Juvenile Myelomonocytic Leukemia
Juvenile myelomonocytic leukemia (JMML), formerly termed juvenile chronic myeloid leukemia, is a rare hematopoietic malignancy of childhood accounting for less than 1% of all childhood leukemias. A number of clinical and laboratory features distinguish JMML from adult chronic myelomonocytic leukemia. The diagnostic criteria that need to be met for JMML are included in Table 6.[2,3]
|Category 1 (all of the following)a||Category 2 (at least one of the following)b,c||Category 3 (two of the following if no category 2 criteria are met)a,d|
|GM-CSF = granulocyte-macrophage colony-stimulating factor; NF1 = neurofibromatosis type 1.|
|aCurrent World Health Organization (WHO) criteria.|
|bProposed additions to the WHO criteria that were discussed by participants attending the JMML Symposium in Atlanta, Georgia in 2008. CBL mutations were discovered subsequent to the symposium and should be screened for in the workup of a patient with suspected JMML.|
|cPatients who are found to have a category 2 lesion need to meet the criteria in category 1 but do not need to meet the category 3 criteria.|
|dPatients who are not found to have a category 2 lesion must meet the category 1 and 3 criteria.|
|eNote that only 7% of patients with JMML will NOT present with splenomegaly, but virtually all patients develop splenomegaly within several weeks to months of initial presentation.|
|Absence of the BCR-ABL1 fusion gene||Somatic mutation in RAS or PTPN11||White blood cell count >10 × 109/L|
|>1 × 109/L circulating monocytes||Clinical diagnosis of NF1 or NF1 gene mutation||Circulating myeloid precursors|
|<20% blasts in the bone marrow||Monosomy 7||Increased hemoglobin F for age|
|Splenomegalyb,e||Clonal cytogenetic abnormality excluding monosomy 7b|
The pathogenesis of JMML has been closely linked to activation of the RAS oncogene pathway, along with related syndromes (see Figure 1).[2,3] In addition, distinctive RNA expression and DNA methylation patterns have been reported; they are correlated with clinical factors such as age and appear to be associated with prognosis.[4,5]
Children with neurofibromatosis type 1 (NF1) and Noonan syndrome are at increased risk for developing JMML,[6,7] and up to 14% of cases of JMML occur in children with NF1. Noonan syndrome, which is usually inherited as an autosomal dominant condition, but can also arise spontaneously, is characterized by facial dysmorphism, short stature, webbed neck, neurocognitive abnormalities, and cardiac abnormalities. Importantly, some children with Noonan syndrome have a hematologic picture indistinguishable from JMML that self-resolves during infancy, similar to what happens in children with Down syndrome and transient myeloproliferative disorder.
There are only a small number of mutations in the leukemia cells of patients with JMML, with exome sequencing identifying approximately one nonsilent mutation per case. Approximately 75% of JMML cases harbor one of three mutually exclusive mutations leading to activated RAS signaling, including direct oncogenic RAS mutations (approximately 20%–30%),[9-11] NF1 inactivating mutations (approximately 10%–25%),[9,12] or protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) (SHP-2) mutations (approximately 35%–40%).[9,13,14]
Mutations in the Casitas B-lineage Lymphoma (CBL) gene, a E3 ubiquitin-protein ligase that is involved in targeting proteins, particularly tyrosine kinases, for proteasomal degradation occur in 10% to 15% of JMML cases,[15,16] with many of these cases occurring in children with germline CBL mutations.[17,18] CBL germline mutations result in an autosomal dominant developmental disorder that is characterized by impaired growth, developmental delay, cryptorchidism, and a predisposition to JMML. Some individuals with CBL germline mutations experience spontaneous regression of their JMML but develop vasculitis later in life. CBL mutations are nearly always mutually exclusive of RAS and PTPN11 mutations.
Recurrent mutations in SETBP1 or JAK3 have been identified in addition to RAS pathway mutations in a proportion of JMML cases (16%). These mutations were generally subclonal and are thus thought to be secondary mutations. There was a suggestion that these mutations worsened overall survival for cases with these mutations.
Historically, more than 90% of patients with JMML died despite the use of chemotherapy, but with the application of hematopoietic stem cell transplant (HSCT), survival rates of approximately 50% are now observed. Patients appeared to follow three distinct clinical courses: (1) rapidly progressive disease and early demise; (2) transiently stable disease followed by progression and death; and (3) clinical improvement that lasted up to 9 years before progression or, rarely, long-term survival. Favorable prognostic factors for survival after any therapy include being younger than 3 years, having a platelet count of greater than 33 × 109/L, and low age-adjusted fetal hemoglobin levels.[8,21] In contrast, being older than 2 years and having high blood fetal hemoglobin levels at diagnosis are predictors of poor outcome.[8,21] Controversy exists about whether specific mutations are predictive of outcome.
