Rapid molecular response during early induction chemotherapy predicts a good outcome in childhood acute lymphoblastic leukemia

Blood ◽  
2000 ◽  
Vol 95 (3) ◽  
pp. 790-794 ◽  
Author(s):  
E. Renate Panzer-Grümayer ◽  
Monika Schneider ◽  
Simon Panzer ◽  
Karin Fasching ◽  
Helmut Gadner
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Risk Stratification ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Early Response ◽  
Response To Therapy ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Induction Treatment ◽  
Molecular Response ◽  
Significant Difference

Early response to therapy is an independent prognostic factor in childhood acute lymphoblastic leukemia. Although most patients have rapid early responses, as detected by morphology, 15% to 20% of patients have relapses. The authors evaluated residual disease by molecular methods on day 15 of minimal residual disease (MRD) therapy and compared these data with their recently established MRD-based risk stratification, defined by MRD levels 5 weeks after induction treatment and before consolidation. All 68 children treated according to current Berlin-Frankfurt-Münster (BFM) protocols went into morphologically complete remission after induction. There was a significant difference in outcome between children with rapid disease clearance and those with high levels of day-15 MRD (P = .035). Among patients with high levels of day-15 MRD, only the MRD-based risk stratification was predictive of the outcome. All patients with negative or low day-15 MRD had excellent prognoses and were in the MRD-based low-risk group. Thus, after only 2 weeks of treatment, the authors were able to identify a patient population of 20% who may benefit from the least intensive treatment.

Detection of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia by 4color Cytometry in International Multicenter Trial Minimini.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1092-1092
Author(s):  
Ester Mejstrikova ◽  
Drago Batinic ◽  
Dubravcic Klara ◽  
Margareth Ng ◽  
Yonna Leung ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Treatment Protocol ◽  
Multicenter Trial ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Treatment Protocols ◽  
Significant Difference ◽  
B Lineage

Abstract FC is still not employed in MRD based treatment protocols. One problem is lack of standardization suitable for prospective trials involving multiple clinical centers and FC laboratories. Therefore, we established a MiniMini Project, an international collateral study within the ALL IC BFM 2002 treatment protocol for childhood acute lymphoblastic leukemia (ALL). The MiniMini Project provides a mainframe of minimal panel of monoclonal antibody combinations to evaluate MRD by FC. Patients (pts) are stratified according non-MRD criteria (prednisone response at day 8 in peripheral blood (PB), percentage of blasts at day 15 and day 33 in bone marrow (BM), leukocytosis, and age at diagnosis and presence of BCR/ABL or MLL/AF4 fusions). Identical immunophenotypic populations are reported in all pts regardless presenting phenotype. Each laboratory investigates at least 2 pts with B lineage ALL by the T ALL combinations and vice versa. These “cross-lineage controls” together with data on subpopulations that are negative at diagnosis were used to set the specificity cutoff values at each time point (diagnosis, day 8 BM and PB, day 15, day 33 day 52 BM). MRD levels obtained by Ig/TCR rearrangements RQ-PCR in 32 pts (24 pts BCP ALL, 8 pts T ALL) were used to define specificity thresholds. 185 pts were investigated in the participating laboratories. We used data from first Czech cohort of pts (92 pts in total, 16 pts T lineage, 74 pts B lineage, in standard risk group (SRG), n=36, IRG, n=40 and HRG, n=16) in whom clinical data as well as standard FC analysis results were available. We compared morphological percentage of blasts (used for stratification) to a level of residual disease by FC. There was high concordance in SRG of both methods, except 1 patient redirected into IRG group (M3 BM vs. only 14% of blasts by FC). In IRG, concordance was in 92.5% of pts, 3 pts should be placed in HRG group according FC. 98.9% of pts morphologically in complete remission at day 33 were confirmed by FC. Although FC data confirm a significant difference between PGR and PPR in PB specimens at day 8 (p=0.0014), there is an overlap in percentage of leukemic cells between these categories. In total, MRD level above 0.1% was observed in BM of 100, 99, 84, 32 and 3.5 % pts in days 0, 8, 15, 33 and 52, respectively and in PB of 95% pts at day 8. Our first results show feasibility of FC standardization. The choice of subpopulations and the cutoff points will be validated in an independent cohort within the same Project.

scholarly journals Pilot Study of Nelarabine in Combination With Intensive Chemotherapy in High-Risk T-Cell Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group

