Children’s Cancer Group CCG-1882 improved outcome for 1–21-year old with high risk acute lymphoblastic leukemia and Induction Day 8 marrow blasts ≥25% (slow early responders, SER) with longer and stronger post induction intensification (PII). This CCG-1961 explored alternative PII strategies. We report 10-year follow-up for patients with rapid early response (RER) and for the first time details our experience for SER patients. A total of 2057 patients were enrolled, and 1299 RER patients were randomized to 1 of 4 PII regimens: standard vs. augmented intensity and standard vs. increased length. At the end of interim maintenance, 447 SER patients were randomized to idarubicin/cyclophosphamide or weekly doxorubicin in the delayed intensification phases. The 10-year EFS for RER were 79.4 ± 2.4% and 70.9 ± 2.6% (hazard ratio = 0.65, 95% CI 0.52–0.82, p < 0.001) for augmented and standard strength PII; the 10-year OS rates were 87.2 ± 2.0% and 81.0 ± 2.2% (hazard ratio = 0.64, 95% CI 0.48–0.86, p = 0.003). Outcomes remain similar for standard and longer PII, and for SER patients assigned to idarubicin/cyclophosphamide and weekly doxorubicin. The EFS and OS advantage of augmented PII is sustained at 10 years for RER patients. Longer PII for RER patients and sequential idarubicin/cyclophosphamide for SER patients offered no advantage. CCG-1961 is the platform for subsequent COG studies.
In all, 2057 high risk ALL patients had a 5- and 10-year EFS of 71.8 ± 1.1% and 68.5 ± 1.5%.The 10-year EFS rate for rapid early responders was 79.4%.
EFS for slow responders was 70.2% and 65.3% at 5 and 10 years. Advantage of augmented intensification seen at 5 years, was sustained at 10 years.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hammond D, Sather H, Nesbit M, Miller D, Coccia P, Bleyer A, et al. Analysis of prognostic factors in acute lymphoblastic leukemia. Med Pediatric Oncol. 1986;14:124–34.
Steinherz PG, Siegel SE, Bleyer WA, Kersey J, Chard R, Coccia P, et al. Lymphomatous presentation of childhood acute lymphoblastic leukemia. A subgroup at high risk of early treatment failure. Cancer. 1991;68:751–8.
Riehm H, Reiter A, Schrappe M, Berthold F, Dopfer R, Gerein V, et al. Corticosteroid-abhängige Dezimierung der Leukämiezellzahl im Blut als Prognosefaktor bei der akuten lymphoblastischen Leukämie im Kindesalter (Therapiestudie ALL-BFM 83). Klin Padiatr. 1987;199:151–60.
Gaynon PS, Desai AA, Bostrom BC, Hutchinson RJ, Lange BJ, Nachman JB, et al. Early response to therapy and outcome in childhood acute lymphoblastic leukemia: a review. Cancer. 1997;80:1717–26.
Borowitz MJ, Wood BL, Devidas M, Loh ML, Raetz EA, Salzer WL, et al. Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children’s Oncology Group study AALL0232. Blood. 2015;126:964–71.
Cave H, van der Werff ten Bosch J, Suciu S, Guidal C, Waterkeyn C, Otten J, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer--Childhood Leukemia Cooperative Group. N Engl J Med. 1998;339:591–8.
van Dongen JJ, Seriu T, Panzer-Grumayer ER, Biondi A, Pongers- Willemse MJ, Corral L, et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet. 1998;352:1731–8.
Gaynon PS, Angiolillo AL, Carroll WL, Nachman JB, Trigg ME, Sather HN, et al. Long-term results of the children’s cancer group studies for childhood acute lymphoblastic leukemia 1983-2002: a Children’s Oncology Group Report. Leukemia. 2010;24:285–97.
Moricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H, et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia. 2010;24:265–84.
Pui CH, Pei D, Sandlund JT, Ribeiro RC, Rubnitz JE, Raimondi SC, et al. Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia. Leukemia. 2010;24:371–82.
Silverman LB, Stevenson KE, O’Brien JE, Asselin BL, Barr RD, Clavell L, et al. Long-term results of Dana- Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985–2000). Leukemia. 2009;24:320–34.
Riehm H, Langermann HJ, Gadner H, et al. The Berlin Childhood Acute Lymphoblastic Leukemia Therapy Study, 1970-1976. Am J Pediatr Hematol Oncol. 1980;2:299–306.
Henze G, Langermann HJ, Bramswig J, Breu H, Gadner H, Schellong G, et al. The BFM 76/79 acute lymphoblastic leukemia therapy study. Klin Padiatr. 1981;193:145–54.
Matloub Y, Bostrom BC, Hunger SP, Stork LC, Angiolillo A, Sather H, et al. 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;118:243–51.
Nachman JB, Sather HN, Sensel MG, Trigg ME, Cherlow JM, Lukens JN, et al. Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med. 1998;338:1663–71.
Seibel NL, Steinherz PG, Sather HN, Nachman JB, Delaat C, Ettinger LJ, et al. Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Blood. 2008;111:2548–55.
Frishman-Levy L, Izraeli S. Advances in understanding the pathogenesis of CNS acute lymphoblastic leukaemia and potential for therapy. Br J Haemat. 2017;176:157–67.
Mattano LA Jr, Sather HN, Trigg ME, Nachman JB. Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children’s Cancer Group. J Clin Oncol. 2000;18:3262–72.
Lobel JS, O’Brien RT, McIntosh S, Aspnes GT, Capizzi RL. Methotrexate and asparaginase combination chemotherapy in refractory acute lymphoblastic leukemia of childhood. Cancer. 1979;43:1089–94.
