Amplification of AML1 Does Not Impact Early Outcome of Children with Acute Lymphoblastic Leukemia (ALL) Treated with Risk-Directed Chemotherapy: A Report From the Children's Oncology Group (COG).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2598-2598
Author(s):  
Nyla A. Heerema ◽  
Andrew J. Carroll ◽  
Michael J. Borowitz ◽  
Meenakshi Devidas ◽  
Eric C. Larson ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Early Response ◽  
Response To Therapy ◽  
Chromosome 21 ◽  
Single Chromosome ◽  
Early Outcome ◽  
Early Results

Abstract Abstract 2598 Poster Board II-574 Amplification of a region of chromosome 21 (which includes the AML1 (RUNX1) locus (amp(AML1)) has been reported as a recurring abnormality in pediatric ALL that is associated with increased age (median 9 years), a low white blood cell (WBC) count, and a poor outcome. (Moorman et al Blood 109:2327, 2007; Attarbaschi et al JCO 26:3046, 2008). Early results in these studies indicated approximately a 75% event-free survival (EFS) at 2 years. Amp(AML1) can be reliably detected only by fluorescence in situ hybridization (FISH), and can be recognized when blasts are tested by FISH for the presence of the TEL(ETV6)/RUNX1 translocation. We reviewed the clinical features and outcome of children with ALL and amp(AML1) treated on current generation COG trials from 2003–2009 (median follow up 1.2 years, range: 0.03–3.83 yrs). Diagnosis of amp(AML1) required at least 5 copies of AML1, with 4 copies on a single chromosome. Children with B-precursor ALL received a 3- or 4-drug induction based on NCI risk group, with post-induction therapy based on further risk stratification variables measured during the first month of induction. Patients with a poor early response to therapy (day 15 bone marrow (BM) with >5% blasts or day 29 BM minimal residual disease (MRD) >0.1%) were non-randomly assigned to receive augmented chemotherapy. Treatment was not altered for patients with amp(AML1). Since June 1, 2007, ETV6/RUNX1 FISH was required on all children enrolled on this study. From Dec 29, 2003 to June 1, 2007, FISH was not required on all patients so ascertainment of amp(AML1) may not be complete. There were 89/5470 (1.6%) children with B-precursor ALL in whom amp(AML1) was detected. Similar to previous reports (see Table), their median age was 9.1 years, median WBC was 4.5×109/l; and 55.1% were female, a higher proportion than previously reported (43%–48%). While the distribution of day 29 MRD by flow cytometry was different, NCI risk group distribution, 2-year EFS and overall survival (OS) were similar between patients with and without amp(AML1). Of the 10 events that occurred in patients with amp(AML1), there were 3 induction failures, 3 induction deaths, and 4 relapses. Thus, early response to risk-adapted therapy is similar in children with and without amp(AML1). We conclude that, using risk-adapted therapy, children with ALL and amp(AML1) have an early outcome similar to those lacking this feature; however, longer follow up is needed to determine the full impact of amp(AML1) on eventual outcome. Disclosures: No relevant conflicts of interest to declare.

iAMP21 Is Associated with Inferior Outcomes in Children with Acute Lymphoblastic Leukemia (ALL) on Contemporary Children's Oncology Group (COG) Studies

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 739-739
Author(s):  
Nyla A. Heerema ◽  
Elizabeth A. Raetz ◽  
Andrew J. Carroll ◽  
Michael J. Borowitz ◽  
Meenakshi Devidas ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Cox Model ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Early Response ◽  
Chromosome 21 ◽  
Single Chromosome ◽  
Cox Regression Analysis ◽  
Cell Counts

