ELANE MUTATION C233TER PREDISPOSES PATIENTS WITH SEVERE CONGENITAL NEUTROPENIA TO ACUTE MYELOID LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. Dale D. 06/09/16; 134561; PB1661
Dr. David Dale
Contributions
Contributions
Abstract
Abstract: PB1661
Type: Publication Only
Background
Mutations in ELANE are the most frequent cause for cyclic and congenital neutropenia. In a genotype-phenotype study, we previously reported that mutations G214R which replaces glycine (nonpolar, neutral) with the much larger arginine (polar, strongly basic) amino acid, and C151Y which disrupts the second disulfide bond of the protein are associated with severe outcomes. (Makaryan et al, Curr Opin Hematol 2015;22:3-11) Termination mutations were associated with leukemic transformation, but the number of these patients was relatively small.
Aims
To investigate the natural history and long-term consequences of mutations in ELANE.
Methods
The Severe Chronic Neutropenia International Registry (SCNIR) has enrolled 3 patients with the termination mutation C223ter. All three have developed acute myeloid leukemia.
Results
Patient #1 is a 38 year old female residing in Michigan USA. She was diagnosed with SCN in 1989 at age 11. She started G-CSF in 1989, 11.5 mcg/kg/day. Because of a poor response, G-CSF was gradually increased to 24 mcg/kg/day. After 15 years, she was switched to peg G-CSF, 3 mg every 10 days for the next 11 years. In February 2015 at age 37, she had blasts in the blood and marrow revealing 65.8% blasts. Ten months ago, she underwent HSCT, GvHD has resolved, platelets are holding at 59K without transfusions and she receives darbepoetin alfa to maintain hemoglobin.Patient #2 is a 25 year old female residing in Western Australia. She was diagnosed with SCN in 1991 at age 4.5 months. She was started at age 5 months on G-CSF at 5 mcg/kg/day and the dose increased to 20 mcg/kg/day because of a poor response. After 12 years, she was switched to peg G-CSF 6 mg q 14 days after 12 years because of her poor neutrophil response. She received Neulasta 6 mg every 14 days for 11 years. She became pregnant in May 2015 having had 3 previous pregnancies (2 terminations and one live birth). In the second month of her fourth pregnancy, she appeared to be losing her response to peg G-CSF. About two months later, she was found to have hypertrophied gums with infiltration of immature myeloid cells, consistent with the abnormal cells also found in her bone marrow. She was maintained on G-CSF, prednisone, and blood products because without the growth factor she was severely ill. With this approach, she delivered a healthy male infant at 30 weeks via C-section. She had a HSCT five weeks after delivery and is now 2 months post-transplant, in serious condition with the donor marrow beginning to respond.Patient # 3 was a 6 year old female who resided in Chile. She was diagnosed with SCN in 1997 at 10 months and started G-CSF at 15 mcg/kg/day. There was a poor response requiring an increase of G-CSF to 37.5 mcg/kg/day. After 3 years on G-CSF, she developed AML presenting with increased blasts, anemia and thrombocytopenia. She received chemotherapy; HSCT was not available. She died from complications of AML in 2002.Mutations in G214R, C152Y and C223ter have no obvious common features in terms of effects on the active site, glycosylation sites, or disulfide bonds of the enzyme. These mutations and others associated with evolution to AML are often relatively resistant to treatment with G-CSF, but the biological basis for resistance to G-CSF as well as the risk of evolution to AML is not known.
Conclusion
Understanding the biological basis for the diversity of genotype-phenotype relationships for mutations in ELANE, particularly how some mutations predispose to a high risk of AML, is critical for improving the diagnosis and treatment of this form of hereditary neutropenia.
Session topic: E-poster
Keyword(s): G-CSF, Leukemia, Neutropenia, Neutrophil elastase
Type: Publication Only
Background
Mutations in ELANE are the most frequent cause for cyclic and congenital neutropenia. In a genotype-phenotype study, we previously reported that mutations G214R which replaces glycine (nonpolar, neutral) with the much larger arginine (polar, strongly basic) amino acid, and C151Y which disrupts the second disulfide bond of the protein are associated with severe outcomes. (Makaryan et al, Curr Opin Hematol 2015;22:3-11) Termination mutations were associated with leukemic transformation, but the number of these patients was relatively small.
Aims
To investigate the natural history and long-term consequences of mutations in ELANE.
Methods
The Severe Chronic Neutropenia International Registry (SCNIR) has enrolled 3 patients with the termination mutation C223ter. All three have developed acute myeloid leukemia.
