scholarly journals Outcomes of Children With BCR-ABL1–Like Acute Lymphoblastic Leukemia Treated With Risk-Directed Therapy Based on the Levels of Minimal Residual Disease

2014 ◽  
Vol 32 (27) ◽  
pp. 3012-3020 ◽  
Author(s):  
Kathryn G. Roberts ◽  
Deqing Pei ◽  
Dario Campana ◽  
Debbie Payne-Turner ◽  
Yongjin Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Kinase Inhibitors ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Ras Signaling ◽  
Abl Tyrosine Kinase ◽  
Minimal Residual

Purpose BCR-ABL1–like acute lymphoblastic leukemia (ALL) is a recently identified B-cell ALL (B-ALL) subtype with poor outcome that exhibits a gene expression profile similar to BCR-ABL1-positive ALL but lacks the BCR-ABL1 fusion protein. We examined the outcome of children with BCR-ABL1–like ALL treated with risk-directed therapy based on minimal residual disease (MRD) levels during remission induction. Patients and Methods Among 422 patients with B-ALL enrolled onto the Total Therapy XV study between 2000 and 2007, 344 had adequate samples for gene expression profiling. Next-generation sequencing and/or analysis of genes known to be altered in B-ALL were performed in patients with BCR-ABL1–like ALL who had available material. Outcome was compared between patients with and those without BCR-ABL1–like ALL. Results Forty (11.6%) of the 344 patients had BCR-ABL1–like ALL. They were significantly more likely to be male, have Down syndrome, and have higher MRD levels on day 19 and at the end of induction than did other patients with B-ALL. Among 25 patients comprehensively studied for genetic abnormalities, 11 harbored a genomic rearrangement of CRLF2, six had fusion transcripts responsive to ABL tyrosine kinase inhibitors or JAK inhibitors, and seven had mutations involving the Ras signaling pathway. There were no significant differences in event-free survival (90.0% ± 4.7% [SE] v 88.4% ± 1.9% at 5 years; P = .41) or in overall survival (92.5% ± 4.2% v 95.1% ± 1.3% at 5 years; P = .41) between patients with and without BCR-ABL1–like ALL. Conclusion Patients who have BCR-ABL1–like ALL with poor initial treatment response can be salvaged with MRD-based risk-directed therapy and may benefit from identification of kinase-activating lesions for targeted therapies.

scholarly journals Genes contributing to minimal residual disease in childhood acute lymphoblastic leukemia: prognostic significance of CASP8AP2

Blood ◽  
2006 ◽  
Vol 108 (3) ◽  
pp. 1050-1057 ◽  
Author(s):  
Christian Flotho ◽  
Elaine Coustan-Smith ◽  
Deqing Pei ◽  
Shotaro Iwamoto ◽  
Guangchun Song ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Induction Treatment ◽  
Minimal Residual

Abstract In childhood acute lymphoblastic leukemia (ALL), early response to treatment is a powerful prognostic indicator. To identify genes associated with this response, we analyzed gene expression of diagnostic lymphoblasts from 189 children with ALL and compared the findings with minimal residual disease (MRD) levels on days 19 and 46 of remission induction treatment. After excluding genes associated with genetic subgroups, we identified 17 genes that were significantly associated with MRD. The caspase 8–associated protein 2 (CASP8AP2) gene was studied further because of its reported role in apoptosis and glucocorticoid signaling. In a separate cohort of 99 patients not included in the comparison of gene expression profiles and MRD, low levels of CASP8AP2 expression predicted a lower event-free survival (P = .02) and a higher rate of leukemia relapse (P = .01) and were an independent predictor of outcome. High levels of CASP8AP2 expression were associated with a greater propensity of leukemic lymphoblasts to undergo apoptosis. We conclude that measurement of CASP8AP2 expression at diagnosis offers a means to identify patients whose leukemic cells are highly susceptible to chemotherapy. Therefore, this gene is a strong candidate for inclusion in gene expression arrays specifically designed for leukemia diagnosis.

