Monosomy Karyotype in Acute Myeloid Leukemia Predicts Adverse Treatment Outcome with Low Complete Remission Rate and Worse Event-Free and Overall Survival, and Associates with High Functional Activity of Multidrug Resistance (MDR).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3112-3112 ◽  
Author(s):  
Hee Kyung Ahn ◽  
Dong Hwan (Dennis) Kim ◽  
Silvia Park ◽  
Jun Ho Jang ◽  
Kihyun Kim ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Complete Remission ◽  
Functional Activity ◽  
Myeloid Leukemia ◽  
Marker Chromosome ◽  
Rhodamine 123 ◽  
Structural Abnormalities ◽  
Acute Myeloid

Abstract Abstract 3112 Poster Board III-49 Background It has been revealed that monosomy karyotype (MK), defined as 1) two or more distinct autosomal chromosome monosomies or 2) one single autosomal monosomy in the presence of structural abnormalities, identifies the highly unfavorable cytogenetic risk group of patients with acute myeloid leukemia (Breems, J Clin Oncol 2008), but lacking validation data. The current study aimed to validate the unfavorable impact of MK not only on overall survival (OS) but also on complete remission (CR) rate and event free survival (EFS) in AML patients. Methods A total of 370 consecutive AML (excluding APL) patients with available cytogenetic data who received treatment between 1995 and 2008 at the Samsung Medical Center, Seoul, Korea were included in this retrospective study, among whom 169 patients (45.7%) showed normal karyotype; 65 patients (17.6%), core binding factor (CBF) positive AML; and 136 patients (36.7%), non-CBF AML, respectively. Karyotypes were scored according to their structural abnormalities, monosomy, trisomy, deletion and marker chromosome. The CR rate, EFS and OS were compared according to the presence of each cytogenetic abnormality. In addition, multidrug resistance (MDR) functional assay (P-glycoprotein assay) was performed and MDR functional activity was calculated by verapamil-inhibited rhodamine-123 efflux activity minus uninhibited rhodamine-123 efflux activity, and positivity was determined as equal to or over 5% MDR activity. Results Among treated non-CBF AML group with any kind of cytogenetic abnormalities (n=136), 95 patients (69.9%) had structural cytogenetic abnormalities, 29 pts (21.3%), autosomal monosomy, 18 pts (13.2%), sex chromosome abnormalities, 59 pts (43.4%), autosomal trisomy, 41 pts (30.1%), deletion of part of a chromosome, 18 pts (13.2%), addition and 18 pts (13.2%), marker chromosome(s). MK was noted in 23 patients (16.9%), and complex karyotype (≥3 abnormalities) were found in 40 pts (29.%), -5 in 5 pts (3.7%), -7 in 12 pts (8.8%), del(5q) in 4 pts (2.9%), del(7q) in 8 pts (5.9%), inv(3) or t(3;3) in 4 pts (2.9%), t(6;9) in 5 pts (3.7%), and t(9;22) in 2 pts (1.5%). In univariate analyses, MK+ group was revealed to be associated with shorter OS and (median 10 vs 31months, p=0.044) EFS duration (median 1.3 vs 10.1 months, p=0.002), and a lower CR rate (70.8% vs 34.8%, p=0.002). In a multivariate analysis, MK was associated with lower CR rate (HR of non-CR 0.33, 95% C.I. 0.12-0.93, p=0.036). MK has been defined as a single monosomy with structural abnormalities or multiple monosomies in a previous study. However, there were no significant difference in survival and CR rate between a single monosomy with (n=9) or without(n=6) structural abnormalities (OS, 23 vs 8 months; p =0.349; EFS, 1 vs 9months; p=0.078; CR rate 33% vs 56%; p=0.608). The group with single autosomal monosomy showed a trend of better survival (n=15, median OS 23 months, EFS 1month) than multiple autosomal monosomy group (n=14, OS 6months, EFS 1month), but it was not significantly different (p = 0.322, p=0.221). The functional MDR activity was measured in 40 patients, and positive MDR activity was found to be significantly associated with the presence of MK (87.5% vs 33.3%, p=.013). In addition, the functional MDR activity was significantly higher in MK+ group (n=8, 45.9±17.8%, mean±S.E.) than in MK- group (n=32, 4.3 ±2.7%, p=0.005 by Mann-Whitney U-test). Conclusion The current study demonstrated that the AML patients harboring MK showed a poor outcome in terms of lower CR rate and worse EFS/OS in an independent cohort of Korean AML patients, and that MK karyotype was associated with high MDR functional activity of leukemic blasts. Disclosures No relevant conflicts of interest to declare.

