Transient leukemia in newborns with Down syndrome

Children with Down syndrome (DS) have a 10- to 20-fold increased risk of developing leukemia, particularly acute megakaryocytic leukemia. Newborns with DS or trisomy 21 mosaicism may exhibit a particularly unique form of leukemia that historically has been associated with a high rate of spontaneous remission. This transient leukemia (TL) has been shown to be a clonal proliferation of blast cells exhibiting megakaryocytic features. Its true incidence remains to be determined. At presentation, many infants are clinically well with only an incidental finding of abnormal blood counts and circulating blasts in the peripheral blood. However, in approximately 20% of cases, the disease is severe and life-threatening, manifesting as hydrops faetalis, multiple effusions, and liver or multi-organ system failure resulting in death. Of those children who enter a spontaneous remission, 13-33% have been found to develop subsequent acute megakaryoblastic leukemia, usually within the first 3 years of life, which if left untreated is fatal. This unique TL of the DS newborn has been the subject of recent clinical cooperative group trials as well as many biological and genetic research efforts. We summarize here the known clinical, biological, and cytogenetic features of TL associated with DS.     

Acute megakaryoblastic leukemia in children identified by immunological marker studies

Acute megakaryoblastic leukemia (AMkL), defined by the presence of the platelet-associated glycoprotein IIb/IIIa complex on malignant cells, was diagnosed in 4 (4%) of 103 consecutive children with untreated acute leukemia or 4 (21%) of 19 children with acute nonlymphoblastic leukemia (ANLL). Particular features in the four children with AMkL were an age below 12 months at diagnosis (two patients), the absence of a significant hepatosplenomegaly (three patients), a leukocyte count below 20 x 10(9)/L with only a few blast cells in the peripheral blood (four patients), a technically difficult bone marrow aspiration (three patients), the presence of many megakaryocytes in marrow particles (two patients), and an inconclusive cytochemistry (four patients). The four children with AMkL were treated according to protocols for ANLL and a complete remission was obtained in all patients. One patient died from relapse after 3 months, one patient is a long-term survivor (38+ months), and two patients still on chemotherapy are disease-free for 11+ and 13+ months.     

Bone marrow fibrosis and radiological changes of the long bones in children with acute megakaryocytic leukaemia

The diagnosis of acute megakaryocytic leukaemia (AMkL) may be difficult to establish owing to difficulties in obtaining adequate bone marrow aspirates secondary to bone marrow fibrosis. We describe three children without Down's syndrome under 2 y of age with AMkL. Although none of the patients had the non-random t (1;22) (p13;q13) translocation, bone marrow cells from all patients exhibited chromosome abnormalities with complex karyotypes, including trisomy 21 in two cases. All patients had profound bone marrow fibrosis and characteristic lamellar diaphyseal radiological changes of the long bones.     

A rare case of GATA1 negative chemoresistant acute megakaryocytic leukemia in an 8‐month‐old infant with trisomy 21

Children with Down syndrome (DS) have a unique form of acute megakaryocytic leukemia (AMKL) characterized by the presence of mutations in the GATA1 gene leading to increased chemosensitivity and a favorable outcome. We describe an 8‐month‐old male with DS who was diagnosed with AMKL without a mutation in the GATA1 gene. The patient was treated according to the DS‐AML‐regimen but his disease progressed and he succumbed 9 months later. This rare case of DS AMKL without a GATA1 mutation with an unfavorable outcome suggests that GATA1 testing may play a useful role in initial stratification. Pediatr Blood Cancer 2010;54:1048–1049 © 2010 Wiley‐Liss, Inc.     

Recent advances in the understanding of transient abnormal myelopoiesis in Down syndrome

