scholarly journals Early Blast Clearance Evaluation after Induction Chemotherapy for Acute Myeloid Leukemia By Multiparameter Flow Cytometry and WT1-RNA Quantification: A Single Center Experience

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5333-5333
Author(s):  
Carlo Messina ◽  
Matteo G Carrabba ◽  
Elisa Sala ◽  
Michela Tassara ◽  
Raffaella Milani ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Predictive Value ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Residual Disease ◽  
Prognostic Impact ◽  
Induction Regimen ◽  
Blast Count ◽  
Acute Myeloid

Abstract Introduction: in acute myeloid leukemia (AML) the response to treatment is evaluated upon full recovery of peripheral blood counts by bone marrow (BM) assessment using morphology and cytogenetics, if appropriate number of metaphases is obtained. Real time quantitative PCR (RQ-PCR) and multiparametric flow citometry (MFC) are sensitive techniques to assess minimal residual disease (MRD) mostly used to refine risk stratification and to guide therapy. Evaluation of response to induction chemotherapy (CT) during aplasia (around day 14 from start of induction) has shown a significant prognostic impact, the presence of residual disease predicting a worse prognosis. All reported studies on early BM blast clearance evaluation rely on morphology as a single technique. Unfortunately, at day 14 BM is often not evaluable for cytology and morphologyc blast count. Unpredictability and intra-observer variability must also be considered when assessing blast count by morphology alone. No studies analysing early BM blast clearance by means of MFC and/or PCR have been published and the correlation between the two assays is unknown in this setting. Moreover, it is to be established if early intensification (around day 15 from start of induction) with a second cycle of CT could increase the CR rate in pts with disease persistence in the BM evaluated at day 14. Matherial and methods: we retrospectively evaluated data of 23 newly diagnosed AML pts who received induction CT at our center between 02/2009 and 05/2014, and for whom analysis of BM both at day 14 and after hematologic recovery (around day 28) was performed. The aim of our study was to define the prognostic value of early MRD quantification by MFC (d14-LAIP) and WT1 quantification by PCR (d14-WT1) in predicting the response to induction. Firstly we compared d14-LAIP and d14-WT1 to identify the more sensitive and specific assay in predicting the response to induction, in particular for cases not evaluable for morphologic blast count. Then we compared the outcome of pts who received or did not receive an early intensification for persistence of disease at d14 BM evaluation. Results: 20 pts received the 3+7 induction regimen, 3 pts the ICE induction regimen. After BM evaluation at day 14, 7 pts received early reinduction CT (FLAG-IDA regimen) starting at day 16 (median), 16 pts did not receive further therapy before BM evaluation at day 28. Overall CR rate was 70% (16 pts), PR/NR 30% (7 pts), TRM 4% (1 pt). At day 14, leukemic blast percentage was not evaluable by morphology in 8 (35%) cases due to marrow aplasia, in 1 (4%) case blasts were <5%, in 14 (61%) cases blasts were ≥5%; by MFC (23 cases), in 9 (39%) cases blasts were ≤2%, in 14 (61%) were >2%; by PCR (17 cases), in 4 (24%) cases WT1 was <250 cp/10e4 ABL, in 13 (76%) WT1 was ≥250 cp/10e4 ABL. At day 28 BM evaluation, of the 8 pts with aplastic marrow at day 14, 6 (75%) were in CR and 2 (25%) in PR/NR, of the 14 pts with blasts ≥5% at day 14, 9 (64%) were in CR and 5 (36%) in PR/NR. Analysis of the paired results from nadir to recovery revealed that d14-LAIP 2% had a positive predictive value (PPV) of CR at day 28 of 71% and negative predictive value (NPV) of 89%, with a sensitivity of 83% and a specificity of 80%, d14-WT1 250 had a PPV of 50% and NPV of 25%, with a sensitivity of 57% and a specificity of 20%. The d14-LAIP analysis was strongly associated with CR after induction (p 0.034). Considering the 14 pts with blasts ≥5% at day 14, 6/7 (86%) who received early reinduction CT and 3/7 (43%) who did not, obtained the CR at day 28 (p ns). Discussion: in our series d14-LAIP proved to be more predictive of response after induction CT than d14-WT1. Although one-third of pts had an early morphologic response not evaluable due to marrow aplasia MFC proved to be a useful assessment tool with a 100% applicability. Moreover, correlation between D14-LAIP and d14-WT1 was > 90%. Our data confirm the prognostic value of day 14 BM evaluation and suggest that MRD detection, also in aplasia, could drive early reinduction CT which probably could increase the CR rate, without significantly clinical complications. Anyway, this last point must be confirmed with a larger study. Disclosures Bordignon: MolMed S.p.A: Chairman and CEO Other.

