Prognostic Impact of the Amount of CD34+ CD38- CD123+ Cells at Diagnosis In Acute Myeloid Leukemia: a Study From the GOELAMS

Abstract Abstract 951 AML cells with CD34+CD38-CD123+ phenotype represent a subset enriched in leukemic stem cells. Moreover, this subpopulation has been described to be resistant to genotoxic agents as compared with leukemic bulk. However, the clinical impact of the amount of CD34+CD38-CD123+ remains poorly described. In this study we evaluated the prognostic impact of the amount of CD34+CD38-CD123+ cells detected at diagnosis in a series of AML patients treated by intensive chemotherapy according to trials from the French GOELAMS group. Quantification of blast cells with the CD34+CD38-CD123+ phenotype was achieved by flow cytometry in 111 patients less than 66 years old with de novo AML treated by 3+7-like chemotherapy. The characteristics of the patients are shown in table 1. Age, WBC count, NPM1 mutation and FLT3-ITD had no impact on achievement of complete response (CR) whereas, CD34+CD38-CD123+ (>15%) and unfavourable karyotype were significantly correlated with lack of CR. By logistic regression, CD34+CD38-CD123+ (>15%) retains significance for CR achievement with an OR of 0.3 (0.11-0.84) (p=0.02). For the 91 complete responders, age, WBC count, karyotype, NPM1 mutation had no impact on disease-free survival (DFS).Interestingly, patients with <1%, 1–15%, >15% CD34+CD38-CD123+ had a median DFS of 57.6 (SE 6.6), 11.2 (SE 7.5) and 9.2 (SE 13.4) months, respectively (p<0.0001, figure 1). FTL3-ITD was also significantly associated with a shorter DFS. In multivariate analysis, CD34+CD38-CD123+<1% was significantly associated with a longer DFS (p=0.00025). Age, %CD34+CD38-CD123+, karyotype, NPM mutation and FLT3-ITD significantly influenced overall survival (OS) whereas WBC count had no impact. Median OS was particularly impressive for patients with CD34+CD38-CD123+<1%. Indeed, median OS was 78.2 (SE 10.7), and 15.3 (SE 5.8) months for CD34+CD38-CD123+<1% vs others, respectively (p<0.0001, figure 1). Multivariate analysis for OS retains two significant factors: adverse karyotype (95%CI, 1.19–4.02, p=0.012) and CD34+CD38-CD123+<1% (95%CI, 0.12–0.52, p=0.00018). Moreover, although the number of patients was low in favourable karyotype (CBF), CD34+CD38-CD123+<1% had a major impact on both DFS, median 57.6 vs 10.2 months for >1% (HR, 0.19, 0.06–0.59, p=0.0038) and OS, median not reached vs 18.5 months (p=0.0025). This study emphasizes the prognosis impact of the CD34+CD38-CD123+ cell burden in AML patients, which is predictive for shorter OS and DFS when representing more than 1% of the leukemic cells, regardless of the usual prognosis categories. We provide here a new prognosis marker that may be easily translated to the clinical practice in AML although it remains to be validated on a large prospective cohort of patients. Moreover, new therapies targeting this subpopulation could help to improve outcome in AML patients.TableCharacteristics of patients.All patients N=111CD34+CD38-CD123+< 1 % N=40CD34+CD38-CD123+ 1-15% N=20CD34+CD38-CD123+> 15% N=20Gender, M/F50/6219/2124/276/14Age, median48 (20–65)47 (20–65)51 (20–64)50 (21–65)WBC,median (G/L)33.2 (1–254)13.8 (1–237.7)41 (1.3–254)32.9 (2.3–193.2)Favourable caryotype231184Intermediate caryotype6924378Unfavourable caryotype19568NPM1 mutation28/957/3116/455/19FLT3-ITD33/1007/3421/475/19Complete Response91 (82%)36 (90%)42 (81.4%)13 (65%)Relapse53 (58.2%)13 (36.1%)30 (71.4%)10 (76.9%)Allogeneic-SCT33 (36.3%)11 (30.6%)15 (35.7%)7 (53.8%) Disclosures: No relevant conflicts of interest to declare.

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Assessment of CEBPA Mutations Might Contribute to a Better Prognostic Assignment in Patients with Intermediate-Risk Cytogenetics Acute Myeloid Leukemia (AML).

Blood ◽

10.1182/blood.v114.22.2611.2611 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2611-2611

Author(s):

Marta Pratcorona ◽

Montserrat Torrebadell ◽

Neus Villamor ◽

Maria Rozman ◽

Mireia Camós ◽

...

