Low numbers of CSF blasts at diagnosis do not predict for the development of CNS leukemia in children with intermediate-risk acute lymphoblastic leukemia: a Childrens Cancer Group report.

PURPOSE This study was designed to evaluate the effect on CNS relapse (CNSR) and overall relapse rates of blast cells in the CSF containing < or = 5 cells/microL at the time of diagnosis of intermediate-risk acute lymphoblastic leukemia (ALL) in children entered onto a large randomized multicenter prospective therapeutic trial (Childrens Cancer Group [CCG]-105). PATIENTS AND METHODS We studied outcome in terms of CNSR and event-free survival (EFS) in 1,544 patients who successfully completed remission-induction therapy and had been randomized to one of four systemic chemotherapy regimens and to one of two CNS prophylaxis regimens. We compared outcome between 1,450 patients who had varying degrees of pleocytosis but no blasts in the CSF at diagnosis (blast-negative group) with 94 who had blasts detected in the CSF after cytocentrifugation but had a total CSF WBC count of < or = 5/microL (blast-positive group). RESULTS No statistically significant differences in overall CNSR or EFS rates were observed between the two groups and no differences were found when analyzed according to age or WBC count at diagnosis, sex, or type of CNS prophylaxis (intrathecal [IT] methotrexate [MTX] alone v IT MTX plus 18 Gy cranial irradiation [CXRT]). CONCLUSION In intermediate-risk ALL, there was no significant difference in CNSR and systemic relapse rates after standard presymptomatic CNS therapy between patients with a CSF WBC count < or = 5/microL and those without identifiable blasts in the CSF. These findings suggest that certain approaches to therapy, such as that used in this study, may eliminate the need for any additional special treatment directed at this subset of patients with CSF blasts.

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Intensification With Intermediate-Dose Intravenous Methotrexate Is Effective Therapy for Children With Lower-Risk B-Precursor Acute Lymphoblastic Leukemia: A Pediatric Oncology Group Study

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.6.1285 ◽

2000 ◽

Vol 18 (6) ◽

pp. 1285-1294 ◽

Cited By ~ 32

Author(s):

Donald H. Mahoney ◽

Jonathan J. Shuster ◽

Ruprecht Nitschke ◽

Stephen Lauer ◽

C. Philip Steuber ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lower Risk ◽

Lymphoblastic Leukemia ◽

Effective Therapy ◽

Remission Induction ◽

Intrathecal Therapy ◽

Continuation Therapy ◽

Increased Risk ◽

Significant Difference ◽

Prevention Of Relapse

PURPOSE: To determine whether early intensification with 12 courses of intravenous (IV) methotrexate (MTX) and IV mercaptopurine (MP) is superior to 12 courses of IV MTX alone for prevention of relapse in children with lower-risk B-lineage acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Six hundred fifty-one eligible patients were entered onto the study. Vincristine, prednisone, and asparaginase were used for remission induction therapy. Patients were randomized to receive intensification with IV MTX 1,000 mg/m2 plus IV MP 1,000 mg/m2 (regimen A) or IV MTX 1,000 mg/m2 alone (regimen C). Twelve courses were administered at 2-week intervals. Triple intrathecal therapy was used for CNS prophylaxis. Continuation therapy included standard oral MP, weekly MTX, and triple intrathecal therapy every 12 weeks for 2 years. RESULTS: Six hundred forty-five patients (99.1%) achieved remission. Three hundred twenty-five were assigned to regimen A and 320 to regimen C. The estimated 4-year overall continuous complete remission for patients treated with regimen A is 82.1% (SE = 2.4%) and for regimen C is 82.2% (SE = 2.6%; P = .5). No significant difference in overall outcome was shown by sex or race. Serious grade 3/4 neurotoxicity, principally characterized by seizures, was observed in 7.6% of patients treated with either regimen. CONCLUSION: Intensification with 12 courses of IV MTX is an effective therapy for prevention of relapse in children with B-precursor ALL who are at lower risk for relapse but may be associated with an increased risk for neurotoxicity. Prolonged infusions of MP combined with IV MTX did not provide apparent advantage.

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Study on the Phenotype Polymorphism of CYP3A4 Gene in Chinese Children with Acute Leukemia.