scholarly journals Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse

Blood ◽  
2011 ◽  
Vol 117 (12) ◽  
pp. 3294-3301 ◽  
Author(s):  
Mark Levis ◽  
Farhad Ravandi ◽  
Eunice S. Wang ◽  
Maria R. Baer ◽  
Alexander Perl ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Randomized Trial ◽  
Myeloid Leukemia ◽  
Remission Rate ◽  
Platelet Recovery ◽  
First Relapse ◽  
Acute Myeloid

AbstractIn a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

scholarly journals Immunophenotyping Investigation of Minimal Residual Disease Is a Useful Approach for Predicting Relapse in Acute Myeloid Leukemia Patients

Blood ◽  
1997 ◽  
Vol 90 (6) ◽  
pp. 2465-2470 ◽  
Author(s):  
J.F. San Miguel ◽  
A. Martı́nez ◽  
A. Macedo ◽  
M.B. Vidriales ◽  
C. López-Berges ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Leukemic Cells ◽  
Rhodamine 123 ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract A high complete remission rate is currently achieved in patients with acute myeloid leukemia (AML). However, many patients eventually relapse due to the persistence of low numbers of residual leukemic cells that are undetectable by conventional cytomorphologic criteria (minimal residual disease [MRD]). Using immunophenotypic multiparametric flow cytometry, we have investigated in sequential studies (diagnosis and follow-up) the impact of MRD detection on the outcome of 53 AML patients that had achieved morphologic remission with standard AML protocols and displayed at diagnosis an aberrant phenotype. Patients were studied at diagnosis with a panel of 35 monoclonal antibodies in triple staining combinations for detection of aberrant or uncommon phenotypic features. According to these features, a patient's probe was custom-built at diagnosis for the identification of possible residual leukemic cells during follow-up. The level of MRD at the end of induction and intensification therapy correlated with the number of relapses and relapse-free survival (RFS). Thus, patients with more than 5 × 10−3 residual cells (5 residual cells among 1,000 normal bone marrow [BM] cells) identified as leukemic by immunophenotyping in the first remission BM showed a significant higher rate of relapse (67% v 20% for patients with less than 5 × 10−3 residual cells; P = .002) and a lower median RFS (17 months v not reached; P = .01). At the end of intensification, with a cut-off value of 2 × 10−3 leukemic cells, AML patients also separated into two distinct groups with relapse rates of 69% versus 32% (P = .02), respectively, and median RFS of 16 months versus not reached (P = .04). In addition, overall survival was also significantly related to the level of residual cells in the marrow obtained at the end of induction and particularly after intensification therapy (P = .008). Furthermore, we have explored whether residual disease was related with the functional expression of multidrug resistance (MDR-1) at diagnosis as assessed by the rhodamine-123 assay. Patients with ≥5 × 10−3 residual leukemic cells at the end of induction therapy had a significantly higher rhodamine-123 efflux (mean, 56% ± 24%) than those with less than 5 × 10−3 residual cells (mean, 32% ± 31%; P = .04). Finally, multivariate analysis showed that the number of residual cells at the end of induction or intensification therapy was the most important prognostic factor for prediction of RFS. Overall, our results show that immunophenotypical investigation of MRD strongly predicts outcome in patients with AML and that the number of residual leukemic cells correlates with multidrug resistance.

