Capizzi-Style Methotrexate with Pegasparagase (C-MTX) Is Superior to High-Dose Methotrexate (HDMTX) in T-Lineage Acute Lymphoblastic Leukemia (T-ALL): Results from Children's Oncology Group (COG) AALL0434

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 794-794 ◽  
Author(s):  
Stuart S. Winter ◽  
Meenakshi Devidas ◽  
Si Chen ◽  
Barbara Asselin ◽  
William L. Carroll ◽  
...  
Keyword(s):  
Young Adults ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Adolescents And Young Adults ◽  
Phase Iii ◽  
High Dose ◽  
Cns Involvement ◽  
Leucovorin Rescue ◽  
To Receive

Abstract Early intensification with MTX is a key component of most treatment regimens used for children, adolescents and young adults with ALL. We have previously shown that HDMTX is superior to C-MTX in B-ALL in COG Study AALL0232. Because there are differences in sensitivity to MTX and pegaspargase (PEG-ASNase) between B- and T-ALL that might affect outcome, we conducted a front-line, Phase III study for patients with T-ALL. COG AALL0434 was a 2 x 2 pseudo-factorial randomization comparing the COG augmented BFM (ABFM) regimen with C-MTX without leucovorin rescue to ABFM with HDMTX plus leucovorin rescue in T-ALL, and randomizing patients with T-ALL and T-lymphoblastic lymphoma to therapy with/without six, five-day courses of nelarabine. Study subjects with T-ALL received either block of MTX therapy during the 8-week Interim Maintenance (IM) phase; those with CNS3 status were non-randomly assigned to receive HDMTX. The T-ALL patients all received prophylactic (1200 cGy) or therapeutic (1800 cGy for CNS3) cranial irradiation (cXRT), except for the ~10% with low-risk T-ALL (NCI standard risk, CNS1 without extramedullary disease, and Day 29 minimal residual disease <0.1%), who did not receive cXRT. AALL0434 accrued 1,895 study subjects between 2007 and 2014. One thousand thirty-one T-ALL subjects without CNS3 status were randomized to receive ABFM with C-MTX or HDMTX. Subjects randomized to C-MTX (n= 518) received cXRT during Consolidation (Week 4 of protocol therapy), while subjects randomized to HDMTX (n=513) received cXRT during Delayed Intensification (DI) Week 26 of protocol therapy. The 4-year disease-free survival rates (DFS) were 89.3% (SE 1.5%) overall and 92.5% (SE 1.8%) for the C-MTX regimen vs. 86.1% (SE 2.4%) for the HDMTX regimen (p = 0.0173) (Figure 1). Interim monitoring resulted in the early release of efficacy results showing that C-MTX is superior to HDMTX, but data for the nelarabine randomization (n = 659) have not yet matured enough to assess its impact. The C-MTX regimen had 11 relapses; 7 without CNS, and 4 with CNS involvement, all occurring after Week 21 in DI phase therapy. In contrast, among those randomized to HDMTX, there were 24 relapses, 14 without CNS and 10 with CNS involvement, 6 with CNS before delivery of HDMTX and cXRT. This result is directly opposite to what we observed in B-ALL (Larsen et al, ASCO 2011), emphasizing the different biology and treatment sensitivities of B- and T-ALL. The reasons for these differences are uncertain, but may be related to different sensitivities to MTX with/without leucovorin rescue, differences in PEG-ASNase scheduling, or near universal use of cXRT in AALL0434 with different timings of cXRT administration between study arms. In conclusion, AALL0434 produced a 4-year DFS rate of 89.3% (SE 1.5%) in children, adolescents, and young adults with T-ALL, and established that ABFM with C-MTX was superior to ABFM plus HDMTX. Figure 1. Figure 1. Disclosures Hunger: Bristol-Myers Squibb: Employment; Jazz Pharmaceuticals; Sigma Tau Pharmaceuticals; Erytech: Honoraria.

Comparison of high-dose methotrexate (HD-MTX) with Capizzi methotrexate plus asparaginase (C-MTX/ASNase) in children and young adults with high-risk acute lymphoblastic leukemia (HR-ALL): A report from the Children’s Oncology Group Study AALL0232.

