ABSTRACT
The evaluation of measurable residual disease (MRD) in acute myeloid leukemia (AML) using comprehensive mutation analysis by next-generation sequencing (NGS) has been investigated in several studies. However controversial results exist regarding the detection of persisting mutations in DNMT3A, TET2, and ASXL1 (DTA). Benchmarking of NGS-MRD taking into account other molecular MRD strategies has to be done. Here, we performed error-corrected-NGS-MRD in 189 patients homogeneously treated in the ALFA-0702 study (NCT00932412). Persistence of non-DTA mutations (HR = 2.23 for RFS and 2.26 for OS), and DTA mutations (HR = 2.16 for OS) were associated with poorer prognosis in multivariate analysis. Persistence of at least two mutations in complete remission (CR) was associated with a higher cumulative incidence of relapse (CIR) (HR = 3.71, p < 0.0001), lower RFS (HR = 3.36, p < 0.0001) and OS (HR = 3.81, p = 0.00023) whereas persistence of only one mutation was not. In 100 analyzable patients, WT1-MRD, but not NGS-MRD, was an independent factor for RFS and OS. In the subset of 67 NPM1 mutated patients, both NPM1 mutation detection (p = 0.0059) and NGS-MRD (p = 0.035) status were associated with CIR. We conclude that detectable NGS-MRD including DTA mutations correlates with unfavorable prognosis in AML. Its integration with alternative MRD strategies in AML management warrants further investigations.
Subject(s)
High-Throughput Nucleotide Sequencing , Leukemia, Myeloid, Acute , Mutation , Neoplasm, Residual , Nucleophosmin , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Female , Male , Middle Aged , Adult , Aged , Young Adult , Prognosis , DNA Methyltransferase 3A , Aged, 80 and over , DNA (Cytosine-5-)-Methyltransferases/genetics , Adolescent , Repressor Proteins/genetics , DNA Mutational AnalysisABSTRACT
PURPOSE: With liquid biopsy's widespread adoption in oncology, an increased number of clonal hematopoiesis-associated mutations (CHm) have been identified in patients with solid tumors. However, its impact on patient outcomes remains unclear. This study aimed to analyze and describe CHm in a cohort of phase I patients. METHODS: Retrospective data collection from medical records and molecular profiles (Foundation One Liquid CDx Assay) was performed before first study drug administration at the Drug Development Department of Gustave Roussy (France) within the STING trial (ClinicalTrials.gov identifier: NCT04932525). CHm prevalence was assessed using any and ≥1% variant allele frequency (VAF) in epigenetic modifier genes (DNMT3A, TET2, and ASXL1). RESULTS: From January 2021 to December 2022, 255 patients were enrolled in a phase I clinical trial. A total of 55% were male, with a median age of 62 years (24-86). Principal tumor locations were GI (27%) and genitourinary (21%). Overall, 104 patients (41%) had at least one CHm in liquid biopsy, with 55 patients (22%) having a VAF of ≥ 1%. The most frequent mutation was DNMT3A 73% at any VAF (n = 76) and 22% at 1% VAF (n = 23). Median progression-free survival (PFS) and overall survival were 3.8 months (m) for the CHm group versus 3.2 m for nonclonal hematopoiesis (CH; P = .08) and 18.26 m CHm versus 15.8 m non-CH (P = .9), respectively. PFS increased in the CHm population treated with targeted therapy (hazard ratio, 0.6 [95% CI, 0.42 to 0.84]; P = .004). CONCLUSION: CHm was commonly found in patients with solid tumors treated in phase I trials, with a prevalence of 41% in our cohort. The most frequently mutated gene was DNMT3A. The presence of CHm had no impact on the population of patients treated in the phase I trials.
