scholarly journals Final Results of the AML12 Trial of the Spanish Cetlam Group in Adults with Acute Myeloid Leukemia (AML) up to the Age of 70 Years: Risk Adapted Post-Remission Allocation Based on Genetic Data and Minimal Residual Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 289-289
Author(s):  
Jorge Sierra ◽  
Ana Garrido ◽  
Marina Diaz Beya ◽  
Montserrat Hoyos ◽  
Marisa Calabuig ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Research Funding ◽  
Residual Disease ◽  
High Dose ◽  
Severe Toxicity ◽  
Group Setting ◽  
Npm1 Mutation ◽  
Allogeneic Hct ◽  
Molecular Features ◽  
Minimal Residual

BACKGROUND: AML risk classification is based on genetics (cytogenetics and molecular features) and more recently also on minimal residual disease (MRD) after chemotherapy. These two aspects allow predicting relapse and supporting or not the most anti-leukemia treatment that remains allogeneic hematopoietic cell transplantation (HCT). We prospectively investigated the combined use of the two predictive markers to allocate post-remission therapy with or without HCT. Objectives of the study were testing: a) if this approach was feasible in a multicenter setting; b) the proportion of patients who were allocated to an allogeneic HCT and finally received the procedure; c) the final distribution into the risk categories and their outcome; d) to analyze the outcome of patients with favorable or intermediate genetics moved to the high risk category because of positive MRD. METHODS: Adult patients with primary AML treated at 15 academic hospitals were included between February 2012 and December 2018. Induction chemotherapy consisted of idarubicin 12 mg/m2 days 1-2-3 and cytarabine 200 mg/m2 days 1 to 7. Consolidation courses were high-dose cytarabine (3 g/m2 or 1.5 g/m2 if ≥60 y/o). The number of consolidation courses was based on genetic risk: 3 in favorable genetics category (FGC) (CBF, NPM1mut/FLT3-ITDwild or ratio<0.5, and CEBPA biallelic mutation); and one in the intermediate genetics category (IGC), including intermediate cytogenetics without favorable or unfavorable (FLT3-ITD, MLL, EVI1) molecular features, as well as in adverse genetics category (AGC). Following, the mandatory option was allogeneic HCT in the AGC and in the other genetic categories when MRD was positive. In the IGC without MRD autologous or HLA preferentially matched allogeneic HCT was a center decision. MRD was assessed by flow (positive >0.1%) and/or quantitative PCR of the specific transcripts (RUNX1/RUNX1T1, CBFβ/MYH11 and NPM1). RESULTS: Seven hundred forty-five patients (median age: 55, range18-70 y/o, 51% male) were enrolled. Cytogenetics according the revised MRC classification in 707 informative cases was: CBF AML 12%, intermediate 65% (75% of them normal karyotype), and adverse 23%. FLT3-ITD was detected in 28% of patients with intermediate risk cytogenetics and NPM1 mutation in the same group was present in the 48%. Complete remission (CR) was achieved in 81% (n=603) of patients, 82% and 80% in patients up to and above 60 yrs, respectively. Induction death occurred in 9% of patients, 7% and 11% the two age groups, and 10% of patients had refractory leukemia; 542 (90%) of the 603 CR patients completed the consolidation phase and were risk allocated taking into account genetics and MRD. The remaining CR patients were not allocated because of early relapse (n=22), death in CR (n=5), severe toxicity (n=22) or others (n=12). After risk allocation, 208 (38%) patients were in the genetics-MRD combined favorable group (CFG), 103 (19%) in combined intermediate group (CIG) and 231 (43%) in the combined adverse group (CAG). In the latter, 185 (80%) of patients received an allogeneic HCT in first CR. Fifty-seven patients (11%) moved from the genetically FGC or IGC to the CAG because of high MRD at the end of consolidations. Median follow-up in survivors was 25 months. Overall 4-years survival (OS) of the whole series is 48±2%; event-free survival (EFS) is 77+3% in the CFG group, 45+6% in the CIG and 34+4% in the CAG (p<0.001) due to difference in the cumulative relapse incidence (19%, 38% and 45%, respectively, p<0.001 ). In the 57 patients who were MRD positive at the end of consolidation (FGC and IGC) had an OS of 53±8% and EFS of 45±7% at 4 years. CONCLUSION Risk adapted therapy for primary AML based on genetics and MRD is feasible in a cooperative group setting. The proportion of CR was high (>80%) even in patients older than 60 y/o. MRD assessment at the end of consolidation moved 57 patients with favorable or intermediate genetics to the CAG. Avoiding HCT in first CR in the FGC patients associated to EFS above 75% at 4 years. Allogeneic transplantation feasibility was 80% when this was the intended treatment because of adverse genetics and/or MRD positivity. Risk assessment based on genetics and MRD continues separating three groups of patients with different outcomes. Since relapses remain frequent when adverse AML features are present, further approaches after transplantation, such as targeted agents and immune therapies deserve investigation. Disclosures Sierra: Astellas: Honoraria; Pfizer: Honoraria; Daiichi-Sankyo: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Roche: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau. Salamero:Daichii Sankyo: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Esteve:Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Daiichi Sankyo: Consultancy; Roche: Consultancy; Astellas: Consultancy, Speakers Bureau; Pfizer: Consultancy.

