Page 25 - Haematologica May 2022

Lymphoblastic leukaemia, paediatric, clofarabine
toxicities. By contrast, clofarabine given at a reduced dose level of 30 mg/m2 x 5 or 20 mg/m2 x 5, respectively, was associated with unacceptably severe infections and myelo- toxicities in heavily pretreated pediatric patients with relapsed/refractory leukemia when combined with cyclophosphamide, etoposide, vincristine, and PEG-ASP in the COG trial AALL1131.7
Since MRD fell short as a surrogate marker in a true end- point analysis of survival of randomized patient cohorts in CoALL 08-09, standard cytarabine treatment has not been replaced by clofarabine, despite its superior cytotoxic effi- cacy. Notwithstanding, given its favorable risk/benefit ratio, a further evaluation of clofarabine in combination with PEG-ASP might be warranted as a second-line replacement or add-on strategy in specific patients, to reduce treatment-related morbidities or to augment the depth of molecular remission after antibody-based immunotherapy.21,22 In particular, clofarabine/PEG-ASP could be tested in high-risk patients and compared with other established anti-leukemic agents that are burdened with severe acute and long-term toxicities, such as anthra- cyclines or the anti-metabolite methotrexate.23,24
Disclosures
No conflicts of interest to disclose.
Contributions
MZ, MAH and GE designed the study with input from FS and UzS; DD, JF, TF, TI, NJ, AP, IS and FS recruited patients; MAH, GE and FS collected, analysed, and interpreted data.
Acknowledgments
Genzyme/Sanofi provided the investigational drug clofarabine. We thank Kseniya Bakharevich for her assistance in collecting and interpreting the data. We gratefully acknowledge all patients, their families and care providers who participated in this study. Finally, we thank all the clinicians, as well as diagnostics and research personnel who were actively involved in this clinical trial.
Data sharing
Individual patient data from the trial will not be shared publicly, since a data-sharing plan had not been included when ethical approval was requested. All original data can be obtained by the corresponding authors, please contact Dr. Gabriele Escherich: escherich@uke.de
References
1. Xie KC, Plunkett W. Deoxynucleotide pool depletion and sustained inhibition of ribo- nucleotide reductase and DNA synthesis after treatment of human lymphoblastoid cells with 2-chloro-9-(2-deoxy-2-fluoro- beta-D-arabinofuranosyl) adenine. Cancer Res. 1996;56(13):3030-3037.
2. Jeha S, Gandhi V, Chan KW, et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukaemia. Blood. 2004;103(3):784-789.
3. Huang M, Inukai T, Miyake K, et al. Clofarabine exerts antileukemic activity against cytarabine-resistant B-cell precursor acute lymphoblastic leukemia with low deoxycytidine kinase expression. Cancer Med. 2018;7(4):1297-1316.
4.Huguet F, Leguay T, Raffoux E, et al. Clofarabine for the treatment of adult acute lymphoid leukemia: the Group for Research on Adult Acute Lymphoblastic Leukemia intergroup. Leuk Lymphoma. 2015;56(4):847-857.
5.Wang H, Jones AK, Dvorak CC, et al. Population pharmacokinetics of cofarabine as part of pretransplantation conditioning in pediatric subjects before hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2019; 25(8):1603-1610.
6. Hochberg J, Zahler S, Geyer MB, et al. The safety and efficacy of clofarabine in combi- nation with high-dose cytarabine and total body irradiation myeloablative conditioning and allogeneic stem cell transplantation in children, adolescents, and young adults (CAYA) with poor-risk acute leukemia. Bone Marrow Transplant. 2019;54(2):226-235.
7.Salzer WL, Burke MJ, Devidas M, et al. Toxicity associated with intensive postin- duction therapy incorporating clofarabine in the very high-risk stratum of patients with newly diagnosed high-risk B-lymphoblastic
leukemia: a report from the Children's Oncology Group study AALL1131. Cancer. 2018;124(6):1150-1159.
8. Escherich G, zur Stadt U, Zimmermann M, Horstmann MA, CoALL study group. Clofarabine in combination with pegylated asparaginase in the frontline treatment of childhood acute lymphoblastic leukaemia: a feasibility report from the CoALL 08-09 trial. Br J Haematol. 2013;163(2):240-247.
9. Schramm F, Zimmermann M, Jorch N, et al. Daunorubicin during delayed intensification decreases the incidence of infectious compli- cations - a randomized comparison in trial CoALL 08-09. Leuk Lymphoma. 2019;60(1):60-68.
10. Van der Velden VHJ, Cazzaniga G, Schrauder A, et al. European Study Group on MRD detection in ALL (ESG-MRD-ALL). Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data. Leukemia. 2007;21(4):604-611.
11. Kaplan EL, Meier P. Nonparametric estima- tion from incomplete observations. J Am Stat Assoc. 1958;53(282):457-481.
12. Aalen OO. 1. The statistical analysis of fail- ure time data (2nd edn). Kalbfleisch JD, Prentice LR, Wiley-Interscience, Hoboken, New Jersey, 2002. Statistics in Medicine. 2004;23(21):3397-3398.
13. Gray RJ. A Class of K-Sample Tests for com- paring the cumulative incidence of a com- peting risk. The Annals of Statistics. 1988;16(3):1141-1154.
14. Margolin BH. Test for Trend in Proportions. In: Kotz S, Johnson NL, Read CB, eds. Encyclopedia of Statistical Sciences. New York: John Wiley & Sons. 1988;vol. 9:334- 336.
15. Borowitz MJ, Devidas M, Hunger SP, et al. Clinical significance of minimal residual dis- ease in childhood acute lymphoblastic leukemia and its relationship to other prog-
nostic factors: a Children's Oncology Group
study. Blood. 2008;111(12):5477-5485.
16. Brüggemann M, Kotrova M. Minimal resid- ual disease in adult ALL: technical aspects and implications for correct clinical interpre-
tation. Blood Adv. 2017;1(25):2456-2466. 17. Galimberti S, Devidas M, Lucenti A, et al. Validation of minimal residual disease as surrogate endpoint for event-free survival in childhood acute lymphoblastic leukemia.
JNCI Cancer Spectr. 2018; 2(4):pky069.
18. Möricke A, Zimmermann M, Valsecchi MG, et al. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL
2000. Blood. 2016;127(17):2101-2112.
19. Borowitz MJ, Wood BL, Devidas M, 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(8):964-971.
20. Kantarjian HM, Gandhi V, Kozuch V, et al. Phase I clinical and pharmacology study of clofarabine in patients with solid and hema- tologic cancers. J Clin Oncol. 2003;
21(6):1167-1173.
21. Locatelli F, Whitlock JA, Peters C, et al.
Blinatumomab versus historical standard therapy in pediatric patients with relapsed/refractory Ph-negative B-cell pre- cursor acute lymphoblastic leukemia. Leukemia. 2020;34(9):2473-2478.
22. Curren E, Stock W. Taking a “BiTE out of ALL”: blinatumomab approval for MRD- positive ALL. Blood. 2019;133(16):1715- 1719.
23. Armenian S, Bhatia S. Predicting and prevent- ing anthracycline-related cardiotoxicity. Am Soc Clin Oncol Educ Book. 2018; 38:3-12.
24.Bhojwani D, Sabin ND, Pei D, et al. Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol. 2014;32(9):949-959.
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