Abstract Abstract 739 Intrachromosomal amplification of a region of chromosome 21 (iAMP21) occurs in a 1–3% of children with ALL and can be identified by RUNX1 fluorescence in situ hybridization (FISH). We monitored the outcome of patients with iAMP21 in recent COG trials for newly diagnosed standard risk (SR; AALL0331) and high risk (HR; AALL0232) B-precursor ALL based on reports of inferior outcomes associated with this cytogenetic alteration. (Moorman et al Blood 2007) We examined the incidence, clinical characteristics and outcome for 7799 children, adolescents and young adults 1–30 years old enrolled on COG AALL0331 and AALL0232 between 2003 and 2011. All patients had testing for prognostically relevant cytogenetic alterations including ETV6-RUNX1 performed in COG central laboratories (2003-2006) or approved local cytogenetics laboratories with central review (2007-2011). Ascertainment of iAMP21 may have been incomplete prior to 2007 as ETV6-RUNX1 was primarily assessed centrally by RT-PCR. Classification as iAMP21 required >4 RUNX1 signals on a single chromosome (>5 total RUNX1 signals). If metaphase FISH was not possible, iAMP21 was identified as multiple copies of RUNX1 clumped in at least some of the nuclei. ALL cases defined as very high risk with t(9;22), hypodiploidy with <44 chromosomes or MLL rearrangements and slow early response to treatment were excluded from this analysis. Treatment on AALL0331 and AALL0232 consisted of a 3- (AALL0331) or 4-drug (AALL0232) induction, with post-induction therapy based on early response and established prognostic cytogenetic features. Therapy was not altered for patients with iAMP21. iAMP21 was identified in 158/7799 (2%) cases; 75/5060 (1.5%) SR cases and 83/2739 (3.0%) HR cases. Patients with iAMP21 were more likely to be ≥10 years old (49% vs. 33%, p<0.0001), have white blood cell counts (WBC) <50,000/μL (96% vs. 85%, p<0.0001), be female (54% vs. 34%, p=0.036) and to have ≥0.01% end Induction bone marrow minimal residual disease (MRD) (41% vs. 21%, p<0.0001) than those without iAMP21. While earlier analyses suggested that iAMP21 was not associated with inferior outcomes in COG AALL0232 and AALL0331 (Heerema et al, ASH 2009 abstract; 114: 2598), new analyses with larger patient numbers and longer follow-up show that the outcome for patients with iAMP21 is worse than for patients without iAMP21 (Table 1). These differences were statistically significant in SR, but not HR patients. Outcome comparisons were also made examining iAMP21 status and end induction MRD (<0.01% vs. ≥0.01%). Pooled SR and HR patients with iAMP21 who were MRD positive (≥0.01%) had significantly inferior outcomes with 4-year event-free survival (EFS) of 55.8±12.4% vs. 76.5±2% among non-iAMP21 MRD positive patients, p=0.037. For MRD negative patients, 4-year EFS for those with iAMP21 was significantly worse (81.4±7.8%) than for those without this feature (92.2±0.6%; p=0.016). In multivariate Cox regression analysis of AALL0331 patients, iAMP21 (hazard ratio (HR) 2.246; p=0.0021), day 29 MRD ≥0.01% (HR 2.430; p<0.0001) and favorable genetics (ETV6-RUNX1 or trisomies of chromosomes 4 and 10 (HR 0.361; p<0.0001) all had high prognostic significance, while iAMP21 was not significant in a multivariate Cox model in AALL0232 patients. In conclusion, patients with iAMP21 have inferior outcomes with contemporary chemotherapy in COG ALL trials and may benefit from more intensive or novel treatment approaches. In particular, lower intensity therapy given to SR ALL patients in COG AALL0331 led to significantly inferior outcomes for those with iAMP21.Table 1.Outcomes in iAMP21 SR and HR ALLiAMP21Othersp-valueAALL0232+AALL0331N15876414-year EFS70.2 ± 7%88.1 ± 0.7%<0.00014-year OS84.7 ± 5.6%93.9 ± 0.5%0.0132AALL0331N7549854-year EFS70.4 ± 9.3%91.8 ± 0.7%<0.00014-year OS87 ± 6.9%96.5 ± 0.5%0.004AALL0232N8326564-year EFS70 ± 10.6%81 ± 1.3%0.464-year OS82.7 ± 9.2%88.9 ± 1.1%0.65 Disclosures: Borowitz: BD Biosciences: Research Funding. Mattano:Pfizer, Inc.: Employment. Wood:BD Biosciences: Research Funding.

scholarly journals Early T Acute Lymphoblastic Leukemia in Childhood: Prevalence and Clinical Characteristics

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3656-3656
Author(s):  
Jorge Gabriel Rossi ◽  
Carolina Carrara ◽  
Patricia L. Rubio ◽  
Cristina N. Alonso ◽  
Andrea Bernasconi ◽  
...  
Keyword(s):  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Poor Response ◽  
Early Response ◽  
Response To Treatment ◽  
Differentiation Potential ◽  
Lineage Switch ◽  
Conventional Cytogenetics