Flowcytometric Minimal Residual Disease Assessment in the EMN-02/HOVON-95 MM Trial: Used Methods and a Comparison of Their Sensitivity

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2072-2072
Author(s):  
Davine Hofste op Bruinink ◽  
Stefania Oliva ◽  
Lucie Rihova ◽  
Bronno van der Holt ◽  
Milena Gilestro ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Quality Assessment ◽  
Minimal Residual Disease ◽  
Plasma Cell ◽  
Research Funding ◽  
Maintenance Treatment ◽  
Residual Disease ◽  
High Dose ◽  
International Trial ◽  
Minimal Residual

Abstract Background The introduction of novel treatment strategies against multiple myeloma (MM) has resulted in a major improvement in the overall outcome, which has led to an increased need for highly sensitive methods to detect minimal residual disease (MRD) in each patient. MRD assessment by multicolor flowcytometry (MFC) has been shown to be of prognostic value in many treatment protocols over the last decade, making it an attractive method to assess response in clinical trials. However, it is currently not known (1) what the best timing is to perform MFC MRD analysis in the context of a treatment protocol including induction, intensification, consolidation and maintenance treatment, (2) which patients should be selected for this analysis, and (3) what its feasibility is in a large international trial. The ongoing EMN-02 MRD Study aims to answer these questions within the framework of the EMN-02/HOVON-95 MM trial. Here, we describe our methods and the results of our first quality assessment round to compare the sensitivity of the used protocols. Methods The EMN-02/HOVON-95 MM trial is a randomized, multicenter, phase 3 trial in which newly diagnosed MM patients 18-65 years received 4 cycles of bortezomib, cyclophosphamide and dexamethasone (VCD) as induction treatment, followed by a first randomization between either 4 cycles of bortezomib, melphalan and prednisone (VMP), or high dose melphalan (HDM) and 1 or 2 ASCT as intensification treatment. Subsequently, patients were randomized between 2 cycles of bortezomib, lenalidomide and dexamethasone (VRD) or no consolidation treatment, followed by lenalidomide maintenance treatment for all until progression or toxicity occurred. Patients undergoing a bone marrow (BM) aspiration for complete response (CR) confirmation according to the International Myeloma Working Group (IMWG) criteria (Rajkumar et al. - Blood 2011) anytime during the trial were eligible for the EMN-02 MRD Study. BM samples from patients from 13 European countries were sent to 4 central MFC MRD laboratories in the Netherlands (A), Czech Republic (B), Denmark (C) and Italy (D), either using the strict Euroflow protocol (A) (Van Dongen et al. - Leukemia 2012) or Euroflow-based methods (B, C & D). In order to check compatibility between protocols, 5 bone marrow samples from MM patients with a clinical response ranging from progressive disease (PD) to CR were each divided in equal volumes and sent to the respective laboratories on 3 different days. MFC MRD analysis was performed on a FACS Canto II (BD) (A-C) or Coulter Navios flowcytometer (D). Protocols A, B & C used the Euroflow Plasma Cell Disorder (PCD) tube 1 and 2 combination of antibodies, containing the backbone markers CD138-PO, CD38-FITC, CD45-PB and CD19-PE-Cy7, with CD56-PE, B2micro-PerCP-Cy5.5, cyIgK-APC and cyIgL-APC-C750 in tube 1, and CD28-PE, CD27-PerCP-Cy5.5, CD117-APC, CD81-APC-H7 in tube 2. Protocol D had the same backbone markers (CD138-PerCP-Cy5.5, CD38-PB, CD45-KO and CD19-PE-Cy7), together with CD27-PE, CD81-FITC and CD20-APC in tube 1 and cyIgK-FITC, cyIgL-PE, CD56-APC and CD117-APC-AF 750 in tube 2. Bulk lysis was performed in protocols A, B and D. Every laboratory acquired at least 2x10e6 leukocytes (or at least 1x10e4 plasma cells) and performed data-analysis in Infinicyt version 1.6 or higher (A, B & C) or Navios Kaluza (D), using a threshold ranging from 10-25 aberrant plasma cell events as cutoff for MFC MRD positivity. Results Acquisition of events occurred the day after BM aspiration for all samples. The total number of acquired events per sample was dependent on the level of MRD, ranging from 3x10e5 to 2x10e7 leukocytes. MFC MRD results were very comparable between labs with a 1:1 correlation between results at every level of residual disease, being 1x10e-2, 1x10e-4, 1x10-4, 1x10e-5 and 1 MRD negative sample at the level of <1x10e-5. Based on these findings, protocols have been further harmonized and a second quality assessment round will be organized in Fall 2016 to validate the suggested improvements. Conclusions This is the first time that a European framework has been set up between laboratories to test MFC MRD analysis in the context of an international trial. The sensitivity of the protocols has been compared in a quality assessment round, which showed a high correlation of results. Disclosures Oliva: Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Boccadoro:CELGENE: Honoraria, Research Funding; Mundipharma: Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Abbivie: Honoraria; SANOFI: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Hajek:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sonneveld:Celgene: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding. Palumbo:Takeda: Employment, Honoraria; Janssen Cilag: Honoraria.

