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Acute lymphoblastic leukemia

Treatment of higher risk acute lymphoblastic leukemia in young people (CCG-1961), long-term follow-up: a report from the Children’s Oncology Group

Subjects

Abstract

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.

Key points

  • 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.

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References

  1. 1.

    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.

    CAS  Article  Google Scholar 

  2. 2.

    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.

    CAS  Article  Google Scholar 

  3. 3.

    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.

    CAS  Article  Google Scholar 

  4. 4.

    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.

    CAS  Article  Google Scholar 

  5. 5.

    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.

    CAS  Article  Google Scholar 

  6. 6.

    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.

    CAS  Article  Google Scholar 

  7. 7.

    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.

    Article  Google Scholar 

  8. 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.

    CAS  Article  Google Scholar 

  9. 9.

    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.

    CAS  Article  Google Scholar 

  10. 10.

    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.

    CAS  Article  Google Scholar 

  11. 11.

    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.

    Article  Google Scholar 

  12. 12.

    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.

    Google Scholar 

  13. 13.

    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.

    CAS  Article  Google Scholar 

  14. 14.

    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.

    CAS  Article  Google Scholar 

  15. 15.

    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.

    CAS  Article  Google Scholar 

  16. 16.

    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.

    CAS  Article  Google Scholar 

  17. 17.

    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.

    Article  Google Scholar 

  18. 18.

    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.

    Article  Google Scholar 

  19. 19.

    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.

    CAS  Article  Google Scholar 

  20. 20.

    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.

    CAS  Article  Google Scholar 

  21. 21.

    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.

    CAS  Article  Google Scholar 

  22. 22.

    Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–81.

    Article  Google Scholar 

  23. 23.

    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.

    CAS  Article  Google Scholar 

  24. 24.

    Sposto R. Cure model analysis in cancer: an application to data from the Childrlen’s Cancer Group. Stat Med. 2002;21:293–312.

    Article  Google Scholar 

  25. 25.

    Fine JP, Gray RJ. A proportional Hazards model for the sub- distribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.

    Article  Google Scholar 

  26. 26.

    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.

    Article  Google Scholar 

  27. 27.

    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.

    Article  Google Scholar 

  28. 28.

    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.

    CAS  Article  Google Scholar 

  29. 29.

    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.

    Article  Google Scholar 

  30. 30.

    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

    CAS  Article  Google Scholar 

  31. 31.

    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.

    Article  Google Scholar 

  32. 32.

    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.

    CAS  Article  Google Scholar 

  33. 33.

    Casazza AM, Pratesi G, Giuliani F, Di Marco A. Antileukemic activity of 4- demethoxydaunorubicin in mice. Tumori. 1980;66:549–64.

    CAS  Article  Google Scholar 

  34. 34.

    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.

    CAS  Article  Google Scholar 

  35. 35.

    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.

    CAS  Article  Google Scholar 

  36. 36.

    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.

    Article  Google Scholar 

  37. 37.

    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.

    CAS  Article  Google Scholar 

  38. 38.

    Patrick K, Vora A. Update on biology and treatment of T-cell acute lymphoblastic leukaemia. Curr Opin Pediatr. 2015;27:44–9.

    CAS  Article  Google Scholar 

  39. 39.

    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.

    CAS  Article  Google Scholar 

  40. 40.

    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.

    CAS  Article  Google Scholar 

  41. 41.

    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.

    CAS  Article  Google Scholar 

  42. 42.

    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.

    Article  Google Scholar 

  43. 43.

    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.

    Article  Google Scholar 

  44. 44.

    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.

    Article  Google Scholar 

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Acknowledgements

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.

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Correspondence to Peter G. Steinherz.

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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

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