Secondary Malignancies Following CAR T-Cell Therapy for B-Cell Malignancies: A Retrospective Analysis.

Introduction

Chimeric antigen receptor T‐cell (CART) therapy revolutionized the treatment landscape for patients with relapsed/refractory B‐cell malignancies, with pivotal trials showing durable response rates and potential for cure in up to 40% of patients [ 1 , 2 , 3 , 4 , 5 , 6 ]. However, despite its clinical efficacy, CART therapy is associated with acute and long‐term toxicities that present significant barriers to patients’ quality of life [ 7 ]. Cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS) are the most notable acute toxicities related to CART therapy [ 8 ]. These acute adverse events can result in multi‐organ dysfunction requiring aggressive intensive measures, but they are potentially reversible with early recognition and appropriate management strategies [ 9 ].

Much of the evidence for adverse events following CART therapy has focused on acute toxicities. However, there is increasing interest in long‐term outcomes such as infections, prolonged cytopenias and hypogammaglobulinemia [ 10 ]. Notably, there has been emerging concern about second primary malignancies (SPM) following CART therapy. Current literature reports a varying incidence of 0.9%–12.9% of secondary malignancies following CART therapy, most commonly myeloid malignancies such as therapy‐related myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) [ 11 ]. In the ZUMA‐7 Phase 3 clinical trial, patients who received CART therapy for relapsed/refractory large B‐cell lymphoma had a numerically higher prevalence of secondary neoplasms compared to those who received standard‐of‐care autologous hematopoietic stem cell transplant (auto‐HSCT) [ 12 ], including two deaths attributed to AML and lung adenocarcinoma. Of note, auto‐HSCT is known to confer risk of SPM associated with the high‐dose conditioning chemotherapy, typically occurring as a late complication following treatment [ 13 , 14 , 15 ]. A recent meta‐analysis found that SPM was the second most common cause of non‐relapse mortality (after infection) following CART therapy for lymphoma and multiple myeloma [ 16 ]. In December 2023, the United States Food and Drug Administration (FDA) issued a class‐wide black box warning for the risk of SPM, namely myeloid malignancies and T‐cell lymphoma, after CART therapy [ 17 , 18 ]. The mechanistic link between CART therapy and SPM remains unclear; possible etiologies include exposure to alkylating agents and/or high‐dose chemotherapy prior to preceding auto‐HSCT, as well as lympho‐depleting chemotherapy required for CART expansion [ 11 , 19 ]. Another postulated mechanism driving secondary malignancies is through a process of insertional oncogenesis, whereby the genetic manipulation of the T‐cell to engineer the CAR activates an oncogene or disrupts a tumor‐suppressor gene [ 20 ].

Given this newly recognized long‐term complication of CART therapy, we measured the incidence and nature of SPM in patients who were treated with CART therapy at our tertiary care center. We also describe the characteristics, management, and outcomes of these patients.

Materials and Methods

Study Design and Setting

This was a retrospective analysis of a prospective observational cohort conducted at the Juravinski Hospital and Cancer Centre (JHCC), a tertiary care center serving 2.3 million people in Ontario, Canada. Consecutive patients, who were referred and approved for commercial CART therapy, were approached to participate in this cohort. Patients were eligible for inclusion into the registry if they received standard of care (SOC) CART therapy. The registry inception was January 2020 and is ongoing. All patients signed an informed consent form to participate in the local prospective CART registry. This study's protocol was approved by the Hamilton Integrated Research Ethics Board.

Population

SOC CART therapy was available for adult patients 18 years of age or older with a diagnosis of relapsed/refractory B‐cell malignancy, including diffuse large B cell lymphoma (DLBCL) including high‐grade double hit lymphomas, primary mediastinal B cell lymphoma (PMBCL), mantle cell lymphoma (MCL), transformed follicular lymphoma (tFL), and B‐cell acute lymphoblastic leukemia (B‐ALL). Patients were referred for CART locally and from regional healthcare centers across central‐west Ontario. Commercial CART products included tisagenlecleucel, axicabtagene ciloleucel, and brexucabtagene autoleucel. Of note, tisagenlecleucel was the only CART product available from January 2020 to December 2022.

