martes, 8 de octubre de 2019

Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Health Professional Version - National Cancer Institute 8/8

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

National Cancer Institute



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

Therapy-Related AML/Myelodysplastic Syndromes

Pathogenesis

The development of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) after treatment with ionizing radiation or chemotherapy, particularly alkylating agents and topoisomerase inhibitors, is termed therapy-related AML (t-AML) or therapy-related MDS (t-MDS). In addition to genotoxic exposures, genetic predisposition susceptibilities (such as polymorphisms in drug detoxification and DNA repair pathway components) may contribute to the occurrence of secondary AML/MDS.[1-4]
The risk of t-AML/t-MDS is regimen-dependent and often related to the cumulative doses of chemotherapy agents received and the dose and field of radiation administered.[5] Regimens previously used that employed high cumulative doses of either epipodophyllotoxins (e.g., etoposide or teniposide) or alkylating agents (e.g., mechlorethamine, melphalan, busulfan, and cyclophosphamide) induced excessively high rates of t-AML/t-MDS that exceeded 10% in some cases.[5,6] However, most current chemotherapy regimens that are used to treat childhood cancers have a cumulative incidence of t-AML/t-MDS no greater than 1% to 2%.
t-AML/t-MDS resulting from epipodophyllotoxins and other topoisomerase II inhibitors (e.g., anthracyclines) usually occur within 2 years of exposure and are commonly associated with chromosome 11q23 abnormalities,[7] although other subtypes of AML (e.g., acute promyelocytic leukemia) have been reported.[8,9] t-AML that occurs after exposure to alkylating agents or ionizing radiation often presents 5 to 7 years later and is commonly associated with monosomies or deletions of chromosomes 5 and 7.[1,7]

Treatment of Therapy-Related AML/MDS

Treatment options for therapy-related AML/MDS include the following:
  1. HSCT.
The goal of treatment is to achieve an initial complete remission (CR) using AML-directed regimens and then, usually, to proceed directly to hematopoietic stem cell transplantation (HSCT) with the best available donor. However, treatment is challenging because of the following:[10]
  1. Increased rates of adverse cytogenetics and subsequent failure to obtain remission with chemotherapy.
  2. Comorbidities or limitations related to chemotherapy for the previous malignancy.
Accordingly, CR rates and overall survival (OS) rates are usually lower for patients with t-AML compared with patients with de novo AML.[10-12] Also, survival for pediatric patients with t-MDS is worse than survival for pediatric patients with MDS not related to previous therapy.[13]
Patients with t-MDS-refractory anemia usually have not needed induction chemotherapy before transplant; the role of induction therapy before transplant is controversial in patients with refractory anemia with excess blasts-1.
Only a few reports describe the outcome of children undergoing HSCT for t-AML.
Evidence (HSCT for t-AML/t-MDS):
  1. One study described the outcomes of 27 children with t-AML who received related and unrelated donor HSCT.[14]
    • Three-year OS rates were 18.5% ± 7.5% and event-free survival (EFS) rates were 18.7% ± 7.5%.
    • Poor survival was mainly the result of very high transplant-related mortality (59.6% ± 8.4%).
  2. Another study reported a second retrospective single-center experience of 14 patients with t-AML/t-MDS who were transplanted between 1975 and 2007.[11]
    • Survival was 29%, but in this review, only 63% of patients diagnosed with t-AML/t-MDS underwent HSCT.
  3. A multicenter study (CCG-2891) examined outcomes of 24 children with t-AML/t-MDS compared with other children enrolled on the study with de novo AML (n = 898) or MDS (n = 62). Children with t-AML/t-MDS were older and low-risk cytogenetics rarely occurred.[15]
    • Although rates of achieving CR and OS at 3 years were worse in the t-AML/t-MDS group (CR, 50% vs. 72%; P = .016; OS, 26% vs. 47%; P = .007), survival was similar (OS, 45% vs. 53%; P = .87) if patients achieved a CR.
  4. The importance of remission to survival in these patients is further illustrated by another single-center report of 21 children who underwent HSCT for t-AML/t-MDS between 1994 and 2009. Of the 21 children, 12 had t-AML (11 in CR at the time of transplant), seven had refractory anemia (for whom induction was not done), and two had refractory anemia with excess blasts.[16]
    • Survival of the entire cohort was 61%; patients in remission or with refractory anemia had a disease-free survival of 66%, and for the three patients with more than 5% blasts at the time of HSCT, survival was 0% (P = .015).
Because t-AML is rare in children, it is not known whether the significant decrease in transplant-related mortality after unrelated donor HSCT noted over the past several years will translate to improved survival in this population. Patients should be carefully assessed for pre-HSCT morbidities caused by earlier therapies, and treatment approaches should be adapted to give adequate intensity while minimizing transplant-related mortality.
References
  1. Leone G, Fianchi L, Voso MT: Therapy-related myeloid neoplasms. Curr Opin Oncol 23 (6): 672-80, 2011. [PUBMED Abstract]
  2. Bolufer P, Collado M, Barragan E, et al.: Profile of polymorphisms of drug-metabolising enzymes and the risk of therapy-related leukaemia. Br J Haematol 136 (4): 590-6, 2007. [PUBMED Abstract]
  3. Ezoe S: Secondary leukemia associated with the anti-cancer agent, etoposide, a topoisomerase II inhibitor. Int J Environ Res Public Health 9 (7): 2444-53, 2012. [PUBMED Abstract]
  4. Ding Y, Sun CL, Li L, et al.: Genetic susceptibility to therapy-related leukemia after Hodgkin lymphoma or non-Hodgkin lymphoma: role of drug metabolism, apoptosis and DNA repair. Blood Cancer J 2 (3): e58, 2012. [PUBMED Abstract]
  5. Leone G, Mele L, Pulsoni A, et al.: The incidence of secondary leukemias. Haematologica 84 (10): 937-45, 1999. [PUBMED Abstract]
  6. Pui CH, Ribeiro RC, Hancock ML, et al.: Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med 325 (24): 1682-7, 1991. [PUBMED Abstract]
  7. Andersen MK, Johansson B, Larsen SO, et al.: Chromosomal abnormalities in secondary MDS and AML. Relationship to drugs and radiation with specific emphasis on the balanced rearrangements. Haematologica 83 (6): 483-8, 1998. [PUBMED Abstract]
  8. Ogami A, Morimoto A, Hibi S, et al.: Secondary acute promyelocytic leukemia following chemotherapy for non-Hodgkin's lymphoma in a child. J Pediatr Hematol Oncol 26 (7): 427-30, 2004. [PUBMED Abstract]
  9. Okamoto T, Okada M, Wakae T, et al.: Secondary acute promyelocytic leukemia in a patient with non-Hodgkin's lymphoma treated with VP-16 and MST-16. Int J Hematol 75 (1): 107-8, 2002. [PUBMED Abstract]
  10. Larson RA: Etiology and management of therapy-related myeloid leukemia. Hematology Am Soc Hematol Educ Program : 453-9, 2007. [PUBMED Abstract]
  11. Aguilera DG, Vaklavas C, Tsimberidou AM, et al.: Pediatric therapy-related myelodysplastic syndrome/acute myeloid leukemia: the MD Anderson Cancer Center experience. J Pediatr Hematol Oncol 31 (11): 803-11, 2009. [PUBMED Abstract]
  12. Yokoyama H, Mori S, Kobayashi Y, et al.: Hematopoietic stem cell transplantation for therapy-related myelodysplastic syndrome and acute leukemia: a single-center analysis of 47 patients. Int J Hematol 92 (2): 334-41, 2010. [PUBMED Abstract]
  13. Xavier AC, Kutny M, Costa LJ: Incidence and outcomes of paediatric myelodysplastic syndrome in the United States. Br J Haematol 180 (6): 898-901, 2018. [PUBMED Abstract]
  14. Woodard P, Barfield R, Hale G, et al.: Outcome of hematopoietic stem cell transplantation for pediatric patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome. Pediatr Blood Cancer 47 (7): 931-5, 2006. [PUBMED Abstract]
  15. Barnard DR, Lange B, Alonzo TA, et al.: Acute myeloid leukemia and myelodysplastic syndrome in children treated for cancer: comparison with primary presentation. Blood 100 (2): 427-34, 2002. [PUBMED Abstract]
  16. Kobos R, Steinherz PG, Kernan NA, et al.: Allogeneic hematopoietic stem cell transplantation for pediatric patients with treatment-related myelodysplastic syndrome or acute myelogenous leukemia. Biol Blood Marrow Transplant 18 (3): 473-80, 2012. [PUBMED Abstract]

