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58. Diffusion of charm quarks in jets in high-energy heavy-ion collisions

Author

Wang, Sa, Dai, Wei, Zhang, Ben-Wei, and Wang, Enke

Subjects
Nuclear Theory, High Energy Physics - Theory
Abstract

The radial distribution of $D^0$ mesons in jets probes the diffusion of charm quark relative to the jet axis and provides a new perspective to study the interaction mechanisms between heavy quarks and the medium in the nucleus-nucleus collisions. The in-medium parton propagations are described by a Monte Carlo transport model which uses the next-to-leading order (NLO) plus parton shower (PS) event generator SHERPA as input and includes elastic (collisional) and inelastic (radiative) interaction for heavy quarks as well as light partons. At low $D^0$ meson $p_T$, the radial distribution significantly shifts to larger radius indicating a strong diffusion effect which is consistent with the recent experimental data. We demonstrate that the angular deviation of charm quarks declines with $p_T$ and is very sensitive to the collisional more than radiative interaction at $p_T<5$~GeV. As predictions, we present the $D^0$ meson radial distribution in jets in p+p and $0-10\%$ Au+Au collisions at $\sqrt{s_{NN}}=200$~GeV at the RHIC, and also estimate the nuclear modification factor of charm jet in central Au+Au collisions at 200~GeV at the RHIC and central Pb+Pb collisions at $5.02$~TeV at the LHC., Comment: 8 pages, 8 figures

Published
2019
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60. Mini-hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, in the subgroup of older patients with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: long-term results of an open-label phase 2 trial

Author

Jabbour, Elias, Short, Nicholas J, Senapati, Jayastu, Jain, Nitin, Huang, Xuelin, Daver, Naval, DiNardo, Courtney D, Pemmaraju, Naveen, Wierda, William, Garcia-Manero, Guillermo, Montalban Bravo, Guillermo, Sasaki, Koji, Kadia, Tapan M, Khoury, Joseph, Wang, Sa A, Haddad, Fadi G, Jacob, Jovitta, Garris, Rebecca, Ravandi, Farhad, and Kantarjian, Hagop M

Published
2023
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61. The production of $b\bar{b}$ dijet in heavy-ion collisions at the LHC

Author

Wang, Sa, Dai, Wei, Zhang, Shan-Liang, Zhang, Ben-Wei, and Wang, Enke

Subjects
Nuclear Theory, High Energy Physics - Phenomenology
Abstract

We report our recent theoretical calculations for $b\bar{b}$ dijet production in high-energy nuclear collisions. The NLO+parton shower (PS) event generator SHERPA has been employed to provide the pp baseline of $b\bar{b}$ dijet production. A framework which combines Langevin transport equation to describe the evolution of heavy quarks and the higher-twist scheme to consider the inelastic energy loss of both light and heavy partons has been implemented. Within this framework, we present the theoretical result of transverse momentum imbalance $x_J=p_{T1}/p_{T2}$ both for inclusive dijet and $b\bar{b}$ dijet in Pb+Pb collision at 5.02 TeV. The energy loss of b jet would shift $x_J$ to smaller value relative to p+p reference which is consistent with the CMS data. In addition, we show the medium modification for angular correlation of $b\bar{b}$ dijet in A+A collision at $\sqrt{s_{NN}}=5.02$~TeV. We observe a stronger suppression in small $\Delta \phi=|\phi_{b1}-\phi_{b2}|$ region where the gluon splitting processes dominate relative to large $\Delta \phi$ region. The difference leads to a modest suppression on near side ($\Delta \phi\sim 0$) and enhancement on away side ($\Delta\phi\sim\pi$)., Comment: 4 pages, 4 figures, Parallel talk presented at Hard Probes 2018

Published
2018
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65. Undetectable Measurable Residual Disease is Associated with Improved Outcomes in AML Irrespective of Treatment Intensity

Author

Bazinet, Alexandre, Kadia, Tapan, Short, Nicholas J., Borthakur, Gautam, Wang, Sa A., Wang, Wei, Loghavi, Sanam, Jorgensen, Jeffrey, Patel, Keyur, DiNardo, Courtney, Daver, Naval, Alvarado, Yesid, Haddad, Fadi G., Pierce, Sherry, Gonzalez, Graciela Nogueras, Maiti, Abhishek, Sasaki, Koji, Yilmaz, Musa, Thompson, Philip, Wierda, William, Garcia-Manero, Guillermo, Andreeff, Michael, Jabbour, Elias, Konopleva, Marina, Huang, Xuelin, Kantarjian, Hagop, and Ravandi, Farhad

Published
2023
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67. Detection of PNH clones can aid in the distinction of aplastic anemia vs inherited BM failure syndromes: a single center experience and review of the literature.

