Childhood Acute Myeloid Leukemia Treatment (PDQ®) 7/12 —Health Professional Version - National Cancer Institute

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

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

Transient Abnormal Myelopoiesis (TAM) or Children With Down Syndrome and AML

In This Section

• TAM Associated With Down Syndrome
• Myeloid Leukemia Associated With Down Syndrome
• Prognosis and Treatment of Children With Down Syndrome and AML
  • Treatment options under clinical evaluation
• Refractory Disease or Relapse in Children With Down Syndrome

TAM Associated With Down Syndrome

In addition to increased risk of AML during the first 3 years of life, about 10% of neonates with Down syndrome develop a TAM (also termed transient myeloproliferative disorder[TMD]).[1] This disorder mimics congenital AML but typically improves spontaneously within the first 3 months of life (median, 49 days), although TAM has been reported to remit as late as 20 months.[2] The late remissions likely reflect a persistent hepatomegaly from TAM-associated hepatic fibrosis rather than active disease.[3]

Although TAM is usually a self-resolving condition, it can be associated with significant morbidity and may be fatal in 10% to 17% of affected infants.[2-6] Infants with progressive organomegaly, visceral effusions, preterm delivery (less than 37 weeks of gestation), bleeding diatheses, failure of spontaneous remission, laboratory evidence of progressive liver dysfunction (elevated direct bilirubin), renal failure, and very high white blood cell (WBC) count are at particularly high risk of early mortality.[3,4,6] Death has been reported to occur in 21% of these patients with high-risk TAM, although only 10% were attributable to TAM and the remaining deaths were caused by coexisting conditions known to be more prominent in neonates with Down syndrome.[3]

The following three risk groups have been identified on the basis of the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms:[3]

• Low risk includes those with neither hepatomegaly nor life-threatening symptoms (38% of patients and 92% ± 8% overall survival [OS]).
• Intermediate risk includes those with hepatomegaly alone (40% of patients and 77% ± 12% OS).
• High risk includes those with hepatomegaly and life-threatening symptoms (21% of patients and 51% ± 19% OS).

Therapeutic intervention is warranted in patients with apparent severe hydrops or organ failure. Because TAM eventually spontaneously remits, treatment is short in duration and primarily aimed at the reduction of leukemic burden and resolution of immediate symptoms. Several treatment approaches have been used, including the following:[7]

• Exchange transfusion.
• Leukapheresis.
• Low-dose cytarabine. Of these approaches, only cytarabine was found to be consistently beneficial.[3,6] Dosing has varied between 0.4 to 1.5mg/kg per dose given intravenously or subcutaneously twice a day for 4 to 12 days [6] or 3.3 mg/kg per day given as a continuous infusion for 5 days.[3] While both were equally effective, the higher continuous dose was associated with severe pancytopenia. The use of the lower dose approach reduced early cumulative death from 72% to 24% (P = .001).[6]

The mean time for the development of AML in the 10% to 30% of children who have a spontaneous remission of TAM but then develop AML has been reported to be approximately 16 months, with a range of 1 to 30 months.[2,3,8] Thus, most infants with Down syndrome and TAM who later develop AML will do so within the first 3 years of life.

Patients with Down syndrome who develop AML with an antecedent TAM have superior event-free survival (EFS) (91% ± 5%) compared with such children without TAM (70% ± 4%) at 5 years,[6] although this was not observed in other studies.[9,10] While TAM is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may connote an increased risk of developing subsequent AML.[4]

Myeloid Leukemia Associated With Down Syndrome

Children with Down syndrome have a tenfold to twentyfold increased risk of leukemia compared with children without Down syndrome; however, the ratio of acute lymphoblastic leukemia to acute myeloid leukemia (AML) is typical for childhood acute leukemia. The exception is during the first 3 years of life, when AML, particularly the megakaryoblastic subtype, predominates and exhibits a distinctive biology characterized by GATA1 mutations and increased sensitivity to cytarabine.[11-19] Importantly, these risks appear to be similar whether a child has phenotypic characteristics of Down syndrome or whether a child has only genetic bone marrow mosaicism.[20]

