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Intensive monitoring of minimal residual disease and chimerism after allogeneic hematopoietic stem cell transplantation for acute leukemia in children

Bone Marrow Transplantation volume 56, pages 2981–2989 (2021)Cite this article

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Abstract

Posttransplant leukemia detection before overt relapse is key to the success of immunotherapeutic interventions, as they are more efficient when leukemia burden is low. However, optimal schedule and monitoring methods are not well defined. We report the intensive bone marrow monitoring of minimal residual disease (MRD) using flow cytometry (FC) and nested reverse transcription polymerase chain reaction (RT-PCR) whenever a fusion transcript allowed it and chimerism by PCR at 11 timepoints in the first 2 years after transplant. Seventy-one transplants were performed in 59 consecutive children, for acute myeloid (n = 38), lymphoid (n = 31), or mixed-phenotype (n = 2) leukemia. MRD was monitored in 62 cases using FC (n = 58) and/or RT-PCR (n = 35). Sixty-seven percent of leukemia recurrences were detected before overt relapse, with a detection rate of 89% by RT-PCR and 40% by FC alone. Increased mixed chimerism was never the first evidence of recurrence. Two patients monitored by RT-PCR relapsed without previous MRD detection, one after missed scheduled evaluation and the other 4.7 years post transplant. Among the 22 cases with MRD detection without overt relapse, 19 received therapeutic interventions. Eight (42%) never relapsed. In conclusion, intensive marrow monitoring by RT-PCR effectively allows for early detection of posttransplant leukemia recurrence.

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Fig. 1: Representative example of nested RT-PCR design and post-HSCT monitoring.
Fig. 2: Flow chart of the population studied.
Fig. 3: Chronology of MRD tracking with respect to overt hematological relapse.
Fig. 4: Screening efficacy according to MRD technique performed.

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Acknowledgements

The authors warmly thank the patients and their families for their support, as well as members of CHUSJ pediatric hematology-oncology team. TP is a recipient of a Charles Bruneau fellowship award.

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Author notes

  1. These authors contributed equally: Thomas Pincez, Raoul Santiago.

  2. These authors jointly supervised this work: Michel Duval, Sonia Cellot.

Authors and Affiliations

  1. Service d’Hématologie-Oncologie Pédiatrique, Centre de Cancérologie Charles-Bruneau, CHU Sainte-Justine, Montréal, QC, Canada

    Thomas Pincez, Raoul Santiago, Henrique Bittencourt, Isabelle Louis, Mélanie Bilodeau, Johanne Richer, Pierre Teira, Michel Duval & Sonia Cellot

  2. Département de Pédiatrie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada

    Henrique Bittencourt, Josette-Renée Landry, Pierre Teira, Michel Duval & Sonia Cellot

  3. Laboratoire de Diagnostic Moléculaire, CHU Sainte-Justine, Montréal, QC, Canada

    Alexandre Rouette & Françoise Couture

  4. Centre Intégré de Génomique Clinique Pédiatrique, CHU Sainte-Justine, Montréal, QC, Canada

    Loubna Jouan

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Contributions

HB, PT, JR, MD, and SC were in charge of the patients and designed the study. MB, AR, LJ, J-RL, and SC performed the transcriptomic analyses. AR, LJ, FC, and IL performed the MRD analyses. TP and RS collected the data. TP, HB, MD, and SC wrote the manuscript. All of the authors analyzed and interpreted the data and revised the manuscript for critical content.

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Correspondence to Michel Duval.

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Competing interests

HB: Novartis Oncology—consulting and Jazz Pharmaceuticals—travel grant and consulting. The authors declare no competing interests.

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Pincez, T., Santiago, R., Bittencourt, H. et al. Intensive monitoring of minimal residual disease and chimerism after allogeneic hematopoietic stem cell transplantation for acute leukemia in children. Bone Marrow Transplant 56, 2981–2989 (2021). https://doi.org/10.1038/s41409-021-01408-5

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