Author

Nasnas, Patrice, primary, Ling, Jianhua, additional, Gerstein, Yoheved, additional, Wang, Sa A., additional, Loghavi, Sanam, additional, Hammond, Danielle, additional, Montalban-Bravo, Guillermo, additional, Senapati, Jayastu, additional, Pemmaraju, Naveen, additional, Corredor, Jessie, additional, Pierce, Sherry, additional, Roth, Michael, additional, Ravandi, Farhad, additional, Cuglievan, Branko, additional, Kadia, Tapan, additional, and DiNardo, Courtney D, additional

Published
2024
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71. Jet tomography in high-energy nuclear collisions

Author

Zhang, Ben-Wei, Ma, Guo-Yang, Dai, Wei, Wang, Sa, and Zhang, Shan-Liang

Subjects
Nuclear Theory, High Energy Physics - Phenomenology
Abstract

When an energetic parton traversing the QCD medium, it may suffer multiple scatterings and lose energy. This jet quenching phenomenon may lead to the suppression of leading hadron productions as well as medium modifications of full jet observables in heavy-ion collisions. In this talk we discuss the nuclear modification factors and yield ratios of identified meson such as $\eta$, $\rho^0$, $\phi$, $\omega$, and $K^0_{\rm S}$ as well as $\pi$ meson at large $p_T$ in A+A collisions at the next-to-leading order (NLO) with high-twist approach of parton energy loss. Then we discuss a newly developed formalism of combing NLO matrix elements and parton shower (PS) for initial hard production with parton energy loss in the QGP, and its application in investigating massive gauge boson ($Z^0$/$W^{\pm}$) tagged jet productions and $b\bar{b}$ dijet correlations in Pb+Pb at the LHC., Comment: Invited talk at ISMD2018 (the International Symposium on Multiparticle Dynamics), the National University of Singapore, Singapore. Submitted to the cofference proceedings. 10 pages, 12 figures

Published
2018
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72. Transverse Momentum Balance and Angular Distribution of $b\bar{b}$ Dijets in Pb+Pb collisions

Author

Dai, Wei, Wang, Sa, Zhang, Shan-Liang, Zhang, Ben-Wei, and Wang, Enke

Subjects
Nuclear Theory, High Energy Physics - Phenomenology, Nuclear Experiment
Abstract

The productions of inclusive b-jet and $b\bar{b}$ dijets in Pb+Pb collisions have been investigated by considering the heavy quark and the light quark in-medium evolution simultaneously. The initial hard processes of inclusive b-jet and $b\bar{b}$ dijets productions are described by a next-to-leading order (NLO) plus parton shower Monte Carlo (MC) event generator SHERPA which can be well-matched with the experimental data in p+p collisions. The framework combines the Langevin transport model to describe the evolution of the bottom quark also its collisional energy loss and the higher-twist description to consider the radiative energy loss of both the bottom and light quarks. We compare the theoretical simulation of inclusive jet and inclusive b-jet $R_{\rm AA}$ in Pb+Pb collisions at $\sqrt{s_{\rm NN}}=2.76$ TeV with the experimental data, and then present the theoretical simulation of the momentum balance of the $b\bar{b}$ dijet in Pb+Pb collisions at $5.02$ TeV with the recent CMS data for the first time. A similar trend as that in inclusive dijets has been observed in $b\bar{b}$ dijets, the production distribution is shifted to smaller $x_J$ due to the jet quenching effect. At last, the prediction of the normalized azimuthal angle distribution of the $b\bar{b}$ dijet in Pb+Pb collisions at $5.02$ TeV has been reported. The medium induced energy loss effect of the $b\bar{b}$ dijets will overall suppress its production, but the same side ($\Delta \phi \to 0$ region) suffers more energy loss than away side ($\Delta \phi \to \pi$ region), therefore lead to the suppression on the same side and the enhancement on the away side in the normalized azimuthal angle distribution in A+A collisions., Comment: 6 pages, 5 figures,the version to appear in CPC