Steinherz PG, Gaynon PS, Breneman JC, Cherlow JM, Grossman NJ, Kersey JH, et al. Cytoreduction and prognosis in acute lymphoblastic leukemia--the importance of early marrow response: report from the Childrens Cancer Group. J Clin Oncol. 1996;14:389–98.
Feig SA, Ames MM, Sather HN, Steinherz L, Reid JM, Trigg M, et al. Comparison of idarubicin to daunomycin in a randomized multidrug treatment of childhood acute lymphoblastic leukemia at first bone marrow relapse: a report from the Children’s Cancer Group. Med Pediatr Oncol. 1996;27:505–14.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–81.
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer. 1977;35:1–39.
Sposto R. Cure model analysis in cancer: an application to data from the Childrlen’s Cancer Group. Stat Med. 2002;21:293–312.
Fine JP, Gray RJ. A proportional Hazards model for the sub- distribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.
O’Connor D, Moorman AV, Wade R, Hancock J1, Tan RM1, Bartram J, et al. Use of minimal residual disease assessment to redefine induction failure in pediatric acute lymphoblastic leukemia. J Clin Onc. 2017;35:660–7.
Ratei R, Basso G, Dworzak M, Gaipa G, Veltroni M, Rhein P, et al. Monitoring treatment response of childhood precursor B-cell acute lymphoblastic leukemia in the AIEOP-BFM-ALL 2000 protocol with multiparameter flow cytometry: predictive impact of early blast reduction on the remission status after induction. Leukemia. 2008;23:528–34.
Sutton R, Venn NC, Tolisano J, Bahar AY, Giles JE, Ashton LJ, et al. Clinical significance of minimal residual disease at day 15 and at the end of therapy in childhood acute lymphoblastic leukaemia. Br J Haematol. 2009;146:292–9.
Keeney M, Wood BL, Hedley BD, DiGiuseppe JA, Stetler-Stevenson M, Paietta E, et al. A QA program for MRD testing demonstrates that systematic education can reduce discordance among experienced interpreters. Cytom B Clin Cytom. 2018;94:239–49.
Mattano LA, Devidas M, Nachman JB, Sather HN, Hunger SP, Steinherz PG, et al. Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG- 1961 randomised cohort trial. Lancet Oncol. 2012;13:906–15. 2012
Vora A, Goulden N, Mitchell C, Hancock J, Hough R, Rowntree C. Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2014;15:809–18.
Vora A, Goulden N, Wade R, Mitchell C, Hancock J, Hough R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2013;14:199–209.
Casazza AM, Pratesi G, Giuliani F, Di Marco A. Antileukemic activity of 4- demethoxydaunorubicin in mice. Tumori. 1980;66:549–64.
Berg SL, Reid J, Godwin K, Murry DJ, Poplack DG, Balis FM, et al. Pharmacokinetics and cerebrospinal fluid penetration of Daunorubicin, Idarubicin, and their metabolites in the nonhuman primate model. J Pediatr Hematol Oncol. 1999;21:26–30.
Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, et al. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from Children’s Oncology Group Study AALL0232. J Clin Oncol. 2016;34:2380–8.
Dunsmore KP, Winter S, Devidas M, Wood BL, Esiashvili N, Eisenberg N. COG AALL0434: a randomized trial testing nelarabine in newly diagnosed t-cell malignancy. J Clin Oncol. 2018;36:10500.
Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, et al. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children’s Oncology Group AALL0434 methotrexate randomization. J Clin Oncol. 2018;36:2926–34.
Patrick K, Vora A. Update on biology and treatment of T-cell acute lymphoblastic leukaemia. Curr Opin Pediatr. 2015;27:44–9.
Pui C-H, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009;360:2730–41.
Stark B, Avrahami G, Nirel R, Abramov A, Attias D, Ballin A, et al. Extended triple intrathecal therapy in children with T-cell acute lymphoblastic leukaemia: a report from the Israeli National ALL- Studies. Br J Haematol. 2009;147:113–24.
Gaynon PS, Qu RP, Chappell RJ, Willoughby ML, Tubergen DG, Steinherz PG, et al. Survival after relapse in childhood acute lymphoblastic leukemia. Cancer. 1998;82:1387–95.
Nguyen K, Devidas M, Cheng S-C, La M, Raetz EA, Carroll WL, et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children’s Oncology Group Study. Leukemia. 2008;12:2142–50.
Masurekar AN, Parker CA, Shanyinde M, Moorman AV, Hancock JP, Sutton R, et al. Outcome of central nervous system relapses in childhood acute lymphoblastic leukaemia – prospective open cohort analyses of the ALLR3 trial. PLoS ONE. 2014;9:e108107.
Ferrara R, Pilotto S, Caccese M, Grizzi G, Sperduti I, Giannarelli D, et al. Do immune checkpoint inhibitors need new studies methodology? J Thor Dis. 2018;10:S1564–80.
We wish to thank Ms. Damaris Morales for secretarial support. The funding for the research was under the auspices of the Childrens Oncology Group and the various NIH grants: NIH grants CA13539, CA 30969, U10 CA98543, U10 CA98413, U10 CA180886, and U10 CA180899.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Steinherz, P.G., Seibel, N.L., Sather, H. et al. Treatment of higher risk acute lymphoblastic leukemia in young people (CCG-1961), long-term follow-up: a report from the Children’s Oncology Group. Leukemia 33, 2144–2154 (2019). https://doi.org/10.1038/s41375-019-0422-z