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-ABL1 fusion 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 CBL mutations.[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., SETBP1 was 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 CBL mutations 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 GeneticsExit Disclaimer (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).

Prognosis (genomic and molecular factors)

Several genomic factors affect the prognosis of patients with 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. 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.[21]
    • 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]
  4. 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.[22]
    • 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 LIN28B overexpression 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.[22]
    • 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]

Prognosis (Clinical Factors)

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] however, 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]

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.[25] 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.[25-29]; [30][Level of evidence: 2B]
HSCT currently offers the best chance of cure for JMML.[24,31-34]
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.[35][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.[36,37]
    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).[38]
    • 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.[24,31,32] While the role of donor lymphocyte infusions is uncertain,[39] reports indicate that approximately 50% of patients with relapsed JMML can be successfully treated with a second HSCT.[40]

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.
References
  1. 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]
  2. 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]
  3. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016. [PUBMED Abstract]
  4. 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]
  5. Loh ML: Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J Haematol 152 (6): 677-87, 2011. [PUBMED Abstract]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. 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]
  11. Kratz CP, Niemeyer CM, Castleberry RP, et al.: The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood 106 (6): 2183-5, 2005. [PUBMED Abstract]
  12. Strullu M, Caye A, Lachenaud J, et al.: Juvenile myelomonocytic leukaemia and Noonan syndrome. J Med Genet 51 (10): 689-97, 2014. [PUBMED Abstract]
  13. 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]
  14. 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]
  15. 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]
  16. 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]
  17. 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. [PUBMED Abstract]
  18. Stieglitz E, Taylor-Weiner AN, Chang TY, et al.: The genomic landscape of juvenile myelomonocytic leukemia. Nat Genet 47 (11): 1326-33, 2015. [PUBMED Abstract]
  19. Murakami N, Okuno Y, Yoshida K, et al.: Integrated molecular profiling of juvenile myelomonocytic leukemia. Blood 131 (14): 1576-1586, 2018. [PUBMED Abstract]
  20. 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]
  21. Stieglitz E, Mazor T, Olshen AB, et al.: Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia. Nat Commun 8 (1): 2127, 2017. [PUBMED Abstract]
  22. Helsmoortel HH, Bresolin S, Lammens T, et al.: LIN28B overexpression defines a novel fetal-like subgroup of juvenile myelomonocytic leukemia. Blood 127 (9): 1163-72, 2016. [PUBMED Abstract]
  23. Freedman MH, Estrov Z, Chan HS: Juvenile chronic myelogenous leukemia. Am J Pediatr Hematol Oncol 10 (3): 261-7, 1988 Fall. [PUBMED Abstract]
  24. 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]
  25. 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]
  26. 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]
  27. 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]
  28. 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]
  29. Hasle H: Myelodysplastic and myeloproliferative disorders in children. Curr Opin Pediatr 19 (1): 1-8, 2007. [PUBMED Abstract]
  30. 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]
  31. 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]
  32. 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]
  33. 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]
  34. Locatelli F, Niemeyer CM: How I treat juvenile myelomonocytic leukemia. Blood 125 (7): 1083-90, 2015. [PUBMED Abstract]
  35. 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]
  36. 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]
  37. 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]
  38. Dvorak CC, Satwani P, Stieglitz E, et al.: Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study. Pediatr Blood Cancer 65 (7): e27034, 2018. [PUBMED Abstract]
  39. 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]
  40. 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]

Chronic Myelogenous Leukemia (CML)

Incidence

Chronic myelogenous leukemia (CML) accounts for less than 5% of all childhood leukemia, and in the pediatric age range, occurs most commonly in older adolescents.[1]

Molecular Abnormality

The cytogenetic abnormality most characteristic of CML is the Philadelphia chromosome (Ph), which represents a translocation of chromosomes 9 and 22 (t(9;22)) resulting in a BCR-ABL1 fusion protein.[2]

Clinical Presentation

CML is characterized by a marked leukocytosis and is often associated with thrombocytosis, sometimes with abnormal platelet function. Bone marrow aspiration or biopsy reveals hypercellularity with relatively normal granulocytic maturation and no significant increase in leukemic blasts. Although reduced leukocyte alkaline phosphatase activity is seen in CML, this is not a specific finding.
CML has the following three clinical phases:
  • Chronic phase. Chronic phase, which lasts for approximately 3 years if untreated, usually presents with symptoms secondary to hyperleukocytosis such as weakness, fever, night sweats, bone pain, respiratory distress, priapism, left upper quadrant pain (splenomegaly), and, rarely, hearing loss and visual disturbances.
  • Accelerated phase. The accelerated phase is characterized by progressive splenomegaly, thrombocytopenia, and increased percentage of peripheral and bone marrow blasts, along with accumulation of karyotypic abnormalities in addition to the Ph chromosome.
  • Blast crisis phase. Blast crisis is notable for the bone marrow, showing greater than 20% blasts or chloromatous lesions and a clinical picture that is indistinguishable from acute leukemia. Approximately two-thirds of blast crisis is myeloid, and the remainder is lymphoid, usually of B lineage. Patients in blast crisis will die within a few months.[3]

Treatment of CML: Historical Perspective

Before the tyrosine kinase inhibitor (TKI) era, allogeneic hematopoietic stem cell transplantation (HSCT) was the primary treatment for children with CML. Published reports from this period described survival rates of 70% to 80% when an HLA–matched-family donor (MFD) was used in the treatment of children in early chronic phase, with lower survival rates when HLA–matched-unrelated donors were used.[4-6]
Relapse rates were low (less than 20%) when transplant was performed in chronic phase.[4,5] The primary cause of death was treatment-related mortality, which was increased with HLA–matched-unrelated donors compared with HLA-MFDs in most reports.[4,5] High-resolution DNA matching for HLA alleles appeared to reduce rates of treatment-related mortality, leading to improved outcome for HSCT using unrelated donors.[7]
Compared with transplantation in chronic phase, transplantation in accelerated phase or blast crisis and in second-chronic phase resulted in significantly reduced survival.[4-6] The use of T-lymphocyte depletion to avoid graft-versus-host disease resulted in a higher relapse rate and decreased overall survival (OS),[8] supporting the contribution of a graft-versus-leukemia effect to favorable outcome after allogeneic HSCT.
The introduction of the TKI imatinib as a therapeutic drug targeted at inhibiting the BCR-ABL fusion kinase revolutionized the treatment of patients with CML, for both children and adults.[9] As most data on the use of TKIs for CML is from adult clinical trials, the adult experience is initially described, followed by a description of the more limited experience in children.