2011 ◽  
Vol 29 (18_suppl) ◽  
pp. 3-3 ◽  
Author(s):  
E. C. Larsen ◽  
W. L. Salzer ◽  
M. Devidas ◽  
J. B. Nachman ◽  
E. A. Raetz ◽  
...  
Keyword(s):  
Young Adults ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Phase Iii ◽  
High Dose ◽  
Interim Monitoring ◽  
Acute Neurotoxicity ◽  
Children And Young Adults ◽  
To Receive ◽  
Cns Control

3 Background: Although EFS continues to improve for children and young adults with HR-ALL, central nervous system (CNS) disease has become an increasing site of treatment failure. AALL0232 was designed to test the safety and efficacy of interventions targeted to enhance CNS control including comparisons of HD-MTX versus Capizzi escalating methotrexate plus PEG asparaginase (C-MTX/ASNase) during interim maintenance-1 (IM-1) and dexamethasone (DEX) versus prednisone (PRED) during Induction. Methods: AALL0232 was a Phase III, randomized trial for patients 1-30 years old with newly diagnosed NCI high risk B-precursor ALL that utilized a 2 x 2 factorial design with an augmented intensity Berlin-Frankfurt-Münster (BFM) backbone. Patients were randomized to receive DEX versus PRED during induction and HD-MTX (5gm/m2 biweekly x 4) versus C-MTX/ASNase during IM-1. To date 2104/3156 AALL0232 patients have completed IM-1. Results: Planned interim monitoring showed 5-year EFS for patients randomized to receive HD-MTX (N=1,209) was 82 + 3.4% versus 75.4 + 3.6% for the C-MTX/ASNase (N=1,217) regimen, p=0.006. Because this difference crossed a pre-defined boundary, enrollment was halted and patients were crossed over from C-MTX/ASNase to HD MTX when feasible. There were fewer marrow and CNS relapses in the HD-MTX versus C-MTX/ASNase arms (42 and 22 versus 68 and 32). The incidence of febrile neutropenia was lower with HD-MTX compared to the C-MTX; 5.2% vs 8.2%, respectively, p=0.005. There were no statistically significant differences in acute neurotoxicity, osteonecrosis, or other clinically relevant toxicities between the two regimens. Conclusions: HD-MTX administered in place of C-MTX, during the IM-1 phase of augmented BFM therapy is associated with superior EFS, with no increase in acute toxicity, in children and young adults with HR-ALL.

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.

scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) for Children and Young Adults with T-Cell Acute Lymphoblastic Leukemia (T-ALL) Treated at Investigator Discretion: A Report from Children's Oncology Group (COG) AALL0434

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 659-659
Author(s):  
Stuart S. Winter ◽  
Meenakshi Devidas ◽  
Brent Wood ◽  
Zhiguo Chen ◽  
Natia Esiashvili ◽  
...  
Keyword(s):  
Young Adults ◽  
Multivariate Analyses ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Hazard Ratio ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Leucovorin Rescue ◽  
Children And Young Adults ◽  
To Receive

