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LYMPHOMA

Romidepsin antagonism with CHOEP

Leukemia volume 37, pages 1160–1161 (2023)Cite this article

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Chiapella et al. [1] recently reported the results of a phase Ib/II multicenter trial which analyzed the maximum tolerated dose (MTD) and outcomes of romidepsin-CHOEP (Ro-CHOEP) followed by high-dose-chemotherapy and stem-cell-transplantation (HDT + SCT) in patients with previously untreated PTCL (PTCL13 study). The trial failed to prove the study hypothesis which was to achieve an 18-month PFS of 70% and thus failed to demonstrate a PFS advantage (primary endpoint) for Ro-CHOEP as induction before HDT. The authors cite the study by Bachy et al. [2] which was a phase III randomized trial which compared romidepsin-CHOP with CHOP in patients with previously untreated PTCL (Ro-CHOP study) whose results also did not demonstrate a PFS advantage (primary endpoint) for romidepsin-CHOP combination. We propose that an antagonistic mechanism among these agents, which we had previously elucidated in our laboratory, may account for this outcome.

Our preclinical experience with HDAC inhibitors for lymphoma, both in cell lines and in patient-derived cell samples, indicates why romidepsin in combination with an anthracycline, epipodophyllotoxin, vinca alkaloid, and steroid may not provide a significant clinical benefit; romidepsin upregulates MDR1 expression leading to an increased efflux of MDR1 ligands [3]. Based on our cellular models, exposure of the PEER T-ALL cell line to romidepsin resulted in 40–50% reduction in mRNA for the drug transporter MRP1 and up to ~500-fold increase in the drug transporter MDR1 mRNA within 32–48 h; the MRP1 protein level concomitantly decreased whereas MDR1 increased [4]. The protein level of MRP1 correlated with cellular sensitivity to busulfan and chlorambucil; thus, romidepsin exposure sensitized cells to these DNA alkylators. A decreased level of MRP1 protein correlated with decreased cellular drug export activity, and an increased level of MDR1 protein correlated with increased cellular export of both the anthracycline, [4] and the other drugs transported by MDR1, i.e. vincristine, etoposide, and steroids.

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Fig. 1

Data availability

Raw data were generated at the University of Texas MD Anderson Cancer Center. Derived data supporting the findings of this study are available from the corresponding author JLR upon reasonable request.

References

  1. Chiappella A, Dodero A, Evangelista A, Re A, Orsucci L, Usai SV, et al. Romidepsin-CHOEP followed by high-dose chemotherapy and stem-cell transplantation in untreated Peripheral T-Cell Lymphoma: results of the PTCL13 phase Ib/II study. Leukemia. 2023;37:433–40. https://doi.org/10.1038/s41375-022-01780-1.

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  2. Bachy E, Camus V, Thieblemont C, Sibon, D, Casasnovas, R, Ysebaert, L, et al. Romidepsin plus CHOP versus CHOP in patients with previously untreated peripheral T-cell lymphoma: Results of the Ro-CHOP Phase III study (Conducted by LYSA). J Clin Oncol. 2021. https://doi.org/10.1200/JCO.21.01815.

  3. Valdez BC, Li Y, Murray D, Brammer J, Liu Y, Hosing C, et al. Differential effects of histone deacetylase inhibitors on cellular drug transporters and their implications for using epigenetic modifiers in combination chemotherapy. Oncotarget. 2016;7:63829–38.

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Authors and Affiliations

  1. Department of Stem Cell Transplantation & Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J. L. Ramdial, B. C. Valdez, B. S. Andersson & Y. Nieto

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  1. J. L. Ramdial
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  2. B. C. Valdez
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  3. B. S. Andersson
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  4. Y. Nieto
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Contributions

JLR, BSA, and YN contributed to writing in each section of the article. BV and BSA have made a substantial contribution to the concept and design of the article and research models in the laboratory.

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Correspondence to J. L. Ramdial.

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Ramdial, J.L., Valdez, B.C., Andersson, B.S. et al. Romidepsin antagonism with CHOEP. Leukemia 37, 1160–1161 (2023). https://doi.org/10.1038/s41375-023-01873-5

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