scholarly journals Impact of Minimal Residual Disease in Transplant Ineligible Myeloma Patients: Results from the UK NCRI Myeloma XI Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 245-245 ◽  
Author(s):  
Ruth Mary de Tute ◽  
Andy C Rawstron ◽  
David A Cairns ◽  
Charlotte Pawlyn ◽  
Faith E Davies ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Research Funding ◽  
Residual Disease ◽  
Prognostic Significance ◽  
Continuous Variable ◽  
Powerful Predictor ◽  
Qualitative Variable ◽  
The Impact ◽  
Minimal Residual ◽  
Support Research

Abstract Introduction. Minimal residual disease (MRD) is a powerful predictor of outcome in multiple myeloma (MM). We have previously demonstrated, in transplant eligible patients, that the level of MRD as a continuous variable independently predicts both PFS and OS, with approximately a one year median OS benefit per log depletion (J Clin Oncol 2013; 31:2540-7 and Blood 2015; 125:1932-5). The impact of MRD also appears to be independent of therapy received. There is more limited data on the applicability of MRD assessment in transplant ineligible patients, largely as a consequence of low rates of CR historically within this patient cohort. Patients and Methods. In this analysis we have assessed the impact of MRD on PFS amongst patients treated within the non-intensive arm of the NCRI Myeloma XI trial. Patients were randomised between thalidomide (CTDa) and lenalidomide (RCDa) based induction therapies with responding patients being subsequently randomised to maintenance with lenalidomide monotherapy, or no further therapy. Bone marrow aspirates were obtained at the end of induction and this analysis represents a subset of 297 patients (median age 74 years). MRD was assessed using flow cytometry (sensitivity 10-4) with a minimum of 500,000 cells evaluated with six-colour antibody combinations including CD138/CD38/CD45/CD19 with CD56/CD27 in all cases and CD81/CD117 in additional cases as required. Results. Overall MRD-negativity was demonstrated in 41/297 (13.8%). When considered according to induction therapy received 25/154 (16.0%) of patients randomized to RCDa were MRD-negative compared to 16/143 (10.8%) of those randomized to CTDa (p=0.24; Fisher's exact test). MRD-negativity was associated with a significant outcome advantage as the median PFS was 34 months versus 18 months for MRD-positive patients (p<0.0001, HR 0.44 [95% confidence interval (CI 0.29-0.67)]). This effect was noted in both RCDa (median PFS 17m v 32m; p=0.001, HR 0.41 [95%CI 0.23-0.69]) and CTDa (median PFS 19m v 34m; p=0.03, HR 0.49 [95%CI 0.26-0.95]). When the impact of MRD was assessed according to induction regimen the outcome of MRD-negative and MRD-positive patients was similar with both regimens (see figure). The impact of MRD was also assessed as a continuous variable across 5 logs of residual disease. Sequential improvements in outcome with each log reduction were demonstrable. Median PFS for the following disease levels; <0.01%, 0.01 - <0.1%, 0.1% - <1%, 1% - <10% and >/=10% were 34, 26, 16, 14 and 9 months respectively (p<0.0001). This pattern was demonstrable in both RCDa and CTDa treated patients (p<0.0001 for both). Multivariate analysis confirmed the independent predictive value of MRD both as a qualitative and continuous quantitative variable (p<0.0001 for both). In both instances achieving an immunofixation-negative CR was not a significant prognostic variable when included in the model with MRD. Conclusions. We would conclude that MRD is a powerful predictor of outcome in transplant ineligible patients and is a meaningful therapeutic goal in