THREE CASES OF CYCLIC NEUTROPENIA WITH ACQUIRED CSF3R MUTATIONS, ONE DEVELOPING AML
(Abstract release date: 05/19/16)
EHA Library. Zeidler C. 06/11/16; 135232; S476
Dr. Cornelia Zeidler
Contributions
Contributions
Abstract
Abstract: S476
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45
Location: Room H5
Background
We recently reported a 17-year-old female with cyclic neutropenia (CyN) harboring ELANE mutations presenting with cycling hematopoiesis involving neutrophils, platelets and reticulocytes who developed AML (FAB M2) (presented at ASH 2015, Blood 126 (23) abstract 885). At the time of AML diagnosis, all CSF3R-expressing BM leukemic blasts were positive for the p.Gln741X mutation. We tested the patient’s BM MNCs, obtained at the time of leukemia development, for RUNX1 mutations, finding that the RUNX1 mutation p.Asp171Asn was present at an allele frequency of 10%. So far, CSF3R mutations have been reported in congenital neutropenia patients (CN) only but never in patients with CyN.
Aims
Our aim was to determine whether other CyN patients harbor CSF3R mutations.
Methods
We performed deep sequencing of CSF3R in 19 additional CyN patients.
Results
Out of these 19 patients we identified two additional patients harboring acquired CSF3R mutations. One CyN patient aged 15.4 years and her sister inherited the ELANE mutation from their father. Time-course analysis of the acquisition of CSF3R mutations in this patient showed that 2.6% of the CSF3R alleles in BM MNCs were obtained at the age of 13 years possessing the p.Gln749X mutation. After additional 1.5 and 2.4 years, respectively, the mutant allele frequency increased to 9% and 8%. A third CyN patient, a 7 year old girl, harboring spontaneous ELANE mutations and revealing typical cycling of neutrophils, platelets, and monocytes was treated with G-CSF at a dose of 4.5 µg/kg/day and recently acquired CSF3R mutation (p.Gln739X) in approx. 30 % of the CSF3R allele. The latter two CyN patients have not yet developed AML or myelodysplastic syndrome (MDS).
Conclusion
Taken together, these findings suggest that CyN patients with typical CyN-associated ELANE mutations may also acquire CSF3R mutations and are therefore at risk for leukemic development. Long-term data of the Severe Chronic Neutropenia International Registry (SCNIR) have shown that the risk of acquisition of CSF3R mutations and of myeloid transformation is low but not absent in patients with CyN compared to patients with CN. This new knowledge is important for prognostic counseling and long-term management of ELANE-CyN patients.
Session topic: Bone marrow failure syndromes incl. PNH - Biology
Keyword(s): Acute myeloid leukemia, G-CSF receptor, Neutropenia
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45
Location: Room H5
Background
We recently reported a 17-year-old female with cyclic neutropenia (CyN) harboring ELANE mutations presenting with cycling hematopoiesis involving neutrophils, platelets and reticulocytes who developed AML (FAB M2) (presented at ASH 2015, Blood 126 (23) abstract 885). At the time of AML diagnosis, all CSF3R-expressing BM leukemic blasts were positive for the p.Gln741X mutation. We tested the patient’s BM MNCs, obtained at the time of leukemia development, for RUNX1 mutations, finding that the RUNX1 mutation p.Asp171Asn was present at an allele frequency of 10%. So far, CSF3R mutations have been reported in congenital neutropenia patients (CN) only but never in patients with CyN.
Aims
Our aim was to determine whether other CyN patients harbor CSF3R mutations.
Methods
We performed deep sequencing of CSF3R in 19 additional CyN patients.
Results
Out of these 19 patients we identified two additional patients harboring acquired CSF3R mutations. One CyN patient aged 15.4 years and her sister inherited the ELANE mutation from their father. Time-course analysis of the acquisition of CSF3R mutations in this patient showed that 2.6% of the CSF3R alleles in BM MNCs were obtained at the age of 13 years possessing the p.Gln749X mutation. After additional 1.5 and 2.4 years, respectively, the mutant allele frequency increased to 9% and 8%. A third CyN patient, a 7 year old girl, harboring spontaneous ELANE mutations and revealing typical cycling of neutrophils, platelets, and monocytes was treated with G-CSF at a dose of 4.5 µg/kg/day and recently acquired CSF3R mutation (p.Gln739X) in approx. 30 % of the CSF3R allele. The latter two CyN patients have not yet developed AML or myelodysplastic syndrome (MDS).
Conclusion
Taken together, these findings suggest that CyN patients with typical CyN-associated ELANE mutations may also acquire CSF3R mutations and are therefore at risk for leukemic development. Long-term data of the Severe Chronic Neutropenia International Registry (SCNIR) have shown that the risk of acquisition of CSF3R mutations and of myeloid transformation is low but not absent in patients with CyN compared to patients with CN. This new knowledge is important for prognostic counseling and long-term management of ELANE-CyN patients.