A Combined Score of Minimal Residual Disease (MRD) Assessment by Flow Cytometry, Cytogenetic and Molecular Markers As Well As Age Predicts Outcome and Can Potentially Guide MRD-Based Therapy in Acute Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 934-934 ◽  
Author(s):  
Thomas Köhnke ◽  
Daniela Sauter ◽  
Katharina Ringel ◽  
Jan Braess ◽  
Wolfgang Hiddemann ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Prognostic Score ◽  
Therapeutic Decisions ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Abstract 934 Background: Induction chemotherapy in acute myeloid leukemia (AML) has been shown to successfully induce complete remission in over 70% of patients. However, a majority of patients experience subsequent relapse. Assessment of minimal residual disease (MRD) by flow cytometry at time of aplasia, after induction and after consolidation therapy has been shown to be of prognostic relevance for relapse free survival (RFS) and overall survival (OS). However, studies utilizing MRD diagnostics to guide therapeutic decisions in adult AML (excluding APL) are yet to be performed. Methods: From the database at the Laboratory of Leukemia Diagnostics at our clinic datasets of 583 patients with newly diagnosed AML treated between 2000 and 2011 were analyzed. Patients with biphenotypic acute leukemia, M3 according to FAB classification, as well as those not treated with intensive induction chemotherapy were excluded. To be eligible for further analysis, at least two samples of bone marrow blood (at primary diagnosis and at one further timepoint during or after treatment) had to be available for MRD assessment by 3-color-flow cytometry at our laboratory. Cytogenetic and molecular risk stratification was performed at our clinic and assigned in accordance to the European LeukemiaNet (ELN) guidelines. We used Cox Proportional Hazards Regression to determine prognostic factors for OS and RFS and Kaplan-Meier estimator to determine OS and RFS of the proposed score. Results: Data of 217 Patients fulfilled the inclusion criteria and were therefore eligible for further analysis. 171 (78,8%) patients achieved CR after induction therapy. Of these patients, 120 had flow cytometry data available at time of aplasia and were included in further analysis. The median age was 54,5 y and the median OS 1007 days. Here, only “favorable” ELN risk stratification was associated with significantly longer OS (favorable vs. intermediate-I, Intermediate-II & adverse, Hazard Ratio, HR 0,36, 95% CI 0,19–0,69, p=0,0019), whereas RFS did not yield a significant difference (HR 0,64, 0,37-1,13, p=0,125). Age > 60y was associated with significantly shorter OS (HR 2,07, 1,23-3,47, p=0,0058) and RFS (HR 1,83, 1,11-3,01, p=0,018). And though leukemia-associated phenotypes (LAIP) ≥0,15% at time of aplasia were not predictive of OS (HR 1,32, 0,79–2,23, p=0,293) they were highly predictive of shorter RFS (HR 2,15, 1,30–3,55, p=0,003). Combining these three factors in a simple prognostic score (ELN risk group “favorable” = 0 points, “intermediate-I”, “intermediate-II” or “adverse” = 1 point; age > 60y = 1 point; LAIP at time of aplasia ≥0,15% = 1 point, see table I) identified three distinct groups (0 points: good, 1 point: intermediate, 2–3 points: poor, see table II) which were predictive of both OS and RFS (see figures 1 and 2). Interestingly, this score was capable of identifying a small group of patients with a very good prognosis (n=18, median OS and RFS not reached after >6 years) while at the same time equally dividing up the remaining patients within the intermediate and poor prognosis group (n=52 vs. 50, median OS 1182 vs. 677 days, median RFS 1180 vs. 334 days). Conclusion: MRD based therapeutic decisions and risk-adapted therapy have long been suggested in management of adult AML. Here, we propose a prognostic score for patients with AML achieving CR under intensive induction chemotherapy. The addition of MRD Flow to established genetic prognostic markers as well as age improves the prediction of relapse free and overall survival. Application of this score in therapeutic decisions could assist the treating physician and avoid over-treatment. To further evaluate our proposed prognostic score, it has to be applied in a prospective study for further evaluation and determination of its clinical significance. These data will be the basis for therapeutic trials guided by MRD assessment. 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.

