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SECONDARY LEUKEMIAS IN GENETIC SUBTYPES OF CONGENITAL NEUTROPENIA (ELANE, HAX1, WASP, G6PC3, ETC.): A LONG-TERM ANALYSIS OF THE SCNIR EUROPE
Author(s):
Cornelia Zeidler
,
Cornelia Zeidler
Affiliations:
SCNIR,Medical School Hannover,Hannover,Germany
Maksim Klimiankou
,
Maksim Klimiankou
Affiliations:
Department of Hematology, Oncology, Clinical Immunology,University of Tuebingen,Tuebingen,Germany
Anna Nickel
,
Anna Nickel
Affiliations:
SCNIR,Medical School Hannover,Hannover,Germany
Sabine Mellor-Heineke
,
Sabine Mellor-Heineke
Affiliations:
SCNIR,Medical School Hannover,Hannover,Germany
Julia Skokowa
,
Julia Skokowa
Affiliations:
Department of Hematology, Oncology, Clinical Immunology,University of Tuebingen,Tuebingen,Germany
Karl Welte
Karl Welte
Affiliations:
Department of General Pediatrics and Pediatric Hematology and Oncology,University of Tuebingen,Tuebingen,Germany
(Abstract release date: 05/18/17) EHA Library. Zeidler C. 06/24/17; 181784; S497
Dr. Cornelia Zeidler
Dr. Cornelia Zeidler
Contributions
PDF Abstract
Abstract

Abstract: S497

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 16:15 - 16:30

Location: Room N104

Background

Leukemia predisposition is well known in congenital neutropenia (CN) subtypes. By taking all patients with known and unclassified CN together the incidence of secondary leukemia accounts for more than 10 percent. Advanced molecular diagnostics and the identification of inherited and acquired gene mutations have improved our understanding of leukemic transformation in CN patients.

Aims
In the European SCNIR 449 patients with congenital neutropenia and 91 patients with cyclic neutropenia (CyN) have been enrolled since 1994. These 449 patients can be differentiated by causative gene mutation in more than 10 genetic subtypes: ELANE, HAX1, G6PT, G6PC3, WAS, SBDS, TAZ1 and p14 or no identified mutation, respectively. Our aim is to assess the risk of leukemic transformation within these genetic subgroups.

Methods

Here we report the leukemia incidence of genetic subtypes analyzing all available long-term data from the European Branch of the Severe Chronic Neutropenia Registry (SCNIR). In addition, we analyzed 91 patients with CyN with or without ELANE mutations.

Results

Results from genetic testing were available for 314 of 449 CN patients, of whom 118 patients revealed ELANE, 48 HAX1, 71 SBDS, 28 G6PT, 9 G6PC3, 7 WAS, 5 TAZ1 mutations and 27 other rare gene mutations (e.g. p14, CXCR4). 135 patients remain unclassified. In addition, 48 of 91 patients with CyN revealed ELANE mutations. Secondary myelodysplastic syndrome (MDS) or leukemia occurred in 49 of the 449 CN patients and in 1 of the 48 ELANE-CyN patients. Acquired CSF3R nonsense truncating mutations have been detected in the bone marrow cells of about 80% of CN patients who progress to MDS or acute myeloid leukemia (AML) and around 30-35% of non-leukemic CN patients, supporting the association between the acquisition of CSF3R mutations and leukemic transformation. These mutations have been shown to be acquired in hematopoietic cells only and therefore are not the primary cause of CN. The time between first detection of CSF3R mutations and signs of malignant transformation is highly variable. Some patients progressed to MDS/AML within a few months. In others, CSF3R mutant clones persisted for many years without progression to leukemia.
The distribution by genetic subtypes and the frequency of CSF3R mutations is shown in the table below:
Gene Mutation
Patients
N
MDS/Leukemia
n/ (%)
Total CN
445
  49 (11,0)
 ELANE
118
17 (14,4)
 HAX1
48
6 (12,5)
 SBDS
71
6 (8,5)
SLC37A4
28
1 (3,6)
WAS
7
2
JAGN1
2
1
gene mutations without leukemia*
36
0
unclassified
135
16 (11,8)
Total CyN
91
1 (0.2)
ELANE CyN
48
         1 (0,2)
CyN unclassified
43
1 (2,3)
*Gene mutations without leukemia :(G6PC3 n=9, TAZ1 n=5, p14 n=4, digenic mutations n=4, COH1 n=4, CXCR4 n=3, germline extracellular CSF3R n=2, C16ORF57 n=2, Pearson syndrome n=2, LYST n=1)
All subgroups benefit from G-CSF treatment. However, patients requiring maintenance doses of G-CSF above 8µg/kg/day are at greater risk of leukemic transformation.