Minimal residual disease by flow cytometry at the end of chemotherapy for remission induction in pediatric patients with acute lymphoblastic leukemia: Experience from a center in a low-income country.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9554-9554
Author(s):  
Eloy Perez ◽  
Primo Cruz-Borja ◽  
Silvia Chavez-Gallegos
Keyword(s):  
Flow Cytometry ◽  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Response To Chemotherapy ◽  
Increased Risk ◽  
Cure Rates ◽  
Minimal Residual

9554 Background: The presence of minimal residual disease (MDR) following therapy for acute lymphoblastic leukemia (ALL) has been shown to be an important prognostic marker in many studies. MRD is typically detected either by polymerase chain reaction amplification or by flow cytometry. Flow-based MRD assessment has the potential for rapidly identifying patients at increased risk of relapsed, allowing for prompt changes in therapy, including earlier intensification. There are not many information about the response by MRD in countries with limited resources. Methods: The patients included were 90 ALL patients treated at the Hospital Infantil de Morelia from June 1, 2009 to January 5, 2012. MRD positivity (+) was defined as >0.01% of the gated population. Results: MRD was obtained in 90 patients, 38 males and 36 females. The median age was 7 years (10 months to 15 years). The levels of MRD were: <0.01, 74 (82.2%), 0.01-1%, 9 (10%), ≥1%, 7 (7.7%). There was not a statistically significant association between the most important ALL prognostic factors (Gender, Age at diagnosis, White blood cell count at diagnosis, Central Nervous System disease, Prednisone response, DNA Index, Immunophenotype). Conclusions: The good response found is similar to that reported by international groups, a situation which suggests that the response to chemotherapy is appropriate. However, cure rates are still not equal making it necessary to review institutional treatment protocols and social characteristics of the population to achieve cure rates reported by international groups.

scholarly journals Use of polymerase chain reactions to monitor minimal residual disease in acute lymphoblastic leukemia patients

Blood ◽  
1991 ◽  
Vol 77 (2) ◽  
pp. 331-339 ◽  
Author(s):  
S Yokota ◽  
TE Hansen-Hagge ◽  
WD Ludwig ◽  
A Reiter ◽  
A Raghavachar ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Clinical Remission ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Remission Induction ◽  
Clinical Relapse ◽  
Polymerase Chain ◽  
Minimal Residual

Abstract T-cell receptor (TCR) delta gene rearrangements are observed in more than 80% of acute lymphoblastic leukemia (ALL) patients. Moreover, a preferential usage of specific genetic elements has been shown in different ALL subtypes: V delta 1 DJ delta 1 rearrangements predominate in T-ALL, while most B-precursor ALLs show a recombination of V delta 2 to D delta 3. Recently we have proposed a strategy for the detection of minimal residual disease (MRD) based on the isolation of clonospecific probes following the in vitro amplification of V delta 1 DJ delta 1 junctions by polymerase chain reaction (PCR) and now have adapted this method to the preparation of specific V delta 2 D delta 3 fragments. In the present study, clonospecific probes were generated from 11 T-ALL and 16 cALL patients (21 children, 6 adults). The sensitivity of these 27 probes in detecting residual leukemia cells varied between 10(-4) to 10(-6) as determined by semiquantitative evaluation of dilution experiments. PCR analysis of 55 bone marrow (BM) and peripheral blood (PB) samples obtained from the 27 patients during complete clinical remission showed the following results: (1) Evidence for MRD was obtained in the BM of all patients (eight of eight) investigated 2 to 6 months after remission induction and also in 6 of 11 cases on maintenance therapy 7 to 19 months after diagnosis. (2) In contrast, all patients but one (10 of 11) analyzed 6 to 41 months after the termination of treatment lacked apparent evidence for leukemia DNA; the exception was a girl exhibiting 10(-4) to 10(-5) residual cells in her PB 5.5 years after diagnosis. (3) Longitudinal analysis in nine patients disclosed marked individual differences in the intervals between achievement of clinical remission and complete eradication of the leukemia cell clone. (4) Differences in the duration of MRD were not associated with distinct clinical-hematologic features. (5) Detection of residual disease by PCR proceeded clinical relapse in two cases.

