Steroids and Asparaginases During Remission Induction Therapy in Childhood Lymphoblastic Leukemia

2007 ◽  
pp. 279-326
Keyword(s):  
Induction Therapy ◽  
Lymphoblastic Leukemia ◽  
Remission Induction

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.

Genome-Wide Association Study Identifies PNPLA3 I148M Variant Associated with Elevated Transaminase Levels after Induction Therapy in Pediatric ALL Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3714-3714 ◽  
Author(s):  
Christian A. Fernandez ◽  
Colton Smith ◽  
Wenjian Yang ◽  
Chengcheng Liu ◽  
Laura B. Ramsey ◽  
...  
Keyword(s):  
Association Study ◽  
Induction Therapy ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
African Ancestry ◽  
Alanine Transaminase ◽  
Genome Wide Association ◽  
Remission Induction ◽  
E Coli ◽  
Genome Wide

Abstract Current regimens for remission induction therapy of pediatric acute lymphoblastic leukemia (ALL) include multiple potentially hepatotoxic drugs, including asparaginase. The objective of our genome-wide association study (GWAS) was to identify genetic loci associated with elevated alanine transaminase (ALT) levels immediately after remission induction in children with ALL. The patients included were enrolled on St. Jude Children's Research Hospital (SJCRH) protocols Total XV (n = 373) or Total XVI (n = 342); germline DNA was genotyped using the Affymetrix 500K, Affymetrix 6.0, or the Illumina Exome Beadchip arrays. In multivariate analysis, risk factors associated with higher ALT included older age, higher body mass index, European (versus African) ancestry, treatment with PEGylated E. coli asparaginase (versus native E. coli asparaginase), and receiving additional doses of asparaginase during induction due to high level of minimal residual disease at day 15-19 of induction. GWAS identified an association between I148M PNPLA3 rs738409 (C>G) variant and post-induction ALT (Figure 1A; P = 7.9x10-9; median ALT of 34, 45, and 58 IU/L in CC, GC and GG genotypes, respectively), and the effect of the PNPLA3 variant was consistent for both protocols, both ALL risk groups, and among patients of European, African, and Hispanic ancestry. The PNPLA3 variant has previously been linked to elevated ALT and to the development of steatosis in adults;[PMID: 22001757; 18820647] in mice, this same variant led to a loss of catalytic function and to an increase of PNPLA3 accumulation in hepatic lipid droplets and to the development of steatosis.[PMID: 24917523] Within patients of African ancestry, we identified a variant near PIGV rs12748152 (C>T) associated with lower ALT levels at P = 1.7x10-8; median ALT of 28 and 6 IU/L in CC and TC genotypes, respectively (Figure 1B), consistent with lower ALT values observed in patients of African ancestry. The PIGV variant explained 7% of the variation in ALT for patients of African ancestry. The results of our study suggest that post-remission induction ALT levels may be related to treatment-related variables, such as increased asparaginase exposure, and to host genetic factors, at least some of which contribute to hepatic dysfunction in settings outside of ALL therapy. Figure 1. Alanine transaminase (ALT) levels by PNPLA3 or PIGV genotype Figure 1. Alanine transaminase (ALT) levels by PNPLA3 or PIGV genotype Disclosures Evans: Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.

scholarly journals Clinical Significance of Minimal Residual Disease at the End of Remission Induction Therapy in Childhood Acute Lymphoblastic Leukemia

2019 ◽  
Vol 7 (17) ◽  
pp. 2818-2823 ◽  
Author(s):  
Aleksandra Jovanovska ◽  
Kata Martinova ◽  
Svetlana Kocheva ◽  
Zorica Trajkova-Antevska ◽  
Biljana Coneska-Jovanova ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Treatment Outcome ◽  
Minimal Residual Disease ◽  
Clinical Significance ◽  
Induction Therapy ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Childhood All ◽  
Minimal Residual

BACKGROUND: Detection of minimal residual disease (MRD) in the early phase of therapy is the most powerful predictor of relapse risk in children with acute lymphoblastic leukaemia (ALL). AIM: We aimed to determine the significance of MRD at the end of remission induction therapy in the prediction of treatment outcome in children with ALL. METHODS: Sixty-four consecutive patients aged 1-14 years with newly diagnosed ALL were enrolled in this study from January 2010 to October 2017. All patients were treated according to the ALL IC BFM 2002 protocol. MRD was detected at the end of remission induction therapy (day 33) by multiparameter 6-colour flow cytometry performed on bone marrow specimens with a sensitivity of 0.01%. RESULTS: Overall, 42.2% of patients had detectable MRD on day 33 of therapy. MRD measurements were not significantly related to presenting characteristics but were associated with a poorer blast clearance on day 8 and 15 of remission induction therapy. Patients with negative MRD status on day 33 had a 5-year event-free survival of 94.6% compared with 76.1% for those with positive MRD status (P = 0.044). CONCLUSION: MRD levels at the end of remission induction therapy measured by multiparameter flow cytometry have clinical significance in childhood ALL. High levels of MRD are strongly related to poor treatment outcome.

CD20 up-Regulation in Childhood B-Cell Precursor Acute Lymphoblastic Leukemia during Induction Treatment Translates into Higher Rituximab-Sensitivity.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 906-906
Author(s):  
Andishe Attarbaschi ◽  
Angela Schumich ◽  
Georg Mann ◽  
Oskar A. Haas ◽  
Helmut Gadner ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Induction Therapy ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Remission Induction ◽  
Induction Treatment ◽  
Cell Precursor ◽  
The Impact

Abstract CD20 is expressed in about one half of childhood acute lymphoblastic leukemia (ALL) cases with B-cell precursor (BCP) origin. We recently observed that this phenotypic marker is further up-regulated in some patients during remission induction treatment containing corticosteroids for up to 5 weeks. To understand the impact of this phenomenon on the potential effectiveness of anti-CD20 immunotherapy (i.e., Rituximab), we studied 237 CD10-positive childhood BCP-ALL patients consecutively enrolled onto the trial AIEOP-BFM-ALL 2000. The analysis included the assessment of CD20 expression changes from diagnosis to the end of induction therapy and complement-induced cytotoxicity by CD20-targeting with Rituximab in-vitro. CD20-positivity significantly increased from diagnosis to the end of induction therapy with respect to the number of positive cases as well as to the levels of expression. After completion of induction therapy, one half of cases showed ≥ 90% CD20pos. leukemic cells, as opposed to 5% at diagnosis and 20% after 2 weeks of chemotherapy. Notably, up-regulation occurred in viable cells sustaining chemotherapy, most probably as a consequence of steroid-induced modulation of gene expression. Rituximab-cytotoxicity was significantly enhanced by CD20 up-regulation and depended on high expression levels. Importantly, CD20 up-regulation was frequent in high-risk patients (mainly poor prednisone responders), patients with high minimal residual disease levels at the end of induction therapy, and patients who suffered later from relapse, but not in TEL/AML1-positive cases. In conclusion, CD20 up-regulation is frequently induced in BCP-ALL during induction therapy and this translates into an acquired state of higher sensitivity to Rituximab.

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 < .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.

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