this patient group. In contrast to conventional CR it retains independent prognostic significance both as a quantitative and qualitative variable. This data further supports the role of MRD as a primary endpoint and surrogate marker for survival in future clinical trials. Figure. Figure. Disclosures Rawstron: Janssen: Research Funding; BD Biosciences: Other: Remuneration; Gilead: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Genzyme: Honoraria; AbbVie: Honoraria; Roche: Honoraria; Celegene: Honoraria. Pawlyn:Celgene: Consultancy, Honoraria, Other: Travel Support; Takeda Oncology: Consultancy. Davies:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kaiser:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support; Chugai: Consultancy. Jones:Celgene: Honoraria, Research Funding. Cook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Jenner:Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel support; Takeda: Consultancy, Honoraria, Other: Travel support. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jackson:MSD: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Bristol Meyers: Consultancy, Honoraria; Janssen: Research Funding; Univ of AR for Medical Sciences: Employment. Owen:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Other: Travel support; Janssen: Consultancy, Other: Travel support.

Moving Beyond Autologous Transplantation in Multiple Myeloma: Consolidation, Maintenance, Allogeneic Transplant, and Immune Therapy

2016 ◽  
pp. 210-221 ◽  
Author(s):  
Amrita Krishnan ◽  
Ravi Vij ◽  
Jesse Keller ◽  
Binod Dhakal ◽  
Parameswaran Hari
Keyword(s):  
Multiple Myeloma ◽  
Disease Control ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
The Other ◽  
Novel Agents ◽  
Patient Specific ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Minimal Residual

For multiple myeloma, introduction of novel agents as part of the front-line treatment followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation (ASCT) induces deep responses in a majority of patients with this disease. However, disease relapse is inevitable, and, with each relapse, the remission duration becomes shorter, ultimately leading to a refractory disease. Consolidation and maintenance strategy after ASCT is one route to provide sustained disease control and prevent repeated relapses. Though the consolidation strategy remains largely confined to clinical trials, significant data support the efficacy of consolidation in improving the depth of response and outcomes. There are also increasing rates of minimal residual disease–negativity with additional consolidation therapy. On the other hand, maintenance with novel agents post-transplant is well established and has been shown to improve both progression-free and overall survival. Evolving paradigms in maintenance include the use of newer proteasome inhibitors, immunotherapy maintenance, and patient-specific maintenance—a concept that utilizes minimal residual disease as the primary driver of decisions regarding starting or continuing maintenance therapy. The other approach to overcome residual disease is immune therapeutic strategies. The demonstration of myeloma-specific alloimmunity from allogeneic transplantation is well established. More sophisticated and promising immune approaches include adoptive cellular therapies, tumor vaccines, and immune checkpoint manipulations. In the future, personalized minimal residual disease–driven treatment strategies following ASCT will help overcome the residual disease, restore multiple myeloma–specific immunity, and achieve sustained disease control while minimizing the risk of overtreatment.