Treatment of Adult CML With TKIs

Imatinib is a potent inhibitor of the ABL tyrosine kinase, platelet-derived growth factor (PDGF) receptors (alpha and beta), and KIT. Imatinib treatment achieves clinical, cytogenetic, and molecular remissions (as defined by the absence of BCR-ABL fusion transcripts) in a high proportion of CML patients treated in chronic phase.[10]
Evidence (imatinib for adults):
  1. Imatinib replaced the use of recombinant interferon alfa in the initial treatment of CML based on the results of a large phase III trial comparing imatinib with interferon plus cytarabine (IRIS).[11,12]
    • Patients receiving imatinib had higher complete cytogenetic response rates (76% vs. 14% at 18 months).[11] The rate of treatment failure diminished over time, from 3.3% and 7.5% in the first and second years of imatinib treatment, respectively, to less than 1% by the fifth year of treatment.[12]
    • After censoring for patients who died from causes unrelated to CML or transplantation, the overall estimated survival rate for patients randomly assigned to imatinib was 95% at 60 months.[12]
Guidelines for imatinib treatment have been developed for adults with CML on the basis of patient response to treatment, including the timing of achieving complete hematologic response, complete cytogenetic response, and major molecular response (defined as attainment of a 3-log reduction in BCR-ABL1/control gene ratio).[13-16]
Poor adherence is a major reason for loss of complete cytogenetic response and imatinib failure for adult CML patients on long-term therapy.[17] The identification of BCR-ABL1 kinase domain mutations at the time of failure or of suboptimal response to imatinib treatment also has clinical implications,[18] because there are alternative BCR-ABL kinase inhibitors (e.g., dasatinib and nilotinib) that maintain their activity against some (but not all) mutations that confer resistance to imatinib.[13,19,20]
Two TKIs, dasatinib and nilotinib, have been shown to be effective in patients who have an inadequate response to imatinib, although not in patients with the T315I mutation. Both dasatinib and nilotinib have also received regulatory approval for the treatment of newly diagnosed chronic-phase CML in adults, on the basis of the following studies:
  • Dasatinib. Dasatinib was approved on the basis of a phase III trial that compared dasatinib (100 mg daily) with imatinib (400 mg daily).[21] There was no significant difference in progression-free survival (PFS) or OS. However, after 12 months of treatment, dasatinib was associated with a higher rate of complete cytogenetic response (83% vs. 72%, P = .001) and major molecular response (46% vs. 28%, P < .0001). Responses were achieved in a shorter time with dasatinib (P < .0001).
  • Nilotinib. Nilotinib (at a dose of either 300 mg or 400 mg twice daily) was compared with imatinib (400 mg daily) in a phase III trial.[22] At 12 months, the rates of complete cytogenetic response were significantly higher for nilotinib (80% for the 300-mg dose and 78% for the 400-mg dose) than were the rates for imatinib (65%) (P < .001 for both comparisons). Also, nilotinib was associated with higher rates of major molecular response (44% for the 300-mg dose and 43% for the 400-mg dose compared with 22% for imatinib, P < .001 for both comparisons). The 300-mg twice-daily dose of nilotinib was associated with a more favorable safety profile compared with the 400-mg dose.
Because of the superiority over imatinib in terms of complete cytogenetic response rate and major molecular response rate, both dasatinib and nilotinib are extensively used as first-line therapy in adults with CML. However, despite more rapid responses with dasatinib and nilotinib than with imatinib when used as frontline therapy, PFS and OS appear to be similar for all three agents.[23,24] Additional follow-up will be required to better define the impact of these agents on long-term PFS and OS.
Bosutinib is another TKI that targets the BCR-ABL fusion and has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of all phases of CML in adults who show intolerance to or whose disease shows resistance to previous therapy with another TKI. Bosutinib has not been studied in the pediatric population.
Ponatinib is a BCR-ABL inhibitor that is effective against the T315I mutation.[25] Ponatinib induced objective responses in approximately 70% of heavily pretreated adults with chronic-phase CML, with responses observed regardless of the baseline BCR-ABL kinase domain mutation.[26] Development of ponatinib has been complicated by the high rate of vascular occlusion observed in patients receiving the agent, with arterial and venous thrombosis and occlusions (including myocardial infarction and stroke) occurring in more than 20% of treated patients.[27] Ponatinib has not been studied in the pediatric population.
For adult CML patients who proceed to allogeneic HSCT, there is no evidence that pretransplant imatinib adversely impacts outcome.
Evidence (imatinib followed by HSCT in adults):
  1. A retrospective study that compared 145 patients who received imatinib before transplant with a historical cohort of 231 patients showed no difference in early hepatic toxic effects or engraftment delay.[28]
    • In addition, OS, disease-free survival, relapse, and nonrelapse mortality were similar between the two cohorts.
    • The only factor associated with poor outcome in the cohort that received imatinib was a poor initial response to imatinib.
  2. Further evidence for a lack of effect of pretransplant imatinib on posttransplant outcomes was supplied by a report from the Center for International Blood and Marrow Transplant Research; this report compared outcomes of 181 pediatric and adult subjects with CML in first chronic phase treated with imatinib before HSCT with that of 657 subjects who did not receive imatinib before HSCT.[29]
    • Among the patients in first chronic phase, imatinib therapy before HSCT was associated with better OS.
  3. A third report of imatinib followed by allogeneic HSCT supports the efficacy of this transplantation strategy in patients with imatinib failure in first chronic phase.[13]
    • The 3-year OS rate was 94% for this group (n = 37), with approximately 90% achieving a complete molecular remission after HSCT.
For adult patients treated with a TKI alone (without HSCT), the optimal duration of therapy remains unknown and most patients continue TKI treatment indefinitely.
Evidence (length of imatinib therapy in adults):
  1. In an attempt to answer the question of length of treatment, a prospective study reported on 69 adults treated with imatinib for more than 2 years who had been in a cytogenetic major response for more than 2 years. The patients were monitored monthly and restarted on imatinib if there was evidence of molecular relapse.[30]
    • Of this group, 61% experienced disease relapse, with about 38% still in cytogenetic major response at 24 months.
    • Of note, all of the patients who had disease recurrence responded again to the reinitiation of imatinib.
  2. Another study reported on 40 chronic-phase CML patients who stopped treatment with imatinib after at least 2 years of sustained undetectable minimal residual disease (MRD) by polymerase chain reaction (PCR).[31]
    • At 24 months, the probability of sustained molecular remission for patients no longer receiving imatinib was 47.1%.
    • Most relapses occurred within 4 months of stopping treatment with imatinib, and no relapses beyond 27 months were observed.
    • All patients with molecular relapse demonstrated a favorable response when imatinib was restarted; with a median follow-up of 42 months, no patients had progressive disease or developed the BCR-ABL fusion.
Additional research is required before cessation of imatinib or other BCR-ABL targeted therapy for selected patients with CML in molecular remission can be recommended as a standard clinical practice.

