Treatment outcomes in younger patients with acute myeloid leukemia (AML) have improved, but optimization and new combinations are needed. We assess three combinations in induction and consolidation.
...Younger untreated patients with AML (median age, 49 years; range, 0 to 73 years) were randomly allocated to two induction courses of daunorubicin and cytarabine (DA) with or without etoposide (ADE; n = 1983) or ADE versus fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-Ida; n = 1268), and to amsacrine, cytarabine, etoposide, and then mitoxantrone/cytarabine (MACE-MidAC) or high-dose cytarabine (n = 1,445) 3 g/m(2) or 1.5 g/m(2) (n = 657) in consolidation, and finally to a fifth course (cytarabine) or not (n = 227).
Overall remission rates were similar for DA versus ADE (84% v 86%; P = .14) and ADE versus FLAG-Ida (86% v 85%; P = .7), with more course 1 remissions after FLAG-Ida (77%) reducing relapse (38% v 55%; P < .001) and improving relapse-free survival (45% v 34%; P = .01), overall and in subgroups, but with increased myelosuppression, reducing participation in the consolidation randomization. Overall outcomes were similar between MACE/MidAc and high-dose cytarabine (1.5/3.0 g/m(2)), but cytarabine required less supportive care. MACE/MidAc was superior for high-risk patients. A fifth course provided no benefit. The outcome for recipients of only two FLAG-Ida courses were not different from that with DA/ADE with consolidation.
FLAG-Ida is an effective remission induction treatment, with a high complete remission rate after course 1 and reduced relapse. Consolidation with MACE/MidAc is similar overall to high-dose cytarabine, but superior in high-risk patients. Cytarabine at 1.5 g/m(2) is equivalent to a 3 g/m(2) dose. A fifth course is unnecessary. In patients receiving FLAG-Ida (two courses) and cytarabine (two courses), 8-year survival was 63% for patients with intermediate-risk and 95% for those with favorable-risk disease.
Summary
The Medical Research Council Acute Myeloid Leukaemia 12 (MRC AML12) trial (children) addressed the optimal anthracenedione/anthracycline in induction and the optimal number of courses of ...consolidation chemotherapy. 504 children (<16 years) with AML were randomized between mitoxantrone/cytarabine/etoposide or daunorubicin/cytarabine/etoposide as induction chemotherapy and 270 entered a second randomization between a total of four or five courses of treatment. Ten‐year event‐free (EFS) and overall survival (OS) was 54% and 63% respectively; the relapse rate was 35%. There was no difference in complete remission rate between the induction regimens, but there was a benefit for mitoxantrone with regard to relapse rate 32% vs. 39%; Hazard ratio (HR) 0·73; 95% confidence interval (CI) 0·54, 1·00 and disease‐free survival (DFS; 63% vs. 55%; HR 0·72; 95% CI 0·54, 0·96). However, this did not translate into a better EFS or OS (HR 0·84; 95% CI 0·63, 1·12). Results of the second randomization did not show a survival benefit for a fifth course of treatment (HR 1·01; 95% CI 0·63, 1·62), suggesting a ceiling of benefit for conventional chemotherapy and demonstrating the need for new agents. EFS was superior compared to the preceding trial AML10, partly due to fewer deaths in remission, highlighting the importance of supportive care.
Diagnosis, treatment, response monitoring, and outcome of pediatric acute myeloid leukemia (AML) have made enormous progress during the past decades. Because AML is a rare type of childhood cancer, ...with an incidence of approximately seven occurrences per 1 million children annually, national and international collaborative efforts have evolved. This overview describes these efforts and includes a summary of the history and contributions of each of the main collaborative pediatric AML groups worldwide. The focus is on translational and clinical research, which includes past, current, and future clinical trials. Separate sections concern acute promyelocytic leukemia, myeloid leukemia of Down syndrome, and relapsed AML. A plethora of novel antileukemic agents that have emerged, including new classes of drugs, are summarized as well. Finally, an important aspect of the treatment of pediatric AML--supportive care--and late effects are discussed. The future is bright, with a wide range of emerging innovative therapies and with more and more international collaboration that ultimately aim to cure all children with AML, with fewer adverse effects and without late effects.
Karyotype is an independent indicator of prognosis in acute myeloid leukemia (AML) that is widely applied to risk-adapted therapy. Because AML is rare in children, the true prognostic significance of ...individual chromosomal abnormalities in this age group remains unclear.
This cytogenetic study of 729 childhood patients classified them into 22 subgroups and evaluated their incidence and risk.
Rearrangements of 11q23 were the most frequent abnormality found in approximately 16% of patients, with 50% of these in infants. The outcome for all patients with 11q23 abnormalities was intermediate; no difference was observed for those with t(9;11)(p21-22;q23). The core binding factor leukemias with the translocations t(8;21)(q22;q22) and inv(16)(p13q22) occurred at incidences of 14% and 7%, respectively, predominantly in older children, and their prognosis was favorable. An adverse outcome was observed in patients with monosomy 7, abnormalities of 5q, and t(6;9)(p23;q34). Abnormalities of 3q and complex karyotypes, in the absence of favorable-risk features, have been associated with an adverse outcome in adults, but the results were not significant in this childhood series. However, the presence of 12p abnormalities predicted a poor outcome.
Because the spectrum of chromosomal changes and their risk association seem to differ between children and adults with AML, biologic differences are emerging, which will contribute to the redefinition of risk stratification for different age groups in the future.
