PDQ® Treatment Health Professionals
This treatment information summary on childhood acute myeloid leukemia (AML) is an overview of prognosis, diagnosis, classification, and treatment. The National Cancer Institute created the PDQ database to increase the availability of new treatment information and its use in treating persons with cancer. Information and references from the most recently published literature are included after review by pediatric oncology specialists.
Cancer in children and adolescents is rare. A team approach that incorporates the skills of the local physician, pediatric surgeon, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, and social workers is imperative to ensure that children with cancer receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. For advances to be made in treating these children, therapy should be delivered in the context of a clinical trial at a major medical center that has expertise in treating children with cancer. Only through the entry of all eligible children into appropriate, well-designed clinical trials will progress be made against these diseases. Guidelines for pediatric cancer centers and their role in the treatment of children with cancer have been outlined by the American Academy of Pediatrics.
Between 75% and 85% of children with AML (also called acute myelogenous leukemia, acute nonlymphocytic leukemia, or ANLL) can achieve a complete remission following appropriate induction chemotherapy. Children with newly diagnosed AML have an event-free 5-year survival rate of approximately 40%.[2,3] In contrast to acute lymphocytic leukemia (ALL), very few clinical, laboratory, or treatment factors have been consistently related to prognosis for children with AML. Children with AML who have a white blood cell count (WBC) greater than 100,000 per cubic milliliter, secondary AML, and leukemic cells with a monosomy 7 karyotype have low remission induction rates, whereas children with leukemia cell chromosomal abnormalities t(8;21) and inv 16 have a high likelihood of achieving remission.[4-7] Children having leukemic cells with inv 16 or t(8;21) abnormalities also have a decreased likelihood of relapse. Translocations of chromosomal band 11q23, including most AML secondary to epipodophyllotoxin, are generally unfavorable for remission duration except possibly where the translocation partner is chromosome 9, i.e., t(9;11). In several studies, M4 and M5 FAB type, WBC greater than 20,000 per cubic milliliter, and requiring more than 1 cycle to achieve remission, predicted for a short duration of remission.[5,7]
Children with Down syndrome have an increased risk of leukemia with a ratio of ALL to AML typical for childhood acute leukemia, except during the first 3 years of life when AML (especially M7) predominates. Neonates with Down syndrome may manifest a transient myeloproliferative syndrome (TMS). This disorder mimics congenital AML but improves spontaneously within 4 to 6 weeks. Retrospective surveys indicate that as many as 30% of infants with Down syndrome and TMS will develop AML before 3 years of age. Interestingly, the majority of children with Down syndrome and AML can be cured of their leukemia. Appropriate therapy for these children is less intensive than current AML therapy and bone marrow transplant (BMT) is not indicated in first remission.
The most comprehensive morphologic-histochemical classification system for acute myeloid leukemia (AML) was developed by the French-American-British (FAB) Cooperative Group.[1-4] This classification system categorizes AML into the following major subtypes:
* Recognition of M0 AML requires reactivity with either monoclonal antibody CD13 or CD33 and must not display specific morphologic or histochemical features of either AML or acute lymphocytic leukemia (ALL).
** Identifying this subtype is critical since the risk of fatal hemorrhagic complication prior to or during induction is high and the appropriate therapy is different. (See sections on cytogenetics and treatment for important details).
*** Diagnosis of M7 can be difficult as the blasts can be confused with lymphoblasts. Characteristically, the blasts display cytoplasmic blebs. Marrow aspiration can be difficult due to myelofibrosis, and marrow biopsy with reticulin stain can be helpful.
Fifty percent to 60% of children with AML can be classified as having M1, M2, M3, M6, or M7 subtypes; approximately 40% have M4 or M5 subtypes. About 80% of children less than 2 years of age with AML have a M4 or M5 subtype. The response to cytotoxic chemotherapy among children with the different subtypes of AML is relatively similar. One exception is FAB subtype M3, for which all- trans-retinoic acid plus chemotherapy achieves remission and cure in the majority of children with AML.
The treatment for children with AML differs significantly from that for ALL. As a consequence, it is crucial to distinguish AML from ALL. Special histochemical stains should be performed on bone marrow specimens of all children with acute leukemia to confirm their diagnosis. The stains most commonly used include myeloperoxidase, PAS, Sudan Black B, and esterase. In most cases the staining pattern with these histochemical stains will distinguish AML from AMML and ALL (see below).