Impact Of The Early Intensification Of Induction Chemotherapy On Complete Remission and Survival Rates For De Novo Adult Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3402-3402
Author(s):  
Seung-Ah Yahng ◽  
Jae-Ho Yoon ◽  
Sung-Eun Lee ◽  
Seung-Hwan Shin ◽  
Byung-Sik Cho ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Remission Induction ◽  
Advisory Committees ◽  
Induction Regimen ◽  
Acute Myeloid

Abstract Background The successful induction chemotherapy of acute myeloid leukemia (AML) depends on the ability to achieve complete remission (CR) and to maintain remission status as long as possible. Approach to improve the rate of CR includes the intensification of induction chemotherapy for AML. The primary goal of this study was to evaluate and compare the long-term outcomes between remission induction therapy with and without early intensification added to the standard 3+7 remission induction regimen. Methods A retrospective analysis was performed on de novo AML patients diagnosed and treated at Catholic Blood and Marrow Transplantation Center between January 2001 and December 2010. Six hundred forty-one adults of ages between 16 and 60 were included, all of whom received induction chemotherapy starting with 3 days of idarubicin and 7 days of cytarabine or behenoyl cytarabine (BHAC). Cases with t(9;22) and t(15;17) were excluded. Bone marrow (BM) aspiration study was assessed on day 7 of induction in all patients. Factors which were considered for early intensification of induction were the presence of ≥ 5% BM blasts, patient performance, and other high risk clinical characteristics, such as karyotype. Groups according to early intensification on days 8 to 10 of induction were as followings: no intensification (3+7), n=156; cytarabine or BHAC for 3 days (3+10), n=233; addition of idarubicin for 2 days to 3+10 regimen (5+10), n=252. After a median duration of 5.5 months (3.3-19.0) from diagnosis, 479 patients underwent stem cell transplantation (autologous [auto-SCT], n=144; allogeneic [allo-SCT], n=335). Conditioning regimen for auto-SCT consisted of fractionated total body irradiation (TBI), melphalan, and cytarabine, whereas 83% (n=278) of patients with allo-SCT received myeloablative conditioning, of which was mostly TBI-based regimen (92%). Donors were matched sibling (n=213), matched unrelated (n=63), mismatched unrelated (n=39), and haploidentical related (n=20). Results The median age at diagnosis was 39 years (16-60). Mean values of BM blast % on day 7 of induction was 3.5 in 3+7 group, 7.9 in 3+10, and 33.6 in 5+10 (p=<0.0001), while no significant difference in the proportion of adverse karyotype was shown (11.7% vs. 12.8%, p=0.804). After first induction (3+7, n=165; 3+10/5+10, n=465), the CR/CRi rate was significantly higher in 3+10/5+10 versus 3+7 (78.1% vs. 69.2%, p=0.023), while the rate for death in aplasia was lower (4.3% vs. 9.6%, p=0.013). After re-induction with various regimens, the CR/CRi rate was still significantly higher in intensified group (p=0.012). The relapse rates between the groups in 536 patients achieving CR (83.6%), however, was not significantly different (8.9% vs. 9.9%, p=0.737). SCT was performed at CR1 (n=459), CR2 (n=10), or relapsed/refractory status (n=10). Patients with auto-SCT mostly had better/intermediate cytogenetic risk (96%) at diagnosis, while 12% of allo-SCT had poor karyotype. After the median follow-up duration of 60.2 months (2.2-143.5), the median overall survival (OS) in all patients (n=641) was 65.6 months. The 5-year disease-free survival (DFS) of patients with auto- and allo-SCT was 58.4±4.2 and 64.9±2.7, respectively. Of 334 patients receiving allo-SCT, the 5-year DFS was significantly higher in patients achieving CR1 (n=299) after first induction therapy (p<0.0001), in whom 75% of them had early intensification. Other factors with significant impact on DFS after allo-SCT (n=334) were karyotype at diagnosis (p=0.032) and donor type (HLA-matched vs. HLA-mismatched sibling or unrelated, 58.1%±3.8 vs. 45.1±8.0, p=0.016). The significances were confirmed in multivariate analysis, which demonstrated that achieving CR1 after first induction regimen and its maintenance until SCT was the most powerful predictor for DFS after allo-SCT (67.1±2.9 vs. 34.6±7.8, p=<0.0001). When all patients were analyzed, according to induction intensification, a statistically significant benefit in 10-year OS was observed in 5+10 intensified group (44.8% vs. 52.9%, p=0.032). Conclusion Our results suggest possible benefit of examining day 7 BM aspiration for the strategy of early intensification of induction chemotherapy for adult AML patients and our intensification doses can be safely added with high efficacy in the achievement of CR1 compared to 3+7 standard regimen, and may have affected for better DFS after allo-SCT. Disclosures: Kim: BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Prognostic Impact of Pretransplantation Minimal Residual Disease Detection for Flow Cytometric, on Outcome of Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia. a Single Center Experience in Colombia over 14 Years