Blood ◽

10.1182/blood.v104.11.4376.4376 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4376-4376

Author(s):

Xiao-jun Yuan ◽

Long-Jun Gu ◽

Hui-jun Zhao ◽

Jin-cai Zhao ◽

Jing-Yan Tang ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Acute Leukemia ◽

Risk Group ◽

Lymphoblastic Leukemia ◽

Healthy Children ◽

Cyp3a4 Activity ◽

Significant Difference ◽

Average Activity ◽

Cyp3a4 Gene ◽

Wbc Count

Abstract In order to offer objective refering paramete for individualized chemotherapy, to clarify the distribution feature of CYP3A4 activity in Chinese children with acute leukemia and in healthy children, to explore the possible correlation between the activity of CYP3A4 gene and the predisposition or chemotherapy effect in acute leukemia children. High performance liquid chromatography (HPLC) was used to detecte the activity of CYP3A4 in 85 healthy children and 120 acute leukemia children, then analyzed the difference of phenotypebetween two groups. The activity coverage of CYP3A4 was 2.34~48.88 in healthy children and the average activity was 9.76±6.99. Among them, CYP3A4 activity was 11.88±8.88 in male group and 7.12±3.37 in female group, the former was obviously higher than the latter (P=0.0077). In less than 12-years group, CYP3A4 activity was 8.97±6.27, while it was 10.43±7.74 in more than 12-years group, there was no significant difference (P>0.05). The change scope of CYP3A4 activity was very large in children with acute lymphoblastic leukemia, from 2.00 to 585.72, the average activity was 53.52, with no dfference in sex and age. According to the clinical risk degree, the activity of CYP3A4 was 4.87±2.93 in standard-risk group, it was 31.63±19.20 in middle-risk group, the latter was significantly higher thanthe former (P=0.0004). Comparison based on WBC count at the beginning of preliminary diagnosis, the CYP3A4 activity was the lowest in WBC count less than 50 x 109/L group, it was second in the group of WBC count between 50 x 109/L to 100 x 109/L, and the activity was the highest in WBC count more than 100 x 109/L group. The mean activity of CYP3A4 in childern with acute lymphoblastic leukemia with P170 less than 5% was 17.56±13.44, while it was 87.62±49.28 in those children with P170 more than 5%Ä, there was statistic difference between the two group(P=0.022). The activity in those preliminary diagnosed children with BCR-ABL(+) or Ph (+) or t (4,11) abnormal karyotype (105.86±44.41) was higher than those with normal karyotype patients (47.61±22.63), P=0.0219. Comparison the activity of CYP3A4 between those chlidren with clinical presentation as prednisone good response (PGR) and those with prednisone poor response, the activity in former group (27.23±13.58) was obviously lower than that of latter group (114.12±48.39), P=0.0358. The average CYP3A4 activity in children with acute myelocytic leukemia (AML) was 13.97±10.84. Of them, it was 15.09±7.52 in AML children with diploid chromosome and only 2.95±1.39 in hypodiploidy group, obviously, the activity of former group higher than that of latter group (P=0.0132). The CYP3A4 activity was respectively 19.78±11.59 and 2.86±1.16 in normal LDH group and in increased LDH group, there was significant difference (P=0.0036). The AML children with exo-marrow infiltration when diagnosis, their CYP3A4 activity (6.50±3.05) was lower than those children with pure marrow infiltration (19.06±11.15), P=0.044. There may be no race difference between the CYP3A4 activity of Chinese healthy children and White people. Increased CYP3A4 activity has closed correlation with ALL risk factors. The general CYP3A4 activity in AML children group was lower than that of ALL chlidren group. Much higher or much lower CYP3A4 activity may produce adverse influence to individuals.

