sábado, 8 de junio de 2019

Childhood Acute Myeloid Leukemia Treatment (PDQ®) 10/12 —Health Professional Version - National Cancer Institute

Childhood Acute Myeloid Leukemia Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute

Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Health Professional Version





Juvenile Myelomonocytic Leukemia (JMML)

Incidence

Juvenile myelomonocytic leukemia (JMML) is a rare leukemia that occurs approximately ten times less frequently than acute myeloid leukemia (AML) in children, with an annual incidence of about 1 to 2 cases per 1 million people.[1] JMML typically presents in young children (median age, approximately 1.8 years) and occurs more commonly in boys (male to female ratio, approximately 2.5:1).

Clinical Presentation and Diagnostic Criteria

Common clinical features at diagnosis include the following:[2]
  • Hepatosplenomegaly (97%).
  • Lymphadenopathy (76%).
  • Pallor (64%).
  • Fever (54%).
  • Skin rash (36%).
In children presenting with clinical features suggestive of JMML, current criteria used for a definitive diagnosis are described in Table 8.[3]
Table 8. Diagnostic Criteria for Juvenile Myelomonocytic Leukemia (JMML) Per the 2016 Revision to World Health Organization Classification
Category 1 (All are Required)Category 2 (One is Sufficient)aCategory 3 (Patients Without Genetic Features Must Have the Following in Addition to Category 1b)
Clinical and Hematologic FeaturesGenetic StudiesOther Features
GM-CSF = granulocyte-macrophage colony-stimulating factor; NF1 = neurofibromatosis type 1.
aPatients 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. Patients who are not found to have a category 2 lesion must meet the category 1 and 3 criteria.
bNote 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-ABL1fusion geneSomatic mutation in KRAS, NRAS, or PTPN11 (germline mutations need to be excluded)Monosomy 7 or other chromosomal abnormality, or at least 2 of the criteria listed below:
>1 × 109/L circulating monocytesClinical diagnosis of NF1 or NF1 gene mutation— Circulating myeloid or erythroid precursors
<20% blasts in the peripheral blood and bone marrowGermline CBL mutation and loss of heterozygosity of CBL— Increased hemoglobin F for age
Splenomegaly — Hyperphosphorylation of STAT5
  — GM-CSF hypersensitivity

Pathogenesis and Related Syndromes

The pathogenesis of JMML has been closely linked to activation of the RAS oncogene pathway, along with related syndromes (refer to Figure 1).[4,5] 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.[6,7]
ENLARGESchematic diagram showing ligand-stimulated Ras activation, the Ras-Erk pathway, and gene mutations contributing to the neuro-cardio-facio-cutaneous congenital disorders and JMML.
Figure 1. Schematic diagram showing ligand-stimulated Ras activation, the Ras-Erk pathway, and the gene mutations found to date contributing to the neuro-cardio-facio-cutaneous congenital disorders and JMML. NL/MGCL: Noonan-like/multiple giant cell lesion; CFC: cardia-facio-cutaneous; JMML: juvenile myelomonocytic leukemia. Reprinted from Leukemia Research, 33 (3), Rebecca J. Chan, Todd Cooper, Christian P. Kratz, Brian Weiss, Mignon L. Loh, Juvenile myelomonocytic leukemia: A report from the 2nd International JMML Symposium, Pages 355-62, Copyright 2009, with permission from Elsevier.
Children with neurofibromatosis type 1 (NF1) and Noonan syndrome are at increased risk of developing JMML:[8,9]
  • NF1. Up to 14% of cases of JMML occur in children with NF1.[2]
  • Noonan syndrome. Noonan syndrome is usually inherited as an autosomal dominant condition, but can also arise spontaneously. It is characterized by facial dysmorphism, short stature, webbed neck, neurocognitive abnormalities, and cardiac abnormalities. Germline mutations in PTPN11 are observed in children with Noonan syndrome and in children with JMML.[10-12]
    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.[5,12]
    Within a large prospective cohort of 641 patients with Noonan syndrome and a germline PTPN11 mutation, 36 patients (~6%) showed myeloproliferative features, with 20 patients (~3%) meeting the consensus diagnostic criteria for JMML.[12] Of the 20 patients meeting the criteria for JMML, 12 patients had severe neonatal manifestations (e.g., life-threatening complications related to congenital heart defects, pleural effusion, leukemia infiltrates, and/or thrombocytopenia), and 10 of 20 patients died during the first month of life. Among the remaining eight patients, none required intensive therapy at diagnosis or during follow-up. All 16 patients with myeloproliferative features not meeting JMML criteria were alive, with a median follow-up of 3 years, and none of the patients received chemotherapy.
Mutations in the CBL gene, an E3 ubiquitin-protein ligase that is involved in targeting proteins, particularly tyrosine kinases, for proteasomal degradation occur in 10% to 15% of JMML cases,[13,14] with many of these cases occurring in children with germline CBLmutations.[15,16] CBL germline mutations result in an autosomal dominant developmental disorder that is characterized by impaired growth, developmental delay, cryptorchidism, and a predisposition to JMML.[15] Some individuals with CBL germline mutations experience spontaneous regression of their JMML but develop vasculitis later in life.[15]CBL mutations are nearly always mutually exclusive of RAS and PTPN11 mutations.[13]

