What do atomic bomb survivors teach us about therapy-free remission in people with chronic myeloid leukaemia?

TO THE EDITOR: People with chronic myeloid leukaemia (CML) who stop tyrosine kinase inhibitors (TKIs) and are in therapy-free remission (TFR) can have minimal residual disease (MRD) [1]. One

explanation is that anti-CML immune responses control CML clone growth [2]. This is controversial [3]. If true, too few leukaemia stem cells (LSCs) and their progeny may fail to stimulate

immunity and too many may overwhelm it [4]. The A-bombings of 1945 generated two mysteries [5]. One is in Hiroshima radiation-induced CML occurred with expected latencies of 5–10 years in 2

of 6 females and in 9 of 10 males, but in 4 of 6 females, onsets were delayed and clustered from 1969 to 1974. The other is in Nagasaki survivors no cases of CML were observed in a dose

cohort in which ~9 were expected (Fig. 1). Why were 4 Hiroshima female radiation-induced cases delayed and why were their onsets clustered? Delays may have occurred because immunity is more

likely to be induced in females who have stronger immune responses compared with males [6]. Clustering may have occurred because the 1968 Hong Kong flu pandemic entered Japan in 1969, the

same year as the first delayed female Hiroshima CML onset case, and evolved into the H3N2 seasonal flu [7]. Put otherwise, we hypothesise that H3N2 exhausted anti-CML immunity in the A-bomb

survivors and that this released latent neoplastic radiation-induced _BCR::ABL1_-positive cells and thus clustered delayed onset Hiroshima females [8]. A study of mice provides some support

for this idea [9]. Why was immunity in Nagasaki so strong that onsets were delayed indefinitely in both sexes? Hiroshima-Nagasaki city differences in CML (Fig. 1) may have occurred via

endogenous HTLV-1 infection present in Nagasaki but not in Hiroshima [10]. This hypothesis has 3 contingencies: (1) CD4-positive cells expanded in numbers before the bombings because of

endemic HTLV-1 infection and were the target of radiation-induced _BCR::ABL1_-positive non-neoplastic clones; (2) numbers of such cells were sufficiently high such that every adult exposed

to >0.2 Sieverts (Sv) in Nagasaki developed ≥1 CD4-positive cell with a _BCR::ABL1_ translocation and consequently developed immunity to CML including CML unassociated with radiation

exposure; and (3) relative to Hiroshima, CD4-positive cells were more effective in both sexes in Nagasaki because there they expressed not only _BCR::ABL1_ but also HTLV-1-infection-related

genes. Put otherwise, we hypothesise CD4-positive T-cells delivered _BCR::ABL1_ immunogenic peptides to invoke immunity, HTLV-1 was an adjuvant that boosted anti-CML immunity, and

CD4-positive, _BCR::ABL1_-positive clones were self-limiting by acting as auto-vaccines [8]. A study of people attempting TFRs claims to have identified 3 types of subjects [4]. We suggest

these cohorts correspond to people who are Hiroshima-male-like (incapable of holding a TFR), Hiroshima-female-like (capable of holding a TFR but at random times of immuno-suppression this

TFR can be lost), and Nagasaki-like (capable of holding TFRs robustly across immuno-compromising perturbations) [8]. To further connect A-bomb survivors to these TFR cohorts we focus on the

founding LSC, which is likely a very primitive, TKI-resistant cell [11]. We suggest that if someone with CML lives sufficiently long this founding LSC will produce a _BCR::ABL1_-positive

CD4-positive T-cell which will form a benign clone that will protect him/her against neoplastic LSCs. The existence of this immune-enhancing LSC founder event is consistent with _BCR::ABL1_

expression in T-cells in 11 of 20 subjects with CML in TFR [12]. It is also consistent with CD4-positive T-cells expanding because of high expression of _ABL1_ [13]. An immune-enhancing

event such as the LSC founder creating a CD4-positive T-cell could create an energy landscape valley in which _BCR::ABL1_ transcripts could stably exist (Fig. 2). Thus, beyond teaching us

that TFR MRD states could arise via energy landscape valleys, A-bomb survivors teach us to look for new ways to control CML via CD4-positive T-cells; new ways are still needed, at least in

the US [14]. In a study of 68 patients attempting TFRs, 5 who succeeded had MRD, perhaps via immuno-control, and 39 who succeeded had undetectable disease, perhaps via eradication [1]. Thus,

as low as 11% (5/44) of TFRs may have been by immuno-control. Of these, half might be Nagasaki-like and half Hiroshima-female-like [4, 8]. Only the latter (~5% of TFRs) are expected to be

susceptible to relapses via flu or COVID infections. Ten of 10 CML cases among Chernobyl accident cleanup workers arose after long delays [15]. As they were all young when exposed, the

delays could reflect 20–30 years being needed to reach ages at which CML is more common. Without an estimate of the number of CML cases expected if Chernobyl accident cleanup workers were

not exposed, it is unclear how many of the 10, if any, were Hiroshima-female-like. Onset clustering in Hiroshima and cases missing in Nagasaki are hard to explain [5]. Evidence for our

explanation includes the alternatives having inconsistencies [8]. Via our explanation, A-bomb survivors teach us to look for a CD4-positive cell role in CML immunity. DATA AVAILABILITY

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editors for their excellent suggestions. RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre. We thank the R community for its support

through free software. This report is the sole responsibility of the authors; it does not represent the views of the Radiation Effects Research Foundation (RERF). AUTHOR INFORMATION AUTHORS

AND AFFILIATIONS * Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA Tomas Radivoyevitch * Centre for Haematology, Department of Immunology and Inflammation,

Imperial College of Science, Technology and Medicine, London, UK Robert Peter Gale * Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA Matt E. Kalaycio

Authors * Tomas Radivoyevitch View author publications You can also search for this author inPubMed Google Scholar * Robert Peter Gale View author publications You can also search for this

author inPubMed Google Scholar * Matt E. Kalaycio View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS The authors conceived the study, prepared

the typescript, took responsibility for the content and agreed to submit it for publication. CORRESPONDING AUTHOR Correspondence to Tomas Radivoyevitch. ETHICS DECLARATIONS COMPETING

INTERESTS RPG is a consultant to Antengene Biotech LLC; Medical Director, FFF Enterprises Inc.; A speaker for Janssen Pharma and Hengrui Pharma; Board of Directors: Russian Foundation for

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teach us about therapy-free remission in people with chronic myeloid leukaemia?. _Leukemia_ 38, 207–209 (2024). https://doi.org/10.1038/s41375-023-02081-x Download citation * Received: 11

September 2023 * Revised: 24 October 2023 * Accepted: 01 November 2023 * Published: 10 November 2023 * Issue Date: January 2024 * DOI: https://doi.org/10.1038/s41375-023-02081-x SHARE THIS

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