Prospective Evaluation of MRD-Kinetics in 274 Children with High-Risk ALL Treated in Trial ALL-BFM 2000: Insights into Development of Resistance and Impact on Further Refinement of Treatment Stratification Strategies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 585-585 ◽  
Author(s):  
André Schrauder ◽  
Martin Stanulla ◽  
Thomas Flohr ◽  
Gunnar Cario ◽  
Rolf Köhler ◽  
...  
Keyword(s):  
High Risk ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Initial Response ◽  
Induction Treatment ◽  
Event Free Survival ◽  
Free Survival ◽  
Development Of Resistance ◽  
Consolidation Phase ◽  
Insight Into

Abstract In trial ALL-BFM 2000, high-risk (HR) acute lymphoblastic leukemia (ALL) is defined by inadequate initial response to induction treatment [poor prednisone response on treatment day eight, non remission on treatment day 33, and/or a high load of minimal residual disease (MRD, ≥10E-3) after 12 weeks of treatment (TP2)] and/or by cytogenetics [t(4;11 or t(9;22)]. Between August 1999 and November 2006, 494 (15%) out of 3255 study patients were stratified into the HR branch of trial ALL-BFM 2000. 431 (87%) of these HR patients underwent successful MRD monitoring at TP2 with 274 (56%) patients having received additional extensive prospective MRD monitoring subsequent to TP2. Patients with an indication for stem cell transplantation (SCT) and a suitable donor were scheduled for SCT within six weeks after the third HR block of the intensive consolidation phase. The estimated 4-years event-free-survival (4y-pEFS) for the entire HR group was 68%+/−3%, estimated survival was 74%+/−3%. Patients with MRD load of ≤10E-4 at TP2 (n=231) had a 4y-pEFS of 82%+/−3%, patients with MRD levels of 10E-3 at TP2 (n=84) had a 4y-pEFS of 74%+/−6%, and patients with MRD of >10E-3 at TP2 (n=116) had a 4y-pEFS of 35%+/−5%. MRD-kinetics subsequent to TP2 revealed, that 85% of all patients with an MRD level of 10E-3 at TP2 continued to decrease their load below 10E-3 during the pulsatile intensive consolidation phase, whereas this was observed in only 35% of patients with an MRD level of >10E-3 at TP2. The 4y-pEFS of patients with an MRD load persisting at 10E-2 after application of three intensive HR blocks after TP2 was 0% if no SCT was performed, and 33%+/−11% after SCT in CR1. Our data reflect that extensive MRD measurements in HR-ALL patients allow a dynamic insight into the development of resistance, and serve as valuable tool for further clinical treatment adjustment. “MRD non-response” after three BFM HR blocks identifies a patient group in urgent need of alternative treatment elements, closely monitored by MRD, before going into SCT in CR1.

scholarly journals Results of two consecutive treatment protocols in Polish children with acute lymphoblastic leukemia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Joanna Zawitkowska ◽  
Monika Lejman ◽  
Michał Romiszewski ◽  
Michał Matysiak ◽  
Magdalena Ćwiklińska ◽  
...  
Keyword(s):  
Medical Records ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Risk Groups ◽  
Event Free Survival ◽  
Treatment Protocols ◽  
Free Survival ◽  
Impact On Survival ◽  
Oncological Centers

AbstractThe aim of the study was to retrospectively compare the effectiveness of the ALL IC-BFM 2002 and ALL IC-BFM 2009 protocols and the distribution of risk groups by the two protocols after minimal residual disease (MRD) measurement as well as its impact on survival. We reviewed the medical records of 3248 patients aged 1–18 years with newly diagnosed ALL who were treated in 14 hemato-oncological centers between 2002 and 2018 in Poland. The overall survival (OS) of 1872 children with ALL treated with the ALL IC 2002 protocol was 84% after 3 years, whereas the OS of 1376 children with ALL treated with the ALL IC 2009 protocol was 87% (P < 0.001). The corresponding event-free survival rates were 82% and 84% (P = 0.006). Our study shows that the ALL IC-BFM 2009 protocol improved the results of children with ALL compared to the ALL IC-BFM 2002 protocol in Poland. This analysis confirms that MRD marrow assessment on day 15 of treatment by FCM-MRD is an important predictive factor.