Abstract Background: Early T precursor ALL has been defined as a poor prognosis subtype, characterized phenotypically by absence of CD1a and CD8, CD5 weak expression and presence of at least one myeloid and progenitor cell marker. Objectives: Our aims were to identify Early T-ALL among our T ALL cases, based on the characteristic phenotype and thus evaluate the prevalence, biological characteristics and outcome of this particular subset of T-ALL Methods: From April ’94 to December ’13, 197 T-ALL cases were diagnosed and 20 of them showed the typical Early T marker profile by flow cytometry (FC). Conventional cytogenetics, FISH and RT-PCR studies were performed according to standard techniques. Clonality assessment for TRG, TRB, TRD, IGH and IGK was performed by PCR (Biomed-2), heteroduplex and sequencing. Results: Sex distribution was: 16 males and 4 females; median of age: 7.9 (range: 0.3-16.6) years; median WBC: 14.9 (range: 0.6-254.0) x109/L. All but one case expressed CD34, 70% HLA-DR, 61% CD117 and 50% TdT. The most frequently expressed myeloid markers were: CD33 (85%) and CD13 (55%). Three cases expressed g/d TCR. Chromosomal abnormalities were detected in 14 of 16 evaluated cases, in 5 of them compromising 12p13 region. TCR/IgH rearrangements were detected in 63% (10/16). FLT3-ITD mutations were found in 14 % (2/14). Patients were treated with BFM-based ALL schedules and were stratified as Intermediate Risk ALL (n: 7) and High Risk ALL (n: 13) according to protocol criteria. Early response to treatment was poor in 16 cases: 6 presented poor response to prednisone (day 8), 3 MRD >10%, 5 presented bone marrow M2-M3 and 2 non response. Seventeen cases (85%) achieved CR on day 33 and 2 achieved CR later. Five patients underwent HSCT in first CR. Three patients relapsed at 5, 6 and 65 months from diagnosis and one showed lineage switch to M5-AML at 12 months from CR. Three pts died in CR (2 after HSCT and 1 patient with primary immunodeficiency due to pneumonia) and one is in palliative care. Twelve patients remain in CR with a median follow-up of 54 (r: 8-144) months. Conclusions: The prevalence of Early T precursor phenotype within T ALL was 10.5% in our setting. The most frequent progenitor marker was CD34 and CD33 among myeloid markers. Of note, translocations involving 12p13 region were found in 5 patients. Sixty percent of patients remain disease free, although longer follow-up is needed in order to define prognosis of this group in our cohort of patients. The lineage switch case supports the notion of the myeloid differentiation potential of these blasts. Disclosures No relevant conflicts of interest to declare.

ETV6/RUNX1-Postitive Childhood Acute Lymphoblastic Leukemia (ALL): Do Additional Aberrations Influence Treatment Response and Outcome?

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2403-2403
Author(s):  
Maria Ampatzidou ◽  
Stephanos I. Papadhimitriou ◽  
George Paterakis ◽  
Loizos Petrikkos ◽  
Dimitrios Pavlidis ◽  
...  
Keyword(s):  
Prognostic Markers ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Clonal Diversity ◽  
Early Response ◽  
Response To Treatment ◽  
Childhood All ◽  
Biological Features

