hans, Semochkin, Sergey, Kim, Hee-Je, Larson, Richard A., Koprivnikar, Jaime, Frankfurt, Olga, Thol, Felicitas, Chromik, Jörg, Byrne, Jenny, Pigneux, Arnaud, Thomas, Xavier, Salamero, Olga, Vidriales, Maria Belen, Doronin, Vadim, Döhner, Hartmut, Fathi, Amir T., Laille, Eric, Yu, Xin, Hasan, Maroof, Martin-Regueira, Patricia, and DiNardo, Courtney D.

Published
2023
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18. Outcomes and adverse events in older acute lymphoblastic Leukemia patients treated with a pediatric-inspired protocol with Pegylated or native Asparaginase.

Author

Perusini, Maria Agustina, Andrews, Claire, Atenafu, Eshetu G., Gupta, Vikas, Maze, Dawn, Schuh, Andre C., Yee, Karen WL., Bankar, Aniket, Davidson, Marta B., Richard-Carpentier, Guillaume, Chan, Steven M., Sibai, Jad, Schimmer, Aaron D., Minden, Mark D., and Sibai, Hassan

Subjects
LYMPHOBLASTIC leukemia, OLDER patients, ACUTE leukemia, OVERALL survival, FEBRILE neutropenia
Abstract

This retrospective report presents the outcomes and adverse events (AEs) observed in 73 patients aged 60 years or older diagnosed with Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia (Ph-negative ALL) treated with a pediatric-inspired protocol incorporating either Pegylated (PEG-ASP) or Native Asparaginase (EC-ASP). Notably, 61% of patients experienced AEs of Grade III-IV severity. The most prevalent AEs included thrombosis (35.6%), febrile neutropenia (38.4%), and transaminitis (34.2%). AEs did not translate into significant differences concerning overall survival, leukemia-free survival, or early mortality. Furthermore, we observed a reduction in early mortality rates (11% vs. 20%) and an increase in median overall survival (54 vs. 48 months) compared to our previous data. These findings suggest that the utilization of a pediatric-inspired chemotherapy protocol, with ASP, is an effective and well-tolerated therapeutic option for older patients with Ph-negative ALL. However, it emphasizes the importance of diligent monitoring and close follow-up throughout treatment. [ABSTRACT FROM AUTHOR]

Published
2024
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19. Evolution from an antecedent chronic myeloid malignancy does not impact survival outcomes in NPM1‐mutated AML.

Author

Smith, Elliot, Atenafu, Eshetu G., Bankar, Aniket, Chan, Steven, Davidson, Marta, Gupta, Vikas, Minden, Mark D., Richard‐Carpentier, Guillaume, Schimmer, Aaron, Schuh, Andre C., Sibai, Hassan, Yee, Karen, and Maze, Dawn

Subjects
ACUTE myeloid leukemia, OVERALL survival, SURVIVAL rate, PROGNOSIS, RETROSPECTIVE studies
Abstract

Nucleophosmin‐1 (NPM1)‐mutated AML is a molecularly defined subtype typically associated with favorable treatment response and prognosis; however, its prognostic significance in AML evolving from an antecedent chronic myeloid malignancy is unknown. This study's primary objective was to determine the impact of mutated NPM1 on the prognosis of AML evolving from an antecedent chronic myeloid malignancy. We conducted a retrospective chart review including patients with NPM1‐mutated de novo and sAML. sAML was defined as those with a preceding chronic‐phase myeloid malignancy before diagnosis of AML. Of 575 NPM1‐mutated patients eligible for inclusion in our study, 51 (8.9%) patients were considered to have sAML. The median time from diagnosis of NPM1‐mutated chronic myeloid malignancy to sAML evolution was 3.6 months (0.5–79.3 months). No significant differences in leukemia‐free (2‐year LKFS 52.0% vs. 51.2%, p =.9922) or overall survival (2‐year OS 56.3% vs. 49.4%, p =.4246) were observed between patients with NPM1‐mutated de novo versus sAML. Our study suggests that evolution from a preceding myeloid malignancy is not a significant predictor of poor prognosis in the setting of an NPM1 mutation. Our study demonstrated a short time to progression to sAML in most patients, which further supports the consideration of NPM1 as an AML‐defining mutation. [ABSTRACT FROM AUTHOR]

