Reduced–dose intensity therapy for pediatric lymphoblastic ...

LYMPHOID NEOPLASIA| APRIL 23, 2020

Reduced–dose intensity therapy for pediatric lymphoblastic leukemia: long-term results of the Recife RELLA05 pilot study

Francisco Pedrosa, Elaine Coustan-Smith, Yinmei Zhou, Cheng Cheng, Arli Pedrosa, Mecneide Mendes Lins, Marcia Pedrosa, Norma Lucena-Silva, Alessandra Maria de Luna Ramos, Ester Vinhas, Gaston K. Rivera, Dario Campana, Raul C. Ribeiro

Blood (2020) 135 (17): 1458–1466.

https://doi.org/10.1182/blood.2019004215

Key Points

Presenting features plus degree of response, assessed by a simple flow assay, identify children with ALL at VLR of relapse.

Substantially reducing treatment intensity does not adversely affect the outcomes of a VLR ALL subset.

Abstract

Treatment-related mortality is common among children with acute lymphoblastic leukemia (ALL) treated in poor-resource settings. We applied a simplified flow cytometric assay to identify patients with precursor B-cell ALL (B-ALL) at very low risk (VLR) of relapse and treated them with a reduced-intensity treatment plan (RELLA05). VLR criteria include favorable presenting features (age ≥ 1 and < 10 years), white blood cell count of <50 ×109/L, lack of extramedullary leukemia, and minimal residual disease level of <0.01% on remission induction day 19. Except for 2 doses of daunorubicin, treatment of patients with VLR B-ALL consisted of a combination of agents with relatively low myelotoxicity profiles, including corticosteroids, vincristine, L-asparaginase, methotrexate, and 6-mercaptopurine. Cyclophosphamide, systemic cytarabine, and central nervous system radiotherapy were not used. Of 454 patients with ALL treated at the Instituto de Medicina Integral Professor Fernando Figueira in Recife, Brazil, between December 2005 and June 2015, 101 were classified as having VLR B-ALL. There were no cases of death resulting from toxicity or treatment abandonment during remission induction. At a median follow-up of 6.6 years, there were 8 major adverse events: 6 relapses, 1 treatment-related death (from septicemia) during remission, and 1 secondary myeloid leukemia. The estimated 5-year event-free and overall survival rates were 92.0% ± 3.9% and 96.0% ± 2.8%, respectively. The 5-year cumulative risk of relapse was 4.24% ± 2.0%. The treatment was well tolerated. Episodes of neutropenia were of short duration. Patients with B-ALL selected by a combination of presenting features and degree of early response can be successfully treated with a mildly myelosuppressive chemotherapy regimen.

Subjects:

Clinical Trials and Observations, Lymphoid Neoplasia, Pediatric Hematology

Topics:

asparaginase, burkitt's lymphoma, chemotherapy regimen, child, leukemia, b-cell, acute, lymphoblastic leukemia, recurrence risk, remission induction, toxic effect, vincristine

REFERENCES

1.Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009;360(26):2730-2741.

2.Pui CH, Pei D, Raimondi SC, et al. Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with response-adapted therapy. Leukemia. 2017;31(2):333-339.

3.Roberts KG, Mullighan CG. Genomics in acute lymphoblastic leukaemia: insights and treatment implications. Nat Rev Clin Oncol. 2015;12(6):344-357.

4.Pieters R, de Groot-Kruseman H, Van der Velden V, et al. Successful therapy reduction and intensification for childhood acute lymphoblastic leukemia based on minimal residual disease monitoring: study ALL10 from the Dutch Childhood Oncology Group. J Clin Oncol. 2016;34(22):2591-2601.

5.Vora A, Goulden N, Wade 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(3):199-209.

6.Schrappe M, Bleckmann K, Zimmermann M, et al. Reduced-intensity delayed intensification in standard-risk pediatric acute lymphoblastic leukemia defined by undetectable minimal residual disease: results of an international randomized trial (AIEOP-BFM ALL 2000). J Clin Oncol. 2018;36(3):244-253.

7.Jankovic M, Haupt R, Spinetta JJ, et al; participants in PanCare. Long-term survivors of childhood cancer: cure and care—the Erice Statement (2006) revised after 10 years (2016). J Cancer Surviv. 2018;12(5):647-650.

8.George SL, Aur RJ, Mauer AM, Simone JV. A reappraisal of the results of stopping therapy in childhood leukemia. N Engl J Med. 1979;300(6):269-273.

9.Ribeiro RC, Pui CH. Saving the children—improving childhood cancer treatment in developing countries. N Engl J Med. 2005;352(21):2158-2160.

10.Howard SC, Pedrosa M, Lins M, et al. Establishment of a pediatric oncology program and outcomes of childhood acute lymphoblastic leukemia in a resource-poor area. JAMA. 2004;291(20):2471-2475.

11.Ribeiro RC, Antillon F, Pedrosa F, Pui CH. Global pediatric oncology: lessons from partnerships between high-income countries and low- to mid-income countries. J Clin Oncol. 2016;34(1):53-61.

