Blood Cancer Risk After CAR-T and Stem Cell Transplants: Systematic Review Maps Latency and Clonal Drivers

Revolutionary cancer therapies that reprogram the immune system have transformed outcomes for patients with relapsed blood cancers, but a new systematic review is drawing attention to an unwelcome consequence that can emerge years after treatment. The analysis, published in Annals of Hematology, synthesizes the reported incidence, timing, and molecular features of therapy-related myeloid neoplasms, a family of secondary blood cancers that includes therapy-related acute myeloid leukemia and myelodysplastic syndrome, arising after two of the most intensive approaches in modern hematology: chimeric antigen receptor T-cell therapy, widely known as CAR-T, and autologous stem cell transplantation, or ASCT. Both approaches are given to patients who have usually already endured multiple lines of chemotherapy, and the review makes clear that this cumulative treatment burden, together with age-related changes in the bone marrow, shapes who goes on to develop a second, treatment-driven malignancy.

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