Immunologic, cytogenetic, and clinical characterization of childhood acute lymphoblastic leukemia with the t(1;19) (q23; p13) or its derivative.

1994 ◽  
Vol 12 (12) ◽  
pp. 2601-2606 ◽  
Author(s):  
C H Pui ◽  
S C Raimondi ◽  
M L Hancock ◽  
G K Rivera ◽  
R C Ribeiro ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Event Free Survival ◽  
Balanced Translocation ◽  
Free Survival ◽  
Antigen Profile ◽  
Treatment Responses

PURPOSE To evaluate the immunophenotypes, karyotypes, and clinical features, including treatment responses, of patients with childhood acute lymphoblastic leukemia (ALL) and either a t(1;19)(q23;p13) or a der(19)t(1;19)(q23;p13) translocation. PATIENTS AND METHODS The lymphoblasts of 45 patients with a balanced translocation, t(1;19) or its derivative form, der(19)t(1;19), were analyzed by cytogenetic and immunologic methods for differences that might suggest distinct subtypes of ALL. This cohort was treated in four consecutive clinical trials with a median overall follow-up duration of 7 years. RESULTS A pre-B immunophenotype was found in 10 cases with the balanced t(1;19) and 31 with the unbalanced der(19)t(1;19). The four remaining cases, each with a derivative t(1;19), were classified as early pre-B ALL. The characteristic surface antigen profile of the 41 pre-B cases was CD19+/CD10+/CD22+/CD34-/CD20+/-, whether the translocation was balanced or derivative. In contrast to the four early pre-B cases, which had hyperdiploid karyotypes (> 50 chromosomes), the pre-B cases were primarily pseudodiploid. Comparison of presenting clinical and laboratory features, as well as event-free survival, failed to disclose any differences that would warrant separation of pre-B cases with a balanced or derivative translocation. However, neither subgroup responded to therapy as well as patients with early pre-B ALL, each of whom remains in complete remission for > or = 3 years. CONCLUSION The t(1;19) and the der(19)t(1;19) identify a relatively homogeneous group of patients with pre-B ALL, who can be expected to respond similarly to intensive chemotherapy. The exceptional cases have an early pre-B phenotype with hyperdiploid karyotypes and appear to have favorable prognosis.

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.

scholarly journals Changing the Fate of Children with Acute Lymphoblastic Leukemia (ALL) in a Limited Resources Setting

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5075-5075
Author(s):  
Yajaira Valentine Jimenez-Antolinez ◽  
Julia Esther Colunga Pedraza ◽  
José Eduardo Mares-Gil ◽  
Emma Lizeth Estrada ◽  
Jesus Mauricio Gonzalez-Diaz ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Relapse Rate ◽  
Lymphoblastic Leukemia ◽  
Limited Resource ◽  
Outcome Evaluation ◽  
Event Free Survival ◽  
Free Survival ◽  
Early Relapse

Introduction Pediatric acute Lymphoblastic Leukemia (ALL) patients have about 90% overall survival (OS) in developed countries. However, many children in low-middle income countries (LMIC) do not have access to appropriate drugs at optimal doses, a multidisciplinary medical team, laboratory resources for diagnosis and follow-up, and appropriate support therapy for morbidities and treatment-related toxicities. A 50-60% five-year OS has been reported in children with ALL in Mexico, and our center is not the exception. This low survival rate has pushed Mexican centers to develop strategies highlighting collaboration between centers with economic, research and teaching resources ("Mexico en Alianza con St. Jude MAS"), and outpatient treatment. However, each center must adapt their chemotherapy protocol to its own supplies and possibilities. We report the results of a risk adapted therapy protocol in a limited-resource treatment setting. Materials and Methods All pediatric patients with a diagnosis of ALL from January 2017 to December 2018 were classified according to risk as shown in Figure 1. Depending on risk classification, modifications to the induction, consolidation and intermediate maintenance regimens were made. The higher the risk, the higher the intensity of the regimen, as defined by the number of anthracycline doses, the presence or absence of high-dose methotrexate, and the duration of the consolidation and maintenance phases (Table 1). Demographic data is reported using distribution analysis, and the Kaplan-Meier method is used to analyze and predict overall survival, event-free survival (EFS) and relapse. Our results were compared with previous results from our institution. Results There were 35 male and 25 female patients; median age at diagnosis was 5.5. B-cell and T-cell lymphoblastic leukemia was the diagnosis in 57 (95%), and 3 (5%) patients, respectively, with a follow-up of 16 (8-30) months. Twenty-three (38%), 21 (35%), and 16 (26%) children were classified as high, intermediate and low risk ALL, respectively. After one week of corticosteroids 46 (77%) of patients had a good response. At the end of induction 53 patients had an evaluable MRD (88%), out of which 9 were positive (17%). Median follow-up was 16 (0.6-30) months. Mortality at induction was 6 (10%) patients. Very early relapse was observed in 3(5%) of patients. Estimated 2-year relapse rate was 6%, event-free survival was 84.1%, and OS was 85%. A comparison of results obtained with previous regimens (protocols 1 and 2) and the risk-adapted treatment (protocol 3) is observed in Table 2. Conclusions The implementation of a modified chemotherapy regimen based on adjusted stratification risk was associated to improved responses as reflected by MRD. A decrease in very early relapse rate to 5%, without increasing the toxicity and death during induction was observed. Periodic and prospective outcome evaluation in a limited-resource setting is fundamental to adjust and to standardize therapy. Long-term follow-up of this patient group is required to compare OS and EFS at 5 years. This is a preliminary report, but it seems that we are changing the fate of Mexican children with ALL. Disclosures Gomez-Almaguer: Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.