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Pentoxifylline During Steroid Window At Induction To Remission Increases Apoptosis In Childhood Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v122.21.2623.2623 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2623-2623

Author(s):

Oscar Gonzalez-Ramella ◽

Jimenez-Lopez Xochiquetzatl ◽

Sergio Gallegos-Castorena ◽

Pablo Ortiz-Lazareno ◽

Jose Manuel Lerma-Diaz ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Complete Remission ◽

Cancer Cells ◽

Lymphoblastic Leukemia ◽

Remission Induction ◽

Control Group ◽

Induction Phase ◽

Study Group ◽

Significant Difference

Abstract Introduction Acute lymphoblastic leukemia (ALL) is the most common cancer diagnostic in children, and it represents the second death cause in this population. Despite advances in the treatment of childhood ALL, there are small portion of patients whom still succumb to this disease. A reduced apoptosis in cells plays an important role in carcinogenesis. This phenomenon is an important component in the cytotoxicity induced by anticancer drugs. A currently challenge is the chemotherapy resistance of tumor cells, inhibiting the apoptosis induced by chemotherapy. Pentoxifylline, (PTX) has been studied for its role on increase of apoptosis on cancer cells by different pathways. Our group has reported its efficacy in vitro and ex vivo in increasing apoptosis induced by chemotherapy drugs such as adriamycin and cisplatin in fresh leukemic human cells, lymphoma murine models and cervical cancer cells. We conducted a phase 1 controlled randomized trial to evaluate the efficacy of adding PTX to the steroid window during the remission induction phase in new diagnosed children with ALL. Methods We included all children from both sexes from 9 months to 17 years old during October 2011 to December 2012. Patients were divided into 3 groups, the first one as a non-malignant control group (NL group) included children with a non-hematology disease in which bone marrow aspiration (BMA) was mandatory in order to reach the diagnosis. The second one, the ALL control group whom received prednisone (PRD group) for the steroid window at 40mg/m2/day PO from day -7 to day 0; and then the third one (PTX group), the study group which included children receiving the steroid phase with PRD as early described, plus PTX at 10mg/kg/day IV divided in 3 doses, at the same days as recommended in our treatment protocol (Total Therapy XV). For all 3 groups a BMA was performed at diagnosis, for PRD group as well as PTX group, a second BMA was also collected at day 0. Apoptosis was evaluated by means of Annexin V Apoptosis Detection Kit FITC/PI (eBioscience¨, San Diego, CA, USA) in 1×106 bone marrow mononuclear cells. We measured minimal residual disease (MRD) by flow cytometry at day 14 to demonstrate complete remission in leukemic patients. Statically analysis was performed by U Man Whitney. Results We enrolled 32 patients: 10 in NL group; 11 in PRD group; and 11 in PTX group. The median age of all groups was 6 years (range 9 months-17 years). In PRD group, patient 1 abandoned treatment after administration of day 0, nevertheless the second BMA sample was collected. Patient number 7 died at day 4 due to complications from tumor lysis syndrome. Consequently, in these patients we were not able to measure MRD and BM aspiration at day 14. Except one patient in PRD group, all achieved complete remission at day 14. We did not find any significant difference between NL group and PRD and PTX groups before intervention (U=32 p=0.7; U=28.5 p=0.48 respectively). There was no significant difference between treatment groups before intervention (U= 37 p=0.79). However, after treatment we found an important difference between PRD and PTX groups, we observed an increase in apoptosis in PTX group in comparison with PRD group (U=17.5 p=0.04). There were no adverse effects during treatment. Conclusions The present study is the first one that shows the efficacy of PTX in increasing apoptosis induced by PRD in new ALL diagnosed children, whom have not received any treatment yet. This might be helpful, not only in patients with relapse, but to increase the overall cure rate in ALL. Further studies are needed to prove this hypothesis. With this objective, our study group is already planning a second trial were PTX will be given during all remission induction phase. Experimental reports strongly suggest that PTX induces inhibition of the transcription factor NF-ĸB, by inhibiting survival gens and facilitating apoptosis. To prove it, we are currently processing these patients' samples to know their genetic expression. Disclosures: No relevant conflicts of interest to declare.

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Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children's Oncology Group CCG-1952 clinical trial

Blood ◽

10.1182/blood-2009-07-230656 ◽

2010 ◽

Vol 115 (14) ◽

pp. 2740-2748 ◽

Cited By ~ 52

Author(s):

Linda C. Stork ◽

Yousif Matloub ◽

Emmett Broxson ◽

Mei La ◽

Rochelle Yanofsky ◽

...