Abstract ETV6/RUNX1 rearrangement, being the most common genetic abnormality in childhood ALL, is combined with controversial prognostic behavior and frequent late relapses, indicating the need for identification of additional prognostic markers. In our study, we examined the relation between ETV6/RUNX1 and presenting clinical/biological features, co-existing subclones/secondary aberrations, early response to treatment (MRD) and their impact on outcome in a pediatric cohort of 133 ALL pts , treated in one Center over a 12-year period. Data from 133 newly diagnosed ALL pts(83 males) with a median age of 5.1 yrs(range 1.2-16.7), have been retrospectively recorded and analyzed. Pts were consecutively diagnosed and homogeneously treated on BFM based protocols during the years 2000-2011. FISH evaluation using commercial probe sets was performed for the detection of ETV6-RUNX1, E2A-PBX1, BCR-ABL fusion genes, MLL gene rearrangements as well as ETV6, RUNX1, CDKN2A/2B and other gene duplications, deletions or amplifications. Twenty seven pts (27/133, 20.3%) were tested positive for the t(12;21)(p13;q22) translocation(16 males), with a median age of 3.9 yrs(range 2.0-16.7). Immunophenotype revealed 22/27 common (81.5%) and 5/32 pre-B cases (18.5%). All pts were characterized as GPR and treated in the IR Arm. 8/27 (29.6%) were positive for the ETV6/RUNX1 fusion gene only with no secondary aberrations. 19/27 ETV6/RUNX1-positive pts (70.4%) harbored additional structural or numerical genetic abnormalities while 8 of those pts showed presence of subclones with multiple patterns of additional ETV6 and RUNX1 aberrations. The most common abnormalities were del12p13(37%), 3-6x21q22(22.2%), del9p21(18.5%), +21(14.8%), and 2-3xETV6/RUNX1(18.5%). On day 15, 13/27 ETV6/RUNX1+ pts (48.1%) presented with FCM-MRD(d15) values≥10-3 while the corresponding percent among IR ETV6/RUNX1- pts was 46.9%. Out the 8 pts with sole t(12;21)(p13;q22) translocation, only 25%(2/8 pts) presented with MRD(d15)>10-3 while among the 19 pts with additional aberrations, the corresponding percent was 52.6% (10/19). Interestingly, referring only to ETV6/RUXN1+ pts with subclones, the percent reflecting MRD(d15)>0.1% rises to 87.5% (7/8 pts). Among the 14 pts with no MRD(d15) detection only 1/14 appeared with clonal heterogeneity. 3/27 pts (11.1%) relapsed, in a median time of 30.3 months (median follow-up time 64 months). Common features of all relapses were sub-clonal diversity at diagnosis, del(9p21) and MRD(d15) positivity. 5-year RFS for the ETV6/RUNX1+ subgroup was 86.4%±7.4 vs 87.7%±3.5 for ETV6/RUNX1- pts. The presence of the ETV6/RUNX1 fusion gene as a favorable genetic marker did not seem to have a statistically significant impact on the probability of relapse (p=0.906). The 5-year RFS for those with MRD≥0.1% was limited to 67.3% ±16.0, while the corresponding rate for MRD- pts reached 100%. ETV6/RUNX1+ childhood ALL is characterized by extreme heterogeneity and the prognostic value of the fusion itself varies, depending on coexisting clinical and biological features. In our series, the presence of additional genetic aberrations/subclones (such as del9p21 or ETV6/RUNX1 duplication) and impaired FCM-MRD clearance, influences patient outcome. Longer follow-up is needed in order to further validate these initial results. FISH and FCM data may help establish new prognostic markers to predict relapse and refine risk stratification. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals IKZF1 Deletion Is An Independent Predictor of Outcome In Pediatric Acute Lymphoblastic Leukemia Treated According to the ALL-BFM 2000 Protocol

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 409-409
Author(s):  
Petra Breithaupt ◽  
Barbara Meissner ◽  
Martin Zimmermann ◽  
Anja Möricke ◽  
André Schrauder ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
High Risk ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Risk Group ◽  
Independent Predictor ◽  
Lymphoblastic Leukemia ◽  
Time Points ◽  
Pediatric All

Abstract Abstract 409 Alteration of the IKZF1 gene – encoding the transcription factor IKAROS, a key player in lymphoid development and tumor suppression – has been reported to be associated with a poor outcome in pediatric precursor B-cell ALL, especially in cases positive for the BCR-ABL1 fusion gene. In order to assess the prognostic value of IKZF1 deletions in a representative cohort of pediatric ALL patients treated on the German ALL-BFM 2000 study protocol, we screened 409 patients by applying a multiplex ligation-dependent probe amplification (MLPA) assay covering all eight IKZF1 exons (P335-A3 ALL-IKZF1 probemix; MRC-Holland, Amsterdam, The Netherlands). In ALL-BFM 2000, risk group stratification (standard, SR; intermediate, MR; high, HR) was based on minimal residual disease (MRD) analysis at two different time points (TP) and required two MRD targets with sensitivities of ≤10−4 (Flohr et al. Leukemia 2008). SR patients were MRD-negative on treatment days 33 (TP1) and 78 (TP2). HR patients had residual disease (≥10−3) at TP2. MRD MR patients had positive MRD detection at either one and or both time points but at a level of <10−3 at TP2. Although MRD-based stratification criteria were introduced in ALL-BFM 2000, established high-risk parameters were also retained: patients with prednisone poor-response or ≥5% leukemic blasts in the bone marrow on day 33 or positivity for a t(9;22) or t(4;11) or their molecular equivalents (BCR/ABL1 or MLL/AF4 fusion RNA) were stratified into the high-risk group independent of their MRD results. First results on MRD and outcome were published earlier (Conter et al. Blood 2010). Out of the 409 patients analyzed in our study, 46 (11%) displayed a deletion in at least one of the eight IKZF1 exons. Forty-three out of the 46 cases showed heterozygous deletions, while 3 patients displayed homozygous loss of IKZF1 exons. MLPA results of 11 patients were validated with results derived from copy number/LOH analyses using Affymetrix SNP 6.0 arrays. IKZF1 deletion was significantly more common in precursor B compared to T cell ALL (13% vs. 4%, P = 0.03) and less frequent in TEL/AML1-positive ALL (3% vs. 13%, P = 0.004). Out of 11 BCR/ABL1-positive samples, only two were characterized by an IKZF1 deletion. Forty-four patients with IKZF1-deleted ALL had results of MRD analyses available for both informative time points (day 33 after induction and day 78 after consolidation). Despite a trend towards increasing incidence of IKZF1 deletion in patients with slow response, the distribution of IKZF1-deleted ALL patients over the risk groups was not significantly different from non-deleted ALL (SR: 40.9 vs. 41.9; MR: 45.5 vs. 52.3; HR: 13.6 vs. 5.7%; P = 0.153). Regarding treatment outcome, patients with an IKZF1 deletion had a significantly lower 5-year event-free survival (EFS) compared to non-deleted patients (0.78±0.06 vs. 0.86±0.02; P = 0.015). This result was due to a higher cumulative incidence of relapses in IKZF1-deleted patients (0.16±0.05 vs. 0.10±0.02; P = 0.031). In multivariate Cox regression analyses including known prognostic variables (gender, immunophenotype, WBC count at diagnosis, TEL/AML1 status, risk group criteria of ALL-BFM 2000), IKZF1 deletion conferred a risk of 2.16 (95% confidence interval 1.14 – 4.10; P = 0.018) for an event when compared to non-deleted patients. We conclude that IKZF1 deletion is an independent predictor of treatment outcome for patients enrolled on the ALL-BFM 2000 protocol and represents a candidate marker to be integrated in future algorithms for early risk stratification in pediatric ALL. Disclosures: No relevant conflicts of interest to declare.

