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Open Access 01-12-2022 | Acute Lymphoblastic Leukemia | Study protocol

Protocol for ICiCLe-ALL-14 (InPOG-ALL-15-01): a prospective, risk stratified, randomised, multicentre, open label, controlled therapeutic trial for newly diagnosed childhood acute lymphoblastic leukaemia in India

Authors: Nandana Das, Shripad Banavali, Sameer Bakhshi, Amita Trehan, Venkatraman Radhakrishnan, Rachna Seth, Brijesh Arora, Gaurav Narula, Subir Sinha, Prakriti Roy, Manash Pratim Gogoi, Sayan Chatterjee, Bindhu Abraham, Parag Das, Vaskar Saha, Shekhar Krishnan

Published in: Trials | Issue 1/2022

Abstract

Background

In the west, survival following treatment of childhood acute lymphoblastic leukaemia (ALL) approaches 90%. Outcomes in India do not exceed 70%. To address this disparity, the Indian Collaborative Childhood Leukaemia group (ICiCLe) developed in 2013 a contemporary treatment protocol for uniform risk-stratified management of first presentation ALL based on cytogenetics and minimal residual disease levels (MRD). A multicentre randomised clinical trial opened in 2016 (ICiCLe-ALL-14) and examines the benefit of randomised interventions to decrease toxicity and improve outcomes.

Methods

Patients 1–18 years with newly diagnosed ALL are categorised into four risk groups based on presentation features, tumour genetics and treatment response. Standard risk includes young (< 10 years) B cell precursor ALL (BCP-ALL) patients with low presentation leucocyte count (< 50 × 10⁹/L) and no high-risk features. Intermediate risk includes BCP-ALL patients with no high-risk features but are older and have high presentation leucocyte counts and/or bulky disease. High risk includes BCP-ALL patients with any high-risk feature, including high-risk genetics, central nervous system leukaemia, poor prednisolone response at treatment day 8 and high MRD (≥ 0·01%) at the end of induction. Patients with T-lineage ALL constitute the fourth risk group. All patients receive four intensive treatment blocks (induction, consolidation, interim maintenance, delayed intensification) followed by 96 weeks of maintenance. Treatment intensity varies by risk group. Clinical data management is based on a web-based remote data capture system. The first randomisation examines the toxicity impact of a shorter induction schedule of prednisolone (3 vs 5 weeks) in young non-high-risk BCP-ALL. The second randomisation examines the survival benefit of substituting doxorubicin with mitoxantrone in delayed intensification for all patients. Primary outcome measures include event-free survival (overall, by risk groups), sepsis rates in induction (first randomisation) and event-free survival rates following second randomisation.

Discussion

ICiCLe-ALL-14 is the first multicentre randomised childhood cancer clinical trial in India. The pre-trial phase allowed standardisation of risk-stratification diagnostics and established the feasibility of collaborative practice, uniform treatment, patient enrolment and data capture. Pre-trial observations confirm the impact of risk-stratified therapy in reducing treatment-related deaths and costs. Uniform practice across centres allows patients to access care locally, potentially decreasing financial hardship and dislocation.

Trial registration

Clinical Trials Registry-India (CTRI) CTRI/2015/12/006434. Registered on 11 December 2015

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Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. N Engl J Med. 2015;373(16):1541–52. https://doi.org/10.1056/NEJMra1400972.CrossRefPubMed

Pui CH, Yang JJ, Hunger SP, Pieters R, Schrappe M, Biondi A, et al. Childhood acute lymphoblastic leukemia: progress through collaboration. J Clin Oncol. 2015;33(27):2938–48. https://doi.org/10.1200/JCO.2014.59.1636.CrossRefPubMedPubMedCentral

Magrath I, Shanta V, Advani S, Adde M, Arya LS, Banavali S, et al. Treatment of acute lymphoblastic leukaemia in countries with limited resources; lessons from use of a single protocol in India over a twenty year period [corrected]. Eur J Cancer. 2005;41(11):1570–83. https://doi.org/10.1016/j.ejca.2004.11.004.CrossRefPubMed

Radhakrishnan V, Gupta S, Ganesan P, Rajendranath R, Ganesan TS, Rajalekshmy KR, et al. Acute lymphoblastic leukemia: a single center experience with Berlin, Frankfurt, and Munster-95 protocol. Indian J Med Paediatr Oncol. 2015;36(4):261–4. https://doi.org/10.4103/0971-5851.171552.CrossRefPubMedPubMedCentral

Trehan A, Bansal D, Varma N, Vora A. Improving outcome of acute lymphoblastic leukemia with a simplified protocol: report from a tertiary care center in north India. Pediatr Blood Cancer. 2017; 64(4). doi: 10.1002/pbc.26281. Epub 2016 Oct 20.