Abstract Introduction: Salvage therapies in children and young adults with relapsed T-ALL are successful in <10% of patients, thus relapse prevention is a first priority. Contemporary strategies have included the use of intensified multi-agent regimens, novel therapies, and alloHSCT. COG AALL0434 did not include an alloHSCT treatment arm. To mitigate the risk of relapse, some patients were taken off study and, at investigator discretion, referred for alloHSCT. We retrospectively collected data to identify which patients were taken off study, either during induction, or after end-induction risk assignment to receive alloHSCT, for reasons other than relapse. In particular, it was unknown how alloHSCT affected the outcomes for patients with specific subsets of disease, such as induction failure (IF) or with the early thymic precursor (ETP) phenotype. Patients and Methods: From 2007-2014, AALL0434 enrolled 1,895 patients (1,596 T-ALL) and included a 2 x 2 pseudo-factorial randomization using a COG-modified BFM regimen. Patients were randomized to receive escalating dose methotrexate without leucovorin rescue plus pegaspargase (CMTX) or High Dose MTX (HDMTX) with leucovorin rescue in a single Interim Maintenance phase, with or without six 5-day courses of nelarabine. No patients were risk stratified on the basis of ETP. Participants with ≥ 25% marrow blasts on day 29 of induction (IF) were assigned to receive HDMTX with nelarabine. All patients with intermediate risk (IR), high risk (HR) or IF received cranial irradiation. Results: Among 1385 eligible, evaluable T-ALL patients for whom survey information was available, 333 (24%) were taken off therapy during induction prior to randomization. Thirty-two (9.6%) of these 333 subsequently underwent alloHSCT (19 with M1, 9 with M2 and 4 with unknown Day 29 marrow status). At the end of induction, 1052 patients were risk stratified and consented to randomization. Of these, 43 patients (4.3%) were subsequently taken off protocol therapy for alloHSCT [0 low risk (LR), 2 IR, 21 HR and 20 IF]. For the 75 patients who were taken off protocol therapy during or after induction and underwent alloHSCT, time to transplantation from end induction ranged from 1 to 9 months (median 5) for the 20 IF patients, and from 1 to 30 months (median 4) for the 55 patients who achieved CR1. A variety of conditioning regimens were used, but most (80%) included total body irradiation. Five types of alloHSCTs were employed: matched unrelated in 37 (50%), matched related in 28 (38%), mismatched unrelated in 7 (10%), and mismatched related and unknown (1 each (1.4%)). Stem cells sources were bone marrow in 50 (67%), umbilical cord blood in 14 (19%) and peripheral blood in 11 (15%). Multivariate analyses on all 75 patients (adjusting for treatment arm and risk group, and using time-dependent covariates for time to HSCT) showed worse outcomes for those who received alloHSCT versus chemotherapy [Hazard ratio 3.46 (95% Confidence Interval 1.39 - 8.60); P = 0.008]. For IF patients, there was no difference in outcome for those receiving chemotherapy versus alloHSCT [Hazard Ratio 0.75 (95% CI 0.27-2.14); P = 0.60]. Centrally determined ETP status was available for 1123 (81%) of the subjects (Table), which were categorized as ETP (11%), Near ETP (17%) and Not ETP (72%) (Wood, BL: Blood 2014: [21]1). Most patients were not taken off therapy during induction, but among those who were and had ETP/Near ETP, 21 of 28 (75%) received alloHSCT versus 71 of 251 (28%) who received chemotherapy alone (Fischer's exact test, P <0.001). In multivariate analyses adjusting for ETP status, alloHSCT (n=66) was associated with inferior EFS compared to chemotherapy [Hazard ratio 2.81 (95% CI of 1.49-5.31); P = 0.001], and ETP status did not have a statistically significant impact on EFS [Hazard Ratio 1.36 (95% CI of 0.87-2.120; P = 0.18]. Conclusions: Our findings showed that only ~5% of participants in AALL0434 received alloHSCT, and that alloHSCT was employed in about half of those patients with IF. There was no EFS advantage for patients who failed induction and subsequently received alloHSCT. Patients were taken off protocol therapy and transplanted for a variety of reasons, which introduced heterogeneity. However, compared to those who received alloHSCT off therapy, we found that survival advantages favored those who received chemotherapy, regardless of ETP status. Table. Table. Disclosures No relevant conflicts of interest to declare.

scholarly journals Children’s Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia

2020 ◽  
Vol 38 (28) ◽  
pp. 3282-3293 ◽  
Author(s):  
Kimberly P. Dunsmore ◽  
Stuart S. Winter ◽  
Meenakshi Devidas ◽  
Brent L. Wood ◽  
Natia Esiashvili ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Phase Iii ◽  
High Dose ◽  
Newly Diagnosed ◽  
Oncology Group ◽  
Leucovorin Rescue ◽  
Cell Acute Lymphoblastic Leukemia ◽  
To Receive

PURPOSE Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed disease. PATIENTS AND METHODS From 2007 to 2014, Children’s Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005 ) enrolled 1,562 evaluable patients with T-ALL age 1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/μL with blasts) received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation. RESULTS The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively ( P = .029). Differences between DFS in a four-arm comparison were significant ( P = .01), with no interactions between the MTX and nelarabine randomizations ( P = .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63% v 6.9% ± 1.4%, respectively; P = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms. CONCLUSION The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.

scholarly journals Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: a report from the Children's Oncology Group phase III study AALL0433