Characterization of high-hyperdiploidy in childhood acute lymphoblastic leukemia with gain of a single chromosome 21

2007 ◽  
Vol 48 (12) ◽  
pp. 2457-2460 ◽  
Author(s):  
Angela Brown ◽  
Felix Niggli ◽  
Heinz Hengartner ◽  
Ueli Caflisch ◽  
Luisa Nobile ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Chromosome 21 ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Single Chromosome

scholarly journals Pre-Enucleation Chemotherapy in Advanced Intraocular Retinoblastoma. Central America Follow Up: AHOPCA II

2016 ◽  
Vol 2 (3_suppl) ◽  
pp. 75s-75s
Author(s):  
Sandra Luna-Fineman ◽  
Soad L. Alabi ◽  
Mauricio E. Castellanos ◽  
Yessika Gamboa ◽  
Ligia Fu ◽  
...  
Keyword(s):  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Central America ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
High Risk Group ◽  
Globe Rupture ◽  
Neo Adjuvant Chemotherapy ◽  
Standard Risk

Abstract 57a Purpose: A significant percentage of patients in Central America present with buphthalmos, carrying a high risk of globe rupture and orbital contamination. In 2007, AHOPCA introduced chemotherapy before enucleation in children with buphthalmos. Methods: Patients with advanced intraocular disease were considered standard-risk and underwent enucleation. Those with diffuse invasion of choroid, postlaminar optic nerve, or anterior chamber invasion received 4-6 cycles of adjuvant chemotherapy (vincristine, carboplatin, etoposide). Patients with buphthalmos or perceived to be at risk for abandonment were considered high-risk, given 2-3 cycles of chemotherapy before enucleation to compete 6 cycles regardless of pathology. All cases were discussed via online meetings. Results: From 2007 to 2014, 396 patients were enrolled; 240 had IRSS stage I (174 unilateral). 143 had upfront enucleation, 95 had pre-enucleation chemotherapy, 1 is pending enucleation and 1 abandoned before enucleation. The standard-risk group 69 had risk pathology and 76 had no risk factors; 125 had no events, 5 abandoned 11 relapsed/progressed and 2 died of toxicity. Of 95 high-risk group, 8 abandoned, 20 relapse/progressive, 6 had toxic deaths and 61 are alive at last follow-up (median time of 4 years). Of high risk group, 55 were unilateral, 82% are alive. At 7 years OS (abandonment-censored) was 95±0.02 and 79±0.04 for standard-risk and high-risk (p=0.008). Conclusion: AHOPCA addressed advanced intraocular disease with an innovative approach. In eyes with buphthalmos and patients with risk of abandonment, neo-adjuvant chemotherapy is effective, when followed by post-enucleation chemotherapy. This approach avoids ocular rupture and intensified therapy, and reduces refusal/abandonment rate. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: No COIs from the authors.

