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Azacitidine (Vidaza®) in Pediatric Patients with Relapsed Advanced MDS and JMML: Results of a Phase I/II Study by the ITCC Consortium and the EWOG-MDS Group (Study ITCC-015)

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Abstract

Background

Advanced myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematological malignancies in children. A second allograft is recommended if a relapse occurs after hematopoietic stem cell transplantation, but the outcome is poor.

Objective

We conducted a phase I/II multicenter study to evaluate the safety, pharmacokinetics, and activity of azacitidine in children with relapsed MDS/JMML prior to the second hematopoietic stem cell transplantation.

Methods

Patients enrolled from June 2013 to March 2019 received azacitidine intravenously/subcutaneously once daily on days 1–7 of a 28-day cycle. The MDS and JMML cohorts followed a two-stage design separately, with a safety run-in for JMML. Response and safety data were used to evaluate efficacy and establish the recommended dose. Pharmacokinetics was also analyzed. The study closed prematurely because of low recruitment.

Results

Six patients with MDS and four patients with JMML received a median of three and five cycles, respectively. Azacitidine 75 mg/m2 was well tolerated and plasma concentration–time profiles were similar to observed in adults. The most prevalent grade 3–4 adverse event was myelotoxicity. No responses were seen in patients with MDS, but 83% achieved stable disease; four patients underwent an allotransplant. Overall response rate in the JMML cohort was 75% (two complete responses; one partial response) and all responders underwent hematopoietic stem cell transplantation. One-year overall survival was 67% (95% confidence interval 38–100) in MDS and 50% (95% confidence interval 19–100) in JMML.

Conclusions

Azacitidine 75 mg/m2 prior to a second hematopoietic stem cell transplantation is safe in children with relapsed MDS/JMML. Although the long-term advantage remains to be assessed, this study suggests that azacitidine is an efficacious option for relapsed JMML.

Clinical Trial Registration

EudraCT 2010-022235-10.

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Acknowledgements

The authors thank all patients and their families, as well as investigators from all participating centers. The authors acknowledge the support of the European Working Group of Myelodysplastic Syndromes (EWOG-MDS).

Author information

Authors and Affiliations

  1. Department of Pediatric Oncology, Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Alba Rubio-San-Simón, Natasha K. A. van Eijkelenburg, Raoull Hoogendijk, Marta Lopez-Yurda, Marry M. van den Heuvel-Eibrink, Harm van Tinteren & Christian M. Zwaan

  2. Department of Pediatric Oncology/Hematology, Niño Jesús Children’s Hospital, Madrid, Spain

    Alba Rubio-San-Simón

  3. Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands

    Natasha K. A. van Eijkelenburg, Raoull Hoogendijk, Marry M. van den Heuvel-Eibrink & Christian M. Zwaan

  4. Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark

    Henrik Hasle

  5. Department of Pediatric Hematology and Oncology, Center for Pediatrics, Medical Center, University of Freiburg, Freiburg, Germany

    Charlotte M. Niemeyer

  6. St. Anna Children’s Cancer Research Institute, Vienna, Austria

    Michael N. Dworzak

  7. Department of Pediatrics, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria

    Michael N. Dworzak

  8. Department of Pediatric Hematology-Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

    Marco Zecca

  9. Department of Biometrics, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands

    Marta Lopez-Yurda

  10. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands

    Julie M. Janssen & Alwin D. R. Huitema

  11. Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands

    Alwin D. R. Huitema

  12. Department of Pharmacology, Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Alwin D. R. Huitema

  13. Cellectis, New York, NY, USA

    Eric J. Laille

  14. Bristol Myers Squibb/Celgene, Summit, NJ, USA

    Eric J. Laille

  15. European Consortium for Innovative Therapies for Children with Cancer (ITCC), Villejuif, France

    Christian M. Zwaan

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  1. Alba Rubio-San-Simón
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  2. Natasha K. A. van Eijkelenburg
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Corresponding author

Correspondence to Alba Rubio-San-Simón.

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Funding

This work was supported by Celgene and Stichting Go4children.

Conflicts of interest/competing interests

Charlotte M. Niemeyer had a consultant role for BMS, Novartis, and Apriligen. Eric J. Laille is an employee of Celletics and a former employee of BMS and Celgene. Alba Rubio-San-Simón, Natasha K.A. van Eijkelenburg, Raoull Hoogendijk, Henrik Hasle, Michael N. Dworzak, Marco Zecca, Marta Lopez-Yurda, Julie M. Janssen, lwin D.R. Huitema, Marry M. van den Heuvel-Eibrink, Harm van Tinteren, and Christian M. Zwaan have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Ethik-Kommission der Albert-Ludwigs-Universität Freiburg in Germany, Ethik-Komission der Medizinischen Universitat Wien und des Allgemeinen Krankenhauses der Stadt Wien AKH in Austria, METC Erasmus MC Rotterdam in the Netherlands, Comitato Bioetica Fondazione Policlinico San Matteo Pavia in Italy, Eticka Komise pro Multicentricke Klinicke Hodnoceni Fakultni Nemocnice v Motole in Czech Republic, and Videnskabsetisk komite Region Midt in Denmark.

Consent to participate

Informed consent was obtained from all participants’ legal guardians included in the study.

Consent for publication

Not applicable.

Availability of data and material

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

Authors’ contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by ARSS, NKAvE, RH, and CMZ. The first draft of the manuscript was written by ARSS, NKAvE, and CMZ and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Rubio-San-Simón, A., van Eijkelenburg, N.K.A., Hoogendijk, R. et al. Azacitidine (Vidaza®) in Pediatric Patients with Relapsed Advanced MDS and JMML: Results of a Phase I/II Study by the ITCC Consortium and the EWOG-MDS Group (Study ITCC-015). Pediatr Drugs 25, 719–728 (2023). https://doi.org/10.1007/s40272-023-00588-5

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