Haematologica ◽  
2020 ◽  
Vol 106 (1) ◽  
pp. 46-55 ◽  
Author(s):  
Glen Lew ◽  
Yichen Chen ◽  
Xiaomin Lu ◽  
Susan R. Rheingold ◽  
James A. Whitlock ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Central Nervous System Relapse ◽  
Oncology Group

Outcomes after relapse of childhood B-acute lymphoblastic leukemia (B-ALL) are poor, and optimal therapy is unclear. Children’s Oncology Group study AALL0433 evaluated a new platform for relapsed ALL. Between March 2007 and October 2013 AALL0433 enrolled 275 participants with late bone marrow or very early isolated central nervous system (iCNS) relapse of childhood B-ALL. Patients were randomized to receive standard versus intensive vincristine dosing; this randomization closed due to excess peripheral neuropathy in 2010. Patients with matched sibling donors received allogeneic hematopoietic cell transplantation (HCT) after the first three blocks of therapy. The prognostic value of minimal residual disease (MRD) was also evaluated in this study. The 3-year event free and overall survival (EFS/OS) for the 271 eligible patients were 63.6% +/- 3.0% and 72.3% +/- 2.8% respectively. MRD at the end of Induction-1 was highly predictive of outcome, with 3-year EFS/OS of 84.9 +/- 4.0% and 93.8 +/- 2.7% for patients with MRD <0.1%, vs. 53.7 +/- 7.8% and 60.6 +/- 7.8% for patients with MRD ≥0.1% (p<0.0001). Patients who received HCT vs. chemotherapy alone had an improved 3-year disease-free survival (77.5 +/- 6.2% vs. 66.9 +/- 4.5%, p=0.03) but not OS (81.5 +/- 5.8% for HCT vs. 85.8 +/- 3.4% for chemotherapy, p=0.46). Patients with early iCNS relapse fared poorly, with a 3-year EFS/OS of 41.4% +/- 9.2% and 51.7% +/- 9.3%, respectively. Infectious toxicities of the chemotherapy platform were significant. The AALL0433 chemotherapy platform is efficacious for late bone marrow relapse of B-ALL, but with significant toxicities. The MRD threshold of 0.1% at the end of Induction-1 was highly predictive of outcome. The optimal role for HCT for this patient population remains uncertain. This trial is registered at clinicaltrials.gov (NCT# 00381680).

Chemoimmunotherapy with a Modified Hyper-CVAD and Rituximab Regimen Improves Outcome for Patients with De Novo Philadelphia Negative Precursor B-Cell Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 836-836
Author(s):  
Deborah A. Thomas ◽  
Hagop M. Kantarjian ◽  
Stefan Faderl ◽  
William G. Wierda ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
B Cell ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
High Dose ◽  
Induction Phase ◽  
Liposomal Daunorubicin ◽  
Cd20 Expression

Abstract Abstract 836 The hyper-CVAD regimen is an effective frontline program for de novo adult ALL and LL [Kantarjian, JCO 18:547, 2000; Kantarjian, Cancer 101:2788, 2004, Thomas, Blood 104:1624, 2004]. Intensive chemotherapy with hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternates with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone). Historical CR rate was 92% with 3-year disease-free survival (DFS) rate of 38%. The regimen was modified in 1999. Induction chemotherapy was given in a protective environment owing to higher mortality in patients (pts) aged 60 years or older (17% vs 3%). Course 2 of liposomal daunorubicin and cytarabine was incorporated owing to reports suggesting benefit of early anthracycline intensification. Rituximab 375 mg/m2 (days 1 & 11 of hyper-CVAD, days 1 & 8 of methotrexate-cytarabine) was given if CD20 expression was 20% or greater due to its association with disease recurrence [Thomas, Blood 113:6330, 2009]. The maintenance phase was extended to 30 months with additional intensifications owing to late relapses after completion of POMP therapy. Newly diagnosed or primary refractory (1 course only) pts with ALL (n=204) or LL (n=27) were treated on the two sequential studies. Burkitt-type leukemia/lymphoma (BLL) and Philadelphia positive ALL were treated on alternative protocols. From May 2000 to December 2001, 69 pts were treated with modified hyper-CVAD with anthracycline intensification (9 induction-consolidation courses). Course 2 was then eliminated from the regimen (8 courses), with an additional 162 pts treated to date (pts age 30 years or less are now treated with augmented BFM). Median age was 43 yrs (range, 15–83). CD20 expression was noted in 49%. Overall CR rate of the evaluable group (n=225) was 93%; 7 pts achieved PR (LL with residual disease), five failed to respond, and 4 died during the induction phase. Three-yr CRD and OS rates were 70% and 62%, respectively after a median follow-up of 50 months (range, 2–106+). In the younger CD20 positive precursor B-cell ALL subset (n=99), rituximab improved outcome compared to historical experience with hyper-CVAD alone (n=127), with 3-yr CRD rates (75% vs 45%, p<.001) and OS rates (65% vs 38%, p<.001) approaching those of their CD20 negative counterparts. In contrast to the Burkitt experience, rituximab was not beneficial for the elderly subgroup (OS rates 28% vs 34%, p NS). Anthracycline intensification did not improve outcome. The addition of rituximab to the hyper-CVAD regimen appears to benefit the younger pts (age less than 60 yrs) with CD20 positive precursor B-cell ALL. Incorporation of rituximab and other monoclonal antibodies (e.g., ofatumumab, epratuzumab) into frontline chemotherapy regimens for ALL should be investigated systematically. Disclosures: No relevant conflicts of interest to declare.

