The ABNL-MARRO 001 study: a phase 1-2 study of randomly allocated active myeloid target compound combinations in MDS/MPN overlap syndromes

Tamara K Moyo, Jason H Mendler, Raphael Itzykson, Ashwin Kishtagari, Eric Solary, Adam C Seegmiller, Aaron T Gerds, Gregory D Ayers, Amy E Dezern, Aziz Nazha, Peter Valent, Arjan A van de Loosdrecht, Francesco Onida, Lisa Pleyer, Blanca Xicoy Cirici, Raoul Tibes, Klaus Geissler, Rami S Komrokji, Jing Zhang, Ulrich Germing, David P Steensma, Daniel H Wiseman, Michael Pfeilstöecker, Chiara Elena, Nicholas C P Cross, Jean-Jacques Kiladjian, Michael Luebbert, Ruben A Mesa, Guillermo Montalban-Bravo, Guillermo F Sanz, Uwe Platzbecker, Mrinal M Patnaik, Eric Padron, Valeria Santini, Pierre Fenaux, Michael R Savona, MDS/MPN International Working Group, Tamara K Moyo, Jason H Mendler, Raphael Itzykson, Ashwin Kishtagari, Eric Solary, Adam C Seegmiller, Aaron T Gerds, Gregory D Ayers, Amy E Dezern, Aziz Nazha, Peter Valent, Arjan A van de Loosdrecht, Francesco Onida, Lisa Pleyer, Blanca Xicoy Cirici, Raoul Tibes, Klaus Geissler, Rami S Komrokji, Jing Zhang, Ulrich Germing, David P Steensma, Daniel H Wiseman, Michael Pfeilstöecker, Chiara Elena, Nicholas C P Cross, Jean-Jacques Kiladjian, Michael Luebbert, Ruben A Mesa, Guillermo Montalban-Bravo, Guillermo F Sanz, Uwe Platzbecker, Mrinal M Patnaik, Eric Padron, Valeria Santini, Pierre Fenaux, Michael R Savona, MDS/MPN International Working Group

Abstract

Background: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response.

Methods: ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability.

Discussion: Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population.

Trial registration: This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421).

Keywords: ABNL MARRO; ASTX727; Itacitinib; MDS/MPN; Phase 1b/2.

Conflict of interest statement

Tamara K. Moyo:

None

Jason Mendler:

None

Raphaël Itzykson:

Research Funding Janssen Novartis, Abbvie

Honoraria: Abbvie, Amgen, Astellas, BMS/Celgene, Daiichi-Sankyo, Jazz, Karyopharm, Servier

Consulting: Abbvie, Amgen, Novartis, Otsuka Pharma, Jazz Pharmaceuticals, Karyopharm, StemLine.

Ashwin Kishtagari:

None

Eric Solary:

Advisor: Stemline therapeutics.

Adam Seegmiller:

None

Aaron T. Gerds:

Consulting/Advisory: Celgene (Bristol-Myers Squibb), Pfizer, Kartos Therapeutics, CTI Biopharma, Promedior.

Research funding: Roche, Celgene (Bristol-Myers Squibb), Incyte, Imago Biosciences.

Gregory D. Ayers:

None

Amy E. DeZern:

Consulting honoraria from Abbie, Taiho, Novartis.

Aziz Nazha:

Amazon (own stocks).

Speaker Bureau: Incyte Corporation, Novartis.

Data monitoring committee: MEI Pharma.

Advisory Board / Consulting (pharmaceutical/biotechnology): Karyopharma, Abbvie, Daiichi Sankyo.

Peter Valent:

COI—study related: no.

COI—unrelated to this study: P.V. received honoraria from Celgene/BMS, Novartis, AOP Orphan Pharmaceuticals, Pfizer, and Incyte.

Arjan A. van de Loosdrecht:

None

Francesco Onida:

None.

Lisa Pleyer:

Honoraria from AbbVie, Agios, Bristol Myers Squibb (BMS), Celgene, Inflection Point Biomedical Advisors, and Novartis.

Blanca Xicoy Cirici:

None

Raoul Tibes:

Employment: AstraZeneca.

Klaus Geissler:

Speaker and Consultancy Honoraria: Abbvie, Celgene, Novartis.

Rami S. Komrokji:

Speaker bureau: JAZZ, BMS.

Honoraria/consulting: Jazz, BMS, Geron, Abbvie, Acceleron, Novartis.

Jing Zhang:

None

Ulrich Germing:

Speakers Honoraria: Celgene, Jazz, Novartis, Janssen.

Institutional Research Support: Celgene, Novartis.

David P. Steensma:

Employment: Novartis.

Daniel H. Wiseman:

Research funding: Astex.

Speaker/consultancy honoraria: Novartis, StemLine, Takeda, Celgene.

Michael Pfeilstoecker:

Speaker and Consultancy Honoraria: Abbvie, Astellas, Takeda, Celgene, and Novartis.

Chiara Elena:

Advisory boards for Novartis, Pfizer, Gilead.