Genomics of JMML

The genomic landscape of JMML is characterized by mutations in one of five genes of the Ras pathway: NF1, NRAS, KRAS, PTPN11, and CBL.[17-19] In a series of 118 consecutively diagnosed JMML cases with Ras pathway–activating mutations, PTPN11 was the most commonly mutated gene, accounting for 51% of cases (19% germline and 32% somatic) (refer to Figure 2).[17] Patients with mutated NRAS accounted for 19% of cases, and patients with mutated KRAS accounted for 15% of cases. NF1 mutations accounted for 8% of cases and CBL mutations accounted for 11% of cases. Although mutations among these five genes are generally mutually exclusive, 4% to 17% of cases have mutations in two of these Ras pathway genes,[17-19] a finding that is associated with poorer prognosis.[17,19]
The mutation rate in JMML leukemia cells is very low, but additional mutations beyond those of the five Ras pathway genes described above are observed.[17-19] Secondary genomic alterations are observed for genes of the transcriptional repressor complex PRC2 (e.g., ASXL1 was mutated in 7%–8% of cases). Some genes associated with myeloproliferative neoplasms in adults are also mutated at low rates in JMML (e.g., SETBP1was mutated in 6%–9% of cases).[17-20] JAK3 mutations are also observed in a small percentage (4%–12%) of JMML cases.[17-20] Cases with germline PTPN11 and germline CBLmutations showed low rates of additional mutations (refer to Figure 2).[17] The presence of mutations beyond disease-defining Ras pathway mutations is associated with an inferior prognosis.[17,18]
A report describing the genomic landscape of JMML found that 16 of 150 patients (11%) lacked canonical Ras pathway mutations. Among these 16 patients, 3 were observed to have in-frame fusions involving receptor tyrosine kinases (DCTN1-ALK, RANBP2-ALK, and TBL1XR1-ROS1). These patients all had monosomy 7 and were aged 56 months or older. One patient with an ALK fusion was treated with crizotinib plus conventional chemotherapy and achieved a complete molecular remission and proceeded to allogeneic bone marrow transplantation.[19]
ENLARGEChart showing alteration profiles in individual JMML cases.
Figure 2. Alteration profiles in individual JMML cases. Germline and somatically acquired alterations with recurring hits in the RAS pathway and PRC2 network are shown for 118 patients with JMML who underwent detailed genetic analysis. Blast excess was defined as a blast count ≥10% but <20% of nucleated cells in the bone marrow at diagnosis. Blast crisis was defined as a blast count ≥20% of nucleated cells in the bone marrow. NS, Noonan syndrome. Reprinted by permission from Macmillan Publishers Ltd: Nature Genetics (Caye A, Strullu M, Guidez F, et al.: Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nat Genet 47 [11]: 1334-40, 2015), copyright (2015).
General characteristics of leukemia cells provide both prognostic information and guidance regarding therapeutic opportunities for JMML:
  • Number of non-RAS pathway mutations. A strong predictor of prognosis for children with JMML is the number of mutations beyond the disease-defining RAS-pathway mutations.[17,18] Of 64 patients (65.3%) at diagnosis, zero or one somatic alteration (pathogenic mutation or monosomy 7) was identified, whereas two or more alterations were identified in 34 (34.7%) patients.[18] In multivariate analysis, mutation number (two or more vs. zero or one) maintained significance as a predictor of inferior event-free survival and overall survival. A higher proportion of patients diagnosed with two or more alterations were older and male, and these patients also demonstrated a higher rate of monosomy 7 or somatic NF1 mutation.[18] Similar findings and observations reported that patients with RAS-pathway double mutations (15 of 96 patients) were at the highest risk of treatment failure.[17]
  • RAS-MAPK pathway inhibitors. Because JMML is a disease defined by mutations in the RAS-MAPK pathway, one might speculate that inhibitors of this pathway (e.g., MEK inhibitors) may have clinical utility in the treatment of JMML. However, preclinical data to support this hypothesis are inconsistent,[21,22] and there are no clinical data available.