Keyword(s):

De Novo ◽

Conflicts Of Interest ◽

Complete Response ◽

Prognostic Impact ◽

Single Mutation ◽

Intermediate Risk ◽

Wild Type ◽

Male Predominance ◽

Cebpa Mutations ◽

Wbc Count

Abstract Abstract 2611 Poster Board II-587 The prognostic heterogeneity of patients with intermediate-risk cytogenetics AML (AML-IR) is mostly clarified by determination of mutations of NPM1 gene (NPMmut) and internal-tandem duplication of FLT3 gene (FLT3-ITD). Nonetheless, other genetic lesions described in this population might contribute to a better prognostic categorization. In this context, we analyzed the presence of CEBPA mutations and associated features in patients with AML-IR lacking both NPMmut and FLT3-ITD. Overall, 136 patients (51% female; median age: 53, range: 17=74) diagnosed with de novo AML-IR (MRC definition) in our institution between 1994 and 2008 who received standard AML chemotherapy were included in the analysis. CEBPA mutations (CEBPAmut) were investigated by whole gene sequencing using 4 primer pairs according to previously reported methods (Fröhling et al, 2004). Sixty-five patients (48%) harbored NPM1 mutations, 30 of them having concomitant FLT3-ITD. Among NPM1 wild-type patients (NPMwt), FLT3-ITD, CEBPA and MLL mutations were detected in 18, 11, and 5 patients, respectively. Regarding cases with CEBPAmut, biallelic mutations were found in 8 patients, including 6 cases with combined mutations of N-terminal and bZIP domains and two homozygous mutations, whereas a single mutation in bZIP domain was found in the three remaining patients. As compared to patients with wild-type CEBPA (CEBPAwt), those with CEBPAmut were younger (29 vs. 53, p=0.027), and showed a trend to male predominance (73 vs. 46%, p=0.09) and lower WBC count at presentation (16 vs. 33.5 × 109/L, p=.095). Of note, CD7 antigen was aberrantly expressed in virtually all CEBPAmut cases (10/11), compared to only 21% of CEBPAwt patients (p<0.001). Moreover, an abnormal karyotype was observed in 4 patients with CEBPAmut. In the overall series, complete response rate (CR), survival (OS), and relapse incidence (RI) were 83%, 39±4% (5-yr), and 50±5% (5-yr), respectively. Independent favorable factors for survival were younger age (<median; RR: 1.9, 95% CI: 1.2-3, p=0.004), low WBC count at diagnosis (< median; RR: 1.7, 95% CI: 1.1–2.6, p=0.025) and NPMmut/FLT3-ITDneg status (RR: 2.4, 95% CI: 1.3–4.2, p=0.003). Remarkably, patients with CEBPAmut showed a favorable outcome, with a trend for a more prolonged survival, compared to patients with a high-risk NPM/FLT3 status (5-year OS in pts <60 years: 74±16% vs. 33±6%, p=0.087). Based on these results, patients were grouped in a favorable (i.e., either NPMmut /FLT3-ITDneg or CEBPAmut, FAV) or unfavorable molecular category (i.e., those with FLT3-ITD, double NPMwt and CEBPAwt configuration, or MLL abnormalities, UNFAV); these two groups had independent prognostic impact on OS (RR: 2.3, 95% CI: 1.3–4, p=0.001; see figure), RI (RR: 2.2, 95% CI: 1.2–4.3, p=0.016), and leukemia-free survival (RR: 2.2, 95% CI: 1.3–3.7, p=0.002). Importantly, the outcome of patients in the FAV group did not differ according to post-remission treatment (autologous vs. allogeneic stem-cell transplantation, SCT), whereas relapse risk was significantly higher in patients with unfavorable markers who received autologous SCT (60±13% vs. 18±12%, p=0.03). In summary, the assessment of CEBPA mutations, especially in patients lacking NPMmut and FLT3-ITD and expressing CD7 antigen, may refine the molecular prediction of prognosis and guide therapeutic strategy in patients with intermediate-risk AML. Disclosures: No relevant conflicts of interest to declare.

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Prognostic impact of cytogenetic abnormalities in patients with de novo acute nonlymphocytic leukemia

Blood ◽

10.1182/blood.v73.1.263.263 ◽

1989 ◽

Vol 73 (1) ◽

pp. 263-270 ◽

Cited By ~ 198

Author(s):

CA Schiffer ◽

EJ Lee ◽

T Tomiyasu ◽

PH Wiernik ◽

JR Testa

Keyword(s):

