Therapy-Related Acute Myeloid Leukemia after CAR-T Cell Therapy with Brexucabtagene Autoleucel for Mantle Cell Lymphoma

Treatment options for mantle cell lymphoma (MCL) have rapidly evolved in the past years with the introduction of Bruton tyrosine kinase (BTK) inhibitors and of CAR-T treatment for relapsed and refractory (r/r) disease [1, 2]. In particular, the single arm ZUMA-2 trial showed a response rate of 91% after CAR-T treatment with brexu-cel for patients with r/r MCL, with promising long-term survival data [1]. Remarkably, these results have been reproduced in real-world reports [3].

With increasing follow-up of patients after CAR-T intervention, novel and possibly rare long-term complications may emerge. Regulatory authorities recently reported concerns for secondary malignancies emerging as late complications after CAR-T treatment [4]. Given that many patients undergoing CAR-T treatment have previously received several lines of cancer treatment, a significant proportion of such patients may harbor premalignant hematological conditions prior to CAR-T cell therapy. In fact, one study reported clonal hematopoiesis of indeterminate potential (CHIP) in 48% of this patient population, while CHIP per se was not associated with worse prognosis [5]. However, inferior prognosis was reported in patients with specific CHIP associated mutations such as PPM1D mutations [6].

Myelodysplastic syndromes (MDSs) have been reported after CAR-T cell therapy in up to 12.9% of lymphoma patients [7]. Moreover, single cases of acute myeloid leukemia (AML) have been reported after CAR-T cell therapy at an incidence of up to 3.1% [8]. To the best of our knowledge, only 2 cases of AML have been reported so far after CAR-T in DLBCL patients [9, 10], whereas this has not been observed until now after brexu-cel treatment for MCL. In this report, we describe the occurrence of acute erythroid leukemia, a rare AML subtype, with TP53 mutation developing 26 months after CAR-T cell therapy for r/r MCL with brexu-cel.

A 74-year-old male Caucasian patient was diagnosed initially with stage IVB MCL. Initial FDG PET-CT showed disseminated supra- and infradiaphragmal lymphadenopathy, as well as pleural and splenic involvement. A cervical lymph node biopsy verified MCL without blastoid features, Ki-67 was 10%, cyclin D1 and Sox11 were negative. Bone marrow biopsy showed 20% lymphoma infiltration.

The patient initially underwent 6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone chemotherapy with two additional cycles of rituximab monotherapy, achieving a partial remission. Four months later, the patient presented with progressive disease, again with supra- and infradiaphragmatic lymphadenopathy and second-line treatment with Ibrutinib was initiated. After 5 months of Ibrutinib, MCL progression was documented with predominantly retroperitoneal manifestations and decision to pursue CAR-T therapy was made. After lymphapheresis, one cycle of bridging therapy with rituximab and bendamustine was given. Lymphodepleting chemotherapy with fludarabine and cyclophosphamide was administered followed by CAR-T cell infusion with brexu-cel. After CAR-T infusion, the patient developed grade 2 cytokine release syndrome, which was treated with dexamethasone and tocilizumab, and immune effector cell associated neurotoxicity syndrome grade 3, which required dexamethasone and levetiracetam antiepileptic prophylaxis, with complete neurologic recovery. Importantly, blood counts normalized and were completely normal after 1-year follow-up.

Twenty five months after CAR-T therapy (40 months after initial diagnosis) anemia and thrombocytopenia (hemoglobin 110 g/L and thrombocytes 27 G/L) were observed, with the patient rapidly becoming dependent on platelet transfusions. A first bone marrow biopsy showed marked dysplasia in all hematopoietic lineages suggesting a diagnosis of MDS, with 5% blast cells. Bone marrow examination was repeated 2 weeks later to obtain cytogenetic information, which revealed a complex karyotype with deletions of 5q, 7q, and of 17p13.1, with an additional trisomy 21. NGS analysis showed a TP53 mutation p.Arg282Gly with an 18% variant allele frequency (VAF). Finally, a third bone marrow examination was done 3 weeks later due to progressing cytopenias, suggesting the development of overt acute erythroid leukemia (corresponding to AML FAB M6) with erythroid precursors representing 80% of the cell count, reduced myelopoiesis (2% myeloid blasts), increased dysplastic megakaryopoiesis and a 25% VAF of the TP53 mutation (shown in Fig. 1 and 2).

