Atypical Chronic Myeloid Leukemia in Two Pediatric Patients

Freedman, Jason L.; Desai, Ami; Bailey, L. Charles; Aplenc, Richard; Burnworth, Bettina; Zehentner, Barbara K.; Teachey, David T.; Wertheim, Gerald

doi:10.1002/pbc.25694

Cited by 24 publications

(23 citation statements)

References 16 publications

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“…In addition, although CSF3R mutations are heavily enriched within the CNL diagnostic subset, there are patients who meet all WHO criteria for aCML and exhibit CSF3R mutations. 19,67,68 Going forward, it will be important to consider whether patients with CSF3R mutations should all be placed into a single category or whether they should sometimes remain stratified into distinct groups according to their disease. The spectrum of additional mutations seen in these patients, as well as the order of acquisition of these mutations, may play a role in deciding which categories patients with CSF3R mutations should be placed in.…”

Section: Diagnostic Implicationsmentioning

confidence: 99%

Genomics of chronic neutrophilic leukemia

Maxson¹,

Tyner

2017

Blood

101

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Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm with a high prevalence (>80%) of mutations in the colony-stimulating factor 3 receptor (CSF3R). These mutations activate the receptor, leading to the proliferation of neutrophils that are a hallmark of CNL. Recently, the World Health Organization guidelines have been updated to include CSF3R mutations as part of the diagnostic criteria for CNL. Because of the high prevalence of CSF3R mutations in CNL, it is tempting to think of this disease as being solely driven by this genetic lesion. However, recent additional genomic characterization demonstrates that CNL has much in common with other chronic myeloid malignancies at the genetic level, such as the clinically related diagnosis atypical chronic myeloid leukemia. These commonalities include mutations in SETBP1, spliceosome proteins (SRSF2, U2AF1), and epigenetic modifiers (TET2, ASXL1). Some of these same mutations also have been characterized as frequent events in clonal hematopoiesis of indeterminate potential, suggesting a more complex disease evolution than was previously understood and raising the possibility that an age-related clonal process of preleukemic cells could precede the development of CNL. The order of acquisition of CSF3R mutations relative to mutations in SETBP1, epigenetic modifiers, or the spliceosome has been determined only in isolated case reports; thus, further work is needed to understand the impact of mutation chronology on the clonal evolution and progression of CNL. Understanding the complete landscape and chronology of genomic events in CNL will help in the development of improved therapeutic strategies for this patient population.

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Section: Diagnostic Implicationsmentioning

confidence: 99%

Genomics of chronic neutrophilic leukemia

Maxson¹,

Tyner

2017

Blood

101

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“…In the aspect of treatment, there was additional chance of a clinical trial with several therapeutic targets, although the patient was lost to follow‐up with disease progression, unfortunately. For T618I of CSF3R , ruxolitinib showed efficacy according to several case reports . The G870S of SETBP1 is reported to imply ruxolitinib unresponsiveness .…”

Section: Discussionmentioning

confidence: 96%

“…For T618I of CSF3R, ruxolitinib showed efficacy according to several case reports. 9,20,21 The G870S of SETBP1 is reported to imply ruxolitinib unresponsiveness. 22 On the other hand, the SETBP1 mutation was suggested as a novel target of fingolimod (FTY720) in an in vitro study.…”

Section: Discussionmentioning

confidence: 99%

Next‐generation sequencing reveals unique combination of mutations in cis of CSF3R in atypical chronic myeloid leukemia

Yun

Yoon

Jung

et al. 2019

Clinical Laboratory Analysis

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Background Atypical chronic myeloid leukemia (aCML) is a hematologic disorder characterized by leukocytosis with increased dysplastic neutrophils and their precursors. In CSF3R gene, the activation mutation including T618I is frequently reported in aCML but is rarely accompanied by truncation mutations. Herein, we report a unique aCML patient with two CSF3R mutations (T618I and Y779*) in the same DNA strand. Methods High‐coverage next‐generation sequencing for 40 genes related with myeloid leukemia was performed. Sanger sequencing was performed to confirm CSF3R mutations. To confirm whether two CSF3R mutations are in cis or not, TA cloning was used. Clinical information and bone marrow pathology were reviewed by two hematopathologists. Results In the patient diagnosed with aCML in bone marrow study, two CSF3R mutations, (T618I and Y779*) a SETBP1 mutation (G870S) and an U2AF1 mutation (Q157P), were identified by high‐coverage next‐generation sequencing. The two CSF3R mutations were confirmed to be located in the same DNA strand by TA cloning, indicating that the two mutations are harbored in one malignant clone. The SETBP1 mutation is known to be related with poor prognosis in aCML. Likewise, the patient was refractory to hydroxyurea and showed disease progression. Additionally, we discussed the potential therapeutic targets by reviewing the molecular profile of the patient. Conclusion We believe that the accurate diagnosis and maximum therapeutic chance could be achieved by profiling the mutations and their characteristics.

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“…In the pediatric setting, ruxolitinib (50 mg/m 2 ) has been used in an 11-year-old girl with aCML. 47 Ruxolitinib decreased the leukocyte count from 101 3 10 9 to 7.9 3 10 9 /L after 1 week, ultimately permitting the patient to be bridged to a successful allogeneic HSCT. Although not well studied, the presence of additional mutations besides CSF3R T618I, such as SETBP1, may reduce responsiveness to JAK inhibitor therapy in aCML.…”

Section: Ruxolitinibmentioning

confidence: 98%

How I treat atypical chronic myeloid leukemia

Gotlib

2017

Blood

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Atypical chronic myeloid leukemia, 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.

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Atypical Chronic Myeloid Leukemia in Two Pediatric Patients

Cited by 24 publications

References 16 publications

Genomics of chronic neutrophilic leukemia

Genomics of chronic neutrophilic leukemia

Next‐generation sequencing reveals unique combination of mutations in cis of CSF3R in atypical chronic myeloid leukemia

How I treat atypical chronic myeloid leukemia

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