Nicholas C.P. Cross:

Novartis: consultancy and research support; Incyte: consultancy.

Jean-Jacques Kiladjian:

Novartis, Celgene, Abbvie, AOP Orphan: advisory boards.

Michael Lübbert:

Research Support: Janssen, Cheplapharm, TEVA.

Travel Support: Janssen.

Ruben Mesa:

Consultant: Novartis, Sierra Oncology, La Jolla, Samus.

Research Support – Incyte, CTI, Celgene, Abbvie, Imago.

Guillermo Montelban-Bravo:

None

Guillermo F. Sanz:

Honoraria: Celgene.

Consulting or Advisory Role: Roche, Novartis, Takeda, Boehringer Ingelheim, Abbvie, Helsinn Healthcare, Amgen, Celgene, Janssen.

Uwe Platzbecker:

Received honoraria and research funding from Celgene, Janssen, Jazz, Novartis and Amgen.

Mrinal M. Patnaik:

Advisory board for Kura Oncology and Stem Line therapeutics.

Eric Padron:

Research funding: Kura Oncology, Incyte Corporation, and BMS, and serves as a consultant for Taiho Oncology and Blueprint Medicines.

Valeria Santini:

Honoraria: Celgene/Bristol-Myers Squibb, Novartis, Janssen-Cilag.

Consulting or Advisory Role: Celgene/Bristol-Myers Squibb, Novartis, Menarini, Takeda, Pfizer, Geron, Gilead Sciences.

Research Funding: Celgene.

Travel, Accommodations, Expenses: Janssen-Cilag, Celgene.

Pierre Fenaux:

Research support, as GFM chairperson, from AbbVie, Celgene, Janssen, Novartis.

Michael R. Savona:

Research funding from ALX Oncology, Astex, Incyte, Takeda and TG Therapuetics; consults or serves on advisory or DSMB for AbbVie, BMS, Forma, Geron, Karyopharm, Novartis, Ryvu, Sierra Oncology, Taiho, Takeda, TG Therapeutics; and has equity in Karyopharm and Ryvu.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Study Design. Once the RP2D and schedule has been determined for a given treatment in the phase 1b, that treatment arm may enter phase 2, which will follow a Simon Two-Stage design. Stage 1 of the phase 2 will include treatment-naïve MDS/MPN patients only. If sufficient efficacy is demonstrated in treatment-naïve patients to proceed to Stage 2 of the phase 2, then patients who have failed or were intolerant to DNMTi-containing regimens, including treatment on other AM-001 arms or prior to enrolling in the study, will also be included. Eligible patients will be randomly allocated to AM-001 arms that are actively accruing and to which they have not had prior exposure. In Stage 2, patients will be stratified based on treatment status (e.g. treatment-naïve vs relapsed/refractory/intolerant)