scholarly journals Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM 86

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 3122-3133 ◽  
Author(s):  
A Reiter ◽  
M Schrappe ◽  
WD Ludwig ◽  
W Hiddemann ◽  
S Sauter ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Multicenter Trial ◽  
Low Risk ◽  
Event Free Survival ◽  
Free Survival ◽  
Risk Patients ◽  
To Receive

Abstract In trial ALL-BFM 86, the largest multicenter trial of the Berlin- Frankfurt-Munster (BFM) study group for childhood acute lymphoblastic leukemia (ALL), treatment response was used as an overriding stratification factor for the first time. In the previous trial ALL-BFM 83, the in vivo response to initial prednisone treatment was evaluated prospectively. A blast cell count of > or = 1,000/microL peripheral blood after a 7-day exposure to prednisone and one intrathecal dose of methotrexate (MTX) identified 10% of the patients as having a significantly worse prognosis. In trial ALL-BFM 86 patients with > or = 1,000/microL blood blasts on day 8 were included in an experimental branch EG. Patients with < 1,000/microL blood blasts on day 8 were stratified by their leukemic cell burden into two branches, Standard Risk Group (SRG) and Risk Group (RG). SRG patients received an eight- drug induction followed by consolidation protocol M (6-mercaptopurine, high-dose [HD] MTX 4 x 5 g/m2) and maintenance. RG patients were treated with an additional eight-drug reinduction element. For EG patients protocol M was replaced by protocol E (prednisone, HD-MTX, HD- cytarabine, ifosfamide, mitoxantrone). All patients received intrathecal MTX therapy; only those of branches RG and EG received cranial irradiation. In branch RG, patients were randomized to receive or not to receive late intensification (prednisone, vindesine, teniposide, ifosfamide, HD-cytarabine) in the 13th month. During the trial reinduction therapy was introduced in branch SRG, because in the follow-up of trial ALL-BFM 83 the randomized low-risk patients receiving reinduction did significantly better. Nine hundred ninety- eight evaluable patients were enrolled, 28.6% in SRG, 61.1% in RG, 10.3% in EG. At a median follow-up of 5.0 (range 3.4 to 6.9) years, the estimated 6-year event-free survival was 72% +/- 2% for the study population, 58% +/- 5% in branch SRG for the first 110 patients without reinduction therapy, 87% +/- 3% for the next 175 patients with reinduction therapy, 75% +/- 2% in branch RG, and 48% +/- 5% in branch EG. Late intensification did not significantly affect treatment outcome of RG patients; however, only 23% of the eligible patients were randomized. Prednisone poor response remained a negative prognostic parameter despite intensified therapy. The results confirmed the benefit of intensive reinduction therapy even for low-risk patients. The strategy of induction, consolidation, and intensive reinduction may offer roughly 75% of unselected childhood ALL patients the chance for an event-free survival.

Early Response to Therapy Is Significantly Associated with Genetic Subtype of Acute Lymphoblastic Leukemia: A Report from the Children’s Oncology Group.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 758-758
Author(s):  
Mignon L. Loh ◽  
Elizabeth Raetz ◽  
Meenakshi Devidas ◽  
Stephen B. Linda ◽  
Michael J. Borowitz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Real Time ◽  
Induction Therapy ◽  
Classification System ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Early Response ◽  
Response To Therapy ◽  
Oncology Group ◽  
Genetic Features