AML,APL AMML AMoL AEL AMKL ALL M0 (M1-M3) (M4) (M5) (M6) (M7) Myeloperoxidase - + + - - - - Nonspecific esterases Chloracetate - + + -/+ - - - Alpha-naphthol acetate - - +* +* - -/+* - Sudan Black B - + + - - - - PAS - - -/+ -/+ + - + * These reactions are inhibited by fluoride.
The use of monoclonal antibodies to determine cell surface antigens of AML cells is helpful to reinforce the histologic diagnosis. Various "lineage- specific" monoclonal antibodies that detect antigens on AML cells should be used at leukemia diagnosis, along with a battery of lineage-specific T- and B- lymphocyte markers to help distinguish AML from ALL and mixed lineage or biphenotypic or biclonal leukemias. Various cluster designations (CD) that are currently thought to be relatively lineage specific for AML include CD33, CD13, CD14, CDw41 (or platelet antiglycoprotein IIB/IIIA), CD15, CD11B, CD36, and antiglycophorin A. Lineage-associated B-lymphocytic antigens CD10, CD19, CD20, CD22, and CD24 may be present in 10%-20% of AMLs, but monoclonal surface immunoglobulin and cytoplasmic immunoglobulin heavy chains are usually absent; similarly, CD2, CD3, CD5, and CD7 lineage-specific T-lymphocytic antigens are present in 20%-40% of AMLs.[6-8] The expression of lymphoid-associated antigens by AML cells is relatively common but has no prognostic significance.[6,7]
Immunophenotyping can also be helpful in distinguishing some FAB subtypes of AML. Testing for the presence of HLA-DR can be helpful in identifying APL. Overall, HLA-DR is expressed on 75%-80% of AML's but rarely expressed on APL. Testing for the presence of glycoprotein Ib, glycoprotein IIB/IIIa, or Factor VIII antigen expression is helpful in making the diagnosis of M7 (megakaryocytic leukemia). Glycophorin expression is helpful in making the diagnosis of M6 (erythroleukemia).
Chromosomal analyses should be performed on children with AML because they are important diagnostic and prognostic markers. Clonal chromosomal abnormalities have been identified in the blasts of about 75% of children with AML and are useful in defining subtypes with particular characteristics (e.g., t(8;21) with M2, t(15;17) with M3, inv 16 with M4 eo, 11q23 abnormalities with M4 and M5, t(1;22) with M7).
Molecular probes and newer cytogenetic techniques (FISH) can detect cryptic abnormalities that were not evident by standard cytogenetic banding studies. This is clinically important when optimal therapy differs, as in APL. Use of these techniques can identify cases of APL when the diagnosis is suspected but the t(15;17) is not identified by routine cytogenetic evaluation. The presence of the Philadelphia chromosome in children with AML most likely represents chronic myelogenous leukemia (CML) that has transformed to AML rather than de novo AML.
There is presently no therapeutically or prognostically meaningful staging system for this disease. Leukemia is always disseminated in the hematopoietic system at diagnosis, even in children with acute myeloid leukemia (AML) who present with isolated chloromas (also called granulocytic sarcomas). If these children do not receive systemic chemotherapy, they invariably develop AML in months or years. AML may invade nonhematopoietic tissue such as meninges, brain parenchyma, testes or ovaries, or skin (leukemia cutis). Extramedullary leukemia is more common in infants than older children with AML.
Childhood AML is diagnosed when bone marrow has more than 30% blasts. The blasts have the morphologic and histochemical characteristics of one of the FAB subtypes of AML. It can also be diagnosed by biopsy of a chloroma. For treatment purposes, children with a t(8;21) and less than 30% marrow blasts should be considered to have AML rather than myelodysplastic syndrome (MDS).
Following remission-induction treatment, remission in children and adolescents with AML is defined as follows: peripheral blood counts (white blood cell count, differential, and platelet count) rising toward normal, a mildly hypocellular to normal cellular marrow with fewer than 5% blasts, and no clinical signs or symptoms of the disease, including in the central nervous system or at other extramedullary sites. Achieving a hypoplastic bone marrow is usually the first step in obtaining remission in this disease with the exception of the M3 (acute promyelocytic leukemia (AProL or APL)) variant; a hypoplastic marrow phase is often not necessary prior to the achievement of remission in AProL. Additionally, early recovery marrows in any of the subtypes of AML may be difficult to distinguish from persistent leukemia; correlation with blood counts and clinical status (perhaps bone marrow cytogenetics as well) is imperative in passing final judgment on the results of early bone marrow findings in this disease. If in doubt, repeat the bone marrow aspirate in about 1 week.
