The study, published in Nature Genetics by a team led by Kelly L. Bolton of Washington University School of Medicine together with collaborators at Memorial Sloan Kettering Cancer Center and other institutions, addresses a pressing clinical problem. PARP inhibitors have transformed treatment for ovarian, breast, pancreatic and prostate cancers driven by defects in homologous recombination repair, and their use is expanding into frontline settings. But these drugs have been associated with an increased risk of therapy-related myeloid neoplasms — lethal cancers of the blood-forming system with a five-year survival of less than 10 percent. Reported five-year risks of these neoplasms in clinical trials and claims-based studies have varied wildly, from under 1 percent to more than 10 percent, and the reasons for this variation have remained unclear.

The origin of most therapy-related myeloid neoplasms is clonal hematopoiesis, an age-related phenomenon in which hematopoietic stem and progenitor cells acquire somatic mutations that allow them to outcompete their normal neighbors. Mutations in TP53, the most commonly mutated gene in therapy-related myeloid neoplasms, are considered a hallmark of the disease. Previous work by this group and others showed that TP53-mutant clones are often present in the blood before cancer therapy begins, and that exposure to cytotoxic treatment gives these mutants a fitness advantage over wild-type stem cells, driving their expansion. In a subset of individuals, these clones acquire additional hits — loss of the second TP53 allele and copy number alterations — marking the transition to full-blown malignancy.

To dissect the contribution of PARP inhibitors, the team first reanalyzed data from 10,156 patients sequenced with the MSK-IMPACT targeted panel at Memorial Sloan Kettering. They found that 18.5 percent of patients exposed to PARP inhibitors carried detectable mutations in DNA damage response genes as clonal hematopoiesis, compared with only 4.5 percent of patients exposed to other therapies and 1.4 percent of untreated individuals. PARP inhibitor exposure showed the strongest association with DNA damage response clonal hematopoiesis of any treatment class, with an odds ratio of 4.4. But a confounding problem loomed: every PARP inhibitor-treated patient in the cohort had also received other systemic therapies, particularly carboplatin, which the same group had previously linked strongly to clonal expansion. When the researchers adjusted statistically for exposure to cytotoxic therapy classes and their cumulative doses, the association between PARP inhibitors and clonal hematopoiesis shrank steadily, from an odds ratio of 4.4 down to 2.9 and finally to 1.5, no longer statistically significant.

To overcome this confounding directly, the investigators turned to prospective serial sampling. They collected blood from 250 patients before and after treatment with either a PARP inhibitor (100 patients) or carboplatin (150 patients), and compared the results with serial samples from 176 age-matched healthy individuals. Using an ultra-deep error-corrected sequencing approach with the ArCH variant calling pipeline at roughly 18,000-fold coverage, they detected 921 putative driver mutations down to a variant allele fraction of just 0.2 percent — half of which were tiny clones undetectable by standard methods. After treatment, 51 percent of patients carried a DNA damage response clonal hematopoiesis mutation, with an average of two mutations per person, compared with 22.7 percent of healthy controls.

The crucial comparison came from modeling the exponential growth rate of each clone between the two time points. Both carboplatin and PARP inhibitor exposure accelerated the growth of clones carrying mutations in the DNA damage response genes PPM1D, TP53 and CHEK2, while clones carrying mutations in the common epigenetic regulator genes DNMT3A, TET2 and ASXL1 remained unchanged. But carboplatin drove significantly faster expansion than PARP inhibitors across all three genes, a difference that held even when the analysis was restricted to patients carrying only a single TP53 or PPM1D mutation. Within the PARP inhibitor class, the drug with the strongest PARP-trapping activity, talazoparib, was a stronger driver of clone expansion than olaparib, consistent with its greater capacity to inflict DNA damage. Interestingly, patients who had received prior cytotoxic or radiation therapy showed reduced clone growth rates during subsequent PARP inhibitor or carboplatin treatment, suggesting that the most expansion-prone clones may have already been depleted or that the cellular landscape changes with repeated exposure.