Abstract Improved outcomes for children with acute lympboblastic leukemia (ALL) have been achieved, in part, from adaptation of risk-stratified therapy. The Children’s Oncology Group (COG) has implemented a real-time risk classification system (AALL03B1) using a combination of NCI-Rome risk criteria, blast cell genetic features, and early treatment response to determine the intensity of post-induction therapy. Between December 29, 2003 and June 1, 2007, more than 4,000 children over 1 year of age with B-precursor ALL were enrolled on AALL03B1, including 2293 (62%) with NCI Standard Risk (SR) and 1406 (38%) with NCI High Risk (HR) features who were subsequently enrolled on companion clinical trials. The most favorable genetic features used in AALL03B1 were identified in legacy COG studies and included TEL/AML1(TEL) or triple trisomies of chromosomes 4, 10, and 17 (TT). Unfavorable genetic features included the presence of BCR/ABL, MLL rearrangements, or extreme hypodiploidy (DNA index <.81 or chromosomes <44). Overall, 26% of patients were TEL+ and 24.7% had TT. These genetic subsets occurred more frequently in NCI SR vs. HR patients (30.7% and 30.9% vs. 14.5% and 11.7% respectively). Children achieving an M1 day 15 bone marrow (BM) who also had minimal residual disease (MRD) < 0.1% measured by flow cytometry on day 29 of induction therapy were deemed rapid early responders (RER), while those with either an M2/M3 day 15 marrow or MRD > 0.1% at day 29 were defined as slow early responders (SER). Among the favorable cytogenetic subsets, patterns of early response differed. The presence of TEL was significantly associated with an RER to induction therapy in both NCI SR and HR groups (p< 0.0001), while the presence of TT was not (p=0.058). For NCI SR patients, the presence of TEL was significantly associated with the achievement of an M1 bone marrow by day 8 (50.9% of TEL+ pts vs. 41.2% of TEL- pts, p< 0.0001). Patients with an M1 or M2 BM on day 29 who had MRD >1% received extended induction (EI) for two weeks followed by an additional evaluation of BM morphology and MRD at day 43 of induction. One hundred and nineteen patients received EI, with 40% having NCI SR features at diagnosis. Of the patients who received EI, 63% achieved an M1 marrow with MRD < 1% by day 43 and were eligible to continue on protocol therapy. This was more likely to occur in NCI SR patients (77% vs. 55%, p<0.013). Not surprisingly, 31% of the NCI HR patients receiving EI were BCR/ABL positive, and the presence of BCR/ABL was associated with a slower early response overall. While the presence of the BCR/ABL was associated with a greater likelihood of EI, MLL rearrangements and hypodiploidy were not. These data indicate that early response to induction therapy differs among genetic subsets of pediatric patients with newly diagnosed ALL. In addition a centralized classification system allows for robust collection of data from local and centralized reference laboratories that can be used for real time treatment assignment of ∼2000 patients/year with ALL from > 220 COG institutions.

Relative Expression of Ikaros Isoforms Has a Prognostic Impact in Phildelphia-Negative Childhood Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1282-1282
Author(s):  
Jana Volejnikova ◽  
Ester Mejstrikova ◽  
Jan Stary ◽  
Jan Trka ◽  
Eva Fronkova
Keyword(s):  
Dna Binding ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
High Expression ◽  
Rapid Screening ◽  
Prognostic Impact ◽  
Altered Expression ◽  
Relative Expression ◽  
Lymphoid Lineage

Abstract Abstract 1282 Poster Board I-304 Ikaros, encoded by the IKZF1 gene, is a zinc-finger transcription factor crucial for normal differentiation of the lymphoid lineage. Multiple isoforms of Ikaros are generated by alternative splicing in lymphoid progenitors. Recent studies based primarily on high-risk (HR) patients with ALL, including Philadelphia-positive cases, have shown an inferior prognosis of patients with Ikaros alterations, leading in most cases to the expression of short, non-DNA binding isoforms of IKZF1. There is only a limited information about the overall frequency and prognostic impact of IKZF1 alterations in non-selected, BCR/ABL-negative ALL cohorts. Using a simplified yet efficient approach based on expression assay described by Iaccobucci et al. together with Agilent-on-chip semi-quantitative electrophoresis, we examined the expression of IKZF1 transcript variants in diagnostic bone marow (BM) samples from 94 children with Ph- ALL. The patients were diagnosed between November 2002 and December 2004 and treated by ALL IC-BFM 2002 protocol. Based on the analysis of peripheral blood from healthy donors and remission BM samples, we determined physiological range for relative expression of IKZF1 isoforms. The ratio between non-DNA binding (IK4, IK4del, IK4A, IK8) and functional IK1 and IK2 isoforms was significantly elevated in 26 of 94 patients (28%). There were no associations between elevated short/long isoforms ratio and age, WBC, ALL IC risk group, TEL/AML1 or hyperdiploidy. Considering the key role of Ikaros in lymphoid lineage specification, we tested whether its altered expression was related to the expression of myeloid markers on leukemic blasts. Neither short/long isoforms ratio, nor single transcript variant expression had any relation to the level of myeloperoxidase (MPO), CD13, CD33, CD65, CD117, CD14 or CD15 expression estimated by flow cytometry. Patients having the short/long isoforms ratio more than 80% had a 5-year RFS 66.7±13.6% compared to 87.5±4.1% in other patients (p=0.04). The main difference between leukemic and normal samples was observed in the relative expression of IK6 dominant-negative isoform. Using a cut-off of 10%, 14 of 94 (15%) ALL samples had increased IK6 expression in relation to other isoforms. Only 2 of 94 patients (2%) expressed IK6 alone. Elevated relative IK6 expression in the range 10-20% (6 patients) had no prognostic impact. Using a cut-off of 20%, 5-year RFS survival was 90.2± 3.3% in the group with low IK6 expression compared to 37.5±17.1% in patients with the high expression (p<0.0001). With the cut-off of 50%, RFS was 20±17.9% in the IK6 high expression group compared to 89.4±3.3% in the group with low expression (p<0.0001). Of the 5 patients with IK6 expression higher than 50%, two were treated in ALL IC HR group (based on poor prednisone response), one in the intermediate risk and two in the standard risk group, based on WBC, age and BM status at day 15. Only 1 of 4 patients with available MRD would be classified as MRD-HR based on MRD higher than 10−3 at week 12. Surprisingly, elevated relative expression of IK4, IK4del, IK4A and IK8 (all non-DNA binding isoforms) had no prognostic impact. The absolute level of IKZF1 expression, which might have indicated IKZF1 haploinsufficiency, had no prognostic impact either. In conclusion, we showed that a substantial proportion of childhood Ph-negative ALL cases had an increased expression of short, non-DNA binding Ikaros transcripts. However, only elevated expression of the IK6 isoform had prognostic impact. Patients with IK6 expression higher than 50% (5% of all patients) had very poor prognosis. The method used in this study could serve as a rapid screening for a new subgroup of HR patients with ALL. Supported by GA UK 7393/2007, MSMT NPV 2B06064, VZ MSM 0021620813 and MZ 000064203. Disclosures No relevant conflicts of interest to declare.