Neonates with Down syndrome (DS) have a propensity to develop the unique myeloproliferative disorder, transient abnormal myelopoiesis (TAM). TAM usually resolves spontaneously in ≤3 months, but approximately 10% of patients with TAM die from hepatic or multi‐organ failure. After remission, 20% of patients with TAM develop acute myeloid leukemia associated with Down syndrome (ML‐DS). Blasts in both TAM and ML‐DS have trisomy 21 and GATA binding protein 1 (GATA1) mutations. Recent studies have shown that infants with DS and no clinical signs of TAM or increases in peripheral blood blasts can have minor clones carrying GATA1 mutations, referred to as silent TAM. Low‐dose cytarabine can improve the outcomes of patients with TAM and high white blood cell count. A number of studies using fetal liver cells, mouse models, or induced pluripotent stem cells have elucidated the roles of trisomy 21 and GATA1 mutations in the development of TAM. Next‐generation sequencing of TAM and ML‐DS patient samples identified additional mutations in genes involved in epigenetic regulation. Xenograft models of TAM demonstrate the genetic heterogeneity of TAM blasts and mimic the process of clonal selection and expansion of TAM clones that leads to ML‐DS. DNA methylation analysis suggests that epigenetic dysregulation may be involved in the progression from TAM to ML‐DS. Unraveling the mechanisms underlying leukemogenesis and identification of factors that predict progression to leukemia could assist in development of strategies to prevent progression to ML‐DS. Investigation of TAM, a unique pre‐leukemic condition, will continue to strongly influence basic and clinical research into the development of hematological malignancies.     

Acute lymphoblastic leukemia in patients with Down syndrome with a previous history of acute myeloid leukemia

Patients with Down syndrome (DS) are predisposed to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in early and later childhood, respectively, but rarely experience both. We herein discuss four patients with DS with ALL and a history of AML who were treated with various chemotherapies, one of whom later received a bone marrow transplantation. Three patients survived and remain in remission. One patient died of fulminant hepatitis during therapy. No common cytogenetic abnormalities in AML and ALL besides constitutional +21 were identified, indicating that the two leukemia types were independent events. However, the underlying pathomechanism of these conditions awaits clarification.     

Phagocytic activity and expression of myeloid-associated cell surface antigens by blast cells in acute lymphoblastic leukemia

The malignant cells of patients with acute lymphoblastic leukemia (ALL) rarely show phagocytic activity. In this retrospective survey, blasts from 7 of 196 patients with newly diagnosed ALL demonstrated phagocytic activity toward platelets and erythrocytes. The morphology and cytochemical staining properties of the cells were typical of ALL. Immunophenotyes were those of common ALL (CALLA+, HLA-DR+) for six patients and of pre-B-cell ALL (positive cytoplasmic immunoglobulin) for one. However, blast cells from six of the seven patients also reacted with myeloid-associated monoclonal antibodies (MCS.2 and/or SJ-D1). The wide overlap in the percentages of blasts expressing CALLA and those expressing myeloid-associated antigens suggests that some cells possessed both lymphoid- and myeloid-associated surface antigens. By a dual staining technique, two patients tested had blasts expressing antigens of both lineages. Each child achieved a complete remission after treatment with agents effective for ALL and remains in remission for 13+ to 20+ months. These morphologic and immunologic findings may define a distinct subtype of acute leukemia.     

Transient abnormal myelopoiesis in non‐Down syndrome neonate

We encountered a case of neonatal acute megakaryoblastic leukemia not associated with Down syndrome (DS). Molecular cytogenetic analysis of leukemic blast cells indicated that increased blast cell status was caused by transient abnormal myelopoiesis with trisomy 21 and GATA1 mutation. Based on these molecular cytogenetic data, intensive chemotherapy was avoided, and the patient was successfully cured with low‐dose cytarabine. Morphologically, leukemic blast cells of acute megakaryoblastic leukemia in a non‐DS neonate are indistinguishable from a blast cell of transient abnormal myelopoiesis. The possibility of transient abnormal myelopoiesis should be carefully considered before intensive chemotherapy is adopted.     

Expression of myeloid differentiation antigens in acute nonlymphocytic leukemia: Increased concentration of CD33 antigen predicts poor outcome—A report from the childrens cancer study group

Ninety-eight cryopreserved specimens of acute nonlymphocytic leukemia (ANLL) cells obtained at initial diagnosis of children enrolled on the Childrens Cancer Study Group 251 protocol (CCG 251) were examined by indirect immunofluorescence using four monoclonal antibodies to myeloid differentiation antigens. The relationship between the level of differentiation of ANLL cells as determined by their antigen phenotype and the clinical outcome of treatment, including complete remission (CR) rate, survival, and event-free survival, was evaluated. Most leukemic specimens were determined to express the CD33 antigen (L4F3), a 67-kD protein. Because the level of differentiation of normal myeloid cells is reflected by the concentration of the CD33 antigen expressed, samples were categorized as CD33-bright (immature) versus CD33-dull (mature). Patients with CD33-bright leukemic blasts had a marginally inferior CR rate to those with CD33-dull blasts (P = 0.08). With respect to survival and event-free survival, there was a significantly inferior outcome in the CD33-bright patients (P = 0.04 and P = 0.06, respectively). Reactions of ANLL with anti-CD15 antibody (1G10), anti-CD36 antibody (5F1), or anti-CD17 antibody (T5A7) did not predict clinical outcome. This study indicates that patients whose ANLL blasts displayed the CD33 antigen in an amount associated with immature myeloid cells experienced a worse outcome than patients with ANLL blasts that expressed a phenotype associated with more mature cells. © 1992 Wiley-Liss, Inc.     

