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Background
IDH1 mutations are detected in 3-4% of MDS, nearly always with one or more co-mutations. Treatment with IDH1 inhibitor ivosidenib typically resulted in regression of the abnormal clone in 15 reported responders. However, in a few cases differentiation was restored from the abnormal clone. Here we report a durable MDS remission despite sustained proliferation of a clone with IDH1 and ZRSR2 mutations.
Case Presentation
A 49-year-old man developed severe neutropenia and macrocytic anemia in January 2019. Mild marrow dysplasia developed by March 2020 with IDH1 (31.1%) and splicing gene ZRSR2 (55.7%) mutations. In October 2022 biopsy showed MDS with 4% blasts, megakaryocytic/granulocytic hypoplasia, normal cytogenetics and 43% IDH1/89% ZRSR2. After azacytidine failure, ivosidenib was started in November 2023 following FDA approval. Within weeks ANCs increased from 170 to 1580 and hemoglobin from 7.9 to 11.6 with MCV 115, reticulocytes 1.72%. At 3 months a CBC was normal except for MCV 111. IDH1 and ZRSR2 were 36.4% and 71%. After 6 months, ANC was 2380, hemoglobin 14.7, MCV 108.6, reticulo-cytes 1.77%. IDH1 PCR showed a 33.1% allele frequency consistent with a clonal remission.
Discussion
IDH1 mutations in MDS/AML frequently co-occur with mutations in RNA splicing genes SRSF2 or ZRSR2. For ZRSR2, we previously reported that isolated mutations of this gene cause refractory macrocytic anemias without dysplasia, thus presenting as clonal cytopenias of undetermined significance (Fleischman et al., Leuk Res, 2017). In this MDS case, after ivosidenib treatment the ZRSR2 splicing defect sustained clonal dominance over polyclonal hematopoiesis while accounting for macrocytosis. Longitudinal data for two ivosidenib-treated IDH1/SRSF2 MDS cases are incomplete, but one case of IDH2/SRSF2 MDS treated with the inhibitor enasidenib similarly achieved complete remission without regression of the mutated clone for 12 months.
Conclusions
Following the FDA approval of ivosidenib, all cases of MDS should have DNA sequencing performed at diagnosis to identify IDH1 mutations. Treatment induces high rates of remission even when polyclonal hematopoiesis does not recover. Moreover, the restoration of hematopoietic differentiation by the abnormal clone provides unique insights into the clinical phenotype and fitness advantage conferred by the co-existing driver mutations.
Background
IDH1 mutations are detected in 3-4% of MDS, nearly always with one or more co-mutations. Treatment with IDH1 inhibitor ivosidenib typically resulted in regression of the abnormal clone in 15 reported responders. However, in a few cases differentiation was restored from the abnormal clone. Here we report a durable MDS remission despite sustained proliferation of a clone with IDH1 and ZRSR2 mutations.
Case Presentation
A 49-year-old man developed severe neutropenia and macrocytic anemia in January 2019. Mild marrow dysplasia developed by March 2020 with IDH1 (31.1%) and splicing gene ZRSR2 (55.7%) mutations. In October 2022 biopsy showed MDS with 4% blasts, megakaryocytic/granulocytic hypoplasia, normal cytogenetics and 43% IDH1/89% ZRSR2. After azacytidine failure, ivosidenib was started in November 2023 following FDA approval. Within weeks ANCs increased from 170 to 1580 and hemoglobin from 7.9 to 11.6 with MCV 115, reticulocytes 1.72%. At 3 months a CBC was normal except for MCV 111. IDH1 and ZRSR2 were 36.4% and 71%. After 6 months, ANC was 2380, hemoglobin 14.7, MCV 108.6, reticulo-cytes 1.77%. IDH1 PCR showed a 33.1% allele frequency consistent with a clonal remission.
Discussion
IDH1 mutations in MDS/AML frequently co-occur with mutations in RNA splicing genes SRSF2 or ZRSR2. For ZRSR2, we previously reported that isolated mutations of this gene cause refractory macrocytic anemias without dysplasia, thus presenting as clonal cytopenias of undetermined significance (Fleischman et al., Leuk Res, 2017). In this MDS case, after ivosidenib treatment the ZRSR2 splicing defect sustained clonal dominance over polyclonal hematopoiesis while accounting for macrocytosis. Longitudinal data for two ivosidenib-treated IDH1/SRSF2 MDS cases are incomplete, but one case of IDH2/SRSF2 MDS treated with the inhibitor enasidenib similarly achieved complete remission without regression of the mutated clone for 12 months.
Conclusions
Following the FDA approval of ivosidenib, all cases of MDS should have DNA sequencing performed at diagnosis to identify IDH1 mutations. Treatment induces high rates of remission even when polyclonal hematopoiesis does not recover. Moreover, the restoration of hematopoietic differentiation by the abnormal clone provides unique insights into the clinical phenotype and fitness advantage conferred by the co-existing driver mutations.
Background
IDH1 mutations are detected in 3-4% of MDS, nearly always with one or more co-mutations. Treatment with IDH1 inhibitor ivosidenib typically resulted in regression of the abnormal clone in 15 reported responders. However, in a few cases differentiation was restored from the abnormal clone. Here we report a durable MDS remission despite sustained proliferation of a clone with IDH1 and ZRSR2 mutations.
Case Presentation
A 49-year-old man developed severe neutropenia and macrocytic anemia in January 2019. Mild marrow dysplasia developed by March 2020 with IDH1 (31.1%) and splicing gene ZRSR2 (55.7%) mutations. In October 2022 biopsy showed MDS with 4% blasts, megakaryocytic/granulocytic hypoplasia, normal cytogenetics and 43% IDH1/89% ZRSR2. After azacytidine failure, ivosidenib was started in November 2023 following FDA approval. Within weeks ANCs increased from 170 to 1580 and hemoglobin from 7.9 to 11.6 with MCV 115, reticulocytes 1.72%. At 3 months a CBC was normal except for MCV 111. IDH1 and ZRSR2 were 36.4% and 71%. After 6 months, ANC was 2380, hemoglobin 14.7, MCV 108.6, reticulo-cytes 1.77%. IDH1 PCR showed a 33.1% allele frequency consistent with a clonal remission.
Discussion
IDH1 mutations in MDS/AML frequently co-occur with mutations in RNA splicing genes SRSF2 or ZRSR2. For ZRSR2, we previously reported that isolated mutations of this gene cause refractory macrocytic anemias without dysplasia, thus presenting as clonal cytopenias of undetermined significance (Fleischman et al., Leuk Res, 2017). In this MDS case, after ivosidenib treatment the ZRSR2 splicing defect sustained clonal dominance over polyclonal hematopoiesis while accounting for macrocytosis. Longitudinal data for two ivosidenib-treated IDH1/SRSF2 MDS cases are incomplete, but one case of IDH2/SRSF2 MDS treated with the inhibitor enasidenib similarly achieved complete remission without regression of the mutated clone for 12 months.
Conclusions
Following the FDA approval of ivosidenib, all cases of MDS should have DNA sequencing performed at diagnosis to identify IDH1 mutations. Treatment induces high rates of remission even when polyclonal hematopoiesis does not recover. Moreover, the restoration of hematopoietic differentiation by the abnormal clone provides unique insights into the clinical phenotype and fitness advantage conferred by the co-existing driver mutations.