De Novo ◽

Disease Free Survival ◽

Complete Response ◽

Prognostic Impact ◽

Acute Nonlymphocytic Leukemia ◽

Trisomy 8 ◽

Cytogenetic Changes ◽

Cytogenetic Analyses ◽

Resolution Banding

Abstract Detailed cytogenetic analyses were performed on specimens from 198 patients with de novo acute nonlymphocytic leukemia (ANLL), including high-resolution banding studies in 79 patients. One hundred ninety-two patients received induction therapy with daunorubicin and cytosine arabinoside (Ara-C) with an overall complete response rate (CR) of 63%. Responding patients received repetitive cycles of Ara-C-based intensification therapy. Clonal abnormalities were detected in 69% of the patients with specimens adequate for cytogenetic analysis. Certain cytogenetic changes were closely associated with French-American- British (FAB) morphology, age, and outcome: t(8;21) (closely associated with FAB M2), t(15;17) (associated with FAB M3), and abn 16q22 (associated with FAB M4EOS) tended to occur in younger patients and were associated with favorable outcomes in terms of both CR rate and long-term disease-free survival. In contrast, 19% of patients who had - 5/5q- and or -7/7q- and seven patients with trisomy 8 were older, had a poor prognosis, and usually failed to achieve remission (CR) because of chemotherapy-resistant leukemia. The adverse effect on CR rate and duration in this group of patients was independent of age, and there was no association with particular morphologic subtypes. These data suggest that cytogenetic findings should influence future therapeutic choices. In particular, patients with abnormalities associated with poor responses may be considered for investigational approaches and may also provide insights into mechanisms of drug resistance.

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Expression of S100A8 in Leukemic Cells Predicts Poor Survival in De Novo AML Patients.

Blood ◽

10.1182/blood.v114.22.276.276 ◽

2009 ◽

Vol 114 (22) ◽

pp. 276-276

Author(s):

Pascal Mossuz ◽

Emmanuelle Nicolas ◽

Claire Ramus ◽

Sylvie Berthier ◽

Marie Arlotto ◽

...

Keyword(s):

Mononuclear Cells ◽

De Novo ◽

Conflicts Of Interest ◽

Treatment Strategies ◽

Disease Free Survival ◽

Independent Set ◽

Roc Curves ◽

Peptide Sequencing ◽

Leukemic Cells ◽

De Novo Aml

Abstract Abstract 276 Treatment strategies of acute myeloid leukaemia (AML) largely depend on their cytogenetic status. However this stratification remains insufficient for almost half of the patients, requiring subsequent molecular investigations. In our study, we used mass spectrometry-based proteomic approaches to characterize de novo-AML. Samples (blood mononuclear cells collected and frozen before any treatment) were retrospectively selected from two independent sets of newly diagnosed AML patients, included in prospective clinical trials of the GOELAMS (Groupe d'Etude Ouest-Est des Leucémies aigues). We showed that protein signature of leukemic cells defined 2 groups of patients that displayed significant variation of overall and disease free survival (Fig-1A). This proteomic classification refined cytogenetic classes. Combination of proteomic and cytogenetic allowed a new stratification highly correlated with outcome. In particular, AML with intermediate and high risk cytogenetic could be respectively subdivided according to their protein profiles in two subgroups with significantly different survival (Fig-1B). Interestingly in both type 2 and type 3 cytogenetic groups, a good proteomic profile identified subsets of patients with significantly increased probability of survival, suggesting that the weigh of a good proteomic risk might predominate over a bad predictive cytogenetic. Among proteins expressed by leukemic cells, we isolated a 10800 Da marker that retained the highest discriminative value between alive and deceased patients. The median intensity of the 10800 peak was 94.3 ± 97.7 (7.5-368.7) in living patients compared to 214.2 ± 163.7 (9.0-693.4) in dead patients (p= 0.009). Among normal cytogenetic patients, intensity levels of the marker was also significantly different between dead (217.4 ± 155.7 range 10.4-612.8) and alive patients (26.0 ± 73.1, range 6-168.1; p= 0.008) (Fig-1C). Using a thresholds of 100 (calculated by ROC curves) we were able to correctly identify 82% of patients who died (patients greater than 100) and 70% of patients who stayed alive (patients lower than 100) with a specificity of 65% and 82% respectively. These data were confirmed in a second independent set of patients. 10800 Da marker was identified by MS peptide sequencing as S100A8 (also designated MRP8 or calgranulin A), a cytosolic protein of mature granulocytes. Western blot analysis confirmed its expression mainly in AML patients with the worst prognostic but not in all AML patients, neither in some leukemic and lymphoma cell lines, arguing for a selective deregulation associated with poor prognosis. These results show that expression of S100A8 in leukemic cells at diagnosis might be considered as a predictor of low survival. Disclosures: No relevant conflicts of interest to declare.

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Fludarabine, High Dose Cytarabine and Idarubicin-Based Induction Is Highly Effective in Young AML Patients with Concomitant NPM1 and FLT3-ITD Mutation Irrespectively of FLT3-ITD Allelic Burden

Blood ◽

10.1182/blood-2019-131303 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3828-3828

Author(s):

Paola Minetto ◽

Anna Candoni ◽

Fabio Guolo ◽

Marino Clavio ◽

Maria Elena Zannier ◽

...