Procedure

Demographic information and characteristics of underlying disease and treatments including stage, prior lines of therapy, receipt of bridging therapies, and treatment outcomes were captured in a REDCap database [ 21 ]. The registry captured details about CART therapy which included treatment details from leukapheresis to 90 days after infusion. We defined bridging therapy as any form of therapy administered between leukapheresis and CART infusion that was intended to treat the B‐cell malignancy; bridging therapies recorded in this study included corticosteroids, systemic chemotherapies, radiation, and other targeted therapies. Lympho‐depleting (LD) chemotherapy occurred prior to CART. Pre‐LD baseline biomarkers (lactate dehydrogenase [LDH], platelet count, C‐reactive protein (CRP), and ferritin levels) were also captured in the registry. The registry captured response to CART with PET scans completed 90 days following CART infusion using Lugano response criteria. Details of subsequent treatment for patients whose disease was refractory, relapsed after CART therapy or achieved only a partial response were also included. Survival and disease status at most recent follow‐up appointment were recorded. If the patient was deceased, date of death was counted as the end of follow‐up.

We retrospectively identified patients who developed a SPM through the electronic medical records (EMR). SPM was defined as any cancer diagnosis not related to the progression or relapse of the underlying lymphoma. The period of onset of SPM was defined as the time from CART infusion to diagnosis of SPM, and was confirmed by pathology. MDS diagnosis was defined according to the minimal diagnostic criteria published by the international MDS working group [ 22 ], and AML was defined according to the fifth edition of the World Health Organization classification of AML [ 23 ]. For patients with SPM, we described prior lines of therapy, CART product received, prior lines of therapy including bridging therapy, and characteristics and treatment of the SPM.

Analysis

Summary statistics were used to describe patient, disease and treatment characteristics, as well as outcomes. The Kaplan–Meier method was used to estimate overall survival (OS), defined from the time of CAR T‐cell infusion until death from any cause. Cumulative incidence function was calculated for the time to SPM, accounting for the competing risk of death, starting from the date of CAR T‐cell infusion. Confidence intervals were constructed at the two‐sided 95% level.

Results

Our cohort included 87 patients who received their CART infusion between January 2020 and May 2023. Last follow‐up was June 2024. Patient characteristics are summarized in Table 1 . The median age at CART infusion was 62 years (Range 22–78 years) and 63.2% of patients were male. Prior to CART infusion, patients had a minimum of two lines of therapy; 56.3% of patients had received auto‐HSCT and 2.3% received allo‐HSCT prior to CART. Bridging therapy was administered to 70.1% of patients. At Day 90, 43.7% of patients had achieved complete response (CR) with Deauville 1‐3 by PET, 6.9% of patients had achieved partial response, 3.4% of patients remained at stable disease, and 33.3% of patients had progressive disease. Approximately, 12.6% did not complete a PET due to death before Day 90 or a PET could not be retrieved from the EMR since June 2024. Patients were followed until last contact or death, with a median duration of follow up of 27.9 months (Range: 0.13–50.6 months). Figure 1b shows the Kaplan–Meier curve of the estimated median OS for all patients who received CART therapy, which was 25.4 months (95% CI, 8.3–41.6 months).

Table 2 demonstrates the characteristics of patients who developed SPMs. Seven patients (8%) developed a SPM with a mean time to onset of 16.9 months (Range: 3–34.5 months) following CART infusion. The median age of patients who developed a SPM was 57 years (Range: 40–77 years). The majority had received three or more lines of therapy prior to CART including four patients who had an ASCT. All seven patients received tisagenlecleucel as their CART product. SPM diagnoses included MDS (2/7) and AML (5/7). Treatments for SPM included hypomethylating agents with or without venetoclax ( n = 5) and allogeneic SCT ( n = 2). Following the diagnosis of SPM, 5/7 (81.4%) patients died. Figure 1a demonstrates the median OS of 8.6 months ((95% CI,1.5 to not reached) for those who developed an SPM, and 1‐year OS of 33% (95% CI, 4.6% to 67.6%). Figure 1b demonstrates the median OS of the entire cohort of patients who received CART of 25.4 months (95% CI, 8.3–41.6 months). Figure 2 demonstrates the cumulative incidence function of SPM was 2.3% (95% CI, 0.4%–7.3%) at 12 months and 6.9% at 24 months (95% CI, 2.4%–14.4%).

Discussion

In our study we identified an incidence rate of SPM of 8.0% over a median follow‐up period of 27.9 months in our population of 87 patients who received CART therapy (majority were tisagenlecleucel) for relapsed/refractory B‐cell malignancies. Our finding is consistent with the incidence of SPM currently reported in other studies, including those of the US Lymphoma CAR T Cell Consortium wherein 9% of 275 patients who received axi‐cel developed SPM over a median follow‐up period of 58 months [ 24 ]. In our study, all patients who developed a SPM developed a myeloid malignancy. The cytogenetic profile of the myeloid malignancies, including del(17p), TP53, and KMT2A mutations, are typically associated with therapy‐related myeloid malignancies and confer a poorer prognosis. In our study, the median time to onset of SPM was 16.9 months after CART infusion, which is in keeping with findings from other studies that report a latency period of 1–3 years [ 25 , 26 ].