12.Howard SC, Davidson A, Luna-Fineman S, et al. A framework to develop adapted treatment regimens to manage pediatric cancer in low- and middle-income countries: the Pediatric Oncology in Developing Countries (PODC) Committee of the International Pediatric Oncology Society (SIOP). Pediatr Blood Cancer. 2017;64(suppl 5):S1-S18.

13.Coustan-Smith E, Ribeiro RC, Stow P, et al. A simplified flow cytometric assay identifies children with acute lymphoblastic leukemia who have a superior clinical outcome. Blood. 2006;108(1):97-102.

14.Rivera GK, Ribeiro RC. Improving treatment of children with acute lymphoblastic leukemia in developing countries through technology sharing, collaboration and partnerships. Expert Rev Hematol. 2014;7(5):649-657.

15.Mahmoud HH, Rivera GK, Hancock ML, et al. Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med. 1993;329(5):314-319.

16.Gajjar A, Harrison PL, Sandlund JT, et al. Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia. Blood. 2000;96(10):3381-3384.

17.Vinhas E, Lucena-Silva N, Pedrosa F. Implementation of a simplified flow cytometric assays for minimal residual disease monitoring in childhood acute lymphoblastic leukemia. Cytometry B Clin Cytom. 2018;94(1):94-99.

18.Smith M, Arthur D, Camitta B, et al. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol. 1996;14(1):18-24.

19.Yeoh AE, Ariffin H, Chai EL, et al. Minimal residual disease-guided treatment deintensification for children with acute lymphoblastic leukemia: results from the Malaysia-Singapore acute lymphoblastic leukemia 2003 study. J Clin Oncol. 2012;30(19):2384-2392.

20.Yang JJ, Cheng C, Devidas M, et al. Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia. Nat Genet. 2011;43(3):237-241.

21.Archer NP, Perez-Andreu V, Stoltze U, et al. Family-based exome-wide association study of childhood acute lymphoblastic leukemia among Hispanics confirms role of ARID5B in susceptibility. PLoS One. 2017;12(8):e0180488.

22.Perez-Andreu V, Roberts KG, Harvey RC, et al. Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse. Nat Genet. 2013;45(12):1494-1498.

23.Pui CH, Pei D, Sandlund JT, 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(2):371-382.

24.Pui CH, Sandlund JT, Pei D, et al; Total Therapy Study XIIIB at St Jude Children’s Research Hospital. Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children’s Research Hospital. Blood. 2004;104(9):2690-2696.

25.Manabe A, Tsuchida M, Hanada R, et al. Delay of the diagnostic lumbar puncture and intrathecal chemotherapy in children with acute lymphoblastic leukemia who undergo routine corticosteroid testing: Tokyo Children’s Cancer Study Group study L89-12. J Clin Oncol. 2001;19(13):3182-3187.

26.Liu HC, Yeh TC, Hou JY, et al. Triple intrathecal therapy alone with omission of cranial radiation in children with acute lymphoblastic leukemia. J Clin Oncol. 2014;32(17):1825-1829.

27.Yao H, Price TT, Cantelli G, et al. Leukaemia hijacks a neural mechanism to invade the central nervous system. Nature. 2018;560(7716):55-60.

28.Pui CH, Mahmoud HH, Rivera GK, et al. Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood. 1998;92(2):411-415.

29.von Stackelberg A, Hartmann R, Bührer C, et al; ALL-REZ BFM Study Group. High-dose compared with intermediate-dose methotrexate in children with a first relapse of acute lymphoblastic leukemia. Blood. 2008;111(5):2573-2580.

30.Stow P, Key L, Chen X, et al. Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia. Blood. 2010;115(23):4657-4663.

31.Navarrete M, Rossi E, Brivio E, et al. Treatment of childhood acute lymphoblastic leukemia in central America: a lower-middle income countries experience. Pediatr Blood Cancer. 2014;61(5):803-809.

32.Brandalise SR, Pinheiro VR, Aguiar SS, et al. Benefits of the intermittent use of 6-mercaptopurine and methotrexate in maintenance treatment for low-risk acute lymphoblastic leukemia in children: randomized trial from the Brazilian Childhood Cooperative Group—protocol ALL-99. J Clin Oncol. 2010;28(11):1911-1918.

33.Place AE, Goldsmith K, Bourquin JP, et al. Accelerating drug development in pediatric cancer: a novel phase I study design of venetoclax in relapsed/refractory malignancies. Future Oncol. 2018;14(21):2115-2129.

34.Wyatt KD, Bram RJ. Immunotherapy in pediatric B-cell acute lymphoblastic leukemia. Hum Immunol. 2019;80(6):400-408.

© 2020 by The American Society of Hematology

This program is developed by Focus Insight with the permission of American Society of Hematology, Inc. The content are excerpted from the journal Blood. Copyright © 2019 The American Society of Hematology. All rights reserved. 「American Society of Hematology」, 「ASH」 and the ASH Logo are registered trademarks of the American Society of Hematology.