CLINICIAL, MORPHOLOGICAL AND GENETIC EVIDENCE FOR TWO INDEPENDENT DISEASES IN PATIENTS CONCURRENTLY POSITIVE FOR JAK2 V617F AND KIT D816V
Author(s): ,
Juliana Schwaab
Affiliations:
Hematology and Oncology,Medical Faculty Mannheim, Heidelberg University,Mannheim,Germany
,
Nicole Naumann
Affiliations:
Hematology and Oncology,Medical Faculty Mannheim, Heidelberg University,Mannheim,Germany
,
Johannes Luebke
Affiliations:
Hematology and Oncology,Medical Faculty Mannheim, Heidelberg University,Mannheim,Germany
,
Claire Oni
Affiliations:
Hematology,Guy's & St Thomas' NHS Foundation Trust,London,United Kingdom
,
Mohamad Jawhar
Affiliations:
Department of Hematology and Oncology,Medical Faculty Mannheim, Heidelberg University,Mannheim,Germany
,
Alice Fabarius
Affiliations:
Department of Hematology and Oncology,Medical Faculty Mannheim, Heidelberg University,Mannheim,Germany
,
Georgia Metzgeroth
Affiliations:
Department of Hematology and Oncology,Medical Faculty Mannheim, Heidelberg University,Mannheim,Germany
,
Lukas Reiter
Affiliations:
Department of Hematology and Oncology,Medical Faculty Mannheim, Heidelberg University,Mannheim,Germany
,
Alicia Schmid
Affiliations:
Department of Hematology and Oncology,Medical Faculty MannheimHeidelberg University, Mannheim, ,Mannheim,Germany
,
Karl Sotlar
Affiliations:
Department of Pathology,University Hospital Salzburg, Paracelsus Medical University, Salzburg,Salzburg,Austria
,
Hans-Peter Horny
Affiliations:
Department of Pathology,Ludwig-Maximilian-University, Munich,Munich,Germany
,
Claire Harrison
Affiliations:
Department of Haematology,Guy's & St Thomas' NHS Foundation Trust,London,United Kingdom
,
Wolf-Karsten Hofmann
Affiliations:
Department of Hematology and Oncology,Medical Faculty Mannheim,Heidelberg University,Mannheim,Germany
,
Deepti Radia
Affiliations:
Department of Haematology,Guy's & St Thomas' NHS Foundation Trust,London,United Kingdom
,
Nicholas Cross
Affiliations:
Wessex Regional Genetics Laboratory,Salisbury,United Kingdom
Andreas Reiter
Affiliations:
Department of Hematology and Oncology,Medical Faculty Mannheim, Heidelberg University,Mannheim,Germany
EHA Library. Schwaab J. 06/12/20; 293577; EP1088
Dr. Juliana Schwaab
Dr. Juliana Schwaab
Contributions
Abstract

Abstract: EP1088

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background

JAK2 V617F is identified in 60-70% of patients with myeloproliferative neoplasms (MPN) while KIT D816V is present in >90% of patients with systemic mastocytosis (SM). Of interest, MPN and SM share the presence of the same additional somatic mutations, e.g. in ASXL1 and SRSF2. Their negative impact on prognosis is at least in part based on the concurrent presence of the phenotypic (KIT, JAK2) and prognostic mutations in the same clone.

Aims
Evaluation of clinical and molecular characteristics of patients concurrently positive for mutations in JAK2 V617F and KIT D816V (JAK2pos./KITpos.).

Methods

Here, we present clinical, morphological and genetic characteristics of 35 JAK2pos./KITpos. patients which were identified within the “German Registry on Disorders of Eosinophils and Mast Cells” and at Guy’s and St. Thomas, London, UK.

Results

The median age was 64 years (range 38-85), the male to female ratio was 1.9 to 1. Typical MPN features included leukocytosis (median 10.0x109/l, range 2.7-17.8) and/or thrombocytosis (median 270x109/l, range 22-993) in 21/35 (60%), elevated LDH (median 205 U/l, range 105-437) in 9/26 (35%), and suppressed erythropoetin in 7/14 (50%) of patients. Typical features of SM included elevated serum tryptase (median 94, range 9-593) and alkaline phosphatase (median 108 U/l, range 52-640) in 28/35 (80%) and 17/35 (49%) patients, respectively, and a median bone marrow (BM) mast cell infiltration of 15% (range 3-70). SM-related symptoms (e.g. urticaria pigmentosa, anaphylaxis) were present in 19/35 (54%) patients. Overlapping features included splenomegaly (26/35, 74%), anemia and/or thrombocytopenia (8/35, 23%) and BM fibrosis (23/35, 66%; grade 1, n=14; grade ≥2, n=9). The variant allele frequency (VAF: high >30%, low <10%) in peripheral blood (JAK2 V617F, median 9%, range 1-78; KIT D816V, median 5%, range 0-50) was JAK2low/KITlow in 8/26, JAK2low/KIThigh in 7/26, JAK2high/KITlow in 9/26 and JAK2high/KIThigh in 2/26 patients suggesting the possibility of two independent clones in the majority of patients. This was supported by the mutational profile of CFU-GM-derived colonies (n=522, median/patient n=56, range 10-84) from 12 patients: in 10 of these patients JAK2 and KIT mutations were mutually exclusive, and only 2 cases showed the concurrent presence of both mutations in the same clone. Additional somatic mutations (n=23) were present in 11/28 (39%) patients with high-risk mutations (SRSF2, n=5; ASXL1, n=1; RUNX1, n=4; EZH2, n=0; IDH1/2, n=0) in 6/28 (21%) patients. To date, 10 patients have been treated with midostaurin (n=8) or ruxolitinib (n=3). To date, 9/35 (26%) have died, if data was available (n=6), those patients either had a high VAF of JAK2 and/or KIT or had additional somatic mutations. The current 3-year survival rate is 73%.