Published
2018
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73. Avalon: Building an Operating System for Robotcenter

Author

Xu, Yuan, Yan, Zhiyuan, Wang, Sa, Yang, Cheng, Xiao, Qingsai, and Bao, Yungang

Subjects
Computer Science - Robotics, Computer Science - Distributed, Parallel, and Cluster Computing
Abstract

This paper envisions a scenario that hundreds of heterogeneous robots form a robotcenter which can be shared by multiple users and used like a single powerful robot to perform complex tasks. However, current multi-robot systems are either unable to manage heterogeneous robots or unable to support multiple concurrent users. Inspired by the design of modern datacenter OSes, we propose Avalon, a robot operating system with two-level scheduling scheme which is widely adopted in datacenters for Internet services and cloud computing. Specifically, Avalon integrates three important features together: (1) Instead of allocating a whole robot, Avalon classifies fine-grained robot resources into three categories to distinguish which fine-grained resources can be shared by multi-robot frameworks simultaneously. (2) Avalon adopts a location based resource allocation policy to substantially reduce scheduling overhead. (3) Avalon enables robots to offload computation intensive tasks to the clouds.We have implemented and evaluated Avalon on robots on both simulated environments and real world.

Published
2018

75. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data

Author

Arber, Daniel A., Orazi, Attilio, Hasserjian, Robert P., Borowitz, Michael J., Calvo, Katherine R., Kvasnicka, Hans-Michael, Wang, Sa A., Bagg, Adam, Barbui, Tiziano, Branford, Susan, Bueso-Ramos, Carlos E., Cortes, Jorge E., Dal Cin, Paola, DiNardo, Courtney D., Dombret, Hervé, Duncavage, Eric J., Ebert, Benjamin L., Estey, Elihu H., Facchetti, Fabio, Foucar, Kathryn, Gangat, Naseema, Gianelli, Umberto, Godley, Lucy A., Gökbuget, Nicola, Gotlib, Jason, Hellström-Lindberg, Eva, Hobbs, Gabriela S., Hoffman, Ronald, Jabbour, Elias J., Kiladjian, Jean-Jacques, Larson, Richard A., Le Beau, Michelle M., Loh, Mignon L.-C., Löwenberg, Bob, Macintyre, Elizabeth, Malcovati, Luca, Mullighan, Charles G., Niemeyer, Charlotte, Odenike, Olatoyosi M., Ogawa, Seishi, Orfao, Alberto, Papaemmanuil, Elli, Passamonti, Francesco, Porkka, Kimmo, Pui, Ching-Hon, Radich, Jerald P., Reiter, Andreas, Rozman, Maria, Rudelius, Martina, Savona, Michael R., Schiffer, Charles A., Schmitt-Graeff, Annette, Shimamura, Akiko, Sierra, Jorge, Stock, Wendy A., Stone, Richard M., Tallman, Martin S., Thiele, Jürgen, Tien, Hwei-Fang, Tzankov, Alexandar, Vannucchi, Alessandro M., Vyas, Paresh, Wei, Andrew H., Weinberg, Olga K., Wierzbowska, Agnieszka, Cazzola, Mario, Döhner, Hartmut, and Tefferi, Ayalew

Published
2022
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76. High-sensitivity next-generation sequencing MRD assessment in ALL identifies patients at very low risk of relapse

Author

Short, Nicholas J., Kantarjian, Hagop, Ravandi, Farhad, Konopleva, Marina, Jain, Nitin, Kanagal-Shamanna, Rashmi, Patel, Keyur P., Macaron, Walid, Kadia, Tapan M., Wang, Sa, Jorgensen, Jeffrey L., Khoury, Joseph D., Yilmaz, Musa, Kebriaei, Partow, Takahashi, Koichi, Garcia-Manero, Guillermo, Daver, Naval, Post, Sean M., Huang, Xuelin, Kornblau, Steven M., Pelletier, Sara, Flores, Wilmer, Matthews, Jairo, Garris, Rebecca, and Jabbour, Elias