Comparable Disease-Free and Overall Survival After “Well-Matched” Unrelated Donor and Matched Sibling Donor Transplantation in Acute Myeloid Leukemia with Adverse Risk Karyotype in First Complete Remission: A Report From the Acute Leukemia Working Committee of the Centre for International Blood and Marrow Transplant Research.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 526-526
Author(s):  
Vikas Gupta ◽  
Martin S. Tallman ◽  
Wensheng He ◽  
Brent Logan ◽  
John F. DiPersio ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Unrelated Donor ◽  
Allogeneic Hsct ◽  
Matched Sibling ◽  
Disease Free ◽  
First Complete Remission ◽  
Acute Myeloid

Abstract Abstract 526 In patients with acute myeloid leukemia (AML) in first complete remission (CR1), the indications for matched sibling donor (MSD) transplants and unrelated donor (URD) haemopoietic stem cell transplantation (HSCT) are different. We sought to determine the prognostic impact of donor type on the outcomes of AML with adverse risk karyotype in CR1, a high-risk AML population considered as a standard indication for MSD and URD HSCT. We evaluated the outcomes of 584 patients undergoing allogeneic HSCT for AML with adverse risk karyotype in CR1 between 1995 and 2006, reported to the CIBMTR. Adverse risk karyotype was defined according to SWOG/ECOG classification. Cytogenetics abnormalities were further classified as: complex karyotype (3 or more abnormalities), 32%; and Non-complex divided as abnormal chromosome 7, 25%; chromosome 5, 9%; MLL gene rearrangements, 18%; t (6;9), 5%; and others, 10%. 226 patients underwent MSD and 358 URD. URD were classified based on high resolution typing as:” well matched” [n=254 (71%)] with no known disparity at HLA A, B, C, DRB1; and, “partially matched” [n=104 (29%)] with one locus known or likely mismatched. Previous MDS was present in 19% and 14% had therapy-induced (t-AML). Conditioning regimens were myeloablative and reduced intensity in 74% and 26%, respectively. At 3 years treatment-related mortality (TRM) incidence was 28% (95% CI 24-31); relapse 36%(32-40); disease-free survival (DFS) 36%(32-41) and overall survival (OS) 39%(35-44). Multivariate analyses are summarized in the table. “Well matched” URD and MSD yielded similar DFS and OS, while outcomes were significantly inferior for “partially matched” URD. Cytogenetically defined subsets had similar outcomes. Evaluated as a time-dependent covariate, chronic GVHD had a significantly lower risk of relapse (RR 0.68, p=0.046), while acute GVHD had no effect (RR 0.99, p=0.96). “Well matched” URD and MSD lead to similar DFS and OS in AML CR1patients with adverse risk karyotype. The pool of patients who may benefit from graft-vs-leukemia effect generated with allogeneic HSCT may be considerably expanded with “well-matched” URD HSCT. If a suitable MSD is not availabel, “well-matched” URD should be strongly considered where a MSD HSCT would otherwise be undertaken. Disclosures: No relevant conflicts of interest to declare.