The team also examined mosaic chromosomal alterations — acquired copy number changes detectable in blood DNA — using SNP array profiling in 347 patients. Nearly a quarter of individuals carried at least one such event at some point. PARP inhibitor exposure significantly increased the expansion of autosomal copy number alterations, driven largely by newly detected events, with a similar but non-significant trend after carboplatin. Most tellingly, patients with pre-existing TP53 clonal hematopoiesis were 6.4-fold more likely to acquire a detectable mosaic chromosomal alteration during therapy, and the risk rose with the size of the pre-existing clone. This finding fits the established narrative that TP53 loss paves the way for the complex aneuploidy characteristic of therapy-related myeloid neoplasms.

The most surprising result concerned inherited genetics. Because many patients receiving PARP inhibitors carry germline pathogenic variants in homologous recombination genes such as BRCA1 and BRCA2, the researchers hypothesized that a single defective copy of these genes in blood stem cells would amplify the fitness advantage of DNA damage response mutations under treatment pressure. The opposite occurred. Clone growth was significantly reduced in germline HRD carriers after both PARP inhibitor and carboplatin treatment, a pattern specific to DNA damage response genes and absent among the epigenetic regulator clones. Even among HRD carriers, carboplatin still outpaced PARP inhibitors in driving expansion. The pattern held for both BRCA1/2 carriers and carriers of mutations in other homologous recombination genes.

Mouse experiments validated and mechanistically explained the human findings. In competitive bone marrow transplantation models, Trp53-mutant hematopoietic cells carrying the murine equivalent of a common human TP53 hotspot mutation expanded markedly after cisplatin treatment and modestly after talazoparib, but showed no advantage with olaparib — mirroring the patient data. When the researchers introduced a heterozygous Brca1 mutation into both the mutant and competitor cells, the picture changed dramatically. Double-mutant cells showed a severe engraftment defect even without treatment, and after cisplatin or talazoparib they failed to expand, with their contribution to blood and bone marrow significantly reduced compared with Brca1-wild-type controls. Notably, mice with heterozygous Brca1-mutant marrow treated with talazoparib developed severe anemia, and 9 of 34 such mice died during the four-week treatment.

Single-cell analyses revealed the mechanism. A single dose of talazoparib increased double-stranded DNA breaks in all genotypes, measured by neutral comet assay and γH2AX staining, but the damage was greatest in Brca1-haploinsufficient cells. Critically, cells carrying both heterozygous Brca1 and Trp53 mutations showed significantly greater apoptosis — measured by cleaved caspase 3 — than cells with either mutation alone, even at baseline. The interpretation is that Brca1 haploinsufficiency renders blood stem cells vulnerable to PARP inhibitor-induced DNA damage, while the concurrent TP53 mutation cripples their ability to resolve that stress, triggering cell death rather than clonal expansion. This challenges the prevailing view, based largely on epithelial tumor cells, that a single functional copy of BRCA1 is sufficient for DNA repair, and suggests blood stem cells are unusually sensitive to BRCA1 dosage. The authors caution that whether these clonal dynamics translate directly into myeloid neoplasm risk requires long-term follow-up, ideally in prospective PARP inhibitor trials. They also note that analyses of the ARIEL2 and ARIEL3 rucaparib trials found that duration of prior platinum exposure, not inherited predisposition, was the greatest predictor of myeloid neoplasm risk. If validated, serial clonal hematopoiesis profiling before and during treatment could become a practical tool for identifying which patients need heightened surveillance — and reinforce the message that the drugs patients received before a PARP inhibitor may matter as much as the inhibitor itself.

Subject of Research: How germline homologous recombination deficiency and platinum or PARP inhibitor therapy shape TP53-mutant clonal hematopoiesis and therapy-related myeloid neoplasm risk

Article Title: Germline homologous recombination deficiency influences TP53-mutant clonal hematopoiesis fitness during platinum and PARP inhibitor treatment

Article References: Baeten, J. T., Chan, I. C. C., Moukarzel, L., Petrone, G. E. M., Liu, J., Tran, D., Tabs, J., Tabet, I., Agashe, S., Nasrollahzadeh, E., Vasireddy, A., Carter, A., Patel, M., Stopsack, K. H., Kantoff, P. W., Zhou, W., Batchi-Bouyou, A. L., Beeler, J. S., Mustion, G., … Bolton, K. L. (2026). Germline homologous recombination deficiency influences TP53-mutant clonal hematopoiesis fitness during platinum and PARP inhibitor treatment. Nature Genetics. https://doi.org/10.1038/s41588-026-02752-2