Published
2022
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80. Myelodysplastic/myeloproliferative neoplasms-unclassifiable with isolated isochromosome 17q represents a distinct clinico-biologic subset: a multi-institutional collaborative study from the Bone Marrow Pathology Group

Author

Kanagal-Shamanna, Rashmi, Orazi, Attilio, Hasserjian, Robert P., Arber, Daniel A., Reichard, Kaaren, Hsi, Eric D., Bagg, Adam, Rogers, Heesun Joyce, Geyer, Julia, Darbaniyan, Faezeh, Do, Kim-Anh, Devins, Kyle M., Pozdnyakova, Olga, George, Tracy I., Cin, Paola Dal, Greipp, Patricia T., Routbort, Mark J., Patel, Keyur, Garcia-Manero, Guillermo, Verstovsek, Srdan, Medeiros, L. Jeffrey, Wang, Sa A., and Bueso-Ramos, Carlos

Published
2022
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84. An International, Retrospective Study of Off-Label Biologic Use in the Treatment of Hypereosinophilic Syndromes

Author

Chen, Michael M., Roufosse, Florence, Wang, Sa A., Verstovsek, Srdan, Durrani, Sandy R., Rothenberg, Marc E., Pongdee, Thanai, Butterfield, Joseph, Lax, Timothy, Wechsler, Michael E., Stein, Miguel L., Ogbogu, Princess U., Kahwash, Basil M., Mathur, Sameer K., Simon, Dagmar, Akuthota, Praveen, Holland, Nicole, Wetzler, Lauren, Ware, JeanAnne M., Guo, Canting, Fay, Michael P., Khoury, Paneez, Klion, Amy D., and Bochner, Bruce S.

Published
2022
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87. Ibrutinib–rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial

Author

Wang, Michael L, Jain, Preetesh, Zhao, Shuangtao, Lee, Hun Ju, Nastoupil, Loretta, Fayad, Luis, Ok, Chi Young, Kanagal-Shamanna, Rashmi, Hill, Holly A, Yao, Yixin, Hagemeister, Fredrick B, Westin, Jason R, Fowler, Nathan, Samaniego, Felipe, Steiner, Raphael, Nair, Ranjit, Iyer, Swaminathan P, Navsaria, Lucy, Badillo, Maria, Feng, Lei, Xuelin, Huang, Nogueras Gonzalez, Graciela M, Xu, Guofan, Wagner-Bartak, Nicolaus, Thirumurthi, Selvi, Santos, David, Tang, Guilin, Lin, Pei, Wang, Sa A, Jorgensen, Jeff, Yin, C Cameron, Li, Shaoying, Patel, Keyur P, Vega, Francisco, Medeiros, L Jeffery, Flowers, Christopher R, and Wang, Linghua

Published
2022
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88. Integrative immunophenotypic and genetic characterization of acute myeloid leukemia with CBFB rearrangement.

Author

Sameeta, Fnu, Wang, Sa A, Tang, Zhenya, Khoury, Joseph D, Fang, Hong, Wang, Dylan, Xu, Jie, Li, Shaoying, Hu, Zhihong, Hu, Shimin, Jorgensen, Jeffrey L, Medeiros, L Jeffrey, and Wang, Wei