Marwaha RK, Kulkarni KP, Bansal D, Trehan A. Pattern of mortality in childhood acute lymphoblastic leukemia: experience from a single center in northern India. J Pediatr Hematol Oncol. 2010;32(5):366–9. https://doi.org/10.1097/MPH.0b013e3181e0d036.CrossRefPubMed

Mallath MK, Taylor DG, Badwe RA, Rath GK, Shanta V, Pramesh CS, et al. The growing burden of cancer in India: epidemiology and social context. Lancet Oncol. 2014;15(6):e205–12. https://doi.org/10.1016/S1470-2045(14)70115-9.CrossRefPubMed

O'Connor D, Bate J, Wade R, Clack R, Dhir S, Hough R, et al. Infection-related mortality in children with acute lymphoblastic leukemia: an analysis of infectious deaths on UKALL2003. Blood. 2014;124(7):1056–61. https://doi.org/10.1182/blood-2014-03-560847.CrossRefPubMed

Bostrom BC, Sensel MR, Sather HN, Gaynon PS, La MK, Johnston K, et al. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood. 2003;101(10):3809–17. https://doi.org/10.1182/blood-2002-08-2454.CrossRefPubMed

10.

Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A, Eden TO, et al. Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol. 2005;129(6):734–45. https://doi.org/10.1111/j.1365-2141.2005.05509.x.CrossRefPubMed

11.

Moricke A, Zimmermann M, Valsecchi MG, Stanulla M, Biondi A, Mann G, et al. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016;127(17):2101–12. https://doi.org/10.1182/blood-2015-09-670729.CrossRefPubMed

12.

Howard SC, Pedrosa M, Lins M, Pedrosa A, Pui CH, Ribeiro RC, et al. Establishment of a pediatric oncology program and outcomes of childhood acute lymphoblastic leukemia in a resource-poor area. JAMA. 2004;291(20):2471–5. https://doi.org/10.1001/jama.291.20.2471.CrossRefPubMed

13.

Smith M, Arthur D, Camitta B, Carroll AJ, Crist W, Gaynon P, et al. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol. 1996;14(1):18–24. https://doi.org/10.1200/JCO.1996.14.1.18.CrossRefPubMed

14.

Krivit W, Brubaker C, Hartmann J, Murphy ML, Pierce M, Thatcher G. Induction of remission in acute leukemia of childhood by combination of prednisone and either 6-mercaptopurine or methotrexate. J Pediatr. 1966;68(6):965–8. https://doi.org/10.1016/S0022-3476(66)80216-0.CrossRefPubMed

15.

Louis J, Sanford HN, Limarzi LR. Treatment of acute leukemia in children and adults. J Am Med Assoc. 1958;167(16):1913–7. https://doi.org/10.1001/jama.1958.02990330009003.CrossRefPubMed

16.

Igarashi S, Manabe A, Ohara A, Kumagai M, Saito T, Okimoto Y, et. al. No advantage of dexamethasone over prednisolone for the outcome of standard- and intermediate-risk childhood acute lymphoblastic leukemia in the Tokyo Children's Cancer Study Group L95-14 protocol. J Clin Oncol. 2005; 23(27):6489-6498, DOI: https://doi.org/10.1200/JCO.2005.01.982.

17.

Winick N, Martin PL, Devidas M, Shuster J, Borowitz MJ, Paul Bowman W, et. al. Randomized assessment of delayed intensification and two methods for parenteral methotrexate delivery in childhood B-ALL: Children's Oncology Group Studies P9904 and P9905. Leukemia. 2020; 34(4):1006-1016, DOI: https://doi.org/10.1038/s41375-019-0642-2.

18.

McNeer JL, Nachman JB. The optimal use of steroids in paediatric acute lymphoblastic leukaemia: no easy answers. Br J Haematol. 2010;149(5):638–52. https://doi.org/10.1111/j.1365-2141.2010.08192.x.CrossRefPubMed

19.

Teuffel O, Kuster SP, Hunger SP, Conter V, Hitzler J, Ethier MC, et.al. Dexamethasone versus prednisone for induction therapy in childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. Leukemia. 2011; 25(8):1232-1238, DOI: https://doi.org/10.1038/leu.2011.84.

20.

Vora A, Goulden N, Mitchell C, Hancock J, Hough R, Rowntree C, et.al. 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(8):809-818, DOI: https://doi.org/10.1016/S1470-2045(14)70243-8.

21.

Inaba H, Pei D, Wolf J, Howard SC, Hayden RT, Go M, et. al. Infection-related complications during treatment for childhood acute lymphoblastic leukemia. Ann Oncol. 2017; 28(2):386-392, DOI: https://doi.org/10.1093/annonc/mdw557.

22.

Schrappe M, Bleckmann K, Zimmermann M, Biondi A, Moricke A, Locatelli F, 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, DOI: https://doi.org/10.1200/JCO.2017.74.4946.

23.

Parker C, Krishnan S, Hamadeh L, Irving JAE, Kuiper RP, Revesz T, et. al. Outcomes of patients with childhood B-cell precursor acute lymphoblastic leukaemia with late bone marrow relapses: long-term follow-up of the ALLR3 open-label randomised trial. Lancet Haematol. 2019; 6(4):e204-e216, DOI: https://doi.org/10.1016/S2352-3026(19)30003-1.

24.

Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, et. al. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010; 376(9757):2009-2017, DOI: https://doi.org/10.1016/S0140-6736(10)62002-8.