References

    1. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–2405. doi: 10.1182/blood-2016-03-643544.
    1. Jaffe ES. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2001.
    1. Neukirchen J, Schoonen WM, Strupp C, Gattermann N, Aul C, Haas R, Germing U. Incidence and prevalence of myelodysplastic syndromes: data from the Dusseldorf MDS-registry. Leuk Res. 2011;35(12):1591–1596. doi: 10.1016/j.leukres.2011.06.001.
    1. Dinmohamed AG, van Norden Y, Visser O, Posthuma EF, Huijgens PC, Sonneveld P, van de Loosdrecht AA, Jongen-Lavrencic M. The use of medical claims to assess incidence, diagnostic procedures and initial treatment of myelodysplastic syndromes and chronic myelomonocytic leukemia in the Netherlands. Leuk Res. 2015;39(2):177–182. doi: 10.1016/j.leukres.2014.11.025.
    1. Ades L, Sekeres MA, Wolfromm A, Teichman ML, Tiu RV, Itzykson R, Maciejewski JP, Dreyfus F, List AF, Fenaux P, et al. Predictive factors of response and survival among chronic myelomonocytic leukemia patients treated with azacitidine. Leuk Res. 2013;37(6):609–613. doi: 10.1016/j.leukres.2013.01.004.
    1. Beran M, Kantarjian H, O'Brien S, Koller C, al-Bitar M, Arbuck S, Pierce S, Moore M, Abbruzzese JL, Andreeff M, et al. Topotecan, a topoisomerase I inhibitor, is active in the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 1996;88(7):2473–2479. doi: 10.1182/blood.V88.7.2473.bloodjournal8872473.
    1. Braun T, Itzykson R, Renneville A, de Renzis B, Dreyfus F, Laribi K, Bouabdallah K, Vey N, Toma A, Recher C, et al. Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial. Blood. 2011;118(14):3824–3831. doi: 10.1182/blood-2011-05-352039.
    1. Wattel E, Guerci A, Hecquet B, Economopoulos T, Copplestone A, Mahe B, Couteaux ME, Resegotti L, Voglova V, Foussard C, A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia et al. Groupe Francais des Myelodysplasies and European CMML Group. Blood. 1996;88(7):2480–2487. doi: 10.1182/blood.V88.7.2480.bloodjournal8872480.
    1. Aul C, Gattermann N, Heyll A, Germing U, Derigs G, Schneider W. Primary myelodysplastic syndromes: analysis of prognostic factors in 235 patients and proposals for an improved scoring system. Leukemia. 1992;6(1):52–59.
    1. Fenaux P, Beuscart R, Lai JL, Jouet JP, Bauters F. Prognostic factors in adult chronic myelomonocytic leukemia: an analysis of 107 cases. J Clin Oncol. 1988;6(9):1417–1424. doi: 10.1200/JCO.1988.6.9.1417.
    1. Germing U, Kundgen A, Gattermann N. Risk assessment in chronic myelomonocytic leukemia (CMML) Leuk Lymphoma. 2004;45(7):1311–1318. doi: 10.1080/1042819042000207271.
    1. Storniolo AM, Moloney WC, Rosenthal DS, Cox C, Bennett JM. Chronic myelomonocytic leukemia. Leukemia. 1990;4(11):766–770.
    1. Breccia M, Biondo F, Latagliata R, Carmosino I, Mandelli F, Alimena G. Identification of risk factors in atypical chronic myeloid leukemia. Haematologica. 2006;91(11):1566–1568.
    1. Hernandez JM, del Canizo MC, Cuneo A, Garcia JL, Gutierrez NC, Gonzalez M, Castoldi G, San Miguel JF. Clinical, hematological and cytogenetic characteristics of atypical chronic myeloid leukemia. Ann Oncol. 2000;11(4):441–444. doi: 10.1023/A:1008393002748.
    1. Kurzrock R, Bueso-Ramos CE, Kantarjian H, Freireich E, Tucker SL, Siciliano M, Pilat S, Talpaz M. BCR rearrangement-negative chronic myelogenous leukemia revisited. J Clin Oncol. 2001;19(11):2915–2926. doi: 10.1200/JCO.2001.19.11.2915.
    1. Wang SA, Hasserjian RP, Fox PS, Rogers HJ, Geyer JT, Chabot-Richards D, Weinzierl E, Hatem J, Jaso J, Kanagal-Shamanna R, et al. Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms. Blood. 2014;123(17):2645–2651. doi: 10.1182/blood-2014-02-553800.
    1. Onida F, Ball G, Kantarjian HM, Smith TL, Glassman A, Albitar M, Scappini B, Rios MB, Keating MJ, Beran M. Characteristics and outcome of patients with Philadelphia chromosome negative, bcr/abl negative chronic myelogenous leukemia. Cancer. 2002;95(8):1673–1684. doi: 10.1002/cncr.10832.
    1. Chaudhury A, Komrokji RS, Al Ali NH, Zhang L, Vafaii P, Lancet JE. Prognosis and outcomes in MDS-MPN unclassifiable: single institution experience of a rare disorder. Blood. 2015;126:1698–1698. doi: 10.1182/blood.V126.23.1698.1698.
