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FLASH radiotherapy for the treatment of acute lymphoblastic leukemia

The LSHL (IRCM/CEA-Jacob) and the radiation oncology department of the Lausanne University Hospital teamed to compare FLASH radiotherapy to conventional radiotherapy in the setting of acute lymphoblastic leukemia. Their results, published in the International Journal of Radiation Oncology * Biology * Physics, open new paths to treat this type of leukemia while preserving normal hematopoiesis.

Published on 19 November 2020

Thanks to numerous technological advances, radiation therapy has become a standard of care in cancerology. However, the efficacy of conventional radiation therapy (CRT) is limited by the damage it may do to healthy neighboring tissues. In other words, maximally-efficacious doses against cancerous tissues are very close to toxic doses for healthy tissues. To address this issue, recent research in radiation oncology has led to the development of ultra-high dose rate "FLASH" radiotherapy (FRT), a novel radiation technique involving the delivery of fast bursts (a few milliseconds) of radiation doses calculated to destroy cancer cells but leave neighboring cells unaffected. Several studies have confirmed that FRT is efficacious against a number of solid tumors while also being relatively innocuous for the surrounding tissues. Among them was a clinical study¹ wherein a first patient was treated with FRT, thus demonstrating the clinical feasibility of the technique.

For a recent study published in the International Journal of Radiation Oncology * Biology * Physics, researchers from the Laboratory of Hematopoietic Stem Cells and Leukemia (LSHL; an IRCM lab) and the radiation oncology laboratory of the Lausanne University Hospital (CHUV) joined forces to assess the effects of FRT on acute lymphoblastic leukemia (ALL)² and normal hematopoiesis. In that work, they used patient-derived T-cell ALL (T-ALL) samples xenografted to immunodeficient mice as the experimental model. Thus, three T-ALL samples and CD34+ hematopoietic stem and progenitor cells (HSPCs) taken from umbilical cord blood were transferred, together or not, to the mice to imitate both normal and pathological blood development. An Oriatron eRT6 linear accelerator enabled the comparison of the biological effects of FRT and CRT. The geometry and dosimetry for those experiments were optimized by a team of physicists from the CHUV's Institute of Radiation Physics. That methodology ensured good reproducibility and homogeneity for the experimental procedures.

Evaluation of the antitumor efficacy of FLASH or conventional radiotherapy on xenografted murine T-ALL models : (A) experimental setup with the linear particle accelerator able to ensure target-adapted irradiation, with the thermoluminescent dosimeters positioned at the exit side; (B) Kaplan-Meier curve showing decreased leukemia development in the T-ALL mice treated by 4Gy FRT. (Image credits: P. Gonçalves Jorge and B. Uzan)


The results of the Franco-Swiss team showed that FRT slowed the spread of leukemia better than CRT did in a particular T-ALL subtype, and thus they went on to identify a gene expression signature indicative of FRT susceptibility. The team also shed light on a differential effect for HSPCs, which appeared able to maintain certain properties when exposed to FRT that were completely lost when exposed to CRT.

In all, the results published by the LSHL/CHUV team provide novel information suggesting that FRT has advantages over CRT for the treatment of children with certain subtypes of T-ALL and furthermore preserves some of the properties of normal blood stem cells in that setting. Their work is an example of the "FLASH effect" (efficacy against tumors; innocuousness for healthy tissues), which will surely bring great benefits to patients once it arrives in the clinic. That arrival however is dependent on the development of pertinent radiological equipment for the clinic.

1 :  Treatment of a first patient with FLASH-radiotherapy I Radiotherapy and Oncology

2 : About 80% of childhood leukemia cases are acute lymphoblastic leukemia (ALL). There are several subtypes, the most important of which are B-ALL (involving B-cells) and T-ALL (involving T-cells). ALL is characterized by the proliferation of malignant blood cell precursors, blocked at an early stage of differentiation, in the blood, the bone marrow and sometimes other organs.

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