Immunophenotyping to Detect Minimal Residual Disease in Adult Acute Lymphoblastic Leukemia - Feasibility and Prognostic Significance.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4489-4489
Author(s):  
Jerzy Holowiecki ◽  
Sebastian Giebel ◽  
Krystyna Jagoda ◽  
Malgorzata Krawczyk-Kulis ◽  
Beata Stella-Holowiecka ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Antigen Expression ◽  
Term Outcome ◽  
Long Term Outcome ◽  
B Lineage ◽  
Minimal Residual

Abstract Although well documented for pediatric patients, the prognostic value of minimal residual disease (MRD) detected with the use of immunophenotyping has not been established for adults with acute lymphoblastic leukemia (ALL) so far. With the use of standard “quadrans” analysis based on evaluation of the number of blasts bearing atypicial antigen combinations, the method may be applied to the majority of T-derived and only approximately half of B-lineage ALL. In this study we tested the feasibility and prognostic significance of a new “empty spaces” method taking into account the individual antigen expression pattern for each blast cell tested. The “forbidden” gates were established with the use of triple staining by comparison with the pattern obtained for healthy volunteer bone marrow donors. At least two antigen combinations were tested for each patient. MRD was evaluated after induction and after consolidation therapy. Only patients who achieved complete remission after a single course of induction were analysed with regard to the impact of MRD on long-term outcome. Thirty adult ALL patients (B-lineage n=24, T-lineage n=6) were included in the study. For all cases it was possible to determine unique antigen expression pattern and to monitor MRD with the use of immunophenotyping at the level of 1/1000 cells. MRD was detected in 8/30 patients after induction and in 7/28 patients after consolidation tharapy (two patients relapsed during consolidation). For 11/30 patients the MRD resulted positive at least once. At 20 months the relapse rate equaled 53% for patients with MRD detected after induction or consolidation and 28% for those with MRD always negative (p=0.08). The difference was more pronounced for patients with B-lineage ALL (67% vs. 26%, p=0.02). A single MRD evaluation after induction therapy had no significant prognostic value for the risk of relapse whereas there was a trend for higher relapse rate in B-lineage ALL patients with positive MRD after completion of consolidation therapy compared to those MRD-negative at that time-point (75% vs. 32%, p=0.06). Results of the study prove the feasibility of immunophenotypic MRD evaluation in ALL. “Empty spaces” in addition to the standard “quadrans” analysis allows monitoring of the vast majority of patients regardless the immune subtype. Even with a small number of cases we were able to demonstrate its prognostic value for long-term outcome of adults with ALL.

Minimal Residual Disease, Long-Term Outcome, and IKZF1 Deletions in Down Syndrome Acute Lymphoblastic Leukemia in a Matched Cohort Study

2021 ◽  
Author(s):  
Naomi Michels ◽  
Judith M. Boer ◽  
Amir Enshaei ◽  
Rosemary Sutton ◽  
Mats Heyman ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Cohort Study ◽  
Acute Lymphoblastic Leukemia ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Matched Cohort ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Minimal Residual

scholarly journals PS963 ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN ADULT PHILADELPHIA-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA: DOES MINIMAL RESIDUAL DISEASE BEFORE TRANSPLANTATION MATTER FOR LONG TERM OUTCOME?

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 433-434
Author(s):  
I. Ormazabal Velez ◽  
A. Figuera Alvarez ◽  
J.L. Steegmann Olmedillas ◽  
R. De la Cámara Llanza ◽  
A. García-Noblejas Moya
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Hematopoietic Stem Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Term Outcome ◽  
Hematopoietic Stem ◽  
Long Term Outcome ◽  
Minimal Residual

Concordance and Prognostic Significance of Minimal Residual Disease Detection in Peripheral Blood and Bone Marrow Samples of Infants with MLL-rearranged Acute Lymphoblastic Leukemia Treated By MLL-Baby Protocol

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2404-2404
Author(s):  
Grigory Tsaur ◽  
Alexander Popov ◽  
Tatyana Riger ◽  
Alexander Solodovnikov ◽  
Tatyana Nasedkina ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Prognostic Value ◽  
Residual Disease ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Remission Induction ◽  
Gene Transcripts ◽  
Minimal Residual