Abstract

Objectives We sought to characterize the immunophenotype of acute myeloid leukemia (AML) with CBFB rearrangement and correlate the results with cytogenetic and molecular data. Methods Sixty-one cases of AML with CBFB rearrangement were evaluated. Results The sample population consisted of 33 men and 28 women, with a median age of 49 years. Flow cytometry immunophenotypic analysis showed that myeloblasts were positive for CD34 and CD117 in all cases, and myeloperoxidase was positive in 52 of 55 (95%) cases. The most common abnormalities included decreased CD38 in 90%, increased CD13 in 85%, increased CD123 in 84%, and decreased HLA-DR in 84% of cases. Monocytes were increased, with a mature immunophenotype, and accounted for 23.7% of total cells. Among 60 cases with available karyotype, inv(16)(p13.1q22) was most common in 50 (83%) cases, followed by t(16;16) (p13.1;q22) in 6 (10%). Type A CBFB::MYH11 transcript was most common, detected in 84% of cases. Mutational analysis showed mutations of NRAS in 37%, FLT3 in 25%, and KIT in 24% of cases. Comparing cases with type A vs non–type A transcripts, blasts in type A cases more frequently exhibited CD64 positivity and increased CD13 levels while showing a lower frequency of CD7 and CD56 expression. Trisomy 22 and mutations in KIT, NF1, and TET2 were identified only in cases with type A transcript. Conclusions Myeloblasts of AML with CBFB rearrangement are positive for CD34, CD117, and myeloperoxidase. These neoplasms most frequently carry inv(16)(p13.1q22) and type A fusion transcript. NRAS mutation was the most common mutation. Some immunophenotypic and genetic correlations occurred with different types of transcripts. [ABSTRACT FROM AUTHOR]

Published
2024
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92. Optical genome mapping improves the accuracy of classification, risk stratification, and personalized treatment strategies for patients with acute myeloid leukemia.

Author

Loghavi, Sanam, Wei, Qing, Ravandi, Farhad, Quesada, Andres E., Routbort, Mark J., Hu, Shimin, Toruner, Gokce A., Wang, Sa A., Wang, Wei, Miranda, Roberto N., Li, Shaoying, Xu, Jie, DiNardo, Courtney D., Daver, Naval, Kadia, Tapan M., Issa, Ghayas C., Kantarjian, Hagop M., Medeiros, L. Jeffrey, and Tang, Guilin

Published
2024
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93. A hypothalamus‐lateral periaqueductal gray GABAergic neural projection facilitates arousal following sevoflurane anesthesia in mice.

Author

Wang, Dan, Bao, Chang, Wu, Huimin, Li, Jiannan, Zhang, Xinxin, Wang, Sa, Zhou, Fang, Li, Huiming, and Dong, Hailong

Subjects
GABAERGIC neurons, INHALATION anesthetics, LOSS of consciousness, GENERAL anesthesia, WAKEFULNESS
Abstract

Background: The lateral hypothalamus (LHA) is an evolutionarily conserved structure that regulates basic functions of an organism, particularly wakefulness. To clarify the function of LHAGABA neurons and their projections on regulating general anesthesia is crucial for understanding the excitatory and inhibitory effects of anesthetics on the brain. The aim of the present study is to investigate whether LHAGABA neurons play either an inhibitory or a facilitatory role in sevoflurane‐induced anesthetic arousal regulation. Methods: We used fiber photometry and immunofluorescence staining to monitor changes in neuronal activity during sevoflurane anesthesia. Opto‐/chemogenetic modulations were employed to study the effect of neurocircuit modulations during the anesthesia. Anterograde tracing was used to identify a GABAergic projection from the LHA to a periaqueductal gray (PAG) subregion. Results: c‐Fos staining showed that LHAGABA activity was inhibited by induction of sevoflurane anesthesia. Anterograde tracing revealed that LHAGABA neurons project to multiple arousal‐associated brain areas, with the lateral periaqueductal gray (LPAG) being one of the dense projection areas. Optogenetic experiments showed that activation of LHAGABA neurons and their downstream target LPAG reduced the burst suppression ratio (BSR) during continuous sevoflurane anesthesia. Chemogenetic experiments showed that activation of LHAGABA and its projection to LPAG neurons prolonged the anesthetic induction time and promoted wakefulness. Conclusions: In summary, we show that an inhibitory projection from LHAGABA to LPAGGABA neurons promotes arousal from sevoflurane‐induced loss of consciousness, suggesting a complex control of wakefulness through intimate interactions between long‐range connections. [ABSTRACT FROM AUTHOR]

Published
2024
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94. Predictors of clinical outcome in myeloproliferative neoplasm, unclassifiable: A Bone Marrow Pathology Group study.