Subject(s)
Clonal Hematopoiesis , Mutation , Neoplasms , Humans , Male , Middle Aged , Female , Aged , Adult , Neoplasms/genetics , Neoplasms/drug therapy , Retrospective Studies , Aged, 80 and over , Young Adult , Clonal Hematopoiesis/geneticsABSTRACT
Next-generation sequencing (NGS) assays based on plasma cell-free DNA (cfDNA) are increasingly used for clinical trials inclusion. Their optimized limit of detection applied to a large number of genes leads to the identification of mutations not confirmed in tissue. It becomes essential to describe the characteristics and consequences of these liquid biopsy-only mutations. In the STING protocol (Gustave Roussy, NCT04932525), 542 patients with advanced solid cancer had cfDNA-based and tissue-based NGS analysis (performed by FoundationOne® Liquid CDx and FoundationOne CDx™, respectively). Mutations identified in the liquid biopsy but not in the paired tissue were considered as liquid biopsy-only mutations irrespective of their variant allelic frequency (VAF). Out of 542 patients, 281 (51.8%) harbored at least one liquid biopsy-only mutation. These patients were significantly older, and more heavily pretreated. Liquid biopsy-only mutations occurring in TP53, and in DDR genes (ATM, CHEK2, ATR, BRCA2, and BRCA1) accounted for 90.8% of all the mutations. The median VAF of these mutations was generally low (0.37% and 0.40% for TP53 and DDR genes respectively). The variant type repartition depended on the gene. Liquid biopsy-only mutations affected hotspot in TP53 codon 273, 125, 195, 176, 237 or 280 and ATM codon 2891 and 3008. In a subset of 37 patients, 75.0%, 53.5% and 83.3% of the liquid biopsy-only mutations occurring respectively in ATM, TP53, and CHEK2 were confirmed in the matching whole blood sample. Although liquid biopsy-only mutations makes the interpretation of liquid biopsy results more complex, they have distinct characteristics making them more easily identifiable.
Subject(s)
Cardiovascular Diseases , Neoplasms , Humans , Clonal Hematopoiesis , Neoplasms/genetics , Aging , Patient Care , Hematopoiesis , MutationABSTRACT
Key Clinical Message: This is the first case of a promyelocytic sarcoma diagnosed on pleural effusion and exposed the difficulty of demonstrating a leukemic phase in patients with bone diseases, such as Gorham's disease. It also showed that promyelocytic sarcoma can be treated by ATRA/ATO-based therapy with an efficient and tolerated response. Abstract: Myeloid sarcoma (MS) is a rare extramedullary tumoral infiltration of immature myeloid cells and can occur in different sites of the body, without leukemic infiltration. A 38-year-old woman patient presented at emergency with a pleural effusion, bicytopenias, and Gorham's disease, a very rare bone disorder. In the following days, she worsened with a chylothorax and pancytopenias. Pleural puncture cytologically revealed promyelocytes with Auer rods. Cytogenetic and molecular analyses subsequently confirmed the presence of the t(15:17) translocation. However, no circulating phase of these atypical promyelocytes was found. Similarly, no other origin was identified. We conclude that the patient had a MS of unknown etiology in the form of a pleural effusion with pathological promyelocytes. The patient was treated with a combination of oral all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) with a cytological and molecular remission persisting 3 months after diagnosis. We report here the first case of a promyelocytic MS of pleural origin without concomitant evidence of acute promyelocytic leukemia. We also show the efficacy of ATRA/ATO treatment in this etiology.