25.

Nickel RS, Keller F, Bergsagel J, Cooper T, Daves M, Sabnis H, et.al. Mitoxantrone as a substitute for daunorubicin during induction in newly diagnosed lymphoblastic leukemia and lymphoma. Pediatr Blood Cancer. 2014; 61(5):810-814, DOI: https://doi.org/10.1002/pbc.24892.

26.

Parihar M, Singh MK, Islam R, Saha D, Mishra DK, Saha V, et al. A triple-probe FISH screening strategy for risk-stratified therapy of acute lymphoblastic leukaemia in low-resource settings. Pediatr Blood Cancer. 2018;65(12):e27366. https://doi.org/10.1002/pbc.27366.CrossRefPubMedPubMedCentral

27.

Riehm H, Reiter A, Schrappe M, Berthold F, Dopfer R, Gerein V, et.al. Corticosteroid-dependent reduction of leukocyte count in blood as a prognostic factor in acute lymphoblastic leukemia in childhood (therapy study ALL-BFM 83). Klin Padiatr. 1987; 199(3):151-160, DOI: https://doi.org/10.1055/s-2008-1026781.

28.

Tembhare PR, Ghogale S, Ghatwai N, Badrinath Y, Kunder N, Patkar NV, et. al. Evaluation of new markers for minimal residual disease monitoring in B-cell precursor acute lymphoblastic leukemia: CD73 and CD86 are the most relevant new markers to increase the efficacy of MRD 2016; 00B: 000-000. Cytometry B Clin Cytom. 2018; 94(1):100-111, DOI: https://doi.org/10.1002/cyto.b.21486.

29.

Vora A, Goulden N, Wade R, Mitchell C, Hancock J, Hough R, Rowntree C, 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, DOI: https://doi.org/10.1016/S1470-2045(12)70600-9.

30.

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(2):265-284, DOI: https://doi.org/10.1038/leu.2009.257.

31.

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(23):1663-1671, DOI: https://doi.org/10.1056/NEJM199806043382304.

32.

Vaishnavi K, Bansal D, Trehan A, Jain R, Attri SV. Improving the safety of high-dose methotrexate for children with hematologic cancers in settings without access to MTX levels using extended hydration and additional leucovorin. Pediatr Blood Cancer. 2018; 65(12):e27241.Holistic support coupled with prospective tracking reduces abandonment in childhood cancers: A report from India. Pediatr Blood Cancer. 2019; 66:e27716

33.

Arora RS, Pizer B, Eden T. Understanding refusal and abandonment in the treatment of childhood cancer. Indian Pediatr. 2010;47(12):1005–10. https://doi.org/10.1007/s13312-010-0172-5.CrossRefPubMed

34.

Mostert S, Arora RS, Arreola M, Bagai P, Friedrich P, Gupta S, et al. Abandonment of treatment for childhood cancer: position statement of a SIOP PODC Working Group. Lancet Oncol. 2011;12(8):719–20. https://doi.org/10.1016/S1470-2045(11)70128-0.CrossRefPubMed

35.

Jatia S, Prasad M, Paradkar A, Bhatia A, Narula G, Chinnaswamy G, et al. Holistic support coupled with prospective tracking reduces abandonment in childhood cancers: a report from India. Pediatr Blood Cancer. 2019;66(6):e27716. https://doi.org/10.1002/pbc.27716.CrossRefPubMed

36.

Ward ZJ, Yeh JM, Bhakta N, Frazier AL, Girardi F, Atun R. Global childhood cancer survival estimates and priority-setting: a simulation-based analysis. Lancet Oncol. 2019;20(7):972–83. https://doi.org/10.1016/S1470-2045(19)30273-6.CrossRefPubMed

37.

Allen L, O’Connell A, Kiermer V. How can we ensure visibility and diversity in research contributions? How the Contributor Role Taxonomy (CRediT) is helping the shift from authorship to contributorship. Learned Publishing. 2019;32(1):71–4. https://doi.org/10.1002/leap.1210.CrossRef

Title: Protocol for ICiCLe-ALL-14 (InPOG-ALL-15-01): a prospective, risk stratified, randomised, multicentre, open label, controlled therapeutic trial for newly diagnosed childhood acute lymphoblastic leukaemia in India
Authors: Nandana Das
Shripad Banavali
Sameer Bakhshi
Amita Trehan
Venkatraman Radhakrishnan
Rachna Seth
Brijesh Arora
Gaurav Narula
Subir Sinha
Prakriti Roy
Manash Pratim Gogoi
Sayan Chatterjee
Bindhu Abraham
Parag Das
Vaskar Saha
Shekhar Krishnan
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Acute Lymphoblastic Leukemia
Mitoxantrone
Prednisolone
Published in: Trials / Issue 1/2022
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-022-06033-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Protocol for ICiCLe-ALL-14 (InPOG-ALL-15-01): a prospective, risk stratified, randomised, multicentre, open label, controlled therapeutic trial for newly diagnosed childhood acute lymphoblastic leukaemia in India

Abstract

Background

Methods

Discussion

Trial registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Discussion

Trial registration

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