Results
Patient #1 is a 38 year old female residing in Michigan USA. She was diagnosed with SCN in 1989 at age 11. She started G-CSF in 1989, 11.5 mcg/kg/day. Because of a poor response, G-CSF was gradually increased to 24 mcg/kg/day. After 15 years, she was switched to peg G-CSF, 3 mg every 10 days for the next 11 years. In February 2015 at age 37, she had blasts in the blood and marrow revealing 65.8% blasts. Ten months ago, she underwent HSCT, GvHD has resolved, platelets are holding at 59K without transfusions and she receives darbepoetin alfa to maintain hemoglobin.Patient #2 is a 25 year old female residing in Western Australia. She was diagnosed with SCN in 1991 at age 4.5 months. She was started at age 5 months on G-CSF at 5 mcg/kg/day and the dose increased to 20 mcg/kg/day because of a poor response. After 12 years, she was switched to peg G-CSF 6 mg q 14 days after 12 years because of her poor neutrophil response. She received Neulasta 6 mg every 14 days for 11 years. She became pregnant in May 2015 having had 3 previous pregnancies (2 terminations and one live birth). In the second month of her fourth pregnancy, she appeared to be losing her response to peg G-CSF. About two months later, she was found to have hypertrophied gums with infiltration of immature myeloid cells, consistent with the abnormal cells also found in her bone marrow. She was maintained on G-CSF, prednisone, and blood products because without the growth factor she was severely ill. With this approach, she delivered a healthy male infant at 30 weeks via C-section. She had a HSCT five weeks after delivery and is now 2 months post-transplant, in serious condition with the donor marrow beginning to respond.Patient # 3 was a 6 year old female who resided in Chile. She was diagnosed with SCN in 1997 at 10 months and started G-CSF at 15 mcg/kg/day. There was a poor response requiring an increase of G-CSF to 37.5 mcg/kg/day. After 3 years on G-CSF, she developed AML presenting with increased blasts, anemia and thrombocytopenia. She received chemotherapy; HSCT was not available. She died from complications of AML in 2002.Mutations in G214R, C152Y and C223ter have no obvious common features in terms of effects on the active site, glycosylation sites, or disulfide bonds of the enzyme. These mutations and others associated with evolution to AML are often relatively resistant to treatment with G-CSF, but the biological basis for resistance to G-CSF as well as the risk of evolution to AML is not known.
Conclusion
Understanding the biological basis for the diversity of genotype-phenotype relationships for mutations in ELANE, particularly how some mutations predispose to a high risk of AML, is critical for improving the diagnosis and treatment of this form of hereditary neutropenia.
Session topic: E-poster
Keyword(s): G-CSF, Leukemia, Neutropenia, Neutrophil elastase
Abstract: PB1661
Type: Publication Only
Background
Mutations in ELANE are the most frequent cause for cyclic and congenital neutropenia. In a genotype-phenotype study, we previously reported that mutations G214R which replaces glycine (nonpolar, neutral) with the much larger arginine (polar, strongly basic) amino acid, and C151Y which disrupts the second disulfide bond of the protein are associated with severe outcomes. (Makaryan et al, Curr Opin Hematol 2015;22:3-11) Termination mutations were associated with leukemic transformation, but the number of these patients was relatively small.
Aims
To investigate the natural history and long-term consequences of mutations in ELANE.
Methods
The Severe Chronic Neutropenia International Registry (SCNIR) has enrolled 3 patients with the termination mutation C223ter. All three have developed acute myeloid leukemia.
Results
Patient #1 is a 38 year old female residing in Michigan USA. She was diagnosed with SCN in 1989 at age 11. She started G-CSF in 1989, 11.5 mcg/kg/day. Because of a poor response, G-CSF was gradually increased to 24 mcg/kg/day. After 15 years, she was switched to peg G-CSF, 3 mg every 10 days for the next 11 years. In February 2015 at age 37, she had blasts in the blood and marrow revealing 65.8% blasts. Ten months ago, she underwent HSCT, GvHD has resolved, platelets are holding at 59K without transfusions and she receives darbepoetin alfa to maintain hemoglobin.Patient #2 is a 25 year old female residing in Western Australia. She was diagnosed with SCN in 1991 at age 4.5 months. She was started at age 5 months on G-CSF at 5 mcg/kg/day and the dose increased to 20 mcg/kg/day because of a poor response. After 12 years, she was switched to peg G-CSF 6 mg q 14 days after 12 years because of her poor neutrophil response. She received Neulasta 6 mg every 14 days for 11 years. She became pregnant in May 2015 having had 3 previous pregnancies (2 terminations and one live birth). In the second month of her fourth pregnancy, she appeared to be losing her response to peg G-CSF. About two months later, she was found to have hypertrophied gums with infiltration of immature myeloid cells, consistent with the abnormal cells also found in her bone marrow. She was maintained on G-CSF, prednisone, and blood products because without the growth factor she was severely ill. With this approach, she delivered a healthy male infant at 30 weeks via C-section. She had a HSCT five weeks after delivery and is now 2 months post-transplant, in serious condition with the donor marrow beginning to respond.Patient # 3 was a 6 year old female who resided in Chile. She was diagnosed with SCN in 1997 at 10 months and started G-CSF at 15 mcg/kg/day. There was a poor response requiring an increase of G-CSF to 37.5 mcg/kg/day. After 3 years on G-CSF, she developed AML presenting with increased blasts, anemia and thrombocytopenia. She received chemotherapy; HSCT was not available. She died from complications of AML in 2002.Mutations in G214R, C152Y and C223ter have no obvious common features in terms of effects on the active site, glycosylation sites, or disulfide bonds of the enzyme. These mutations and others associated with evolution to AML are often relatively resistant to treatment with G-CSF, but the biological basis for resistance to G-CSF as well as the risk of evolution to AML is not known.