Session topic: Bone marrow failure syndromes incl. PNH - Biology
Keyword(s): Acute myeloid leukemia, G-CSF receptor, Neutropenia
Abstract: S476
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45
Location: Room H5
Background
We recently reported a 17-year-old female with cyclic neutropenia (CyN) harboring ELANE mutations presenting with cycling hematopoiesis involving neutrophils, platelets and reticulocytes who developed AML (FAB M2) (presented at ASH 2015, Blood 126 (23) abstract 885). At the time of AML diagnosis, all CSF3R-expressing BM leukemic blasts were positive for the p.Gln741X mutation. We tested the patient’s BM MNCs, obtained at the time of leukemia development, for RUNX1 mutations, finding that the RUNX1 mutation p.Asp171Asn was present at an allele frequency of 10%. So far, CSF3R mutations have been reported in congenital neutropenia patients (CN) only but never in patients with CyN.
Aims
Our aim was to determine whether other CyN patients harbor CSF3R mutations.
Methods
We performed deep sequencing of CSF3R in 19 additional CyN patients.
Results
Out of these 19 patients we identified two additional patients harboring acquired CSF3R mutations. One CyN patient aged 15.4 years and her sister inherited the ELANE mutation from their father. Time-course analysis of the acquisition of CSF3R mutations in this patient showed that 2.6% of the CSF3R alleles in BM MNCs were obtained at the age of 13 years possessing the p.Gln749X mutation. After additional 1.5 and 2.4 years, respectively, the mutant allele frequency increased to 9% and 8%. A third CyN patient, a 7 year old girl, harboring spontaneous ELANE mutations and revealing typical cycling of neutrophils, platelets, and monocytes was treated with G-CSF at a dose of 4.5 µg/kg/day and recently acquired CSF3R mutation (p.Gln739X) in approx. 30 % of the CSF3R allele. The latter two CyN patients have not yet developed AML or myelodysplastic syndrome (MDS).
Conclusion
Taken together, these findings suggest that CyN patients with typical CyN-associated ELANE mutations may also acquire CSF3R mutations and are therefore at risk for leukemic development. Long-term data of the Severe Chronic Neutropenia International Registry (SCNIR) have shown that the risk of acquisition of CSF3R mutations and of myeloid transformation is low but not absent in patients with CyN compared to patients with CN. This new knowledge is important for prognostic counseling and long-term management of ELANE-CyN patients.
Session topic: Bone marrow failure syndromes incl. PNH - Biology
Keyword(s): Acute myeloid leukemia, G-CSF receptor, Neutropenia
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45
Location: Room H5
Background
We recently reported a 17-year-old female with cyclic neutropenia (CyN) harboring ELANE mutations presenting with cycling hematopoiesis involving neutrophils, platelets and reticulocytes who developed AML (FAB M2) (presented at ASH 2015, Blood 126 (23) abstract 885). At the time of AML diagnosis, all CSF3R-expressing BM leukemic blasts were positive for the p.Gln741X mutation. We tested the patient’s BM MNCs, obtained at the time of leukemia development, for RUNX1 mutations, finding that the RUNX1 mutation p.Asp171Asn was present at an allele frequency of 10%. So far, CSF3R mutations have been reported in congenital neutropenia patients (CN) only but never in patients with CyN.
Aims
Our aim was to determine whether other CyN patients harbor CSF3R mutations.
Methods
We performed deep sequencing of CSF3R in 19 additional CyN patients.
Results
Out of these 19 patients we identified two additional patients harboring acquired CSF3R mutations. One CyN patient aged 15.4 years and her sister inherited the ELANE mutation from their father. Time-course analysis of the acquisition of CSF3R mutations in this patient showed that 2.6% of the CSF3R alleles in BM MNCs were obtained at the age of 13 years possessing the p.Gln749X mutation. After additional 1.5 and 2.4 years, respectively, the mutant allele frequency increased to 9% and 8%. A third CyN patient, a 7 year old girl, harboring spontaneous ELANE mutations and revealing typical cycling of neutrophils, platelets, and monocytes was treated with G-CSF at a dose of 4.5 µg/kg/day and recently acquired CSF3R mutation (p.Gln739X) in approx. 30 % of the CSF3R allele. The latter two CyN patients have not yet developed AML or myelodysplastic syndrome (MDS).
Conclusion
Taken together, these findings suggest that CyN patients with typical CyN-associated ELANE mutations may also acquire CSF3R mutations and are therefore at risk for leukemic development. Long-term data of the Severe Chronic Neutropenia International Registry (SCNIR) have shown that the risk of acquisition of CSF3R mutations and of myeloid transformation is low but not absent in patients with CyN compared to patients with CN. This new knowledge is important for prognostic counseling and long-term management of ELANE-CyN patients.
Session topic: Bone marrow failure syndromes incl. PNH - Biology
Keyword(s): Acute myeloid leukemia, G-CSF receptor, Neutropenia
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