scholarly journals Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group

Blood ◽  
2011 ◽  
Vol 118 (2) ◽  
pp. 243-251 ◽  
Author(s):  
Yousif Matloub ◽  
Bruce C. Bostrom ◽  
Stephen P. Hunger ◽  
Linda C. Stork ◽  
Anne Angiolillo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Oncology Group ◽  
Event Free Survival ◽  
Free Survival ◽  
Cancer Group ◽  
Leucovorin Rescue ◽  
Standard Risk

Abstract Children's Cancer Group-1991 selected 2 components from the Children's Cancer Group studies shown to be effective in high-risk acute lymphoblastic leukemia and examined them in children with National Cancer Institute standard-risk acute B-precursor lymphoblastic leukemia. These were (1) vincristine and escalating IV methotrexate (MTX) without leucovorin rescue during the interim maintenance (IM) phases and (2) addition of a second delayed intensification (DI) phase. Eligible patients (n = 2078) were randomly assigned to regimens containing either oral (PO) MTX, PO mercaptopurine, dexamethasone, and vincristine or IV MTX during IM phases, and regimens with either single DI or double DI. Five-year event-free survival (EFS) and overall survival for patients on the PO MTX arms were 88.7% ± 1.4% and 96% ± 0.9% versus 92.6% ± 1.2% and 96.5% ± 0.8% for those on the IV MTX arms (P = .009, P = .66). Five-year EFS and overall survival for patients who received single DI were 90.9% ± 1.3% and 97.1% ± 0.8% versus 90.5% ± 1.3% and 95.4% ± 3.8% for those who received double DI (P = .71, P = .12). No advantage was found for a second DI; however, replacement of PO MTX, PO mercaptopurine, vincristine, and dexamethasone during IM with vincristine and escalating IV MTX improved EFS.

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 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

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 Pediatric-Based Versus Adult Treatment Protocols in Young Adults (18-40 years) with Standard Risk Acute Lymphoblastic Leukemia: The BC Cancer Agency Experience

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3770-3770 ◽  
Author(s):  
David Simon Kliman ◽  
Michael J Barnett ◽  
Raewyn Broady ◽  
Donna L. Forrest ◽  
Alina S. Gerrie ◽  
...  
Keyword(s):  
British Columbia ◽  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
High Dose ◽  
Event Free Survival ◽  
Free Survival ◽  
Small Cohort ◽  
Standard Risk

