Juvenile myelomonocytic leukemia is a rare myeloproliferative disease in young children. While hematopoietic stem cell transplantation remains the only curative therapeutic option for most patients, children with juvenile myelomonocytic leukemia increasingly receive novel agents in phase I-II clinical trials as pre-transplant therapy or therapy for relapse after transplantation. However, response criteria or definitions of outcome for standardized evaluation of treatment effect in patients with juvenile myelomonocytic leukemia are currently lacking. Here we propose criteria to evaluate the response to the non-transplant therapy and definitions of remission status after hematopoietic stem cell transplantation. For the evaluation of non-transplant therapy, we defined 6 clinical variables (white blood cell count, platelet count, hematopoietic precursors and blasts in peripheral blood, bone marrow blast percentage, spleen size and extramedullary disease) and 3 genetic variables (cytogenetic, molecular and chimerism response) which serve to describe the heterogeneous picture of response to therapy in each individual case. It is hoped that these criteria will facilitate the comparison of results between clinical trials in juvenile myelomonocytic leukemia.

Aflac Cancer and Blood Disorders Center Children's Healthcare of Atlanta Emory University Atlanta GA USA

Department of Genetics Hôpital Robert Debré and Paris Diderot University Paris France

Department of Hematology and Oncology University Children's Hospital Zurich Switzerland

Department of Hematology and Transfusiology Comenius University Bratislava Slovakia

Department of Hematology Hospital Germans Trias i Pujol and Institut Català d'Oncologia José Carreras Leukemia Research Institute Badalona Spain

Department of Hematology Hospital Sant Joan de Déu Barcelona Spain

Department of Hematology Oncology and Clinical Immunology Heinrich Heine University Düsseldorf Germany

Department of Pediatric Hemato Oncology Ghent University Hospital Belgium

Department of Pediatric Hematology and Oncology Bambino Gesù Children's Hospital Rome University of Pavia Italy

Department of Pediatric Hematology and Oncology Charles University and University Hospital Motol Czech Pediatric Hematology Working Group Prague Czech Republic

Department of Pediatric Hematology of Robert Debré Hospital and Paris Diderot University Paris France

Department of Pediatric Oncology and Hematology University of Bologna Italy

Department of Pediatric Oncology Hematology and BMT Wroclaw Medical University Poland

Department of Pediatrics Aarhus University Hospital Skejby Aarhus Denmark

Department of Pediatrics and Adolescent Medicine Division of Pediatric Hematology and Oncology University of Freiburg Germany

Department of Pediatrics and the Helen Diller Comprehensive Cancer Center University of California San Francisco CA USA

Department of Pediatrics Nagoya University Graduate School of Medicine Japan

Department of Pediatrics St Luke's International Hospital Tokyo Japan

Department of Pediatrics The Herman B Wells Center for Pediatric Research Indiana University School of Medicine Indianapolis IN USA

Division of Pediatric Allergy Immunology and Bone Marrow Transplant Benioff Children's Hospital University of California San Francisco CA USA

ErasmusMC Sophia Children's Hospital Erasmus Medical Center Rotterdam and Dutch Childhood Oncology Group The Hague The Netherlands

ErasmusMC Sophia Children's Hospital Erasmus Medical Center Rotterdam and the Netherlands and ITCC

Pediatric Oncology and Hematology Our Lady's Children's Hospital Crumlin Dublin Ireland

St Anna Children's Hospital and Children's Cancer Research Institute Department of Pediatrics Medical University of Vienna Austria

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Niemeyer CM, Kratz CP. Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia: molecular classification and treatment options. Br J Haematol. 2008;140(6):610–24. PubMed

Loh ML. Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J Haematol. 2011; 152(6):677–87. PubMed

Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick H, et al. The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposals by the French-American- British Cooperative Leukaemia Group. Br J Haematol. 1994; 87(4):746–54. PubMed

Niemeyer CM, Arico M, Basso G, Biondi A, Cantu RA, Creutzig U, et al. Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Blood. 1997;89(10):3534–43. PubMed

Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, et al. Somatic PTPN11 mutations in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003; 34(2):148–50. PubMed

Kratz CP, Niemeyer CM, Castleberry RP, Cetin M, Bergsträsser E, Emanuel PD, et al. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood. 2005;106(6):2183–5. PubMed PMC

Miyauchi J, Asada M, Sasaki M, Tsunematsu Y, Kojima S, Mizutani S. Mutations of the N-ras gene in juvenile chronic myelogenous leukemia. Blood. 1994;83(8):2248–54. PubMed

Side LE, Emanuel PD, Taylor B, Franklin J, Thompson P, Castleberry RP, et al. Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1. Blood. 1998;92(1):267–72. PubMed

Flotho C, Valcamonica S, Mach-Pascual S, Schmahl G, Corral L, Ritterbach J, et al. Ras mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML). Leukemia. 1999;13(1):32–7. PubMed

Loh ML, Sakai DS, Flotho C, Kang M, Fliegauf M, Archambeault S, et al. Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood. 2009; 114(9):1859–63. PubMed PMC