    1. Broseus J, Alpermann T, Wulfert M, Florensa Brichs L, Jeromin S, Lippert E, Rozman M, Lifermann F, Grossmann V, Haferlach T, et al. Age, JAK2(V617F) and SF3B1 mutations are the main predicting factors for survival in refractory anaemia with ring sideroblasts and marked thrombocytosis. Leukemia. 2013;27(9):1826–1831. doi: 10.1038/leu.2013.120.
    1. Broseus J, Florensa L, Zipperer E, Schnittger S, Malcovati L, Richebourg S, Lippert E, Cermak J, Evans J, Mounier M, et al. Clinical features and course of refractory anemia with ring sideroblasts associated with marked thrombocytosis. Haematologica. 2012;97(7):1036–1041. doi: 10.3324/haematol.2011.053918.
    1. Wang SA, Hasserjian RP, Loew JM, Sechman EV, Jones D, Hao S, Liu Q, Zhao W, Mehdi M, Galili N, et al. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis harbors JAK2 mutation and shows overlapping myeloproliferative and myelodysplastic features. Leukemia. 2006;20(9):1641–1644. doi: 10.1038/sj.leu.2404316.
    1. Onida F, Kantarjian HM, Smith TL, Ball G, Keating MJ, Estey EH, Glassman AB, Albitar M, Kwari MI, Beran M. Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients. Blood. 2002;99(3):840–849. doi: 10.1182/blood.V99.3.840.
    1. Schuler E, Schroeder M, Neukirchen J, Strupp C, Xicoy B, Kundgen A, Hildebrandt B, Haas R, Gattermann N, Germing U. Refined medullary blast and white blood cell count based classification of chronic myelomonocytic leukemias. Leuk Res. 2014;38(12):1413–1419. doi: 10.1016/j.leukres.2014.09.003.
    1. Tefferi A, Hoagland HC, Therneau TM, Pierre RV. Chronic myelomonocytic leukemia: natural history and prognostic determinants. Mayo Clin Proc. 1989;64(10):1246–1254. doi: 10.1016/S0025-6196(12)61287-7.
    1. Worsley A, Oscier DG, Stevens J, Darlow S, Figes A, Mufti GJ, Hamblin TJ. Prognostic features of chronic myelomonocytic leukaemia: a modified Bournemouth score gives the best prediction of survival. Br J Haematol. 1988;68(1):17–21. doi: 10.1111/j.1365-2141.1988.tb04173.x.
    1. Goasguen JE, Bennett JM, Bain BJ, Vallespi T, Brunning R, Mufti GJ. International Working Group on Morphology of Myelodysplastic S: Morphological evaluation of monocytes and their precursors. Haematologica. 2009;94(7):994–997. doi: 10.3324/haematol.2008.005421.
    1. Loghavi S, Sui D, Wei P, Garcia-Manero G, Pierce S, Routbort MJ, Jabbour EJ, Pemmaraju N, Kanagal-Shamanna R, Gur HD, et al. Validation of the 2017 revision of the WHO chronic myelomonocytic leukemia categories. Blood Adv. 2018;2(15):1807–1816. doi: 10.1182/bloodadvances.2018019224.
    1. Such E, Cervera J, Costa D, Sole F, Vallespi T, Luno E, Collado R, Calasanz MJ, Hernandez-Rivas JM, Cigudosa JC, et al. Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica. 2011;96(3):375–383. doi: 10.3324/haematol.2010.030957.
    1. Such E, Germing U, Malcovati L, Cervera J, Kuendgen A, Della Porta MG, Nomdedeu B, Arenillas L, Luno E, Xicoy B, et al. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood. 2013;121(15):3005–3015. doi: 10.1182/blood-2012-08-452938.
    1. Wassie EA, Itzykson R, Lasho TL, Kosmider O, Finke CM, Hanson CA, Ketterling RP, Solary E, Tefferi A, Patnaik MM. Molecular and prognostic correlates of cytogenetic abnormalities in chronic myelomonocytic leukemia: a Mayo Clinic-French Consortium Study. Am J Hematol. 2014;89(12):1111–1115. doi: 10.1002/ajh.23846.
    1. Elena C, Galli A, Such E, Meggendorfer M, Germing U, Rizzo E, Cervera J, Molteni E, Fasan A, Schuler E, et al. Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. Blood. 2016;128(10):1408–1417. doi: 10.1182/blood-2016-05-714030.
    1. Itzykson R, Kosmider O, Renneville A, Gelsi-Boyer V, Meggendorfer M, Morabito M, Berthon C, Ades L, Fenaux P, Beyne-Rauzy O, et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol. 2013;31(19):2428–2436. doi: 10.1200/JCO.2012.47.3314.
    1. Patnaik MM, Itzykson R, Lasho TL, Kosmider O, Finke CM, Hanson CA, Knudson RA, Ketterling RP, Tefferi A, Solary E. ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia. 2014;28(11):2206–2212. doi: 10.1038/leu.2014.125.
    1. Padron E, Garcia-Manero G, Patnaik MM, Itzykson R, Lasho T, Nazha A, Rampal RK, Sanchez ME, Jabbour E, Al Ali NH, et al. An international data set for CMML validates prognostic scoring systems and demonstrates a need for novel prognostication strategies. Blood Cancer J. 2015;5:e333. doi: 10.1038/bcj.2015.53.
