IDALLO study: A retrospective multicenter study of the SFGM-TC evaluating the efficacy and safety of ivosidenib in relapsed IDH1-mutated AML after allogeneic hematopoietic cell transplantation.
Ontology highlight
ABSTRACT:
SUBMITTER: Caillet A
PROVIDER: S-EPMC10925725 | biostudies-literature | 2024 Mar
REPOSITORIES: biostudies-literature
Publications
IDALLO study: A retrospective multicenter study of the SFGM-TC evaluating the efficacy and safety of ivosidenib in relapsed IDH1-mutated AML after allogeneic hematopoietic cell transplantation.
Caillet Adrien A Simonet-Boissard Marion M Forcade Edouard E Robin Marie M Rubio Marie-Thérèse MT Couturier Marie-Anne MA Srour Micha M Maillard Natacha N Devillier Raynier R Huynh Anne A Bourhis Jean-Henri JH Simand Célestine C Chantepie Sylvain S Boisson Cyril C Kroemer Marie M Deconinck Eric E Berceanu Ana A
HemaSphere 20240310 3
Similar Datasets
Project description:Usually self-limited, hepatitis E virus (HEV) infection may evolve to chronicity and cirrhosis in immunosuppressed patients. HEV infection has been described in solid-organ transplantation and hematology patients, but for allogeneic hematopoietic stem cell transplant (alloHSCT) recipients, only small cohorts are available. This retrospective nationwide multi-center series aimed to describe HEV diagnostic practices in alloHSCT French centers, and the course of infection in the context of alloHSCT. Twenty-nine out of 37 centers participated. HEV search in case of liver function tests (LFT) abnormalities was never performed in 24% of centers, occasionally in 55%, and systematically in 21%. Twenty-five cases of active HEV infection were diagnosed in seven centers, all because of LFT abnormalities, by blood nucleic acid testing. HEV infection was diagnosed in three patients before alloHSCT; HEV infection did not influence transplantation planning, and resolved spontaneously before or after alloHSCT. Twenty-two patients were diagnosed a median of 283 days after alloHSCT. Nine patients (41%) had spontaneous viral clearance, mostly after immunosuppressive treatment decrease. Thirteen patients (59%) received ribavirin, with sustained viral clearance in 11/12 evaluable patients. We observed three HEV recurrences but no HEV-related death or liver failure, nor evolution to cirrhosis.
| S-EPMC6669459 | biostudies-literature
Project description:Isocitrate dehydrogenase (IDH) 1 and 2 mutations result in overproduction of D-2-hydroxyglutarate (2-HG) and impaired cellular differentiation. Ivosidenib, a targeted mutant IDH1 (mIDH1) enzyme inhibitor, can restore normal differentiation and results in clinical responses in a subset of patients with mIDH1 relapsed/refractory (R/R) acute myeloid leukemia (AML). We explored mechanisms of ivosidenib resistance in 174 patients with confirmed mIDH1 R/R AML from a phase 1 trial. Receptor tyrosine kinase (RTK) pathway mutations were associated with primary resistance to ivosidenib. Multiple mechanisms contributed to acquired resistance, particularly outgrowth of RTK pathway mutations and 2-HG-restoring mutations (second-site IDH1 mutations, IDH2 mutations). Observation of multiple concurrent mechanisms in individual patients underscores the complex biology of resistance and has important implications for rational combination therapy design. This trial was registered at www.clinicaltrials.gov as #NCT02074839.
| S-EPMC7218420 | biostudies-literature
Project description:This multicenter prospective phase 2 trial analyzed disease-free survival (DFS) in myelofibrosis patients receiving ruxolitinib for 6 months before transplantation. Seventy-six patients were recruited. Age-adjusted dynamic international prognostic scoring system was intermediate-1, intermediate-2, and high in 27 (36%), 31 (41%), and 18 (24%) patients. All patients received ruxolitinib from inclusion to conditioning regimen (fludarabine-melphalan) or to progression. A donor was found in 64 patients: 18 HLA-matched sibling donor (MSD), 32 HLA-matched unrelated (UD10/10), and 14 HLA mismatched unrelated donor (UD9/10. Among 64 patients with a donor, 20 (31%) achieved a partial response before transplantation and 59 (92%) could be transplanted after ruxolitinib therapy (18/18 MSD, 30/21 UD10/10, 11/34 UD9/10), of whom 19 (32%) were splenectomized. Overall survival from inclusion was 68% at 12 months. One-year DFS after transplantation was 55%: 83%, 40%, and 34% after MSD, UD10/10 or UD9/10, respectively. Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) was 66% and non-relapse-mortality was 42% at 12 months. Short course of ruxolitinib before transplantation is followed by a high rate of transplantation. With the platform used in this protocol, outcome was much better in patients transplanted with HLA-matched sibling donor as compared to unrelated donor.
| S-EPMC7992510 | biostudies-literature
Project description:The prognosis of patients with relapsed or refractory acute myeloid leukemia (R/R AML) is discouraging with salvage standard approaches. Mutations of isocitrate dehydrogenase 1 (IDH1 mut ), present in 7-14% of AML patients, have been discovered recently, opening the door to targeted agents aiming to improve the outcomes in this setting. Several oral selective IDH1 mut inhibitors are under investigation, ivosidenib being the first approved for R/R AML. We performed a systematic review to analyze the clinical outcomes and safety reported with IDH1 mut inhibitors and other agents in adult patients with IDH1 mut R/R AML. Ivosidenib in monotherapy achieved complete remission (CR) of 24%, overall response of 42%, and median overall survival of 9 months in R/R AML, and promising outcomes were reported with IDH305 and FT-2102. IDH1 mut inhibitors were generally well tolerated, but some therapy-related toxicities should be monitored, including IDH-differentiation syndrome, prolongation of the QT interval, and leukocytosis, all manageable and reversible. Also, venetoclax, CB-839, PARP inhibitors, and IDH1 peptide vaccine are being studied in IDH1mut AML. The results of the ongoing and upcoming clinical trials will bring new evidence to establish the role of IDH1 mut inhibitors in therapeutic strategies of AML.