SPMs have been extensively documented in survivors of hematologic malignancies, especially those who have undergone auto‐HSCT [ 27 , 28 , 29 , 30 ]. This risk is largely due to the myelotoxic nature of preconditioning chemotherapies, particularly alkylating agents and topoisomerase II inhibitors [ 31 ]. However, the time of onset of these malignancies tends to be much later, typically occurring 5–10 years following transplantation, compared to the 1–3 years noted in studies with CART therapy. While fewer studies have reported on SPM incidence after CART therapies, the emergence of long‐term follow up data is increasing awareness of this intermediate‐term toxicity.

The mechanism of SPM development is unknown. A postulated mechanistic link between CART therapy and SPM risk is the cumulative effects of prior lines of therapy. Six out of the seven patients who developed SPM in our study had three or more prior lines of therapy; of note, our study was conducted prior to approval of CART as second‐line therapy in Canada). All patients who developed SPM received anthracyclines and alkylating agents in prior lines of therapy. An additional potential risk factor for development of SPM is the use of purine analogue/alkylator combinations and bendamustine in CART lymphodepletion regimens, which have been associated with the development of SPM when used to treat patients with lymphoid neoplasms [ 32 ]. Another theory is that CART therapy is increasingly used in elderly patients who would typically be considered transplant‐ineligible but be able to tolerate the generally reversible acute toxicities of CART therapy [ 33 ]. Previous studies have shown age to be a significant variable in the risk of development of secondary malignancy [ 25 ], likely due to the accumulation of clonal hematopoietic mutations as a marker of aging and its associated risk for development of hematologic, particularly myeloid malignancies [ 34 ]. Patients who developed SPM in our cohort had a younger median age (57 years); however, given the small sample size, we cannot make conclusive remarks on age as a factor. Three patients who developed SPM were noted to have cytopenias prior to their CART therapy; only one had a bone marrow biopsy prior to CART infusion and there was no evidence of clonal hematopoiesis. The possibility of underlying myeloid mutations impacting risk of development of SPM raises an important question as to whether bone marrow biopsies with next generation sequencing should be routinely performed prior to patients receiving CART therapy. There is also increasing interest in clonal hematopoiesis especially TET2 and DNMT3A mutations in lymphoid cells, and their influence on CART biology and activity [ 35 , 36 ]. Lastly, one other mechanism is the potential disruption of genetic regions controlling T‐cell growth, or insertional mutagenesis, as a cause of the development of T‐cell lymphoma secondary malignancy [ 20 , 37 ].

It is undetermined whether the type of CART product has an impact on SPM risk. Tisagenlecleucel was the only CART product available in Canada for a large portion of time during our study, and therefore had the longest follow‐up period. The risk of SPM has been reported for five out of the six currently available CART products suggesting that the specific construct does not necessarily play a role in SPM development [ 38 ].

A major strength of our study is the prospective registry, allowing for robust and granular clinical data collection. Our study was however, limited by a number of factors. This was a single‐center study limited by a relatively small cohort size and institutional practice patterns. We also did not collect information on genetic and environmental factors; it is therefore unknown how these factors may have contributed to SPM risk. Lastly, SPM data collection was retrospective and as such the analysis was subject to limitation of possible confounding.

Over the last 2 years in Canada, the indications for CART therapy have expanded across a broader range of B‐cell malignancies, and moved into second line of therapy for patients with primary refractory or early relapsed disease. Future research directions include the use of our registry to explore the roles of number of prior lines of therapy and specific CART product to elucidate the mechanistic link between CART therapy and SPM risk.

Conclusion

In our single‐center cohort of 87 patients who received CART therapy for relapsed/refractory B‐cell malignancies, we reported an incidence of SPM of 8.0% with a median time to onset of 16.9 months. Continued follow up of these patients is ongoing. Further investigation with larger multicenter cohorts is needed to confirm these findings. While the benefits of CART therapy outweigh their potential risks, understanding the long‐term risks of developing secondary malignancies is important for informed and shared patient decision‐making.