Published
2024
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22. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial

Author

DiNardo, Courtney D, Schuh, Andre C, Stein, Eytan M, Montesinos, Pau, Wei, Andrew H, de Botton, Stéphane, Zeidan, Amer M, Fathi, Amir T, Kantarjian, Hagop M, Bennett, John M, Frattini, Mark G, Martin-Regueira, Patricia, Lersch, Frederik, Gong, Jing, Hasan, Maroof, Vyas, Paresh, and Döhner, Hartmut

Published
2021
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23. Prognostic impact of the adverse molecular-genetic profile on long-term outcomes following allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia

Author

Daher-Reyes, Georgina, Kim, TaeHyung, Novitzky-Basso, Igor, Kim, Kyuoung Ha, Smith, Adam, Stockley, Tracy, Capochichi, Jose-Mario, Al-Shaibani, Zeyad, Pasic, Ivan, Law, Arjun, Lam, Wilson, Michelis, Fotios V., Gerbitz, Armin, Viswabandya, Auro, Lipton, Jeffrey, Kumar, Rajat, Mattsson, Jonas, Schimmer, Aaron, McNamara, Caroline, Murphy, Tracy, Maze, Dawn, Gupta, Vikas, Sibai, Hassan, Chan, Steven, Yee, Karen, Minden, Mark, Zhang, Zhaolei, Schuh, Andre, and Kim, Dennis D. H.

Published
2021
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24. 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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28. A Phase 1 study of intravenous infusions of tigecycline in patients with acute myeloid leukemia

Author

Reed, Gregory A, Schiller, Gary J, Kambhampati, Suman, Tallman, Martin S, Douer, Dan, Minden, Mark D, Yee, Karen W, Gupta, Vikas, Brandwein, Joseph, Jitkova, Yulia, Gronda, Marcela, Hurren, Rose, Shamas‐Din, Aisha, Schuh, Andre C, and Schimmer, Aaron D

Subjects
Pediatric Research Initiative, Clinical Research, Pediatric, Rare Diseases, Cancer, Hematology, Childhood Leukemia, Clinical Trials and Supportive Activities, Pediatric Cancer, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Adult, Aged, Aged, 80 and over, Antimetabolites, Antineoplastic, Drug Monitoring, Drug Resistance, Neoplasm, Female, Humans, Infusions, Intravenous, Leukemia, Myeloid, Acute, Male, Maximum Tolerated Dose, Middle Aged, Minocycline, Mitochondria, Recurrence, Retreatment, Risk Assessment, Tigecycline, Treatment Outcome, Cox-1, Cox-4, mitochondrial protein synthesis, pharmacodynamics, pharmacokinetics, Biochemistry and Cell Biology, Oncology and Carcinogenesis
Abstract

Acute myeloid leukemia (AML) cells meet the higher energy, metabolic, and signaling demands of the cell by increasing mitochondrial biogenesis and mitochondrial protein translation. Blocking mitochondrial protein synthesis through genetic and chemical approaches kills human AML cells at all stages of development in vitro and in vivo. Tigecycline is an antimicrobial that we found inhibits mitochondrial protein synthesis in AML cells. Therefore, we conducted a phase 1 dose-escalation study of tigecycline administered intravenously daily 5 of 7 days for 2 weeks to patients with AML. A total of 27 adult patients with relapsed and refractory AML were enrolled in this study with 42 cycles being administered over seven dose levels (50-350 mg/day). Two patients experienced DLTs related to tigecycline at the 350 mg/day level resulting in a maximal tolerated dose of tigecycline of 300 mg as a once daily infusion. Pharmacokinetic experiments showed that tigecycline had a markedly shorter half-life in these patients than reported for noncancer patients. No significant pharmacodynamic changes or clinical responses were observed. Thus, we have defined the safety of once daily tigecycline in patients with refractory AML. Future studies should focus on schedules of the drug that permit more sustained target inhibition.