High Efficacy and Good Tolerability with Rituximab In Vivo Purging Followed by High Dose Chemotheraphy and Autologous Peripheral Blood Stem Cell Transplantation (APBSCT) in Non-Hodgkin’s Lymphoma (NHL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4626-4626
Author(s):  
Yuankai Shi ◽  
Sheng Yang ◽  
Xiaohong Han ◽  
Peng Liu ◽  
Xiaohui He ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Complete Remission ◽  
Minimal Residual Disease ◽  
Median Time ◽  
Residual Disease ◽  
High Dose ◽  
Platelet Recovery ◽  
Minimal Residual

Abstract Purpose: High-dose chemotherapy (HDC) supported by APBSCT has been shown to be superior to standard therapy in NHL. However, many patients relapse due to minimal residual disease (MRD) in vivo or in the graft. Rituximab has the potential to clear both blood and bone marrow of malignant CD20+ cells, prompting this multicenter trial of in vivo purging with rituximab and HDC with APBSCT in China. Methods: Cyclophosphamide 4g/m2 was used as the mobilization regimen, CY/TBI, BEAM or CBV could be used as HDC at the discretion of the institution. Four infusions of rituximab (375 mg/m2) were given: one day before mobilization, one day before harvesting, one day before transplantation and on day 8 after transplantation. BCL-2/Ig-H translocation was measured as a marker of minimal residual disease in blood or bone marrow before mobilization and during transplantation using real-time quantitative PCR. Results: Thirty-one patients from 12 centers with histologically proven CD20+ NHL (28 aggressive, 3 indolent NHL) were enrolled. Twenty-four patients were previously untreated, and 7 patients had relapsed disease. Median yields of CD34+ cells and mononuclear cells were 5.9×106/kg and 4.4×108 /kg respectively. Median time to recovery of WBC >1.5×109/L, ANC >0.5×109/L and platelets >20×109/L after APBSCT was 10 days in each case. Median time to platelet recovery >50×109/L was 13 days. Generally, this therapeutic strategy was well tolerated with few side effects attribute to rituximab. All patients achieved a complete remission after APBSCT. At a median-follow-up of 12 months, overall survival and progression-free survival (PFS) are 87% and 73% respectively for all patients. In patients with aggressive NHL, overall survival and PFS are 85% and 73% respectively and in indolent NHL are 100% and 67% respectively. PFS and overall survival were slightly higher in previously untreated compared with relapsed patients (88% vs. 83% for PFS, 73% vs. 69% for overall survival). One of five 5 patients who were initially found to be PCR-positive and achieved PCR-negative status subsequently experienced progression accompanied by a return to PCR positivity. The remaining four patients are still in complete remission and are PCR negative. Conclusion: These results suggest that the regimen of rituximab combined with HDCT and APBSCT is effective and well tolerated for the treatment of patients with NHL.

Minimal Residual Disease Status Is the Most Important Preditive Factor in Adults with Acute Lymphoblastic Leukemia. Prospective, Multicenter PALG 4-2002 MRD Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2821-2821 ◽  
Author(s):  
Jerzy Holowiecki ◽  
Malgorzata Krawczyk-Kulis ◽  
Sebastian Giebel ◽  
Krystyna Jagoda ◽  
Beata Stella-Holowiecka ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Disease Status ◽  
High Dose ◽  
Risk Criteria ◽  
Minimal Residual

