Contributions
Abstract: PB1387
Type: Publication Only
Session title: Acute myeloid leukemia - Biology & Translational Research
Background
Ollier disease (OD) is a rare congenital, non hereditary disorder, characterized by early development of multiple enchondromas and genetically by mutations in isocitrate dehydrogenase (IDH) 1 and 2. Mutations are found in chondromas, but not in other tissues, suggesting that they occur during embryonic development in mesoderm, giving rise to a somatic genetic mosaicism, with the gene being mutated only in tissues of mesodermal origin. Clinically, OD is associated with an increased risk of cancer, including chondrosarcomas and gliomas. Haematopoietic cells precursors (hemangioblasts) embriologically derive from mesoderm and thus bone marrow may be involved in OD manifestations. Furthermore, IDH 1 and 2 are frequently mutated in AML. However, AML cases in OD are anecdotal and reported only in paediatric patients.
Aims
We report the case of a patient affected by OD, who at 35 years developed AML harbouring IDH1, NPM1 and FLT3 TKD mutation and speculate about etiopathogenesis.
Methods
Patient's diagnostic and therapeutic management was performed according to our centre policy as indicated in 'Results'.
Results
In November 2020 a 35 years old man was admitted to our unit with haemorrhagic symptoms. He had a diagnosis of OD and had underwent surgery at 14 and 22 years to remove enchondromas in the left hand. His blood counts were: WBC 85.470/mm3, Hb 9,9 g/dl, platelets 11.000/mm3. A bone marrow evaluation led to a diagnosis of AML, FAB M2, with normal karyotype, NPM1 exon 11 (W288Cfs*12), FLT3 TKD (D835Y and I836del) and IDH1 (R132H) mutation. An induction chemotherapy with “7+3” associated with midostaurin (days 8-21) was administered and complete remission was obtained. Subsequently the patient underwent three consolidation cycles with HD Ara-C and midostaurin (days 8-21). At a molecular level NPM1 and FLT3TKD mutations were not detectable by qualitative nested PCR after induction, while IDH1 mutation was present at all bone marrow evaluations, even after the last consolidation.
Conclusion
Mutations of the IDH 1 and/or 2 gene are found in about 16% of AMLs. IDH proteins catalyze the conversion of isocitrate to α-ketoglutarate. Mutations lead to gain of function and an enhanced production of 2-hydroxyglutarate, responsible for increased DNA methylation. According to recent AML pathogenetic models, mutations in genes encoding epigenetic modifiers, such as DNMT3A, ASXL1, TET2, IDH1,and IDH2, are acquired early in a founding clone and may be found in the context of a clonal haeatopoiesis (CHIP), even in healthy subjects. Additional mutations, such as those involving NPM1 or signalling molecules (FLT3, RAS), are secondary events occurring later during leukemogenesis. IDH 1 and 2 mutations may persist in a patient treated for AML after therapy and represent, rather than a molecular marker of MRD, a risk factor for disease relapse.
In our patient IDH1 mutation was still detectable in bone marrow after achievement of CR, indicating the persistence of a clone of haematopoietic precursors harbouring a congenital mutation, associated with OD. It is important to note that the patient had remained free from leukaemia during three decades and a half, with AML developing only after acquisition of two other gene mutations (NPM1 and FLT3 TKD). These observations shed light on the paradigm of multiple genetic hits hypothesis of leukemogenesis and, after demonstration of the same IDH1 (R132H) mutation in chondroma tissue, prompt us to monitor the patient rather than candidate him to alloHCT in I CR.
Keyword(s): Acute myeloid leukemia
Abstract: PB1387
Type: Publication Only
Session title: Acute myeloid leukemia - Biology & Translational Research
Background
Ollier disease (OD) is a rare congenital, non hereditary disorder, characterized by early development of multiple enchondromas and genetically by mutations in isocitrate dehydrogenase (IDH) 1 and 2. Mutations are found in chondromas, but not in other tissues, suggesting that they occur during embryonic development in mesoderm, giving rise to a somatic genetic mosaicism, with the gene being mutated only in tissues of mesodermal origin. Clinically, OD is associated with an increased risk of cancer, including chondrosarcomas and gliomas. Haematopoietic cells precursors (hemangioblasts) embriologically derive from mesoderm and thus bone marrow may be involved in OD manifestations. Furthermore, IDH 1 and 2 are frequently mutated in AML. However, AML cases in OD are anecdotal and reported only in paediatric patients.
Aims
We report the case of a patient affected by OD, who at 35 years developed AML harbouring IDH1, NPM1 and FLT3 TKD mutation and speculate about etiopathogenesis.
Methods
Patient's diagnostic and therapeutic management was performed according to our centre policy as indicated in 'Results'.
Results
In November 2020 a 35 years old man was admitted to our unit with haemorrhagic symptoms. He had a diagnosis of OD and had underwent surgery at 14 and 22 years to remove enchondromas in the left hand. His blood counts were: WBC 85.470/mm3, Hb 9,9 g/dl, platelets 11.000/mm3. A bone marrow evaluation led to a diagnosis of AML, FAB M2, with normal karyotype, NPM1 exon 11 (W288Cfs*12), FLT3 TKD (D835Y and I836del) and IDH1 (R132H) mutation. An induction chemotherapy with “7+3” associated with midostaurin (days 8-21) was administered and complete remission was obtained. Subsequently the patient underwent three consolidation cycles with HD Ara-C and midostaurin (days 8-21). At a molecular level NPM1 and FLT3TKD mutations were not detectable by qualitative nested PCR after induction, while IDH1 mutation was present at all bone marrow evaluations, even after the last consolidation.
Conclusion
Mutations of the IDH 1 and/or 2 gene are found in about 16% of AMLs. IDH proteins catalyze the conversion of isocitrate to α-ketoglutarate. Mutations lead to gain of function and an enhanced production of 2-hydroxyglutarate, responsible for increased DNA methylation. According to recent AML pathogenetic models, mutations in genes encoding epigenetic modifiers, such as DNMT3A, ASXL1, TET2, IDH1,and IDH2, are acquired early in a founding clone and may be found in the context of a clonal haeatopoiesis (CHIP), even in healthy subjects. Additional mutations, such as those involving NPM1 or signalling molecules (FLT3, RAS), are secondary events occurring later during leukemogenesis. IDH 1 and 2 mutations may persist in a patient treated for AML after therapy and represent, rather than a molecular marker of MRD, a risk factor for disease relapse.
In our patient IDH1 mutation was still detectable in bone marrow after achievement of CR, indicating the persistence of a clone of haematopoietic precursors harbouring a congenital mutation, associated with OD. It is important to note that the patient had remained free from leukaemia during three decades and a half, with AML developing only after acquisition of two other gene mutations (NPM1 and FLT3 TKD). These observations shed light on the paradigm of multiple genetic hits hypothesis of leukemogenesis and, after demonstration of the same IDH1 (R132H) mutation in chondroma tissue, prompt us to monitor the patient rather than candidate him to alloHCT in I CR.
Keyword(s): Acute myeloid leukemia