Abstract Background. Minimal residual disease (MRD) is powerful tool for prediction of treatment outcome in leukemia patients of various age groups, including infants with acute lymphoblastic leukemia (ALL). In the vast majority of cases only bone marrow (BM) samples are used for MRD detection. Objective. To estimate prognostic significance of MRD in peripheral blood (PB) and BM by qualitative detection of different MLL fusion gene transcripts in infant ALL enrolled into MLL-Baby protocol. Methods. Fifty three infants (20 boys and 33 girls) with median age of 5.3 months (range 0.03-11.80) and defined MLL rearrangements were included in the current study. Among them there were 25 patients (47.2%) carrying MLL-AFF1 fusion gene transcripts, 10 (18.9%) MLL-MLLT3-positive cases, 9 (17.0%) MLL-MLLT1-positive cases, 5 (9.4%) MLL-MLLT10-positive cases and 4 (7.5%) MLL-EPS15-positive ones. MRD evaluation was performed by detection of MLL fusion gene transcripts in BM and PB samples using real-time PCR and nested RT-PCR with sensitivity non-less than 1E-04. MRD-negativity was defined as absence of fusion gene transcripts in both assays. Median of follow-up period in the observed group was 5.2 years. Time points (TP) for MRD assessment were as follows: day 15 of remission induction (TP1), at the end of remission induction (TP2), after each course of ATRA administration (TP3-TP7). Informed consent was obtained in all cases. Results. We estimated 142 paired BM/PB samples. 77 samples were double positive, 43 were double negative Thus concordance between MRD results in BM and PB samples achieved 84.5%. Concordance varied between different TPs of MLL-Baby protocol from 79.0% to 100%. The highest concordance rate was at TP4 and TP7 (92.3% and 100%, respectively). Interestingly, all discrepant results (22 samples 15.5%) were BM-positive/PB-negative. Median level of ABL gene, used for normalization, was similar in BM and PB samples (4.85E+04 vs 4.95E+04, respectively, p=0.760). Evaluation of prognostic significance of MRD in BM in TP1-TP7 revealed that TP4 was the earliest TP when discriminative data between MRD-positive and MRD-negative patients were obtained. MRD-positivity at TP4 in BM led to unfavorable outcome. Event-free survival was significantly lower in MRD-positive group (n=22) in comparison to MRD-negative one (n=31) (0.06±0.06 vs 0.70±0.09 p=0.0001), while cumulative incidence of relapse in MRD-positive patients was remarkably higher (0.92±0.01 vs 0.29±0.08, p<0.0001). MRD-positivity at this TP in BM was the only significant factor in the diagnostic model where initial risk factors (age at diagnosis, initial WBC count, immunophenotype, CNS disease, presence of MLL-AF4) were combined to response criteria (number of blast cells at day 8 of dexamethasone prophase and MRD in BM at TP4) (Table). The only TP when MRD data obtained from PB samples had prognostic value was TP6. In this TP cumulative incidence of relapse in MRD-positive patients was significantly higher in comparison to MRD-negative ones (0.88±0.11 vs 0.25±0.13, respectively, p=0.003). However these data did not bring any extra advantages as compared to TP4 in BM. Conclusions. Despite high qualitative concordance rate between MRD detection in BM and PB samples we could not show prognostic value of MRD monitoring in PB by fusion gene transcripts. Univariate and multivariate analysis revealed that MRD-positivity at TP4 in BM was the only significant and independent prognostic factor of unfavorable outcome in the observed group of patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Prognostic Significance of Minimal Residual Disease in Adult Patients with B-Lineage Acute Lymphoblastic Leukemia by 8-Color Flow Cytometry

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4789-4789
Author(s):  
Xiang-Qin Weng ◽  
Yang Shen ◽  
Yan Sheng ◽  
Bing Chen ◽  
Jing-han Wang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Lymphoblastic Leukemia ◽  
Treatment Response ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Color Flow ◽  
B Lineage ◽  
Minimal Residual

