ALBERT

Description: BACKGROUND: The clinical course of splenic marginal zone lymphoma (SMZL) is usually indolent, but development of transformation to aggressive lymphoma (SMZL-T) is seen in 10 to 15% of the cases. Risk factors to predict SMZL-T are poorly defined. AIM: The aims of our study were: 1.- to assess the risk of transformation in a large series of SMZL patients; 2.- to analyze the prognostic factors for this event and 3.- to analyze clinical and biological features of SMZL-T. PATIENT AND METHODS: We identified 84 SMZL diagnosed at the HCB between 1994 and 2017 and 15 of them (18%) had developed histological transformation (SMZL-T). In addition, we reviewed 21 SMZL with transformation referred to HCB from other centers. Median age at diagnosis of low-grade SMZL in the 84 patients was 63 years (range, 32-91), and male/female ratio was 34/50. Complex karyotype (CK) defined as ≥3 chromosomal aberrations by conventional cytogenetics was observed in 22% and del(7q) in 59% of cases. The risk distribution according to the Splenic Marginal Zone Lymphoma Study Group simplified score HPLL/ABC was: low: 34, intermediate: 51 and high: 15. After a median follow-up of 80 months (range, 1-265), 37 of 84 (44%) patients have died, with a median overall survival (OS) of 146 months. To assess the risk of transformation and to identify predictive factors for such event, we exclusively evaluated the cohort of 84 patients from HCB. RESULTS: Fifteen of the 84 patients in the HCB cohort (18%) developed histological transformation. The cumulative incidence of transformation at 60 months from diagnosis was 15% (95% CI: 7 - 23) (Figure). In univariate analysis, variables predicting transformation were anemia, lymphopenia, thrombocytopenia, hypoalbuminemia, CK and high-risk scores of Intergruppo Italiano Linfomi (IIL) and HPLL (p

Description: Introduction Current diagnosis of chronic myelomonocytic leukemia (CMML) requires peripheral blood (pb) monocytosis ≥1×109/L. Accordingly, cases which fulfill other diagnostic criteria of CMML but not reaching the required pb monocytosis threshold would be classified as MDS or unclassifiable MPN/MDS according to WHO classification (Arber et al, Blood 2016) Recently, a group of authors (Geyer et al, Modern Pathology 2017) proposed the term oligomonocytic CMML (OM-CMML) for these patients with blood monocytes ≥10% of the WBCs, but only accounting for 0.5-1 × 109/L as an absolute value and fulfilling all other criteria of CMML and suggested that they should be managed as other patients with classical CMML despite lacking pb monocytosis ≥1×109/L. To address clinical value of this proposed newly entity, we analyzed the incidence, clinico-biological characteristics and outcome of a series of patients fulfilling the proposed criteria for OM-CMML from a single center with a long follow-up. Methods We included patients diagnosed between 1997 and 2019 who gathered the proposed criteria for OM-CMML (Geyer et al, Modern Pathology 2017). These patients were compared with a cohort of patients from the same study period diagnosed with classical CMML. 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 Overall, we included in the study 213 patients, including 35 (16%) who fulfilled the proposed criteria for OM-CMML. Median follow-up of alive patients was 42 months. In the OM-CMML group, 71% were males, median age was 74 years (51-92). OM-CMML patients presented at diagnosis with a lower leucocyte count (WBC) (median value, 4.6(2.2-7.5)x109/L vs 10(3-119)x109/L, p

Description: 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.