Prognosis

Several factors affect prognosis in JMML, including the following:
  1. Number of non–Ras pathway mutations. A predictor of prognosis for children with JMML is the number of mutations beyond the disease-defining Ras pathway mutations.[17,18]
    • One study observed that zero or one somatic alteration (pathogenic mutation or monosomy 7) was identified in 64 patients (65.3%) at diagnosis, whereas two or more alterations were identified in 34 patients (34.7%).[18] In multivariate analysis, mutation number (2 or more vs. 0 or 1) maintained significance as a predictor of inferior event-free survival (EFS) and overall survival (OS). A higher proportion of patients diagnosed with two or more alterations were older and male, and these patients also demonstrated a higher rate of monosomy 7 or somatic NF1 mutations.[18]
    • Another study observed that approximately 60% of patients had one or more additional mutations beyond their disease-defining Ras pathway mutation. These patients had an inferior OS compared with patients who had no additional mutations (3-year OS, 61% vs. 85%, respectively).[17]
    • A third study observed a trend for an inferior OS for patients with two or more mutations compared with patients with zero or one mutation.[19]
  2. Ras pathway double mutations. Although mutations in the five canonical Ras pathway genes associated with JMML (NF1, NRAS, KRAS, PTPN11, and CBL) are generally mutually exclusive, 4% to 17% of cases have mutations in two of these Ras pathway genes,[17,18] a finding that has been associated with a poorer prognosis.[17,18]
    • Two Ras pathway mutations were identified in 11% of JMML patients in one report, and these patients had significantly inferior EFS (14%) compared with patients who had a single Ras pathway mutation (62%). Patients with Noonan syndrome were excluded from the analyses.[18]
    • Similar findings for Ras pathway mutations were reported in a second study that observed that patients with Ras pathway double mutations (15 of 96 patients) had lower survival rates than did patients with either no additional mutations or with additional mutations beyond the Ras pathway mutation.[17]
  3. Age, platelet count, and fetal hemoglobin level after any treatment. Historically, more than 90% of patients with JMML died despite the use of chemotherapy,[23] but with the application of hematopoietic stem cell transplantation (HSCT), survival rates of approximately 50% are now observed.[24] Patients appeared to follow three distinct clinical courses:
    • Rapidly progressive disease and early demise.
    • Transiently stable disease followed by progression and death.
    • Clinical improvement that lasted up to 9 years before progression or, rarely, long-term survival.
    Favorable prognostic factors for survival after any therapy include age younger than 2 years, platelet count greater than 33 × 109/L, and low age-adjusted fetal hemoglobin levels.[1,2] In contrast, being older than 2 years and having high blood fetal hemoglobin levels at diagnosis are predictors of poor outcome.[1,2]
  4. DNA methylation profile. One study applied DNA methylation profiling to a discovery cohort of 39 patients with JMML and to a validation cohort of 40 patients. Distinctive subsets of JMML with either high, intermediate, or low methylation levels were observed in both cohorts. Patients with the lowest methylation levels had the highest survival rates, and all but 1 of 15 patients experienced spontaneous resolution in the low methylation cohort. High methylation status was associated with lower EFS rates.[25]
    Another study applied DNA methylation profiling to a cohort of 106 patients with JMML and observed one subgroup of patients with a hypermethylation profile and one subgroup of patients with a hypomethylation profile. Patients in the hypermethylation group had a significantly lower OS rate than did patients in the hypomethylation group (5-year OS, 46% vs. 73%, respectively). Patients in the hypermethylation group also had a significantly poorer 5-year transplant-free survival rate than did patients in the hypomethylation group (2.2%; 95% CI, 0.2%–10.1% vs. 41.2%; 95% CI, 27.1%–54.8%). Hypermethylation status was associated with two or more mutations, higher fetal hemoglobin levels, older age, and lower platelet count at diagnosis. All patients with Noonan syndrome were in the hypomethylation group.[19]
  5. LIN28B overexpression. LIN28B overexpression is present in approximately one-half of children with JMML and identifies a biologically distinctive subset of JMML. LIN28B is an RNA-binding protein that regulates stem cell renewal. LIN28B overexpression was positively correlated with high blood fetal hemoglobin level and age (both of which are associated with poor prognosis), and it was negatively correlated with presence of monosomy 7 (also associated with inferior prognosis). Although LIN28Boverexpression identifies a subset of patients with increased risk of treatment failure, it was not found to be an independent prognostic factor when other factors such as age and monosomy 7 status are considered.[26] Another study also observed a subset of JMML patients with elevated LIN28B expression and identified LIN28B as the gene for which expression was most strongly associated with hypermethylation status.[19]