Outcomes with reduced intensity therapy in a low-risk subset of children with National Cancer Institute (NCI) standard-risk (SR) B-lymphoblastic leukemia (B-ALL): A report from Children’s Oncology Group (COG) AALL0932.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10509-10509
Author(s):  
Reuven J. Schore ◽  
Anne J. Angiolillo ◽  
John A Kairalla ◽  
Meenakshi Devidas ◽  
Karen R. Rabin ◽  
...  
Keyword(s):  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Alkylating Agents ◽  
Disease Free Survival ◽  
Low Risk ◽  
Free Survival ◽  
Leucovorin Rescue ◽  
Drug Induction ◽  
Pre Treatment ◽  
Post Hoc

10509 Background: Post-hoc analysis of COG P9904 identified a low risk (LR) group of SR B-ALL patients aged 1-9.99 years with WBC < 50,000/µL, no CNS3, and either ETV6/RUNX1 or double trisomies (DT) of chromosomes 4 and 10 with day 8 peripheral blood (PB) and day 29 marrow (BM) minimal residual disease (MRD) < 0.01% who had a 5-year event-free survival (EFS) of 97±2% and overall survival (OS) 98.8±0.8%. Outstanding results were also obtained for LR patients on COG AALL0331 using CCG-based ALL therapy. AALL0932 tested prospectively whether LR B-ALL patients could attain a 5-year EFS ≥95% with these regimens. Methods: Following a 3-drug induction, eligible AALL0932 LR patients had NCI SR B-ALL (no testicular leukemia, unfavorable genetics or Down syndrome) with DT or ETV6/RUNX1 fusion, CNS1, no steroid pre-treatment, with Day 8 PB and Day 29 BM MRD < 0.01%. Between 2010-16, 603 LR patients were randomized to P9904-based regimen LR-M (n = 301) or CCG 1991/COG AALL0331-based regimen LR-C (n = 302). LR-M included 6 24-hour infusions of 1 gm/m2 of methotrexate (MTX) with leucovorin rescue, but no anthracyclines or alkylating agents. Maintenance followed with daily 6-mercaptopurine (6-MP) and weekly oral MTX, and every 16 week 7-day pulses of dexamethasone (DEX) with vincristine (VCR) on days 1 and 8. Boys and girls were treated for 2.5 years from diagnosis. LR-C had no 24-hour MTX infusions, but included 2 Interim Maintenance (IM) phases with VCR and escalating IV MTX without leucovorin rescue given every 10 days for 5 doses, flanking an 8-week Delayed Intensification (DI) phase that included DEX, VCR, pegasparagase, doxorubicin (75 mg/m2), cyclophosphamide (1 gm/m2) and 8 doses of low-dose cytarabine (75 mg/m2/dose). LR-C Maintenance included daily 6-MP and weekly oral MTX with 5-day pulses of DEX and 1 dose of VCR given every 12 weeks. Girls received 2 years and boys 3 years of therapy from the start of IM I. Results: Both regimens achieved outstanding outcomes: 5-yr disease-free survival (±SE) 98.8%±0.8% for LR-M and 98.5%±0.9% for LR-C (p = 0.67). Both had 5-yr OS 100%. Therapies were well tolerated with higher rates of mucositis (12.9 vs 6.3%; p = 0.008) and allergic reactions (2.3% vs 0%; p = 0.02) on LR-C. Conclusions: AALL0932 demonstrated that application of stringent risk criteria can identify a favorable B-ALL subgroup almost certain to be cured with either LR-M or LR-C, allowing physicians and families to select the optimal treatment approach in the future. Clinical trial information: NCT01190930.