Abstract Current therapeutic protocols for adult acute lymphoblastic leukemia (ALL) take into account the risk of relapse, in order adjust the treatment intensity to individual patient needs. It is postulated that in addition to “classical” risk criteria the status of minimal residual disease (MRD) should be considered for treatment decisions. The aim of this study was to prospectively evaluate the feasibility and prognostic significance of MRD detected with the use of immunophenotyping for outcome of ALL patients treated according to 4-2002 protocol of the Polish Adult Leukemia Group (PALG). Induction therapy included PDN, Asp and 4x epirubicin+VCR. Consolidation consisted of 2x high-dose AraC+Cy, 2x Mtx+Vep, 6MP, and CNS prophylaxis. Patients stratified to high risk (HR) group according to “classical” criteria based on those formerly developed by GMALL (bcr/abl(+), WBC>30 G/L, prepreB, early or mature T phenotype, age>35y, or prolonged time to achieve CR) were further referred for hematopoietic cell transplantation (HCT), whereas those assigned to standard risk (SR) group were treated with maintenance for 2 years. MRD was tested at the level of 0.1% after completion of induction and consolidation therapy in patients achieving CR, employing multicolor flow-cytometry, including a new “empty spaces” method taking into account an individual pattern of antigen expression on blast cells. 165 ALL pts (B-lineage 79%, T-lineage 21%), aged 29 y (17–60) were included. CR rate equaled 85,5%. 23% of CR pts were assigned to SR, 77%- to HR according to classical criteria. MRD evaluation was possible in all but 8 pts. After induction 37% of CR pts were found MRD(+). Among those who remained in CR, MRD after consolidation was detected in 26% of cases. 64% of patients were MRD(−) at both time-points, whereas in the remaining 36% of cases MRD was detected at least once. MRD status affected both relapse incidence (RI) and leukemia-free survival (LFS). After 3 years the RI was higher for pts with MRD(+) vs. MRD(−) if assessed after induction (82%vs.29%,p=0.00007) and after consolidation (62%vs.41%,p=0.05). For pts with MRD(−) at both study end-points the probability of LFS was 65% whereas for those with MRD(+) after either induction and/or consolidation − 26% (p=0.008). In the respective subgroups RI equaled 28% and 73% (p=0.004). The difference was observed for patients assigned to SR group (20%vs.92%,p=0.01) as well as to HR group (33%vs.70%,p=0.05). In a multivariate analysis including classical risk criteria the MRD status remained the only significant factor predictive for RI (HR: 2.5(1.3–4.8),p=0.006) and LFS (HR: 2.1(1.2–3.9),p=0.01). We conclude that immunophenotyping employing “empty spaces” method is feasible for MRD evaluation in adults with ALL. MRD stzatus after induction and consolidation is the most important predictive factor for RI and LFS. Based on our findings patients with MRD detected after induction and/or consolidation should be offered intensified treatment with the use of HCT irrespective of the absence of other risk factors.

Monitoring of Minimal Residual Disease in NPM1 Mutated Acute Myeloid Leukemia (AML) – a Single Center Experience in 27 Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4672-4672
Author(s):  
Dana Dvorakova ◽  
Zdenek Racil ◽  
Ivo Palasek ◽  
Marketa Protivankova ◽  
Ivana Jeziskova ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
Npm1 Mutation ◽  
Mgb Probe ◽  
Minimal Residual