    1. Nazha A, Hu ZH, Wang T, Lindsley RC, Abdel-Azim H, Aljurf M, Bacher U, Bashey A, Cahn JY, Cerny J, et al. A Personalized Prediction Model for Outcomes after Allogeneic Hematopoietic Cell Transplant in Patients with Myelodysplastic Syndromes. Biol Blood Marrow Transplant. 2020;26(11):2139–2146. doi: 10.1016/j.bbmt.2020.08.003.
    1. Patnaik MM, Lasho TL, Finke CM, Hanson CA, King RL, Ketterling RP, Gangat N, Tefferi A. Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) and the role of next-generation sequencing. Am J Hematol. 2016;91(5):492–498. doi: 10.1002/ajh.24332.
    1. Meggendorfer M, Haferlach T, Alpermann T, Jeromin S, Haferlach C, Kern W, Schnittger S. Specific molecular mutation patterns delineate chronic neutrophilic leukemia, atypical chronic myeloid leukemia, and chronic myelomonocytic leukemia. Haematologica. 2014;99(12):e244–246. doi: 10.3324/haematol.2014.113159.
    1. Meggendorfer M, Jeromin S, Haferlach C, Kern W, Haferlach T. The mutational landscape of 18 investigated genes clearly separates four subtypes of myelodysplastic/myeloproliferative neoplasms. Haematologica. 2018;103(5):e192–e195. doi: 10.3324/haematol.2017.183160.
    1. Piazza R, Valletta S, Winkelmann N, Redaelli S, Spinelli R, Pirola A, Antolini L, Mologni L, Donadoni C, Papaemmanuil E, et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet. 2013;45(1):18–24. doi: 10.1038/ng.2495.
    1. Bose P, Nazha A, Komrokji RS, Patel KP, Pierce SA, Al-Ali N, Sochacki A, Shaver A, Ma W, Su X, et al. Mutational landscape of myelodysplastic/myeloproliferative neoplasm-unclassifiable. Blood. 2018;132(19):2100–2103. doi: 10.1182/blood-2018-05-848473.
    1. Patnaik MM, Barraco D, Lasho TL, Finke CM, Reichard K, Hoversten KP, Ketterling RP, Gangat N, Tefferi A. Targeted next generation sequencing and identification of risk factors in World Health Organization defined atypical chronic myeloid leukemia. Am J Hematol. 2017;92(6):542–548. doi: 10.1002/ajh.24722.
    1. Duchmann M, Yalniz FF, Sanna A, Sallman D, Coombs CC, Renneville A, Kosmider O, Braun T, Platzbecker U, Willems L, et al. Prognostic role of gene mutations in chronic myelomonocytic leukemia patients treated with hypomethylating agents. EBioMedicine. 2018;31:174–181. doi: 10.1016/j.ebiom.2018.04.018.
    1. Koreth J, Pidala J, Perez WS, Deeg HJ, Garcia-Manero G, Malcovati L, Cazzola M, Park S, Itzykson R, Ades L, et al. A Decision Analysis of Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Older Patients with De-Novo Myelodysplastic Syndrome (MDS): Early Transplantation Offers Survival Benefit in Higher-Risk MDS. Blood. 2011;118:115–115. doi: 10.1182/blood.V118.21.115.115.
    1. de Witte T, Bowen D, Robin M, Malcovati L, Niederwieser D, Yakoub-Agha I, Mufti GJ, Fenaux P, Sanz G, Martino R, et al. Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel. Blood. 2017;129(13):1753–1762. doi: 10.1182/blood-2016-06-724500.
    1. Itzykson R, Fenaux P, Bowen D, Cross NCP, Cortes J, De Witte T, Germing U, Onida F, Padron E, Platzbecker U, et al. Diagnosis and Treatment of Chronic Myelomonocytic Leukemias in Adults: Recommendations From the European Hematology Association and the European LeukemiaNet. HemaSphere. 2018;2(6):e150. doi: 10.1097/HS9.0000000000000150.
    1. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223–232. doi: 10.1016/S1470-2045(09)70003-8.
    1. Drummond MW, Pocock C, Boissinot M, Mills J, Brown J, Cauchy P, Cross NC, Hartley S, Kell J, Szubert A, et al. A multi-centre phase 2 study of azacitidine in chronic myelomonocytic leukaemia. Leukemia. 2014;28(7):1570–1572. doi: 10.1038/leu.2014.85.
    1. Tantravahi SK, Szankasi P, Khorashad JS, Dao KH, Kovacsovics T, Kelley TW, Deininger MW. A phase II study of the efficacy, safety, and determinants of response to 5-azacitidine (Vidaza(R)) in patients with chronic myelomonocytic leukemia. Leuk Lymphoma. 2016;57(10):2441–2444. doi: 10.3109/10428194.2016.1138295.
    1. Santini V, Allione B, Zini G, Gioia D, Lunghi M, Poloni A, Cilloni D, Sanna A, Masiera E, Ceccarelli M, et al. A phase II, multicentre trial of decitabine in higher-risk chronic myelomonocytic leukemia. Leukemia. 2018;32(2):413–418. doi: 10.1038/leu.2017.186.
    1. Merlevede J, Droin N, Qin T, Meldi K, Yoshida K, Morabito M, Chautard E, Auboeuf D, Fenaux P, Braun T, et al. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents. Nat Commun. 2016;7:10767. doi: 10.1038/ncomms10767.