Abstract Introduction In recent decades, overall survival rates for children with acute lymphoblastic leukemia (ALL) have improved dramatically. Unfortunately, older patients have not experienced the same benefit. Recent years have seen investigation into the use of pediatric protocols for younger adults with ALL. Increased toxicity has often limited use to patients 40 years or younger. The Leukemia/Bone Marrow Transplant Program of BC is the referral center for adults with ALL in British Columbia. Approximately 20 patients are newly diagnosed with ALL each year. Until 2008, an adult protocol (known as ALL 89-1) was used in patients over 18 years. Since 2008, pediatric-based chemotherapy has been offered to patients 40 years or younger. We analyzed whether this change altered complete remission (CR), relapse and survival rates. We assessed whether the more intense protocol increased toxicity. Methods A retrospective analysis was performed on patients treated for ALL on a pediatric-based protocol. These protocols (ALL 08-01 and ALL 13-01) were modifications of the Donna Farber Cancer Institute 01-175 protocol. The format included induction with high dose methotrexate, followed by central nervous system (CNS) therapy including cranial irradiation. A single cycle of etoposide and high-dose cytarabine was given. Consolidation and continuation cycles included doxorubicin, asparaginase, vincristine and dexamethasone. Patients were included if they were aged 18-40 years and had standard risk, Philadelphia chromosome negative ALL. Between February 2008 and November 2014, 25 eligible patients were identified. These were compared with the 23 consecutive standard risk patients most recently treated with ALL 89-1. They had been diagnosed between February 2003 and July 2008. Exclusion criteria were age greater than 40 and non-standard risk ALL. Demographic and clinical data were collected on all patients from the Leukemia Program databases. Overall survival (OS) was calculated from time of diagnosis until death. Event free survival (EFS) was calculated from diagnosis until death, induction failure or relapse. Estimation of OS and EFS was performed using the Kaplan-Meier method. Patient characteristics were compared using Chi-squared test or Fisher's exact test. Ethics approval was obtained from the University of British Columbia ethics board. Results The median age of the combined patient group was 24.5 years. There were no statistically significant differences pre-treatment between groups. Combined median follow up was 28.7 months All 25 patients receiving a pediatric protocol achieved a CR, compared to 19 of 22 with the adult protocol. Despite the more intense chemotherapy dosing regimen in the pediatric protocol, there was no increase in hospitalizations, invasive fungal infections or deaths from treatment toxicity (Table 1). There was a trend towards increased thrombotic events in the pediatric-treated group, at 32% versus 9%. These included deep vein thrombosis in 4 patients, pulmonary emboli in 2, and cerebral sinus thrombosis in 2. Relapse occurred in 24% of the pediatric-treated patients and 45% of the adult-treated ones (p=0.215). Allogeneic stem cell transplantation was performed in 4 patients in the former group and 7 in the latter. Nine of these were carried out in CR2 or later, with two patients going into transplant with active disease. Overall survival following transplant was 44%. Two year event free survival was significantly improved in the group treated on the pediatric protocol (Figure 1), at 79% versus 36% (p=0.011). There was a trend towards improved overall survival in this small cohort, at 83% versus 49% (Figure 2). Conclusions A pediatric-based ALL treatment protocol was tolerated in patients up to the age of 40 years. In our centre, this is associated with an increase in EFS, and a trend towards increased OS, even considering the small cohort. We await with interest the results of larger studies investigating the ideal upfront therapy for young patients with ALL. Table 1. Results All Patients N=47 Adult N=22 Pediatric N=25 P Number % Number % Number % CR after induction 44 of 47 94 19 of 22 86 25 of 25 100 .095 Severe infection 20 of 47 43 9 of 22 41 11 of 25 44 .831 Thrombosis 10 of 47 21 2 of 22 9 8 of 25 32 .079 Pancreatitis 2 of 47 4 0 of 22 0 2 of 25 8 .491 Toxicity deaths 3 of 47 6 2 of 22 9 1 of 25 4 .593 Relapse 16 of 47 34 10 of 22 45 6 of 25 24 .215 AlloHSCT 11 of 47 23 7 of 22 32 4 of 25 16 .303 Disclosures No relevant conflicts of interest to declare.

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

scholarly journals Improved Survival for Children and Young Adults With T-Lineage Acute Lymphoblastic Leukemia: Results From the Children’s Oncology Group AALL0434 Methotrexate Randomization

2018 ◽  
Vol 36 (29) ◽  
pp. 2926-2934 ◽  
Author(s):  
Stuart S. Winter ◽  
Kimberly P. Dunsmore ◽  
Meenakshi Devidas ◽  
Brent L. Wood ◽  
Natia Esiashvili ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Disease Free Survival ◽  
High Dose ◽  
Oncology Group ◽  
Cns Involvement ◽  
Free Survival ◽  
Leucovorin Rescue