Treatment of Childhood CML

Treatment options for children with CML may include the following:
  1. Tyrosine kinase inhibitor, such as imatinib.
Imatinib has shown a high level of activity in children with CML that is comparable with the activity observed in adults.[32-36]
Evidence (imatinib in children):
  1. In a prospective trial, 44 pediatric patients with newly diagnosed CML were treated with imatinib (260 mg/day).[36]
    • The PFS rate at 36 months was 98%.
    • A complete hematologic response was achieved in 98% of the patients.
    • The rate of complete cytogenetic response was 61% and the rate of major molecular response was 31% at 12 months, similar to the rates seen in adult chronic-phase CML patients treated with imatinib.
As a result of this high level of activity, it is common to initiate imatinib treatment in children with CML rather than proceeding immediately to allogeneic stem cell transplantation.[37] The pharmacokinetics of imatinib in children appears consistent with previous results in adults.[38]
Doses of imatinib used in phase II trials for children with CML have ranged from 260 mg/m2 to 340 mg/m2, which provide comparable drug exposures as the adult flat-doses of 400 mg to 600 mg.[34-36]
Evidence (imatinib dose in children):
  1. In an Italian study of 47 pediatric chronic-phase CML patients treated with 340 mg/m2 per day of imatinib, complete cytogenetic response was achieved in 91.5% of patients at a median time of 6 months, and the rate of major molecular response at 12 months was 66.6%.[36]
    Thus, it appears that starting with the higher dose of 340 mg/m2 has superior efficacy and is typically tolerable, with dose adjustment as needed for toxicity.[35,36]
  2. Early molecular responses, such as PCR-based MRD measurement at 3 months of therapy showing up to 10% BCR-ABL1/ABL, have been reported to be associated with improved PFS, similar to early molecular response data in adults.[39]
The monitoring guidelines described above for adults with CML are reasonable to use in children.
Imatinib is generally well tolerated in children, with adverse effects generally being mild to moderate and reversible with treatment discontinuation or dose reduction.[34,35] Growth retardation occurs in most prepubertal children receiving imatinib.[40] Children receiving imatinib and experiencing growth impairment may show some catch-up growth during their pubertal growth spurts, but they are at risk of having lower-than-expected adult height, as most patients do not achieve midparental height.[40,41]
There are fewer published data regarding the efficacy and toxicities of the two other TKIs approved by the FDA for use in children with CML—dasatinib and nilotinib.
Evidence (dasatinib in children):
  1. A phase I trial of dasatinib in children showed that drug disposition, tolerability, and efficacy of this agent was similar to that observed in adults.[42,43]
  2. A phase II trial of dasatinib, which included 84 children with newly diagnosed CML in chronic phase, utilized a dose of 60 mg/m2 (tablets) or 72 mg/m2 (oral solution) given to patients once daily.[44]
    • Complete cytogenetic response and major molecular response (≥3-log reduction or ≤0.1% on the International Scale) were achieved in 92% and 52% of patients, respectively, after 12 months of therapy, with a 4-year PFS of 93%.
    • Dasatinib was well tolerated, with very few grade 3 or grade 4 adverse events. No pleural or pericardial effusions or pulmonary complications were observed.
Evidence (nilotinib in children):
  1. The approval of nilotinib by the FDA in March 2018 for the treatment of children with CML was based on two sponsored trials.[45,46] An initial study (NCT01077544 [CAMN107A2120]) of 11 patients evaluated pharmacokinetic, safety, and preliminary efficacy data; a second study (NCT01844765 [CAMN107A2203; AAML1321]) of 58 patients evaluated efficacy and safety. Data from both studies were combined for a pooled-data analysis of 69 patients, which included 25 patients with newly diagnosed CML and 44 patients with resistant or intolerant CML. Both studies utilized a dose of 230 mg/m2 given twice daily (rounded to the nearest 50 mg; maximum dose, 400 mg).[45]
    • Sixty percent of patients with newly diagnosed CML achieved a major molecular response at 1 year, with one patient experiencing progression.
    • The tolerability of nilotinib in children was similar to that observed in adults. Primary side effects affecting more than 30% of children included headache, fever, and hyperbilirubinemia.
    • Prolongation of QTc interval (defined in this trial as an increase of >30 msec over baseline) is a recognized side effect of nilotinib, and it was observed in 25% of children in these trials. The investigators recommend obtaining an electrocardiogram at baseline, 1 week, periodically afterward, and after dose adjustments.
A safe pediatric dose has not yet been established for other TKIs (e.g., bosutinib and ponatinib).