Author Contributions

Joanne Britto : analysis and interpretation of data. Audrey Y. H. Dong : data collection, analysis and interpretation of data. Gregory Pond : analysis and interpretation of data. Amaris K. Balitsky : conception and design, data collection, analysis and interpretation of data. All the authors were involved in writing of the manuscript and approval of final article.

Conflicts of Interest

Gregory Pond: Honorarium from Takeda and Astra‐Zeneca, consulting fees from Merck, Profound Medical and Traferox Technologies, and close family member who is employed by Roche Canada and who owns stock in Roche Ltd. Tobias Berg: Research funding from Imago Biosciences (a subsidiary of Merck) and honoraries from AVIR Pharma, Jazz Pharmaceuticals, Bristol Myers Squibb, and Riemser Pharma GmbH, as well as travel funding from Incyte, Abbvie, Astellas, Alexion, and Celgene. Kylie Lepic: Consultancy and honoraria from Sanofi, consultancy for Novartis. Gwynivere A. Davies: Honoraria from Janssen, Astra‐Zeneca, Roche. RF: Novartis and Gilead: Other: Advisory boards; Novartis, Gilead and Janssen: Honoraria; Gilead, Novartis, Celgene: Speakers Bureau. AKB: Honoraria—Beigene, Kite/Gilead, Sobi, BMS; research funding: Novartis. All the other authors declare no conflicts of interest.

Britto J., Dong A. Y. H., Pond G., et al. “Secondary Malignancies Following CAR T‐Cell Therapy for B‐Cell Malignancies: A Retrospective Analysis.” eJHaem 6, no. 6 (2025): e70164. 10.1002/jha2.70164

Funding : This work was supported by the Juravinski Hospital and Cancer Centre Foundation Grant (Dr. Amaris K Balitsky is the recipient of this grant). Tobias Berg received support from the Marta and Owen Boris Foundation (Boris Family Chair for Leukemia and Hematopoietic Stem Cell Translational Research), the Ontario Institute for Cancer Research through funding provided by the Government of Ontario, the Leukemia Lymphoma Society of Canada (LLSC), the Cancer Research Society (CRS) and the Juravinski Hospital and Cancer Centre Foundation.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

1. Neelapu S. S., Locke F. L., Bartlett N. L., et al., “Axicabtagene Ciloleucel CAR T‐Cell Therapy in Refractory Large B‐Cell Lymphoma,” New England Journal of Medicine 377, no. 26 (2017): 2531–2544, 10.1056/NEJMoa1707447.

2. Schuster S. J., Bishop M. R., Tam C. S., et al., “Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B‐Cell Lymphoma,” New England Journal of Medicine 380, no. 1 (2019): 45–56, 10.1056/NEJMoa1804980.

3. Abramson J. S., Palomba M. L., Gordon L. I., et al., “Lisocabtagene Maraleucel for Patients With Relapsed or Refractory Large B‐Cell Lymphomas (TRANSCEND NHL 001): A Multicentre Seamless Design Study,” Lancet 396, no. 10254 (2020): 839–852, 10.1016/S0140-6736(20)31366-0.

4. Locke F. L., Miklos D. B., Jacobson C. A., et al., “Axicabtagene Ciloleucel as Second‐Line Therapy for Large B‐Cell Lymphoma,” New England Journal of Medicine 386, no. 7 (2022): 640–654, 10.1056/NEJMoa2116133.

5. Bishop M. R., Dickinson M., Purtill D., et al., “Second‐Line Tisagenlecleucel or Standard Care in Aggressive B‐Cell Lymphoma,” New England Journal of Medicine 386, no. 7 (2022): 629–639, 10.1056/NEJMoa2116596.

6. Kamdar M., Solomon S. R., Arnason J., et al., “Lisocabtagene Maraleucel Versus Standard of Care With Salvage Chemotherapy Followed by Autologous Stem Cell Transplantation as Second‐Line Treatment in Patients With Relapsed or Refractory Large B‐Cell Lymphoma (TRANSFORM): Results From an Interim Analysis of an Open‐Label, Randomised, Phase 3 Trial,” Lancet 399, no. 10343 (2022): 2294–2308, 10.1016/S0140-6736(22)00662-6.

7. Johnson P. C., Dhawale T., Newcomb R. A., et al., “Longitudinal Patient‐Reported Outcomes in Patients Receiving Chimeric Antigen Receptor T‐Cell Therapy,” Blood Advances 7, no. 14 (2023): 3541–3550, 10.1182/bloodadvances.2022009117.