scholarly journals CD2 antigen expression on leukemic cells as a predictor of event-free survival after chemotherapy for T-lineage acute lymphoblastic leukemia: a Children's Cancer Group study

Blood ◽  
1996 ◽  
Vol 88 (11) ◽  
pp. 4288-4295 ◽  
Author(s):  
FM Uckun ◽  
PG Steinherz ◽  
H Sather ◽  
M Trigg ◽  
D Arthur ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Antigen Expression ◽  
Leukemic Cells ◽  
Event Free Survival ◽  
Free Survival ◽  
Cancer Group ◽  
Standard Risk

Abstract We examined the prognostic impact of CD2 antigen expression for 651 patients with T-lineage acute lymphoblastic leukemia (ALL), who were enrolled in front-line Childrens Cancer Group treatment studies between 1983 and 1994. There was a statistically significant correlation between the CD2 antigen positive leukemic cell content of bone marrow and probability of remaining in bone marrow remission, as well as overall event-free survival (EFS) (P = .0003 and P = .002, log-rank tests for linear trend). When compared with patients with the highest CD2 expression level (> 75% positivity), the life table relative event rate (RER) was 1.22 for patients with intermediate range CD2 expression level (30% to 75% positivity) and 1.81 for “CD2-negative” patients (< 30% positivity). At 6 years postdiagnosis, the EFS estimates for the three CD2 expression groups (low positivity to high positivity) were 52.8%, 65.5%, and 71.9%, respectively. CD2 expression remained a significant predictor of EFS after adjustment for the effects of other covariates by multivariate regression, with a RER of 1.47 for CD2- negative patients (P = .04). Analysis of T-lineage ALL patients shows a significant separation in EFS after adjustment for the National Cancer Institute (NCI) age and white blood cell (WBC) criteria for standard and high-risk ALL (P = .002, RER = 1.67). The determination of CD2 expression on leukemic cells helped identify patients with the better and poorer prognoses in both of these risk group subsets. For standard risk T-lineage ALL, CD2-negative patients had a worse outcome (P = .0007, RER = 2.92) with an estimated 5-year EFS of 55.9% as compared with 78.3% for the CD2-positive patients. Thus, CD2 negativity in standard risk T-lineage ALL identified a group of patients who had a worse outcome than high-risk T-lineage ALL patients who were CD2 positive. The percentage of CD2 antigen positive leukemic cells from T- lineage ALL patients is a powerful predictor of EFS after chemotherapy. This prognostic relationship is the first instance in which a biological marker in T-lineage ALL has been unequivocally linked to treatment outcome.

scholarly journals Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Retrospective Multinational Study

2019 ◽  
Vol 37 (10) ◽  
pp. 770-779 ◽  
Author(s):  
Ching-Hon Pui ◽  
Paola Rebora ◽  
Martin Schrappe ◽  
Andishe Attarbaschi ◽  
Andre Baruchel ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Survival Rate ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Allogeneic Transplantation ◽  
Remission Induction ◽  
Event Free Survival ◽  
Free Survival

PURPOSE We determined the prognostic factors and utility of allogeneic hematopoietic cell transplantation among children with newly diagnosed hypodiploid acute lymphoblastic leukemia (ALL) treated in contemporary clinical trials. PATIENTS AND METHODS This retrospective study collected data on 306 patients with hypodiploid ALL who were enrolled in the protocols of 16 cooperative study groups or institutions between 1997 and 2013. The clinical and biologic characteristics, early therapeutic responses as determined by minimal residual disease (MRD) assessment, treatment with or without MRD-stratified protocols, and allogeneic transplantation were analyzed for their impact on outcome. RESULTS With a median follow-up of 6.6 years, the 5-year event-free survival rate was 55.1% (95% CI, 49.3% to 61.5%), and the 5-year overall survival rate was 61.2% (95% CI, 55.5% to 67.4%) for the 272 evaluable patients. Negative MRD at the end of remission induction, high hypodiploidy with 44 chromosomes, and treatment in MRD-stratified protocols were associated with a favorable prognosis, with a 5-year event-free survival rate of 75% (95% CI, 66.0% to 85.0%), 74% (95% CI, 61.0% to 89.0%), and 62% (95% CI, 55.0% to 69.0%), respectively. After exclusion of patients with high hypodiploidy with 44 chromosomes and adjustment for waiting time to transplantation and for covariables in a Poisson model, disease-free survival did not differ significantly ( P = .16) between the 42 patients who underwent transplantation and the 186 patients who received chemotherapy only, with an estimated 5-year survival rate of 59% (95% CI, 46.5% to 75.0%) versus 51.5% (95% CI, 44.7% to 59.4%), respectively. Transplantation produced no significant impact on outcome compared with chemotherapy alone, especially among the subgroup of patients who achieved a negative MRD status upon completion of remission induction. CONCLUSION MRD-stratified treatments improved the outcome for children with hypodiploid ALL. Allogeneic transplantation did not significantly improve outcome overall and, in particular, for patients who achieved MRD-negative status after induction.