Pediatric Precursor-B ALL with BTG1 Deletions Show a Distinct Genomic Profile.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3244-3244
Author(s):  
Esmee Waanders ◽  
Frank N. van Leeuwen ◽  
Eugene Verwiel ◽  
Simon V van Reijmersdal ◽  
Marloes R Levers ◽  
...  
Keyword(s):  
B Cell ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
B Cell Differentiation ◽  
Chi Square ◽  
Genome Wide ◽  
Intron 1 ◽  
Number Variation ◽  
Unselected Cohort

Abstract Abstract 3244 Poster Board III-181 Recent genome-wide profiling studies have revealed that childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent microdeletions, including the cell cycle regulator CDKN2A, the B-cell differentiation genes PAX5, EBF1 and IKZF1 (Ikaros) and the anti-proliferative gene B-cell translocation gene 1 (BTG1). In a previous study, we have shown that BTG1 is an important determinant of glucocorticoid sensitivity (Van Galen et al. Blood/ ASH Annual Meeting Abstracts, 2008). In the present study we have characterized these cases in more detail and elucidated the frequency of recurrent lesions in BTG1 deletion cases. Using locus-specific MLPA screening of an unselected cohort of 305 precursor B-ALL cases, we identified 26 microdeletions (8.5%). All deletions encompassed BTG1 only. We were able to genomically profile 22 diagnosis samples using Affimetrix SNP6.0 arrays. Of these, 12 did not develop a relapse during a minimal of 4,5 years of follow up. The mean number of CNVs was 29.6 of which 10.3 gains and 22.5 losses (median size 512 kb and 115 kb respectively). BTG1 deletions were generally focal, varying in size from 104 kb to 1,4 Mb. In all but one patient the breakpoints at the 5' end of the deletion tightly clustered and subsequent fine-mapping using qPCR revealed that this breakpoint cluster was located within intron 1 of the BTG1 gene. At the 3'end of the deletion, four breakpoint clusters could be identified. Analysis of the copy number variation (CNV) profiles showed that patients with a BTG1 deletion more often harbored a deletion in IKZF1 compared to an unselected cohort of pre-B ALL cases (27% vs 7%, chi-square p=0.042). In contrast, recurrent CNVs like PAX5, EBF1 and CDKN2A/B occur in similar frequencies (23%, 9% and 32% vs 17%, 0% and 23% respectively). In addition, the BTG1 deletion cases that developed into a relapse showed significantly more often a deletion in CDKN2A/B compared to the BTG1 deletion cases that did not develop a relapse (60% vs 8%, p=0.02). Together, these data indicate that pediatric precursor-B ALL carrying BTG1 deletions have distinct genomic profiles, showing increased frequencies of deletions in IKZF1 and CDKN2A. Disclosures No relevant conflicts of interest to declare.

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