Conclusion

JAK2pos./KITpos. patients present with diverse clinical and morphological characteristics of both diseases. Molecular data derived from VAFs and CFU-GM-derived colonies suggest two independent clonal neoplasms rather than a double-mutated, monoclonal disease in most patients. This is in contrast to other somatic mutations, e.g. SRSF2 or ASXL1, which are usually present in the same clone as JAK2 V617F or KIT D816V. We suggest that targeted treatment shpuld be guided, at least initially, by quantitative assessment of the clone size and severity of associated clinical characteristics.

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Mastocytosis, Mutation analysis, Myelofibrosis, Myeloproliferative disorder

Abstract: EP1088

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background

JAK2 V617F is identified in 60-70% of patients with myeloproliferative neoplasms (MPN) while KIT D816V is present in >90% of patients with systemic mastocytosis (SM). Of interest, MPN and SM share the presence of the same additional somatic mutations, e.g. in ASXL1 and SRSF2. Their negative impact on prognosis is at least in part based on the concurrent presence of the phenotypic (KIT, JAK2) and prognostic mutations in the same clone.

Aims
Evaluation of clinical and molecular characteristics of patients concurrently positive for mutations in JAK2 V617F and KIT D816V (JAK2pos./KITpos.).

Methods

Here, we present clinical, morphological and genetic characteristics of 35 JAK2pos./KITpos. patients which were identified within the “German Registry on Disorders of Eosinophils and Mast Cells” and at Guy’s and St. Thomas, London, UK.

Results

The median age was 64 years (range 38-85), the male to female ratio was 1.9 to 1. Typical MPN features included leukocytosis (median 10.0x109/l, range 2.7-17.8) and/or thrombocytosis (median 270x109/l, range 22-993) in 21/35 (60%), elevated LDH (median 205 U/l, range 105-437) in 9/26 (35%), and suppressed erythropoetin in 7/14 (50%) of patients. Typical features of SM included elevated serum tryptase (median 94, range 9-593) and alkaline phosphatase (median 108 U/l, range 52-640) in 28/35 (80%) and 17/35 (49%) patients, respectively, and a median bone marrow (BM) mast cell infiltration of 15% (range 3-70). SM-related symptoms (e.g. urticaria pigmentosa, anaphylaxis) were present in 19/35 (54%) patients. Overlapping features included splenomegaly (26/35, 74%), anemia and/or thrombocytopenia (8/35, 23%) and BM fibrosis (23/35, 66%; grade 1, n=14; grade ≥2, n=9). The variant allele frequency (VAF: high >30%, low <10%) in peripheral blood (JAK2 V617F, median 9%, range 1-78; KIT D816V, median 5%, range 0-50) was JAK2low/KITlow in 8/26, JAK2low/KIThigh in 7/26, JAK2high/KITlow in 9/26 and JAK2high/KIThigh in 2/26 patients suggesting the possibility of two independent clones in the majority of patients. This was supported by the mutational profile of CFU-GM-derived colonies (n=522, median/patient n=56, range 10-84) from 12 patients: in 10 of these patients JAK2 and KIT mutations were mutually exclusive, and only 2 cases showed the concurrent presence of both mutations in the same clone. Additional somatic mutations (n=23) were present in 11/28 (39%) patients with high-risk mutations (SRSF2, n=5; ASXL1, n=1; RUNX1, n=4; EZH2, n=0; IDH1/2, n=0) in 6/28 (21%) patients. To date, 10 patients have been treated with midostaurin (n=8) or ruxolitinib (n=3). To date, 9/35 (26%) have died, if data was available (n=6), those patients either had a high VAF of JAK2 and/or KIT or had additional somatic mutations. The current 3-year survival rate is 73%.

Conclusion

JAK2pos./KITpos. patients present with diverse clinical and morphological characteristics of both diseases. Molecular data derived from VAFs and CFU-GM-derived colonies suggest two independent clonal neoplasms rather than a double-mutated, monoclonal disease in most patients. This is in contrast to other somatic mutations, e.g. SRSF2 or ASXL1, which are usually present in the same clone as JAK2 V617F or KIT D816V. We suggest that targeted treatment shpuld be guided, at least initially, by quantitative assessment of the clone size and severity of associated clinical characteristics.

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Mastocytosis, Mutation analysis, Myelofibrosis, Myeloproliferative disorder

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