Abstract Abstract 4672 Background Mutations within NPM1 gene occurs in about 60% of adult cytogenetic normal AML (CN-AML) and represent the single most frequent molecular aberration in this subgroups of patients. These mutations usually occur at exon 12 and induce most frequently a net insertion of four base pairs. Aims To examine the applicability and sensitivity of DNA-based real-time quantitative polymerase chain reaction (RQ-PCR) with mutation-specific reverse primers and common minor groove binding (MGB) probe and to evaluate whether minimal residual disease levels are of prognostic relevance in CN-AML patients with NPM1 mutations. Methods Patients were treated within different AML trials and follow-up samples of peripheral blood or bone marrow were referred to perform an RQ-PCR. Samples were analysed at diagnosis, during, and after therapy. The NPM1 mutations were A (17 pts), B (1 pt), D (2 pts) and 7 patients with individual rare types. For all cases, levels of minimal residual disease were determined by DNA-based RQ-PCR with mutation-specific reverse primer, one common forward primer and one common MGB probe. The NPM1 mutation value was normalized on the number of albumin gene copies and expressed as the number of NPM1 mutations every 106 genomic equivalents. This assay is highly specific as no wildtype NPM1 could be detected. Maximal reproducible sensitivity was 10 plasmide molecules per reaction. Results A total of 950 samples of bone marrow and/or peripheral blood from 27 patients have been analyzed. Twenty of 27 patients (74%) achieved molecular remission (MR), twenty-six of 27 patients (96%) achieved hematological remission (HR). 6 of 27 (22%) patients achieved HR without MR and one patient failed therapy. 8 of 20 patients (40%) with MR after treatment relapsed at molecular level and except one in all these patients hematological relaps occured (one patient is still in HR with bone marrow blast present, but < 5%). Considering relapsed patients, time from molecular to hematological relapse was 1 to 5 months (median: 3 months). Considering all 14 patients with HR without MR (6 pts) or with molecular relapse (8 pts), in 11 of them hematological relaps occured (79%) and molecular positivity anticipating hematological relaps with median of 3,5 month (1-7 months). 3 of these 14 patients are still in HR. Conclusions Mutations within NPM1 gene are a sensitive marker for monitoring minimal residual disease in CN-AML patients. RQ-PCR using a MGB probe is an efficient approach to long-term follow-up of residual leukemia cells and frequent quantitative monitoring is useful for reliably predicting hematological relapse. Achievement of negativity appears to predict favorable clinical outcome. This work was partially supported by research grant No. MSM0021622430 Disclosures: No relevant conflicts of interest to declare.

Switching to Nilotinib Is Associated with Continued Deeper Molecular Responses in CML-CP Patients with Minimal Residual Disease After ≥ 2 Years On Imatinib: Enestcmr 2-Year Follow-up Results

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 694-694 ◽  
Author(s):  
Timothy P. Hughes ◽  
Jeffrey H. Lipton ◽  
Nelson Spector ◽  
Brian Leber ◽  
Ricardo Pasquini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Minimal Residual Disease ◽  
Research Funding ◽  
Residual Disease ◽  
Molecular Response ◽  
Advisory Committees ◽  
Molecular Responses ◽  
The Difference ◽  
Minimal Residual

