Dirk Reinhardt

Treatment with all-trans retinoic acid in acute promyelocytic leukemia reduces early deaths in children

Abstract. All-trans retinoic acid (ATRA) is a known inducer of differentiation in acute promyelocytic leukemia. To improve the outcome of children with acute promyelocytic leukemia, ATRA has been applied since 1994 as an additional induction element inthe AML-BFM 93 study. In a retrospective study, we compared 22 children treated with ATRA (median age: 9.3xa0years; range: 1.8–16.3) with 22 patients receiving conventional therapy (median age: 12.3xa0years; range: 3.2–16.7). Twenty-one of the children achieved complete remission. Only one patient died early from bleeding complications after 3xa0days administration of ATRA. In the control group, seven early deaths occurred (Fisher exact test; p<0.04). Two children died from intracerebral hemorrhages. Two patients suffered from sepsis during aplasia after induction therapy, and one child did not respond to treatment. The 5-year overall survival (OS) and event-free survival (EFS) of the children who received ATRA followed by chemotherapy were significantly bettercompared with conventionally treated children [OS: 0.87±0.9 vs 0.45±0.11, p (log rank) <0.003; EFS: 0.76±0.11 vs 0.43±0.11 p (log rank) <0.02]; the median observation time was 2.8xa0years (19–76xa0months). However, nearly all children suffered from common side effects such as headache, fever, joint, muscle and bone pain, weight gain, or dermatitis. In three patients, a retinoic acid syndrome was observed. Interruption of ATRA treatment and application of dexamethasone, necessary in 12 children, controlled theadverse effects. ATRA treatment could be resumed in 18 patients. In conclusion, ATRA treatment during induction could avoid early deaths in children with acute promyelocytic leukemia with considerable but manageable toxic side effects.

Immunophenotypic differences between diagnosis and relapse in childhood AML: Implications for MRD monitoring

Determination of antigen expression patterns is, in addition to morphologic analysis, essential to the diagnosis of acute myeloid leukemia (AML). The present study was performed to determine (a) the degree of changes in immunophenotype and their consequences on the monitoring of minimal residual disease (MRD) in childhood AML and (b) whether certain clusters of changes in antigen expression patterns exist between diagnosis and relapse.

Longitudinal evaluation of early and late anthracycline cardiotoxicity in children with AML.

Anthracyclines are effective antineoplastic drugs in acute myelogenous leukemia (AML). However, their use is limited by cardiomyopathy, which occurs in children already at cumulative doses of 300 mg/m2 (given as daunorubicin equivalent).

Different types of NPM1 mutations in children and adults: evidence for an effect of patient age on the prevalence of the TCTG-tandem duplication in NPM1-exon 12

Different types of NPM1 mutations in children and adults: evidence for an effect of patient age on the prevalence of the TCTG-tandem duplication in NPM1 -exon 12

Janus kinase mutations in the development of acute megakaryoblastic leukemia in children with and without Down's syndrome

Janus kinase mutations in the development of acute megakaryoblastic leukemia in children with and without Downs syndrome

Primary myelosarcomas are associated with a high rate of relapse: report on 34 children from the acute myeloid leukaemia-Berlin-Frankfurt-Münster studies.

Primary myelosarcomas are rare manifestations of acute myeloid leukaemia (AML) that precede bone marrow involvement. Out of 744 children observed during the AML–Berlin–Frankfurt–Münster (BFM) studies 87 and 93, 34 children presented with extramedullar myelosarcomas and no blasts (nu2003=u200321; 2·8%), or a low blast count (nu2003=u200313; 1·7%) in the bone marrow. Owing to the initially mild and variable symptoms, in some children (nu2003=u200312) diagnostic procedures were delayed and treatment intensity was reduced. At 0·65u2003±u20030·13, the cumulative incidence of relapse was significantly higher than in other AML patients (0·28u2003±u20030·02). The 5‐year event‐free survival was 0·19u2003±u20030·08 (compared with 0·48u2003±u20030·02 in AML‐BFM studies 87/93; P(log rank)u2003<u20030·03). Overall, 18 out of 34 patients died from disease (estimated 5u2003year survival 0·44u2003±u20030·09 compared with 0·55u2003±u20030·02 in the AML‐BFM‐studies 87/93; P(log rank)u2003=u20030·35, n.s.). An early diagnostic workup is needed in children with unusual skin lesions or tumours, considering myelosarcoma as a primary manifestation of AML. Intensive AML‐specific chemotherapy is recommended soon after diagnosis.