Molecular Minimal Residual Disease After Induction Is Related to ABC Proteins' Activity and Associated with Survival in 26 Patients with NPM1 Mutated Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4909-4909
Author(s):  
Pierre Hirsch ◽  
Ruoping Tang ◽  
Christophe Marzac ◽  
Fanny Fava ◽  
Jean-Yves Perrot ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Induction Chemotherapy ◽  
Cytogenetic Analysis ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Abc Proteins ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Abstract 4909 Background: A major issue in the treatment of acute myeloid leukemia (AML) is resistance to chemotherapeutic drugs. The role of ABC proteins, and specially ABCB1 (PgP/mdr1), in this resistance has been well established, and higher ABC proteins' activity, assessed with functional tests, has been associated with poorer complete remission rates and poorer overall prognosis (Marzac et al, Haematologica, 2011). Furthermore, the evaluation of molecular minimal residual disease (MRD), using mutated nucleophosmin (NPM1)expression quantification has been related to patients' global prognosis (Krönke et al, J. Clin. Oncol., 2011), and to response to treatments. In this study, we evaluate the impact of ABC proteins' activity on MRD after one course of induction chemotherapy, in 26 patients with NPM1 mutated AML. Material and methods: We retrospectively identified 26 AML patients with NPM1 mutation treated in our center and with MRD data. MRD was evaluated as the ratio of NPM1 mutated allele and total NPM1, using PCR DNA quantification and the delta delta Ct method. MRD was measured at the time of diagnosis and after one course of anthracycline-based induction chemotherapy. ABC proteins' activity was evaluated at the time of diagnosis using JC1 +/− cyclosporine A assay (Legrand et al, Blood, 2001). Correlations between ABC proteins' activity and the level of post induction MRD were evaluated with the Mann-Whitney test. Survival was evaluated using the Cox model. For all analyses, P values were considered significant when lower than 0. 05. Results: Median age at diagnosis was 53 years old. Twenty-two patients had normal cytogenetic analysis at diagnosis, and the other 4 patients had intermediate prognosis cytogenetic analysis. Nine patients harboured FLT3-ITD mutation. Median ABC proteins' activity was 0. 11 (0 – 0. 77). After one course of induction chemotherapy, 3 patients did not reach cytological complete remission. In 17 patients MRD level after induction therapy was inferior to 1 %, in 11 patients MRD was inferior to 0. 1 % and in 7 patients MRD was inferior to 0. 01 %. Overall, higher MRD level after induction (defined by MRD level higher than 0. 1 %) was associated with poorer prognosis for disease free survival (HR= 4. 25 [95% CI 1. 049–17. 27]; p=0. 04), and for overall survival HR=11. 25 [95% CI 1. 22–103. 23]; p=0. 03). Higher ABC proteins' activity was associated with higher MRD levels post induction, and patients who did not reach MRD level lower than 0. 1 % had significantly higher ABC proteins' activity than other patients (p=0. 008). ABC proteins' activity was also associated with overall survival in our patients (p=0. 04). Conclusion: Higher ABC proteins' activity is associated with higher MRD levels after one course of induction chemotherapy in 26 NPM1 mutated AML patients, and is also associated with poorer overall survival. The poorer prognosis associated with high ABC proteins' activity in AML seems to be in part related to direct resistance to chemotherapy. These data should be confirmed in larger studies. Disclosures: No relevant conflicts of interest to declare.

Assessment of Patients Fitness at Diagnosis in Elderly Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4012-4012
Author(s):  
Semra Aydin ◽  
Ernesta Audisio ◽  
Stefano D'Ardia ◽  
Bernardino Allione ◽  
Barbara Nicolino ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Intensive Chemotherapy ◽  
Advisory Committees ◽  
Perfect Agreement ◽  
Medical Board ◽  
Acute Myeloid