Treatment of Recurrent or Refractory Childhood CML

Treatment options for children with recurrent or refractory CML may include the following:
  1. Alternative kinase inhibitors such as dasatinib or nilotinib.
  2. Allogeneic HSCT.
In children who develop a hematologic or cytogenetic relapse during treatment with imatinib or who have an inadequate initial response to imatinib, determination of BCR-ABL kinase domain mutation status should be considered to help guide subsequent therapy. Depending on the patient’s mutation status, alternative kinase inhibitors such as dasatinib or nilotinib can be considered on the basis of the adult and pediatric experience with these agents.[21,22,44,47-49]
Evidence (dasatinib in children with resistant or intolerant CML):
  1. In 14 children with resistant or intolerant CML, 76% of patients were in complete cytogenetic remission, and 41% of patients had a major molecular response after 12 months of dasatinib therapy. PFS was 78% at 48 months.[44]
Evidence (nilotinib in children with resistant or intolerant CML):
  1. In 44 children with CML who were resistant or intolerant to imatinib or dasatinib, 40.7% of patients achieved a major molecular response after 12 months of nilotinib therapy. After a median of 11.3 months, no patients had experienced disease progression.[45]
Dasatinib and nilotinib are active against many BCR-ABL mutations that confer resistance to imatinib, although the agents are ineffective in patients with the T315I mutation. In the presence of the T315I mutation, which is resistant to all FDA-approved kinase inhibitors, an allogeneic transplant should be considered.
The question of whether a pediatric patient with CML should receive an allogeneic transplant when multiple TKIs are available remains unanswered; however, reports suggest that PFS does not improve when using HSCT, compared with the sustained use of imatinib.[36] The potential advantages and disadvantages need to be discussed with the patient and family. While HSCT is currently the only known definitive curative therapy for CML, patients discontinuing treatment with TKIs after sustained molecular remissions, who remained in molecular remission, have been reported.[31]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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  39. Millot F, Guilhot J, Baruchel A, et al.: Impact of early molecular response in children with chronic myeloid leukemia treated in the French Glivec phase 4 study. Blood 124 (15): 2408-10, 2014. [PUBMED Abstract]
  40. Shima H, Tokuyama M, Tanizawa A, et al.: Distinct impact of imatinib on growth at prepubertal and pubertal ages of children with chronic myeloid leukemia. J Pediatr 159 (4): 676-81, 2011. [PUBMED Abstract]
  41. Millot F, Guilhot J, Baruchel A, et al.: Growth deceleration in children treated with imatinib for chronic myeloid leukaemia. Eur J Cancer 50 (18): 3206-11, 2014. [PUBMED Abstract]
  42. Aplenc R, Blaney SM, Strauss LC, et al.: Pediatric phase I trial and pharmacokinetic study of dasatinib: a report from the children's oncology group phase I consortium. J Clin Oncol 29 (7): 839-44, 2011. [PUBMED Abstract]
  43. Zwaan CM, Rizzari C, Mechinaud F, et al.: Dasatinib in children and adolescents with relapsed or refractory leukemia: results of the CA180-018 phase I dose-escalation study of the Innovative Therapies for Children with Cancer Consortium. J Clin Oncol 31 (19): 2460-8, 2013. [PUBMED Abstract]
  44. Gore L, Kearns PR, de Martino ML, et al.: Dasatinib in Pediatric Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Phase II Trial. J Clin Oncol 36 (13): 1330-1338, 2018. [PUBMED Abstract]
  45. Novartis Pharmaceuticals Corporation: TASIGNA (nilotinib): Prescribing Information. East Hanover, NJ: Novartis, 2018. Available online. Last accessed April 11, 2019.
  46. Hijiya N, Maschan A, Rizzari C, et al.: Efficacy and safety of nilotinib in pediatric patients with Philadelphia chromosome–positive (PH+) chronic myeloid leukemia (CML): results from a PHASE 2 trial. [Abstract] Pediatr Blood Cancer 64 (Suppl 3): A-O-032, 2017. Also available onlineExit Disclaimer. Last accessed April 11, 2019.
  47. Hochhaus A, Baccarani M, Deininger M, et al.: Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 22 (6): 1200-6, 2008. [PUBMED Abstract]
  48. le Coutre P, Ottmann OG, Giles F, et al.: Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood 111 (4): 1834-9, 2008. [PUBMED Abstract]
  49. Kantarjian H, O'Brien S, Talpaz M, et al.: Outcome of patients with Philadelphia chromosome-positive chronic myelogenous leukemia post-imatinib mesylate failure. Cancer 109 (8): 1556-60, 2007. [PUBMED Abstract]