Published
2016

31. Correction: Corrigendum: Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia

Author

Shlush, Liran I, Zandi, Sasan, Mitchell, Amanda, Chen, Weihsu Claire, Brandwein, Joseph M, Gupta, Vikas, Kennedy, James A, Schimmer, Aaron D, Schuh, Andre C, Yee, Karen W, McLeod, Jessica L, Doedens, Monica, Medeiros, Jessie JF, Marke, Rene, Kim, Hyeoung Joon, Lee, Kwon, McPherson, John D, Hudson, Thomas J, Pan-Leukemia Gene Panel Consortium, The HALT, Brown, Andrew MK, Yousif, Fouad, Trinh, Quang M, Stein, Lincoln D, Minden, Mark D, Wang, Jean CY, and Dick, John E

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Stem Cell Research, Cancer, Cardiovascular Medicine and Haematology, Hematology, Childhood Leukemia, Stem Cell Research - Nonembryonic - Human, Regenerative Medicine, Pediatric, Pediatric Cancer, Stem Cell Research - Nonembryonic - Non-Human, Rare Diseases, Genetics, 2.1 Biological and endogenous factors, Animals, Cell Differentiation, Cell Division, Cell Lineage, Clone Cells, DNA (Cytosine-5-)-Methyltransferases, DNA Methyltransferase 3A, Drug Resistance, Neoplasm, Female, Hematopoiesis, Hematopoietic Stem Cells, Heterografts, Humans, Isocitrate Dehydrogenase, Leukemia, Myeloid, Acute, Mice, Mice, Inbred NOD, Mice, SCID, Mutation, Neoplasm Transplantation, Neoplastic Stem Cells, Nuclear Proteins, Nucleophosmin, Remission Induction, T-Lymphocytes, HALT Pan-Leukemia Gene Panel Consortium, General Science & Technology
Abstract

In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3A(mut) arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance.

Published
2014

32. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.

Author

Shlush, Liran I, Zandi, Sasan, Mitchell, Amanda, Chen, Weihsu Claire, Brandwein, Joseph M, Gupta, Vikas, Kennedy, James A, Schimmer, Aaron D, Schuh, Andre C, Yee, Karen W, McLeod, Jessica L, Doedens, Monica, Medeiros, Jessie JF, Marke, Rene, Kim, Hyeoung Joon, Lee, Kwon, McPherson, John D, Hudson, Thomas J, HALT Pan-Leukemia Gene Panel Consortium, Brown, Andrew MK, Yousif, Fouad, Trinh, Quang M, Stein, Lincoln D, Minden, Mark D, Wang, Jean CY, and Dick, John E

Subjects
HALT Pan-Leukemia Gene Panel Consortium, T-Lymphocytes, Hematopoietic Stem Cells, Clone Cells, Animals, Mice, Inbred NOD, Humans, Mice, Mice, SCID, Isocitrate Dehydrogenase, Nuclear Proteins, Remission Induction, Neoplasm Transplantation, Cell Division, Cell Differentiation, Hematopoiesis, Cell Lineage, Drug Resistance, Neoplasm, Mutation, Female, Neoplastic Stem Cells, Leukemia, Myeloid, Acute, Heterografts, DNA (Cytosine-5-)-Methyltransferases, Cancer, Childhood Leukemia, Hematology, Genetics, Rare Diseases, Stem Cell Research - Nonembryonic - Non-Human, Pediatric, Pediatric Cancer, Stem Cell Research, 2.1 Biological and endogenous factors, General Science & Technology
Abstract

In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3A(mut) arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance.