ABSTRACT
We report the results from a multicentre retrospective study of 220 adult patients who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) for therapy-related acute myeloid leukaemia (t-AML). Median age at t-AML diagnosis was 56 years, with a prior history of haematological (45%) or breast (34%). Median time from cytotoxic exposure to t-AML diagnosis was 54.7 months. At transplant, around 20% of patients had measurable residual disease and 3% of patients were not in complete remission. The median follow-up was 21.4 months (Q1-Q3, 5.9-52.8). At 12 months, overall survival (OS), event-free survival (EFS), and graft-versus-host-disease (GVHD)-free-relapse-free survival (GRFS) were 60.7% (95% CI 54.6-67.5), 52.8% (95% CI 46.5-68.4), and 44.1% (95% CI 37.6-51.8), respectively. At 5 years, OS, EFS, and GRFS were 44.1% (95% CI 37.4-52.1), 40.4% (95% CI 33.9-48.1), and 35.3% (95% CI 28.8-43.3), respectively. At last follow-up, 44% of patients were in complete remission (n = 96) and transplant-related mortality accounted for 21% of all deaths (n = 119). Multivariable analysis revealed that uncontrolled t-AML at transplant was associated with lower EFS (HR 1.94, 95% CI 1.0-3.7, p = 0.041). In conclusion, alloHSCT for t-AML shows encouraging results and offers additional opportunity with the emergence of novel pre-graft therapies.
Subject(s)
Antineoplastic Agents , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Humans , Adult , Middle Aged , Retrospective Studies , Neoplasm Recurrence, Local , Leukemia, Myeloid, Acute/therapy , Transplantation Conditioning/methodsABSTRACT
Therapy-related myelodysplastic syndromes (t-MDS) represent a heterogeneous group of malignancies that arise as a late complication of prior exposure to chemotherapy and/or radiotherapy administered for a primary condition. T-MDS account for approximately 20% of all MDS and are characterized by resistance to current treatment strategies and poor prognosis. Our understanding of t-MDS pathogenesis has considerably improved over the last 5 years with the availability of deep sequencing technologies. T-MDS development is now considered as a multifactorial process resulting from complex interactions between an underlying germline genetic susceptibility, the stepwise acquisition of somatic mutations in hematopoietic stem cells, the clonal selection pressure exerted by cytotoxic therapies, and alterations of the bone marrow microenvironment. The survival of patients with t-MDS is generally poor. This can be explained by both patient-related factors including poor performance status and less tolerance to treatment and disease-related factors, such as the presence of chemoresistant clones, high-risk cytogenetic alterations and molecular features (e.g. high frequency of TP53 mutations). Around 50% of t-MDS patients are classified as high/very high risk based on IPSS-R or IPSS-M scores, versus 30% in de novo MDS. Long-term survival is only achieved in a minority of t-MDS patients who receive allogeneic stem cell transplantation, but the development of novel drugs may open new therapeutic opportunities, especially in unfit patients. Further investigations are needed to improve the identification of patients at higher risk of developing t-MDS and determine whether primary disease treatment can be modified to prevent the occurrence of t-MDS.
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Neoplasms, Second Primary , Humans , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/therapy , Leukemia, Myeloid, Acute/genetics , Bone Marrow , Neoplasms, Second Primary/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Prognosis , Tumor MicroenvironmentABSTRACT
Tandem duplications (TDs) of the UBTF gene have been recently described as a recurrent alteration in pediatric acute myeloid leukemia (AML). Here, by screening 1946 newly diagnosed adult AML, we found that UBTF-TDs occur in about 3% of patients aged 18-60 years, in a mutually exclusive pattern with other known AML subtype-defining alterations. The characteristics of 59 adults with UBTF-TD AML included young age (median 37 years), low bone marrow (BM) blast infiltration (median 25%), and high rates of WT1 mutations (61%), FLT3-ITDs (51%) and trisomy 8 (29%). BM morphology frequently demonstrates dysmyelopoiesis albeit modulated by the co-occurrence of FLT3-ITD. UBTF-TD patients have lower complete remission (CR) rates (57% after 1 course and 76% after 2 courses of intensive chemotherapy [ICT]) than UBTF-wild-type patients. In patients enrolled in the ALFA-0702 study (n = 614 patients including 21 with UBTF-TD AML), the 3-year disease-free survival (DFS) and overall survival of UBTF-TD patients were 42.9% (95%CI: 23.4-78.5%) and 57.1% (95%CI: 39.5-82.8%) and did not significantly differ from those of ELN 2022 intermediate/adverse risk patients. Finally, the study of paired diagnosis and relapsed/refractory AML samples suggests that WT1-mutated clones are frequently selected under ICT. This study supports the recognition of UBTF-TD AML as a new AML entity in adults.
