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 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.

A Report of the Event Free Survival (EFS) for Children with Newly Diagnosed Standard Risk Acute Lymphoblastic Leukemia (ALL) Treated on Pediatric Oncology Group (POG) Protocol 9605.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 875-875
Author(s):  
Beverly A. Bell ◽  
Sharon B. Abish ◽  
Allen Chauvenet ◽  
Joanne Kurtzberg ◽  
Jeanette Pullen ◽  
...  
Keyword(s):  
Factorial Design ◽  
Lymphoblastic Leukemia ◽  
Intrathecal Chemotherapy ◽  
Remission Induction ◽  
Event Free Survival ◽  
Free Survival ◽  
Continuation Therapy ◽  
Leucovorin Rescue ◽  
Dose Oral ◽  
Standard Risk

Abstract POG 9605 opened in 1996, as a randomized 2x2 factorial design for children with standard risk ALL to determine: 1) whether the addition of 6 months of delayed intensification with divided dose oral methotrexate (ddMTX) improves the event free survival (EFS) and 2) the effect on EFS of delivering oral 6-mercaptopurine (MP) on a divided (twice daily) vs. once daily schedule, during delayed intensification and continuation. A total of 1063 eligible patients were randomized to the post induction therapy. Following remission induction, consolidation was defined as weeks (wk) 5–24 from diagnosis, and all patient received MTX 1 g/m2 IV over 24 hours q3 wks x 6 courses, with leucovorin rescue 10 mg/m2 p.o./IV q6h for 5 doses beginning 42 hours after the start of MTX infusion, oral MP 50 mg/m2/day, prednisone/vincristine (VCR) pulses, (prednisone 40 mg/m2/day x 7 days, with VCR 1.5mg/m2/dose (max 2 mg) IV days 1 and 8, on wks 8.17 and 25. Late intensification was defined as wks 25–52. Patients were randomized to the following regimens: 1) MTX 20 mg/m2 IM q wk, MP 75 mg/m2 p.o. qhs, 2)ddMTX 25 mg/m2 p.o. q6h x 4 doses q2wks, leucovorin 5 mg/m2 p.o. q12h x 2 doses, (beginning 48 h after the start of ddMTX), MP 75 mg/m2 po qhs, 3)MTX 20 mg/m2 IM q wk, MP 37.5mg/m2 p.o. BID 4)ddMTX (as in regimen 2) MP 37.5 mg/m2 p.o. BID. All regimens received prednisone/VCR pulses wks 25, 41, 57, 73 89 and 105. Continuation therapy was defined as wks 53 to 130. All patients received MTX 20mg/m2 IM weekly. Reg 1&2: MP 75 mg/m2 qhs; Reg 3&4: MP 37.5 mg/m2/dose BID. CNS prophylaxis was age adjusted, initially with triple intrathecal chemotherapy (TIT), amended in 1999 to deliver IT MTX alone, and leucovorin rescue was subsequently added because of projected excessive neurotoxicity. The overall EFS for this study is 77%±1.6 %(s.e.) at 6 years. This study had a 2x2 factorial design to answer the two questions related to MTX and MP delivery, respectively. However, the results showed statistically significant interaction between the MTX and MP questions (P=0.0081). There were significant differences in EFS between the four arms (stdMTX-stdMP 70.7%±3.6%, ddMTX-stdMP 82.7%±2.9%, stdMTX-ddMP 80.7%±3.2%, ddMTX-ddMP 76.4%±3.2%), P=0.0141. Although ddMTX-stdMP and stdMTX-ddMP had significantly better EFS compared to the stdMTX-stdMP arm (P=0.005 and P=0.01, respectively), this was not designed as a four arm study and has insufficient power to determine which arm was superior.

scholarly journals RAS Pathway Mutations As Predictive Biomarker for Treatment Adaptation in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4087-4087 ◽  
Author(s):  
Isabel S. Jerchel ◽  
Alex Q. Hoogkamer ◽  
Ingrid M. Ariës ◽  
Elisabeth M.P. Steeghs ◽  
Judith M. Boer ◽  
...  
Keyword(s):  
High Risk ◽  
Ex Vivo ◽  
Lymphoblastic Leukemia ◽  
Mek Inhibitor ◽  
Initial Diagnosis ◽  
Event Free Survival ◽  
Cell Precursor ◽  
Free Survival ◽  
Ras Pathway ◽  
Standard Risk