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence.[2] This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life.
  • Primary care physicians.
  • Pediatric surgical subspecialists.
  • Radiation oncologists.
  • Pediatric medical oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of children with cancer have been outlined by the American Academy of Pediatrics.[3] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
References
  1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
  2. Wolfson J, Sun CL, Wyatt L, et al.: Adolescents and Young Adults with Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia: Impact of Care at Specialized Cancer Centers on Survival Outcome. Cancer Epidemiol Biomarkers Prev 26 (3): 312-320, 2017. [PUBMED Abstract]
  3. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PUBMED Abstract]

Survivorship and Adverse Late Sequelae

While the issues of long-term complications of cancer and its treatment cross many disease categories, several important issues related to the treatment of myeloid malignancies are worth emphasizing. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Selected studies of the late effects of AML therapy in adult survivors who were not treated with hematopoietic stem cell transplant (HSCT) include the following:
  1. Cardiac.
    1. The Children’s Cancer Survivor Study examined 272 survivors of childhood acute myeloid leukemia (AML) who did not undergo a HSCT.[1]
      • This study identified second malignancies (cumulative incidence, 1.7%) and cardiac toxic effects (cumulative incidence, 4.7%) as significant long-term risks.
      • Cardiomyopathy has been reported in 4.3% of survivors of AML based on Berlin-Frankfurt-Münster studies. Of these, 2.5% showed clinical symptoms.[2]
    2. A retrospective study of cardiac function of children treated with United Kingdom Medical Research Council–based regimens at a median of 13 months after treatment reported a mean detrimental change in left ventricular stroke volume of 8.4% compared with baseline values.[3]
    3. For pediatric patients, the risk of developing early toxicity was 13.7%, and the risk of developing late cardiac toxic effects (defined as 1 year after completing first-line therapy) was 17.4%. Early cardiac toxic effects was a significant predictor of late cardiac toxic effects and the development of clinical cardiomyopathy requiring long-term therapy.[4]
    4. Retrospective analysis of a single study suggests cardiac risk may be increased in children with Down syndrome,[5] but prospective studies are required to confirm this finding.
  2. Psychosocial.
    1. A Nordic Society for Pediatric Hematology and Oncology retrospective trial of children with AML treated with chemotherapy only at a median follow-up of 11 years, based on self-reported uses of health care services, demonstrated similar health care usage and marital status as their siblings.[6]
    2. A population-based study of survivors of childhood AML who had not undergone an HSCT reported equivalent rates of educational achievement, employment, and marital status compared with siblings. AML survivors were, however, significantly more likely to be receiving prescription drugs, especially for asthma, than were siblings (23% vs. 9%; P = .03). Chronic fatigue has also been demonstrated to be a significantly more likely adverse late effect in survivors of childhood AML than in survivors of other malignancies.[7]
Renal, gastrointestinal, and hepatic late adverse effects have been reported to be rare for children undergoing chemotherapy only for treatment of AML.[8]
Selected studies of the late effects of AML therapy in adult survivors who were treated with HSCT include the following:
  1. In a review from one institution, the highest frequency of adverse long-term sequelae for children treated for AML included the following incidence rates: growth abnormalities (51%), neurocognitive abnormalities (30%), transfusion-acquired hepatitis (28%), infertility (25%), endocrinopathies (16%), restrictive lung disease (20%), chronic graft-versus-host disease (20%), secondary malignancies (14%), and cataracts (12%).[9]
    • Most of these adverse sequelae are the consequence of myeloablative, allogeneic HSCT. Although cardiac abnormalities were reported in 8% of patients, this is an issue that may be particularly relevant with the current use of increased anthracyclines in clinical trials for children with newly diagnosed AML.
  2. Another study examined outcomes for children younger than 3 years with AML or acute lymphoblastic leukemia (ALL) who underwent HSCT.[10]
    • The toxicities reported include growth hormone deficiency (59%), dyslipidemias (59%), hypothyroidism (35%), osteochondromas (24%), and decreased bone mineral density (24%).
    • Two of the 33 patients developed secondary malignancies