Author

Crane, Genevieve M, Geyer, Julia T, Thakral, Beenu, Wang, Sa A, Wool, Geoffrey D, Li, Ke David, Davis, Adam R, Boiocchi, Leonardo, Bosler, David, Bueso-Ramos, Carlos E, Arber, Daniel A, George, Tracy I, Bagg, Adam, Hasserjian, Robert P, Orazi, Attilio, Hsi, Eric D, and Rogers, Heesun J

Subjects
OVERALL survival, PROGNOSIS, MYELOPROLIFERATIVE neoplasms, TREATMENT effectiveness, NUCLEOTIDE sequencing
Abstract

Objectives Myeloproliferative neoplasm, unclassifiable (MPN-U, revised to MPN, not otherwise specified in the fifth edition of the World Health Organization classification) is a heterogeneous category of primary marrow disorders with clinical, morphologic, and/or molecular features that preclude classification as a more specific MPN subtype due to stage at diagnosis, overlapping features between MPN subtypes, or the presence of coexisting disorders. Compared with other MPN subtypes, the contribution of the mutational landscape in MPN-U in conjunction with other clinical and morphologic biomarkers to prognosis has been less well investigated. Methods We performed a multicenter, retrospective study of MPN-U (94 cases) to better define the clinicopathologic features, genetic landscape, and clinical outcomes, including subgroups of early-stage, advanced-stage, and coexisting disorders. The Dynamic International Prognostic Scoring System (DIPSS) plus scoring system was applied to assess its relevance to MPN-U prognosis. Results Multivariate analysis demonstrated bone marrow blast count and DIPSS plus score as statistically significant in predicting overall survival. Univariate analysis identified additional potential poor prognostic markers, including abnormal karyotype and absence of JAK2 mutation. Secondary mutations were frequent in the subset analyzed by next-generation sequencing (26/37 cases, 70.3%) with a borderline association between high molecular risk mutations and overall survival. Conclusions This study, as one of the largest of MPN-U studies incorporating both clinicopathologic and molecular data, moves toward identification of biomarkers that better predict prognosis in this heterogeneous category. [ABSTRACT FROM AUTHOR]

Published
2024
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95. Long-term results of the sequential combination of cladribine and rituximab in Hairy cell leukemia.

Author

Marvin-Peek, Jennifer, Jen, Wei-Ying, Kantarjian, Hagop M., McCue, David, Haddad, Fadi G., Wierda, William, Ferrajoli, Alessandra, Burger, Jan, Abusab, Tareq, Jorgensen, Jeffrey, Wang, Sa A., Patel, Keyur, Loghavi, Sanam, O'Brien, Susan, and Ravandi, Farhad

Subjects
HAIRY cell leukemia, DISEASE relapse, OVERALL survival, PATIENTS' attitudes, RITUXIMAB
Abstract

We report on the long-term efficacy and safety of a phase 2 trial of sequential cladribine and rituximab in hairy cell leukemia (HCL). One-hundred and thirty-nine patients were enrolled: 111 in the frontline setting, 18 in first relapse, and 10 with variant HCL (HCLv). A complete response (CR) was achieved in 133 of 137 evaluable participants (97%) with measurable residual disease (MRD) negativity in 102 (77%). MRD status was not associated with significant differences in event-free survival (EFS) or overall survival (OS). With a median follow-up of 7.8 years (range: 0.40–18.8), eight patients have experienced disease relapse (5.8%), 4/111 with newly diagnosed HCL (3·6%) and 4/10 with HCLv (40%) (p = 0.002). The 10-year EFS and OS rates were 86.7% and 91.1%, respectively. Grade 3 adverse events were observed in 28 participants (20·1%), mostly due to infections. Treatment of HCL with sequential cladribine followed by rituximab is associated with excellent efficacy and safety results both in the frontline and relapsed settings. [ABSTRACT FROM AUTHOR]

Published
2024
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98. Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) regimen for chronic lymphocytic leukemia (CLL) with mutated IGHV and without TP53 aberrations

Author

Jain, Nitin, Thompson, Philip, Burger, Jan, Ferrajoli, Alessandra, Takahashi, Koichi, Estrov, Zeev, Borthakur, Gautam, Bose, Prithviraj, Kadia, Tapan, Pemmaraju, Naveen, Sasaki, Koji, Konopleva, Marina, Jabbour, Elias, Garg, Naveen, Wang, Xuemei, Kanagal-Shamanna, Rashmi, Patel, Keyur, Wang, Wei, Jorgensen, Jeffrey, Wang, Sa, Lopez, Wanda, Ayala, Ana, Plunkett, William, Gandhi, Varsha, Kantarjian, Hagop, O’Brien, Susan, Keating, Michael, and Wierda, William G.