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5411-5411
Author(s):  
Andres Armando Borda Molina ◽  
Iris Cordoba ◽  
Virginia Abello ◽  
Carmen Rosales ◽  
Rosales Manuel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Prognostic Impact ◽  
Allogeneic Bone ◽  
Flow Cytometric ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Background: The accumulated evidence from studies of multiparameter flow cytometric MRD (MFC-MRD) assessment in AML leaves little doubt that this method of MRD detection can be used to risk stratify both younger and older patients at treatment time points. Persistence of disease or high levels of pretransplantation minimal residual disease (MRD) have been reported to predict disease relapse after Allogeneic bone marrow transplantation (BMT). The prognostic impact of MFC-MRD is strong enough to have emerged despite study differences in the MFC assays and the limitations of now outdated restricted antibody panels. Aims: To determine the value of Minimal Residual Disease (MRD) assessed by Multi-parameter Flow Cytometry (MFC) pretransplantation Allogeneic BMT, in predicting outcome in patients with acute myeloid leukemia (AML). Methods: We performed a retrospective analysis the predictive value of MRD assessment by MFC pre trasnplantation alogeneic in 119 patients (diagnosed AML treated between january 2010 and october 2014 submitted at our institution who had available MRD assessment). MRD by MFC on bone marrow specimens obtained approximately 30 days before transplantation. MRD was identified as a cell population showing deviation from normal antigen expression patters compared with normal or regenerating marrow. The detection threshold for defining pre transplantation positive MRD was >0.3%. Results - Of the 119 patients, 80 (67%) were in complete remission (CR1) , 31 (26%) CR2 and > CR2 8 (6%). Their median age was 38 years (Range, 10-64). Hyperleucocytosis in 39 (32%) and Cytogenetics was favorable risk in 32 (26%), intermediate risk in 39 (32.%), adverse risk in 35 (29%) and unknown in 13 (14%). There were a total of 44 deaths and 17 relapses; these contributed to the probability estimates for overall survival (OS) and disease free survival (DFS), stratified by MRD status and shown in figure 1. The median follow-up after BMT among survivors was 8.3 years (range, 6.9 to 9,6 years). The 7.5-years estimates of OS for MRD-positive and MRD-negative patients were 43.1% (range, 23,2% to 58,6%) and 68% (range 56% to 78.3%), respectively, and the 7,5 year estimates for DFS for MRD-positive and MRD-negative patients were 40.5% (range 21.4% to 52.6%) and 56% (range 42.5% to 65.8%). After adjustment for various covariates, age, cytogenetics risk, hyperleucocytosis, secundary AML, the hazard ratios of MRD positive versus MRD negative were 2.06 (range 1.52 to 6.24; P=0,003) for overall mortality, 3.45 ( range 2.14 to 7.32; p=0.014) for DFS. Conclusion: That detection of MRD pre transplantation define a population of patients with AML who are at higher risk for adverse outcome, even after adjusting for other factors that influence post-BMT outcome. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value

Blood ◽  
2010 ◽  
Vol 116 (12) ◽  
pp. 2122-2126 ◽  
Author(s):  
Saman Abbas ◽  
Sanne Lugthart ◽  
François G. Kavelaars ◽  
Anita Schelen ◽  
Jasper E. Koenders ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Single Case ◽  
Lymphoblastic Leukemia ◽  
Prognostic Impact ◽  
Isocitrate Dehydrogenase 1 ◽  
Idh Mutations ◽  
Idh1 And Idh2 Mutations ◽  
Acute Myeloid