Pediatric-Based Therapy for Young Adults with Newly Diagnosed Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2037-2037 ◽  
Author(s):  
Michael Rytting ◽  
Deborah A. Thomas ◽  
Anna R Franklin ◽  
Elias Jabbour ◽  
William Wierda ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Young Adults ◽  
De Novo ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Unknown Origin ◽  
High Dose ◽  
Days Of Therapy ◽  
Grade Iii

Abstract Abstract 2037 Poster Board II-14 Adolescents 14 to 21 years of age with de novo acute lymphoblastic leukemia (ALL) have improved outcomes if treated on pediatric chemotherapy regimens as opposed to adult regimens. Young adults with ALL may also benefit from chemotherapy modeled after pediatric regimens, though toxicities may be limiting. We report on 48 young adult patients between the ages of 12 to 40 years with de novo Philadelphia chromosome negative ALL treated with the augmented Berlin-Frankfurt-Munster (BFM) chemotherapy regimen. All patients have completed at least the initial 28 days of therapy (induction) consisting of high dose prednisone, pegylated asparaginase (PEG-asp), vincristine, daunorubicin and intrathecal treatments. The median age of the group was 20 yrs (14-36); 40 patients had pre-B ALL and 8 T-ALL, No infectious deaths were observed during induction. 45 (95%) patients achieved a remission by 29 days and 2 achieved remission after a 2 week extension of induction. One patient was refractory to therapy. 39 (81%) patients achieved a morphological marrow remission (<5% blasts) by day 15 of treatment (rapid early responders). Minimal residual disease (MRD) assessed by flow cytometry was negative at the end of induction for 30 (62%), positive in 10 (21%), suspicious in 6 (12%) and not available for 2 patients. In the 41 patients who completed 12 weeks of therapy, MRD was negative in 35 (85%) and positive in 6 (15%). 7 (15%) patients have relapsed or have refractory disease; 1 patient died in CR. Admission for fever of unknown origin with neutropenia occurred in 10 (21%) patients, an additional 10 (21%) patients had documented infections. Grade III-IV hepatic toxicity has been prominent: 22 (45%) increased transaminase, 14 (29%) hyperbilirubinemia. 9 (19%) patients had allergic reactions to PEG-asp, and 10 (21%) had thrombotic events. The majority of grade III-IV adverse events have been reversible. The median complete remission duration is 57 weeks (range 5-143). The overall survival at two years is 82%. In summary, this pediatric-based regimen for young adults with ALL effectively induces remission, both by morphology and by flow cytometry. Toxicity has been significant, but mostly transient and tolerable. Longer follow-up is needed to determine the long-term efficacy of this regimen in young adults with ALL. Disclosures: Rytting: Enzon: Speakers Bureau. Jabbour:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau.

scholarly journals Validation of MRD Quantification By Flow Cytometry for Pediatric BCP ALL Relapsed Patients Treated on the Intreall Protocol

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1414-1414 ◽  
Author(s):  
Ester Mejstrikova ◽  
Julie Irving ◽  
Leonid Karawajew ◽  
Marian Case ◽  
Jenny Jesson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Clinical Decision Making ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Induction Treatment ◽  
High Dose ◽  
Risk Patients ◽  
To Receive

