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Combination of chemotherapy and all-trans retinoic acid for the treatment KMT2A-rearranged infant acute lymphoblastic leukemia. Results of the MLL-Baby trial

Leukemia volume 37, pages 2276–2281 (2023)Cite this article

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KMT2A gene rearrangements (KMT2A-r) are mostly found in infants (children less than 1 year old) with acute lymphoblastic leukemia (ALL). They mediate an aggressive type of leukemia with a unique biology [1] that responds poorly to currently available therapies ranging from conventional chemotherapy to hematopoietic stem cell transplantation (HSCT) [2]. Several avenues have been explored in the past to improve outcomes in infant ALL [2], including many attempts to use different therapeutics to disrupt known molecular signaling pathways of KMT2A-r ALL [2,3,4]. All-trans retinoic acid (ATRA) is known to induce differentiation in vitro in several cell lines derived from hematopoietic neoplasia [5], including those with t(4;11)(q21;q23)/KMT2A::AFF1, the most common KMT2A-r in infants with ALL. Here we report the results of the MLL-Baby study based on reduced-intensity chemotherapy ALL-MB 91 [6] with additional cycles of ATRA after each course of chemotherapy, with the aim of targeting the leukemia cells that survived the previous chemotherapy.

The prospective, non-randomized study MLL-Baby was conducted in 18 clinics in the Russian Federation and the Republic of Belarus. From September 2003 to April 2006, patients were initially recruited at the individual center in Ekaterinburg [7]. The study was then expanded to a multi-center study by April 2016. Patients were eligible for the study if they were diagnosed with Ph-negative B-cell precursor ALL (BCP-ALL) before the age of 365 days and had no prior antileukemic therapy other than life-saving therapy clinically required. KMT2A-r was detected by FISH and/or reverse transcriptase PCR as previously described [8]. Patients with t(4;11)(q21;q23)/KMT2A::AFF1 were assigned to the high risk (HR) group [9] and patients with all other KMT2A-r types and germline KMT2A (KMT2A-g) to the intermediate risk (ImR) group. Patients from the ImR group were transferred to the HR group if they had not achieved hematologic remission at the end of induction therapy (EOI, day 36). A lumbar puncture was performed in all patients prior to the start of specific therapy. Minimal residual disease (MRD) monitoring was performed centrally in parallel by PCR-based detection of fusion gene transcripts (FGT) and multicolor flow cytometry (MFC) as described previously at the time-points (TPs) indicated on Fig. S1.

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Fig. 1: MLL-Baby study results.

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Acknowledgements

The authors would like to thank all doctors, nurses and laboratory personnel in MLL-Baby participating institutions, who were involved in patients’ diagnostics and management.

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Authors and Affiliations

  1. Regional Children’s Hospital, Ekaterinburg, Russian Federation

    Larisa Fechina, Grigory Tsaur, Olga Makarova, Olga Khlebnikova, Yulia Zhukova, Oleg Arakaev, Olga Streneva, Tatiana Verzhbitskaya & Tatiana Riger

  2. Research Institute of Medical Cell Technologies, Ekaterinburg, Russian Federation

    Larisa Fechina, Grigory Tsaur, Oleg Arakaev, Olga Streneva, Tatiana Verzhbitskaya & Tatiana Riger

  3. National Research and Clinical Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation

    Alexander Popov, Olga Aleinikova, Natalia Myakova, Galina Novichkova, Alexander Karachunskiy & Alexander Roumiantsev

  4. Ural State Medical University, Ekaterinburg, Russian Federation

    Grigory Tsaur & Alexander Solodovnikov

  5. Department of Pediatric Oncology Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany

    Guenter Henze

  6. PET-Technology Center of Nuclear Medicine, Ekaterinburg, Russian Federation

    Egor Shorikov

  7. Belarussian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus

    Elena Lapotentova & Olga Aleinikova

  8. City Children’s Hospital №1, Saint-Petersburg, Russian Federation

    Elmira Boichenko

  9. Morozov Children’s Hospital, Moscow, Russian Federation

    Konstantin Kondratchik

  10. Regional Children’s Clinical Hospital, Perm, Russian Federation

    Olga Nikonova

  11. Orenburg Regional Clinical Oncology Center, Orenburg, Russian Federation

    Alexander Shapochnik

  12. Kuzbass Children’s Clinical Hospital, Novokuznetsk, Russian Federation

    Marina Goroshkova

  13. Republican Children’s Hospital, Moscow, Russian Federation

    Natalia Ponomareva

Authors
  1. Larisa Fechina
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  2. Alexander Popov
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Contributions

LF – protocol concept and design of the study, writing the paper. AP – initial diagnostics, MRD monitoring, data analysis, writing the paper. GT – initial diagnostics, MRD monitoring, writing the paper. GH – data interpretation, writing the paper. ES – database handling, data analysis and interpretation. OM – patients handling. OK – patients handling. YZ – patients handling. OA – patients handling. OS – database handling, patients handling. TV – initial diagnostics, MRD monitoring. TR - initial diagnostics, MRD monitoring. AS – statistics, data analysis. EL – patients handling. OA – patients handling. NM – patients handling. EB – patients handling. KK – patients handling. ON – patients handling. ASh – patients handling. MG – patients handling. NP – patients handling. GN - general supervising. AK - general supervising. AR - general supervising. All authors have read and approved the final version of manuscript.

Corresponding author

Correspondence to Grigory Tsaur.

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Fechina, L., Popov, A., Tsaur, G. et al. Combination of chemotherapy and all-trans retinoic acid for the treatment KMT2A-rearranged infant acute lymphoblastic leukemia. Results of the MLL-Baby trial. Leukemia 37, 2276–2281 (2023). https://doi.org/10.1038/s41375-023-02034-4

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