Keyword(s):

Multivariate Analysis ◽

Leukemic Cells ◽

High Dose ◽

Prognostic Impact ◽

Allogeneic Bone ◽

Wild Type ◽

Npm1 Mutation ◽

Mutational Status ◽

High Dose Cytarabine ◽

Allelic Burden

Background: The presence of FLT3 "internal tandem duplication" (FLT3-ITD) mutation is associated with poor prognosis in acute myeloid leukemia (AML). However, the concomitant presence of NPM1 mutation (NPM1-mut) partially overcomes the negative prognostic impact of FLT3-ITD, which is also modulated by FLT3-ITD/wild-type allelic ratio. NPM1 and FLT3 mutational status assessment is strongly recommended for risk stratificationat diagnosis by the last European Leukemia Net (ELN) guidelines. Aims: To investigate the efficacy of an intensive fludarabine-containing induction regimen (FLAI) for fit, de novo AML patients according to NPM1 and FLT3-ITD mutational status. Methods: One-hundred and sixteen consecutive AML patients, treated in 3 Hematology Italian centers from January 2008 to January 2018, were included in this analysis. Twenty five patients showed isolated FLT3-ITD, 39 concomitant FLT3-ITD and NPM1-mutation and 52 isolated NPM-1-mutation.Median age was 52 yrs (range: 18-65 years). All patients received fludarabine, high dose cytarabine-based induction (fludarabine 30 mg/sqm and ARA-C 2g/sqm ondays 1 to 5 plus idarubicin 10 mg/sqm on days 1-3-5). For patients achieving CR fludarabine was omitted on II induction course and idarubicin dose was increased to 12 mg/sqm. Before2017 patients with isolated FLT3-ITD mutation were scheduled to receive allogeneic bone marrow transplantation (BMT) in first complete remission regardless of allelic burden whereas after 2017 only patients with high allelic burden received BMT in 1st CR. Minimal residual disease was evaluated on marrow samples using multicolor flow-cytometry (MFC)or NPM1 expression levels. Negative MFC-MRD wasdefined by the presence of less than 25 clustered leukemic cells/105 total events (threshold of 0.025% residual leukemic cells, Minetto et. al, BJH 2019). NPM1mutation (NPM1-A, B and D) was measured using Muta Quant Kit Ipsogen from Qiagen. FLT3-ITD allelic burden was available in31/64 of FLT3-ITD patients. Results: Overall 60-days mortality was 4%. After two induction cycles, 101 patients achieved CR (87%). Thirty-three/101 (33%) CR patients underwent BMT in first CR. After a median follow up of 61 months, 3-year overall survival (OS) was 56.8% (median not reached). In univariate analysis OS duration was favorably affected by age <55 yrs (p<0.05), MRD-negative status after induction (both MFC and NPM1 based MRD) (p<0.001) and wild-type FLT3(p<0.05). However, in multivariate analysis only MRD status significantly affected OS (p<0.003). The probability of achieving a molecular MRD negative CR after first cycle among NPM1-mut patients was similar between patients with or without concomitant FLT3-ITD mutation (61% and 66%, respectively, p=n.s.). Interestingly, in younger patients (< 55yrs) OS was comparable in case of isolated NPM1 mutation or concomitant NPM1/FLT3-ITD mutation (3-year OS 68.4% and 62.3%, respectively, p= n.s, Figure 1), regardless of FLT3-ITD allelic burden.Patients with isolated FLT3-ITD mutation had a significantly worse prognosis (3-year OS 34.4%, p<0.05). Again, multivariate analysis showed that persistence of MRD (by any method, p <0.05) was the strongest predictor of outcome. Moreover, performing BMT infirst CR did not impact OS neither in univariate or multivariate analysis. Conclusion: Despite the potential bias due to the retrospective nature of the analysis, our data indicate that intensive fludarabine-high dose cytarabine-based induction exerts a strong anti-leukemic efficacy in younger AML patients carrying NPM1 mutation irrespectively of FLT3 mutational status.Thus, the synergism of fludarabine and cytarabine seems to affect the intrinsic chemosensitivity of NPM1-mut leukemic cells, overcoming the negative impact of FLT3-ITD. Moreover, our data suggest the strong prognostic impact on survival of MRD clearance and question the role of BMT in I CR in this setting of patients. Figure 1 Disclosures Candoni: Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Merck SD: Honoraria, Speakers Bureau. Bocchia:Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria.

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Clinico-Biological Characteristics and Prognosis of Non-M3 Acute Myeloid Leukemia with High Percentage of Myeloperoxisase Positive Blasts. Single Center Experience.