Abstract At acute lymphoblastic leukemia (ALL) relapse, about 40% of children can be salvaged with intensified multi-agent, high dose chemotherapy and in very high risk patients, with additional stem cell transplantation (SCT). To improve on this, the International BFM Study Group has led a consortium of 19 countries to develop the world's largest trial for relapsed ALL (IntReALL). Standard risk patients will be randomized to receive the ALL-REZ BFM 2002 or UK ALL R3 therapy and post induction will be randomised to receive the additional targeted anti-CD22 drug, Epratuzumab, during consolidation, to clear residual disease. Children with end of re-induction MRD positive bone marrow will undergo SCT following consolidation. Both ALL-REZ BFM 2002 and UK ALL R3 used MRD PCR-based quantification of clonal Ig/TCR rearrangements, with different cut offs (10-3 for ALL-REZ BFM 2002 and 10-4 for UK ALL R3) and this is the reference assay for IntReALL. However, flow MRD may also play a role for patients without PCR targets. Flow MRD relies on the discrimination of leukaemic blasts from hematogones and this can be hampered depending on the degree of haematopoietic regeneration which varies depending on the treatment protocol and is especially important after intensive induction treatment in relapsed protocols. Thus, prospective MRD quantification of patients entered onto the UKALLR3 and ALL-REZ BFM 2002 clinical trials was performed by a standardised, quality assured, 4-8colour Flow MRD assay in end of re-induction bone marrow aspirates, by laboratories in the IBFM FLOW consortium (n=221). Flow MRD in both treatment protocols was classed as a prospective biological add on study and not used for clinical decision making. Median MRD levels were 0.026 +/-9.9% SD for BFM versus 0.027+/-18% SD for UK protocols, with comparative MRD positivity rates of 45% versus 54%, respectively. Comparison with MRD levels as assessed by molecular analysis of antigen receptor gene rearrangements was performed in 170 samples (BFM,128; UK R3, 42). The Spearman rank correlation of all samples was 0.90 (p<0.0001) for patients treated on the BFM protocol, compared to 0.82 (p<0.0001) for those on UK ALL R3. Risk category concordance was 88% (ALL-REZ BFM) and 88% (UKALLR3). For the 21 discordant samples, 5 were MRD positive by flow but negative by PCR and 17 were negative by flow and positive by PCR. When analysing the accuracy, with which flow MRD classified specimens identically as PCR, the sensitivity of flow MRD in the ALL-REZ BFM protocol was 81% (cut off 0.1%) and in UK ALL R3 was 79% (cut off 0.01%). Specificity values were 93% versus 100%, respectively. Although sample processing and quantification of MRD differ between PCR and FC MRD, in both re-induction protocols, there was good correlation of MRD levels assessed by flow cytometry and PCR, validating the use of Flow MRD as a method of choice in patients without PCR targets in the IntReALL trial. Flow MRD also has the advantage of enabling levels of CD22 to be assayed on MRD cells, prior to treatment with Epratuzumab. This research has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 278514 - IntReALL", Deutsche Kinderkrebsstiftung for its funding support of the ALL-REZ BFM 2002 clinical trial and the minimal residual disease studies by PCR and the Deutsche Jose Carreras Leukämiestiftung for support of the international principal investigator, Leukaemia and Lymphoma Research and North East Children's Cancer Research Fund, NT 13462-4, NV15-28525A, NV15-26588A, UNCE 204012. Disclosures No relevant conflicts of interest to declare.

scholarly journals Acute Lymphoblastic Leukemia in Adolescents and Young Adults

2020 ◽  
Author(s):  
Martha Alvarado-Ibarra ◽  
José Antonio De la Peña Celaya ◽  
Luara Luz Arana-Luna ◽  
Eleazar Hernández-Ruiz ◽  
José Luis Alvarez Vera ◽  
...  
Keyword(s):  
Young Adults ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Complete Response ◽  
Good Prognosis ◽  
Research Field ◽  
Adolescents And Young Adults ◽  
Age Group ◽  
Long Time ◽  
Disease Free

When diagnosed with ALL the age group between 18 and 45 years old (AYA, adolescents and young adults) do not have the good prognosis factors generally observed in children with this diagnosis. For a long time, it was undetermined whether they should be treated with continuous and sustained chemotherapy as children or whether receive sustained chemotherapy, but with longer rest periods like old adults. The medical care of adolescents and young adults with neoplastic diseases, grouped between 15 and 45 years of age, became an emerging research field of treatment in hematological diseases. Outcomes have asses complete response disease-free survival, and overall survival as markers of response, with very poor results reported. Relevant challenges have been identified in the AYA group with ALL that have drawn attention to the need to increase research in this area, particularly in the care of the population under 45 years of age with hematological malignancies.

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