Prognosis and Treatment of Children With Down Syndrome and AML

Outcome is generally favorable for children with Down syndrome who develop AML (called myeloid leukemia associated with Down syndrome in the World Health Organization classification).[9,10,21]

Prognostic factors for children with Down syndrome and AML include the following:

• Age. The prognosis is particularly good (EFS exceeding 85%) in children aged 4 years or younger at diagnosis; this age group accounts for the vast majority of Down syndrome patients with AML.[9,10,22,23] Children with Down syndrome who are older than 4 years have a significantly worse prognosis.[24]
• White blood cell count. A large international Berlin-Frankfurt-Münster (BFM) retrospective study of 451 children with AML and Down syndrome (aged >6 months and <5 years) observed a 7-year EFS of 78% and 7-year OS of 79%. In multivariate analyses, WBC count (≥20 × 109/L) and age (>3 years) were independent predictors of lower EFS. The 7-year EFS for the older population (>3 years) and for the higher WBC-count population still exceeded 60%.[25]
• AML karyotype. Normal karyotypic AML (other than trisomy 21), which was observed in 29% of patients, independently predicted for inferior OS and EFS (7-year EFS of 65% compared with 82% for patients with aberrant karyotypes).[25] However, this was not seen in a later trial.[23] In this same trial, the presence of trisomy 8 was shown to adversely impact prognosis.
• Minimal residual disease (MRD). MRD at the end of induction 1 was found to be a strong prognostic factor;[10] this was consistent with the BFM finding that early response correlated with improved OS.[23]

Approximately 29% to 47% of Down syndrome patients present with myelodysplastic syndromes (MDS) (<20% blasts) but their outcomes are similar to those with AML.[9,10,23]

Treatment options for newly diagnosed children with Down syndrome and AML include the following:

1. Chemotherapy.

Appropriate therapy for younger children (aged ≤4 years) with Down syndrome and AML is less intensive than current standard childhood AML therapy. Hematopoietic stem cell transplant is not indicated in first remission.[8-10,13,21-24,26-28]

Evidence (chemotherapy):

1. In a Children's Oncology Group (COG) trial for newly diagnosed children with Down syndrome and AML (AAML0431 [NCT00369317]), 204 children were enrolled on a regimen that substituted high-dose cytarabine for the second of four induction cycles (thereby reducing cumulative anthracycline exposure from 320 mg to 240 mg), moving this cycle from intensification where it was used in the previous COG A2971 (NCT00003593) trial.[9,10] Intrathecal doses were reduced from seven to two total injections and intensification included two cycles of cytarabine/etoposide.
   • When compared with the previous trial, these changes resulted in an overall improvement of approximately 10%.
   • EFS was 89.9%, and OS was 93%.
   • Relapse occurred in 14 patients and there were two treatment-related deaths, both related to pneumonia, neither of which occurred during induction 2.
   • No patient had central nervous system (CNS) involvement on this trial or the preceding COG A2971 (NCT00003593) trial.[9]
   • The only prognostic factor identified was MRD using flow cytometry on day 28 of induction 1. Among those who were MRD negative (≤0.01%), DFS was 92.7%; in the 14.4% of patients who were MRD positive, DFS was 76.2% (P = .011).
2. In a joint trial (ML-DS 2006) from the BFM, Dutch Childhood Oncology Group (DCOG), and Nordic Society of Pediatric Hematology and Oncology (NOPHO), 170 children with Down syndrome were enrolled in a trial that focused on reducing therapy by eliminating etoposide during consolidation, reducing the number of intrathecal doses from 11 to 4, and the elimination of maintenance from the reduced therapy Down syndrome arm of AML-BFM 98.[23] As in the COG trials, no patient had CNS disease at diagnosis.
   • Outcomes were no worse despite reduction in chemotherapy. OS was 89% ± 3% and EFS was 87% ± 3%, similar to that observed in AML-BFM 98 (OS, 90% ± 4% [P = NS]; EFS, 89% ± 4% [P = NS]). Cumulative incidence of relapse (CIR) was 6% in both trials.
   • Nine patients relapsed, and seven of those patients died.
   • Patients with a good early response (<5% blasts by morphology before induction cycle 2, n = 123 [72%]) had better outcomes (OS, 92% ± 3% vs. 57% ± 16%, P < .0001; EFS, 88% ± 3% vs. 58% ± 16%, P = .0008; and CIR, 3% ± 2% vs. 27% ± 18%, P = .003).
   • Less toxicity was seen in this new trial, and treatment-related mortality remained low (2.9% vs. 5%, P = .276).
   The following two prognostic factors were identified:[23]
   • Trisomy 8 was an adverse factor (n = 37; OS, 77% vs. 95%, P = .07; EFS, 73% ± 8% vs. 91% ± 4%, P = .018; CIR, 16% ± 7% vs. 3% ± 2%, P = .02).
   • This was confirmed in multivariate analysis, where lack of good early response and trisomy 8 maintained their adverse impact on relapse, with relative risks of 8.55 (95% confidence interval [CI], 1.96–37.29, P = .004) and 4.36 (1.24–15.39, P = .022), respectively.