Conclusion

Conclusion: The incidence of secondary AML reflects the genetic heterogeneity of CN.

Session topic: 12. Bone marrow failure syndromes incl. PNH - Clinical

Keyword(s): neutropenia, Leukemogenesis, G-CSF

Abstract: S497

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 16:15 - 16:30

Location: Room N104

Background

Leukemia predisposition is well known in congenital neutropenia (CN) subtypes. By taking all patients with known and unclassified CN together the incidence of secondary leukemia accounts for more than 10 percent. Advanced molecular diagnostics and the identification of inherited and acquired gene mutations have improved our understanding of leukemic transformation in CN patients.

Aims
In the European SCNIR 449 patients with congenital neutropenia and 91 patients with cyclic neutropenia (CyN) have been enrolled since 1994. These 449 patients can be differentiated by causative gene mutation in more than 10 genetic subtypes: ELANE, HAX1, G6PT, G6PC3, WAS, SBDS, TAZ1 and p14 or no identified mutation, respectively. Our aim is to assess the risk of leukemic transformation within these genetic subgroups.

Methods

Here we report the leukemia incidence of genetic subtypes analyzing all available long-term data from the European Branch of the Severe Chronic Neutropenia Registry (SCNIR). In addition, we analyzed 91 patients with CyN with or without ELANE mutations.

Results

Results from genetic testing were available for 314 of 449 CN patients, of whom 118 patients revealed ELANE, 48 HAX1, 71 SBDS, 28 G6PT, 9 G6PC3, 7 WAS, 5 TAZ1 mutations and 27 other rare gene mutations (e.g. p14, CXCR4). 135 patients remain unclassified. In addition, 48 of 91 patients with CyN revealed ELANE mutations. Secondary myelodysplastic syndrome (MDS) or leukemia occurred in 49 of the 449 CN patients and in 1 of the 48 ELANE-CyN patients. Acquired CSF3R nonsense truncating mutations have been detected in the bone marrow cells of about 80% of CN patients who progress to MDS or acute myeloid leukemia (AML) and around 30-35% of non-leukemic CN patients, supporting the association between the acquisition of CSF3R mutations and leukemic transformation. These mutations have been shown to be acquired in hematopoietic cells only and therefore are not the primary cause of CN. The time between first detection of CSF3R mutations and signs of malignant transformation is highly variable. Some patients progressed to MDS/AML within a few months. In others, CSF3R mutant clones persisted for many years without progression to leukemia.
The distribution by genetic subtypes and the frequency of CSF3R mutations is shown in the table below:
Gene Mutation
Patients
N
MDS/Leukemia
n/ (%)
Total CN
445
  49 (11,0)
 ELANE
118
17 (14,4)
 HAX1
48
6 (12,5)
 SBDS
71
6 (8,5)
SLC37A4
28
1 (3,6)
WAS
7
2
JAGN1
2
1
gene mutations without leukemia*
36
0
unclassified
135
16 (11,8)
Total CyN
91
1 (0.2)
ELANE CyN
48
         1 (0,2)
CyN unclassified
43
1 (2,3)
*Gene mutations without leukemia :(G6PC3 n=9, TAZ1 n=5, p14 n=4, digenic mutations n=4, COH1 n=4, CXCR4 n=3, germline extracellular CSF3R n=2, C16ORF57 n=2, Pearson syndrome n=2, LYST n=1)
All subgroups benefit from G-CSF treatment. However, patients requiring maintenance doses of G-CSF above 8µg/kg/day are at greater risk of leukemic transformation.

Conclusion

Conclusion: The incidence of secondary AML reflects the genetic heterogeneity of CN.

Session topic: 12. Bone marrow failure syndromes incl. PNH - Clinical

Keyword(s): neutropenia, Leukemogenesis, G-CSF

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