| S-EPMC6663038 | biostudies-literature
Project description:Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Overall, 153 IDH1 inhibitor-naive patients with mIDH1R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) received olutasidenib monotherapy 150 mg twice daily in the pivotal cohort of this study. The median age of participants was 71 years (range, 32-87 years) and the median number of prior regimens received by patients was 2 (1-7). The rate of complete remission (CR) plus CR with partial hematologic recovery (CRh) was 35%, and the overall response rate was 48%. Response rates were similar in patients who had, and who had not, received prior venetoclax. With 55% of patients censored at the time of data cut-off, the median duration of CR/CRh was 25.9 months. The median duration of overall response was 11.7 months, and the median overall survival was 11.6 months. Of 86 patients who were transfusion dependent at baseline, a 56-day transfusion independence was achieved in 29 (34%), which included patients in all response groups. Grade 3 or 4 treatment-emergent adverse events (≥10%) were febrile neutropenia and anemia (n = 31; 20% each), thrombocytopenia (n = 25; 16%), and neutropenia (n = 20; 13%). Differentiation syndrome adverse events of special interest occurred in 22 (14%) patients, with 14 (9%) grade ≥3 and 1 fatal case reported. Overall, olutasidenib induced durable remissions and transfusion independence with a well-characterized and manageable side effect profile. The observed efficacy represents a therapeutic advance in this molecularly defined, poor-prognostic population of patients with mIDH1 R/R AML. This trial was registered at www.clinicaltrials.gov as #NCT02719574.
| S-EPMC10362540 | biostudies-literature
Project description:The safety and efficacy of combining the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO + VEN) ± azacitidine (AZA; IVO + VEN + AZA) were evaluated in four cohorts of patients with IDH1-mutated myeloid malignancies (n = 31). Most (91%) adverse events were grade 1 or 2. The maximal tolerated dose was not reached. Composite complete remission with IVO + VEN + AZA versus IVO + VEN was 90% versus 83%. Among measurable residual disease (MRD)-evaluable patients (N = 16), 63% attained MRD--negative remissions; IDH1 mutation clearance occurred in 64% of patients receiving ≥5 treatment cycles (N = 14). Median event-free survival and overall survival were 36 [94% CI, 23-not reached (NR)] and 42 (95% CI, 42-NR) months. Patients with signaling gene mutations appeared to particularly benefit from the triplet regimen. Longitudinal single-cell proteogenomic analyses linked cooccurring mutations, antiapoptotic protein expression, and cell maturation to therapeutic sensitivity of IDH1-mutated clones. No IDH isoform switching or second-site IDH1 mutations were observed, indicating combination therapy may overcome established resistance pathways to single-agent IVO.SignificanceIVO + VEN + AZA is safe and active in patients with IDH1-mutated myeloid malignancies. Combination therapy appears to overcome resistance mechanisms observed with single-agent IDH-inhibitor use, with high MRD-negative remission rates. Single-cell DNA ± protein and time-of-flight mass-cytometry analysis revealed complex resistance mechanisms at relapse, highlighting key pathways for future therapeutic intervention. This article is highlighted in the In This Issue feature, p. 247.
| S-EPMC10320628 | biostudies-literature
Project description: Not available
| S-EPMC8464620 | biostudies-literature
Project description: Not available
| S-EPMC7933161 | biostudies-literature
Project description:Immune evasion is a hallmark of cancer and a central mechanism underlying acquired resistance to immune therapy. In allogeneic hematopoietic cell transplantation (alloHCT), late relapses can arise after prolonged alloreactive T-cell control, but the molecular mechanisms of immune escape remain unclear. To identify mechanisms of immune evasion, we performed a genetic analysis of serial samples from 25 patients with myeloid malignancies who relapsed ≥1 year after alloHCT. Using targeted sequencing and microarray analysis to determine HLA allele-specific copy number, we identified copy-neutral loss of heterozygosity events and focal deletions spanning class 1 HLA genes in 2 of 12 recipients of matched unrelated-donor HCT and in 1 of 4 recipients of mismatched unrelated-donor HCT. Relapsed clones, although highly related to their antecedent pretransplantation malignancies, frequently acquired additional mutations in transcription factors and mitogenic signaling genes. Previously, the study of relapse after haploidentical HCT established the paradigm of immune evasion via loss of mismatched HLA. Here, in the context of matched unrelated-donor HCT, HLA loss provides genetic evidence that allogeneic immune recognition may be mediated by minor histocompatibility antigens and suggests opportunities for novel immunologic approaches for relapse prevention.
| S-EPMC6650729 | biostudies-literature
Project description:To study the mechanism of resistance to ivosidenib, we developed a model of acquired drug resistance by treating ivosidenib-sensitive OCI-mIDH1/N cells continuously with ivosidenib in culture for a period of 2 months followed by a drug washout period. The resulting cell population (OCI-mIDH1/N-R cells) failed to differentiate upon ivosidenib treatment. We then performed RNA sequencing (RNA-seq) analysis of OCI-mIDH1/N and OCI-mIDH1/N-R cells.
2022-11-08 | GSE217441 | GEO