Many of the improvements in survival for children and adolescents with acute myeloid leukemia (AML) have been made using new therapies that have attempted to improve on the best available therapy. The mainstay of the therapeutic approach is systemically administered combination chemotherapy. Optimal treatment of AML requires control of bone marrow and systemic disease. Treatment of the central nervous system is an integral component of most AML protocols, but has not yet been shown to contribute directly to an improvement in survival.
Treatment is ordinarily divided into 2 or 3 phases: 1) induction (to attain remission), 2) postremission consolidation, and/or 3) postremission intensification. Maintenance therapy in aggressively-treated AML does not appear to be of any value. Treatment of AML is usually associated with severe and protracted myelosuppression and other complications. For these reasons, children with this disease must have their care coordinated by specialists in pediatric oncology, and they must be treated in cancer centers or hospitals with the necessary supportive care facilities (for example, to administer irradiated, filtered, or cytomegalovirus-negative red blood cell and platelet transfusions; to manage infectious complications; and to provide emotional and developmental support).
With increasing rates of survival for children treated for AML comes an increased awareness of long-term sequelae of various treatments. For children who receive intensive chemotherapy, including anthracyclines, continued monitoring of cardiac function is critical. Periodic renal and auditory examinations are also suggested. In addition, total-body irradiation before bone marrow transplant increases the risk for growth failure, gonadal and thyroid dysfunction, and cataract formation.
The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.
The general principles of therapy for children and adolescents with acute myeloid leukemia (AML) are discussed below, followed by a more specific discussion of the treatment of children with acute promyelocytic leukemia (APL), and the treatment of children with both AML and Down syndrome.
The 2 most effective drugs used to induce remission in children with acute myeloid leukemia (AML) are cytarabine and an anthracycline. These 2 agents form the mainstay of the most effective remission induction regimens but may also be given in conjunction with other reasonably effective induction agents, such as etoposide and thioguanine, in an attempt to increase the disease-free interval and disease-free survival rate.
To achieve a complete remission, inducing profound bone marrow aplasia (with the exception of the M3 (AProL) variant) is usually necessary. Because induction chemotherapy produces severe myelosuppression, morbidity and mortality from infection or hemorrhage during the induction period may be significant.
Equivalent complete remission rates for greater than 75% of children with AML have been achieved with induction regimens containing an anthracycline and cytarabine with or without thioguanine and/or etoposide. Of the remaining 15%-25% who do not go into remission, about one half have resistant leukemia and one half succumb to the complications of the disease or its treatment.
The addition of hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G- CSF) to AML induction therapy may shorten the duration of neutropenia but has not been shown to improve long-term survival.
Although the presence of central nervous system (CNS) leukemia at diagnosis (i.e., clinical neurologic features and/or leukemic cells in cerebral spinal fluid on cytocentrifuge preparation) is more common in childhood AML than in childhood acute lymphocytic leukemia (ALL), reduction in overall survival directly attributable to CNS involvement is presently less common in childhood AML. This finding is perhaps related to both the higher doses of chemotherapy used in AML (with potential cross-over to the CNS) and the fact that marrow disease has not yet been as effectively brought under long-term control in AML as in ALL. Children with M4 and M5 AML have the highest incidence of CNS leukemia (especially those with inv 16 or 11q23 chromosomal abnormalities). The use of some form of CNS treatment (intrathecal chemotherapy with or without cranial irradiation) is now incorporated into most protocols for the treatment of childhood AML and is considered a standard part of the treatment for this disease.
A major challenge in the treatment of children with acute myeloid leukemia (AML) is to prolong the duration of the initial remission with additional chemotherapy or bone marrow transplantation (BMT). In the absence of a suitable marrow donor, most centers use some form of intensive chemotherapy after remission is achieved. Such therapy includes the drugs used in induction or intensification with high-dose cytarabine, etoposide, and anthracyclines, many of which should be non-cross resistant with the drugs and doses used in remission induction.
Although the practice has been to use a third phase of treatment (maintenance chemotherapy), no data conclusively demonstrate that maintenance therapy given after intensive postremission therapy significantly prolongs remission duration, especially for children receiving very aggressive postremission therapy; it may result in poorer survival.
The current Childrens Cancer Group (CCG) AML trial is examining immune modulatory therapy in a randomized comparison of interleukin-2 versus standard follow-up in children who have completed consolidation chemotherapy.