The role of conventional antileukemia therapy in the treatment of JMML is not defined. The absence of consensus response criteria for JMML complicates determination of the role of specific agents in the treatment of JMML. Some of the agents that have shown antileukemia activity against JMML include etoposide, cytarabine, thiopurines (thioguanine and 6-mercaptopurine), isotretinoin, and farnesyl inhibitors, but none of these have been shown to improve outcome.[22-26]; [Level of evidence: 2B]
HSCT currently offers the best chance of cure for JMML.[20,28-30] A report from the European Working Group on Childhood Myelodysplastic Syndrome notes a 55% and 49% 5-year event-free survival for a large group of children with JMML transplanted with HLA-identical matched family donors or unrelated donors, respectively. The trial included 100 recipients at multiple centers using a common preparative regimen of busulfan, cyclophosphamide, and melphalan, with or without antithymocyte globulin. Recipients had been treated with varying degrees of pretransplant chemotherapy or differentiating agents and some patients had splenectomy performed. Multivariate analysis showed no effect on survival of prior acute myeloid leukemia-like chemotherapy versus low-dose chemotherapy or none; no effect on survival was observed for the presence or absence of a spleen, difference in spleen size, or related versus unrelated donors. Only gender and age older than 4 years were shown to be poor prognostic factors for outcome and increased risk of relapse (relative risk [RR], 2.24 [1.07–4.69]; P = .032, RR, 2.22 [1.09–4.50]; P = .028 for older age and female gender, respectively). Cord blood transplantation results in a 5-year disease-free survival of 44%, with improved outcome in children younger than 1.4 years at diagnosis, those with nonmonosomy 7 karyotype, and those receiving 5/6 to 6/6 HLA-matched cord units. [Level of evidence: 3iiDii] This suggests that cord blood can provide an additional donor pool for this group of children. The use of reduced-intensity preparative regimens to reduce the adverse side effects of transplantation have also been reported in small numbers of patients, with variable success.[32,33]
Disease recurrence is the primary cause of treatment failure for children with JMML after HSCT and occurs in 30% to 40% of cases.[20,28,29] While the role of donor lymphocyte infusions is uncertain, reports indicate that approximately 50% of patients with relapsed JMML can be successfully treated with a second HSCT.
Treatment Options Under Clinical Evaluation
The following is an example of national and/or institutional clinical trial that is currently being conducted for patients with newly diagnosed JMML. Information about ongoing clinical trials is available from the NCI Web site.
- ASCT1221 (NCT01824693) (Busulfan, Cyclophosphamide, and Melphalan or Busulfan and Fludarabine Phosphate Before Donor Hematopoietic Cell Transplant in Treating Younger Patients With JMML): This randomized phase II clinical trial is evaluating the efficacy of busulfan, cyclophosphamide, and melphalan compared with busulfan and fludarabine phosphate as preparative regimens administered prior to allogeneic stem cell transplantation for children with newly diagnosed JMML.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with juvenile myelomonocytic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
- Aricò M, Biondi A, Pui CH: Juvenile myelomonocytic leukemia. Blood 90 (2): 479-88, 1997. [PUBMED Abstract]
- Chan RJ, Cooper T, Kratz CP, et al.: Juvenile myelomonocytic leukemia: a report from the 2nd International JMML Symposium. Leuk Res 33 (3): 355-62, 2009. [PUBMED Abstract]
- Loh ML: Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J Haematol 152 (6): 677-87, 2011. [PUBMED Abstract]
- Bresolin S, Zecca M, Flotho C, et al.: Gene expression-based classification as an independent predictor of clinical outcome in juvenile myelomonocytic leukemia. J Clin Oncol 28 (11): 1919-27, 2010. [PUBMED Abstract]
- Olk-Batz C, Poetsch AR, Nöllke P, et al.: Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome. Blood 117 (18): 4871-80, 2011. [PUBMED Abstract]
- Stiller CA, Chessells JM, Fitchett M: Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br J Cancer 70 (5): 969-72, 1994. [PUBMED Abstract]
- Choong K, Freedman MH, Chitayat D, et al.: Juvenile myelomonocytic leukemia and Noonan syndrome. J Pediatr Hematol Oncol 21 (6): 523-7, 1999 Nov-Dec. [PUBMED Abstract]
- Niemeyer CM, Arico M, Basso G, et al.: Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS) Blood 89 (10): 3534-43, 1997. [PUBMED Abstract]
- Sakaguchi H, Okuno Y, Muramatsu H, et al.: Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet 45 (8): 937-41, 2013. [PUBMED Abstract]