Keyword(s):

Clinical Trial ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Occlusive Disease ◽

Intrathecal Methotrexate ◽

Remission Induction ◽

Intrathecal Therapy ◽

Cancer Group ◽

Starting Dose ◽

Standard Risk

Abstract The Children's Cancer Group 1952 (CCG-1952) clinical trial studied the substitution of oral 6-thioguanine (TG) for 6-mercaptopurine (MP) and triple intrathecal therapy (ITT) for intrathecal methotrexate (IT-MTX) in the treatment of standard-risk acute lymphoblastic leukemia. After remission induction, 2027 patients were randomized to receive MP (n = 1010) or TG (n = 1017) and IT-MTX (n = 1018) or ITT (n = 1009). The results of the thiopurine comparison are as follows. The estimated 7-year event-free survival (EFS) for subjects randomized to TG was 84.1% (± 1.8%) and to MP was 79.0% (± 2.1%; P = .004 log rank), although overall survival was 91.9% (± 1.4%) and 91.2% (± 1.5%), respectively (P = .6 log rank). The TG starting dose was reduced from 60 to 50 mg/m2 per day after recognition of hepatic veno-occlusive disease (VOD). A total of 257 patients on TG (25%) developed VOD or disproportionate thrombocytopenia and switched to MP. Once portal hypertension occurred, all subjects on TG were changed to MP. The benefit of randomization to TG over MP, as measured by EFS, was evident primarily in boys who began TG at 60 mg/m2 (relative hazard rate [RHR] 0.65, P = .002). The toxicities of TG preclude its protracted use as given in this study. This study is registered at http://clinicaltrials.gov as NCT00002744.

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DNA-thioguanine nucleotide as a treatment marker in acute lymphoblastic leukemia patients with NUDT15 variant genotypes

PLoS ONE ◽

10.1371/journal.pone.0245667 ◽

2021 ◽

Vol 16 (1) ◽

pp. e0245667

Author(s):

Hee Young Ju ◽

Ji Won Lee ◽

Hee Won Cho ◽

Ju Kyung Hyun ◽

Youngeun Ma ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Wild Type ◽

Spectrometry Method ◽

Chromatography Tandem Mass Spectrometry ◽

Individual Variations ◽

Significant Difference ◽

Liquid Chromatography Tandem Mass ◽

Thioguanine Nucleotide ◽

Wbc Count

Background Large inter-individual variations in drug metabolism pose a challenge in determining 6-mercaptopurine (6MP) doses. As the last product of 6MP metabolism, DNA-thioguanine nucleotide (DNA-TGN) could reflect the efficacy of 6MP, especially in patients harboring variants in the 6MP metabolism pathway. The aim of this study was to investigate the clinical significance of DNA-TGN monitoring in Korean pediatric acute lymphoblastic leukemia (ALL) patients, focusing on the NUDT15 genotype. Methods The subjects of this study were patients who underwent ALL treatment with 6MP. Tests for the NUDT15 and TPMT genotypes were performed, and prospective DNA-TGN and erythrocyte TGN samples were collected after two weeks or more of 6MP treatment. DNA-TGN was quantified using the liquid chromatography-tandem mass spectrometry method. Results A total of 471 DNA-TGN measurements in 71 patients were analyzed, which ranged from 1.0 to 903.1 fmol thioguanine/μg DNA. The 6MP intensity demonstrated a significant relationship with DNA-TGN concentration (P<0.001). Patients harboring NUDT15 variants were treated with a lower dose of 6MP (P<0.001); however, there was no significant difference in DNA-TGN concentration when compared to patients carrying wild-type NUDT15 (P = 0.261). These patients also presented higher variation in DNA-TGN levels (P = 0.002) and DNA-TGN/6MP intensity (P = 0.019) compared to patients carrying wild-type NUDT15. DNA-TGN concentration did not show a significant correlation with WBC count (P = 0.093). Conclusions Patients harboring NUDT15 variants demonstrated similar DNA-TGN concentrations even at low doses of 6MP and showed high variability in DNA-TGN. Particularly in patients with NUDT15 variants who need a reduced 6MP dose, DNA-TGN could be applied as a useful marker to monitor the therapeutic effect of 6MP.