Abstract Abstract 4789 Monitoring of minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) by immunophenotyping and/or molecular techniques provides a way to precisely evaluate early treatment response and predict relapse. In this study, we have investigated the prognostic significance of MRD in adult patients with B-lineage acute lymphoblastic leukemia (B-ALL) by 8-color flow cytometry. A cohort of 106 patients with B-ALL who had achieved a complete remission (CR) and at least 1 LAIP characteristics were enrolled to perform MRD assessment at the end of induction and 1 cycle of consolidation. LAIPs were identifiable in 96% of the patients by 8-color flow cytometric assay, in which, most cases (90.6%) containing 2 or more LAIPs had a sensitivity as high as identifying 1 leukemic blast among 1×105 BM nucleated cells. MRD negative status could clearly predict a favorable 1 year relapse free survival (RFS) and 2 year overall survival (OS) when a cut-off level of 0.01% was used to define MRD positivity at the point of achieving CR (P=0.000 and 0.000, respectively) and after 1 cycle of consolidation (P=0.000 and 0.000, respectively), respectively. In multivariate analysis including cytogenetic abnormalities, clinical factors and MRD status, late CR (P=0.046), MRD status at the points of obtaining CR (P=0.016) and 1 consolidation (P=0.007) were associated with RFS independently, while only MRD status after 1 course of consolidation was independent prognostic factor for OS (P=0.000). Of note, in exploring the fewer patients with MRD negative status experienced recent relapse, we have identified that most of such patients had a MRD level of 10−4−10−5 comparing to undetectable MRD level. Furthermore, our evidences showed that MRD assessed by flow cytometry and by RQ-PCR assay targeting to BCR-ABL fusion gene yielded concordant results in the vast majority of cases (90%). In conclusion, immunophenotypic evaluation of MRD by 8-color flow cytometry could work as an important tool to assess the treatment response and prognosis precisely in adult B-ALL. Disclosures: No relevant conflicts of interest to declare.

ZAP-70 expression in acute lymphoblastic leukemia: association with the E2A/PBX1 rearrangement and the pre-B stage of differentiation and prognostic implications

Blood ◽  
2006 ◽  
Vol 107 (1) ◽  
pp. 197-204 ◽  
Author(s):  
Sabina Chiaretti ◽  
Anna Guarini ◽  
Maria Stefania De Propris ◽  
Simona Tavolaro ◽  
Stefania Intoppa ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Term Outcome ◽  
Oligonucleotide Arrays ◽  
Long Term Outcome ◽  
Molecular Abnormalities ◽  
Prognostic Implications ◽  
B Lineage ◽  
Using Data

Abstract We evaluated the expression of 2 members of the Syk family, ZAP-70 and Syk, in acute lymphoblastic leukemia (ALL) samples, using data derived from a series of 33 T-ALL and 95 B-lineage adult ALL patients analyzed by oligonucleotide arrays. Of the B-lineage ALL cases, 37 were BCR/ABL+, 10 were ALL1/AF4+, 5 were E2A/PBX1+, and 43 carried no known molecular abnormality. ZAP-70 was highly expressed in T-ALL. A high ZAP-70 expression was also found in a proportion of B-lineage ALL, the highest levels being associated with the E2A/PBX1+ group and the lowest with ALL1/AF4+ cases (P < .001). A higher ZAP-70 expression was also observed in the pre-B group (P < .001). Remarkably, Syk expression was always preserved, suggesting that ZAP-70 expression is not substitutive of Syk. At the protein level, ZAP-70 was evaluated on 39 newly diagnosed ALL patients (25 adults, 14 children) and was detected in 23 cases (59%). ZAP-70 expression was consistently found in Igμ+ cases. Evaluation of long-term outcome in cases without molecular abnormalities showed that the higher levels of ZAP-70 were coupled to a higher relapse rate. In ALL, ZAP-70 expression is associated with the E2A/PBX1 rearrangement and pre-B stage and may have a prognostic role and be a candidate molecule for targeted therapies.

scholarly journals PB2324 LONG TERM OUTCOME OF AUTOLOGOUS STEM CELL TRANSPLANTATION IN ADULT ACUTE MYELOID LEUKEMIA PATIENTS: THE ROLE OF MINIMAL RESIDUAL DISEASE

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 1036
Author(s):  
S. Paolini ◽  
L. Romani ◽  
E. Ottaviani ◽  
G. Marconi ◽  
C. Papayannidis ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Minimal Residual ◽  
Acute Myeloid