Abstract Background Despite significant improvements in the outcome of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), therapeutic strategies for high risk and relapsed patients are limited and cause severe side effects. Reliable risk assessment and new therapeutic targets with high specificity are therefore warranted. The RAS pathway is the most frequently mutated pathway in cancer, and the RAF-MEK-ERK kinase axis is crucial for mediating the oncogenic effects of RAS. We and others have previously shown that in pediatric BCP-ALL, RAS pathway mutations can be retrospectively linked to relapse and chemotherapy resistance. However, data on the frequency of (sub-)clonal mutations at diagnosis and hence information about the prognostic relevance at initial diagnosis is lacking. Aim Guide therapy adaptation in pediatric BCP-ALL by evaluating the prognostic relevance of RAS pathway mutations and investigating the sensitivity to MEK inhibition. Methods We performed targeted next-generation sequencing of mutational hotspots in 13 RAS pathway genes to determine the frequency and clonality of RAS pathway mutations in a large, clinically and biologically characterized cohort of BCP-ALL patients. Initial diagnosis samples of 461 patients and 19 matched diagnosis-relapse sets were included. Mutations were considered clonal at ≥25% variant allele frequency, and high coverage allowed detection of subclones with down to 1% variant allele frequency. Clinical outcome was evaluated in 244 patients treated according to a contemporary, minimal residual disease (MRD)-based protocol (DCOG ALL10). The evolution of RAS pathway mutations was studied in 19 matched sets from diagnosis and relapse. Ex vivo sensitivity of RAS pathway mutated cells towards chemotherapeutic agents and trametinib was evaluated in an MTT-based cytotoxicity assay. Results Variants in RAS pathway genes were observed in 44% of initial diagnosis pediatric BCP-ALL cases, mostly affecting NRAS, KRAS, PTPN11, and FLT3. Clonal and subclonal mutations were found in 24% and 20% of patients, respectively. The mutation frequency was highest in high hyperdiploid, infant t(4;11)-positive, BCR-ABL1-like, and B-other cases (50-70%), whereas mutations were rare in ETV6-RUNX1-positive (27%), TCF3-PBX1-positive (8%) and BCR-ABL1-positive cases (4%). In matched diagnosis-relapse sets, clonal mutations at diagnosis were preserved at relapse, whereas the kinetics of subclones was variable. Interestingly, most RAS pathway mutations at relapse were clonal and exclusive. Cells carrying RAS pathway mutations, especially KRAS G13 mutations, were more often ex vivo resistant to prednisolone and vincristine. No association was found with ex vivo response to daunorubicine, L-asparaginase, 6-mercaptopurine, and 6-thioguanine. Mutant primary leukemic cells were ex vivo sensitive to the MEK-inhibitor trametinib. In addition, trametinib could enhance the cytotoxic effect of prednisolone ex vivo. In DCOG-ALL10 and COALL-97/-03 patients with clonal but not subclonal mutations, MRD levels tended to be more often high compared to wildtype cases (31% vs. 19%, p=0.057), while other risk factors (age, gender, white blood cell count, CNS, prednisone response) where not different. Event-free survival was lower in the standard risk and high risk arms of the DCOG ALL10 protocol (69% vs. 96%, p=0.027 and 56% vs. 100%, p=0.015, respectively). Conclusions Collectively, analysis of 461 diagnostic BCP-ALL patient samples identified RAS pathway mutations in 44% of patients, and one out of four carried a clonal mutation. MRD was the only risk factor associated with clonal RAS pathway mutations. MRD is essential to treatment stratification in many contemporary protocols, such as the DCOG ALL10 protocol, where only patients with negative MRD after induction courses are treated with a reduced regimen (standard risk arm). Given their unfavorable event-free survival, therapy should be adapted for mutated patients in future protocols. Since treatment intensification is not feasible for high risk or relapsed cases, addition of MEK inhibitors may be of benefit especially because they enhance the cytotoxicity of prednisolone. RAS pathway mutation status may therefore serve as biomarker to select patients for MEK-inhibitor treatment in new treatment protocols for children with BCP-ALL. Disclosures No relevant conflicts of interest to declare.

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.

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.

Augmented Berlin-Frankfurt-Muenster (ABFM) regimen for children with standard-risk acute lymphoblastic leukemia (SR-ALL) and slow early response (SER)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9511-9511
Author(s):  
Y. H. Matloub ◽  
A. Angiolillo ◽  
B. Bostrom ◽  
L. Stork ◽  
S. P. Hunger ◽  
...  
Keyword(s):  
Negative Impact ◽  
Lymphoblastic Leukemia ◽  
Early Response ◽  
Event Free Survival ◽  
Eligibility Criteria ◽  
Standard Regimen ◽  
Free Survival ◽  
E Coli ◽  
Cancer Group ◽  
Standard Risk

9511 Background: Numerous studies have shown that SER in ALL has a negative impact on outcome. Children's Cancer Group CCG-1882 demonstrated that post-induction intensification greatly improved the outcome of children with high-risk ALL and SER. Five year event-free-survival (EFS), and overall survival (OS) for the augmented regimen was 75 ± 4% vs 55 ± 4.5%, and 78 ± 4% vs 67 ± 5% for the standard regimen, p <0.001 and 02 respectively (N Engl J Med 1998; 338:1663–71). Methods: Therefore, COG-1952 and COG- 1991, studies for patients with SR-ALL, assigned the slow early responders to augmented therapy, while others were randomized according to the study design. Study eligibility criteria were similar for both, and included newly diagnosed children with National Cancer Institute SR criteria. COG-1952 accrued a total of 2,027 patients and COG-1991 accrued 3,054. In COG-1952 patients were deemed SER if their day-7 marrow had >5% blasts, and their day-14 marrow >25%. COG-1991 used the same criteria for SER, but also added patients whose day-7 marrow had >25% blasts and their day-14 marrow had >5% blasts to the SER group. This was based on the unfavorable outcome of this subgroup in COG-1952. The augmented therapy in COG-1991 like the CCG-1882 and COG-1952, was based on a COG-modified ABFM, but differed in using dexamethasone as the sole steroid and pegylated asparaginase as the asparaginase preparation, as compared to prednisone in induction and maintenance, and native E coli asparaginase. Results: Comparative groups with days 7 and 14 M3 marrows and unfavorable cytogenetics included 126 patients from COG-1991 and 81 from the COG-1952 were assigned to their corresponding ABFM regimens. Four year EFS and OS were 85% ± 5% and 90 ± 4% for CCG-1991 vs 61 ± 5.6% and 75 ± 5% for CCG-1952, p = 0.003 and 0.04 respectively. Conclusion: We conclude that the use of dexamethasone, and pegylated asparaginase greatly improves the outcome of children with NCI-SR with SER treated on a modified augmented BFM therapy, thus supporting the use of these agents in ALL therapy. No significant financial relationships to disclose.

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 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.

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