Amrolia, P

Gattens, M

Rao, A

Veys, D

Veys, P

Vora, A

English

UCL Discovery

 Journal Pre-proofThe Role of Blood and Marrow Transplantation in Treating PediatricChronic Myelogenous Leukaemia in the Era of Tyrosine KinaseInhibitorsDelphine Veys , Persis Amrolia , Ajay Vora , Paul Veys ,Anupama Rao , Michael GattensPII: S1083-8791(20)30665-0DOI: https://doi.org/10.1016/j.bbmt.2020.10.011Reference: YBBMT 56185To appear in: Biology of Blood and Marrow TransplantationReceived date: 4 September 2020Accepted date: 7 October 2020Please cite this article as: Delphine Veys , Persis Amrolia , Ajay Vora , Paul Veys , Anupama Rao ,Michael Gattens , The Role of Blood and Marrow Transplantation in Treating Pediatric Chronic Myel-ogenous Leukaemia in the Era of Tyrosine Kinase Inhibitors, Biology of Blood and Marrow Transplan-tation (2020), doi: https://doi.org/10.1016/j.bbmt.2020.10.011This is a PDF file of an article that has undergone enhancements after acceptance, such as the additionof a cover page and metadata, and formatting for readability, but it is not yet the definitive version ofrecord. This version will undergo additional copyediting, typesetting and review before it is publishedin its final form, but we are providing this version to give early visibility of the article. Please note that,during the production process, errors may be discovered which could affect the content, and all legaldisclaimers that apply to the journal pertain.© 2020 Published by Elsevier Inc. on behalf of the American Society for Transplantation and CellularTherapyThe Role of Blood and Marrow Transplantation in Treating Pediatric Chronic Myelogenous Leukaemia in the Era of Tyrosine Kinase Inhibitors   Delphine Veys1, Persis Amrolia2, Ajay Vora3, Paul Veys2, Anupama Rao3  and Michael Gattens4 1St John’s College Cambridge, UK 2 Department of Blood and Marrow Transplantation,Great Ormond Street (GOS) Hospital for Children NHS Foundation Trust and Molecular and Cellular Immunology University College London GOS Institute of Child Health, London UK. 3Department of Haematology Great Ormond Street (GOS) Hospital for Children NHS Foundation Trust, London UK. 4Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge UK Corresponding author: Professor Paul Veys Department of BMT, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. Email paul.veys@gosh.nhs.uk  Key Words: Pediatric CML; TKI; BMT            To the editor,  The introduction of tyrosine kinase inhibitors (TKIs) in 2001 revolutionised the treatment of CML in adults, largely supplanting blood and marrow transplantation (BMT). Within 5 years these revolutionary drugs had also been approved for use in pediatric patients with CML. However, due to the low disease incidence and subsequent lack of robust clinical trial data in pediatric CML, the management of pediatric CML is largely extrapolated from adult data.    Hijiya et al. [1] outlined how paediatric CML exhibits more aggressive clinical features than adult CML, demonstrating accumulating evidence of the unique biology of the pediatric CML stem cell and host . This suggests a different approach may be required within the pediatric population.   With this in mind, Andolina and colleagues [2] designed and distributed a survey to pediatric hemato-oncologists/BMT consultants in the US/Canada to assess their willingness to recommend BMT for a patient with CML, based on various clinical scenarios. The results of this survey were then published in Biology of Blood and Marrow Transplantation. In accordance with adult practice and pediatric CML recommendations [3], their survey found that the majority of physicians only tend to recommend BMT after failure of first- and second-generation TKIs. In addition, they found there was significant interest in performing a clinical trial evaluating the safety and efficacy of stopping TKIs in children with CML who achieve and maintain a deep molecular response.  In light of these important findings and with permission from the authors we sent out this same survey to 140 pediatric haemato-oncologists and pediatric BMT specialists in the UK. We received 34 responses (24.3% response rate). The responses from the UK physicians were largely similar to those from the North American survey, although UK respondents showed an increased tendency to recommend BMT across all scenarios presented in the survey (see table 1).   