In acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) and/or arsenic trioxide can induce a differentiation syndrome (DS) with massive pulmonary infiltration of differentiating leukemic cells. Because chemokines are implicated in migration and extravasation of leukemic cells, chemokines might play a role in DS. ATRA stimulation of the APL cell line NB4 induced expression of multiple CC-chemokines (CCLs) and their receptors (> 19-fold), resulting in increased chemokine levels and chemotaxis. Induction of CCL2 and CCL24 was directly mediated by ligand-activated retinoic acid receptors. In primary leukemia cells derived from APL patients at diagnosis, ATRA induced chemokine production as well. Furthermore, in plasma of an APL patient with DS, we observed chemokine induction, suggesting that chemokines might be important in DS. Dexamethasone, which efficiently reduces pulmonary chemokine production, did not inhibit chemokine induction in APL cells. Finally, chemokine production was also induced by arsenic trioxide as single agent or in combination with ATRA. We propose that differentiation therapy may induce chemokine production in the lung and in APL cells, which both trigger migration of leukemic cells. Because dexamethasone does not efficiently reduce leukemic chemokine production, pulmonary infiltration of leukemic cells may induce an uncontrollable hyperinflammatory reaction in the lung. IntroductionAcute promyelocytic leukemia (APL) is characterized by a specific t(15;17) chromosomal translocation, which fuses the promyelocytic leukemia (PML) gene on chromosome 15 to the retinoic acid receptor-␣ (RARA) gene on chromosome 17. This translocation results in blockage of terminal granulocytic differentiation at the promyelocytic stage. 1,2 Treatment with high dosage of the RARA ligand all-trans retinoic acid (ATRA) relieves this blockage, resulting in terminal differentiation of the APL blasts. Presently, standard therapy for patients with newly diagnosed APL consists of a combination of ATRA and anthracycline-based chemotherapy, which results in the induction of a complete remission in more than 90% of the patients and a 5-year overall survival rate of more than 80%. [3][4][5][6][7][8][9][10][11] In addition, arsenic trioxide (ATO) treatment has been shown to be highly effective in relapsed APL patients and has also been used successfully as a single agent or in combination with ATRA in newly diagnosed APL patients. [12][13][14][15][16][17][18][19][20][21] Despite the high cure rates, induction mortality is a still a problem in APL. In a large series of 732 APL patients who received ATRA plus idarubicin, induction mortality was 9%. The most common causes of death were hemorrhage, infection, and the differentiation syndrome (DS), formerly known as retinoic acid syndrome. 22 DS is reported in 2.5% to 31% of the APL patients who receive induction therapy with ATRA and/or ATO. [5][6][7]10,14,16,19,20,[23][24][25][26][27][28][29][30] DS is not observed during consolidation o...

In acute myeloid leukemia (AML), aberrant expression and mutations of transcription factors have been correlated with disease outcome. In the present study, we performed expression and mutation screening of GATA2, which is an essential transcription factor for regulation of myeloid lineage determination, in de novo pediatric AML patients. GATA2 mutations were detected in 5 of 230 patients, representing a frequency of 2.2% overall and 9.8% in cytogenetically normal AML. GATA2 expression analysis demonstrated that in 155 of 237 diagnostic samples (65%), GATA2 expression was higher than in normal BM. In complete remission, normalization of GATA2 expression was observed, whereas GATA2 expression levels stayed high in patients with resistant disease. High GATA2 expression at diagnosis was an independent poor prognostic factor for overall survival (hazard ratio [HR] ‫؍‬ 1.7, P ‫؍‬ .045), event-free survival (HR ‫؍‬ 2.1, P ‫؍‬ .002), and disease-free survival (HR ‫؍‬ 2.3, P ‫؍‬ .004). The prognostic impact of GATA2 was particularly evident in specific AML subgroups. In patients with French-American-British M5 morphology, inv(16), or high WT1 expression, significant differences in survival were observed between patients with high versus normal GATA2 expression. We conclude that high GATA2 expression is a novel poor prognostic marker in pediatric AML, which may contribute to better risk-group stratification and risk-adapted therapy in the future.

SummaryIn acute promyelocytic leukaemia (APL), differentiation therapy can be complicated by the development of a differentiation syndrome (DS). Pulmonary infiltration of differentiating leukaemic cells is a key event in the development of DS. Several mediators have been identified that may promote migration and extravasation of differentiating APL cells from the bloodstream into the tissue. Adhesion of APL cells to each other and to the endothelium is induced by upregulation of the expression of adhesion molecules and constitutively active b2-integrins during differentiation therapy. The expression of chemokines and their receptors is significantly upregulated as well. Pulmonary chemokine production can trigger transendothelial migration of differentiating APL cells from the bloodstream into the underlying tissue (initiation phase of DS). Massive production of chemokines by infiltrated APL cells can further enhance transendothelial migration of differentiating APL cells, causing an uncontrollable hyperinflammatory reaction in the lung (aggravation phase), which is not efficiently switched-off by corticosteroids.

Treatment of chronic myeloid leukemia has improved significantly with the introduction of tyrosine kinase inhibitors (TKIs), and treatment guidelines based on numerous clinical trials are available for chronic phase disease. However for CML in the blast phase (CML-BP), prognosis remains poor and treatment options are much more limited. The spectrum of treatment strategies for children and adolescents with CML-BP has largely evolved empirically and includes treatment principles derived from adult CML-BP and pediatric acute leukemia. Given this heterogeneity of treatment approaches, we formed an international panel of pediatric CML experts to develop recommendations for consistent therapy in children and adolescents with this high-risk disease based on the current literature and national standards. Recommendations include detailed information on initial diagnosis and treatment monitoring, differentiation from Philadelphia-positive acute leukemia, subtype-specific selection of induction therapy, and combination with tyrosine kinase inhibitors. Given that allogeneic hematopoietic stem cell transplantation currently remains the primary curative intervention for CML-BP, we also provide recommendations for the timing of transplantation, donor and graft selection, selection of a conditioning regimen and prophylaxis for graft-versus-host disease, post-transplant TKI therapy, and management of molecular relapse. Management according to the treatment recommendations presented here is intended to provide the basis for the design of future prospective clinical trials to improve outcomes for this challenging disease.

Children with primary immunodeficiencies, sickle cell disease and cystic fibrosis are at risk to develop invasive bacterial infections caused by respiratory tract pathogens, in particular Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus. This review article evaluates the role of nasopharyngeal colonization by these pathogens in the high prevalence of respiratory and invasive infections in children with inherited disorders affecting the immune system or the respiratory tract. We conclude that respiratory and invasive diseases that occur in children with primary immunodeficiencies or sickle cell disease are probably a result of increased nasopharyngeal colonization rates compared with healthy children. However, when the inherited disorder is characterized by local airway abnormalities such as in cystic fibrosis, enhanced nasopharyngeal colonization does not seem to play a major role in invasive disease risk. As the evidence for the role of nasopharyngeal colonization in disease risk in these specific patient groups partly comes from experimental studies and animal models, longitudinal studies in children are needed. Detailed understanding of the effect of colonization on the development of respiratory and invasive infections in children with primary immunodeficiencies, sickle cell disease or cystic fibrosis provides a justification for the selective introduction of vaccination and prophylactic antibiotic treatment. Recommendations for the use of (preventive) therapeutic strategies in these patient groups taking into account disease-specific immunologic mechanisms underlying colonization and disease are described.