Subject(s)
Leukemia, Myeloid, Acute , Adult , Child , Humans , Disease-Free Survival , fms-Like Tyrosine Kinase 3/genetics , Leukemia, Myeloid, Acute/genetics , Mutation , Prognosis , Remission InductionABSTRACT
PURPOSE: High-risk clonal hematopoiesis (CH) is frequently incidentally found in patients with solid tumors undergoing plasma cell-free DNA sequencing. Here, we aimed to determine if the incidental detection of high-risk CH by liquid biopsy may reveal occult hematologic malignancies in patients with solid tumors. MATERIALS AND METHODS: Adult patients with advanced solid cancers enrolled in the Gustave Roussy Cancer Profiling study (ClinicalTrials.gov identifier: NCT04932525) underwent at least one liquid biopsy (FoundationOne Liquid CDx). Molecular reports were discussed within the Gustave Roussy Molecular Tumor Board (MTB). Potential CH alterations were observed, and patients referred to hematology consultation in the case of pathogenic mutations in JAK2, MPL, or MYD88, irrespective of the variant allele frequency (VAF), or in DNMT3A, TET2, ASXL1, IDH1, IDH2, SF3B1, or U2AF1 with VAF ≥ 10%, while also considering patient cancer-related prognosis. TP53 mutations were discussed case-by-case. RESULTS: Between March and October 2021, 1,416 patients were included. One hundred ten patients (7.7%) carried at least one high-risk CH mutation: DNMT3A (n = 32), JAK2 (n = 28), TET2 (n = 19), ASXL1 (n = 18), SF3B1 (n = 5), IDH1 (n = 4), IDH2 (n = 3), MPL (n = 3), and U2AF1 (n = 2). The MTB advised for hematologic consultation in 45 patients. Overall, 9 patients of 18 actually addressed had confirmed hematologic malignancies that were occult in six patients: two patients had myelodysplastic syndrome, two essential thrombocythemia, one a marginal lymphoma, and one a Waldenström macroglobulinemia. The other three patients were already followed up in hematology. CONCLUSION: The incidental findings of high-risk CH through liquid biopsy may trigger diagnostic hematologic tests and reveal an occult hematologic malignancy. Patients should have a multidisciplinary case-by-case evaluation.
Subject(s)
Circulating Tumor DNA , Hematologic Neoplasms , Hematology , Neoplasms, Unknown Primary , Adult , Humans , Circulating Tumor DNA/genetics , Splicing Factor U2AF , Hematologic Neoplasms/genetics , Transcription Factors , Liquid BiopsyABSTRACT
PURPOSE: To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi). EXPERIMENTAL DESIGN: In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort. RESULTS: From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4-14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046; P = 0.02), olaparib compared with other PARPi (HR, 5.82; P = 0.003) and acute myeloid leukemia (HR, 2.485; P = 0.01) were associated with shorter OS. CONCLUSIONS: In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.
