No prognostic significance of immunophenotypic changes at the end of remission induction therapy in children with B-lineage acute lymphoblastic leukemia

2018 ◽  
Vol 68 ◽  
pp. 57-61 ◽  
Author(s):  
Qingkai Dai ◽  
Xiaojuan Liu ◽  
Hui Yang ◽  
Siqi Guo ◽  
Yuefang Wang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Induction Therapy ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Remission Induction ◽  
B Lineage

scholarly journals Response Adapted Therapy in ETV6/RUNX1-Positive Childhood Acute Lymphoblastic Leukemia Treated per Modified St Jude Total XV Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-29
Author(s):  
Mayada Abu Shanap ◽  
Iyad Sultan ◽  
Amal Abu-Ghosh ◽  
Hasan Hashem ◽  
Abdelghani Tbakhi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Induction Therapy ◽  
Leukocyte Count ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Low Risk ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Standard Risk

Introduction: ETV6-RUNX1 is the most common genetic aberration in childhood acute lymphoblastic leukemia (ALL), occurring in approximately 25% of cases with a precursor-B phenotype. The presence of ETV6-RUNX1 has been associated with a relatively low rate of relapse in multiple studies. Relapses tend to occur late and have a better salvage rate than other ALL subtypes. Moreover, conflicting data in literature regarding the prognostic significance of ETV6-RUNX1 after accounting for age, initial count and treatment intensity. We sought to study the clinical features, therapy response in newly diagnosed ETV6-RUNX1-positive treated at King Hussein Cancer Center. Methods: Patients were treated per modified St Jude Total (XV) study, risk stratification was further refined by including minimal residual disease (MRD)measurements on day 15 and day 46 of remission induction therapy. Patients with the ETV6- RUNX1 fusion or hyperdiploidy without CNS or testicular disease and a satisfactory early MRD decline (<1% on day 15 and <0.01% on day 46) were classified as being low-risk for relapse and were treated on lower -risk arm regardless of age and leukocyte count. Results: Seventy patients (n=70) with ETV6-RUNX1-positive treated at our institution between May 2006 to October 2017. The median age at diagnosis, 5.8 years (range, 1.5-10.8). ETV6-RUNX1 was associated with favorable age between 1- and 6-years in 55 patients (79%), male gender in 41 patients (59%), initial leukocyte count <10 in 39 patients (56%), CNS status 1 in 100% of patients. The majority, n= 58 (83%) of patients had NCI standard risk (SR) and n=12 (17%) had NCI high risk (HR). Sixty-six patients (94%) had MRD <1% at day 15 and all patients achieved remission with MRD<0.01% at day 46 of remission induction. All patients were treated as LR ALL per modified St Jude total XV protocol. At median follow up of (36 months; range, 26 to 154), in the subgroups of ETV6-RUNX1-positive patients classified as NCI standard risk (SR)and NCI high risk (HR) the 5-year EFS estimates were 94.1% ± 3.2 and 82%±1(P=.13), 5-year OS estimates were 100% and 92% ± 8 (p=0.31) respectively. Conclusion: MRD treatment schema in ETV6/RUNX1 -positive patients have excellent outcomes if they achieved favorable response at day 15 and end of remission induction regardless of the age and Initial leukocyte count. Treatment reduction is feasible and declared safe for children with NCI-HR who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD post remission induction therapy. Disclosures No relevant conflicts of interest to declare.

Clinical significance of translocation t(1;19) in childhood acute lymphoblastic leukemia in the context of contemporary therapies: a report from the Children's Cancer Group.