Acute myeloid leukemia (AML) develops when there is a block in differentiation and uncontrolled proliferation of myeloid precursors, resulting in bone marrow failure. AML is a clinically, ...morphologically, and genetically heterogeneous disease, and biological differences between adult and childhood AML have been identified. AML comprises 15%–20% of all children <15 years of age diagnosed with acute leukemia. Relapse occurs in up to 40% of children with AML and is the most common cause of death. Relapse arises from leukemic stem cells (LSCs) that persist after conventional chemotherapy. The treatment of AML is challenging, and new strategies to target LSCs are required. The cell surface marker CD33 has been identified as a therapeutic target, and novel anti-CD33 immunotherapies are promising new agents in the treatment of AML. This review summarizes recent developments emphasizing the genetic differences in adult and childhood AML and highlights the rationale for CD33 as a target for therapy in all age groups.
•This review provides a summary of the genetic, biological, and cellular differences between adult and childhood acute myeloid leukemia (AML).•The role of leukemic stem cells in AML is reviewed.•The rationale for anti-CD33 therapy in adult and childhood AML is discussed.
Acute myeloid leukemia (AML) is a heterogenous disease of hematopoietic stem cells (HSCs) and progenitor cells (HSPCs). The pathogenesis of AML involves cytogenetic abnormalities, genetic mutations, ...and epigenetic anomalies. Although it is widely accepted that the cellular biology, gene expression, and epigenetic landscape of normal HSCs change with age, little is known about the interplay between the age at which the cell becomes leukemic and the resultant leukemia. Despite its rarity, childhood AML is a leading cause of childhood cancer mortality. Treatment is in general extrapolated from adult AML on the assumption that adult AML and pediatric AML are similar biological entities. However, distinct biological processes and epigenetic modifications in pediatric and adult AML may mean that response to novel therapies in children may differ from that in adults with AML. A better understanding of the key pathways involved in transformation and how these differ between childhood and adult AML is an important step in identifying effective treatment. This review highlights both the commonalities and differences between pediatric and adult AML disease biology with respect to age.
•This overview covers the major epigenetic mutations and mechanisms contributing to pediatric and adult acute myeloid leukemia (AML).•Different clinical trials with epigenetic implications in ...pediatric and adult AML are summarized.•A rationale for epigenetic therapies in AML is described.
There is a desperate need for new and effective therapeutic approaches to acute myeloid leukemia (AML) in both children and adults. Epigenetic aberrations are common in adult AML, and many novel epigenetic compounds that may improve patient outcomes are in clinical development. Mutations in epigenetic regulators occur less frequently in AML in children than in adults. Investigating the potential benefits of epigenetic therapy in pediatric AML is an important issue and is discussed in this review.
IKAROS family zinc finger 1/IKZF1 is a transcription factor important in lymphoid differentiation, and a known tumor suppressor in acute lymphoid leukemia. Recent studies suggest that IKZF1 is also ...involved in myeloid differentiation. To investigate whether IKZF1 deletions also play a role in pediatric acute myeloid leukemia, we screened a panel of pediatric acute myeloid leukemia samples for deletions of the IKZF1 locus using multiplex ligation-dependent probe amplification and for mutations using direct sequencing. Three patients were identified with a single amino acid variant without change of IKZF1 length. No frame-shift mutations were found. Out of 11 patients with an IKZF1 deletion, 8 samples revealed a complete loss of chromosome 7, and 3 cases a focal deletion of 0.1-0.9Mb. These deletions included the complete IKZF1 gene (n=2) or exons 1-4 (n=1), all leading to a loss of IKZF1 function. Interestingly, differentially expressed genes in monosomy 7 cases (n=8) when compared to non-deleted samples (n=247) significantly correlated with gene expression changes in focal IKZF1-deleted cases (n=3). Genes with increased expression included genes involved in myeloid cell self-renewal and cell cycle, and a significant portion of GATA target genes and GATA factors. Together, these results suggest that loss of IKZF1 is recurrent in pediatric acute myeloid leukemia and might be a determinant of oncogenesis in acute myeloid leukemia with monosomy 7.
Patients with acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21) comprise a novel and distinct biological subgroup. We prospectively screened 1630 ...(84%) patients treated on the UK MRC ALL97 protocol for iAMP21 and herein present demographic, clinical, and survival data on the 28 (2%) children found to harbor this abnormality. They had a common or pre-B ALL immunophenotype, were significantly older (median 9 years vs 5 years), and had a lower white cell count (median 3.9 vs 12.4) compared with children without this abnormality. Notably, patients with iAMP21 had a significantly inferior event-free and overall survival at 5 years compared with other patients: 29% (95% confidence interval CI, 13%-48%) versus 78% (95% CI, 76%-80%) and 71% (95% CI, 51%-84%) versus 87% (95% CI, 85%-88%), respectively. As a result of this 3-fold increase in relapse risk, newly diagnosed patients with iAMP21 recruited to the current UK MRC ALL2003 trial are being treated on the high-risk arm and are considered for bone marrow transplantation in first remission.
Summary
These guidelines address developmental aspects of neonatal haemostasis and thrombosis, the laboratory investigation of the neonate, and the diagnosis and clinical management of haemostatic ...and thrombotic conditions occurring in this period (defined as the first 4 weeks of life following birth). Relevant scientific papers were identified by a systematic literature review from Medline 1975–2000 using index terms which incorporated the various component subjects of these guidelines. Further publications were obtained from the references cited and from reviews known to the members of the working party and to the Haemostasis and Thrombosis Task Force. Evidence and graded recommendations presented in these guidelines are in accordance with the US Agency for Health Care Policy and Research, as described in the Appendix. It will be noted that there is a lack of a strong evidence base for many of the recommendations suggested, as the appropriate clinical and laboratory trials have not been and perhaps never will be undertaken in neonates. Most of the recommendations are therefore of Grade C evidence levels IV: higher levels are mentioned specifically throughout the document when relevant.
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