Subject(s)
Neoplasms, Second Primary , Ovarian Neoplasms , Female , Humans , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Carcinoma, Ovarian Epithelial , Mutation , Germ-Line Mutation , Neoplasms, Second Primary/diagnosis , Neoplasms, Second Primary/epidemiologyABSTRACT
BACKGROUND: Acute abdominal complications (AAC) in patients with deep neutropenia (DN) is challenging to manage because of the expected influence of AAC on oncological prognosis and higher surgical complication rate in a period of DN. In practice, these parameters are difficult to appreciate. This study reported our experience in managing these patients. METHODS: All consecutive patients treated in our tertiary care cancer center between 2010 and 2020 who developed AAC in the context of a DN were retrospectively analyzed. AAC was defined as an infection (intra-abdominal, perineal, or cutaneous), bowel obstruction, or intra-abdominal hemorrhage. FINDINGS: Among 105 patients, 18 (17%) required emergent surgery (group 1), 34 patients had a complication requiring surgical oversight (group 2), and 53 patients had a non-surgical etiology (group 3). Fifteen patients underwent surgery in the group 1, three in group 2, and one in group 3. Overall, 28 patients died during hospitalization. Mortality was statistically different between the groups (p = 0·01), with a higher rate in group 1 (n = 9/18, 50%) than in group 2 (n = 11/34, 32%) and group 3 (n = 8/53, 15%). All groups together had a median overall survival (OS) of 14 months and disease-free survival (DFS) of 10 months. OS was not comparable between the groups, and the median length of survival in group 1 was 6 months versus 8 months in group 2 and 23 months in group 3. In group 1, five patients (5/18, 28%) did not relapse at the end of the follow-up compared to 13 in group 2 (13/34, 38%) and 25 in group 3 (25/53, 47%). After discharge, OS and DFS were similar between the groups. INTERPRETATION: The advent of an AAC necessitating surgery in the context of DN is a deadly event associated with a 50% mortality; nonetheless, in case of unpostponable emergencies, surgery can provide long-term survival in selected patients.
Subject(s)
Hematology , Intestinal Obstruction , Disease-Free Survival , Humans , Intestinal Obstruction/etiology , Intestinal Obstruction/surgery , Prognosis , Retrospective StudiesABSTRACT
FDA-approved next-generation sequencing assays based on cell-free DNA offers new opportunities in a molecular-tumor-board context thanks to the noninvasiveness of liquid biopsy, the diversity of analyzed parameters and the short turnaround time. It gives the opportunity to study the heterogeneity of the tumor, to elucidate complex resistance mechanisms and to adapt treatment strategies. However, lowering the limit of detection and increasing the panels' size raise new questions in terms of detection of incidental germline alterations, occult malignancies and clonal hematopoiesis of indeterminate potential mutations. In this review, after a technological discussion and description of the common problematics encountered, we establish recommendations in properly using these FDA-approved tests in a molecular-tumor-board context.
Subject(s)
Cell-Free Nucleic Acids , Circulating Tumor DNA , Neoplasms , Circulating Tumor DNA/genetics , High-Throughput Nucleotide Sequencing , Humans , Liquid Biopsy , Neoplasms/genetics , United States , United States Food and Drug AdministrationABSTRACT
DDX41 germline mutations (DDX41MutGL) are the most common genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia (AML). Recent reports suggest that DDX41MutGL myeloid malignancies could be considered as a distinct entity, even if their specific presentation and outcome remain to be defined. We describe here the clinical and biological features of 191 patients with DDX41MutGL AML. Baseline characteristics and outcome of 86 of these patients, treated with intensive chemotherapy in 5 prospective Acute Leukemia French Association/French Innovative Leukemia Organization trials, were compared with those of 1604 patients with DDX41 wild-type (DDX41WT) AML, representing a prevalence of 5%. Patients with DDX41MutGL AML were mostly male (75%), in their seventh decade, and with low leukocyte count (median, 2 × 109/L), low bone marrow blast infiltration (median, 33%), normal cytogenetics (75%), and few additional somatic mutations (median, 2). A second somatic DDX41 mutation (DDX41MutSom) was found in 82% of patients, and clonal architecture inference suggested that it could be the main driver for AML progression. DDX41MutGL patients displayed higher complete remission rates (94% vs 69%; P < .0001) and longer restricted mean overall survival censored at hematopoietic stem cell transplantation (HSCT) than 2017 European LeukemiaNet intermediate/adverse (Int/Adv) DDX41WT patients (5-year difference in restricted mean survival times, 13.6 months; P < .001). Relapse rates censored at HSCT were lower at 1 year in DDX41MutGL patients (15% vs 44%) but later increased to be similar to Int/Adv DDX41WT patients at 3 years (82% vs 75%). HSCT in first complete remission was associated with prolonged relapse-free survival (hazard ratio, 0.43; 95% confidence interval, 0.21-0.88; P = .02) but not with longer overall survival (hazard ratio, 0.77; 95% confidence interval, 0.35-1.68; P = .5).