Abstract Background:Acute myeloid leukemia (AML) is a disease which predominantly affects patients with a median age at diagnosis over 65 years. The elderly population is highly heterogeneous and assessment strategies are needed to define the frailty profile. To date, evaluation of disease-related and patients specific factors in the context of clinic decision making has been largely subjective. Concerning AML therapy, several studies demonstrated improved survival for older patients receiving intensive induction chemotherapy compared to those receiving supportive care alone. Defining this subset of patients who are eligible or "fit" for intensive chemotherapy involves a great deal of subjectivity. Criteria yet have to be standardized across or within institutions. Aim:Aim of this study was to investigate the validity of four scores for assessment of patient fitness at diagnosis in parallel to physician evaluation. Further patient outcome according the respective evaluation was compared. Methods: In a single hematology center a total of 85 clinically and molecularly well characterized consecutive elderly (>60 years) patients with newly diagnosed AML were treated from 2012 to 2015 according to age, performance status and co-morbidities. Therapy response was defined according to ELN criteria. Therapy intensity decision was based on an initial haematologist evaluation followed by discussion of the patient case in an interdisciplinary board. Independently from the medical board, in parallel the local geriatric G8 screening tool, consisting of seven items from the Mini Nutritional Assessment (MNA) questionnaire and age, the HCT-CI comorbidity score as well as the AML scores proposed by the German Acute Myeloid Leukemia Cooperative Group, predicting probability of complete remission (CR) and early death (ED) were performed. Overall survival from diagnosis was compared between groups using the Cox model. Results:A total of 42 (49,4%) patients were evaluated "fit" by the medical board and treated by intensive chemotherapy ("7+3" regimen), whereas 4 patients (4,7%) underwent semi-intensive with hypomethylating agents and 39 patients (45,8%) received palliative therapy (low dose Cytarabine or Hydroxyurea). Twenty-six patients (30,6%) achieved a complete remission after induction chemotherapy, could follow consolidation chemotherapy and six of them underwent allogeneic hematopoietic stem cell transplantation. Fourty-four (51,8%) were non responders and 15 patients (17,6%) died during the first cycle. Overall, the median survival time was 6,7 months (95% CI 3,7-9,5). Primary physician care evaluation was able to define in a statistically significant manner a "fit" from an "unfit" patient. Median survival time from the "fit" patients was 10 moths (95%CI 5-not reached) compared to the "unfit" evaluated patients with 3,4 months (95%CI 1,4-5), p<0.001 with a HR (95%CI) of 3,18 (1,81 to 5,59). Parallel evaluation of patients unfitness according the proposed cut-point of the G8 (≤14), AML for CR (<40) and AML for ED (≥30) scores discriminated significantly patients survival with HRs equal to 3.03 (p<0,001), 2.11 (p=0,007) and 2.83 (p<0.001), respectively. The agreement between the frailty scores and physician evaluation on the prediction of fitness classification was analyzed by calculating the Cohens' Kappa. In this approach a Kappa level of 1,0 denotes perfect agreement. The agreement of was moderate for HCT-CI score and AML score for CR (0.47 and 0.46, respectively). The agreement was fair for G8 and AML score for ED (0.27 and 0.33, respectively). Summary/Conclusion: In conclusion, in the present AML cohort the applied frailty scores at diagnosis correlated significantly with the median overall survival. Since no perfect agreement was found respect to physician for fitness classification, frailty scores can help to improve the prognosis prediction. These results may encourage a following multi-centre analysis in order to increase the statistic power of the performed analysis. Disclosures Vitolo: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Gilead: Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Takeda: Other: Honoraria for lectures.