scholarly journals Genome-wide association study identifies germline polymorphisms associated with relapse of childhood acute lymphoblastic leukemia

Blood ◽  
2012 ◽  
Vol 120 (20) ◽  
pp. 4197-4204 ◽  
Author(s):  
Jun J. Yang ◽  
Cheng Cheng ◽  
Meenakshi Devidas ◽  
Xueyuan Cao ◽  
Dario Campana ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Genome Wide ◽  
Minimal Residual ◽  
Risk Of Relapse

Abstract With the use of risk-directed therapy for childhood acute lymphoblastic leukemia (ALL), outcome has improved dramatically in the past 40 years. However, a substantial portion of patients, many of whom have no known risk factors, experience relapse. Taking a genome-wide approach, in the present study, we evaluated the relationships between genotypes at 444 044 single nucleotide polymorphisms (SNPs) with the risk of relapse in 2535 children with newly diagnosed ALL after adjusting for genetic ancestry and treatment regimen. We identified 134 SNPs that were reproducibly associated with ALL relapse. Of 134 relapse SNPs, 133 remained prognostic after adjusting for all known relapse risk factors, including minimal residual disease, and 111 were significant even among patients who were negative for minimal residual disease after remission induction therapy. The C allele at rs7142143 in the PYGL gene was associated with 3.6-fold higher risk of relapse than the T allele (P = 6.7 × 10−9). Fourteen of the 134 relapse SNPs, including variants in PDE4B and ABCB1, were also associated with antileukemic drug pharmacokinetics and/or pharmacodynamics. In the present study, we systematically identified host genetic variations related to treatment outcome of childhood ALL, most of which were prognostic independent of known risk factors for relapse, and some of which also influenced outcome by affecting host dis-position of antileukemic drugs. All trials are registered at www.clinicaltrials.gov or www.cancer.gov (COG P9904: NCT00005585; COG P9905: NCT00005596; COG P9906: NCT00005603; St Jude Total XIIIB: NCI-T93-0101D; and St Jude Total XV: NCT00137111).

Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2691-2696 ◽  
Author(s):  
Elaine Coustan-Smith ◽  
Jose Sancho ◽  
Michael L. Hancock ◽  
James M. Boyett ◽  
Frederick G. Behm ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Induction Therapy ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Induction Phase ◽  
Continuation Therapy ◽  
Flow Cytometric ◽  
Minimal Residual

Abstract By using rapid flow cytometric techniques capable of detecting one leukemic cell in 104 normal cells, we prospectively studied minimal residual disease (MRD) in 195 children with newly diagnosed acute lymphoblastic leukemia (ALL) in clinical remission. Bone marrow aspirates (n = 629) were collected at the end of remission induction therapy and at 3 intervals thereafter. Detectable MRD (ie, ≥0.01% leukemic mononuclear cells) at each time point was associated with a higher relapse rate (P &lt; .001); patients with high levels of MRD at the end of the induction phase (≥1%) or at week 14 of continuation therapy (≥0.1%) had a particularly poor outcome. The predictive strength of MRD remained significant even after adjusting for adverse presenting features, excluding patients at very high or very low risk of relapse from the analysis, and considering levels of peripheral blood lymphoblasts at day 7 and day 10 of induction therapy. The incidence of relapse among patients with MRD at the end of the induction phase was 68% ± 16% (SE) if they remained with MRD through week 14 of continuation therapy, compared with 7% ± 7% if MRD became undetectable (P = .035). The persistence of MRD until week 32 was highly predictive of relapse (all 4 MRD+patients relapsed vs 2 of the 8 who converted to undetectable MRD status; P = .021). Sequential monitoring of MRD by the method described here provides highly significant, independent prognostic information in children with ALL. Recent improvements in this flow cytometric assay have made it applicable to more than 90% of all new patients.

Sign in / Sign up

Export Citation Format

Share Document