The use of BMT in first remission has been under evaluation since the late 1970s. Long-term results on limited numbers of children with AML suggest that nearly 60% of children with matched donors available who undergo allogeneic bone marrow transplantation during their first remission experience long-term remissions (in excess of 3 years) without severe graft versus host disease.[4-9] Allogeneic marrow transplantation from an HLA-identical sibling donor appears to offer the child with AML in first remission the best chance for long-term leukemia-free survival compared to intensive conventional maintenance chemotherapy regimens.[6-9] The German BFM Group has concluded from their studies that a group of children with AML with a somewhat better prognosis can be identified at diagnosis and that the use of BMT in first remission should be reserved for those with a worse prognosis. The low- risk group, comprising 37% of the children who achieved complete remission, included the FAB types with granulocytic differentiation and specific additional features: FAB M1 with Auer rods, FAB M2 with white blood cell count of less than 20,000/microliter, all children with FAB M3, and FAB M4 with eosinophilia. Several large cooperative group clinical trials for children with AML have found no benefit for autologous bone marrow transplantation over intensive chemotherapy.[1,5,7,9] Most trials of autologous transplantation have included marrow purging, although there have been no prospective randomized trials looking at the role of marrow purging in autologous transplant. The role of alternative donor transplants (unrelated marrow or cord blood) in first remission of AML has not been established.
The following trials exclude children with Down syndrome and/or acute promyelocytic leukemia (APL).
Two nationwide studies are in progress:
2. In a CCG study, children with AML are treated with multiagent induction chemotherapy. Induction consists of 5 drugs (idarubicin, etoposide, dexamethasone, cytarabine, and 6-thioguanine) given on days 0-3 followed by 5 drugs (daunorubicin, etoposide, dexamethasone, cytarabine and 6-thioguanine) given on days 10-13. When white blood cell and platelet counts recover, children are randomly assigned to consolidation consisting of the same sequence of 5 and 5 drugs or to fludarabine/cytarabine/idarubicin. CNS prophylaxis consists of intrathecal cytarabine. G-CSF is given from 2 days after completion of induction and consolidation until the absolute neutrophil count is greater than 1,500. Children with matched-related donors are assigned to allogeneic marrow transplant intensification. Transplant cytoreduction consists of age-adjusted busulfan and cyclophosphamide. Children without a donor are given high-dose cytarabine/L-asparaginase (Capizzi II) and additional intrathecal cytarabine. After recovery from cytarabine, children are randomly assigned to interleukin-2 or standard follow-up care.
The majority of children with AML Down syndrome can be cured of their leukemia. Appropriate therapy for these children is less intensive than current AML therapy and BMT is not indicated in first remission.
APL with a 15;17 translocation is a distinct subtype of AML. The characteristic chromosomal abnormality associated with the subtype, the t(15;17), involves a breakpoint which includes the retinoic acid receptor (PML- RAR alpha transcript).[12,13] Clinically this subtype is characterized by a severe coagulopathy usually present at the time of diagnosis. Mortality during induction due to bleeding complications is more common in this subtype than other FAB classifications. Most children with acute promyelocytic leukemia (APL, FAB-M3) achieve a complete remission with the differentiating agent all- trans-retinoic acid (ATRA).[14-17] ATRA is given at a dose of 45 milligrams per square meter per day (given orally twice a day) for 30-45 days. The presence of the PML-RAR alpha transcript predicts response to retinoic acid. Remission occurs via differentiation of blasts. Note should be made of an uncommon variant of APL associated with a t(11;17) resulting in a PLZF-RARalpha fusion protein. This subtype of APL does not appear to respond to ATRA and has a distinctly worse prognosis than t(15;17) APL.
It has been postulated that use of ATRA as an induction agent would decrease the morbidity and mortality of the coagulopathy of APL during induction. However, in a randomized trial of chemotherapy versus ATRA, there was no difference in the severe hemorrhagic complications between the groups. Importantly, though, this study demonstrated that ATRA used as induction or maintenance treatment improves disease-free and overall survival as compared with chemotherapy alone for children with APL. The use of ATRA and chemotherapy (cytarabine and daunomycin) during the treatment of APL has improved the 2-year survival rate from 40% to 70%-80% in both children and adults. It is important that persons with APL be recognized and treated with ATRA and chemotherapy.
Arsenic has also been indicated as an active agent in APL. Multicenter studies evaluating the ideal administration of ATRA and chemotherapy and the role of arsenic are being developed at this time.
Despite second remission induction in about one half of children with acute myeloid leukemia (AML) treated with drugs similar to drugs used in initial induction therapy, the prognosis for a child with recurrent or progressive AML is poor. The selection of further treatment depends on prior treatment as well as individual considerations. Clinical trials, including new chemotherapy and/or biologic agent studies and/or novel bone marrow transplant (autologous, mismatched unrelated donor) programs, should be considered. Consult the PDQ protocol file for a listing of current clinical trials.
Date Last Modified: 10/1999