Secondary Myeloid Neoplasms after CD19 CAR-T Cell Therapy: Real-Life Multicenter Data from the Clonhema Study
Authors: Farina Mirko , Galli Eugenio , Riva Marcello , Cutini Ilaria , Bernardi Simona , Martino Massimo , Ferrari Silvia , Battipaglia Giorgia , Novo Mattia , Musso Maurizio , Grillo Giovanni , Santarone Stella , Krampera Mauro , Aroldi Andrea , Polverelli Nicola , Arcaini Luca , Re Alessandro , Xhahysa Besjana , Leoni Alessandro , Tisi Maria Chiara , Chiusolo Patrizia , Malagola Michele , Russo Domenico 
Published: December 2024

Background
Chimeric antigen receptor T (CAR-T) cells are an advanced immunotherapy. Prolonged cytopenia is a common late adverse event of CAR-T cell therapy and it may hesitate to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). We retrospectively evaluated the development of secondary myeloid neoplasia (SMN) following CAR-T therapy in a multicenter, real-life study as part of the ClonHema trial.
Methods
SMN development was assessed in patients (pts) treated with commercial anti-CD19 CAR-T cells (axicabtagene ciloleucel, axi-cel; tisagenlecleucel, tisa-cel; and brexucabtagene autoleucel, brexu-cel) for Large B-cells Lymphomas, Mantle cell lymphomas (MCL), Follicular lymphoma (FL) and Acute Lymphoblastic Leukemia across 16 Italian Centers from November 2019 to May 2024. The study protocol was approved by the local ethics committee (BS-NP5554).
Potential risk factors for post-CAR-T SMN were analyzed, including previous treatments, cytopenia, clonal hematopoiesis, CRS, ICANS, immune effector cell-associated haematotoxicity (ICAHT), and the CAR-HEMATOTOX score.
Results
Since November 2019, 555 pts received CAR-T cells. Overall, 13 pts (2.3%) developed SMN, including 12 with MDS and 1 with AML. Two MDS pts subsequently developed AML. The median time from CAR-T cell infusion to SMN was 6.7 months (1.3-40.6). The median age was 61 years. Nine pts had Diffuse Large B-Cell Lymphoma (DLBCL), 3 had DLBCL transformed from FL, and 1 had MCL. Eleven pts had an Ann Arbor Stage III-IV, while 3 pts had bone marrow involvement. The median number of treatment lines before CAR-T was 3 (2-6), and 6 pts received autologous stem cell transplantation (ASCT).
SMN onset was not related to a specific CAR-T cell product (n=6 for both Axi-cel and Tisa-cel). Eleven pts had CRS grade 1-2, and 5 had ICANS grade 1-3. Nine pts (69%) had a high CAR-HEMATOTOX risk score. Further studies are needed to explore its potential role also as a predictor of SMN. Eight pts (62%) experienced severe and prolonged neutropenia in the first 30 days (Early ICATH grade 3-4), and 7 (54%) had neutropenia beyond day + 30 (Late ICATH grade 3-4). Six pts received G-CSF, and 7 received erythropoietin. Ten pts (77%) had a low platelet count at day +90, supporting its potential role as a risk factor for SMN onset, as previously described. Two pts (15%) had lymphoma relapse before MDS onset.
At MDS onset, 7 pts had altered karyotypes: 5 (42%) showed chromosome 7 deletion (del7), 1 complex karyotype, and 1 hyperdiploidy. The AML patient had a complex karyotype. Before CAR-T, 2 pts showed already del7. The high frequency of del7 and complex karyotype (54%) may supportthe potential role of CAR-T in SMN onset (only 1/6 received ASCT).
NGS analysis at SMN onset was available in 10 pts (77%). TP53 was the most frequently mutated gene, detected in 4 pts (40%, 1 AML and 3 MDS). One of the 2 MDS pts who developed AML acquired the FLT3 mutation, while the other one was TP53+. RUNX1 and DNMT3A were mutated in 2 pts, while KIT, JAK3, BCOR, EZH2 and NPM1 were mutated once. Clonal hematopoiesis (CH) before CAR-T was positive in 4 of the 5 tested pts. At the time of SMN onset, 2 pts acquired the RUNX1 mutation, while 1 pts the BCOR+.
Nine pts had intermediate2-high IPSS risk MDS (Int2: 6, High: 3), while 3 pts were Low-Int1 IPSS risk. Four Int2-High MDS pts received hypomethylating agents (HMA): 2/4 (50%) achieved complete response (CR) and underwent allogenic stem cell transplantation (allo-SCT), 1 obtained CR and is still on HMA, while 1 progressed to AML. Two MDS pts underwent allo-SCT upfront. Six 6 pts (46%) received only supportive therapy. The AML pts was treated with HMA and Venetoclax, achieving CR, and underwent allo-SCT. Three out of 5 (60%) allotransplanted pts died for infections, while one died of AML relapse. Overall, the median OS after SMN onset was 8.7 months (IQR 6.0-10.6). Two of the 3 Low-Int1 pts are currently alive, while 1 pts died of lymphoma relapse.
Conclusion
The incidence of SMN was relatively low (2.3%). Most patients had del7 and TP53+, which were characterized by poor survival. Two pts already had del7, but only a few pts were tested for CH prior to CAR-T. The evaluation of CH and karyotype not only at SMN onset, but also before CAR-T therapy, as prospectively outlined in the ClonHema trial, can be crucial to identify potential alterations predicting SMN and to assess whether pts harboring HR-mutations should receive CAR-T cells, given the dismal outcomes of high-risk SMN.