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Xenograft-directed personalized therapy for a patient with post-transplant relapse of ALL

Bone Marrow Transplantation volume 51, pages 1279–1282 (2016)Cite this article

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The outcome for ALL relapsing after BM transplantation (BMT) remains poor. International Bone Marrow Transplant Register data suggest that about 30% of patients can be cured with a second BMT and that younger age (<20 years), longer interval between transplants (>6 months) and deeper molecular remission contribute to greater likelihood of success.1 The selection of chemotherapy to achieve deep remission before second BMT is often complicated by the patient’s previous exposures to agents with cumulative toxicities such as anthracyclines and/or slow minimal residual disease (MRD) responses to previous induction therapy. The use of novel therapies targeted to specific ALL biology is attractive and has been pioneered for tyrosine kinase inhibitors in Ph-like ALL.2 Although integrated genomic analysis may identify novel treatment options for relapsed ALL, it is important to establish if targeted therapy will be more effective than conventional remission induction which works in 60–70% of cases. Xenograft models accurately reproduce ALL in preclinical studies and patient-derived xenografts (PDX) could be used to assess this and to prioritize therapy for individual ALL relapse cases. We demonstrate that biologic, genetic and expression analyses combined with the treatment of a patient’s ALL in PDX mice were able to provide relevant information in time to guide therapy selection for a patient with a post-transplant relapse resulting in a complete molecular remission and enabling a second BMT.

A 3-year-old girl diagnosed with pre-B-ALL was treated as a high standard-risk patient following the Children’s Oncology Group protocol (ALL0331) due to a slow early marrow response with high minimal residual disease (MRD>10−3; Supplementary Table S1). She completed therapy but had an isolated BM relapse 35 months after diagnosis. The patient was enrolled in the UKALL-R3 trial3 in the intermediate risk group and had high MRD (1 × 10−4) at end of induction. As per trial recommendation, she received a matched-sibling-donor BMT. She had low level MRD (positive <5 × 10−5) pre-BMT and a second isolated BM relapse occurred 15 months after the first transplant.

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Acknowledgements

This research was funded by the Children’s Cancer Institute and grants from the National Cancer Institute (NOI-CM-42216 and NOI-CM-91001-03) and National Health and Medical Research Council of Australia (NHMRCAPP1024232 and APP1044884). RBL is supported by an NHMRC Fellowship (1059804). We acknowledge funding from the Sporting Chance Cancer Foundation (RS), Leukaemia and Lymphoma Research UK (JAI). Children’s Cancer Institute Australia is affiliated with UNSW Australia and the Sydney Children’s Hospitals Network. SAR3419 was provided by Sanofi through the Cancer Therapy Evaluation Program, NCI.

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Authors and Affiliations

  1. Kids Cancer Centre, Sydney Children’s Hospital, High Street, Randwick, NSW, Australia

    T N Trahair

  2. Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, NSW, Australia

    T N Trahair, R B Lock, R Sutton, K C S Sia, K Evans, J Richmond, T Law & N C Venn

  3. School of Women’s and Children’s Health, UNSW Australia, Sydney, NSW, Australia

    T N Trahair, R B Lock, R Sutton & K C S Sia

  4. Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK

    J A Irving

  5. Department of Genetic Pathology, SA Pathology, Adelaide, SA, Australia

    S Moore

  6. South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia

    E Nievergall, P Dang, S L Heatley & D L White

  7. Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia

    E Nievergall, S L Heatley & D L White

  8. Discipline of Paediatrics, University of Adelaide, Adelaide, SA, Australia

    D L White & T Revesz

  9. SA Pathology (at Women’s and Children’s Hospital), Adelaide, SA, Australia

    T Revesz

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  1. T N Trahair
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  14. D L White
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  15. T Revesz
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Correspondence to T N Trahair.

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The authors declare no conflict of interest.

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Supplementary Information accompanies this paper on Bone Marrow Transplantation website

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Trahair, T., Lock, R., Sutton, R. et al. Xenograft-directed personalized therapy for a patient with post-transplant relapse of ALL. Bone Marrow Transplant 51, 1279–1282 (2016). https://doi.org/10.1038/bmt.2016.122

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