Published
2014

33. Preclinical characterization and clinical trial of CFI-400945, a polo-like kinase 4 inhibitor, in patients with relapsed/refractory acute myeloid leukemia and higher-risk myelodysplastic neoplasms

Author

Murphy, Tracy, primary, Mason, Jacqueline M., additional, Leber, Brian, additional, Bray, Mark R., additional, Chan, Steven M., additional, Gupta, Vikas, additional, Khalaf, Dina, additional, Maze, Dawn, additional, McNamara, Caroline J., additional, Schimmer, Aaron D., additional, Schuh, Andre C., additional, Sibai, Hassan, additional, Trus, Michael, additional, Valiquette, Debbie, additional, Martin, Kylie, additional, Nguyen, Linh, additional, Li, Xuan, additional, Mak, Tak W., additional, Minden, Mark D., additional, and Yee, Karen W. L., additional

Published
2023
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36. AML-432 Overall Survival (OS) by IDH2 Mutant Allele (R140 or R172) in Patients With Late-Stage, Mutant-IDH2 Relapsed/Refractory Acute Myeloid Leukemia (AML) Treated With Enasidenib or Conventional Care Regimens (CCR) in the Randomized, Open-Label, Phase 3 IDHENTIFY Trial

Author

DiNardo, Courtney D., de Botton, Stéphane, Risueño, Alberto, Schuh, Andre C., Löwenberg, Bob, Kim, Hee-Je, Vyas, Paresh, Wei, Andrew H., Stein, Eytan M., Döhner, Hartmut, Fathi, Amir T., Martin-Regueira, Patricia, Taningco, Lilia, Bluemmert, Iryna, Yu, Xin, See, Wendy L., and Hasan, Maroof

Published
2022
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37. AML-295 AGILE: A Global, Randomized, Double-Blind, Phase 3 Study of Ivosidenib + Azacitidine Versus Placebo + Azacitidine in Patients With Newly Diagnosed Acute Myeloid Leukemia With an IDH1 Mutation

Author

Dohner, Hartmut, Montesinos, Pau, Polo, Susana Vives, Zarzycka, Ewa, Wang, Jianxiang, Bertani, Giambattista, Heuser, Michael, Calado, Rodrigo T., Schuh, Andre C., Yeh, Su-Peng, de la Fuente, Adolfo, Cerchione, Claudio, Daigle, Scott R., Hui, Jianan, Pandya, Shuchi S., Gianolio, Diego A., Recher, Christian, and de Botton, Stephane

Published
2022
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38. The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes

Author

McNamara, Caroline J., Panzarella, Tony, Kennedy, James A., Arruda, Andrea, Claudio, Jaime O., Daher-Reyes, Georgina, Ho, Jenny, Siddiq, Nancy, Devlin, Rebecca, Tsui, Hubert, Su, Jie, Stockley, Tracy, Sukhai, Mahadeo, Kanwar, Nisha, Chan, Steven, Maze, Dawn, Schimmer, Aaron, Schuh, Andre, Sibai, Hassan, Viswabandya, Auro, Yee, Karen, Minden, Mark D., Kamel-Reid, Suzanne, and Gupta, Vikas

Published
2018
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42. AML refractory to primary induction with Ida-FLAG has a poor clinical outcome

Author

Kavanagh, Simon, Heath, Emily, Hurren, Rose, Gronda, Marcela, Barghout, Samir H., Liyanage, Sanduni U., Siriwardena, Thirushi P., Claudio, Jaime, Zhang, Tong, Sukhai, Mahadeo, Stockley, Tracy L., Kamel-Reid, Suzanne, Rostom, Amr, Lutynski, Andrzej, Khalaf, Dina, Rydlewski, Anna, Chan, Steven M., Gupta, Vikas, Maze, Dawn, Sibai, Hassan, Schuh, Andre C., Yee, Karen, Minden, Mark D., and Schimmer, Aaron D.

Published
2018
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44. AML-469 Ivosidenib + Azacitidine vs Placebo + Azacitidine in Patients With Newly-Diagnosed Acute Myeloid Leukemia: Updated Long-term Efficacy and Safety Results From the AGILE Study

Author

de Botton, Stéphane, primary, Montesinos, Pau, additional, Polo, Susana Vives, additional, Zarzycka, Ewa, additional, Wang, Jianxiang, additional, Riva, Marta, additional, Heuser, Michael, additional, Calado, Rodrigo T., additional, Schuh, Andre C., additional, Yeh, Su-Peng, additional, Hui, Jianan, additional, Gianolio, Diego A., additional, Patel, Prapti, additional, Recher, Christian, additional, and Döhner, Hartmut, additional

