Therapy-Related Myeloid Neoplasms Following CAR-T Therapy: Emerging Patterns, Risk Factors, and Clinical Challenges

Safwan Muhammad, MD, Amna Shaukat, MD

INTRODUCTION

CAR-T therapy has transformed outcomes for patients with relapsed/refractory hematologic malignancies, creating an expanding population of long-term survivors.
Secondary malignancies, particularly therapy-related myeloid neoplasms (t-MNs), are increasingly recognized after CAR-T therapy.
Reported t-MNs include myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and MDS/AML.
Attribution to CAR-T remains challenging given extensive prior exposure to cytotoxic chemotherapy and hematopoietic transplantation.
Emerging data implicate pre-existing clonal hematopoiesis (CH), TP53 abnormalities, and treatment-related hematopoietic stress in t-MN development.
Objective: To characterize the incidence, clinical patterns, risk factors, molecular features, and outcomes of t-MNs following CAR-T therapy.

Focused systematic literature review of published studies reporting MDS, AML, or other t-MNs following CAR-T therapy.
Included studies involving any CAR-T target/product and underlying hematologic malignancy.
Prioritized primary cohort studies with extractable data on incidence, risk factors, molecular findings, or outcomes.
Duplicate/overlapping cohorts, systematic reviews, and isolated case reports were excluded from the primary evidence synthesis.
15 studies were selected for qualitative synthesis following assessment of relevance and potential cohort overlap.
Extracted variables included:
- CAR-T product/target and underlying malignancy
- Patient and t-MN numbers
- MDS vs AML
- Follow-up and time to t-MN
- Prior chemotherapy/ASCT
- Cytopenias and hematologic toxicity
- CH/CHIP and molecular abnormalities
- Cytogenetics and clinical outcomes

Reported t-MN incidence across contemporary cohorts was generally ~2–6%, with cumulative incidence increasing with longer follow-up.
Contemporary cohorts demonstrated cumulative incidence approaching ~9–10% with extended follow-up.
t-MNs generally developed within 1–2 years after CAR-T, although later events were observed.
MDS was more frequently reported than AML among post-CAR-T myeloid neoplasms.

Patients developing t-MNs were typically heavily pretreated.
Common prior exposures included:
- Alkylating agents/bendamustine
- Platinum-based chemotherapy
- Melphalan in multiple myeloma
- Autologous stem-cell transplantation
Persistent/prolonged cytopenias and hematologic toxicity following CAR-T were frequently observed.
Older age and greater cumulative treatment exposure were associated with increased risk in several cohorts.

Pre-existing clonal hematopoiesis was increasingly identified among patients who subsequently developed t-MN.
Recurrent alterations included TP53, DNMT3A, RUNX1, and other myeloid-associated genes.
Poor-risk/complex cytogenetic abnormalities were frequently reported.
Detection of pre-existing clones supports a model of clonal selection/expansion rather than purely de novo leukemogenesis.

MDS predominated, followed by AML.
t-MNs have been reported after both CD19- and BCMA-directed CAR-T.
Cases occurred across lymphoma, ALL, and multiple myeloma populations.
Emerging BCMA CAR-T data suggest that t-MN risk is not restricted to CD19-directed therapy.

Development of t-MN was associated with substantial morbidity and poor clinical outcomes.
Patients frequently presented with persistent cytopenias, adverse cytogenetics, and high-risk molecular features.
Available data suggest poor survival after development of AML/MDS, highlighting the need for early recognition.

The available evidence does not establish CAR-T as an independent leukemogenic exposure.
Extensive prior cytotoxic therapy and transplantation remain major potential contributors to t-MN risk.
Increasing evidence of baseline CH and TP53-associated clones suggests that pre-existing hematopoietic vulnerability may precede CAR-T therapy.
CAR-T-associated immune/hematopoietic stress may provide selective pressure favoring expansion of pre-existing abnormal clones.
Differences in follow-up, patient selection, surveillance, and competing mortality contribute to variability in reported incidence.
Persistent cytopenias after CAR-T should prompt consideration of bone marrow evaluation, particularly in heavily pretreated patients.
Prospective assessment of CH and myeloid-associated mutations may improve risk stratification.
Long-term hematologic surveillance is warranted as CAR-T survivors live longer.

Predominantly retrospective cohort data with heterogeneous follow-up.
Variable definitions and ascertainment of t-MN across studies.
Significant confounding from prior chemotherapy and transplantation.
Molecular data were available only in a subset of patients.
Potential cohort overlap required careful study selection.
Limited event numbers restrict the ability to establish independent risk factors.

Therapy-related myeloid neoplasms are uncommon but clinically serious complications following CAR-T therapy.
MDS appears to be the predominant phenotype, with AML representing an important subset.
Risk is likely multifactorial, involving prior cytotoxic therapy, transplantation, persistent hematologic toxicity, and pre-existing clonal hematopoiesis.
Emerging molecular evidence suggests CAR-T-associated hematopoietic stress may select for pre-existing vulnerable clones rather than directly causing de novo myeloid neoplasia.
Long-term follow-up and prospective molecular surveillance are needed to define true incidence, identify high-risk patients, and clarify the contribution of CAR-T therapy itself.