Blood ◽

10.1182/blood.v108.11.4462.4462 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4462-4462

Author(s):

Pau Montesinos ◽

Lorenzo Algarra ◽

Jaime Sanz ◽

Mari Luz Perez ◽

Leonor Senent ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Multivariate Analysis ◽

Prognostic Factors ◽

Myeloid Leukemia ◽

De Novo ◽

Disease Free Survival ◽

Favourable Outcome ◽

Biological Characteristics ◽

Prognostic Impact ◽

Acute Myeloid

Abstract Introduction: It has been suggested that acute myeloid leukemia (AML) showing mature phenotype is associated with favourable outcome. In a study recently published by JALSG, myeloperoxidase (MPO) positivity in over 50% of blasts had favourable prognostic impact, independent from karyotype, on achieving complete remission (CR), overall survival (OS) and disease free survival (DFS). No other studies have established the independent prognostic value of MPO expression. Objectives: Analyze the clinico-biological characteristics of AML with high percentage of MPO+ blasts and its impact on CR, OS and DFS. Material and methods: Between 1986 and 2005, 418 adult patients (median 53 years, range 15–80) were diagnosed with de novo non-APL AML and evaluated for percentage of MPO+ blasts. All patients received intensive chemotherapy. Diagnosis was made by optic microscopy of bone marrow (BM) aspirates stained with May-Grumwald giemsa, MPO, butyrate esterase and or non specific esterase. Cytogenetic and immunophenotype analysis was evaluated in 66% and in 76% of the cases respectively. Results: 118 patients (28%) showed a percentage of MPO+ blasts >75%. AML with MPO+ blasts >75% was associated with M1-M2-M4 subtypes, leucocytes >50×109/L, blasts in BM >70% and HLA-DR negativity (p<0.01). It was also significantly associated with favourable karyotype (11% vs 3% favourable, 52% vs 48% intermediate and 3% vs 15% unfavourable). Patients with AML and MPO+ blasts >75% obtained higher CR rate (71% vs 55%), due to less resistant disease (9% vs 22%, p<0.01). In multivariate analysis favourable karyotype, leukocytes <50×109/L and age <60 were favourable prognostic factors for CR. Median OS and DFS was higher in patients with AML and MPO+ blasts >75% (15 vs 7 months, p<0.001, y 41 vs 12 months, p<0.001, respectively). ). In multivariate analysis, favourable karyotype, leukocytes <50×109/L, age <60 years and MPO+ >50% were favourable prognostic factors for OS; and age <60 and MPO+ >75% were the only independent factors for DFS. Median DFS was higher in patients with AML and MPO+ blasts >75% in the intermediate cytogenetic risk group (59 vs 13 months, p=0.015), age <60 (109 vs 15 months, p=0.003), age >60 (13 vs 7 months, p=0.03), autologous stem cell transplantation (100 vs 9 months, p=0.04) and chemotherapy alone (16 vs 8 months, p=0.003). Conclusion: In our series, patients with AML and MPO+ blasts >75% show less chemoresistant disease and a longer remission duration, the latter independently from the karyotype. This biological characteristic could be useful in designing therapeutic strategies in patients that lack other prognostic markers.

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Prognostic Value of Monosomal Karyotype in Patients with Primary Acute Myeloid Leukemia On Behalf of Spanish CETLAM Group.

Blood ◽

10.1182/blood.v114.22.1003.1003 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1003-1003 ◽

Cited By ~ 3

Author(s):