In line with current guidelines and the US survey, the majority of UK respondents recommended against BMT until failure of second TKI, with one notable exception. The majority 58.9% of UK respondents opted for BMT in a          2 year-old patient who relapsed during initial TKI therapy. Presumably this reflects the perceived lifetime burden of TKI therapy in such a young child and highlights the need for clear, age-specific criteria on when to proceed with BMT in young paediatric patients. Although there were no data presented from the US survey to compare against, UK respondents were more likely to recommend BMT (in the presence of a MUD donor) at an early stage in patients presenting in CML- Acute Phase (61.7%) and CML- Blast Crisis (84.8%).    North American Survey  UK Survey  Recommend BMT for a patient with optimal response to initial TKI therapy  MSD: 8.0%  MUD: 1.9% MSD: 0% (16 yr old)             11.8% (2 yr old)  MUD: not assessed*   Recommend BMT for a patient with an initial poor response to TKI  MSD: 40.2%  MUD: 31.4%  MSD: not assessed* MUD: 35.1%  Recommend BMT for a patient who relapsed during initial TKI therapy  MSD: 36.5%  MUD: 23.3%  MSD:  48.6% (16 yr old)             58.9% (2 yr old)  MUD: not assessed*  Recommend BMT for a patient who met the response criteria for treatment failure during a second course of TKI therapy  MSD: 81.7%  MUD: 69.8%  MSD: not assessed*  MUD: 85.3%   Table 1: Comparison North American vs UK responses across four clinical scenarios.   * not assessed in 4 specific scenarios (included in supplementary table 1).  We postulated that the propensity for BMT in UK respondents may be due to a higher proportion of BMT specialists and/or physicians in service for >10 years, a correlation observed by Andolina et al. in the North American Study [2]. However, demographics between the surveys were comparable          (BMT specialists: 11.8% vs 13.8%, physicians in practice > 10 yrs: 44% vs 51% in the UK and North American surveys respectively).   Another interesting comparison to draw between the two surveys was the choice of initial TKI at diagnosis. Andolina et al. [2] found whilst the majority (67.4%) chose to start with imatinib, a significant minority (30.1%) chose to start with dasatinib. In contrast, 100% of respondents in the UK survey chose to start with Imatinib. This is most likely reflective of the cost restraints presented in the NHS.   GIven the universal concern over long term TKI toxicity in children it is not surprising that   the majority (86.7%) of North American respondents and 100% of UK respondents would consider participating in a clinical trial to assess the feasibility of stopping TKI therapy in children and adolescents with CP -CML who achieved a sustained MR 4.5 for >2 years.   A number of questions within the UK survey elicited a heterogeneous response. As an example, 32.3% of respondents said they routinely administer TKIs post-transplant for CML, whereas 36.2% do not, highlighting one of the existing controversies in managing paediatric CML.mThe heterogeneous responses within the UK survey, and the subtle but important differences observed between the two surveys confirms the need for further research and evidence-based, pediatric specific guidelines for the optimal management of children and adolescents with CML.            References [1] Hijiya N, Schultz KR, Metzler M, Millot F, Suttorp M. Pediatric chronic myeloid leukemia is a unique disease that requires a different approach. Blood. 2016;127:392–399. [2] Andolina JR, Burke MJ, Hijiya N, Chaudhury S, Schultz KR, Roth ME. Practice Patterns  of Physician Treatment for Pediatric Chronic Myelogenous Leukemia. Biol Blood Marrow Transplant. 2019;25(2):321-327. [3] Andolina JR, Neudorf SM, Corey SJ. How I treat childhood CML. Blood. 2012;119:1821–1830.            

The Role of Blood and Marrow Transplantation in Treating Pediatric Chronic Myelogenous Leukaemia in the Era of Tyrosine Kinase Inhibitors

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The Role of Blood and Marrow Transplantation in Treating Pediatric Chronic Myelogenous Leukaemia in the Era of Tyrosine Kinase Inhibitors

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