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Prevention of CNS disease in intermediate-risk acute lymphoblastic leukemia: comparison of cranial radiation and intrathecal methotrexate and the importance of systemic therapy: a Childrens Cancer Group report.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.3.520 ◽

1993 ◽

Vol 11 (3) ◽

pp. 520-526 ◽

Cited By ~ 110

Author(s):

D G Tubergen ◽

G S Gilchrist ◽

R T O'Brien ◽

P F Coccia ◽

H N Sather ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Survival Rate ◽

Systemic Therapy ◽

Lymphoblastic Leukemia ◽

Intrathecal Methotrexate ◽

Intermediate Risk ◽

Relapse Free Survival ◽

Free Survival ◽

Cancer Group ◽

Cns Relapse

PURPOSE This study (Childrens Cancer Group [CCG]-105) was designed in part to determine in a prospective randomized trial whether intrathecal methotrexate (IT MTX) administered during induction, consolidation, and maintenance could provide protection from CNS relapse equivalent to that provided by cranial radiation (CXRT) in children with acute lymphoblastic leukemia (ALL) and intermediate-risk features. PATIENTS AND METHODS We randomized 1,388 children with intermediate-risk ALL to the two CNS regimens. They received either IT MTX at intervals throughout their course of therapy or CXRT (18 Gy) during consolidation with IT MTX during induction, consolidation, and delayed intensification. Systemic therapy was randomized to one of four treatment regimens derived from a regimen used by CCG in recent studies for this patient population and three more intensive regimens based on the Berlin-Frankfurt-Munster trials. RESULTS Life-table estimates at 7 years show a 93% and 91% CNS relapse-free survival rate for the CXRT and IT MTX groups, respectively. The corresponding event-free survival (EFS) rates are 68% and 64%. The differences are not significant. Patients who received more intensive systemic therapy had a 94% CNS relapse-free survival rate on either CXRT or IT MTX, while patients who received standard systemic therapy had 90% and 80% rates for CXRT and IT MTX, respectively (P < .0001). Patients less than 10 years of age who received CXRT or IT MTX had 72% and 71% EFS rates if they received more intensive systemic therapy. Patients 10 years or older who received CXRT had an improved EFS (61% v 53%) with a more intensive systemic program. This was primarily due to fewer bone marrow relapses (P = .04). CONCLUSIONS IT MTX during induction, consolidation, and maintenance provides protection from CNS relapse in patients with intermediate-risk ALL equivalent to that provided by CXRT if more intensive systemic therapy is given. The CNS relapse rate with either CXRT or IT MTX is in part dependent on the associated systemic therapy. For intermediate-risk patients less than 10 years of age, IT MTX with an intensified systemic regimen provided CNS prophylaxis comparable to that provided by CXRT, whereas older patients had fewer systemic relapses if they received CXRT.

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Improved results of treatment of adult acute lymphoblastic leukemia

Blood ◽

10.1182/blood.v69.4.1242.1242 ◽

1987 ◽

Vol 69 (4) ◽

pp. 1242-1248 ◽

Cited By ~ 64

Author(s):

CA Linker ◽

LJ Levitt ◽

M O'Donnell ◽

CA Ries ◽

MP Link ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Disease Free Survival ◽

Remission Induction ◽

Induction Phase ◽

Free Survival ◽

Results Of Treatment ◽

Kaplan Meier ◽

Wbc Count ◽

Disease Free

Abstract We designed a treatment program to improve the outcome for adults with acute lymphoblastic leukemia (ALL). Treatment included a remission- induction phase followed by intensive alternating cycles of non-cross- resistant chemotherapy and prolonged oral maintenance therapy. Eighty- one consecutive previously untreated patients were entered on this study. Ninety-four percent of patients entered complete remission. A Kaplan-Meier analysis predicts that 53% +/- 9% (SEM) of patients in remission will remain free of disease at 3 years. Neither age, sex, WBC count, nor immunophenotype had a significant effect on remission duration. This program of intensive cyclical chemotherapy has improved the disease-free survival of patients with adult ALL.