    1. Pleyer L, Leisch M, Kourakli A, Padron E, Maciejewski JP, Xicoy Cirici B, Kaivers J, Ungerstedt J, Heibl S, Patiou P, et al. Outcomes of patients with chronic myelomonocytic leukaemia treated with non-curative therapies: a retrospective cohort study. Lancet Haematol. 2021;8(2):e135–e148. doi: 10.1016/S2352-3026(20)30374-4.
    1. Itzykson R, Santini V, Chaffaut C, Lionel A, Thepot S, Giagounidis A, Morabito M, Droin N, Luebbert M, Sapena R, et al. Decitabine Versus Hydroxyurea for Advanced Proliferative CMML: Results of the Emsco Randomized Phase 3 Dacota Trial. Blood. 2020;136(Supplement 1):53–54. doi: 10.1182/blood-2020-138680.
    1. Padron E, Dezern A, Andrade-Campos M, Vaddi K, Scherle P, Zhang Q, Ma Y, Balasis ME, Tinsley S, Ramadan H, et al. A Multi-Institution Phase I Trial of Ruxolitinib in Patients with Chronic Myelomonocytic Leukemia (CMML) Clin Cancer Res. 2016;22(15):3746–3754. doi: 10.1158/1078-0432.CCR-15-2781.
    1. Francke S, Mies A, Meggendorfer M, Oelschlaegel U, Balaian E, Gloaguen S, Haferlach T, Ehninger G, Bornhauser M, Platzbecker U. Disease-modifying activity of ruxolitinib in a patient with JAK2-negative CMML-2. Leuk Lymphoma. 2017;58(5):1271–1272. doi: 10.1080/10428194.2016.1225209.
    1. Assi R, Kantarjian HM, Garcia-Manero G, Cortes JE, Pemmaraju N, Wang X, Nogueras-Gonzalez G, Jabbour E, Bose P, Kadia T, et al. A phase II trial of ruxolitinib in combination with azacytidine in myelodysplastic syndrome/myeloproliferative neoplasms. Am J Hematol. 2018;93(2):277–285. doi: 10.1002/ajh.24972.
    1. Masarova L, Verstovsek S, Hidalgo-Lopez JE, Pemmaraju N, Bose P, Estrov Z, Jabbour EJ, Ravandi-Kashani F, Takahashi K, Cortes JE, et al. A phase 2 study of ruxolitinib in combination with azacitidine in patients with myelofibrosis. Blood. 2018;132(16):1664–1674. doi: 10.1182/blood-2018-04-846626.
    1. Patnaik MM, Sallman DA, Sekeres MA, Luger S, Bejar R, Hobbs GS, DeZern AE, Bolognese J, Traynor M, Mishra V, et al. Preliminary results from an open-label, phase 2 study of tipifarnib in Chronic Myelomonocytic Leukemia (CMML) Blood. 2017;130:2963–2963.
    1. Patnaik MM, Haris A, Gupta V, Yacoub A, Gary S, Lee S, et al. Results from Ongoing Phase 1/2 Clinical Trial of Tagraxofusp (SL-401) in Patients with Relapsed/Refractory Chronic Myelomonocytic Leukemia (CMML). In: 24th Annual Congress of the European Hematology Association. Amsterdam: HemaSphere; 2019. p. PF672.
    1. Padron E, Painter JS, Kunigal S, Mailloux AW, McGraw K, McDaniel JM, Kim E, Bebbington C, Baer M, Yarranton G, et al. GM-CSF–dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia. Blood. 2013;121:5068–5077. doi: 10.1182/blood-2012-10-460170.
    1. Giagounidis A, Mufti GJ, Fenaux P, Sekeres MA, Szer J, Platzbecker U, Kuendgen A, Gaidano G, Wiktor-Jedrzejczak W, Hu K, et al. Results of a randomized, double-blind study of romiplostim versus placebo in patients with low/intermediate-1-risk myelodysplastic syndrome and thrombocytopenia. Cancer. 2014;120(12):1838–1846. doi: 10.1002/cncr.28663.
    1. Oliva EN, Alati C, Santini V, Poloni A, Molteni A, Niscola P, Salvi F, Sanpaolo G, Balleari E, Germing U, et al. Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single-blind, randomised, controlled, phase 2 superiority trial. Lancet Haematol. 2017;4(3):e127–e136. doi: 10.1016/S2352-3026(17)30012-1.
    1. Ramadan H, Duong VH, Al Ali N, Padron E, Zhang L, Lancet JE, List AF, Komrokji RS. Eltrombopag use in patients with Chronic Myelomonocytic Leukemia (CMML): a cautionary tale. Clin Lymphoma Myeloma Leuk. 2016;16(Suppl):S64–66. doi: 10.1016/j.clml.2016.02.009.
    1. Dao K-H, Collins RH, Cortes JE, Deininger MW, Druker BJ, Gotlib JR, Macey TA, Oh ST, Tyner JW, Winton EF. Phase 2 study of ruxolitinib in patients with chronic neutrophilic leukemia or atypical chronic myeloid leukemia. Blood. 2018;132:350–350. doi: 10.1182/blood-2018-99-119476.
    1. Gotlib J, Maxson JE, George TI, Tyner JW. The new genetics of chronic neutrophilic leukemia and atypical CML: implications for diagnosis and treatment. Blood. 2013;122(10):1707–1711. doi: 10.1182/blood-2013-05-500959.
    1. Maxson JE, Gotlib J, Pollyea DA, Fleischman AG, Agarwal A, Eide CA, Bottomly D, Wilmot B, McWeeney SK, Tognon CE, et al. Oncogenic CSF3R Mutations in Chronic Neutrophilic Leukemia and Atypical CML. N Engl J Med. 2013;368(19):1781–1790. doi: 10.1056/NEJMoa1214514.
