The circadian schedule for childhood acute lymphoblastic leukemia maintenance therapy does not influence event-free survival in the NOPHO ALL92 protocol

Abstract Abstract 2577 Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have an inferior prognosis compared to non-DS ALL patients. We reviewed Methotrexate (MTX)/Mercaptopurine (6MP) maintenance therapy data for children with DS treated according to the NOPHO ALL92 or the NOPHO ALL2000 protocols between 1992 and 2007. The five year event-free survival (pEFS5y) for the DS patients was inferior to the non-DS patients (0.50 ± 0.07 vs 0.77 ± 0.01, p<0.001). The 48 DS patients in 1st remission at the beginning of maintenance therapy had pEFS10y below the 522 non-DS control patients (pEFS10y: 0.58, 95%-CI 0.43–0.77 vs. 0.83, 95%-CI 0.80–0.86, p<0.0001). The DS patients received lower median doses of MTX (Median: 11.8 vs 15.4, p<0.0001) and 6MP (median: 45.6 vs. 59.4, p<0.0001). In Cox regression analysis male gender, presence of DS, and high median maintenance therapy white blood cell levels (mWBC) were associated with increased risk for relapse. The mWBC hazard ratio for DS-ALL patients was 2.0, p<0.0005). This supports that DS children with ALL should be treated as vigorously as non-DS ALL patients. Obtaining WBC levels within target range could potentially increase their cure rates. Figure 1: Kaplan-Meier curves for event free survival for DS and non-DS children. Figure 1:. Kaplan-Meier curves for event free survival for DS and non-DS children. Non-DS 513 464 443 433 418 DS 47 25 19 12 6 Disclosures: No relevant conflicts of interest to declare.

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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

10.21203/rs.3.rs-25689/v1 ◽

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.

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

Blood ◽

10.1182/blood.v99.7.2620 ◽

2002 ◽

Vol 99 (7) ◽

pp. 2620-2623 ◽

Cited By ~ 16

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.

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

Blood ◽

10.1182/blood.v90.11.4559 ◽

1997 ◽

Vol 90 (11) ◽

pp. 4559-4566 ◽

Cited By ~ 52

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.

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The outcomes of childhood acute lymphoblastic leukemia with hyperleukocytosis

Paediatrica Indonesiana ◽

10.14238/pi58.4.2018.186-91 ◽

2018 ◽

Vol 58 (4) ◽

pp. 186-91

Author(s):

Din Alfina ◽

Pudjo Hagung Widjajanto ◽

Suryono Yudha Patria

Keyword(s):

Overall Survival ◽

Acute Lymphoblastic Leukemia ◽

Survival Rate ◽

Lymphoblastic Leukemia ◽

Tumor Lysis Syndrome ◽

Childhood Acute Lymphoblastic Leukemia ◽

Significant Prognostic Factor ◽

Bleeding Tendency ◽

Event Free Survival ◽

Free Survival

Background Hyperleukocytosis in childhood acute lymphoblastic leukemia (ALL) is an emergency in oncology. This condition showed high mortality and relapse rates, as well as low survival rate. The outcomes of this group of patients are not yet well studied. Objective To evaluate the characteristics and outcomes of childhood acute lymphoblastic leukemia (ALL) with hyperleukocytosis. Methods This was a retrospective cohort study. The patients were children less than 18 year of age who were diagnosed as ALL in Dr. Sardjito Hospital, Yogyakarta, from January 1st 2010 to November, 30th 2016. Event-free survival rate and overall survival rate were estimated for group of patients with the white blood cell (WBC) groups 50-200x109/L and >200x109/L using the Kaplan-Meier method. Results There were 705 children diagnosed as ALL during the study period, 129 (18%) with hyperleukocytosis and 111 of them met the inclusion criteria, consisted of 76 children in a group of WBC 50-200 x 109/L and 35 children in a group of WBC >200 x 109/L. Presentation at diagnosis: median age were 7 years (range 1 month-18 years), male was 1.5 higher than female, 92% of cases with lymphoid infiltration, 5% with CNS involvement, 40% had bleeding tendency, and 10% had clinical tumor lysis syndrome (TLS). Median WBC was 122 (range 53.4-876) x 109/L; mean Hb was 8 (SD 3) g/dL; median platelet count was 30 (range 1-221) x 109/L. Immunophenotyping was done in 23 patients, 5/23 (8%) was T cell. The patients in lower WBC group showed lower death (26% vs. 34%, P=0,389), higher two-year event-free survival (EFS) 68% vs. 45%, P=0.003, and overall survival (77% vs. 68%, P= 0.16), compared to patients in higher WBC group. Univariate and multivariate Cox regression analyses revealed that none of the variables was a significant prognostic factor for 2 years EFS or overall survival. Conclusion The group of children with ALL and hyperleukocytosis with lower WBC at diagnoses showed better outcomes than the higher WBC.