2012 ◽  
Vol 30 (22) ◽  
pp. 2753-2759 ◽  
Author(s):  
Kimberly P. Dunsmore ◽  
Meenakshi Devidas ◽  
Stephen B. Linda ◽  
Michael J. Borowitz ◽  
Naomi Winick ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Chemotherapy Regimen ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Poor Response ◽  
Early Response ◽  
Oncology Group ◽  
Significant Difference ◽  
Cell Acute Lymphoblastic Leukemia

Purpose Children's Oncology Group study AALL00P2 was designed to assess the feasibility and safety of adding nelarabine to a BFM 86–based chemotherapy regimen in children with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL). Patients and Methods In stage one of the study, eight patients with a slow early response (SER) by prednisone poor response (PPR; ≥ 1,000 peripheral blood blasts on day 8 of prednisone prephase) received chemotherapy plus six courses of nelarabine 400 mg/m2 once per day; four patients with SER by high minimal residual disease (MRD; ≥ 1% at day 36 of induction) received chemotherapy plus five courses of nelarabine; 16 patients with a rapid early response (RER) received chemotherapy without nelarabine. In stage two, all patients received six 5-day courses of nelarabine at 650 mg/m2 once per day (10 SER patients [one by MRD, nine by PPR]) or 400 mg/m2 once per day (38 RER patients; 12 SER patients [three by MRD, nine by PPR]). Results The only significant difference in toxicities was decreased neutropenic infections in patients treated with nelarabine (42% with v 81% without nelarabine). Five-year event-free survival (EFS) rates were 73% for 11 stage one SER patients and 67% for 22 stage two SER patients treated with nelarabine versus 69% for 16 stage one RER patients treated without nelarabine and 74% for 38 stage two RER patients treated with nelarabine. Five-year EFS for all patients receiving nelarabine (n = 70) was 73% versus 69% for those treated without nelarabine (n = 16). Conclusion Addition of nelarabine to a BFM 86–based chemotherapy regimen was well tolerated and produced encouraging results in pediatric patients with T-ALL, particularly those with a SER, who have historically fared poorly.

Pharmacokinetics, pharmacodynamics, efficacy, and safety of a new recombinant asparaginase preparation in children with previously untreated acute lymphoblastic leukemia: a randomized phase 2 clinical trial

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4832-4838 ◽  
Author(s):  
Rob Pieters ◽  
Inge Appel ◽  
Hans-Juergen Kuehnel ◽  
Iris Tetzlaff-Fohr ◽  
Uwe Pichlmeier ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Residual Disease ◽  
Remission Rate ◽  
Lymphoblastic Leukemia ◽  
Disease Status ◽  
Time Profile ◽  
Induction Treatment ◽  
Efficacy And Safety ◽  
Significant Difference ◽  
Phase 2 Clinical Trial

Abstract The pharmacokinetics, pharmacodynamics, efficacy, and safety of a new recom-binant Escherichia coli–asparaginase preparation was compared with Asparaginase medac. Thirty-two children with acute lymphoblastic leukemia were randomized to receive one of both agents at a dose of 5000 U/m2 every 3 days, for a total of 8 doses during induction treatment. The serum activity-time profile after the first dose of recombinant asparaginase was similar to that of Asparaginase medac. The trough serum activities were greater than the desired threshold of 100 U/L in both treatment groups. Asparagine was completely depleted in serum and in cerebrospinal fluid, whereas glutamine levels were only moderately influenced. No significant difference between the 2 treatments regarding the degree of asparagine depletion, duration of depletion, complete remission rate, and minimal residual disease status at the end of induction, overall frequency or intensity of adverse events was seen. Observed adverse reactions are known as possible and labeled side effects of asparaginase treatment and chemotherapy. We conclude that the new recombinant asparaginase and other native Asparaginase medac are bioequivalent and have the same pharmacodynamic effects and the same direct toxicity profile in children with acute lymphoblastic leukemia. This trial was registered at http://www.controlled-trials.com as no. ISRCTN 75734403.

scholarly journals A set of genes that regulate cell proliferation predicts treatment outcome in childhood acute lymphoblastic leukemia

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1271-1277 ◽  
Author(s):  
Christian Flotho ◽  
Elaine Coustan-Smith ◽  
Deqing Pei ◽  
Cheng Cheng ◽  
Guangchun Song ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Acute Lymphoblastic Leukemia ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Remission Induction ◽  
Induction Treatment ◽  
Childhood All

