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A Proactive Approach to Prevent Hematopoietic Exhaustion During Cancer Chemotherapy in Older Patients: Temporary Cell-Cycle Arrest

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Abstract

Age is associated with the decline of multiple organ systems. In older patients, hematological toxicities associated with chemotherapy are often dose limiting, impairing dose intensity and treatment efficacy. Contrary to the classical path using growth factors to activate tissue regeneration, a novel strategy is emerging to prevent chemotherapy toxicity that involves temporary cell-cycle arrest of normal cells, such as hematopoietic or epithelial precursors. This proactive approach may allow the sparing of the stem cell reserve of these tissues. Two molecules are included in this new category, trilaciclib and ALRN-6924, which induce cell-cycle arrest by two different pathways. Previous approaches, such as the use of myelopoietic growth factors, were reactive and they might even have accelerated the depletion of stem cells by enhancing the commitment of these elements. Trilaciclib causes cell-cycle arrest by CDK 4/6 inhibition and ALRN-6924 by p53 activation. In a pooled analysis of three randomized phase II studies of patients with small cell lung cancer, trilaciclib prevented neutropenia, thrombocytopenia, and anemia. Similar chemoprotective results were observed with ALRN-6924 in an open-label phase Ib study of patients with p53-mutated small cell lung cancer. Trilaciclib is now approved as a myelopreservation agent in patients with extensive-stage small cell lung cancer. ALRN-6924 is currently in phase Ib clinical development in patients with p53-mutated cancer. In addition to preserving the normal hemopoietic pool, these drugs promise to preserve the stem cell reserve of other normal tissues with high turnover, preventing potentially other dose-limiting toxicities, such as mucositis and diarrhea. An “ex vivo” study provided early evidence that ALRN-6924 may prevent chemotherapy-induced alopecia. By affording protection from multiple toxicities with a single drug, trilaciclib and ALRN-6924 have the potential to transform the current standards of supportive care for oncology patients and may prevent the depletion of tissue stem cells already compromised with age.

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Authors and Affiliations

  1. Emeritus Moffitt Cancer Center, 12902 Usf Magnolia Dr, Tampa, FL, 33612, USA

    Lodovico Balducci

  2. Service de Gériatrie, Centre Hospitaliser Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France

    Claire Falandry

  3. Laboratoire CarMeN, Inserm U1060, INRA U1397, Université Claude Bernard Lyon, Lyon, France

    Claire Falandry

  4. Precision Bioscience, Durham, NC, USA

    Alan List

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Lodovico Balducci is a consultant for Aileron. Alan List is a consultant for Aileron. Claire Falandry has no conflicts of interest that are directly relevant to the content of this article.

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Authors’ Contributions

LB generated the idea of this review and wrote the original draft. CF reviewed and revised the geriatric portion. Alan List reviewed and revised the information related to growth factors, ALRN-6924, and trilaciclib, and highlighted the proactive approach that is the most novel aspect of this review.

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Balducci, L., Falandry, C. & List, A. A Proactive Approach to Prevent Hematopoietic Exhaustion During Cancer Chemotherapy in Older Patients: Temporary Cell-Cycle Arrest. Drugs Aging 40, 263–272 (2023). https://doi.org/10.1007/s40266-022-01005-1

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