    1. Patnaik MM, Lasho TL, Finke CM, Hanson CA, King RL, Ketterling RP, Gangat N, Tefferi A. Vascular events and risk factors for thrombosis in refractory anemia with ring sideroblasts and thrombocytosis. Leukemia. 2016;30(11):2273–2275. doi: 10.1038/leu.2016.216.
    1. Huls G, Mulder AB, Rosati S, van de Loosdrecht AA, Vellenga E, de Wolf JT. Efficacy of single-agent lenalidomide in patients with JAK2 (V617F) mutated refractory anemia with ring sideroblasts and thrombocytosis. Blood. 2010;116(2):180–182. doi: 10.1182/blood-2010-01-263087.
    1. Girodon F, Plocque A, Voillat L, Broséus J, Guerci A. Efficacy of Lenalidomide in Myelodysplastic/Myeloproliferative Neoplasms with Ring Sideroblasts. Blood. 2017;130:5317–5317.
    1. Melody M, Al Ali N, Sallman DA, Padron E, List AF, Lancet JE, Komrokji RS. Lenalidomide Is Effective Treatment Option for Patients with Refractory Anemia with Ring Sideroblasts and Thrombocytosis. Blood. 2018;132:4383–4383. doi: 10.1182/blood-2018-99-110237.
    1. Naqvi K, Sasaki K, Montalban-Bravo G, Teach MS, Pierce SA, Kantarjian HM, Garcia-Manero G. Characteristics and role of lenalidomide therapy in patients with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis. Blood. 2018;132:5513–5513. doi: 10.1182/blood-2018-99-117266.
    1. Nicolosi M, Mudireddy M, Vallapureddy R, Gangat N, Tefferi A, Patnaik MM. Lenalidomide therapy in patients with myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) Am J Hematol. 2018;93(1):E27–E30. doi: 10.1002/ajh.24952.
    1. Komrokji R, Garcia-Manero G, Ades L, Prebet T, Steensma DP, Jurcic JG, Sekeres MA, Berdeja J, Savona MR, Beyne-Rauzy O, et al. Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial. Lancet Haematol. 2018;5(2):e63–e72. doi: 10.1016/S2352-3026(18)30002-4.
    1. Platzbecker U, Germing U, Gotze KS, Kiewe P, Mayer K, Chromik J, Radsak M, Wolff T, Zhang X, Laadem A, et al. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol. 2017;18(10):1338–1347. doi: 10.1016/S1470-2045(17)30615-0.
    1. Savona MR, Malcovati L, Komrokji R, Tiu RV, Mughal TI, Orazi A, Kiladjian JJ, Padron E, Solary E, Tibes R, et al. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. 2015;125(12):1857–1865. doi: 10.1182/blood-2014-10-607341.
    1. Mason CC, Khorashad JS, Tantravahi SK, Kelley TW, Zabriskie MS, Yan D, Pomicter AD, Reynolds KR, Eiring AM, Kronenberg Z, et al. Age-related mutations and chronic myelomonocytic leukemia. Leukemia. 2016;30(4):906–913. doi: 10.1038/leu.2015.337.
    1. Deininger MWN, Tyner JW, Solary E. Turning the tide in myelodysplastic/myeloproliferative neoplasms. Nat Rev Cancer. 2017;17(7):425–440. doi: 10.1038/nrc.2017.40.
    1. Makishima H, Yoshida K, Nguyen N, Przychodzen B, Sanada M, Okuno Y, Ng KP, Gudmundsson KO, Vishwakarma BA, Jerez A, et al. Somatic SETBP1 mutations in myeloid malignancies. Nat Genet. 2013;45(8):942–946. doi: 10.1038/ng.2696.
    1. Itzykson R, Kosmider O, Renneville A, Morabito M, Preudhomme C, Berthon C, Ades L, Fenaux P, Platzbecker U, Gagey O, et al. Clonal architecture of chronic myelomonocytic leukemias. Blood. 2013;121(12):2186–2198. doi: 10.1182/blood-2012-06-440347.
    1. Meldi K, Qin T, Buchi F, Droin N, Sotzen J, Micol JB, Selimoglu-Buet D, Masala E, Allione B, Gioia D, et al. Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia. J Clin Invest. 2015;125(5):1857–1872. doi: 10.1172/JCI78752.
    1. Reynaud D, Pietras E, Barry-Holson K, Mir A, Binnewies M, Jeanne M, Sala-Torra O, Radich JP, Passegue E. IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development. Cancer Cell. 2011;20(5):661–673. doi: 10.1016/j.ccr.2011.10.012.
    1. Welner RS, Amabile G, Bararia D, Czibere A, Yang H, Zhang H, Pontes LL, Ye M, Levantini E, Di Ruscio A, et al. Treatment of chronic myelogenous leukemia by blocking cytokine alterations found in normal stem and progenitor cells. Cancer Cell. 2015;27(5):671–681. doi: 10.1016/j.ccell.2015.04.004.
    1. Lucas N, Duchmann M, Rameau P, Noel F, Michea P, Saada V, Kosmider O, Pierron G, Fernandez-Zapico ME, Howard MT, et al. Biology and prognostic impact of clonal plasmacytoid dendritic cells in chronic myelomonocytic leukemia. Leukemia. 2019;33(10):2466–2480. doi: 10.1038/s41375-019-0447-3.