Prospective Validation of a New Method of Monitoring Minimal Residual Disease in Childhood Acute Myelogenous Leukemia

Purpose: This study evaluated the prognostic impact of a novel, simple, and standardized assay for monitoring minimal residual disease (MRD) in pediatric acute myelogenous leukemia (AML). Experimental Design: The expression of seven leukemia-associated genes (WT1, PRAME, CCL23, GAGED2, MSLN, SPAG6, and ST18) was measured by TaqMan Low Density Arrays in 112 patients and 52 healthy controls. Patients were treated according to the multicenter study AML-BFM 2004. Samples were collected prospectively at standard time points. The laboratory that measured MRD was blinded to patient outcome. Results: Relapse-free survival (RFS) was 95% (N = 19; SE = 5%) if expression of all genes was down to normal on day 15, 63% (N = 41; SE = 8%) if expression was normalized on day 28, and 38% (N = 21; SE = 11%) in patients who still showed elevated expression on day 28. The prognostic impact of MRD remained significant (P = 0.002) when patients were stratified for the AML-BFM 2004 risk group. Multivariate analysis identified the MRD risk group and day 28 cytology as the only independent prognostic factors. Patients with a cytologic nonremission on day 28, which was confirmed by MRD, had a dismal prognosis. Only 1 out of 8 patients survived without relapse. Conclusions: This novel method of monitoring MRD has a strong prognostic impact that is independent from established risk factors in childhood AML. Clin Cancer Res; 21(6); 1353–9. ©2014 AACR.

Spontaneous complete and sustained remission of a rearrangement CBP (16p13)-positive disseminated congenital myelosarcoma

Dear Sir, Congenital myeloid neoplasms may occur as acute myeloid leukemia (AML) or as myelosarcoma, e.g., as subcutaneous infiltrates. In this age group, pathophysiology and prognosis are completely different from diseases occurring later in life. Besides the transitory myeloproliferative disorder (TMD) of Down syndrome, AMLs in neonates may also regress spontaneously within a few weeks. However, therapy-refractory progress or fatal outcome have also been reported [1, 3, 5]. At present, data are insufficient to predict the prognosis of individual cases [1, 3, 5]. Here, we present a case of congenital disease showing the translocation (8;16)(p11;p13) including a rearrangement of the CBP (16p13) gene, with a subcutaneous and epidural myelosarcoma. Within several months, it resolved spontaneously. After birth, the girl presented with multiple blueish, partially prominent skin infiltrates on her forehead, trunk, and extremities, with a maximum diameter of 2 cm. Otherwise, the clinical status was normal. Blood count, uric acid, lactic dehydrogenase (LDH), transaminases, coagulation parameters, and bone marrow morphology, including immunocytology, and cytogenetics, were normal. Magnetic resonance imaging (MRI) of the head showed an epidural, subperiostal, well-vascularized process of 2.5×3 cm, with irregular structure of the temporal bone (Fig. 1a). Skin biopsy, spanning from epidermis to subcutaneous fat, showed a monotonous infiltrate of monocytoid blasts (Fig. 1b), which were positive for CD68, CD45, and vimentin and negative for S100 protein, CD1a, CD1b, and T-cell markers. Further, lysozyme, esterase, and irregularly myeloperoxidase were positive. The proliferation marker KiS5 was high. A biopsy from the temporal bone showed a similar, partially necrotizing infiltrate. Cytogenetic and molecular genetic examination revealed a translocation (8;16)(p11;p13), suggesting the presence of a fusion between the MOZ and CBP genes, which was confirmed by fluorescent in situ hybridization (FISH). Beginning during the first days of life, the skin infiltrates regressed spontaneously within weeks, with the last lesion disappearing at around 3 months. The intracranial infiltrate had disappeared after 1 year. Five years later, the girl still is in complete continuous remission and developing normally. The constellation of our patient, disseminated congenital extramedullary myelosarcoma with translocation (8;16) (p11;p13) and CBP (16p13) gene rearrangement, has not yet been described. Primary isolated myelosarcoma is found in 2-8% of pediatric AML patients [1, 3, 5]. Especially in infants, skin infiltrates are most typical, followed by orbital and lymph node sites [1]. Relapse-free survival is significantly lower in isolated myelosarcoma than in other AML patients. This may be due to insufficient initial therapy, since progress to overt AML occurred in nearly all patients who did not C. F. Classen (*) . K.-M. Debatin University Children’s Hospital Ulm, Prittwitzstr.43, 89070 Ulm, Germany e-mail: cfclassen@gmx.de Tel.: +49-731-5027790 Fax: +49-731-5026685