Given the advanced age, the reduced general condition and the genetic features of the disease, palliative treatment with azacytidine and venetoclax was initiated. Bone marrow analysis after the first cycle, unfortunately, showed refractory disease and a 27% VAF of the TP53 mutation. Due to clinical disease progression with progressive asthenia and increasing transfusion needs, best supportive care was initiated, and the patient died within few days.

A retrospective analysis of the bone marrow sample which had been documented with a 20% lymphoma infiltration at first diagnosis of MCL identified a NOTCH3 p.Y2211* mutation and a (different) TP53 p.Y220C mutation. These mutations were also observed in the initial lymph node biopsy, confirming a lymphoma-specific mutation. In contrast, NGS analysis of peripheral blood obtained at the day of the CAR-T reinfusion failed to identify the TP53 p.Arg282Gly mutation.

To our knowledge, this is the first report of the development of acute erythroid leukemia after CAR-T treatment. However, this rare AML subtype can typically occur therapy-related and is associated with “multi-hit” TP53 mutations and thereby confers a poor prognosis with median overall survival of only 1.8 months in a recent case series [11]. The course of AML in the patient reported here appears typical for this condition.

The absence of the AML-related TP53 mutation at the beginning of lymphoma therapy underlines the concept of a therapy-related disease. Exposure of the patient to drugs known or suspected to be associated with AML including fludarabine, cyclophosphamide, doxorubicin, and bendamustin may have played a crucial part in the development of AML. Whether CAR-T treatment per se may have contributed through its immunosuppressive effect [9, 12, 13] remains unclear.

Reports on MDS and/or AML after CAR-T treatment are limited; one MDS and 1 AML patient each after CAR-T cell therapy have been reported with the combination of a RUNX1 mutation and deletion 7q, and a stepwise leukemogenic evolution with an eventually characteristic genetic pattern after CAR-T cell therapy was postulated [9, 13]. However, our patient showed no RUNX1 mutation while having a 7q deletion. Similarly, another report of AML after CAR-T cell therapy also failed to identify this specific combination of RUNX1 mutation and 7q deletion [10].

Our patient presented with an initial (different) p.Y220C TP53 mutation in the MCL tissue, whereas the patient acquired the p.R282G TP53 mutation and a 17q deletion (harboring the TP53 locus) in the myeloid cells after CAR-T cell therapy. This biallelic TP53 deficiency is typically observed in acute erythroid leukemia [14], while the occurrence of different abnormalities in the TP53 gene in two different hematologic neoplasms (in this case, in the bone marrow accompanying the myeloid disease and previously in the lymphoma tissue) in the same patient is remarkable. TP53 mutations are the most common mutation in human cancer. The reasons for the high incidence of mutations in this gene appear due to both mutagenic drugs and to the structure of the TP53 gene itself [15]. However, we did not find similar reports in the literature for the subsequent development of distinct somatic TP53 mutations in different histological entities in the same patient. As the frequency of TP53 mutations in cancer is high, the genetic presentation of our patient may be a random event. However, a genetic predisposition for developing malignancies may play a role, which awaits its ultimate elucidation.

Patients after CAR-T cell therapy seem to be at increased risk for the development of subsequent malignancies, eventually both through their exposure to previous leukemogenic chemotherapies and through an additional immunosuppression of the CAR-T cells themselves. A thoughtful use of leukemogenic drugs in our treatment algorithms should be recommended in patients in which eventual CAR-T treatment is an option in later lines. Also, an effort should be made to develop lymphodepleting chemotherapies free of at least alkylating agents and antimetabolites. Alternatively, use of CAR-T cell therapy in earlier lines merits consideration. Given the (so far) rare occurrence of secondary AML after CAR-T, a comprehensive NGS and cytogenetic analysis of the bone marrow before CAR-T treatment cannot be recommended at this time. However, in the case of unclear cytopenia, comprehensive genetic analyses aiming to screen for clonal hematopoiesis and/or myeloid malignancies may be initiated in candidates for CAR-T cell therapies. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000541256).

Written informed consent was obtained from the patient for publication of the details of his medical case and any accompanying images or data. Ethical approval is not required for this study in accordance with local guidelines.

The authors declare no conflict of interest.

This article was funded by the Department of Oncology of the University Hospital of Bern (Inselspital).

The authors confirm contribution to the paper as follows: study conception and design: T.P. and F.V.; data collection: M-N.K., M.D., D.S., Y.B., and U.B.; analysis and interpretation of results: T.P., F.V., A.H., and U.B.; draft manuscript preparation: F.V. All authors reviewed the results and approved the final version of the manuscript.

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.