    1. Selimoglu-Buet D, Riviere J, Ghamlouch H, Bencheikh L, Lacout C, Morabito M, Diop M, Meurice G, Breckler M, Chauveau A, et al. A miR-150/TET3 pathway regulates the generation of mouse and human non-classical monocyte subset. Nat Commun. 2018;9(1):5455. doi: 10.1038/s41467-018-07801-x.
    1. Selimoglu-Buet D, Wagner-Ballon O, Saada V, Bardet V, Itzykson R, Bencheikh L, Morabito M, Met E, Debord C, Benayoun E, et al. Characteristic repartition of monocyte subsets as a diagnostic signature of chronic myelomonocytic leukemia. Blood. 2015;125(23):3618–3626. doi: 10.1182/blood-2015-01-620781.
    1. Niyongere S, Lucas N, Zhou JM, Sansil S, Pomicter AD, Balasis ME, Robinson J, Kroeger J, Zhang Q, Zhao YL, et al. Heterogeneous expression of cytokines accounts for clinical diversity and refines prognostication in CMML. Leukemia. 2019;33(1):205–216. doi: 10.1038/s41375-018-0203-0.
    1. Geissler K, Ohler L, Fodinger M, Virgolini I, Leimer M, Kabrna E, Kollars M, Skoupy S, Bohle B, Rogy M, et al. Interleukin 10 inhibits growth and granulocyte/macrophage colony-stimulating factor production in chronic myelomonocytic leukemia cells. J Exp Med. 1996;184(4):1377–1384. doi: 10.1084/jem.184.4.1377.
    1. Pochlauer S, Jager E, Jager U, Geissler K. Recombinant human interleukin-10 in patients with chronic myelomonocytic leukemia. Ann Hematol. 2014;93(10):1775–1776. doi: 10.1007/s00277-014-2012-5.
    1. Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126(3):291–299. doi: 10.1182/blood-2015-01-621664.
    1. Kantarjian HM, O'Brien S, Huang X, Garcia-Manero G, Ravandi F, Cortes J, Shan J, Davisson J, Bueso-Ramos CE, Issa JP. Survival advantage with decitabine versus intensive chemotherapy in patients with higher risk myelodysplastic syndrome: comparison with historical experience. Cancer. 2007;109(6):1133–1137. doi: 10.1002/cncr.22508.
    1. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20(10):2429–2440. doi: 10.1200/JCO.2002.04.117.
    1. Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC, Faderl S, Harb W, Kantarjian H, Lowder J, et al. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol. 2019;6(4):e194–e203. doi: 10.1016/S2352-3026(19)30030-4.
    1. Savona MR, McCloskey JK, Griffiths EA, Yee KWL, Al-Kali A, Zeidan AM, Deeg HJ, Patel PA, Sabloff M, Keating M-M, et al. Clinical Efficacy and Safety of Oral Decitabine/Cedazuridine in 133 Patients with Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) Blood. 2020;136(Supplement 1):37–38. doi: 10.1182/blood-2020-133855.
    1. Mascarenhas JO, Talpaz M, Gupta V, Foltz LM, Savona MR, Paquette R, Turner AR, Coughlin P, Winton E, Burn TC, et al. Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis. Haematologica. 2017;102(2):327–335. doi: 10.3324/haematol.2016.151126.
    1. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10(1):1–10. doi: 10.1016/0197-2456(89)90015-9.
    1. Valent P, Horny HP, Bennett JM, Fonatsch C, Germing U, Greenberg P, Haferlach T, Haase D, Kolb HJ, Krieger O, et al. Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: Consensus statements and report from a working conference. Leuk Res. 2007;31(6):727–736. doi: 10.1016/j.leukres.2006.11.009.
    1. Valent P, Orazi A, Savona MR, Patnaik MM, Onida F, van de Loosdrecht AA, Haase D, Haferlach T, Elena C, Pleyer L, et al. Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions. Haematologica. 2019;104(10):1935–1949. doi: 10.3324/haematol.2019.222059.
    1. Boiocchi L, Espinal-Witter R, Geyer JT, Steinhilber J, Bonzheim I, Knowles DM, Fend F, Orazi A. Development of monocytosis in patients with primary myelofibrosis indicates an accelerated phase of the disease. Mod Pathol. 2013;26(2):204–212. doi: 10.1038/modpathol.2012.165.
    1. Boiocchi L, Gianelli U, Iurlo A, Fend F, Bonzheim I, Cattaneo D, Knowles DM, Orazi A. Neutrophilic leukocytosis in advanced stage polycythemia vera: hematopathologic features and prognostic implications. Mod Pathol. 2015;28(11):1448–1457. doi: 10.1038/modpathol.2015.100.
    1. Barraco D, Cerquozzi S, Gangat N, Patnaik MM, Lasho T, Finke C, Hanson CA, Ketterling RP, Pardanani A, Tefferi A. Monocytosis in polycythemia vera: clinical and molecular correlates. Am J Hematol. 2017;92(7):640–645. doi: 10.1002/ajh.24740.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