Isabel Granada ◽

Salut Brunet ◽

Montserrat Hoyos ◽

Dolors Costa ◽

Anna Aventín ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

De Novo ◽

Conflicts Of Interest ◽

Treatment Strategies ◽

Disease Free Survival ◽

Prognostic Impact ◽

Complex Karyotype ◽

Monosomal Karyotype ◽

Acute Myeloid

Abstract Abstract 1003 Poster Board I-25 Introduction: Recently, the cooperative group HOVON-SAKK has refined the prognostic impact of cytogenetic abnormalities in acute myeloid leukemia (AML) by introducing the concept of monosomal karyotype (MK). This consists of ≥ 2 autosomal monosomies or one autosomal monosomy in addition to a structural alteration. In their experience, MK would explain the poor prognosis of AML with a complex karyotype. Objective: To investigate the prognostic impact of MK in patients with primary (de novo) AML enrolled in the Spanish CETLAM group protocols (AML 94/99/03). Also, to determine whether considering MK added predictive value to the cytogenetic classification of the Medical Research Council (MRC). Methods: Retrospective analysis of data from 1149 AML patients. Chromosomal formula was centrally reviewed with karyotypes being classified by the presence of MK and allocated into the MRC risk categories. Complete remission (CR) rate, disease-free survival (DFS) and overall survival (OS) were calculated. Results: The karyotype was assessable in 904 (79%) of the 1149 cases. In 145 of the 904 cases (16%), abnormalities involving CBF gene were detected and in 437 (48%) the karyotype was normal (NK). In 253 (28%) additional patients the karyotype was not monosomal; of them, 61 (24%) belonged to the unfavorable MRC with 17 cases harboring a complex karyotype ≥ 5 abnormalities, 7 cases with rearrangements 3q, 13 cases with -7, 9 cases with 5q abnormalities and 16 cases with t(6;9)). The remaining 69 (7.7%) patients had a MK; of them, 59 (85.5%) were from the unfavorable MRC category and included 43 cases with complex karyotype ≥ 5 abnormalities, 6 cases with rearrangements 3q, 5 cases with -7, 5 cases with alterations of 5q). The following table summarizes the results in terms of CR rate, DFS and OS: Conclusions: The addition of MK to the MRC cytogenetic classification refines the prognostic prediction. In our series, the dismal outcome of patients with MK is confirmed; these patients had worse prognosis than those with adverse cytogenetics without MK. Alternative treatment strategies are mandatory for MK+ patients. Supported in part by grants: GR1-01075, ECO07/90065, PI080672 and RD06/0020/0101. Disclosures: No relevant conflicts of interest to declare.

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Efficacy and Safety of 5-Azacytidine Based Regimens in Old AML patients: a Retrospective Study of 29 Patients.

Blood ◽

10.1182/blood.v114.22.4148.4148 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4148-4148

Author(s):

France Roszkiewicz ◽

Berengere Gruson ◽

Ioana Vaida ◽

Gandhi Damaj ◽

Bruno Royer ◽

...

Keyword(s):

Overall Survival ◽

Retrospective Study ◽

De Novo ◽

Conflicts Of Interest ◽

Complete Response ◽

Newly Diagnosed ◽

Overall Response ◽

Co Morbidity ◽

Significant Difference ◽

Wbc Count

Abstract Abstract 4148 Background 5-azacytidine (AZA) is an hypomethylating drug. The international multicenter AZA-001 trial established that AZA significantly improves overall survival (OS) in patients with high risk myelodysplastic syndromes (MDS) compared with conventional care regimens (Fenaux, Lancet Oncol 2009). Some recent reports have raised the question of a possible efficacy of AZA in selected patients with acute myeloid leukaemia (AML). In this study we retrospectively analysed the safety and efficacy of a 7 days-schedule of AZA alone or in combination with an HDAC inhibitor, Valproic acid (VA) and with All-trans retinoic acid (ATRA) in patients with newly-diagnosed and refractory/relapsed AML not eligible for intensive chemotherapy. Patients and Methods A monocentric retrospective study from October, 2006 until March, 2009 analysed 29 patients with AML. Among these patients. There were 11 males and 18 females, median age 70,8 years (range 51,2-84,1), AML de novo in 15 patients (3 relapse) and secondary in 14 patients (2 post MPD and 12 post MDS). Median WBC count was 2,5 (range 0,7-140).109/L, 4 patients had WBC more than 10.109/L. The median rate of bone marrow blasts is 30%. 12/27 (44%) patients and 15/26 (56%) have respectively an intermediate and poor risk caryotype. Fifteen (54%) were newly-diagnosed patients, 14 (46%) were refractory/relapsed patients. Median co morbidity index (Sorror, J Clin Oncol 2007) of patients is 2 (0-7). Patients received daily AZA 75mg/m2 J1-J7, ± VA 35 to 50 mg/kg J1-J7 and ATRA 45mg/m2 J8-J28 every 4 weeks. Results 5 azacytidine was used alone for 6/29 (21%) patients and in combination with VA and ATRA for 23/29 (79%) patients. Compliance to the planned therapy was good. Average number of AZA administration was 6 days. To date a total 150 treatment-cycles with a median of 5 cycles/patient were applied (1-14). Treatment was well tolerated. Neutropenia grade3III and thrombopenia grade3III occurred respectively in 26/150 cycles (17%) and in 31/150 (20%). Infections grade3III were observed in 14/150 cycles (9,3 %). Overall response was 62% (17/29): 9 complete response (CR=31%), 3 partial response (PR=10%), 5 haematological improvement (HI=21%), There were 2 stable diseases (SD=7%). 28% of responses were obtained after 1 cycle, 56% after 3 and 89% after 4. Median overall survival (OS) was 13,2 months (0.3-26). We did not observe any significant difference on OS regarding: age, cytogenetics, de novo vs secondary AML, newly diagnosed vs refractory/relapsed patients. OS for patients with SD was similar to patients with CR, PR or HI. WBC >10.109/L before treatment was not correlated with a shorter survival (7.73 months vs 13.2 months p=0,6). Correlation was found between OS and clearance of the creatinine (p=0.005). In conclusion, AZA based regimens seems well tolerated and an effective treatment in AML, with an overall response of 62% and an OS of 13,2 months. A minimum of 4 cycles of treatment is necessary to evaluate the efficacy. OS of patients achieving CR, PR or HI is not significantly different of those with SD. Treatment should be continued until progression of the disease. Disclosures: No relevant conflicts of interest to declare.