VP 16–213 and cyclophosphamide in the treatment of refractory acute nonlymphocytic leukemia with monocytic features

The treatment of refractory acute nonlymphocytic leukemia remains a major clinical problem in leukemia therapy. VP 16–213 is an investigational agent that may have specificity for monocytic blasts, and the combination of VP 16–213 and cyclophosphamide is synergistic in experimental leukemia. Seven patients with highly refractory acute nonlymphocytic leukemia, which demonstrated monocytic features, were treated with a combination of VP 16–213 and cyclophosphamide after they had failed to respond to multiple courses of intensive induction regimens. Three complete remissions and one partial remission were achieved. The times to complete remission were 21, 23, and 34 days. The durations of complete remission were 5, 9, and 12+ months. Myelo-suppression was the most common side effect; one patient experienced nausea and stomatitis. There were no documented infections or hemorrhage, and no one died as a result of therapy. This combination is both well tolerated and effective in the treatment of refractory leukemia with monocytic features.     

L-asparaginase used with cytosine arabinoside in treatment of childhood acute lymphocytic leukemia refractory to vincristine and prednisone

Eleven patients with acute lymphocytic leukemia in relapse were treated with L-asparaginase and cytosine arabinoside (1-β-D-arabinofuranosylcytosine) in induction therapy and the same drugs plus cyclophosphamide in maintenance therapy. Three patients had complete remissions lasting 6, 16, and 78+ weeks. One patient experienced partial remission and four had decreased bone marrow or peripheral blasts but were not clinically improved. The responses, which were brief, lasted 1-16 weeks with one exception of 78+ weeks. Four patients had allergic reactions to L-asparaginase that were unpredictable with assays of antibodies against L-asparaginase.     

Comparison of childhood myelodysplastic syndrome, AML FAB M6 or M7, CCG 2891: report from the Children's Oncology Group

BACKGROUND: Myelodysplastic syndromes (MDS), acute erythroleukemia (FAB M6), and acute megakaryocytic leukemia (FAB M7) have overlapping features. PROCEDURE: Children without Down syndrome or acute promyelocytic leukemia who were newly diagnosed with primary myelodysplastic syndrome or acute myeloid leukemia (AML) M6 or M7 were compared to children with de novo AML M0-M5. All children were entered on the Children's Cancer Group therapeutic research study CCG 2891. RESULTS: The presentation and outcomes of the 132 children diagnosed with MDS (60 children), AML FAB M6 (19 children), or AML FAB M7 (53 children) were similar. Children with AML FAB M7 were diagnosed at a significantly younger age (P = 0.001). Children with MDS, M6, or M7 had significantly lower white blood cell (WBC) counts (P = 0.001), lower peripheral blast counts (P < 0.001), and an increased frequency of -7/7q- (P = 0.003) at presentation. All three groups had significantly inferior overall survival (OS) (P < 0.001) and event free survival (P < 0.001) compared with the 748 children diagnosed with AML FAB M0-M5 when assessed from entry on study. This poor survival was largely attributable to induction death and failure. However, when assessed from successful completion of induction therapy, the 5-year OS (P = 0.090)(49.1 vs. 56.9%) and disease-free survival (DFS) (P = 0.113)(38.0 vs. 46.3%) therapy were not significantly different from other children with AML. CONCLUSIONS: Childhood AML FAB M6 and AML M7 resemble MDS in presentation, poor induction success rates, and outcomes.     