scholarly journals Excellent Outcome of Children with Down Syndrome (DS) and Acute Lymphoblastic Leukemia (ALL) Treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocols 00-001 and 05-001

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 761-761
Author(s):  
Uma H. Athale ◽  
Maneka Puligandla ◽  
Kristen E. Stevenson ◽  
Barbara L. Asselin ◽  
Luis A. Clavell ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Acute Lymphoblastic Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Event Free Survival ◽  
Free Survival ◽  
Children With Down Syndrome ◽  
Dana Farber Cancer Institute ◽  
Induction Failure

Abstract Background Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) are shown to have increased therapy-related morbidity and mortality. Hence, therapy modifications and/or dose-reductions are common treatment strategies for this patient (pt) population. Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols have used same risk-stratified treatment for children with and without DS and ALL. Aim: To define the toxicity profile and outcome of children with DS and de novo ALL treated on DFCI ALL Consortium therapy protocols 00-001 and 05-001 using therapy identical to non-DS patients. Methods: Demographic, clinical and outcome data of DS and non-DS patients enrolled on the DFCI ALL protocols 00-001 (2000-2004) and 05-001 (2005-2011) were analyzed. Risk categorization and protocol therapy have previously been described (J Clin Oncol 2013; 31:1202-10; Lancet Oncol 2015;16:1677-90). On both protocols, DS ALL pts were treated identically to non-DS pts without any dose reduction or modification, except for the option for DS ALL pts to receive 3 doses of leucovorin after IT methotrexate. Fisher's exact test was used to compare toxicities in the DS and non-DS pts and Gray test was used to compare the cumulative incidence of fracture and osteonecrosis. Overall survival (OS) was defined as time from registration to death. Event-free survival (EFS) was defined as time from registration to first event (defined as induction failure, relapse, second malignant neoplasm (SMN) or death due to any cause). Induction failure and induction death were included as events at time zero. Disease-free survival (DFS) was defined as time from complete remission (CR) to relapse, SMN or death. Pts without an event were censored at the last known follow-up. The Kaplan-Meier method was used for survival estimation and Greenwood's formula for calculation of 95% confidence interval (CI) of survival estimates. Outcome of DS patients was also examined using Ponte di Legno (PdL) risk group [Low risk (LR) was defined as age at diagnosis ≤ 6 yr. and white cell count < 10X109/L and, remainder as high risk (HR)].(Blood 2014;123:70-7). Two-sided p values <0.05 were considered significant. Results: Of 1286 eligible pts aged 1-18 yrs. with de novo ALL enrolled on protocols 00-001 and 05-001, 38 (3%) had DS. There was no difference in demographic or presenting clinical features between DS and non-DS ALL pts except immunophenotype (absence of T-ALL in DS vs 11.7% in non-DS, p=0.017) and presence of high hyperdiploidy (51-65 chromosomes) (8.8% in DS vs 25.1% in non-DS, p=0.027) (Table 1). Two DS-ALL pts withdrew from the study after achieving CR. There was no difference in the CR rates (DS: 100% vs non-DS: 95.2%, p=0.47) or proportion of pts with low end of induction minimal residual disease (MRD) between DS and non-DS groups (p=0.73). Toxicities were comparable except DS pts had significantly higher rates of ≥Grade 3 mucositis (data available for protocol 05-001 only) (DS: 52.0% vs. non-DS: 12.0%, p<0.001), non-CNS thrombosis/bleed (18.4% vs. 8.2%; p=0.036), and seizure (15.8% vs. 4.7%, p=0.010). DS pts also had marginally higher rate of bacterial and fungal infections (55.3% vs. 41.3%, p=0.096) (Table 2). All 38 DS pts achieved a CR and there were 4 relapses with 1 death due to disease. There were no treatment-related deaths in DS-ALL pts. With a median follow-up of 6.2 yrs. the 5-yr EFS, DFS, and OS of DS pts were similar to non-DS pts (90.7% [81.1-100.0] vs. 83.7% [81.7-85.9]; 90.7% [81.1-100.0] vs. 87.4% [85.5-89.3]; 97.1% [91.8-100.0] vs. 91.4% [89.8-93.0]), with the 95% CI overlapping for each comparison (Figures 1a and 1b). There was no difference in outcomes of DS-ALL PdL LR pts (n=13) compared to PdL HR pts (n=25) (5-yr EFS 90.0% [73.2-100.0]. vs. 91.0% [79.9-100.0]; 5-yr OS 100.0% [100.0-100.0] vs. 95.8% [88.2-100.0]). Conclusion: DS pts treated on DFCI ALL Consortium protocols without dose reduction or modifications achieved similar outcomes to non-DS pts. DS pts had a higher frequency of mucositis, infection, and seizures, but did not experience any treatment-related deaths. Other than a higher risk of thrombotic complications, they did not develop excessive toxicity to asparaginase. The low rates of relapse and toxicity-related mortality support the approach of unified therapy protocol for DS and non-DS ALL pts with emphasis on supportive care interventions to prevent toxicities. Overall and event free survival Overall and event free survival Disclosures Asselin: Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Sigma Tau Pharamceuticals: Consultancy.