Improved Outcome of Adult Acute Lymphoblastic Leukemia Treated with Individualized Protocol Adjusted to the Status of Minimal Residual Disease and Age. Interim Analysis of PALG ALL 5–2007 Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2138-2138
Author(s):  
Sebastian Giebel ◽  
Jerzy Holowiecki ◽  
Malgorzata Krawczyk-Kulis ◽  
Krystyna Jagoda ◽  
Jaroslaw Piszcz ◽  
...  
Keyword(s):  
High Risk ◽  
Minimal Residual Disease ◽  
Bone Marrow Cells ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Minimal Residual ◽  
Improved Outcome

Abstract Abstract 2138 In a previous study by the Polish Adult Leukemia Group (PALG 4–2002) we demonstrated that status of minimal residual disease (MRD) during induction-consolidation is the most important factor predicting long-term outcome of adult ALL (Br J Haematol 2008). In a new PALG 5–2007 protocol the treatment was intensified for patients with MRD level >0.1% of bone marrow cells and adjusted to age. Induction consisted of Epirubicine(4×), Vincristine(4×), Prednisone and PEG-asparaginase. Patients with complete remission (CR) but MRD >0.1% obtained additional 2nd phase of induction: AraC+Cyclophosphamide(Ctx) + 6MP. Consolidation consisted of 2 courses of Methotrexate(Mtx) + Etoposide + Dexamethasone and subsequent 2 cycles of Ctx + high dose AraC, asparaginase, intrathecal prophylaxis and CNS irradiation. Doses of Mtx were 500 mg/m2 for patients with MRD<0.1%, aged >35y and 1500 mg/m2 for all remaining ones. For Ph+ ALL imatinib 600 mg/d was administered in parallel to chemotherapy. Patients with standard risk disease continued with 2 years maintenance while those with high-risk were referred for alloHSCT. High risk was defined as the presence of at least one of: initial WBC >30×10e9/L, age >35y, pro-B, early-T, mature-T, late CR, t(9;22), t(4;11) or MRD >0.1% at any time during induction-consolidation. Results of PALG 5–2007 protocol (N=108, median age 32y, range 16–55y) were compared to PALG 4–2002 (N=253, age 28y, range 16–55y), in which MRD status was not taken into account for treatment decisions. CR rate was 92% for PALG 5–2007 compared to 89% for PALG 4–2002. The probability of the overall survival at 36 months was 56% vs. 33% (p=0.02), while leukemia-free survival was 53% vs. 28% (p=0.04), respectively. The probability of relapse decreased from 54% in PALG 4–2002 to 16% in PALG 5–2007 (p=0.002). In a multivariate analysis adjusted to age, initial WBC and the presence of t(9;22) treatment according to PLAG 5–2007 protocol was associated with decreased risk of mortality (HR=0.57, p=0.02), relapse (HR=0.37, p=0.006) and treatment failure (HR=0.64, p=0.049). We conclude that individualized therapeutic approach with treatment intensity adjusted to MRD status and age may result in improved outcome of adults with ALL. *This multi-institutional study was supported by Polish Ministry of Sciences Grant NN-402366433 Disclosures: Off Label Use: Dasatinib as first line therapy in Ph ALL.

NPM Mutations in Adult AML with Normal Karyotype: A Retrospective Study of the Acute Leukemia French Association (ALFA).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2359-2359
Author(s):  
Nicolas Boissel ◽  
Aline Renneville ◽  
Valeria Biggio ◽  
Nathalie Philippe ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Residual Disease ◽  
Univariate Analysis ◽  
Normal Karyotype ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Mutational Status ◽  
Relapse Time ◽  
Minimal Residual