Niemeyer CM, Kang MW, Shin DH, Furlan I, Erlacher M, Bunin NJ, et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet. 2010;42(9):794–800. PubMed PMC

de Vries AC, Zwaan CM, van den Heuvel-Eibrink MM. Molecular basis of juvenile myelomonocytic leukemia. Haematologica. 2010; 95(2):179–82. PubMed PMC

Locatelli F, Nöllke P, Zecca M, Korthof E, Lanino E, Peters C, et al. Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood. 2005;105(1):410–9. PubMed

Yabe M, Sako M, Yabe H, Osugi Y, Kurosawa H, Nara T, et al. A conditioning regimen of busulfan, fludarabine, and melphalan for allogeneic stem cell transplantation in children with juvenile myelomonocytic leukemia. Pediatr Transplant. 2008; 12(8):862–7. PubMed

Locatelli F, Crotta A, Ruggeri A, Eapen M, Wagner JE, Macmillan ML, et al. Analysis of risk factors influencing outcomes after cord blood transplantation in children with juvenile myelomonocytic leukemia: a EURO-CORD, EBMT, EWOG-MDS, CIBMTR study. Blood. 2013;122(12):2135–41. PubMed PMC

Castleberry RP, Emanuel PD, Zuckerman KS, Cohn S, Strauss L, Byrd RL, et al. A pilot study of isotretinoin in the treatment of juvenile chronic myelogenous leukemia. N Engl J Med. 1994;331(25):1680–4. PubMed

Castleberry RP, Loh ML, Jayaprakash N, Peterson A, Casey V, Chang M, et al. Phase II window study of the farnesyltransferase inhibitor R115777 (Zarnestra®) in untreated juvenile myelomonocytic leukemia (JMML): A Children’s Oncology Group study [abstract]. Blood. 2005; 106:727a.

Shimada H, Shima H, Shimasaki N, Yoshihara H, Mori T, Takahashi T. Little response to zoledronic acid in a child of juvenile myelomonocytic leukemia (JMML) harboring the PTPN11 mutation. Ann Oncol. 2005;16(8):1400. PubMed

Furlan I, Batz C, Flotho C, Mohr B, Lübbert M, Suttorp M, et al. Intriguing response to azacitidine in a patient with juvenile myelomonocytic leukemia and monosomy 7. Blood. 2009;113(12):2867–8. PubMed

Cseh A, Niemeyer CM, Catalá A, Dworzak M, Hasle H, van den Heuvel-Eibrink MM, et al. Therapy with azacitidine in pediatric MDS and JMML A retrospective survey of the EWOG-MDS study. Haematologica. 2012;97:S3.

Lyubynska N, Gorman MF, Lauchle JO, Hong WX, Akutagawa JK, Shannon K, et al. A MEK inhibitor abrogates myeloproliferative disease in Kras mutant mice. Sci Transl Med. 2011;3:76ra27. PubMed PMC

Chang T, Krisman K, Theobald EH, Xu J, Akutagawa J, Lauchle JO, et al. Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J Clin Invest. 2013;123(1):335–9. PubMed PMC

Goodwin CB, Li XJ, Mali RS, Chan G, Kang M, Liu Z, et al. PI3K p110delta uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML. Blood. 2014;23(18):2838–42. PubMed PMC

Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000;96(12):3671–4. PubMed

Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108(2):419–25. PubMed

Bergstraesser E, Hasle H, Rogge T, Fischer A, Zimmermann M, Noellke P, et al. Non-hematopoietic stem cell transplantation treatment of juvenile myelomonocytic leukemia: a retrospective analysis and definition of response criteria. Pediatr Blood Cancer. 2007;49(5):629–33. PubMed

Chan RJ, Cooper T, Kratz CP, Weiss B, Loh ML. Juvenile myelomonocytic leukemia: a report from the 2nd International JMML Symposium. Leuk Res. 2009;33(3):355–62. PubMed PMC

Ades L, Sekeres MA, Wolfromm A, Teichman ML, Tiu RV, Itzykson R, et al. Predictive factors of response and survival among chronic myelomonocytic leukemia patients treated with azacitidine. Leuk Res. 2013;37(6):609–13. PubMed

Aribi A, Borthakur G, Ravandi F, Shan J, Davisson J, Cortes J, et al. Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia. Cancer. 2007;109(4):713–7. PubMed

Wattel E, Guerci A, Hecquet B, Economopoulos T, Copplestone A, Mahé B, et al. A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Francais des Myelodysplasies and European CMML Group. Blood. 1996;88(7):2480–7. PubMed

Lamb PM, Lund A, Kanagasabay RR, Martin A, Webb JA, Reznek RH, et al. Spleen size: how well do linear ultrasound measurements correlate with three-dimensional CT volume assessments? Br J Radiol. 2002; 75(895):573–7. PubMed

Sakaguchi H, Okuno Y, Muramatsu, Yoshida K, Shiraishi Y, Takahashi M, et al. Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet. 2013;45(8):937–41. PubMed

Yoshimi A, Niemeyer CM, Bohmer V, Duffner U, Strahm B, Kreyenberg H, et al. Chimaerism analyses and subsequent immunological intervention after stem cell transplantation in patients with juvenile myelomonocytic leukaemia. Br J Haematol. 2005;129(4):542–9. PubMed

Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial