# Alkylating agents and therapy-related myeloid neoplasms

Source: https://onco.cc/terms/rejuv-second-alkylating-agents-and-myeloid-neoplasms/  
OnCo record `rejuv-second-alkylating-agents-and-myeloid-neoplasms` (Term). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Alkylating chemotherapy can damage a blood stem cell in a way that shows up years later as myelodysplastic syndrome or acute myeloid leukaemia. It is uncommon, it depends on the total dose, and the risk falls away after about ten years. Knowing the cumulative dose you were given is the single most useful thing on your treatment summary.

## Summary

What is done about it. Nothing is given to prevent it, so the whole of the answer sits at the time of treatment: the lowest cumulative alkylator dose that achieves the result, and an alkylator-free option where an equivalent one exists. Afterwards, a full blood count is the test, and an unexplained and persistent drop in any cell line is the reason to look further rather than wait.

The pattern. Alkylating agents and radiotherapy produce a myeloid neoplasm with a characteristic shape: a latency of several years, a phase of myelodysplasia before frank leukaemia, and losses or deletions of chromosomes 5 and 7. In 306 consecutive patients with therapy-related myelodysplasia or myeloid leukaemia referred to the University of Chicago from 1972 onwards, 240 (78 per cent) had received alkylating agents and 115 (39 per cent) topoisomerase II inhibitors. At diagnosis, 282 (92 per cent) had a clonal chromosome abnormality: chromosome 5 in 63, chromosome 7 in 85, both in 66, a recurring balanced rearrangement in 31, another clonal change in 39, and a normal karyotype in 24. Abnormalities of chromosome 5, 7 or both accounted for 76 per cent of all abnormal karyotypes. Median latency in the group without balanced rearrangements was 67 months.

Dose matters, and it has been measured. The National Surgical Adjuvant Breast and Bowel Project pooled six adjuvant trials that tested doxorubicin and cyclophosphamide at different cyclophosphamide intensities. With two or four cycles of cyclophosphamide at 2,400 mg/m2 supported by granulocyte colony-stimulating factor, the cumulative incidence of acute myeloid leukaemia or myelodysplastic syndrome at five years was 1.01 per cent (95% CI 0.63 to 1.62). With standard doxorubicin and cyclophosphamide, 600 mg/m2 every 21 days for four cycles, it was 0.21 per cent (0.11 to 0.41). Patients who also had breast radiotherapy had more secondary leukaemia than those who did not (relative risk 2.38, P = .006). The authors state that the incidence "was small relative to that of breast cancer relapse", which is the comparison a reader needs to hold both numbers at once.

How often, across all solid cancers. Among 700,612 adults aged 20 to 84 diagnosed with a first solid cancer between 2000 and 2013 in SEER, who received initial chemotherapy and survived at least a year, there were 1,619 cases of therapy-related myelodysplastic syndrome or acute myeloid leukaemia. Risk was raised after chemotherapy for 22 of 23 solid cancers, every one except colon. Relative risks ran from 1.5 to more than 10, and excess absolute risks from 1.4 to more than 15 cases per 10,000 person-years compared with the general population. The paper's estimate is that for people treated now, "approximately three-quarters of tMDS/AML cases expected to occur within the next 5 years will be attributable to chemotherapy".

What happens then, with its cohort. In the Chicago series, median survival after a diagnosis of therapy-related myelodysplasia or myeloid leukaemia was 8 months and survival at five years was under 10 per cent; that is a median in a referral series treated between 1972 and 2002, so half of those counted lived longer and treatment has changed since. In the SEER cohort treated from 2000 onwards, 1,270 of 1,619 people (78.4 per cent) had died by the end of follow-up, with a median overall survival of 7 months. Therapy-related and spontaneous myeloid neoplasms share the same genetic pathways, which is why the argument has been made for decades that they should be classified and treated the same way.

