scholarly journals Long-term follow-up results of the combination of topotecan and cytarabine and other intensive chemotherapy regimens in myelodysplastic syndrome

Cancer ◽  
2006 ◽  
Vol 106 (5) ◽  
pp. 1099-1109 ◽  
Author(s):  
Hagop Kantarjian ◽  
Miloslav Beran ◽  
Jorge Cortes ◽  
Susan O'Brien ◽  
Francis Giles ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Intensive Chemotherapy ◽  
Long Term Follow Up

scholarly journals Emergence ofNPM1Wild-Type Myeloid Neoplasms after Chemotherapy for Acute Leukemia withNPM1Mutation: Proposed Mechanisms of Clonal Evolution

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Sandra Castaño-Díez ◽  
Monica Lopez-Guerra ◽  
Francesca Guijarro ◽  
Alex Bataller Torralba ◽  
Daniel Esteban ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Intensive Chemotherapy ◽  
Next Generation ◽  
Genetic Event ◽  
Clonal Hematopoiesis ◽  
Paired Samples ◽  
Myeloid Neoplasm ◽  
Long Term Follow Up

Introduction NPM1mutation is considered a founder genetic event of acute myeloid leukemia withNPM1mutation (NPM1mut-AML). Nonetheless, growing evidence of pre-existing genetic mutations and clonal hematopoiesis (clonal response) after intensive AML treatment in many patients is being generated, although the precise clinical impact of this genetic background is mostly unknown. Thus, the emergence of a wild-typeNPM1myeloid neoplasm (NPM1wt-MN) after intensive chemotherapy treatment forNPM1mut-AML is a well-known phenomenon, but poorly described in long-term follow-up. Sequential genetic analysis with next generation sequencing (NGS) has the potential to elucidate the clonal origin of diverse emerging clinical scenarios occurring during clinical follow-up based on tracking of genetic evolution of clonal hematopoiesis status after AML treatment, as recently proposed (Hasserjian et al, Blood 2020). We aimed to analyze the incidence and clinico-biological characteristics ofNPM1wt-MN emerging after treatment forNPM1mut-AML in a long-term follow-up series from a single institution. Patients and Methods We included in the study 62 patients diagnosed withNPM1mutAML patients and treated with intensive chemotherapy according to two consecutive protocols of the Spanish CETLAM cooperative group (CETLAM-2003 and -2012). Patients were diagnosed between 2005 and May 2019.NPM1wt-MN has been classified according to recent criteria proposed by Hasserjian et al, Blood 2020. Statistical analyses were performed using Rv3.1 and SPSS v20. Next generation targeted sequencing (NGS) was performed with Ion Ampliseq AML Research and Oncomine Myeloid Research Assay panel. Results The cohort included 62 patients (median age, 53 years, 25-73) with a median follow-up of alive patients of 44 months. After induction therapy, 58 patients (pt) achieved complete remission (CR) and 21 pt relapsed asNPM1mut-AML. Additionally, 9 pts (15%) developed aNPM1wt-MN: 4 (7%) presented aNPM1wt-AML relapse and 5 (8%) developed otherNPM1wt-MN (non-AMLNPM1wt-MN) that would be classified as residual myeloid neoplasm according to proposed criteria: 1 myelodysplastic syndrome, 3 myeloproliferative/myelodysplastic syndrome [2 CMML and 1 atypical chronic myeloid leukemiaBCR-ABLnegative (aCML)] and 1 polycythemia vera (PV) Characteristics of the 3 groups (NPM1mut-AML,NPM1wt-AML, non-AMLNPM1wt-MN) are shown in the Table. Median time from CR achievement to progression was longer in the group who developed a non-AMLNPM1wt(24 vs 8 months; p=0.016), and an statistical trend of younger ager in pts with AML-NPM1mutgroup (48 vs 69 vs 60 years-old, respectively, p=0.056) and lower leucocyte count in pt presenting a non-AMLNPM1wt-MN (5.5 vs 29 vs 50 x109/L, respectively, p=0.065) were observed. Moreover, among 19 pts with available NGS at diagnosis,DNMT3Amutation was more frequently comutated inNPM1mut-AML (71% vs 0%vs 40%, respectively p=0.034) andSRSF2was more frequently mutated in non-AMLNPM1wt-MN (60% vs others (0%), p=0.01). Interestingly, outcome of patients presenting with AML relapse did not differ according to NPM1 status at relapse (NPM1mut-AML vs.NPM1wt-AML), with a similar response rate after salvage chemotherapy (80% vs 75%, p=NS) and OS (5-year OS: 75±40% vs 60±20%; p=NS). NGS analysis of paired samples at diagnosis and emergentNPM1wt-MN in pts who lostNPM1mutation at progression is detailed in Figure. Frequently persisting mutations were those usually found in clonal hematopoiesis such as DNA methylation (TET2, DNMT3A, IDH1, IDH2), chromatin remodeling ASXL1, and splicing factor SRSF2, whereasFLT3mutation was the most frequently lost at relapse.TP53, PTPN11,SETBP1, JAK2, IDH1oASXL1were mutations gained at time of NPM1wt-MN emergence. Conclusions A proportion of pts withNPM1mut-AML will develop an NPM1 wild-type myeloid neoplasm after intensive chemotherapy-induced CR, emerging from preleukemic clonal hematopoiesis. Given this possible evolution, which can not be predicted byNPM1mutmeasurable residual disease monitoring, an active surveillance of these pts is recommended, including genetic re-testing at time of disease relapse or progression. Acknowledgement:PI16/01027 (JE; MDB), PI19/01476 (JE; MDB) Table:Characteristics at diagnosis depending on type of progression. Figure:Mutations in paired samples (diagnosis/relapse) of patients who developed aNMPwt-MN. Figure Disclosures No relevant conflicts of interest to declare.