Abstract Somatic mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) were recently demonstrated in acute myeloid leukemia (AML), but their prevalence and prognostic impact remain to be explored in large extensively characterized AML series, and also in various other hematologic malignancies. Here, we demonstrate in 893 newly diagnosed cases of AML mutations in the IDH1 (6%) and IDH2 (11%) genes. Moreover, we identified IDH mutations in 2 JAK2 V617F myeloproliferative neoplasias (n = 96), a single case of acute lymphoblastic leukemia (n = 96), and none in chronic myeloid leukemias (n = 81). In AML, IDH1 and IDH2 mutations are more common among AML with normal karyotype and NPM1mutant genotypes. IDH1 mutation status is an unfavorable prognostic factor as regards survival in a composite genotypic subset lacking FLT3ITD and NPM1mutant. Thus, IDH1 and IDH2 mutations are common genetic aberrations in AML, and IDH1 mutations may carry prognostic value in distinct subtypes of AML.

scholarly journals Prognostic Value of Minimal Residual Disease before Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5733-5733
Author(s):  
Olga Pérez-López ◽  
Teresa Caballero-Velázquez ◽  
Enrique Colado ◽  
Sara Alonso ◽  
José González-Campos ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Residual Disease ◽  
Hematopoietic Stem ◽  
Multiparametric Flow Cytometry ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Introduction Several studies have shown that the minimal residual disease (MRD) in acute myeloid leukemia (AML) patients has a prognostic value after induction and consolidation therapy. Nevertheless the relapse is the most important cause of treatment failure in these patients, although they achieved a negative MRD, and even after an allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nowadays, the value of the MRD before allogeneic BMT is still controversial. Method Multicentric study where we have studied correlative AML patients who went under an allo-HSCT in a situation of complete response, between 2012 and April'18. The MRD was analyzed by 8-coloured multiparametric flow cytometry, at least with 2 tubes per patient and 1,000,000 events per tube. We evaluated the prognostic value of the MRD before allo-HSCT. Results Between January'12 and April'18 we have gathered 90 allogeneic BMT in AML patients who were in CR, with a median age of 45 years old (17 - 66). The pre-HSCT situation was 1st complete remission (CR) in 75 patients and 2nd CR in 15. In 45 patients the conditioning regimen was myeoablative. In the group of patients (67) where we could know the risk group at diagnosis, the distribution was: low risk 18%, intermediate risk 59.7% and high risk 22.4%. The 46.7% of the donors were not related. In the last follow-up after allo-HSCT 24 patients have suffered a relapse (26.7%) and 41 (45.5%) have died (17 cases of mortality related to the transplant and 24 not related). In the global analysis the median follow-up of the overall survival (OS) was 37.5 months. Among the 90 patients, MRD was valuable in 86. Ten of 59 patients (16.9%) with negative MRD relapsed vs 12/27 (44.4%) with positive MRD, p= 0.016. If we consider only patients in 1st CR, 9/50 (18%) patients with negative MRD relapsed vs 10/22 (45.5%) with positive MRD, p= 0.02. This statistically significant difference does not exist if we consider only patients in 2nd CR. The median follow-up of OS and event free survival (EFS) was not reached in the negative MRD group and 571 days and 299 days in the positive MRD group. OS and EFS at 2 years after transplantation were 65% and 64% in the negative MRD group and 42% and 37% in the positive MRD group, p= 0.03 and p= 0.008 respectively (figure 1). Conclusions The detected MRD by 8-colour multiparametric flow cytometry previous an allo-HSCT in patients with AML in 1st CR is a prognostic factor in terms of relapse. Patients with a positive MRD before the allo-HSCT have a poorer OS and EFS than the patients with a negative MRD. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals High Blood BAALC Copy Numbers Determined By Digital Droplet PCR at Timepoint of Allogeneic Transplantation in Complete Remission Predicts Relapse in Patients with Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 517-517
Author(s):  
Madlen Jentzsch ◽  
Marius Bill ◽  
Julia Schulz ◽  
Juliane Grimm ◽  
Stefanie Beinicke ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Residual Disease ◽  
Absolute Quantification ◽  
Prognostic Impact ◽  
Healthy Controls ◽  
Copy Numbers ◽  
Acute Myeloid