scholarly journals Prognostic Impact of the Interaction between DNMT3A mutation and Internal Tandem Duplication of the FLT3 Gene (FLT3-ITD) in Patients with De Novo Mutated NPM1 (NPM1mut) acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1492-1492
Author(s):  
Guadalupe Oñate ◽  
Ana Garrido ◽  
Jordi Esteve ◽  
Rosa Coll ◽  
Montserrat Arnan Sangerman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Impact ◽  
Intermediate Risk ◽  
Mutational Status ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Introduction The association of NPM1mut and FLT3-ITD in de novo acute myeloid leukemia (AML) with intermediate-risk cytogenetics has different prognostic impact depending on the FLT3 allelic burden. Previous studies published by our cooperative group showed that patients with de novo AML of intermediate-risk cytogenetics with NPM1mut and FLT3-ITD low ratio (<0.5, FLT3low) at diagnosis presented an overall survival and relapse rate similar to those with NPM1mut and FLT3wt. Therefore, in the CETLAM-2012 protocol, patients with FLT3low NPM1mut AML are not considered for allogenic hematopoietic stem cell transplant (allo-HSCT) in first complete remission (CR1). Recent studies suggest that the co-occurrence of DNMT3A mutation in FLT3-ITD NPM1mut AML patients confers a worse prognosis regardless of FLT3-ITD ratio. We analysed our data to determine whether these findings were confirmed in our cohort, specifically in the low FLT3-ITD ratio patients, since this could have therapeutic implications. Methods and patients A total of 163 patients with de novo AML, intermediate-risk cytogenetics and NPM1mut were analysed (median age 53 years (18-72); male:female 72:91 (0.79)). Eighty patients (49%) harboured an FLT3-ITD, with a high allelic ratio in 42 of 76 patients with available ITD/wt ratio (55%). They were included in the AML-2003 (n=49) and AML-2012 (n=114) CETLAM protocols. Proportion of patients undergoing alloHSCT in CR1 is detailed in table 1. Bone marrow samples from diagnosis were studied for DNMT3A mutations as previously described. The definition of complete remission (CR), overall survival (OS), leukemia-free survival (LFS) and risk of relapse (RR) followed recommended ELN criteria. The Kaplan-Meier method was used to estimate the distribution of LFS and OS, for RR cumulative incidence was used. Results Out of the 163 patients with AML of intermediate risk cytogenetics and NPM1mut, 78 presented DNMT3A mutations (48%). Of these, 62 (79%) presented mutations in codon R882 or corresponded to DNA insertions/deletions while 16 (21%) harboured missense mutations. Presence of DNMT3A mutation did not associate with FLT3-ITD (ITD/85 DNMT3Awt vs ITD/78 DNMT3Amut, p=0.394). In the entire cohort, 5-year OS, LFS and RR were 58±4.5%, 59±4.6% and 27±13.9%. FLT3-ITD ratio confirmed its prognostic impact when analysing FLT3wt (n=83) vs FLT3low (n=34) vs FLT3high (n=42) patients (5-year OS of 68±6% vs 62±8.7% vs 37±8.6%; p=0.002; and 5-year RR of 18±9.4% vs 27±16.1% vs 41±23.2%; p=0.023). On the contrary, DNMT3Amut did not exert any effect on overall outcome (5-yr OS DNMT3Awt vs DNMT3Amut 61±6.2% vs 55±6.2%; p=0.234) When DNTM3A mutational status was considered, the impact of FLT3-ITD on outcome was mitigated in wild-type DNMT3A population. Thus, we found that DNMT3Awt patients presented no statistical differences in OS according to FLT3 mutational status or ratio: FLT3wt (n=46) vs FLT3-ITD (n=39) was 67±8.5% vs 57±8.2%; p=0.122, whereas FLT3wt (n=46) vs FLT3low (n=18) vs. FLT3high (n=19) was 67±8.5% vs. 66±11.5% vs 46±11.8%; p=0.088 (image 1A).This was also seen in relation to LFS and RR according to FLT3 ratio: 5-yr LFS of FLT3wt vs FLT3low vs FLT3high was 72±7.9% vs 61±12.6% vs 51±13.4%; p=0.244 and 5-year RR of the same groups: 19±8.8% vs 26±12.5% vs 27±21.9%; p=0.724 (image 2A). In the DNMT3Amut group, patients with FLT3-ITD (n=41) presented shorter OS than those with FLT3wt (n=37) with an OS of 37±10.7% vs 69±7.8%; p=0.028. When FLT3 ratio was considered, FLT3wt (n=37) vs FLT3low (n=16) vs FLT3high (n=23) showed an OS of 69±7.8% vs. 58±13.2% vs 27±13.1%; p=0.038 (image 1B). Similar results were seen in LFS according to FLT3 ratio (FLT3wt (n=29) vs FLT3low (n=16) vs FLT3high (n=20) 71±8.6% vs 53±12.9% vs 18±13.8%; p=0.012). Finally, we observed significant differences in the 5-year RR when considering DNMT3Amut patients in relation to FLT3 ratio (FLT3wt vs FLT3low vs FLT3high 18±10.6% vs 27±20% vs 54±28.8%; p=0.021)(image 2B). Conclusions In this study, patients with NPM1mut and FLT3-ITDlow presented a similar outcome to patients with NPM1mut and FLT3wt regardless of DNMT3A mutational status. These results support the modification of alloHCST policy in CR1 in CETLAM-2012, which do not consider alloHSCT for patients with FLT3low. On the other hand, concurrence of DNMT3A mutation may have an added negative effect in patients with NPM1mut and FLT3-ITDhigh, which should be further confirmed in larger studies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Long-term survival after intensive chemotherapy or hypomethylating agents in AML patients aged 70 years and older: a large patient data set study from European registries

Leukemia ◽  
2021 ◽  
Author(s):  
Christian Récher ◽  
Christoph Röllig ◽  
Emilie Bérard ◽  
Sarah Bertoli ◽  
Pierre-Yves Dumas ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Intensive Chemotherapy ◽  
Hypomethylating Agents ◽  
Term Survival ◽  
Acute Myeloid