Dexamethasone and Individualized Asparaginase Dosing Are Each Associated with Superior Event-Free Survival in Childhood Acute Lymphoblastic Leukemia: Results From DFCI-ALL Consortium Protocol 00-01.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 321-321 ◽  
Author(s):  
Lynda M. Vrooman ◽  
Donna S. Neuberg ◽  
Kristen E. Stevenson ◽  
Jeffrey G. Supko ◽  
Stephen E. Sallan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Multivariable Analysis ◽  
Hazard Ratio ◽  
Induction Treatment ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Free Survival ◽  
To Receive

Abstract Abstract 321 BACKGROUND: The DFCI-ALL Consortium Protocol 00-01 aimed to determine the relative efficacy and toxicity of 1) dexamethasone (DEX) vs. prednisone (PRED) and 2) asparaginase (ASP) with individualized dosing (ID) based on pharmacokinetic measurements vs. standard fixed dosing (FD) based on body surface area, in the treatment of children with newly diagnosed acute lymphoblastic leukemia (ALL). PATIENTS and METHODS: Between 2000 and 2004, 492 eligible patients (pts) ages 1-18 years (yrs) with newly diagnosed ALL enrolled on Protocol 00-01 from 10 institutions. 282 pts were standard risk (SR) and 210 high risk (HR). Post-induction treatment for all patients included 30 weeks of intramuscular E. coli ASP (beginning at week 7) and vincristine/corticosteroid pulses every 3 weeks for 24 months. Pts who achieved complete remission (CR) were eligible for two randomized comparisons: 1) Steroids: Pts were randomized to receive either DEX or PRED given as 5-day pulses every 3-weeks, and 2) ASP: Pts were randomized to receive either FD (25,000IU/m2) or ID (starting dose 12,500 IU/m2) for 30 weeks. Nadir serum ASP activity (NSAA) was assessed every 3 weeks, and ASP doses on the ID arm were adjusted to maintain NSAA between 0.10-0.14 IU/mL. NSAA was assayed centrally by a validated biochemical assay. RESULTS: 473 pts (96%) achieved CR. With a median follow-up of 4.9 years, the 5-year event-free survival (EFS) ± standard error for all 492 pts was 80 ± 2% and overall survival (OS) was 91 ± 1%. Steroid randomization: 408/473 pts (86%) participated in the steroid randomization (DEX: 201, PRED: 207). Pts randomized to DEX had 5-yr EFS of 90 ± 2% compared with 81 ± 3% for PRED (p=0.01) [Table I]. For pts 10-18 yrs of age, there was a significant increase in the rate of osteonecrosis (ON) with DEX, with 5-yr cumulative incidence (CI) of 23% compared with 4.7% for PRED (p=0.02). There was no difference in the 5-yr CI of ON based on steroid type in pts 1-10 yrs of age (DEX: 2.6% vs. PRED: 4.3%, p=0.43). Fractures were also more common in pts 10-18 yrs of age randomized to DEX (p=0.06), but not in younger pts (p=0.25). Infection (positive blood culture or radiographic evidence of invasive fungal disease) developed in 38 pts (18.8%) randomized to DEX compared with 22 pts (10.6%) randomized to PRED (p=0.03). There was no difference in remission death rate based on steroid randomization (DEX 0% vs. PRED 2%, p=0.5). ASP randomization: 384/473 pts (81%) participated in the ASP randomization (FD: 195, ID: 189). Pts randomized to ID had superior EFS with 5-yr EFS of 90 ± 2% compared with 82 ± 3% for FD (p=0.04) [Table I]. There was no difference between the two arms in the frequency of ASP-related allergy (p=0.46), pancreatitis (p=0.66) or thrombosis (p=0.77). There was also no difference by treatment arm in the proportion of pts able to complete at least 25 weeks of ASP (FD: 88% vs. ID: 87%, p=0.76). There was no difference between the two arms in the proportion of pts with non-detectable NSAA, although fewer pts on the ID arm had high NSAA (>0.14 IU/mL). On multivariable analysis, both DEX and ID ASP were independent predictors of favorable outcome (hazard ratio 0.49 for DEX, p=0.02; hazard ratio 0.52 for ID, p=0.04), with no indication of an interaction. Only 5/92 (5%) pts randomized to both DEX and ID ASP experienced an event. CONCLUSIONS: DEX was associated with superior EFS, but also more bone and infectious toxicities, especially in older children/adolescents. Future studies should focus on minimizing DEX toxicity in older pediatric pts without compromising efficacy. ID of ASP was feasible and was associated with superior EFS. The improved EFS with ID was not due to a reduction in ASP-related toxicity or improved tolerability, but was associated with a reduction in the proportion of pts with high NSAA. Disclosures: Supko: Enzon Inc.: Research Funding. Sallan:Enzon Inc.: Research Funding; Enzon Inc.: Contributed to support of an investigator meeting.

Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis

Blood ◽  
2003 ◽  
Vol 101 (10) ◽  
pp. 3835-3839 ◽  
Author(s):  
Anja Borgmann ◽  
Arend von Stackelberg ◽  
Reinhard Hartmann ◽  
Wolfram Ebell ◽  
Thomas Klingebiel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Matched Pair ◽  
Event Free Survival ◽  
Free Survival ◽  
Matched Pair Analysis ◽  
Pair Analysis

Abstract Allogeneic stem cell transplantation (SCT) is frequently considered as treatment for relapsed childhood acute lymphoblastic leukemia (ALL). For patients without a matched sibling donor, SCT from unrelated donors (UD-SCT) has been increasingly performed during the past years. However, UD-SCT–related mortality and morbidity is still considerable, and the question remains as to which patients are at such high risk of recurrence that UD-SCT is indicated and, conversely, which patients do not require transplantation for long-term disease control. A matched-pair analysis was performed among patients treated according to Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Münster (ALL-REZ BFM) Study Group protocols after first relapse with chemotherapy or UD-SCT. Altogether 81 pairs were identified that could be matched exactly for site of relapse and immunophenotype, and as closely as possible for duration of first remission, age, diagnosis date, and peripheral blast cell count at relapse. No significant difference in the probability of event-free survival (pEFS) between UD-SCT and chemotherapy existed regarding 28 pairs with an intermediate prognosis (0.39 ± 0.10 vs 0.49 ± 0.11,P = .105), whereas the pEFS was significantly different in the 53 pairs with a poor prognosis (0.44 ± 0.07 vs 0.00 ± 0.00, P < .001). The major reasons of treatment failure among patients who underwent UD-SCT were therapy-related death (TRD; 24/81) and relapses (20/81). In contrast, TRD rarely occurred in patients treated with chemotherapy alone (3/81), but relapse was much more common (62/81). In conclusion, UD-SCT provides better event-free survival for children with high-risk relapsed ALL. However, there is no clear advantage of UD-SCT in patients with intermediate prognosis.

scholarly journals Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia

JAMA ◽  
2021 ◽  
Vol 325 (9) ◽  
pp. 843
Author(s):  
Franco Locatelli ◽  
Gerhard Zugmaier ◽  
Carmelo Rizzari ◽  
Joan D. Morris ◽  
Bernd Gruhn ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Event Free Survival ◽  
Free Survival ◽  
Cell Acute Lymphoblastic Leukemia ◽  
First Relapse

scholarly journals IKZF1plus Defines a New Minimal Residual Disease–Dependent Very-Poor Prognostic Profile in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia

2018 ◽  
Vol 36 (12) ◽  
pp. 1240-1249 ◽  
Author(s):  
Martin Stanulla ◽  
Elif Dagdan ◽  
Marketa Zaliova ◽  
Anja Möricke ◽  
Chiara Palmi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Event Free Survival ◽  
Cell Precursor ◽  
Free Survival ◽  
Prognostic Profile ◽  
Minimal Residual

Purpose Somatic deletions that affect the lymphoid transcription factor–coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica–Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1plus. The IKZF1plus group comprised 6% of patients with BCP ALL, with a 5-year event-free survival of 53 ± 6% compared with 79 ± 5% in patients with IKZF1 deletion who did not fulfill the IKZF1plus definition and 87 ± 1% in patients who lacked an IKZF1 deletion ( P ≤ .001). Respective 5-year cumulative relapse incidence rates were 44 ± 6%, 11 ± 4%, and 10 ± 1% ( P ≤ .001). Results were confirmed in the replication cohort, and multivariable analyses demonstrated independence of IKZF1plus. The IKZF1plus prognostic effect differed dramatically in analyses stratified by minimal residual disease (MRD) levels after induction treatment: 5-year event-free survival for MRD standard-risk IKZF1plus patients was 94 ± 5% versus 40 ± 10% in MRD intermediate- and 30 ± 14% in high-risk IKZF1plus patients ( P ≤ .001). Corresponding 5-year cumulative incidence of relapse rates were 6 ± 6%, 60 ± 10%, and 60 ± 17% ( P ≤ .001). Conclusion IKZF1plus describes a new MRD-dependent very-poor prognostic profile in BCP ALL. Because current AIEOP-BFM treatment is largely ineffective for MRD-positive IKZF1plus patients, new experimental treatment approaches will be evaluated in our upcoming trial AIEOP-BFM ALL 2017.

scholarly journals Validation of Minimal Residual Disease as Surrogate Endpoint for Event-Free Survival in Childhood Acute Lymphoblastic Leukemia

2018 ◽  
Vol 2 (4) ◽  
Author(s):  
Stefania Galimberti ◽  
Meenakshi Devidas ◽  
Ausiliatrice Lucenti ◽  
Giovanni Cazzaniga ◽  
Anja Möricke ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Surrogate Endpoint ◽  
Phase Iii ◽  
Event Free Survival ◽  
Free Survival ◽  
The Individual ◽  
Minimal Residual

Abstract Background The aim of this study was to assess whether minimal residual disease (MRD) at the end of induction front-line treatment can serve as a surrogate endpoint for event-free survival (EFS) in childhood B-lineage acute lymphoblastic leukemia. Methods The analysis was based on individual data of 4830 patients from two large phase III trials that asked a randomized question on the effect of different corticosteroids (dexamethasone vs prednisone) during induction chemotherapy on EFS. The association between MRD classified in three ordered categories [negative = 0, low positive = (>0 and <5 × 10−4), and positive = (≥5 × 10-4)] and EFS at the individual and trial levels was evaluated with the meta-analytic approach based on the Plackett copula model. Centers within trial were grouped according to geographical area, and a total of 28 units were identified for the analysis. Results MRD at the end of induction was a poor surrogate for treatment effect on EFS at the trial level, with Rtrial2 = 0.09 (95% confidence interval [CI] = 0.00 to 0.29), whereas at the individual level it was strongly associated with EFS, with an odds ratio of 3.90 (95% CI = 3.35 to 4.44) of failure for patients with higher compared with lower MRD levels. Additional sensitivity and relevant subgroup analyses confirmed these findings at both trial- and patient-level association. Conclusions Although MRD is a robust biomarker highly predictive of outcome for individual patients, clinicians and regulatory bodies should be cautious in using early MRD response in the context of complex multiagent acute lymphoblastic leukemia therapy as an early surrogate endpoint to predict the effect of a randomized treatment intervention on long-term EFS.