Immunodiagnosis of childhood all: Problems associated with the use of peripheral blood alone

The immunologic classification of acute lymphoblastic leukemia (ALL) based solely on peripheral blood (PB) cell phenotypes may lead to conflicting results. This was demonstrated by the simultaneous assay of five immunologic markers on PB and bone marrow (BM) cells from 13 children with untreated ALL. We assayed erythrocyte (E) rosettes at 4°C and 37°C, presence of membrane Ig(mIg), and binding of antisera raised against thymus (T), and E^? ALL blasts, respectively. At diagnosis, the PB of these children contained > 90% lymphoid cells with 0–48% E rosettes and 1-84% cells with T antigen(s). Of 7 children with WBC < 10,000/cu mm there were 4 who had 20% or more E rosettes and T-antigen-positive cells. Of 6 children with WBC > 10,000/cu mm there were only 2 who had more than 20% E rosettes and T-antigen-positive cells. Based on examination of PB alone, six children may have been classified as having T-like ALL. However, these results were due to the presence of circulating normal T lymphocytes, and assay of BM cells established that only one of the 13 children had T-like ALL and none had B-cell ALL. Bone marrow blasts from 12 patients did not form rosettes at 37°C, did not have mIg, and did not react with anti-T serum. A high proportion of BM blasts from these 12 patients (39-96%) did react with antiserum against E^? ALL blasts. Of these 12 patients 11 had a higher proportion of E^? ALL antiserum-positive blasts in the BM than PB. Thus, immunologic classification of ALL should be based on the study of BM blasts, or both PB and BM cells.     

Transient myeloproliferative disorder in Down's syndrome: three cases with megakaryocytic markers.

In this paper we describe three infants with Down's syndrome and transient myeloproliferative disorder. The blast cells of all three displayed positive megakaryocytic markers. One patient developed acute megakaryoblastic leukemia in his second year, with blasts identical to those of the initial episode. The other two cases remain well at 12 and 15 months of age.     

Acute myeloid leukemia in children: Current status and future directions

Acute myeloid leukemia (AML) accounts for 25% of pediatric leukemia and affects approximately 180 patients annually in Japan. The treatment outcome for pediatric AML has improved through advances in chemotherapy, hematopoietic stem cell transplantation (HSCT), supportive care, and optimal risk stratification. Currently, clinical pediatric AML studies are conducted separately according to the AML subtypes: de novo AML, acute promyelocytic leukemia (APL), and myeloid leukemia with Down syndrome (ML‐DS). Children with de novo AML are treated mainly with anthracyclines and cytarabine, in some cases with HSCT, and the overall survival (OS) rate now approaches 70%. Children with APL are treated with an all‐trans retinoic acid (ATRA)‐combined regimen with an 80–90% OS. Children with ML‐DS are treated with a less intensive regimen compared with non‐DS patients, and the OS is approximately 80%. HSCT in first remission is restricted to children with high‐risk de novo AML only. To further improve outcomes, it will be necessary to combine more accurate risk stratification strategies using molecular genetic analysis with assessment of minimum residual disease, and the introduction of new drugs in international collaborative clinical trials.     

Establishment of leukaemia cell lines and their significance for clinical and experimental oncology (author's transl)]

Permanent in vitro growing leukemic cell lines have been established from all types of immunologically classified childhood leukemias. Essential characteristics of primary blasts and cultured cells are identical. In contrast to lymphoblastoid, non-leukemic cell lines, the Epstein-Barr-virus specific nuclear angiten (EBNA) is not detected. Up to now 8 Non-B-non-T cell lines (6 of them were derived from children with acute lymphoblastic leukemia, 2 from patients with chronic myeloid leukemia), 8 T-lines and one B-line have been established. Three Non-B-non-T lines from children with acute lymphoblastic leukemia (KM-3, RU-3, MH-3) and one T-cell line (JM) were cultivated by ourselves. Cultured blasts represent a pure tumor material which can be propagated in large quantities. Leukemic cell lines reveal a new approach for the search after leukemia-associated proteins and represent another possibility for the experimental investigation of the etiology of leukemia.     

Blinatumomab activity in a patient with Down syndrome B‐precursor acute lymphoblastic leukemia

Persistent minimal residual disease (MRD) after consolidation may indicate chemotherapy insensitivity in B‐precursor acute lymphoblastic leukemia (BP‐ALL). Given the strong association of MRD and outcome in non‐Down syndrome (non‐DS) BP‐ALL, it is likely that MRD levels are also of prognostic significance in DS BP‐ALL. We report here the successful use of blinatumomab, a bispecific T‐cell engager antibody construct, in a patient with DS BP‐ALL and persistent MRD at the end of consolidation. Blinatumomab has been shown to have excellent results in patients with relapsed/refractory BP‐ALL. This patient had no significant toxicity and achieved MRD negativity after only one cycle of blinatumomab.