- Flotho C, Valcamonica S, Mach-Pascual S, et al.: RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML). Leukemia 13 (1): 32-7, 1999. [PUBMED Abstract]
- Miyauchi J, Asada M, Sasaki M, et al.: Mutations of the N-ras gene in juvenile chronic myelogenous leukemia. Blood 83 (8): 2248-54, 1994. [PUBMED Abstract]
- Side LE, Emanuel PD, Taylor B, et al.: Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1. Blood 92 (1): 267-72, 1998. [PUBMED Abstract]
- Tartaglia M, Niemeyer CM, Fragale A, et al.: Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 34 (2): 148-50, 2003. [PUBMED Abstract]
- Loh ML, Vattikuti S, Schubbert S, et al.: Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 103 (6): 2325-31, 2004. [PUBMED Abstract]
- Loh ML, Sakai DS, Flotho C, et al.: Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood 114 (9): 1859-63, 2009. [PUBMED Abstract]
- Muramatsu H, Makishima H, Jankowska AM, et al.: Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia. Blood 115 (10): 1969-75, 2010. [PUBMED Abstract]
- Niemeyer CM, Kang MW, Shin DH, et al.: Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet 42 (9): 794-800, 2010. [PUBMED Abstract]
- Pérez B, Mechinaud F, Galambrun C, et al.: Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia. J Med Genet 47 (10): 686-91, 2010. [PUBMED Abstract]
- Freedman MH, Estrov Z, Chan HS: Juvenile chronic myelogenous leukemia. Am J Pediatr Hematol Oncol 10 (3): 261-7, 1988 Fall. [PUBMED Abstract]
- Locatelli F, Nöllke P, Zecca M, et al.: Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood 105 (1): 410-9, 2005. [PUBMED Abstract]
- Passmore SJ, Chessells JM, Kempski H, et al.: Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival. Br J Haematol 121 (5): 758-67, 2003. [PUBMED Abstract]
- Loh ML: Childhood myelodysplastic syndrome: focus on the approach to diagnosis and treatment of juvenile myelomonocytic leukemia. Hematology Am Soc Hematol Educ Program 2010: 357-62, 2010. [PUBMED Abstract]
- Bergstraesser E, Hasle H, Rogge T, et al.: Non-hematopoietic stem cell transplantation treatment of juvenile myelomonocytic leukemia: a retrospective analysis and definition of response criteria. Pediatr Blood Cancer 49 (5): 629-33, 2007. [PUBMED Abstract]
- Castleberry RP, Emanuel PD, Zuckerman KS, et al.: A pilot study of isotretinoin in the treatment of juvenile chronic myelogenous leukemia. N Engl J Med 331 (25): 1680-4, 1994. [PUBMED Abstract]
- Woods WG, Barnard DR, Alonzo TA, et al.: Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: a report from the Children's Cancer Group. J Clin Oncol 20 (2): 434-40, 2002. [PUBMED Abstract]
- Hasle H: Myelodysplastic and myeloproliferative disorders in children. Curr Opin Pediatr 19 (1): 1-8, 2007. [PUBMED Abstract]
- Stieglitz E, Ward AF, Gerbing RB, et al.: Phase II/III trial of a pre-transplant farnesyl transferase inhibitor in juvenile myelomonocytic leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 62 (4): 629-36, 2015. [PUBMED Abstract]
- Smith FO, King R, Nelson G, et al.: Unrelated donor bone marrow transplantation for children with juvenile myelomonocytic leukaemia. Br J Haematol 116 (3): 716-24, 2002. [PUBMED Abstract]
- Yusuf U, Frangoul HA, Gooley TA, et al.: Allogeneic bone marrow transplantation in children with myelodysplastic syndrome or juvenile myelomonocytic leukemia: the Seattle experience. Bone Marrow Transplant 33 (8): 805-14, 2004. [PUBMED Abstract]
- Baker D, Cole C, Price J, et al.: Allogeneic bone marrow transplantation in juvenile myelomonocytic leukemia without total body irradiation. J Pediatr Hematol Oncol 26 (3): 200-3, 2004. [PUBMED Abstract]
- Locatelli F, Crotta A, Ruggeri A, et al.: Analysis of risk factors influencing outcomes after cord blood transplantation in children with juvenile myelomonocytic leukemia: a EUROCORD, EBMT, EWOG-MDS, CIBMTR study. Blood 122 (12): 2135-41, 2013. [PUBMED Abstract]
- Yabe M, Sako M, Yabe H, et al.: A conditioning regimen of busulfan, fludarabine, and melphalan for allogeneic stem cell transplantation in children with juvenile myelomonocytic leukemia. Pediatr Transplant 12 (8): 862-7, 2008. [PUBMED Abstract]
- Koyama M, Nakano T, Takeshita Y, et al.: Successful treatment of JMML with related bone marrow transplantation after reduced-intensity conditioning. Bone Marrow Transplant 36 (5): 453-4; author reply 454, 2005. [PUBMED Abstract]
- Yoshimi A, Bader P, Matthes-Martin S, et al.: Donor leukocyte infusion after hematopoietic stem cell transplantation in patients with juvenile myelomonocytic leukemia. Leukemia 19 (6): 971-7, 2005. [PUBMED Abstract]
- Yoshimi A, Mohamed M, Bierings M, et al.: Second allogeneic hematopoietic stem cell transplantation (HSCT) results in outcome similar to that of first HSCT for patients with juvenile myelomonocytic leukemia. Leukemia 21 (3): 556-60, 2007. [PUBMED Abstract]