Post-Remission Treatment with Autologous or Allogeneic Bone Marrow Transplantation or Intensive Chemotherapy in Younger AML Patients: Long-Term Follow-up Results of the EORTC/Gimema AML-8A Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2288-2288
Author(s):  
Frederic Baron ◽  
Fabio Efficace ◽  
Laura Cannella ◽  
Franco Mandelli ◽  
Roelof Willemze ◽  
...  
Keyword(s):  
Bone Marrow ◽  
England Journal ◽  
Bone Marrow Transplantation ◽  
New England ◽  
Research Funding ◽  
Intensive Chemotherapy ◽  
Long Term Follow Up ◽  
Disease Free

Abstract *The 2 first authors contributed equally to the work. Background. The best post-remission treatment for younger acute myeloid leukemia (AML) patients has remained controversial (Cornelissen JJ &Blaise D, Blood 2016, 127, 62-70) and there is paucity of studies comparing intensive chemotherapy to autologous (auto) or allogeneic (allo) bone marrow transplantation (BMT). Aim. The main objective of this study was to provide a long-term follow-up evaluation of patients previously enrolled in the pivotal EORTC/GIMEMA AML-8A (Zittoun et al., New England Journal of Medicine 1995, 332, 217-223). Methods. The EORTC/GIMEMA AML-8A prospectively assessed the impact of 3 post-remission treatments on disease-free survival (DFS) and overall survival (OS) in younger (<60 years of age) AML patients who reached a complete remission (CR) after induction with cytarabine and daunorubicin. All patients received a consolidation chemotherapy course (ICT1) including intermediate-dose cytarabine and amsacrine. Patients who had an HLA-identical sibling donor were then allocated to allo-BMT while remaining patients, at the start of ICT1, were randomized to receive auto-BMT or a second course of intensive chemotherapy consisting of high-dose cytarabine and daunorubicin (ICT2 group) after recovery of ICT1. At the time of the publication of the results (Zittoun et al., New England Journal of Medicine 1995, 332, 217-223), the median follow-up from inclusion was 3.3 years. Results. In the current report, median follow-up was 11.1 (range, 0-28) years. For the whole population (n=422), the 5-, 10 and 15-year OS rates from inclusion were 35%, 32% and 31%, respectively. After the completion of ICT1, 168 patients were allocated to theallo-BMT arm, while 254 patients were randomized to auto-BMT (n=128) or ICT2 (n=126). DFS from CR was longer afterallo-BMT than auto-BMT and DFS from CR was longer after auto-BMT than ICT2, due to a lower relapse incidence (P<0.001). Details are provided in table 1. Patients randomized to the auto-BMT arm had still a longer DFS from CR than patients in the ICT2 group (P=0.11) due to a lower incidence of relapse (P=0.047). Regarding OS, the differences between the 3 groups was no longer significant. In the ICT2, the improved outcome regarding OS as compared to DFS was due to a higher proportion of ICT2 patients who received a salvage auto-BMT. Conclusions. This long-term follow-up of the EORTC/GIMEMA AML-8A study confirms a better DFS with allo-BMT or auto-BMT when compared to ICT2 for AML patients in first CR. Further, this long-term follow-up study revealed that the vast majority of patients alive in first CR at 5-year remains disease-free survivors 5 years later. Although indications of allogeneic hematopoietic stem cell transplantation (allo-HCT) are nowadays largely driven by cytogenetic/molecular AML profile, long-term results of AML8A study demonstrate that auto-BMT remained superior to ICT2 in younger AML patients not candidate for an allo-HSCT. Disclosures Efficace: TEVA: Consultancy, Research Funding; Seattle Genetics: Consultancy; Bristol Myers Squibb: Consultancy; Lundbeck: Research Funding. Martinelli:Celgene: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Genentech: Consultancy; Roche: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; MSD: Consultancy; Pfizer: Consultancy, Speakers Bureau.

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