Abstract NPM mutation (NPMm) has been recently reported as the most frequent mutation in AML, especially in the presence of a normal karyotype. Association of NPMm with an increased complete remission (CR) rate has been suggested, but the long-term prognosis is not known. The abnormal mutated NPM protein shows an aberrant cytoplasmic localization that allows an immunohistochemical detection of NPM status. However, all mutations reported are insertion/deletion of exon 12 resulting in a global insertion of 4 nucleotides. We therefore developed a NPMm detection test based on DNA PCR amplification and fragment length analysis. As previously reported, we observed a higher frequency of NPMm in AML with normal karyotype (47%, 50/106) than in CBF AML (0%, 0/7) or in AML with poor risk cytogenetic (13%, 4/32). We further evaluated the clinical profile and the prognosis of NPM mutations in a retrospective cohort of 106 patients with normal karyotype treated according to the ALFA-9000 or ALFA-9802 protocols between 1990 and 2004. In these patients aged 17–65 years, NPMm was significantly associated with a high white blood cell count (69 vs 18 G/L, p&lt;.001) and an involvement of the monocytic lineage (FAB AML-M4/M5, p=.009). NPMm was also associated with a low rate of CEBPA mutation (CEBPAm, 10% vs 27%, p=.05) and a higher rate of FLT3 internal tandem duplication (FLT3/ITD, 38% vs 25%, p=NS). We did not find any correlation between NMPm and CR rate (86% vs 88%, p=NS). Long-term outcome did not differ between NPMm and NPM wild-type (NPMwt) patients neither in univariate analysis (6y-OS, 43% vs 37%; 6y-RFS, 47% vs 34%, p=NS) nor in multivariate analysis after adjustment on covariates significantly associated with prognosis in univariate analysis (age, CEBPAm, FLT3/ITD). NPM mutational status was available for 15 patients at relapse time. Ten patients out of 15 had NPM mutations at diagnosis and still displayed NPM mutations at relapse time. None of the 5 NPMwt patients acquired NPM mutation at relapse. Recently, we developed a RQ PCR technique to study minimal residual disease. Fifteen patients were evaluated at diagnosis and follow-up. In the majority of the cases a sensitivity of 10−4 was obtained. The high frequency, the stability, and the homogeneity of NPMm provide a promising minimal residual disease marker that we are prospectively evaluating. Prospective studies are also needed to confirm the definitive role of NPM mutation in the prognosis of AML patients.

scholarly journals Minimal Residual Disease Dynamics after Venetoclax-Obinutuzumab Treatment: Extended Off-Treatment Follow-up From the Randomized CLL14 Study

2021 ◽  
Author(s):  
Othman Al-Sawaf ◽  
Can Zhang ◽  
Tong Lu ◽  
Michael Z. Liao ◽  
Anesh Panchal ◽  
...  
Keyword(s):  
Overall Survival ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Hazard Ratio ◽  
Lymphocytic Leukemia ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Minimal Residual

PURPOSE The CLL14 study has established one-year fixed-duration treatment of venetoclax and obinutuzumab (Ven-Obi) for patients with previously untreated chronic lymphocytic leukemia. With all patients off treatment for at least three years, we report a detailed analysis of minimal residual disease (MRD) kinetics and long-term outcome of patients treated in the CLL14 study. PATIENTS AND METHODS Patients were randomly assigned to receive six cycles of obinutuzumab with 12 cycles of venetoclax or 12 cycles of chlorambucil (Clb-Obi). Progression-free survival (PFS) was the primary end point. Key secondary end points included rates of undetectable MRD and overall survival. To analyze MRD kinetics, a population-based growth model with nonlinear mixed effects approach was developed. RESULTS Of 432 patients, 216 were assigned to Ven-Obi and 216 to Clb-Obi. Three months after treatment completion, 40% of patients in the Ven-Obi arm (7% in the Clb-Obi arm) had undetectable MRD levels < 10−6 by next-generation sequencing in peripheral blood. Median MRD doubling time was longer after Ven-Obi than Clb-Obi therapy (median 80 v 69 days). At a median follow-up of 52.4 months, a sustained significant PFS improvement was observed in the Ven-Obi arm compared with Clb-Obi (median not reached v 36.4 months; hazard ratio 0.33; 95% CI, 0.25 to 0.45; P < .0001). The estimated 4-year PFS rate was 74.0% in the Ven-Obi and 35.4% in the Clb-Obi arm. No difference in overall survival was observed (hazard ratio 0.85; 95% CI, 0.54 to 1.35; P = .49). No new safety signals occurred. CONCLUSION Appearance of MRD after Ven-Obi is significantly slower than that after Clb-Obi with more effective MRD reduction. These findings translate into a superior long-term efficacy with the majority of Ven-Obi–treated patients remaining in remission.

Sign in / Sign up

Export Citation Format

Share Document