Published
2023
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45. POSTER: AML-469 Ivosidenib + Azacitidine vs Placebo + Azacitidine in Patients With Newly-Diagnosed Acute Myeloid Leukemia: Updated Long-term Efficacy and Safety Results From the AGILE Study

Author

de Botton, Stéphane, primary, Montesinos, Pau, additional, Polo, Susana Vives, additional, Zarzycka, Ewa, additional, Wang, Jianxiang, additional, Riva, Marta, additional, Heuser, Michael, additional, Calado, Rodrigo T., additional, Schuh, Andre C., additional, Yeh, Su-Peng, additional, Hui, Jianan, additional, Gianolio, Diego A., additional, Patel, Prapti, additional, Recher, Christian, additional, and Döhner, Hartmut, additional

Published
2023
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46. P459: DISEASE MONITORING OF NPM1-MUTANT (MUT) ACUTE MYELOID LEUKEMIA (AML) USING MEASURABLE RESIDUAL DISEASE (MRD) ASSESSMENTS DURING ORAL AZACITIDINE (ORAL-AZA) TREATMENT (TX): A QUAZAR AML-001 SUBANALYSIS

Author

Lopes De Menezes, Daniel, primary, Roboz, Gail, additional, Döhner, Hartmut, additional, Wei, Andrew, additional, Teresa Voso, Maria, additional, Schuh, Andre, additional, See, Wendy L., additional, Ugidos, Manuel, additional, Amzallag, Arnaud, additional, Risueño, Alberto, additional, H. Eng, Kevin, additional, Nvs Suragani, Rajasekhar, additional, Skikne, Barry, additional, Beach, CL, additional, Prebet, Thomas, additional, and Gandhi, Anita, additional

Published
2023
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47. P490: UPDATED SURVIVAL, BLOOD COUNT RECOVERY AND SAFETY RESULTS FROM THE AGILE STUDY IN PATIENTS WITH ACUTE MYELOID LEUKEMIA TREATED WITH IVOSIDENIB + AZACITIDINE COMPARED TO PLACEBO + AZACITIDINE

Author

Döhner, Hartmut, primary, Montesinos, Pau, additional, Vives Polo, Susana, additional, Zarzycka, Ewa, additional, Wang, Jianxiang, additional, Riva, Marta, additional, Heuser, Michael, additional, Calado, Rodrigo, additional, Schuh, Andre, additional, Yeh, Su-Peng, additional, Hui, Jianan, additional, Gianolio, Diego, additional, A Patel, Prapti, additional, Recher, Christian, additional, and de Botton, Stephane, additional

Published
2023
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48. P385: COMPARISON OF CLINICAL OUTCOMES AND ADVERSE EVENTS IN OLDER ADULTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA TREATED WITH NATIVE VS PEGYLATED ASPARAGINASE

Author

Agustina Perusini, Maria, primary, Gupta, Vikas, additional, Bankar, Aniket, additional, Sibai, Jad, additional, Minden, Mark, additional, Maze, Dawn, additional, Davidson, Marta, additional, Richard-Carpentier, Guillaume, additional, M Chan, Steven, additional, Schuh, Andre, additional, Yee, Karen, additional, Atenafu, Eshetu, additional, and Sibai, Hassan, additional

Published
2023
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49. P411: LONGITUDINAL CHARACTERIZATION OF MOLECULAR VARIANTS AT REMISSION AND RELAPSE: SUBANALYSIS OF THE QUAZAR AML-001 TRIAL

Author

Lopes De Menezes, Daniel, primary, Wei, Andrew, additional, Döhner, Hartmut, additional, Roboz, Gail, additional, Teresa Voso, Maria, additional, Schuh, Andre, additional, See, Wendy L., additional, Ugidos, Manuel, additional, Amzallag, Arnaud, additional, Risueño, Alberto, additional, Kyriakopoulos, Charalampos, additional, Nvs Suragani, Rajasekhar, additional, Skikne, Barry, additional, Beach, CL, additional, Prebet, Thomas, additional, and Gandhi, Anita, additional

Published
2023
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