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Prognostic impact of cytogenetic abnormalities in patients with de novo acute nonlymphocytic leukemia

Blood ◽

10.1182/blood.v73.1.263.bloodjournal731263 ◽

1989 ◽

Vol 73 (1) ◽

pp. 263-270 ◽

Cited By ~ 2

Author(s):

CA Schiffer ◽

EJ Lee ◽

T Tomiyasu ◽

PH Wiernik ◽

JR Testa

Keyword(s):

De Novo ◽

Disease Free Survival ◽

Complete Response ◽

Prognostic Impact ◽

Acute Nonlymphocytic Leukemia ◽

Trisomy 8 ◽

Cytogenetic Changes ◽

Cytogenetic Analyses ◽

Resolution Banding

Detailed cytogenetic analyses were performed on specimens from 198 patients with de novo acute nonlymphocytic leukemia (ANLL), including high-resolution banding studies in 79 patients. One hundred ninety-two patients received induction therapy with daunorubicin and cytosine arabinoside (Ara-C) with an overall complete response rate (CR) of 63%. Responding patients received repetitive cycles of Ara-C-based intensification therapy. Clonal abnormalities were detected in 69% of the patients with specimens adequate for cytogenetic analysis. Certain cytogenetic changes were closely associated with French-American- British (FAB) morphology, age, and outcome: t(8;21) (closely associated with FAB M2), t(15;17) (associated with FAB M3), and abn 16q22 (associated with FAB M4EOS) tended to occur in younger patients and were associated with favorable outcomes in terms of both CR rate and long-term disease-free survival. In contrast, 19% of patients who had - 5/5q- and or -7/7q- and seven patients with trisomy 8 were older, had a poor prognosis, and usually failed to achieve remission (CR) because of chemotherapy-resistant leukemia. The adverse effect on CR rate and duration in this group of patients was independent of age, and there was no association with particular morphologic subtypes. These data suggest that cytogenetic findings should influence future therapeutic choices. In particular, patients with abnormalities associated with poor responses may be considered for investigational approaches and may also provide insights into mechanisms of drug resistance.

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DNMT3Awt NPM1-Mutation Defines a Subgroup of MDS with Special Favorable Outcomes Towards Decitabine Therapy

Blood ◽

10.1182/blood-2019-124008 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1724-1724

Author(s):

Lingyun Wu ◽

Xiao Li ◽

Feng Xu ◽

He Qi ◽

Zheng Zhang ◽

...

Keyword(s):

Median Survival ◽

De Novo ◽

Conflicts Of Interest ◽

Statistical Significance ◽

Complete Response ◽

Subsequent Treatment ◽

Induction Treatment ◽

Wild Type ◽

Npm1 Mutation ◽

Randomized Controlled Studies

Hypomethylating agents (HMA) (including decitabine and azacitidine) are considered standard of care for higher risk myelodysplastic syndrome (MDS). Clinical data showed only about 30% cases achieved complete response (CR) by decitabine. Mutations in the nucleophosmin-1 (NPM1) gene is one of the most common somatic mutations identified in de novo acute myeloid leukemia (AML) and have also been found in 1% to 5% of MDS patients although with different mutation locus (L287fs) when compared to that in AML (W288fs). Till now, the response and survival of NPM1-mutated MDS patients treated with HMA remains unknown. Here, we retrospectively analyzed higher risk MDSs who accepted decitabine therapy in our center. From December 2009 to July 2018, a total of 194 patients received decitabine induction treatment by 20mg/m2 intravenously for 5 consecutive days every 4-6 weeks. The median therapy course was four. Among them, twelve patients (6.2%) harbored NPM1/L287fs mutation. The median decitabine therapy cycle for the 12 NPM1 mutated patients was also four. To our interest, patients harboring NPM1 mutations achieved a relatively higher CR rate (6 of 12 cases, 50%) when compared to that of patients without NPM1 mutations (59 of 182 cases, 32.4%) , although without statistical significance (p = 0.304). Moreover, when the most common co-mutated genes DNMT3A (6 of 12 cases, 50%) (Figure 1a) was ruled out, patients harboring NPM1 mutation (DNMT3A wild type) achieved a CR rate of 83.3% (five of six), which is significantly higher than that of patients without NPM1 mutation (p = 0.018) (Figure 1b). Of note, when paired sequencing were analyzed, six patients who achieved CR by decitabine showed loss of mutated NPM1; One patients who achieved hematological improvement (HI) showed decreased variant allele frequency (VAF) of NPM1 mutation; Whereas two patients with no response (NR) showed unchanged NPM1 mutation (Figure 1d). Notably, a prolonged relapse-free survival (PFS) was observed in CR patients with NPM1 mutation and DNMT3A wild type (NPM1mut DNMT3Awt) even without any subsequent therapies after receiving 4-5 cycles of decitabine (Figure 1c). The median RFS of CR patients with NPM1mut DNMT3Awt was 66 months, which is significantly longer than that in patients without NPM1mutation (13.5M, p = 0.006) (Figure 1e). A remarkably prolonged median survival was also shown in patients harboring NPM1mut DNMT3Awt (median survival of 80M), which is significantly longer than that of patients without NPM1 mutation (18M) (p = 0.012) (Figure 1f). Interestingly, except with DNMT3A and PTPRD co-mutations, the response and survival of patients harboring NPM1 mutations treated with decitabine were favorable even when co-mutated with IDH2, NRAS, FLT3. In conclusion, NPM1 mutation with DNMT3A wild type defines a specific subgroup of MDS with a good response and prolonged survival by decitabine therapy, even when they were with some prognosis-poor co-mutations and without subsequent treatment. Enlarged sample of randomized controlled studies are needed to confirm our preliminary findings. Figure 1 Disclosures No relevant conflicts of interest to declare.