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , DEAD-box RNA Helicases/genetics , Female , Germ-Line Mutation , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/therapy , Male , Prognosis , Prospective Studies , Retrospective StudiesABSTRACT
The germline predisposition associated with the autosomal dominant inheritance of the 14q32 duplication implicating ATG2B/GSKIP genes is characterized by a wide clinical spectrum of myeloid neoplasms. We analyzed 12 asymptomatic carriers and 52 patients aged 18-74 years from six families, by targeted sequencing of 41 genes commonly mutated in myeloid malignancies. We found that 75% of healthy carriers displayed early clonal hematopoiesis mainly driven by TET2 mutations. Molecular landscapes of patients revealed two distinct routes of clonal expansion and leukemogenesis. The first route is characterized by the clonal dominance of myeloproliferative neoplasms (MPN)-driver events associated with TET2 mutations in half of cases and mutations affecting splicing and/or the RAS pathway in one-third of cases, leading to the early development of MPN, mostly essential thrombocythemia, with a high risk of transformation (50% after 10 years). The second route is distinguished by the absence of MPN-driver mutations and leads to AML without prior MPN. These patients mostly harbored a genomic landscape specific to acute myeloid leukemia secondary to myelodysplastic syndrome. An unexpected result was the total absence of DNMT3A mutations in this cohort. Our results suggest that the germline duplication constitutively mimics hematopoiesis aging by favoring TET2 clonal hematopoiesis.
Subject(s)
Autophagy-Related Proteins/genetics , Chromosomes, Human, Pair 14/genetics , Clonal Hematopoiesis , Gene Duplication , Leukemia, Myeloid, Acute/pathology , Myelodysplastic Syndromes/pathology , Myeloproliferative Disorders/pathology , Repressor Proteins/genetics , Vesicular Transport Proteins/genetics , Adolescent , Adult , Aged , Biomarkers, Tumor/genetics , Case-Control Studies , DNA Copy Number Variations , Disease Susceptibility , Female , Follow-Up Studies , Germ Cells , Humans , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Mutation , Myelodysplastic Syndromes/genetics , Myeloproliferative Disorders/genetics , Prognosis , Retrospective Studies , Survival Rate , Young AdultABSTRACT
WT1 overexpression is frequently identified in acute myeloid leukemia (AML) and has been reported to be a potential marker for monitoring measurable residual disease (MRD). We evaluated the use of postinduction WT1 MRD level as a prognostic factor, as well as the interaction between postinduction WT1 MRD response and the effect of allogeneic stem cell transplantation (allo-SCT) in the first complete remission (CR). In the ALFA-0702 trial, patients with AML, aged 18 to 59, had a prospective quantification of WT1 MRD. The occurrence of a WT1 MRD ratio >2.5% in bone marrow or >0.5% in peripheral blood was defined as MRDhigh, and ratios below these thresholds were defined as MRDlow. The prognostic value of MRD after induction chemotherapy was assessed in 314 patients in first CR by comparing the risk of relapse, the relapse-free survival (RFS), and the overall survival (OS). Interaction between MRD response and the allo-SCT effect was evaluated in patients by comparing the influence of allo-SCT on the outcomes of patients with MRDhigh with those with MRDlow. The results showed that patients with MRDhigh after induction had a higher risk of relapse and a shorter RFS and OS. The MRD response remained of strong prognostic value in the subset of 225 patients with intermediate-/unfavorable-risk AML who were eligible for allo-SCT, because patients with MRDhigh had a significantly higher risk of relapse resulting in worse RFS and OS. The effect of allo-SCT was higher in patients with MRDlow than in those with MRDhigh, but not significantly different. The early WT1 MRD response highlights a population of high-risk patients in need of additional therapy.