AbstractThe outcome of acute myeloid leukemia patients aged 70 years or older is poor. Defining the best treatment option remains controversial especially when choosing between intensive chemotherapy and hypomethylating agents. We set up a multicentric European database collecting data of 3 700 newly diagnosed acute myeloid leukemia patients ≥70 years. The primary objective was to compare overall survival in patients selected for intensive chemotherapy (n = 1199) or hypomethylating agents (n = 1073). With a median follow-up of 49.5 months, the median overall survival was 10.9 (95% CI: 9.7–11.6) and 9.2 months (95% CI: 8.3–10.2) with chemotherapy and hypomethylating agents, respectively. Complete remission or complete remission with incomplete hematologic recovery was 56.1% and 19.7% with chemotherapy and hypomethylating agents, respectively (P < 0.0001). Treatment effect on overall survival was time-dependent. The Royston and Parmar model showed that patients treated with hypomethylating agents had a significantly lower risk of death before 1.5 months of follow-up; no significant difference between 1.5 and 4.0 months, whereas patients treated with intensive chemotherapy had a significantly better overall survival from four months after start of therapy. This study shows that intensive chemotherapy remains a valuable option associated with a better long-term survival in older AML patients.

scholarly journals Immunophenotyping Investigation of Minimal Residual Disease Is a Useful Approach for Predicting Relapse in Acute Myeloid Leukemia Patients

Blood ◽  
1997 ◽  
Vol 90 (6) ◽  
pp. 2465-2470 ◽  
Author(s):  
J.F. San Miguel ◽  
A. Martı́nez ◽  
A. Macedo ◽  
M.B. Vidriales ◽  
C. López-Berges ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Leukemic Cells ◽  
Rhodamine 123 ◽  
Minimal Residual ◽  
Acute Myeloid

A high complete remission rate is currently achieved in patients with acute myeloid leukemia (AML). However, many patients eventually relapse due to the persistence of low numbers of residual leukemic cells that are undetectable by conventional cytomorphologic criteria (minimal residual disease [MRD]). Using immunophenotypic multiparametric flow cytometry, we have investigated in sequential studies (diagnosis and follow-up) the impact of MRD detection on the outcome of 53 AML patients that had achieved morphologic remission with standard AML protocols and displayed at diagnosis an aberrant phenotype. Patients were studied at diagnosis with a panel of 35 monoclonal antibodies in triple staining combinations for detection of aberrant or uncommon phenotypic features. According to these features, a patient's probe was custom-built at diagnosis for the identification of possible residual leukemic cells during follow-up. The level of MRD at the end of induction and intensification therapy correlated with the number of relapses and relapse-free survival (RFS). Thus, patients with more than 5 × 10−3 residual cells (5 residual cells among 1,000 normal bone marrow [BM] cells) identified as leukemic by immunophenotyping in the first remission BM showed a significant higher rate of relapse (67% v 20% for patients with less than 5 × 10−3 residual cells; P = .002) and a lower median RFS (17 months v not reached; P = .01). At the end of intensification, with a cut-off value of 2 × 10−3 leukemic cells, AML patients also separated into two distinct groups with relapse rates of 69% versus 32% (P = .02), respectively, and median RFS of 16 months versus not reached (P = .04). In addition, overall survival was also significantly related to the level of residual cells in the marrow obtained at the end of induction and particularly after intensification therapy (P = .008). Furthermore, we have explored whether residual disease was related with the functional expression of multidrug resistance (MDR-1) at diagnosis as assessed by the rhodamine-123 assay. Patients with ≥5 × 10−3 residual leukemic cells at the end of induction therapy had a significantly higher rhodamine-123 efflux (mean, 56% ± 24%) than those with less than 5 × 10−3 residual cells (mean, 32% ± 31%; P = .04). Finally, multivariate analysis showed that the number of residual cells at the end of induction or intensification therapy was the most important prognostic factor for prediction of RFS. Overall, our results show that immunophenotypical investigation of MRD strongly predicts outcome in patients with AML and that the number of residual leukemic cells correlates with multidrug resistance.

Sign in / Sign up

Export Citation Format

Share Document