Conclusion
Understanding the biological basis for the diversity of genotype-phenotype relationships for mutations in ELANE, particularly how some mutations predispose to a high risk of AML, is critical for improving the diagnosis and treatment of this form of hereditary neutropenia.
Session topic: E-poster
Keyword(s): G-CSF, Leukemia, Neutropenia, Neutrophil elastase
Type: Publication Only
Background
Mutations in ELANE are the most frequent cause for cyclic and congenital neutropenia. In a genotype-phenotype study, we previously reported that mutations G214R which replaces glycine (nonpolar, neutral) with the much larger arginine (polar, strongly basic) amino acid, and C151Y which disrupts the second disulfide bond of the protein are associated with severe outcomes. (Makaryan et al, Curr Opin Hematol 2015;22:3-11) Termination mutations were associated with leukemic transformation, but the number of these patients was relatively small.
Aims
To investigate the natural history and long-term consequences of mutations in ELANE.
Methods
The Severe Chronic Neutropenia International Registry (SCNIR) has enrolled 3 patients with the termination mutation C223ter. All three have developed acute myeloid leukemia.
Results
Patient #1 is a 38 year old female residing in Michigan USA. She was diagnosed with SCN in 1989 at age 11. She started G-CSF in 1989, 11.5 mcg/kg/day. Because of a poor response, G-CSF was gradually increased to 24 mcg/kg/day. After 15 years, she was switched to peg G-CSF, 3 mg every 10 days for the next 11 years. In February 2015 at age 37, she had blasts in the blood and marrow revealing 65.8% blasts. Ten months ago, she underwent HSCT, GvHD has resolved, platelets are holding at 59K without transfusions and she receives darbepoetin alfa to maintain hemoglobin.Patient #2 is a 25 year old female residing in Western Australia. She was diagnosed with SCN in 1991 at age 4.5 months. She was started at age 5 months on G-CSF at 5 mcg/kg/day and the dose increased to 20 mcg/kg/day because of a poor response. After 12 years, she was switched to peg G-CSF 6 mg q 14 days after 12 years because of her poor neutrophil response. She received Neulasta 6 mg every 14 days for 11 years. She became pregnant in May 2015 having had 3 previous pregnancies (2 terminations and one live birth). In the second month of her fourth pregnancy, she appeared to be losing her response to peg G-CSF. About two months later, she was found to have hypertrophied gums with infiltration of immature myeloid cells, consistent with the abnormal cells also found in her bone marrow. She was maintained on G-CSF, prednisone, and blood products because without the growth factor she was severely ill. With this approach, she delivered a healthy male infant at 30 weeks via C-section. She had a HSCT five weeks after delivery and is now 2 months post-transplant, in serious condition with the donor marrow beginning to respond.Patient # 3 was a 6 year old female who resided in Chile. She was diagnosed with SCN in 1997 at 10 months and started G-CSF at 15 mcg/kg/day. There was a poor response requiring an increase of G-CSF to 37.5 mcg/kg/day. After 3 years on G-CSF, she developed AML presenting with increased blasts, anemia and thrombocytopenia. She received chemotherapy; HSCT was not available. She died from complications of AML in 2002.Mutations in G214R, C152Y and C223ter have no obvious common features in terms of effects on the active site, glycosylation sites, or disulfide bonds of the enzyme. These mutations and others associated with evolution to AML are often relatively resistant to treatment with G-CSF, but the biological basis for resistance to G-CSF as well as the risk of evolution to AML is not known.
Conclusion
Understanding the biological basis for the diversity of genotype-phenotype relationships for mutations in ELANE, particularly how some mutations predispose to a high risk of AML, is critical for improving the diagnosis and treatment of this form of hereditary neutropenia.
Session topic: E-poster
Keyword(s): G-CSF, Leukemia, Neutropenia, Neutrophil elastase
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