Image Credits: AI Generated

DOI: 10.1038/s41588-026-02752-2

Keywords: clonal hematopoiesis, PARP inhibitors, carboplatin, TP53, BRCA1, homologous recombination deficiency, therapy-related myeloid neoplasms, PPM1D, mosaic chromosomal alterations, hematopoietic stem cells, DNA damage response, Nature Genetics

The research team, led by Adeena Musheer and colleagues working across institutions in Pakistan and the United States, conducted the review according to PRISMA 2020 guidelines, the current international standard for systematic evidence synthesis. They searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and grey literature sources from database inception through December 2025. To be included, studies had to report myeloid neoplasms diagnosed after CAR-T therapy or ASCT and provide extractable data on at least one of three parameters: incidence, latency, or molecular characteristics. Because the included studies varied enormously in design, patient populations, and reporting conventions, the authors synthesized their findings descriptively rather than attempting a meta-analysis, a decision that reflects an honest assessment of the state of the evidence. Nine studies comprising 2,933 patients ultimately met the inclusion criteria, and within those cohorts a total of 195 therapy-related myeloid neoplasm cases were reported.

One of the most striking findings concerns latency, the interval between the initial therapy and the diagnosis of the secondary cancer. The review found that median latency varied widely across studies, but the pattern differed meaningfully between the two treatment modalities. Following CAR-T therapy, reported median latency ranged from just 3 to 78 months, a window that in some cohorts was remarkably short. In contrast, ASCT cohorts reported longer intervals, spanning from 2.4 to as much as 262.8 months, meaning that some secondary leukemias appeared more than two decades after transplantation. This difference in timing is biologically intriguing. CAR-T therapy itself is not a classical DNA-damaging agent in the way that alkylating chemotherapy or total body irradiation are, so the shorter latency observed after CAR-T likely reflects the fact that these patients arrive at the therapy with bone marrows already heavily scarred by prior cytotoxic exposure, with pre-existing mutant clones poised for outgrowth once the selective pressures of treatment remove competing normal hematopoiesis.

That mechanistic picture is supported by the molecular data the review assembled. Half of the included studies assessed clonal haematopoiesis, the age-related phenomenon in which blood cells descended from a single mutated stem cell progressively dominate the marrow. Clonal haematopoiesis is increasingly understood as the soil in which therapy-related myeloid neoplasms grow: pre-leukemic clones carrying mutations in specific genes tolerate chemotherapy better than normal stem cells, expand to fill the void left by treatment, and in some patients acquire additional hits that drive full-blown malignancy. In the studies reviewed, the prevalence of clonal haematopoiesis ranged from 20 percent to over 80 percent, and crucially, higher rates were observed among patients who went on to develop therapy-related myeloid neoplasms. Recurrent mutations in three genes in particular, DNMT3A, TET2, and TP53, were consistently identified across both CAR-T and ASCT cohorts, underscoring that the two treatments share common biological underpinnings for this complication.

The identity of those three genes tells a coherent story. DNMT3A and TET2 are the two most commonly mutated genes in age-related clonal haematopoiesis in the general population, and both encode enzymes involved in DNA methylation regulation, a key epigenetic control mechanism in stem cells. Mutant TET2 and DNMT3A clones are known to be chemotherapy-resistant and to expand preferentially after cytotoxic treatment. TP53, by contrast, is the guardian of the genome, and mutations in it confer both resistance to certain therapies and a propensity toward genomic instability and aggressive leukemic transformation. The consistent finding of TP53 mutations in therapy-related myeloid neoplasms after both CAR-T and ASCT suggests that, in a subset of patients, the seeds of the secondary cancer are present before the transplant or CAR-T infusion even occurs, having been selected and amplified by earlier chemotherapy cycles.

