Bridging to transplant with azacitidine in juvenile myelomonocytic leukemia: a retrospective analysis of the EWOG-MDS study group

Cseh, Annámaria; Niemeyer, Charlotte M.; Yoshimi, Ayami; Dworzak, Michael; Hasle, Henrik; Heuvel‐Eibrink, Marry M. van den; Locatelli, Franco; Masetti, Riccardo; Schmugge, Markus; Groß‐Wieltsch, Ute; Candás, Andrea; Kulozik, Andreas E.; Olcay, Lale; Suttorp, Meinolf; Furlan, Ingrid; Strahm, Brigitte; Flotho, Christian

doi:10.1182/blood-2015-01-619734

Cited by 63 publications

(58 citation statements)

References 9 publications

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“…This makes it possible to evaluate pharmaceuticals with delayed activity, in particular the DNA-hypomethylating agent azacitidine which has recently gained clinical interest for use in JMML. 42,43 In contrast to previous JMML xenotransplantation models, Rag2 -/-γc -/-mice efficiently sustained engrafting JMML cells in the absence of exogenous human GM-CSF. Weekly application of human GM-CSF enhanced myeloid differentiation but did not influence the total level of engraftment or time to leukemia.…”

Section: Discussionmentioning

confidence: 90%

Long-term serial xenotransplantation of juvenile myelomonocytic leukemia recapitulates human disease in Rag2-/- c-/- mice

et al. 2016

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Section: Discussionmentioning

confidence: 90%

Long-term serial xenotransplantation of juvenile myelomonocytic leukemia recapitulates human disease in Rag2-/- c-/- mice

et al. 2016

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“…Therefore, new therapies using molecular-targeting antileukemic drugs and demethylating agents are currently being investigated. 2,12 In the long run, these approaches might either complement or (partially) replace current HSCT approaches. However, further advances in the treatment of JMML will require a better understanding of JMML disease biology.…”

Section: Cd38mentioning

confidence: 99%

LIN28B overexpression defines a novel fetal-like subgroup of juvenile myelomonocytic leukemia

Helsmoortel

Bresolin

Lammens

et al. 2016

Blood

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Key Points• LIN28B is overexpressed in about half of juvenile myelomonocytic leukemia patients and defines a novel fetal-like disease subgroup. • LIN28B expression is correlated with high fetal hemoglobin levels and the absence of monosomy 7.Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive stem cell disease of early childhood. RAS activation constitutes the core component of oncogenic signaling. In addition, leukemic blasts in one-fourth of JMML patients present with monosomy 7, and more than half of patients show elevated age-adjusted fetal hemoglobin (HbF) levels. Hematopoietic stem cell transplantation is the current standard of care and results in an event-free survival rate of 50% to 60%, indicating that novel molecular-driven therapeutic options are urgently needed. Using gene expression profiling in a series of 82 patient samples, we aimed at understanding the molecular biology behind JMML and identified a previously unrecognized molecular subgroup characterized by high LIN28B expression. LIN28B overexpression was significantly correlated with higher HbF levels, whereas patients with monosomy 7 seldom showed enhanced LIN28B expression. This finding gives a biological explanation of why patients with monosomy 7 are rarely diagnosed with high age-adjusted HbF levels. In addition, this new fetal-like JMML subgroup presented with reduced levels of most members of the let-7 microRNA family and showed characteristic overexpression of genes involved in fetal hematopoiesis and stem cell self-renewal. Lastly, high LIN28B expression was associated with poor clinical outcome in our JMML patient series but was not independent from other prognostic factors such as age and age-adjusted HbF levels. In conclusion, we identified elevated LIN28B expression as a hallmark of a novel fetal-like subgroup in

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“…In contrast, there are few published data on the use of these agents in children, primarily limited to the use of 5-azacitidine as a bridge to HSCT in children with juvenile myelomonocytic leukemia[124] and of decitabine as a bridge to HSCT in a few children with refractory or relapsed AML[125]. Although likely the agents of choice in this setting, hypomethylating agents should be used cautiously in the setting of inherited BMF due to a potential risk of profound myelosuppression, requiring close monitoring for cytopenias and a prompt and established plan for HSCT rescue.…”

Section: Pre-transplant Therapy In Patients With Mds/aml Secondary Tomentioning

confidence: 99%

Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults

Babushok

Bessler

Olson

2015

Leukemia & Lymphoma

104

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Myelodysplastic syndrome (MDS) is a clonal blood disorder characterized by ineffective hematopoiesis, cytopenias, dysplasia and an increased risk of acute myeloid leukemia (AML). With the growing availability of clinical genetic testing, there is an increasing appreciation that a number of genetic predisposition syndromes may underlie apparent de novo presentations of MDS/AML, particularly in children and young adults. Recent findings of clonal hematopoiesis in acquired aplastic anemia add another facet to our understanding of the mechanisms of MDS/AML predisposition. As more predisposition syndromes are recognized, it is becoming increasingly important for hematologists and oncologists to have familiarity with the common as well as emerging syndromes, and to have a systematic approach to diagnosis and screening of at risk patient populations. Here, we provide a practical algorithm for approaching a patient with a suspected MDS/AML predisposition, and provide an in-depth review of the established and emerging familial MDS/AML syndromes caused by mutations in the ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72 genes. Finally, we discuss recent data on the role of somatic mutations in malignant transformation in acquired aplastic anemia, and review the practical aspects of MDS/AML management in patients and families with predisposition syndromes.

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Bridging to transplant with azacitidine in juvenile myelomonocytic leukemia: a retrospective analysis of the EWOG-MDS study group

Cited by 63 publications

References 9 publications

Long-term serial xenotransplantation of juvenile myelomonocytic leukemia recapitulates human disease in Rag2-/- c-/- mice

Long-term serial xenotransplantation of juvenile myelomonocytic leukemia recapitulates human disease in Rag2-/- c-/- mice

LIN28B overexpression defines a novel fetal-like subgroup of juvenile myelomonocytic leukemia

Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults

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