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Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: a report from the Children's Cancer Group.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.3.920 ◽

1998 ◽

Vol 16 (3) ◽

pp. 920-930 ◽

Cited By ~ 83

Author(s):

J Nachman ◽

H N Sather ◽

J M Cherlow ◽

M G Sensel ◽

P S Gaynon ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Induction Therapy ◽

Lymphoblastic Leukemia ◽

Early Response ◽

Cranial Irradiation ◽

Cancer Group ◽

Pediatric All ◽

Wbc Count ◽

To Receive

PURPOSE Intensified intrathecal (i.t.) chemotherapy without cranial radiation therapy (CRT) prevents CNS relapse in children with low-risk and intermediate-risk acute lymphoblastic leukemia (ALL). In the current study, high-risk ALL patients who achieved a rapid early response (RER) to induction chemotherapy were randomized to receive intensive systemic chemotherapy and presymptomatic CNS therapy that consisted of either i.t. methotrexate (MTX) and CRT or intensified i.t. MTX alone. PATIENTS AND METHODS Children (n = 636) with high-risk ALL (aged 1 to 9 years and WBC count > or = 50,000/microL or age > or = 10 years, excluding those with lymphomatous features) who achieved an RER (< or = 25% marrow blasts on day 7) to induction therapy and lacked CNS disease at diagnosis were randomized to receive systemic therapy with either i.t. MTX and CRT (regimen A, n = 317) or intensified i.t. MTX alone (regimen B, n = 319). RESULTS Interim analysis in July 1993 revealed 3-year event-free survival (EFS) estimates of 82.1% +/- 4.0% (SD)and 70.4% +/- 4.2% for patients treated on regimens A and B, respectively (P = .004). As of January 1996, outcome had changed: 5-year EFS estimates were 69.1% +/- 3.4% and 75.0% +/- 2.7% for regimens A and B, respectively (P = 0.50). Marrow relapses comprised 57 events on regimen A and 43 events on regimen B. Fewer late events occurred on regimen B. CONCLUSION For high-risk pediatric ALL patients who show an RER to induction therapy and are treated with systemic Children's Cancer Group (CCG)-modified Berlin-Frankfurt-Munster (BFM) chemotherapy, presymptomatic CNS therapy that consists of either i.t. MTX plus CRT or intensified i.t. MTX alone results in a similar 5-year EFS outcome. Furthermore, intensified i.t. MTX may protect against late bone marrow relapse.

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Minimal Residual Disease–Guided Treatment Deintensification for Children With Acute Lymphoblastic Leukemia: Results From the Malaysia-Singapore Acute Lymphoblastic Leukemia 2003 Study

Journal of Clinical Oncology ◽

10.1200/jco.2011.40.5936 ◽

2012 ◽

Vol 30 (19) ◽

pp. 2384-2392 ◽

Cited By ~ 69

Author(s):

Allen Eng Juh Yeoh ◽

Hany Ariffin ◽

Elaine Li Leng Chai ◽

Cecilia Sze Nga Kwok ◽

Yiong Huak Chan ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Minimal Residual Disease ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Remission Induction ◽

Intermediate Risk ◽

Risk Patients ◽

Standard Risk ◽

Minimal Residual

Purpose To improve treatment outcome for childhood acute lymphoblastic leukemia (ALL), we designed the Malaysia-Singapore ALL 2003 study with treatment stratification based on presenting clinical and genetic features and minimal residual disease (MRD) levels measured by polymerase chain reaction targeting a single antigen-receptor gene rearrangement. Patients and Methods Five hundred fifty-six patients received risk-adapted therapy with a modified Berlin-Frankfurt-Münster–ALL treatment. High-risk ALL was defined by MRD ≥ 1 × 10−3 at week 12 and/or poor prednisolone response, BCR-ABL1, MLL gene rearrangements, hypodiploid less than 45 chromosomes, or induction failure; standard-risk ALL was defined by MRD ≤ 1 × 10−4 at weeks 5 and 12 and no extramedullary involvement or high-risk features. Intermediate-risk ALL included all remaining patients. Results Patients who lacked high-risk presenting features (85.7%) received remission induction therapy with dexamethasone, vincristine, and asparaginase, without anthracyclines. Six-year event-free survival (EFS) was 80.6% ± 3.5%; overall survival was 88.4% ± 3.1%. Standard-risk patients (n = 172; 31%) received significantly deintensified subsequent therapy without compromising EFS (93.2% ± 4.1%). High-risk patients (n = 101; 18%) had the worst EFS (51.8% ± 10%); EFS was 83.6% ± 4.9% in intermediate-risk patients (n = 283; 51%). Conclusion Our results demonstrate significant progress over previous trials in the region. Three-drug remission-induction therapy combined with MRD-based risk stratification to identify poor responders is an effective strategy for childhood ALL.

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