1998 ◽  
Vol 16 (2) ◽  
pp. 527-535 ◽  
Author(s):  
F M Uckun ◽  
M G Sensel ◽  
H N Sather ◽  
P S Gaynon ◽  
D C Arthur ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Free Survival ◽  
Cancer Group ◽  
Improved Outcomes ◽  
B Lineage ◽  
The Individual

PURPOSE The nonrandom translocation t(1;19) has been associated with poor outcome in pediatric B-lineage acute lymphoblastic leukemia (ALL). Because most patients treated by contemporary therapies now achieve improved outcomes, we have reassessed the prognostic significance of t(1;19). PATIENTS AND METHODS Cytogenetic data were accepted for 1,322 children (<21 years old) with newly diagnosed ALL enrolled between 1988 and 1994 on risk-adjusted studies of the Children's Cancer Group (CCG). Forty-seven patients (3.6%) were t(1;19) positive (+); 1,275 (96.4%) were t(1;19) negative (-). Clinical characteristics and treatment outcome were compared using standard methods. RESULTS Translocation (1;19)+ patients were more likely than t(1;19)- patients to be 10 years of age or greater (P < .001) or CD10+ CD19+ CD34- (P < .0001), or nonwhite (P = .02). Patients with a balanced t(1;19) were less likely to be hyperdiploid than patients with an unbalanced der(19)t(1;19). Event-free survival (EFS) was similar for the overall group of t(1;19)+ and t(1;19)- patients, with 4-year estimates of 69.5% (SD, 6.8%) and 74.8% (SD, 1.3%; P = .48), respectively. However, patients with unbalanced der(19)t(1;19) had significantly better outcomes than patients with balanced t(1;19): 4-year EFS were 80.6% (SD, 7.1%) and 41.7% (SD, 13.5%), respectively (P = .003). These differences were maintained within the individual studies analyses and after exclusion of t(1;19)+ patients whose cells were hyperdiploid with more than 50 chromosomes. CONCLUSION The overall group of t(1;19)+ patients, as well as the subgroup with an unbalanced der(19)+ (1;19) had outcomes similar to that of t(1;19)- patients, whereas patients with balanced t(1;19) had poorer outcomes. Thus, although the overall prognostic significance of t(1;19) has been obviated by contemporary risk-adjusted protocols, the balanced t(1;19) translocation remains an adverse prognostic factor.

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.

Kinase-Activating Fusions in Pediatric High-Risk B-Lineage Acute Lymphoblastic Leukemia (ALL): a Report from the Dana-Farber Cancer Institute (DFCI) ALL Consortium

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1729-1729
Author(s):  
Thai Hoa Tran ◽  
Marian H. Harris ◽  
Jonathan V. Nguyen ◽  
Traci M. Blonquist ◽  
Kristen E. Stevenson ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Statistical Significance ◽  
Chromosomal Rearrangements ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Philadelphia Chromosome ◽  
B Lineage