8. Lee D. W., Santomasso B. D., Locke F. L., et al., “ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated With Immune Effector Cells,” Biology of Blood and Marrow Transplantation 25, no. 4 (2019): 625–638, 10.1016/j.bbmt.2018.12.758.

9. Neelapu S. S., Tummala S., Kebriaei P., et al., “Chimeric Antigen receptor T‐Cell Therapy — Assessment and Management of Toxicities,” Nature Reviews Clinical Oncology 15, no. 1 (2018): 47–62, 10.1038/nrclinonc.2017.148.

10. Wudhikarn K., Pennisi M., Garcia‐Recio M., et al., “DLBCL Patients Treated With CD19 CAR T Cells Experience a High Burden of Organ Toxicities but Low Nonrelapse Mortality,” Blood Advances 4, no. 13 (2020): 3024–3033, 10.1182/bloodadvances.2020001972.

11. Zhao A., Zhao M., Qian W., Liang A., Li P., and Liu H., “Secondary Myeloid Neoplasms After CD19 CAR T Therapy in Patients With Refractory/Relapsed B‐Cell Lymphoma: Case Series and Review of Literature,” Frontiers in Immunology 13 (2023): 1063986, 10.3389/fimmu.2022.1063986.

12. Westin J. R., Oluwole O. O., Kersten M. J., et al., “Survival With Axicabtagene Ciloleucel in Large B‐Cell Lymphoma,” New England Journal of Medicine 389, no. 2 (2023): 148–157, 10.3389/fimmu.2022.1063986.

13. Darrington D. L., Vose J. M., Anderson J. R., et al., “Incidence and Characterization of Secondary Myelodysplastic Syndrome and Acute Myelogenous Leukemia Following High‐Dose Chemoradiotherapy and Autologous Stem‐Cell Transplantation for Lymphoid Malignancies,” Journal of Clinical Oncology 12, no. 12 (1994): 2527–2534, 10.1200/JCO.1994.12.12.2527.

14. Stone R. M., Neuberg D., Soiffer R., et al., “Myelodysplastic Syndrome as a Late Complication Following Autologous Bone Marrow Transplantation for Non‐Hodgkin's Lymphoma,” Journal of Clinical Oncology 12, no. 12 (1994): 2535–2542, 10.1200/JCO.1994.12.12.2535.

15. Milligan D. W., Ruiz De Elvira M. C., Kolb H.‐J., et al., “Secondary Leukaemia and Myelodysplasia After Autografting for Lymphoma: Results From the EBMT,” British Journal of Haematology 106, no. 4 (1999): 1020–1026, 10.1046/j.1365-2141.1999.01627.x.

16. Tix T., Alhomoud M., Shouval R., et al., “Second Primary Malignancies After CAR T‐Cell Therapy: A Systematic Review and Meta‐Analysis of 5,517 Lymphoma and Myeloma Patients,” Clinical Cancer Research 30, no. 20 (2024): 4690–4700, 10.1158/1078-0432.CCR-24-1798.

17. Manalac T., “FDA Calls for Boxed Warnings on CAR‐T Therapies Regarding Secondary Cancer Risks,” BioSpace (January 23, 2024), https://www.biospace.com/fda-calls-for-boxed-warnings-on-car-t-therapy-labels-regarding-secondary-cancer-risks?keywords=cancer .

18. Legend Biotech Corporation , Form 6‐K: Legend Biotech Announces US FDA Label Update for CARVYKTI (Ciltacabtagene Autoleucel; Cilta‐Cel) (US Securities and Exchange Commission, 2024).

19. Levine B. L., Pasquini M. C., Connolly J. E., et al., “Unanswered Questions Following Reports of Secondary Malignancies After CAR‐T Cell Therapy,” Nature Medicine 30 (2024): 338–341, 10.1038/s41591-023-02767-w.

20. Brudno J. N., Maus M. V., and Hinrichs C. S., “CAR T Cells and T‐Cell Therapies for Cancer,” JAMA 332 (2024): 1924–1935, 10.1001/jama.2024.19462.

21. Harris P. A., Taylor R., Minor B. L., et al., “The REDCap Consortium: Building an International Community of Software Platform Partners,” Journal of Biomedical Informatics 95 (2019): 103208, 10.1016/j.jbi.2019.10320.

22. Valent P., Orazi A., Steensma D. P., et al., “Proposed Minimal Diagnostic Criteria for Myelodysplastic Syndromes (MDS) and Potential Pre‐MDS Conditions,” Oncotarget 8, no. 43 (2017): 73483–73500, 10.18632/oncotarget.19008.

