Issue Archive

In this issue of Blood, Taub et al report improved survival with reduced-intensity therapy and the prognostic significance of end-induction residual disease from the largest prospective trial to date in children with myeloid leukemia of Down syndrome (ML-DS): the Children’s Oncology Group AAML0431 study.¹ 

It is well documented that young children with Down syndrome (DS) have both a 500-fold increased incidence of acute myeloid leukemia (ML-DS) and a decreased tolerance of intensive chemotherapy. In this issue of Blood, Uffmann et al present the results of a large, multicentered, international, nonrandomized trial reducing the etoposide exposure while preserving the excellent outcomes reported in previous trials.¹  This trial builds on international experience demonstrating that most young children with ML-DS may be cured with less intensive therapy, and confirms that there remains a significant subset of patients for whom we have limited therapeutic options.

In this issue of Blood, Gardner et al report results of a phase 1 trial of 45 children and young adults with relapsed or refractory B-lineage acute lymphoblastic leukemia (ALL) who received a T-cell product of defined CD4/CD8 composition that was genetically modified with a CD19-4-1BB:ζ chimeric antigen receptor (CAR) lentiviral vector.¹ 

In this issue of Blood, Miyawaki et al identify the most primitive progenitor cell population that makes only megakaryocytes and platelets in adult humans and show it is expanded in myeloproliferative neoplasms such as essential thrombocythemia (ET).¹  Approximately 10¹¹ platelets are produced on a daily basis in humans, but their exact journey from undifferentiated hematopoietic stem cells (HSCs) is still highly debated. Platelets have the shortest half-life of all blood components and are rapidly recruited when injury occurs, yet have long been thought to be among the cell types to be specified as the furthest from the HSCs in the hematopoietic hierarchy. For several decades, it was understood that differentiation proceeds by a series of binary fates choices, in particular with a common myeloid progenitor (CMP) downstream of HSCs that would give rise to a restricted myeloid progenitor (granulocyte-macrophage progenitor) and to a megakaryocyte-erythrocyte progenitor (MEP). Only downstream of MEPs would unilineage megakaryocyte and unilineage erythrocyte progenitors arise. Recently though, several groups have reported that megakaryocyte and platelet production may not follow this strict hierarchical branching path. Instead, committed megakaryocyte precursors could be found much earlier, either within the HSC^2,-4  or the multipotent progenitor compartment.⁵  An early precursor that exclusively produces human megakaryocytes in humans, however, had not been described.

In this issue of Blood, Fares et al¹ demonstrate that endothelial protein C receptor (EPCR) is a reliable marker of human cord blood (CB) hematopoietic stem cells (HSCs), both from uncultured cells and those expanded with UM171, a pyrimidoindole derivative previously shown to expand CB HSCs.² 

In this issue of Blood, Reshmi et al¹  report a study that defines a protocol for identifying kinase-driven high-risk (HR) features, known as “Ph-like” expression profile, in patients with acute lymphocytic leukemia (ALL). Revealing the underlying genetic aberration allows better prognostication and may point to potential therapeutic options for specific patients. Originally identified in pediatric patients, this Ph-like or kinase-driven ALL (KD-ALL) subtype has also been found to be common among adults.^2,3  The journey to the routine identification of these kinase-activating genetic alternations started 8 years ago and required extensive efforts and use of different laboratory methods to become feasible. The most important take-home message from this work is that the time has come for routine screening for kinase-activating alterations in ALL. Although this study is published before clinical outcome data of the patients enrolled in the Children’s Oncology Group study have matured, the clinical significance of identification of KD-ALL is well established.⁴  Reshmi et al confirm the complexity of the genetic alteration map of these potentially targetable aberrations. The authors also provide a working diagnostic paradigm starting with a simple gene expression screening test, which reliably identifies patients in whom genetic testing for kinase-activating alterations is futile. Of 202 patients whose suggested score for screening was below 0.5, only in 1 was a potentially targetable fusion detected (HOOK3-FGFR1 genes).

In this issue of Blood, Malcovati et al show that somatic mutations can identify patients with unexplained cytopenias who have, or are at a high risk of developing, myeloid malignancies. This study provides clear evidence that supports integration of gene-panel sequencing into routine clinical evaluation of unexplained cytopenias.¹ 

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.