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Characteristics and outcomes of patients diagnosed with DNMT3A mutated acute myeloblastic leukemia.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e19018 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e19018-e19018

Author(s):

Daniel Rivera ◽

Hagop M. Kantarjian ◽

Tapan M. Kadia ◽

Naval Guastad Daver ◽

Courtney Denton Dinardo ◽

...

Keyword(s):

Tp53 Mutation ◽

De Novo ◽

Negative Impact ◽

Prognostic Significance ◽

Disease Free Survival ◽

Complete Response ◽

P Value ◽

Prognostic Impact ◽

Intensive Chemotherapy ◽

Secondary Aml

e19018 Background: Advances in molecular profiling have identified recurring gene mutations in acute myeloid leukemia (AML) that have independent prognostic significance with several being targets for the development of new small molecule inhibitors. DNMT3A mutations have been reported in up to 34% of patients with AML. Mutations of this gene are associated with silencing of tumor suppressor genes, thereby leading to leukemogenesis. Several prior reports have suggested an association with worse outcomes. Methods: We retrospectively reviewed records of 258 patients with ND AML with DNMT3A mutations who presented to our institution from 2002 to 2020. We analyzed their clinical and laboratory characteristics. We estimated their overall survival (OS) and disease-free survival (DFS) through the Kaplan-Meier method. P-value was 2-tailed, ≤ 0.05 was considered statistically significant with a confidence interval of 95%. Univariate and multivariate analyses were also applied. Results: Our cohort had a median age of 66 years, 56% were female. The majority of the patients (77%) had de novo AML and the M0 FAB subtype was predominantly observed in 70%. Diploid karyotype was detected in 60% while complex karyotype in 14% of patients. DNMT3A was most frequently mutated at codon 882 (64%). NPM1 was the most frequent concomitant mutation followed by FLT3-ITD and IDH2. Age > 65 years (p = 0.001) and presence of concomitant TP53 mutation (p < 0.001) were associated with worse survival and concomitant NPM1 was associated with a 40% reduction of death, p = 0.003. Secondary AML and concurrent TP53 mutation were associated with a higher risk of relapse, (p < 0.001 for both). Intensive chemotherapy (ICT) was administered to 82 patients of which 68 achieved a complete response or CR with incomplete count recovery (CRi). Nineteen patients were treated with Cladribine plus low dose Ara-C (Clad-LDAC) and CR or CRi was achieved in 16 patients. Eleven treated with Clad-LDAC-Ven and all achieved CR/CRi. Hypomethylating agents (HMA) were given to 22 patients of which 10 achieved CR/CRi. Twenty-five received HMA-Ven, of these, CR/CRi was achieved in 20 patients (p = 0.02). There was an 80% and 90% reduction of death with ICT, p < 0.001 and Clad-LDAC-Ven, p = 0.04 respectively. Moreover, the risk for relapse was reduced by 70% and 90% with ICT and Clad-LDAC-Ven respectively. Ninety-seven patients were treated with immunotherapy, FLT3 inhibitors, and IDH inhibitors, which were not included in this analysis. Conclusions: DNMT3A mutations have an independent prognostic impact in patients diagnosed with AML. Among these patients, older age, secondary AML, a concomitant mutation in TP53 showed a significant negative impact in terms of OS and DFS. Concomitant mutations in NPM1 and IDH2 were associated with better outcomes. Treatment with intensive chemotherapy or clad-LDAC-Ven was associated with the highest response rates.

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