scholarly journals L-Asparaginase Toxicity in the Treatment of Children and Adolescents with Acute Lymphoblastic Leukemia

2021 ◽  
Vol 10 (19) ◽  
pp. 4419
Author(s):  
Madalina-Petronela Schmidt ◽  
Anca-Viorica Ivanov ◽  
Daniel Coriu ◽  
Ingrith-Crenguta Miron
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Children And Adolescents ◽  
Lymphoblastic Leukemia ◽  
Event Free Survival ◽  
Long Term Outcomes ◽  
Term Survival ◽  
Free Survival ◽  
The Impact

Asparaginase is a basic component of chemotherapy in pediatric acute lymphoblastic leukemia (ALL) and has played a crucial role in improving the long-term survival of this disease. The objectives of this retrospective study were to elucidate the toxicity profile associated with asparaginase in children and adolescents with ALL, to analyze the impact of each type of toxicity on long-term outcomes, and to identify risk factors. We analyzed the medical charts of 165 patients diagnosed with ALL at Sf. Maria Iasi Children’s Hospital from 2010 to 2019 and treated according to a chemotherapeutic protocol containing asparaginase. The median duration of follow-up was 5 years (0.1–11.5 years). Groups of patients with specific types of toxicity were compared to groups of patients without toxicity. We found the following incidence of asparaginase-associated toxicity: 24.1% clinical hypersensitivity, 19.4% hepatotoxicity, 6.7% hypertriglyceridemia, 4.2% hyperglycemia, 3.7% osteonecrosis, 3% pancreatitis, 2.4% thrombosis, and 1.2% cerebral thrombosis. Overall, 82 patients (49.7%) had at least one type of toxicity related to asparaginase. No type of toxicity had a significant impact on overall survival or event-free survival. Being older than 14 years was associated with a higher risk of osteonecrosis (p = 0.015) and hypertriglyceridemia (p = 0.043) and a lower risk of clinical hypersensitivity (p = 0.04). Asparaginase-related toxicity is common and has a varied profile, and its early detection is important for realizing efficient and appropriate management.

scholarly journals Reduced intensity of induction does not increase the risk of relapse in childhood acute lymphoblastic leukemia - A multi-centric clinical study of GD-2008-ALL protocol