Delayed Intensification (DI) Enhances Event-Free Survival (EFS) of Children with B-Precursor Acute Lymphoblastic Leukemia (ALL) Who Received Intensification Therapy with Six Courses of Intravenous Methotrexate (MTX): POG 9904/9905: A Childrens Oncology Group Study (COG).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 583-583 ◽  
Author(s):  
Naomi Winick ◽  
Paul L. Martin ◽  
Meenakshi Devidas ◽  
Jonathan Shuster ◽  
Michael J. Borowitz ◽  
...  
Keyword(s):  
High Risk ◽  
Lymphoblastic Leukemia ◽  
P Value ◽  
Event Free Survival ◽  
Logrank Test ◽  
Free Survival ◽  
Leucovorin Rescue ◽  
The Difference ◽  
Std Risk ◽  
Standard Risk

Abstract Post-induction (ind) intensification with non-anti-metabolite based blocks of therapy, improved EFS on BFM 76/79, CCG 105 and UKALL X. The DI phase of reinduction-reconsolidation (BFM protocol II) was a major component of these strategies. An anti-metabolite based (MTX/mercaptopurine [MP]) intensification also improved EFS (POG 9005/9006). COG 9904 and 9905 addressed whether addition of DI improved EFS for a subset of lower, standard (std) and a subset of NCI high risk (HR) pts who all received 6 courses (cs) of IV MTX (1 gm/m2/24 hrs vs 2 gm/m2/4 hrs) plus oral MP as intensification. The results of the MTX randomization (4 vs 24 hrs) are still blinded. Ind was a dexamethasone (dex)-based 3-drug (NCI std risk) or prednisone-based 4-drug (NCI HR or std with extramedullary disease) regimen. The 3-drug ind was modified because of excessive mortality with the intrathecal (IT) MTX on day 1 changed to IT Ara-C and 6 doses of native asparaginase (asp) (10,000 IU/m2) replaced with 1 dose of PEG asp. 1124 pts were treated pre-; 477 post-amendment. Post-ind, NCI std risk pts with trisomies of chromosomes 4 and 10 or a TELAML1 (TEL) translocation were classified as lower risk and enrolled on 9904. Only the TEL pts participated in the DI randomization. Std risk pts without and HR pts with favorable blast cytogenetics, or pts who did not meet refined NCI high risk age and WBC criteria were eligible for 9905. Pts with CNS3 disease, t(9;22), t(4;11), or hypodiploidy were excluded from both studies. Consolidation on 9904/9905 included 6 cs of IV MTX with leucovorin rescue for all pts. DI began at wk 16 after the 3rd course of IV MTX and was delivered over 8 wks: 1.5 mg/m2 vincristine and 30 mg/m2 daunomycin (wks 1, 2 and 3), daily dex (6 mg/m2 × 21 days), 2500 IU/m2 PEG asp (wk 1), age adjusted IT MTX (wks 1, 5, 6), 75 mg/m2 Ara-C (IV /SC) daily × 4 days (wks 5 and 6), 1 gm/m2 cyclophosphamide (wk 5) and 60 mg/m2 6-thioguanine daily × 14 doses (wks 6–7). A total of 1403 patients were randomized to +/− DI between April 7, 2000 and April 15, 2005. There were only 2 remission deaths; 1 each in +/− DI arms. There was a statistically significant improvement in EFS for all pts receiving the DI, with no statistically significant interaction (size of treatment differences in 4 yr EFS) between any pair of subsets. The difference, though not significant (study not powered to look at subsets), for the 9905 NCI HR pts with and without favorable cytogenetics, was in the same direction as the overall results, but still suboptimal with EFS below 80%. This may reflect differences between the dex and anthracycline used during the DI phase in this study versus BFM 76/69 and CCG 105 and/or the need for an intervention other than this DI in NCI HR patients. No DI DI Cohort 4 yr EFS N 4 yr EFS N 1 sided p-value* *p-values are by the logrank test Overall (9904/9905 NCI Std & High Risk) 81.6±2.0% 710 86.5±1.7% 693 0.0049 9904/9905 NCI Standard Risk 84.5±2.1% 517 90.3±1.7% 512 0.0012 9904 NCI Std Risk with TELAML1 91.1±2.6% 217 93.6±2.2% 216 0.0900 9905 NCI Std Risk 79.8±3.2% 300 87.9±2.5% 296 0.0027 9905 NCI HR 74.3±4.3% 93 76.2±4.5% 181 0.3839

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