    • Survivors had average intelligence but frequent attention-deficit problems and fine-movement abnormalities, compared with population controls.
  3. In contrast, The Bone Marrow Transplant Survivor Study compared childhood AML or ALL survivors with siblings using a self-reporting questionnaire.[11] The median follow-up was 8.4 years, and 86% of patients received total-body irradiation (TBI) as part of their preparative transplant regimen.
    • Survivors of leukemia who received an HSCT had significantly higher frequencies of several adverse effects, including diabetes, hypothyroidism, osteoporosis, cataracts, osteonecrosis, exercise-induced shortness of breath, neurosensory impairments, and problems with balance, tremor, and weakness than did siblings.
    • The overall assessment of health was significantly decreased in survivors compared with siblings (odds ratio, 2.2; P = .03).
    • Significant differences were not observed between regimens using TBI compared with chemotherapy only, which mostly included busulfan.
    • The outcomes were similar for patients with AML and ALL, suggesting that the primary cause underlying the adverse late effects was undergoing an HSCT.
  4. A Children's Oncology Group (COG) study using a health-related, quality-of-life comparison reported an overall 21% of 5-year survivors having a severe or life-threatening chronic health condition; when compared by type of treatment, this percentage was 16% for the chemotherapy-only treated group, 21% for the autologous HSCT treated group, and 33% for those who received an allogeneic HSCT.[12]
New therapeutic approaches to reduce long-term adverse sequelae are needed, especially for reducing the late sequelae associated with myeloablative HSCT.
Important resources for details on follow-up and risks for survivors of cancer have been developed, including the COG’s Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult CancersExit Disclaimer and the National Comprehensive Cancer Network's Guidelines for Acute Myeloid LeukemiaExit Disclaimer. Furthermore, having access to past medical history that can be shared with subsequent medical providers has become increasingly recognized as important for cancer survivors.
References
  1. Mulrooney DA, Dover DC, Li S, et al.: Twenty years of follow-up among survivors of childhood and young adult acute myeloid leukemia: a report from the Childhood Cancer Survivor Study. Cancer 112 (9): 2071-9, 2008. [PUBMED Abstract]
  2. Creutzig U, Diekamp S, Zimmermann M, et al.: Longitudinal evaluation of early and late anthracycline cardiotoxicity in children with AML. Pediatr Blood Cancer 48 (7): 651-62, 2007. [PUBMED Abstract]
  3. Orgel E, Zung L, Ji L, et al.: Early cardiac outcomes following contemporary treatment for childhood acute myeloid leukemia: a North American perspective. Pediatr Blood Cancer 60 (9): 1528-33, 2013. [PUBMED Abstract]
  4. Temming P, Qureshi A, Hardt J, et al.: Prevalence and predictors of anthracycline cardiotoxicity in children treated for acute myeloid leukaemia: retrospective cohort study in a single centre in the United Kingdom. Pediatr Blood Cancer 56 (4): 625-30, 2011. [PUBMED Abstract]
  5. O'Brien MM, Taub JW, Chang MN, et al.: Cardiomyopathy in children with Down syndrome treated for acute myeloid leukemia: a report from the Children's Oncology Group Study POG 9421. J Clin Oncol 26 (3): 414-20, 2008. [PUBMED Abstract]
  6. Molgaard-Hansen L, Glosli H, Jahnukainen K, et al.: Quality of health in survivors of childhood acute myeloid leukemia treated with chemotherapy only: a NOPHO-AML study. Pediatr Blood Cancer 57 (7): 1222-9, 2011. [PUBMED Abstract]
  7. Jóhannsdóttir IM, Hjermstad MJ, Moum T, et al.: Increased prevalence of chronic fatigue among survivors of childhood cancers: a population-based study. Pediatr Blood Cancer 58 (3): 415-20, 2012. [PUBMED Abstract]
  8. Skou AS, Glosli H, Jahnukainen K, et al.: Renal, gastrointestinal, and hepatic late effects in survivors of childhood acute myeloid leukemia treated with chemotherapy only--a NOPHO-AML study. Pediatr Blood Cancer 61 (9): 1638-43, 2014. [PUBMED Abstract]
  9. Leung W, Hudson MM, Strickland DK, et al.: Late effects of treatment in survivors of childhood acute myeloid leukemia. J Clin Oncol 18 (18): 3273-9, 2000. [PUBMED Abstract]
  10. Perkins JL, Kunin-Batson AS, Youngren NM, et al.: Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age. Pediatr Blood Cancer 49 (7): 958-63, 2007. [PUBMED Abstract]
  11. Baker KS, Ness KK, Weisdorf D, et al.: Late effects in survivors of acute leukemia treated with hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study. Leukemia 24 (12): 2039-47, 2010. [PUBMED Abstract]
  12. Schultz KA, Chen L, Chen Z, et al.: Health conditions and quality of life in survivors of childhood acute myeloid leukemia comparing post remission chemotherapy to BMT: a report from the children's oncology group. Pediatr Blood Cancer 61 (4): 729-36, 2014. [PUBMED Abstract]