Abstract Abstract 694 Background: Superior rates of deeper molecular responses were achieved with nilotinib vs imatinib in patients newly diagnosed with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials—newly diagnosed patients (ENESTnd) trial. In addition, the 12-month (mo) analysis of the ENEST—complete molecular response (ENESTcmr) study demonstrated that switching to nilotinib after a minimum of 2 years on imatinib led to increased rates of major molecular response (MMR) and deeper molecular responses vs remaining on imatinib. Results from ENESTcmr are presented here with minimum 24 mo of patient follow-up. Methods: Patients with Ph+ CML-CP who had achieved complete cytogenetic responses but still had persistent BCR-ABL positivity by real-time quantitative polymerase chain reaction (RQ-PCR) after ≥ 2 years on imatinib were eligible. Patients (n = 207) were randomized to switch to nilotinib 400 mg twice daily (BID; n = 104) or to continue on the same dose of imatinib (400 or 600 mg once daily [QD]; n = 103). Rates of MMR, MR4 (BCR-ABL ≤ 0.01% according to the International Scale [IS], corresponding to a 4-log reduction), MR4.5 (BCR-ABL ≤ 0.0032%IS, corresponding to 4.5-log reduction), and undetectable BCR-ABL via RQ-PCR with ≥ 4.5-log sensitivity were measured. Results: Among all randomized patients (intent-to-treat population), significantly more patients treated with nilotinib continued to achieve undetectable BCR-ABL by 24 mo (32.7% on nilotinib vs 16.5% on imatinib; P =.005; Table).The difference between the arms in achievement of this endpoint increased between 1 and 2 years (from 12.4% to 16.2%). The median time to MR4.5 and undetectable BCR-ABL was also significantly faster on nilotinib than on imatinib (P = .005 and .003, respectively). Cumulative rates of MR4.5 and undetectable BCR-ABL continued to be higher with nilotinib in patients without those responses at baseline, and the difference between arms appeared to increase over time. The safety profiles for nilotinib and imatinib were consistent with prior studies. By 24 mo, no patients in either arm progressed to accelerated phase/blast crisis. No patients on nilotinib died since the 12-mo analysis; 1 patient on imatinib died from metastatic prostate cancer in follow-up after discontinuation from the study. Conclusions: Switching to nilotinib led to significantly faster, deeper molecular responses in patients with minimal residual disease on long-term imatinib therapy. Since the 12-mo analysis, rates of deep molecular response (MR4.5 and undetectable BCR-ABL) have remained significantly higher in patients who did not have the response at baseline and were switched to nilotinib (vs those remaining on imatinib). In fact, the difference in favor of nilotinib increased between 1 and 2 years. These results suggest that switching to the more potent, selective tyrosine kinase inhibitor nilotinib is beneficial in patients with minimal residual disease after long-term imatinib therapy. Achievement of these deeper molecular responses (MR4.5 and undetectable BCR-ABL) after switching to nilotinib may enable a greater proportion of CML-CP patients to be eligible for future discontinuation studies. Cumulative rates of confirmed undetectable BCR-ABL by 24 mo will be presented as the confirmation assessments for several responders were not available at the time of this analysis. Disclosures: Hughes: Novartis Pharmaceuticals Corp: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy; CSL: Research Funding. Lipton:Novartis: Consultancy, Research Funding, Speakers Bureau. Spector:Novarits: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy. Leber:Novartis: Advisory Board Other, Honoraria, Speakers Bureau. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Etienne:Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding. Purkayastha:Novartis Pharmaceuticals Corp: Employment. Collins:Novartis Pharmaceuticals Corp: Employment. Szczudlo:Novartis Pharmaceuticals Corp: Employment. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Minimal residual disease levels assessed by NPM1 mutation–specific RQ-PCR provide important prognostic information in AML

Blood ◽  
2009 ◽  
Vol 114 (11) ◽  
pp. 2220-2231 ◽  
Author(s):  
Susanne Schnittger ◽  
Wolfgang Kern ◽  
Claudia Tschulik ◽  
Tamara Weiss ◽  
Frank Dicker ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Residual Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
World Health ◽  
Prognostic Information ◽  
Npm1 Mutation ◽  
Blast Count ◽  
Relevant Prognostic Factor ◽  
Health Organization ◽  
Minimal Residual

Abstract Nucleophosmin (NPM1)–mutated acute myeloid leukemia (AML), which is recognized as a provisional entity in the World Health Organization 2008 classification of myeloid neoplasms, accounts for 30% of AML. We analyzed 1227 diagnostic and follow-up samples in 252 NPM1-mutated AML patients with 17 different NPM1 mutation–specific real-time quantitative polymerase chain reaction (RQ-PCR) assays. Paired diagnostic/relapse samples of 84 patients revealed stable NPM1 mutations in all cases, suggesting that they are pathogenetically early events and thus applicable for minimal residual disease detection. A total of 47 relapses were predictable because of an NPM1 mutation level (%NPM1/ABL1) increase of at least 1 log or in 15 cases because of NPM1 mutation levels not decreasing less than 3 log ranges. A high prognostic value of NPM1 levels was shown for 4 different intervals after therapy was initiated. Furthermore, thresholds of 0.1 and 0.01%NPM1/ABL1 during/after treatment discriminated between prognostic subgroups. Univariate analyses, including age, white blood cell count, blast count, CD34 positivity, FLT3 mutations status, FAB type, karyotype, NPM1 mutation type, and pretreatment NPM1 mutational level, showed that, besides NPM1 mutation level, only age and FLT3-LM mutation status were prognostically significant for EFS. Multivariate analysis, including age, FLT3-LM status, and NPM1 mutation level at different time points, demonstrated that NPM1 level was the most relevant prognostic factor during first-line treatment. Similar results were obtained in patients undergoing second-line chemotherapy or allogeneic stem cell transplantation.

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