Atypical Chronic Myeloid Leukemia: New Developments from Molecular Diagnosis to Treatment

Atypical Chronic Myeloid Leukemia, BCR-ABL1 negative (aCML) is a rare hematological entity, included in the group of myelodysplastic (MDS)/myeloproliferative (MPN) overlap syndromes. It is characterized by an aggressive course, a high rate of acute myeloid leukemia (AML) transformation, and a dismal outcome. The clinical presentation includes splenomegaly and leukocytosis with neutrophilia and left-shifted granulocytosis accompanied by granulocytic dysplasia and sometimes multilineage dysplasia. In past years, the disease incidence was likely underestimated, as diagnosis was only based on morphological features. Recently, the improving knowledge in the molecular biology of MDS/MPN neoplasms has made it possible to distinguish aCML from other overlapping syndromes, basing on next generation sequencing. Among the most commonly mutated genes, several involve the Jak-STAT, MAPK, and ROCK signaling pathways, which could be actionable with targeted therapies that are already used in clinical practice, opening the way to tailored treatment in aCML. However, currently, there are few data available for small samples, and allogeneic transplant remains the only curative option for eligible patients.

Download Full-text

Atypical Chronic Myeloid Leukemia: Where Are We Now?

International Journal of Molecular Sciences ◽

10.3390/ijms21186862 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6862

Author(s):

Elena Crisà ◽

Maura Nicolosi ◽

Valentina Ferri ◽

Chiara Favini ◽

Gianluca Gaidano ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Treatment Options ◽

Myeloproliferative Neoplasm ◽

High Rate ◽

Molecular Profile ◽

Poor Survival ◽

Myeloid Neoplasms ◽

Atypical Chronic Myeloid Leukemia ◽

Generation Sequencing

Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with a high rate of transformation to acute myeloid leukemia, and poor survival. Until now, the diagnosis has been based on morphological grounds only, possibly making the real frequency of the disease underestimated. Only recently, new insights in the molecular biology of MDS/MPN syndromes have deepened our knowledge of aCML, enabling us to have a better molecular profile of the disease. The knowledge gleaned from next generation sequencing has complemented morphologic and laboratory WHO criteria for myeloid neoplasms and can provide greater specificity in distinguishing aCML from alternative MDS/MPN or MPNs. The most commonly mutated genes (>20%) in aCML are SETBP1, ASXL1, N/K-RAS, SRSF2, and TET2, and less frequently (< 10%) CBL, CSFR3, JAK2, EZH2, and ETNK1. Several of these mutations affect the JAK-STAT, MAPK, and ROCK signaling pathways, which are targetable by inhibitors that are already in clinical use and may lead to a personalized treatment of aCML patients unfit for allogeneic transplant, which is currently the only curative option for fit patients. In this review, we present two emblematic clinical cases and address the new molecular findings in aCML and the available treatment options.

Download Full-text

How I treat atypical chronic myeloid leukemia

Blood ◽

10.1182/blood-2016-08-693630 ◽

2017 ◽

Vol 129 (7) ◽

pp. 838-845 ◽

Cited By ~ 25

Author(s):

Jason Gotlib

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Myeloproliferative Neoplasm ◽

Treatment Strategies ◽

Standard Of Care ◽

High Rate ◽

Current Standard ◽

Hematopoietic Stem ◽

Genetic Features ◽

Atypical Chronic Myeloid Leukemia

Abstract Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) for which no current standard of care exists. The challenges of aCML relate to its heterogeneous clinical and genetic features, high rate of transformation to acute myeloid leukemia, and historically poor survival. Therefore, allogeneic hematopoietic stem cell transplantation should always be an initial consideration for eligible patients with a suitable donor. Nontransplant approaches for treating aCML have otherwise largely relied on adopting treatment strategies used for MDS and MPN. However, such therapies, including hypomethylating agents, are based on a paucity of data. With an eye toward making a more meaningful impact on response rates and modification of the natural history of the disease, progress will rely on enrollment of patients into clinical trials and molecular profiling of individuals so that opportunities for targeted therapy can be exploited.

Download Full-text