Minimising the Long-Term Adverse Effects of Childhood Leukaemia Therapy

Malignancies in childhood occur with an incidence of 13–14 per 100 000 children under the age of 15 years. Acute lymphoblastic leukaemia with an incidence of 29% is the most common paediatric malignancy, whereas acute myeloid leukaemias account for about 5%. The treatment of acute leukaemias consists of sequential therapy cycles (induction, consolidation, intensification, maintenance therapy) with different cytostatic drugs over a time period of up to 1.5–3 years. Over the last 25 years of clinical trials, a significant rise in the rate of complete remissions as well as an increase in long-term survival has been achieved. Therefore, growing attention is now focused on the long-term effects of anti-leukaemic treatment.Several cytostatic drugs administered in the treatment of acute leukaemia in childhood are known to cause long-term adverse effects. Anthracyclines may induce chronic cardiotoxicity, alkylating agents are likely to cause gonadal damage and secondary malignancies and the use of glucocorticoids may cause osteonecrosis. Most of the long-term adverse effects have not been analysed systematically.Approaches to minimising long-term adverse effects without jeopardising outcome have included: (i) the design of new drugs such as a liposomal formulation of anthracyclines, the development of anthracycline-derivates with lower toxicity, the development of cardioprotective agents or, more recently, the use of targeted therapy; (ii) alternative administration schedules like continuous infusion or timed sequential therapy; and (iii) risk group stratification by the monitoring of minimal residual disease.Several attempts have been made to minimise the cardiotoxicity of anthracyclines: decreasing concentrations delivered to the myocardium by either prolonging infusion time or using liposomal formulated anthracyclines or less cardiotoxic analogues, or the additional administration of cardioprotective agents. The advantage of these approaches is still controversial, but there are ongoing clinical trials to evaluate the long-term effects. The use of new diagnostic methods, such as diagnosis of minimal residual disease, which allow reduction or optimisation of dose, offer potential advantages compared with conventional treatment in terms of reducing the risk of severe long-term adverse effects. Most options for minimising long-term adverse effects have resulted from theoretical models and in vitro studies, but only some of the modalities such as the use of dexrazoxane, the continuous infusion of anthracyclines or timed sequential therapy, have been evaluated in prospective, randomised studies in patients. Future approaches to predict severe toxicity may be based upon pharmacogenetics and gene profiling.

Coexpression of Multiple ABC-Transporters is Strongly Associated with Treatment Response in Childhood Acute Myeloid Leukemia

To analyze whether expression of ABC‐transporters is associated with remission rate and long‐term outcome in a prospective clinical trial of childhood acute myeloid leukemia (AML).