Published
2021
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99. Cladribine and low-dose cytarabine alternating with decitabine as front-line therapy for elderly patients with acute myeloid leukaemia: a phase 2 single-arm trial

Author

Kadia, Tapan M, Cortes, Jorge, Ravandi, Farhad, Jabbour, Elias, Konopleva, Marina, Benton, Christopher B, Burger, Jan, Sasaki, Koji, Borthakur, Gautam, DiNardo, Courtney D, Pemmaraju, Naveen, Daver, Naval, Ferrajoli, Alessandra, Wang, Xuemei, Patel, Keyur, Jorgensen, Jeffrey L, Wang, Sa, O'Brien, Susan, Pierce, Sherry, Tuttle, Carla, Estrov, Zeev, Verstovsek, Srdan, Garcia-Manero, Guillermo, and Kantarjian, Hagop

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Oncology and Carcinogenesis, Cancer, Pediatric, Rare Diseases, Hematology, Pediatric Cancer, Patient Safety, Clinical Trials and Supportive Activities, Clinical Research, 6.2 Cellular and gene therapies, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Good Health and Well Being, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Cladribine, Cytarabine, Decitabine, Disease-Free Survival, Dose-Response Relationship, Drug, Female, Humans, Leukemia, Myeloid, Acute, Male, Middle Aged, Survival Analysis, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular medicine and haematology
Abstract

BACKGROUND:Front-line therapy for elderly or unfit patients with acute myeloid leukaemia (AML) remains unsatisfactory with poor outcomes and excessive toxicity. We studied a new low-intensity regimen of cladribine combined with low-dose cytarabine alternating with decitabine, aimed at improving outcomes in this population. Based on our previous experience, we hypothesised that this combination would be safe and more effective than current approaches with hypomethylating agents. METHODS:In this single-arm, open-label, single-centre phase 2 study, we enrolled patients aged 60 years or older with previously untreated AML or high-risk myelodysplastic syndrome who had adequate organ function and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were treated with cladribine plus low-dose cytarabine for two 28-day cycles alternating with decitabine for two 28-day cycles, for up to 18 cycles. Induction therapy (cycle 1) consisted of cladribine 5 mg/m2 intravenously over 1-2 h on days 1-5 and cytarabine 20 mg subcutaneously twice daily on days 1-10. Patients who had remission during this induction regimen moved on to consolidation therapy (cladribine 5 mg/m2 intravenously over 1-2 h on days 1-3 and cytarabine 20 mg twice daily on days 1-10, alternating with decitabine 20 mg/m2 intravenously on days 1-5). The primary outcome measure was disease-free survival. Secondary outcomes were overall survival, proportion of patients achieving complete response, proportion of patients achieving response, toxicity, and induction mortality. All treated patients were included in the analyses. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01515527. FINDINGS:Between Feb 17, 2012, and July 6, 2017, 118 patients were enrolled and treated, among whom 48 (41%) had an adverse karyotype, 20 (17%) had therapy-related AML, 18 (15%) had treated secondary AML, and 20 (17%) had TP53 mutations. Median disease-free survival was 10·8 months (IQR 5·4-25·9). 80 (68%) patients achieved objective response: 69 (58%) achieved a complete response and 11 (9%) patients had complete response with incomplete count recovery. The median overall survival was 13·8 months (6·9-28·6). The regimen was well tolerated, with one (1%) death within the first 4 weeks and eight (7%) deaths within the first 8 weeks. The most common non-haematological adverse events of grade 3 or worse were infection (88 [75%] patients), elevated total bilirubin (26 [22%] patients), rash (13 [11%] patients), and nausea (13 [11%] patients). INTERPRETATION:The combination of cladribine and low-dose cytarabine alternating with decitabine appears to be a safe and highly effective regimen for the treatment of elderly or unfit patients with newly diagnosed AML. Further testing of this regimen is warranted, and could help to provide a new, effective option for reduced-intensity therapy in this population. FUNDING:Part supported by the National Institutes of Health.

Published
2018

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