2020 ◽  
Author(s):  
Xin-Yu Li ◽  
Jia-Qiang Li ◽  
Xue-Qun Luo ◽  
Xue-Dong Wu ◽  
Xin Sun ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Induction Therapy ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Event Free Survival ◽  
Childhood All ◽  
Free Survival ◽  
Reduced Intensity ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Background The prognosis of childhood acute lymphoblastic leukemia (ALL) is optimistic with a 5-year event-free survival (EFS) rate of 70%-85%. However, the major causes of mortality are chemotherapy toxicity, infection and relapse. The Guangdong(GD)-2008-ALL collaborative protocol was carried out to study the effect of reduced intensity in terms of duration in ALL chemotherapy on chemotherapy related mortality. The study was designed to elucidate weather the reduced intensity of induction is effective and safe for children with ALL, compared with Berlin-Frankfurt-Münster (BFM) backbone treatment. Methods The clinical data was obtained from February 28, 2008 to June 30, 2016. A total of 1,765 childhood ALL cases from 9 medical centers were collected and data was retrospectively analyzed. Bone marrow morphology, prednisone response, age, genotype, and karyotype information was evaluated for the stratification of chemotherapy intensity. Patients were stratified into 3 groups: standard risk (SR), intermediate risk (IR) and high risk (HR). The dose of cyclophosphamide (CTX), Cytarabine (Ara-c) and 6-mercaptopurine (6-MP) during induction for the SR group was half that of the BFM backbone treatment. Results The 5-year and 8-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 83.5±0.9% and 83.1±1.0%, 71.9±1.1% and 70.9±1.2%, and 19.5±1.0% and 20.5±1.1%, respectively. The 2-year treatment-related mortality (TRM) was 5.2±0.5%. The 5-year and 8-year OS were 90.7±1.4% and 89.6±1.6% in the SR group, while the 5-year and 8-year EFS were 81.5±1.8% and 80.0±2.0%. In the SR group, 74 (15.2 %) patients measured minimal residual disease (MRD) on Day 15 and Day 33 of induction therapy. Among them, 7 patients (9.46%) were MRD positive (≥ 0.01%) on Day 33. The incidence of relapse in the MRD Day33 positive group (n=7) was 28.6%, while the incidence of relapse in the MRD Day33 negative group (n=67) was 7.5% (p=0.129).Conclusions The results of GD-2008-ALL protocol are outstanding for reducing treatment related mortality in childhood ALL in China with excellent long term EFS. This protocol provided the evidence for further reducing intensity of induction therapy in the SR group according to the risk stratification. MRD levels on Day 15 and Day 33 are appropriate indexes for stratification.

Prognostic Significance of Blasts in the Cerebrospinal Fluid Without Pleiocytosis or a Traumatic Lumbar Puncture in Children With Acute Lymphoblastic Leukemia: Experience of the Dutch Childhood Oncology Group

2006 ◽  
Vol 24 (15) ◽  
pp. 2332-2336 ◽  
Author(s):  
D. Maroeska W.M. te Loo ◽  
Willem A. Kamps ◽  
Anna van der Does-van den Berg ◽  
Elisabeth R. van Wering ◽  
Siebold S.N. de Graaf
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lumbar Puncture ◽  
Cox Regression ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Event Free Survival ◽  
Free Survival ◽  
Cox Regression Analysis ◽  
Significant Difference

Purpose To determine the significance of blasts in the CSF without pleiocytosis and a traumatic lumbar puncture in children with acute lymphoblastic leukemia (ALL). Patients and Methods We retrospectively studied a cohort of 526 patients treated in accordance with the virtually identical Dutch protocols ALL-7 and ALL-8. Patients were classified into five groups: CNS1, no blasts in the CSF cytospin; CNS2, blasts present in the cytospin, but leukocytes less than 5/μL; CNS3, blasts present and leukocytes more than 5/μL. Patients with a traumatic lumbar puncture (TLP; > 10 erythrocytes/mL) were classified as TLP+ (blasts present in the cytospin) or TLP− (no blasts). Results Median duration of follow-up was 13.2 years (range, 6.9 to 15.5 years). Event-free survival (EFS) was 72.6% (SE, 2.5%) for CNS1 patients (n = 304), 70.3% (SE, 4.7%) for CNS2 patients (n = 111), and 66.7% (SE, 19%) for CNS3 patients (n = 10; no significant difference in EFS between the groups). EFS was 58% (SE, 7.6%) for TLP+ patients (n = 62) and 82% (SE, 5.2%) for TLP− patients (n = 39; P < .01). Cox regression analysis identified TLP+ status as an independent prognostic factor (risk ratio, 3.5; 95% CI, 1.4 to 8.8; P = .007). Cumulative incidence of CNS relapses was 0.05 and 0.07 in CNS1 and CNS2 patients, respectively (not statistically significant). Conclusion In our experience, the presence of a low number of blasts in the CSF without pleiocytosis has no prognostic significance. In contrast, a traumatic lumbar puncture with blasts in the CSF specimen is associated with an inferior outcome.

p16INK4a immunocytochemical analysis is an independent prognostic factor in childhood acute lymphoblastic leukemia