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Association of ITPA Genotype with Event-Free Survival and Relapse Rates in Children with Acute Lymphoblastic Leukemia Undergoing Maintenance Therapy

PLoS ONE ◽

10.1371/journal.pone.0109551 ◽

2014 ◽

Vol 9 (10) ◽

pp. e109551 ◽

Cited By ~ 6

Author(s):

Alenka Smid ◽

Natasa Karas-Kuzelicki ◽

Miha Milek ◽

Janez Jazbec ◽

Irena Mlinaric-Rascan

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Maintenance Therapy ◽

Lymphoblastic Leukemia ◽

Event Free Survival ◽

Free Survival ◽

Relapse Rates

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Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia

Blood ◽

10.1182/blood.v100.10.3832 ◽

2002 ◽

Vol 100 (10) ◽

pp. 3832-3834 ◽

Cited By ~ 158

Author(s):

Caroline Laverdière ◽

Sonia Chiasson ◽

Irina Costea ◽

Albert Moghrabi ◽

Maja Krajinovic

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Plasma Levels ◽

Lymphoblastic Leukemia ◽

Underlying Mechanism ◽

The Other ◽

Childhood Acute Lymphoblastic Leukemia ◽

Reduced Folate Carrier ◽

Event Free Survival ◽

Childhood All ◽

Free Survival

Methotrexate (MTX) is a key compound of chemotherapeutic regimens used in the treatment of childhood acute lymphoblastic leukemia (ALL). Resistance to this drug may arise by, among other factors, altered cellular uptake that may hamper the efficacy of the treatment. Recently, a G80A polymorphism has been described in the reduced folate carrier gene (RFC1), which encodes the major MTX transporter. Here, we assessed the association between the genetic polymorphisms G80A and both MTX plasma levels and childhood ALL outcome. Children with the A80 variant had worse prognoses than patients with the GG genotype (P = .04), as shown by event-free survival estimates. Patients homozygous for A80 had higher levels of MTX (P = .004) than the other genotype groups. Possible explanations for observed associations are discussed; however, additional experiments are required to achieve understanding of the underlying mechanism.

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CNS-Directed Therapy for Childhood Acute Lymphoblastic Leukemia: Childhood ALL Collaborative Group Overview of 43 Randomized Trials

Journal of Clinical Oncology ◽

10.1200/jco.2003.08.047 ◽

2003 ◽

Vol 21 (9) ◽

pp. 1798-1809 ◽

Cited By ~ 97

Author(s):

M. Clarke ◽

P. Gaynon ◽

I. Hann ◽

G. Harrison ◽

G. Masera ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Childhood Acute Lymphoblastic Leukemia ◽

Intrathecal Therapy ◽

Event Free Survival ◽

Childhood All ◽

Free Survival ◽

Significant Difference ◽

Different Types

Purpose: A collaborative meta-analysis was performed to clarify the relative effects on relapse and survival of different types of therapies directed at the CNS in childhood acute lymphoblastic leukemia. Materials and Methods: Data were sought for each individual patient in all trials started in or before 1993 that included unconfounded randomized comparisons of such treatments. Log-rank survival analyses were performed for each trial, and overall results for groups of trials addressing similar questions were obtained from the totals of the observed minus expected number of events and their variances. Results: Radiotherapy and long-term intrathecal therapy gave similar outcomes, with no significant difference in event-free survival despite random assignment of treatment to 2,848 patients, 1,001 of whom suffered relapse or death. Intravenous methotrexate reduced non-CNS rather than CNS relapses, and hence, the addition of intravenous methotrexate to a treatment regimen including radiotherapy or long-term intrathecal therapy improved event-free survival, with a 17% reduction in the event rate (95% confidence interval, 6% to 27%; P = .003). The event-free survival at 10 years in these trials was 61.9% without intravenous methotrexate and 68.1% with intravenous methotrexate. There was no significant difference in survival (14% death rate reduction; P = .09). There were insufficient randomly assigned patients to adequately address other questions, such as effect of different doses. No evidence was found of differences, between trials or between subgroups of different types of patients, in the relative effects of treatment. Conclusion: Radiotherapy can be replaced by long-term intrathecal therapy. Intravenous methotrexate gives some additional benefit by reducing non-CNS relapses.

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

Journal of Clinical Oncology ◽

10.1200/jco.1994.12.12.2601 ◽

1994 ◽

Vol 12 (12) ◽

pp. 2601-2606 ◽

Cited By ~ 66

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.

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