Abstract Background. Recurrent chromosomal rearrangements carry prognostic significance in pediatric B-lineage acute lymphoblastic leukemia (B-ALL). Recent genome-wide analyses identified a diverse spectrum of chromosomal rearrangements resulting in novel chimeric fusions associated with poor prognosis when treated with conventional chemotherapy. These fusions are observed more frequently in NCI High-Risk (HR) B-ALL compared with NCI Standard Risk (SR) patients. They often activate ABL and JAK-STAT signaling pathways and have demonstrated sensitivity to the relevant tyrosine kinase inhibitors (TKIs) in in vitro assays and ex vivomodels. The objective of this study was to determine the frequency of NCI HR B-ALL patients enrolled on DFCI ALL Consortium Protocol 05-001 with a kinase-activating fusion that would be amenable to TKI therapy and to describe their associated clinical characteristics and outcomes. Methods. Between 2005-2011, 219 NCI HR, Philadelphia chromosome (Ph)-negative, B-ALL patients were enrolled on DFCI ALL Consortium Protocol 05-001, 105 of whom had sufficient material to undergo kinase fusion testing by validated multiplex reverse transcription polymerase chain reaction (RT-PCR) assays. A total of 35 kinase fusions of ABL-class (ABL1, ABL2, PDGFRB, CSF1R), JAK2 and CRLF2 rearrangements were examined. IGH@-CRLF2 and EPOR rearrangements were not assessed. Fusion products were predicted by NCBI BLAST algorithms, confirmed by singleplex PCR and Sanger sequencing and aligned using CLC Main Workbench Version 7.6.1. IKZF1 deletion (del) status had previously been assessed by multiplex ligation-dependent probe amplification (MLPA). Fisher's exact test and the Wilcoxon rank sum test were used to compare patient characteristics to those with and without any identified fusion for categorical and continuous variables respectively. Event-free survival (EFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared using a log rank test. Univariate and multivariable Cox proportional hazards models of EFS were constructed. Results. Among 105 NCI HR, Ph-negative, B-ALL patients, 16 (15%) were found to harbor an ABL-class fusion (ETV6-ABL1: n=1; FOXP1-ABL1: n=1; SFPQ-ABL1: n=1; ZC3HAV1-ABL2: n=1) or a fusion activating the JAK-STAT pathway (P2RY8-CRLF2: n=8; PAX5-JAK2: n=4). Sixty-nine percent of patients with an identified fusion (Fusion +) had a concomitant IKZF1 del (n=11). Features associated with fusion-positivity were age of 10 years or older (p=0.003), male sex (p=0.03), Hispanic ethnicity (p=0.01) and IKZF1 del (p=0.0005) (Table 1). Fifty percent of Fusion+ patients experienced an event (induction death (n=1); induction failure (n=1); or relapse (n=6)) compared to 24% of patients without a fusion. The 5-year EFS and OS were 48% (95% CI 22-70%) and 68% (95% CI 39-85%) for Fusion+ patients compared to 78% (95% CI 67-85%) and 88% (95% CI 79-93%) for those without fusions (Figure 1). In univariate analysis, fusion-positivity (HR: 2.66, p=0.02) and IKZF1 del (HR: 3.21; p=0.0018) were each significantly associated with inferior EFS, while age and presenting leukocyte count were not. In multivariable analysis, IKZF1 del, but not fusion-positivity, retained statistical significance (HR: 2.64, p=0.02). Conclusion. Fifteen percent of NCI HR, Ph-negative, B-ALL patients enrolled on DFCI ALL Consortium 05-001 were found to have a kinase-activating fusion. Fusion+ patients frequently harbored concomitant IKZF1 deletion and had an inferior outcome. Future studies should focus on developing clinical strategies to rapidly identify these patients at diagnosis and to test whether the addition of the relevant TKIs to their treatment will improve their outcome. Disclosures Asselin: Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Sigma Tau Pharamceuticals: Consultancy. Loh:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding.

Is CDKN2A +/− CDKN2B and MTAP Inactivation of Prognostic Significance in B-Precursor Childhood Acute Lymphoblastic Leukemia? Results of EORTC Studies 58881 and 58951.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1076-1076
Author(s):  
Delphine Mirebeau ◽  
Cécile Acquaviva ◽  
Stefan Suciu ◽  
Raphaëlle Bertin ◽  
Alain Robert ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Promoter Methylation ◽  
Gene Dosage ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
High Risk Group ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
B Lineage ◽  
Wbc Count