The survival data in the review are sobering and represent perhaps its most clinically consequential message. Once a therapy-related myeloid neoplasm developed, outcomes were poor in both settings, but the prognosis was markedly worse after CAR-T therapy. Patients in CAR-T cohorts had a median overall survival of only 4.5 months following diagnosis of the secondary neoplasm, while ASCT cohorts fared better with a median overall survival of 18.4 months. Several factors could contribute to this disparity. Patients receiving CAR-T in the included studies may have had more heavily pretreated disease, more advanced clonal evolution by the time of the CAR-T infusion, or less reserve to tolerate intensive induction chemotherapy for the secondary leukemia. The authors themselves caution that these observations should be interpreted in the context of heterogeneous study designs and differing degrees of prior treatment exposure, so the comparison between modalities is not a head-to-head trial result but a signal that warrants prospective investigation.

The methodological limitations of the underlying evidence base are significant and the review does not shy away from them. Risk of bias was judged to be moderate to high across the included studies, primarily because of retrospective designs, confounding, and heterogeneity in how outcomes were reported. Retrospective cohort studies are vulnerable to incomplete follow-up, ascertainment bias in detecting secondary cancers, and the impossibility of fully adjusting for the many differences between patients who receive CAR-T versus those who proceed to ASCT. Because pooled incidence estimates could not be calculated, clinicians reading this review will not find a single number they can quote to a patient about their absolute risk. What they will find instead is a consistent qualitative picture: therapy-related myeloid neoplasms are a real and clinically significant complication in both settings, they occur with distinct latency patterns, and they are driven by shared clonal biology.

The implications for clinical practice are already taking shape. As CAR-T therapy expands from relapsed and refractory lymphomas and myelomas into earlier lines of treatment, the population of long-term survivors exposed to this modality is growing rapidly, and the review’s findings argue strongly for structured long-term surveillance of these patients. The authors highlight the need to incorporate molecular risk stratification strategies into the care of heavily pretreated patients. In practical terms, this could mean screening for clonal haematopoiesis before or after CAR-T infusion or transplant, with the presence of high-variant-allele-fraction TP53 or other high-risk mutations flagging patients who merit closer blood count monitoring and earlier referral for evaluation. Such an approach mirrors what is already being explored in solid tumor oncology, where clonal haematopoiesis testing is increasingly used to interpret circulating tumor DNA and to anticipate chemotherapy-associated complications.

For the field at large, this systematic review arrives at a pivotal moment. CAR-T cell therapy is one of the most celebrated advances in cancer medicine of the past decade, producing durable remissions in patients whose disease had exhausted every conventional option, and autologous transplantation remains a cornerstone of treatment for myeloma and lymphoma. The finding that 195 secondary myeloid cancers occurred among roughly 2,900 patients across nine studies does not diminish the value of these therapies, but it does define the frontier of the next challenge: preserving their remarkable benefits while identifying, before treatment, the minority of patients whose marrow clones place them at highest risk of a second malignancy. The review’s central contribution is to consolidate scattered single-center reports into a coherent evidence map, one that shows shorter latency and poorer survival after CAR-T, longer and more variable latency after ASCT, and a common molecular signature rooted in DNMT3A, TET2, and TP53. Converting that map into prospective screening programs, standardized reporting, and ultimately preventive strategies is the task the authors have set for the field, and it is one that will only grow more urgent as these therapies reach ever larger numbers of patients.

Subject of Research: Therapy-related myeloid neoplasms following CAR-T cell therapy and autologous stem cell transplantation

Article Title: Therapy-related myeloid neoplasms after CAR-T therapy and autologous stem cell transplantation: a systematic review of reported incidence, latency, and clonal haematopoiesis

Article References: Musheer, A., Mannan, M. S., Khan, M. W., Bhatti, A., Hafeez, A. S., Junaid, A., & Muhammad, S. (2026). Therapy-related myeloid neoplasms after CAR-T therapy and autologous stem cell transplantation: a systematic review of reported incidence, latency, and clonal haematopoiesis. Annals of Hematology. https://doi.org/10.1007/s00277-026-07305-5

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07305-5

Keywords: therapy-related myeloid neoplasms, CAR-T therapy, autologous stem cell transplantation, clonal haematopoiesis, acute myeloid leukemia, myelodysplastic syndrome, DNMT3A, TET2, TP53, latency, systematic review, hematology