Children with mosaicism for trisomy 21 are treated similarly to those children with clinically evident Down syndrome.[3,9,20] Although an optimal treatment for these children has not been defined, they are usually treated on AML regimens designed for children without Down syndrome.

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:

1. COG AAML1531 (NCT02521493) (Response-Based Chemotherapy in Treating Newly Diagnosed AML or Myelodysplastic Syndrome in Younger Patients With Down Syndrome): This is a phase III, single-arm trial for newly diagnosed children with Down syndrome–associated AML which uses response to induction therapy to stratify patients to less intensive therapy if they have no MRD and more intensive therapy if they do have MRD at the end of induction cycle one.

Refractory Disease or Relapse in Children With Down Syndrome

A small number of publications address outcomes in children with Down syndrome who relapse after initial therapy or who have refractory AML. All of these retrospective analyses with varying approaches to therapy found that for these children who relapse or have refractory outcomes, the outlook is poor. Thus, these children are treated similarly to children without Down syndrome, with an intensive reinduction chemotherapy regimen, and if a remission is achieved, therapy is followed by an allogeneic hematopoietic stem cell transplant (HSCT).

Treatment options for children with Down syndrome with refractory or relapsed AML include the following:

1. Chemotherapy, which may be followed by an allogeneic HSCT.

Evidence (treatment of children with Down syndrome with refractory or relapsed AML):

1. The Japanese Pediatric Leukemia/Lymphoma Study Group reported the outcomes of 29 Down syndrome patients with relapsed (n = 26) or refractory (n = 3) AML. As expected with Down syndrome, the children in this cohort were very young (median age, 2 years); relapses were almost all early (median, 8.6 months; 80% <12 months from diagnosis); and 89% had M7 French-American-British classification.[29][Level of evidence: 3iiA]
   • In contrast to the excellent outcomes achieved after initial therapy, only 50% of the children attained a second remission, and the 3-year OS rate was 26%.
   • Approximately one-half of the children underwent allogeneic transplant, and no advantage was noted with transplant compared with chemotherapy, but the number of patients was small.
2. A Center for International Blood and Marrow Transplant Research study of children with Down syndrome and AML who underwent HSCT reported a similarly poor outcome, with a 3-year OS of 19%.[30][Level of evidence: 3iiA] The main cause of failure after transplant was relapse, which exceeded 60%; transplant-related mortality was approximately 20%.
3. A Japanese registry study reported better survival after transplant of children with Down Syndrome using reduced-intensity conditioning regimens compared with myeloablative approaches, but the number of patients was very small (n = 5) and the efficacy of reduced-intensity approaches in children with Down syndrome and AML requires further study.[31][Level of evidence 3iDi]

References

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