Abstract Background: Deletions of the 9p21 chromosomal region which encompasses CDKN2A, a gene encoding both p16INK4a and p14ARF, are frequent in childhood acute lymphoblastic leukemia (ALL). Their prognostic relevance is controversial. Indeed, small retrospective series of patients were analysed so far, which usually mixed B- and T-lineage ALL. Moreover, the prognosis could vary according to the extent of the deletion since the inactivation of contiguous genes such as CDKN2B encoding p15INK4b or MTAP encoding methylthioadenosine phosphorylase, may influence chemosensitivity. Methods: 9p21 deletions were retrospectivelly studied in 227 children (aged 2 mo to 16 yrs) with B-lineage ALL, using a real-time PCR assay for CDKN2B, CDKN2A (e1b and e3), and MTAP gene dosage, and loss of heterozygosity analysis (Bertin et al., 2003). CDKN2A and CDKN2B inactivation by promoter methylation was also investigated. TEL-AML1 fusion was screened in 182 (80%) of these patients. All patients were enrolled in EORTC trials 58 881 or 58 951. Median follow-up was 6 years; total number of events was 55 and the overall 6-year EFS rate was 74%. Results: CDKN2A bi- and mono-allelic inactivation was found in 38 (17%), and 31 (14%) B-lineage ALL respectively. Patients with a bi-allelic inactivation did not differ from undeleted ones regarding age, sex, immunophenotype and response to prephase treatment, but tended to have a higher WBC count at diagnosis and were more often allocated to the NCI high risk group (42% vs 27%). Genetic defects, including TEL-AML1, were independent of 9p21 alteration with exception of hyperdiploidy (&gt;50 chromosomes) which was less frequent in patients with CDKN2A inactivation (5% vs 34%). The 6-year EFS rates of patients with bi-allelic, mono allelic and no inactivation did not differ significantly (68%, 80%, and 75% respectively). Bi-allelic CDKN2B inactivation by either deletion or promoter methylation was found in 36 (16%) patients and the 6-year EFS rate of these patients was similar to that of undeleted patients (71% vs 74%). MTAP bi-allelic inactivation was found in 24 (11%) of patients. Although MTAP deficient cells are in vitro very sensitive to methotrexate, the 6-year EFS rate (70% vs 75%) did not differ from that of MTAP positive patients even when the analysis was restricted to CDKN2A inactivated ALL. Conclusion: Although bi-alleic CDKN2A inactivation was more often associated with bad prognostic parameters in B-lineage ALL, it failed to significantly influence the outcome of the patients. We did not observe either any influence of the co-inactivation of CDKN2B and MTAP on the outcome. Considering that our study is the largest so far using molecular analysis of the 9p21 region, we assume that any bad prognosis associated with 9p21 alteration, if present, should be weak in B-lineage ALL, and would probably require larger cohorts of patients to be ascertained.

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.

Residual disease at the end of induction therapy as a predictor of relapse during therapy in childhood B-lineage acute lymphoblastic leukemia.

1992 ◽  
Vol 10 (12) ◽  
pp. 1879-1888 ◽  
Author(s):  
R Wasserman ◽  
N Galili ◽  
Y Ito ◽  
J H Silber ◽  
B A Reichard ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Induction Therapy ◽  
Clinical Remission ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Induction Phase ◽  
Increased Risk ◽  
B Lineage ◽  
Wbc Count

PURPOSE More than 95% of children with B-lineage acute lymphoblastic leukemia (ALL) achieve a clinical remission after the induction phase of chemotherapy (first 28 days) as evaluated by morphologic criteria. However, relapse occurs in approximately 30% of these children. The objective of this study was to determine whether the outcome of patients in clinical remission at the end of induction therapy could be predicted using a highly sensitive method to detect residual disease. PATIENTS AND METHODS All children diagnosed with B-lineage ALL at the Children's Hospital of Philadelphia during a 2-year period were eligible. The extent of residual leukemia was quantitated in remission marrow samples obtained at the end of induction therapy in 44 children using a phage clonogenic assay in association with complementarity-determining-region 3 (CDR3)-polymerase chain reaction (PCR). RESULTS Residual disease was a significant predictor of outcome independent of WBC count, age, or sex. The estimated relapse-free survival (RFS) during therapy was 50.4% (+/- 12.6%) for patients with high residual disease (> or = 0.6% leukemia cells among total marrow B cells) versus 91.9% (+/- 5.5%) for those with lower levels (P < .002). There were no significant differences in off-treatment RFS between patients with high or low residual disease who completed therapy in continuous remission (P = .82). The overall estimated RFS was 32.3% (+/- 11.6%) for patients with high residual disease versus 62.6% (+/- 10.7%) for patients with lower levels of residual leukemia cells, with a median follow-up of 5.3 years for patients in continuous remission (P < .008). CONCLUSION PCR detection of high residual disease at the end of induction therapy identifies patients at increased risk for relapse during therapy.

Sign in / Sign up

Export Citation Format

Share Document