Abstract To identify novel predictors of outcome in childhood acute lymphoblastic leukemia (ALL), we analyzed gene expression in the leukemic cells of 187 children with newly diagnosed ALL and compared the findings with minimal residual disease (MRD) results obtained on day 19 of remission induction treatment. Genes that showed a significant relationship to MRD were then tested for their capacity to predict leukemic relapse in an independent cohort of 99 patients. We identified 674 probe sets that were associated with MRD on day 19 (P < .006); 40 of the identified genes predicted relapse (P < .03). Among these, 14 showed independent prognostic significance after adjustment for age, leukocyte count at diagnosis, and genetic subtype. More than half of the 40 genes and nearly all of the 14 genes were functionally related, as indicated by their roles in the regulation of cell proliferation. Underexpression of genes promoting cell proliferation was associated with resistance to chemotherapy. The biologic processes regulated by the genes we identified appear to be key determinants of the early cytoreductive response to remission induction therapy and subsequent clinical outcome in childhood ALL. Incorporation of the expression levels of these genes into existing strategies of risk classification could improve clinical management.

scholarly journals Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study

Blood ◽  
2010 ◽  
Vol 115 (16) ◽  
pp. 3206-3214 ◽  
Author(s):  
Valentino Conter ◽  
Claus R. Bartram ◽  
Maria Grazia Valsecchi ◽  
André Schrauder ◽  
Renate Panzer-Grümayer ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Receptor Gene ◽  
Cell Receptor ◽  
Early Response ◽  
Response To Treatment ◽  
Molecular Response ◽  
First Time ◽  
Standard Risk

Abstract The Associazione Italiana di Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster Acute Lymphoblastic Leukemia (AIEOP-BFM ALL 2000) study has for the first time introduced standardized quantitative assessment of minimal residual disease (MRD) based on immunoglobulin and T-cell receptor gene rearrangements as polymerase chain reaction targets (PCR-MRD), at 2 time points (TPs), to stratify patients in a large prospective study. Patients with precursor B (pB) ALL (n = 3184) were considered MRD standard risk (MRD-SR) if MRD was already negative at day 33 (analyzed by 2 markers, with a sensitivity of at least 10−4); MRD high risk (MRD-HR) if 10−3 or more at day 78 and MRD intermediate risk (MRD-IR): others. MRD-SR patients were 42% (1348): 5-year event-free survival (EFS, standard error) is 92.3% (0.9). Fifty-two percent (1647) were MRD-IR: EFS 77.6% (1.3). Six percent of patients (189) were MRD-HR: EFS 50.1% (4.1; P < .001). PCR-MRD discriminated prognosis even on top of white blood cell count, age, early response to prednisone, and genotype. MRD response detected by sensitive quantitative PCR at 2 predefined TPs is highly predictive for relapse in childhood pB-ALL. The study is registered at http://clinicaltrials.gov: NCT00430118 for BFM and NCT00613457 for AIEOP.

Genome-wide Studies in Childhood Acute Lymphoblastic Leukemia

2009 ◽  
Vol 02 ◽  
pp. 40
Author(s):  
Deepa Bhojwani ◽  
Ching-Hon Pui ◽  
◽  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Molecular Mechanisms ◽  
Lymphoblastic Leukemia ◽  
Expression Patterns ◽  
Early Response ◽  
Response To Therapy ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Genome Wide

The convergence of multiple genome-wide platforms for molecular studies allows exceptionally high-resolution interrogation of the total complement of genetic and epigenetic alterations of the cancer cell. The influence of inherited host pharmacogenomics on drug responsiveness can likewise be examined in a high-throughput manner with single-nucleotide polymorphism (SNP) profiling. Childhood acute lymphoblastic leukemia (ALL) is easily investigated by modern genomic tools. Gene-expression patterns can classify ALL into various known and novel subtypes. Within these subtypes, multiple genomic lesions have been systematically characterized and have identified abnormalities in major pathways, including cell-cycle regulation, lymphoid differentiation and signaling, regulation of apoptosis, and tumor suppression. Clinically important phenotypes such as early response to therapy, long-term outcome, and development of adverse events have been correlated to genes and pathways identified in integrated analyses of the genome and transcriptome, providing valuable information for improved risk stratification. Uncovering the molecular mechanisms responsible for therapy failure will lead to strategies to circumvent resistance and to the development of biologically based 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.

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