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Adolescent , Adult , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/therapy , Middle Aged , Neoplasm, Residual , Prognosis , WT1 Proteins , Young AdultABSTRACT
Translocation t(4;12)(q11-13;p13) is a recurrent but very rare chromosomal aberration in acute myeloid leukaemia (AML) resulting in the non-constant expression of a CHIC2/ETV6 fusion transcript. We report clinico-biological features, molecular characteristics and outcomes of 21 cases of t(4;12) including 19 AML and two myelodysplastic syndromes (MDS). Median age at the time of t(4;12) was 78 years (range, 56-88). Multilineage dysplasia was described in 10 of 19 (53%) AML cases and CD7 and/or CD56 expression in 90%. FISH analyses identified ETV6 and CHIC2 region rearrangements in respectively 18 of 18 and 15 of 17 studied cases. The t(4;12) was the sole cytogenetic abnormality in 48% of cases. The most frequent associated mutated genes were ASXL1 (n = 8/16, 50%), IDH1/2 (n = 7/16, 44%), SRSF2 (n = 5/16, 31%) and RUNX1 (n = 4/16, 25%). Interestingly, concurrent FISH and molecular analyses showed that t(4;12) can be, but not always, a founding oncogenic event. Median OS was 7.8 months for the entire cohort. In the 16 of 21 patients (76%) who received antitumoral treatment, overall response and first complete remission rates were 37% and 31%, respectively. Median progression-free survival in responders was 13.7 months. Finally, t(4;12) cases harboured many characteristics of AML with myelodysplasia-related changes (multilineage dysplasia, MDS-related cytogenetic abnormalities, frequent ASXL1 mutations) and a poor prognosis.
Subject(s)
Chromosomes, Human, Pair 12 , Chromosomes, Human, Pair 4 , Genetic Predisposition to Disease , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/genetics , Translocation, Genetic , Aged , Aged, 80 and over , Biomarkers, Tumor , Chromosome Aberrations , Cytogenetic Analysis , Female , Genetic Association Studies , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/etiology , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/etiology , Myelodysplastic Syndromes/mortality , Myelodysplastic Syndromes/therapy , Myeloproliferative Disorders/mortality , Myeloproliferative Disorders/therapy , PrognosisABSTRACT
Definition of therapy-related myeloid neoplasms (TRMN) is only based on clinical history of exposure to leukemogenic therapy. No specific molecular classification combining therapy-related acute myeloid leukemia and therapy-related myelodysplastic syndromes has been proposed. We aimed to describe the molecular landscape of TRMN at diagnosis, among 77 patients with previous gynecologic and breast cancer with a dedicated next-generation sequencing panel covering 74 genes. We investigated the impact of clonal hematopoiesis of indeterminate potential-associated mutations (CHIP-AMs defined as presence at TRMN stage of mutations described in CHIP with a frequency >1%) on overall survival (OS) and the clinical relevance of a modified genetic ontogeny-based classifier that categorized patients in 3 subgroups. The most frequently mutated genes were TP53 (31%), DNMT3A (19%), IDH1/2 (13%), NRAS (13%), TET2 (12%), NPM1 (10%), PPM1D (9%), and PTPN11 (9%). CHIP-AMs were detected in 66% of TRMN patients, with no impact on OS. Yet, patients with CHIP-AM were older and had a longer time interval between solid tumor diagnosis and TRMN. According to our modified ontogeny-based classifier, we observed that the patients with TP53 or PPM1D mutations had more treatment lines and complex karyotypes, the "MDS-like" patients were older with more gene mutations, while patients with "De novo/pan-AML" mutations were younger with more balanced chromosomal translocations. Median OS within each subgroup was 7.5, 14.5, and 25.2 months, respectively, with statistically significant difference in multivariate analysis. These results support the integration of cytogenetic and molecular markers into the future TRMN classification to reflect the biological diversity of TRMN and its impact on outcomes.