23. Khoury J. D., Solary E., Abla O., et al., “The 5th Edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms,” Leukemia 36, no. 7 (2022): 1703–1719, 10.1038/s41375-022-01613-1.

24. Jain M. D., Spiegel J. Y., Nastoupil L. J., et al., “Five‐Year Follow‐Up of Standard‐of‐Care Axicabtagene Ciloleucel for Large B‐Cell Lymphoma: Results From the US Lymphoma CAR T Consortium,” Journal of Clinical Oncology 42 (2024): 3581–3592, 10.1200/JCO.23.02786.

25. Ghilardi G., Fraietta J. A., Gerson J. N., et al., “T Cell Lymphoma and Secondary Primary Malignancy Risk After Commercial CAR T Cell Therapy,” Nature Medicine 30, no. 4 (2024): 984–989, 10.1038/s41591-024-02826-w.

26. Habib A., Welkie R., Butman J., et al., “Secondary Myeloid Malignancy After CAR T Cell Therapy for Non‐Hodgkin Lymphoma (NHL),” Journal of Clinical Oncology 42, no. 16 (2024): 7033, 10.1200/JCO.2024.42.16_suppl.7033.

27. Tichelli A., Beohou E., Labopin M., et al., “Evaluation of Second Solid Cancers After Hematopoietic Stem Cell Transplantation in European Patients,” JAMA Oncology 5, no. 2 (2019): 229, 10.1001/jamaoncol.2018.4934.

28. Al‐Juhaishi T., Khurana A., and Shafer D., “Therapy‐Related Myeloid Neoplasms in Lymphoma Survivors: Reducing Risks,” Best Practice & Research Clinical Haematology 32, no. 1 (2019): 47–53, 10.1016/j.beha.2019.02.008.

29. Travis L. B., Curtis R. E., Glimelius B., et al., “Second Cancers Among Long‐Term Survivors of Non‐Hodgkin's Lymphoma,” JNCI Journal of the National Cancer Institute 85, no. 23 (1993): 1932–1937, 10.1093/jnci/85.23.1932.

30. Dahi P. B., Lee J., Devlin S. M., et al., “Toxicities of High‐Dose Chemotherapy and Autologous Hematopoietic Cell Transplantation in Older Patients With Lymphoma,” Blood Advances 5, no. 12 (2021): 2608–2618, 10.1182/bloodadvances.2020004167.

31. McNerney M. E. and Godley L. A., “Therapy‐related Myeloid Neoplasms: When Genetics and Environment Collide,” Nature Reviews Cancer 17, no. 9 (2017): 513–527, 10.1038/nrc.2017.60.

32. Benjamini O., Jain P., Trinh L., et al., “Second Cancers in Patients With Chronic Lymphocytic Leukemia Who Received Frontline Fludarabine, Cyclophosphamide and Rituximab Therapy: Distribution and Clinical Outcomes,” Leukemia & Lymphoma 56, no. 6 (2015): 1643–1650, 10.3109/10428194.2014.957203.

33. Vic S., Lemoine J., Armand P., Lemonnier F., and Houot R., “Transplant‐Ineligible but Chimeric Antigen Receptor T‐Cells Eligible: A Real and Relevant Population,” European Journal of Cancer 175 (2022): 246–253, 10.1016/j.ejca.2022.08.019.

34. Shlush L. I., “Age‐Related Clonal Hematopoiesis,” Blood 131, no. 5 (2018): 496–504, 10.1182/blood-2017-07-746453.

35. Beck K., “Lymphoid Clonal Hematopoiesis: Implications for Malignancy, Immunity, and Treatment,” Blood Cancer Journal 13 (2023): 5, 10.1038/s41408-022-00773-8.

36. Miller P. G., Sperling A. S., Brea E. J., et al., “Clonal Hematopoiesis in Patients Receiving Chimeric Antigen Receptor T‐Cell Therapy,” Blood Advances 5, no. 15 (2021): 2982–2986, 10.1182/bloodadvances.2021004554.

37. Bhagwat A. S., Torres L., Shestova O., et al., “Cytokine‐Mediated CAR T Therapy Resistance in AML,” Nature Medicine 30, no. 12 (2024): 3697–3708, 10.1038/s41591-024-03271-5.

38. Verdun N. and Marks P., “Secondary Cancers After Chimeric Antigen Receptor T‐Cell Therapy,” New England Journal of Medicine 390, no. 7 (2024): 584–586, 10.1056/NEJMp2400209.

Associated Data

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.