Abstract Allogeneic hematopoietic cell transplantation (HSCT) is a powerful consolidation option for acute myeloid leukemia (AML) patients (pts) in hematologic complete remission (CR). Disease recurrence after HSCT remains a major clinical problem & early identification of AML pts at risk of relapse is crucial to improve outcomes. High expression of the AML associated gene BAALC (Brain and acute leukemia, cytoplasmic) at diagnosis adversely impacts on outcomes in AML pts. Little is known about its prognostic capacity during disease course & as a marker of residual disease. Here we adopted digital droplet polymerase chain reaction (ddPCR) for absolute quantification of BAALC copy numbers in peripheral blood (PB) prior to HSCT in AML pts in hematologic CR. We identified 82 AML pts with PB in first (60%) or second CR (23%) or CRi (17%) up to 28 days prior to HSCT available. Median age at HSCT was 63.9 (range 50.8-76.2) years (y). All pts received non-myeloablative (NMA) conditioning (fludarabine 3x30 mg & 2 Gy total body irradiation). At diagnosis, mutation status (mut) of the NPM1, CEBPA, IDH1, IDH2,& DNMT3A gene & presence of FLT3-ITD or FLT3-TKD were assessed. In pre-HSCT PB, absolute quantification of BAALC copy numbers was performed by ddPCR & results were normalized to ABL1 copy numbers.Additionally, absolute BAALC copy numbers wereassessedin PB of healthy controls (n=7) with a median age of 62.7 (range 39.6-82.0) y. Pts were grouped according to the European LeukemiaNet (ELN) classification in 21% favorable, 23% intermediate-I, 24% intermediate-II, 23% adverse & 9% unknown. Pts & healthy control were evenly matched in age (P=1) & sex (P=1). BAALC/ABL1 copy numbers did not differ between AML pts at HSCT (median 0.03 [range 0.01-2.48]) & the healthy controls (median 0.04 [range 0.03-0.10], P=.34, Figure 1). A cut-off point of 0.14absolute BAALC/ABL1 copies was determined using the R package 'OptimalCutpoints' & used to define pts with high (26%) & low (74%) pre-HSCT BAALC/ABL1 copy numbers. The copy number at this cut-off point was higher than the two-fold standard deviation over the median of the healthy controls (0.10 BAALC/ABL1). Pts with high & low pre-HSCT BAALC/ABL1 copy numbers did not differ significantly in pre-treatment characteristics (i.e. hemoglobin, white blood count, platelets, blasts in bone marrow or PB, ELN genetic group, FLT3-ITD, FLT3-TKD, NPM1, CEBPA, DNMT3A, IDH1 or IDH2 mut) or remission status at HSCT (CR1 vs. CR2 vs. CRi). However, pts with high pre-HSCT BAALC/ABL1 copy numbers had a significantly higher cumulative incidence of relapse (CIR, P=.02, Figure 2a) & shorter overall survival (OS, P=.02, Figure 2b). High pre-HSCT BAALC/ABL1 copy numbers especially impacted on CIR when we restricted our analysis to pts with normal cytogenetics (P=.003). In multivariate analysis for the entire cohort, high pre-HSCT BAALC/ABL1 copy numbers retained the prognostic impact on CIR (Hazard Ratio [HR] 3.6, Confidence Interval [CI] 1.6-8.2, P=.002) after adjustment for disease status at HSCT (P=.006) & the prognostic impact on OS (HR 2.2, CI 1.1-4.3, P=.02). In conclusion, ddPCR is a feasible method for absolute quantification of BAALC copy numbers in PB, which may indicate residual disease burden in AML pts. High PB BAALC/ABL1 copy numbers (>0.14) in AML pts in hematologic CR at HSCT associated with higher CIR & shorter OS in univariate & multivariate models. AML pts with high PB BAALC/ABL1 copy numbers at HSCT should be closely monitored for relapse in the post-transplant period. In the future prospective studies will be required to validate the absolute PB BAALC/ABL1 copy number cut-off point & to evaluate whether AML pts with high BAALC/ABL1 copy numbersmight benefit from additional treatment before HSCT. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Poenisch: Mundipharma: Research Funding. Niederwieser:Amgen: Speakers Bureau; Novartis Oncology Europe: Research Funding, Speakers Bureau.

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