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ACUTE MYELOID LEUKEMIA

Patients with Down syndrome can be included in early phase clinical trials- a report from the T2016-003 Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) study

Leukemia volume 37, pages 1138–1140 (2023)Cite this article

Subjects

Children, adolescents and young adults with Down syndrome (DS) have higher rates of developing acute leukemia, both B-lineage acute lymphoblastic leukemia (B-ALL) and myeloid leukemia of DS (ML-DS) [1]. Patients with DS have significantly increased chemotherapy related toxicities and dismal outcomes in the setting of relapsed leukemia [2,3,4,5,6]. Historically, DS patients have been excluded from enrollment on clinical trials for relapsed leukemia due to the presumption of intolerance to intensive experimental regimens and the uncertainty of novel agent toxicity in this population [7]. Additionally, the small number of children with DS and relapsed leukemia makes it infeasible to conduct early phase clinical trials devoted to this population [2, 8]. Recently, the introduction of novel targeted therapies have begun to offer promise in reducing toxicities and improving treatment efficacy, which is of particular interest for this vulnerable population. As an example, epigenetic modifying therapies may have efficacy in this population based on the biological features of ML-DS [9, 10] in addition to anecdotal clinical reports showing response [11, 12].

We recently completed a phase 1 clinical trial for relapsed or refractory (R/R) acute myeloid leukemia (AML) in children, adolescents, and young adults through the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) consortium (T2016-003, NCT03263936) [13], which investigated two epigenetic modifying agents, decitabine and vorinostat, in combination with chemotherapy. Patients received decitabine (dose level 1: 7.5 mg/m2; dose level 2: 10 mg/m2 and dose level 3: 15 mg/m2; IV) and vorinostat (180 mg/m2/day if <18 years and 200 mg/m2/twice daily if ≥18 years; orally) on days 1–5, followed by fludarabine (30 mg/m2/day; IV) and cytarabine (2000 mg/m2/day; IV) on days 6–10 and granulocyte-colony stimulating factor (5 µ/kg/dose; SubQ or IV) starting on day 5 until neutrophil recovery to >1500/μl. Thoughtful trial design and intentional caution enabled the inclusion of patients with DS on a separate stratum. The 3 + 3 phase 1 design enrolled DS patients at one dose level below the established safety dose in the non-DS cohort. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria version 4.0. A TACL data safety monitoring committee (DSMC) conducted regular assessments to ensure patient safety and informed consent was obtained from all eligible subjects as per local and federal requirements. The study enrolled two patients with DS-AML who were included in our primary publication [13]. We herein expand upon their clinical course and outcomes (Table 1).

Table 1 Patient characteristics.
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Fig. 1: Change in methylation after epigenetic treatment.

Data availability

De-identified participant data that support the findings of this article will be shared upon approved written request at 2 years after this article publication, for 7 years from the publication date. These data will be available to researchers who provide a methodologically sound proposal for the purposes of achieving specific aims outlined in that proposal. Proposals should be directed to TACL Consortium Central Inbox: TACL@chla.usc.edu (Attention: TACL Consortium Administrative Director, Erika Shin-Kashiyama, JD) and will be reviewed by TACL Steering & Prioritization Committee. Requests to access data to undertake hypothesis-driven research will not be unreasonably withheld. To gain access, data requesters will need to sign a data access agreement and to confirm that data will only be used for the agreed purpose for which access was granted.

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Acknowledgements

We thank the patients and families who participated in this study. We also acknowledge the TACL Consortium’s scientific contribution to and participation in this study, including participating member institutions, investigators, research teams, and the TACL Operations Center. This trial was supported by partial funding from Higgins Charitable Foundation (DB), Bear Necessities, Pediatric Cancer Foundation (MJB), Children’s Cancer Research Fund (CCRF) (MJB), Midwest Athletes Against Childhood Cancer (MACC) Fund (MJB), The Medical College of Wisconsin Cancer Center—Advancing Healthier Wisconsin Partnership Program (MJB), and the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number T32HL007209 (LP).

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Authors and Affiliations

  1. Center for Cancer and Blood Disorders, Children’s Minnesota, Minneapolis, MN, USA

    N. Gossai

  2. Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    D. Bhojwani, J. Malvar & Y. Y. Chi

  3. Texas Children’s Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    E. S. Schafer & K. R. Rabin

  4. Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA

    B. H. Chang

  5. Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    L. Pommert

  6. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    L. Pommert

  7. Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    A. Verma

  8. Division of Hematology Oncology, The Hospital for Sick Children, Toronto, ON, Canada

    J. Hitzler

  9. Division of Pediatric Hematology-Oncology, Medical College of Wisconsin, Milwaukee, WI, USA

    M. J. Burke

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  1. N. Gossai
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Contributions

NG, DB, MJB, and KRR developed the initial intent of the letter and contributed to the outline. NG, ESS, KRR, and LP completed primary manuscript preparation. All authors contributed to the drafting and revision of the letter and provided final approval to submit the paper for publication.

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Correspondence to N. Gossai.

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Gossai, N., Bhojwani, D., Schafer, E.S. et al. Patients with Down syndrome can be included in early phase clinical trials- a report from the T2016-003 Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) study. Leukemia 37, 1138–1140 (2023). https://doi.org/10.1038/s41375-023-01856-6

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