Purpose Early intensification with methotrexate (MTX) is a key component of acute lymphoblastic leukemia (ALL) therapy. Two different approaches to MTX intensification exist but had not been compared in T-cell ALL (T-ALL): the Children’s Oncology Group (COG) escalating dose intravenous MTX without leucovorin rescue plus pegaspargase escalating dose, Capizzi-style, intravenous MTX (C-MTX) regimen and the Berlin-Frankfurt-Muenster (BFM) high-dose intravenous MTX (HDMTX) plus leucovorin rescue regimen. Patients and Methods COG AALL0434 included a 2 × 2 randomization that compared the COG-augmented BFM (ABFM) regimen with either C-MTX or HDMTX during the 8-week interim maintenance phase. All patients with T-ALL, except for those with low-risk features, received prophylactic (12 Gy) or therapeutic (18 Gy for CNS3) cranial irradiation during either the consolidation (C-MTX; second month of therapy) or delayed intensification (HDMTX; seventh month of therapy) phase. Results AALL0434 accrued 1,895 patients from 2007 to 2014. The 5-year event-free survival and overall survival rates for all eligible, evaluable patients with T-ALL were 83.8% (95% CI, 81.2% to 86.4%) and 89.5% (95% CI, 87.4% to 91.7%), respectively. The 1,031 patients with T-ALL but without CNS3 disease or testicular leukemia were randomly assigned to receive ABFM with C-MTX (n = 519) or HDMTX (n = 512). The estimated 5-year disease-free survival ( P = .005) and overall survival ( P = .04) rates were 91.5% (95% CI, 88.1% to 94.8%) and 93.7% (95% CI, 90.8% to 96.6%) for C-MTX and 85.3% (95% CI, 81.0%–89.5%) and 89.4% (95% CI, 85.7%–93.2%) for HDMTX. Patients assigned to C-MTX had 32 relapses, six with CNS involvement, whereas those assigned to HDMTX had 59 relapses, 23 with CNS involvement. Conclusion AALL0434 established that ABFM with C-MTX was superior to ABFM plus HDMTX for T-ALL in approximately 90% of patients who received CRT, with later timing for those receiving HDMTX.

Double Delayed Intensification (DDI) Is Equivalent to Single DI (SDI) in Children with National Cancer Institute (NCI) Standard-Risk Acute Lymphoblastic Leukemia (SR-ALL) Treated on Children’s Cancer Group (CCG) Clinical Trial 1991 (CCG-1991).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 146-146 ◽  
Author(s):  
Yousif Matloub ◽  
Anne Angiolillo ◽  
Bruce Bostrom ◽  
Stephen P. Hunger ◽  
James Nachman ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Early Response ◽  
Event Free Survival ◽  
Free Survival ◽  
Cancer Group ◽  
Leucovorin Rescue ◽  
Drug Induction ◽  
To Receive ◽  
Standard Risk ◽  
Improved Outcome

Abstract Intensification of therapy has improved outcome of children with ALL. CCG 1891 demonstrated that children with intermediate risk ALL (a subset of SR-ALL) had a superior outcome with DDI vs SDI using a modified Berlin-Frankfurt-Muenster (BFM) backbone therapy that included prednisone, in a 3 drug induction (Blood.2002;99:825–33). This benefit was limited to patients with > 5% marrow blasts on Day 7 of induction. CCG-1921 best arm had similar outcome with dexamethasone in induction, and SDI (Blood.2003;101:3809–17). The question remained as to whether DDI would benefit SR patients if they received dexamethasone in induction. Therefore, one hypothesis tested by CCG-1991 was that a regimen with DDI phases would have a superior event free survival (EFS) and overall survival (OS) compared with one that had a SDI phase in children with SR-ALL treated with a modified BFM backbone therapy that included dexamethasone in induction. SR-ALL patients with an unfavorable early response (> 25% marrow blasts at day 14, or >25% marrow blasts at day 7 and >5% marrow blasts at day 14) were not eligible for randomization and were assigned to receive augmented therapy. CCG-1991 used a 2 X 2 factorial design to compare outcome in patients who received SDI vs DDI phases, and oral vs escalating intravenous methotrexate without leucovorin rescue during the interim maintenance phases of therapy. The results of the methotrexate question remain blinded at this time. There were 52 relapses among the 1029 patients randomized to the SDI regimens vs 58 among the 1021 patients randomized to the DDI regimens. Four year EFS was 88.3% (SE = 3.6) for the SDI regimens, and 88.1% (SE = 3.9) for the DDI regimens, p = 0.45, RHR 1.15. The 4 year OS estimate is 96.2% for the SDI, and 94.2% for the DDI; p = 0.25, RHR 1.41. We conclude that there are no benefits to DDI vs SDI in children with SR-ALL and a favorable early marrow response to induction chemotherapy.

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