Changes to This Summary (10/04/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Treatment of Childhood AML
Added evidence for the use of a reduced-anthracycline induction regimen, including the results of the St. Jude Children's Research Hospital AML08 protocol where patients were randomly assigned to receive either clofarabine/cytarabine or high-dose cytarabine combined with daunorubicin and etoposide for induction I (cited Rubnitz et al. as reference 18).
Added text to state that outstanding outcomes have been noted for patients who were treated with treosulfan-based regimens; however, trials comparing treosulfan with busulfan or total-body irradiation are lacking (cited Nemecek et al. as reference 86).
Added second transplant after relapse following a first transplant as a treatment option for children with recurrent AML.
Added text to state that the Berlin-Frankfurt-Münster group examined outcomes of children with AML over a 35-year period and found that the greatest improvement in overall outcome was the improvement in survival after relapse. This improved event-free survival after relapse or refractory disease was only seen in patients who received a stem cell transplant as part of their salvage therapy (cited Rasche et al. as reference 112).
Revised text to state that survival was associated with late relapse, achievement of complete response before the second procedure, and use of a second myeloablative regimen if possible (cited Yaniv et al. as reference 124).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute myeloid leukemia and other myeloid malignancies. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment are:
  • Alan Scott Gamis, MD, MPH (Children's Mercy Hospital)
  • Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Michael A. Pulsipher, MD (Children's Hospital Los Angeles)
  • Lewis B. Silverman, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Malcolm A. Smith, MD, PhD (National Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389454]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.
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