Treatment of JMML

Treatment options for JMML include the following:
  • Hematopoietic stem cell transplant (HSCT).
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.[27] Some agents that have shown antileukemia activity against JMML include etoposide, cytarabine, thiopurines (thioguanine and mercaptopurine), isotretinoin, and farnesyl inhibitors, but none of these have been shown to improve outcome.[27-31]; [32][Level of evidence: 2B]
HSCT currently offers the best chance of cure for JMML.[24,33-36]
Evidence (HSCT):
  1. A report from the European Working Group on Childhood Myelodysplastic Syndromes included 100 transplant recipients at multiple centers treated with 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.[24]
    • The 5-year EFS rate was 55% for children with JMML transplanted with HLA-identical matched family donor cells and 49% for children with JMML transplanted with unrelated donor cells.
    • The multivariate analysis showed no effect on survival of previous AML-like chemotherapy versus low-dose chemotherapy or no chemotherapy.
    • No effect on survival was observed for splenectomy pretransplant or difference in spleen size.
    • Comparison of outcomes based on related versus unrelated donors also found no difference.
    • Only age older than 4 years and sex 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 for older age; RR, 2.22 [1.09–4.50]; P = .028 for females).[24]
  2. Cord blood transplantation results in a 5-year disease-free survival rate 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.[37][Level of evidence: 3iiDii] This suggests that cord blood can provide an additional donor pool for this group of children.
  3. The use of reduced-intensity preparative regimens to decrease the adverse side effects of transplantation have also been reported in small numbers of patients, generally for patients ineligible for myeloablative HSCT.[38,39]
    COG conducted a randomized trial in children with JMML that compared a standard-intensity preparative regimen (busulfan/cyclophosphamide/melphalan) with a reduced-intensity regimen (busulfan/fludarabine).[40]
    • The trial closed to enrollment early when an interim analysis revealed a higher frequency of relapse/disease persistence (7 of 9 patients) in children who received the reduced-intensity regimen than in children who received the standard-intensity regimen (1 of 6 patients).
Disease recurrence is the primary cause of treatment failure for children with JMML after HSCT and occurs in 30% to 40% of cases.[24,33,34] While the role of donor lymphocyte infusions is uncertain,[41] reports indicate that approximately 50% of patients with relapsed JMML can be successfully treated with a second HSCT.[42]

Treatment Options Under Clinical Evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  • COG-ADVL1521 (NCT03190915) (Trametinib in Treating Patients With Relapsed or Refractory JMML): This trial is evaluating the activity of trametinib (inhibitor of MEK1/2, which is downstream of RAS/MAPK signaling) in pediatric patients with relapsed or refractory JMML. The rationale for studying this agent is based on the finding that nearly all genetic mutations found in JMML lead to aberrant RAS pathway signaling. Eligible patients are those who have relapsed or have persistent disease after intravenous chemotherapy (such as fludarabine or cytarabine) and/or hematopoietic stem cell transplant, but not after low-dose oral chemotherapy (such as mercaptopurine). The primary objective is to determine the response rate of trametinib administered orally once daily in 28-day cycles.
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