Blood ◽  
2002 ◽  
Vol 99 (7) ◽  
pp. 2620-2623 ◽  
Author(s):  
Jean Hughes Dalle ◽  
Martine Fournier ◽  
Brigitte Nelken ◽  
Françoise Mazingue ◽  
Jean-Luc Laı̈ ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Prognostic Factor ◽  
Lymphoblastic Leukemia ◽  
Independent Prognostic Factor ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Significant Prognostic Factor ◽  
Event Free Survival ◽  
Childhood All ◽  
Free Survival ◽  
First Relapse

We investigated the prognostic value of p16INK4aimmunocytochemistry (ICC) analysis in 126 cases of newly diagnosed childhood acute lymphoblastic leukemia (ALL). The incidence of negative p16INK4a ICC was 38.1% and was more frequent in T-lineage ALL. Overall survival (OS) and event-free survival (EFS) were significantly higher in patients with positive p16INK4a ICC than in patients with negative ICC (6 years OS, 90% versus 63%,P = .0014; 6 years EFS, 77.8% versus 55%,P = .0033). The p16INK4a ICC remained a significant prognostic factor within the subgroup of B-precursor ALL. Multivariate analysis showed that negative p16INK4a ICC was an independent prognostic factor for OS (relative risk [RR], 3.38;P = .02) and EFS (RR, 2.49; P = .018). Sequential study showed that p16INK4a expression remained stable during first relapse in most patients. These findings indicate that p16INK4a ICC is an independent factor of outcome in childhood ALL.

scholarly journals 12p Abnormalities and the TEL Gene (ETV6) in Childhood Acute Lymphoblastic Leukemia

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4559-4566 ◽  
Author(s):  
S.C. Raimondi ◽  
S.A. Shurtleff ◽  
J.R. Downing ◽  
J. Rubnitz ◽  
S. Mathew ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Genetic Material ◽  
Fusion Transcript ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Similar Distribution ◽  
Event Free Survival ◽  
Childhood All ◽  
Free Survival ◽  
The Status

Abstract Although abnormalities involving the short arm of chromosome 12 (12p) are one of the most frequently observed rearrangements in childhood acute lymphoblastic leukemia (ALL), little is known about the frequency of different structural abnormalities and their relationship to the status of the ETV6 (also named TEL) gene in this region. Of 815 children with newly diagnosed ALL, 94 (11.5%) had a total of 104 cytogenetic 12p abnormalities. Loss of genetic material was observed in 67 (64%) of these abnormalities. Cases with 12p alterations had a much lower frequency of hyperdiploidy greater than 50 (7%) than did the ALL population in general, but these cases had a similar distribution of immunophenotype and similar 5-year event-free survival (70% ± 5% SE v 64% ± 2%, P = .64). Rearrangement of the ETV6 gene was identified in 36 (56%) of 64 cases evaluated. The ETV6-CBFA2 (TEL-AML1) fusion transcript was found in 25 (66%) of 38 cases evaluated, and all but one of these showed ETV6 rearrangement. Importantly, ETV6 rearrangement was associated with a favorable prognosis (5-year event-free survival: 89% ± 6% v 60% ± 1%, P < .01). We conclude that most but not all 12p cytogenetic abnormalities in childhood ALL involve ETV6, and that rearrangement of ETV6 is associated with a favorable treatment outcome.

scholarly journals Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia

Blood ◽  
2009 ◽  
Vol 114 (7) ◽  
pp. 1383-1386 ◽  
Author(s):  
Marc Ansari ◽  
Géraldine Sauty ◽  
Malgorzata Labuda ◽  
Vincent Gagné ◽  
Caroline Laverdière ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Nucleotide Polymorphisms ◽  
Event Free Survival ◽  
Free Survival ◽  
Gene Reporter Assay ◽  
Leukemia Treatment ◽  
Treatment Responses ◽  
Gene 4

Abstract Methotrexate and 6-mercaptopurine, important components of acute lymphoblastic leukemia treatment, are substrates for multidrug resistance-associated protein MRP4. Eight single nucleotide polymorphisms were analyzed in MRP4 gene, and 4 variants were identified as tagSNPs with frequency more than or equal to 5%. They were investigated for association with treatment responses in 275 children with acute lymphoblastic leukemia. The TC genotype of the regulatory T-1393C polymorphism was associated with better event-free survival (P = .02) and lower methotrexate plasma levels (P = .01). The CA genotype of A934C (Lys304Asn) substitution correlated in contrast with lower event-free survival (P = .02) and higher frequency of high-grade thrombocytopenia (P = .01). Gene reporter assay showed that the promoter haplotype uniquely tagged by the C-1393 allele conferred higher promoter activity compared with remaining haplotypes (P < .001). Further analyses are needed to replicate this pilot study and get closer insight into the functional effect of these polymorphisms.

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