When the risk ends. The review by Leone and colleagues states that treatment for breast cancer and germ-cell tumours has been associated with a 1 to 5 per cent lifetime risk of leukaemia, and that "in all cases the risk of t-MDS/AML drops sharply by 10 years after treatment". That is the one genuinely reassuring sentence in this literature, and it is specific to the myeloid neoplasms: the solid second cancers after radiotherapy behave in the opposite way and keep rising.

## Fields

- Kind: Term
- Last checked: 2026-10-02
- Also known as: t-MDS; t-AML; Therapy-related myelodysplastic syndrome; Secondary leukaemia after chemotherapy
- Tags: rejuvenation; survivorship; second-cancers; blood; chemotherapy

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Alkylating_antineoplastic_agent
- Smith et al., Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series (Blood 2003): https://doi.org/10.1182/blood-2002-11-3343
- Smith et al., Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the NSABP experience (JCO 2003): https://doi.org/10.1200/JCO.2003.03.114
- Morton et al., Association of chemotherapy for solid tumors with development of therapy-related myelodysplastic syndrome or acute myeloid leukemia in the modern era (JAMA Oncol 2019): https://doi.org/10.1001/jamaoncol.2018.5625
- Leone et al., Therapy-related leukemia and myelodysplasia: susceptibility and incidence (Haematologica 2007): https://doi.org/10.3324/haematol.11034
- Pedersen-Bjergaard et al., Genetics of therapy-related myelodysplasia and acute myeloid leukemia (Leukemia 2008): https://doi.org/10.1038/sj.leu.2405078

## Connected records

- terms: [Bladder cancer after cyclophosphamide](https://onco.cc/terms/second-primary-bladder-after-cyclophosphamide/), [Choices made at the time of treatment that change the second cancer risk](https://onco.cc/terms/rejuv-second-choices-made-at-treatment/), [From a clone in the blood to a leukaemia: what is known, and what is done](https://onco.cc/terms/rejuv-second-from-clone-to-disease/), [Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [Platinum drugs and PARP inhibitors: the newer leukaemia risk](https://onco.cc/terms/rejuv-second-platinum-and-parp-inhibitors/), [Second cancers after treatment: what the risk is, and what is done about it](https://onco.cc/terms/rejuv-second-cancers-overview/), [Secondary malignancy (therapy-related cancer)](https://onco.cc/terms/secondary-malignancy/), [Topoisomerase II inhibitors and the shorter latency](https://onco.cc/terms/rejuv-second-topoisomerase-inhibitors-short-latency/)
- technologies: [Clonal haematopoiesis after cancer treatment](https://onco.cc/technologies/rejuv-age-clonal-haematopoiesis-after-therapy/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [Survivorship care and late-effects surveillance](https://onco.cc/technologies/survivorship-care-plan/)
- cancers: [Acute myeloid leukaemia](https://onco.cc/cancers/aml/), [Breast cancer (all types)](https://onco.cc/cancers/breast-cancer/), [Multiple myeloma](https://onco.cc/cancers/multiple-myeloma/), [Myelodysplastic syndromes / neoplasms (MDS)](https://onco.cc/cancers/mds/), [Ovarian cancer](https://onco.cc/cancers/ovarian/), [Secondary and therapy-related acute myeloid leukaemia](https://onco.cc/cancers/aml-secondary/)
- fronts: [Recovery & Rejuvenation](https://onco.cc/fronts/rejuvenation/), [Supportive Care & Survivorship](https://onco.cc/fronts/supportive-care/)
- drugs: [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Doxorubicin](https://onco.cc/drugs/doxorubicin/), [Mechlorethamine (chlormethine)](https://onco.cc/drugs/mechlorethamine/), [Melphalan (including hepatic delivery system)](https://onco.cc/drugs/melphalan/), [Procarbazine](https://onco.cc/drugs/procarbazine/)
- bottlenecks: [Survivorship and late effects are neglected](https://onco.cc/bottlenecks/b-survivorship/), [Toxicity and quality of life are undervalued](https://onco.cc/bottlenecks/b-toxicity-qol/)

---
JSON: https://onco.cc/api/v1/entities/rejuv-second-alkylating-agents-and-myeloid-neoplasms.json