Anti-CD19 CAR-T cell therapy is approved for patients up to 25 years of age and for adult affect by ALL based on the ELIANA (tisagenlecleucel-tisa-cel) (18) and ZUMA-3 trial (brexucabtagene autoleucel – brex-cel) (19). Most trials of CAR-T cells in relapsed/refractory (RR) ALL demonstrate impressive response rates, with >70% of patients achieving complete remission (CR) (20). Given the poor prognosis, there appears to be no evidence of secondary malignancy in this setting, where we emphasize there are no therapeutic alternatives.

Anti-CD19 CAR-Ts, axicabtagene ciloleucel (axi-cel) (21), tisa-cel (22), and lisocaptagene maraleucel (liso-cel) (23), showed impressive activity in the third and higher treatment line in a non-comparative clinical trial.

ZUMA−1 is a multicenter, single−arm, registrational phase 1/2 study of axi−cel in patients with refractory LBCL after ≥2 lines of therapy (24). Long−term results from ZUMA−1 demonstrated sustained overall survival (OS), with a median of 25.8 months and a 5−year estimate of 43%. Initial assessments in ZUMA−1 suggested axi−cel may be curative for a subset of patients (25, 26).

In the primary analysis of the pivotal JULIET trial of tisa-cel, the best ORR was 52% and the CR rate was 40% in adult patients with RR LBCL (22). At a median follow-up of 40.3 months, tisa-cel continued to show durable activity (27). The safety profile analysis did not show any secondary tumor, and no deaths were attributed to tisa-cel.

Liso-cel demonstrated significant efficacy with a manageable safety profile as third-line or later treatment in patients with RR LBCL (23). After 2-year follow-up, the ORR was 73% and CR rate was 53% with no new safety signals (28).

Axi-cel and liso-cel showed a significant improvement in PFS and a strong trend in OS in two phase III clinical studies in high-risk RR LBCL compared with salvage therapy (ST) followed by autologous stem cell transplantation (ASCT) (29–32). Kersten et al. reported an updated efficacy and safety results from the primary OS analysis among ZUMA-7 patients aged ≥65 and ≥70 years (33). No new treatment-related deaths occurred. One patient died for an acute myeloid leukemia.

ZUMA-12 is a phase 2, multicenter, single-arm study of axi-cel as part of first-line treatment in patients with high-risk LBCL (34). In the updated analysis with a median follow-up of ≥40 months (35), axi-cel confirmed a high rate of durable responses and no new safety signals. There were 8 deaths due to progressive disease (n=5) and other causes not related to axi-cel (1 COVID-19, 1 esophageal adenocarcinoma, 1 septic shock on Days 350, 535, and 287 post axi-cel infusion, respectively). Two of the 8 deaths (1 progressive disease and 1 esophageal adenocarcinoma) occurred after the primary analysis.

Current guidelines indicate that CAR-T is the standard of care in DLBCL patients with refractory disease, early relapse after first-line chemotherapy, and in third line of treatment (36).

Crombie et. presented the results of patients who were followed in the CIBMTR Cellular Therapy Registry after infusion with commercial liso-cel for the treatment of R/R LBCL (37). Of the 396 patients evaluated, 14 patients developed a second malignancy (5 squamous cell skin malignancy; 3 myelodysplasia; 2 basal cell skin malignancy; 2 a gastrointestinal malignancy; 1 melanoma; 1 myeloproliferative neoplasm, respectively.

In LBCL patients not intended to receive ASCT after failure of first-line therapy outcomes have been poor (38, 39). The phase 2 PILOT study evaluated the efficacy and safety of liso-cel in this setting (40). Sehgal et al. reported the final analysis after 24 months of follow-up or study discontinuation (41). There were no new safety signals. Two patients developed a second primary malignancy (squamous cell carcinoma of skin and malignant external ear neoplasm, n = 1; myelodysplastic syndrome, n = 1).

Ghilardi et al. reported a T cell lymphoma occurring 3 months after CAR-T infusion for non-Hodgkin B cell lymphoma (42). The T cell clone was identified at low levels in the blood before CAR T infusion and in lung cancer. Moreover, the authors evaluated the risk of secondary primary malignancy after commercial CAR-T therapy in 449 patients treated in a cancer center in the United States. Sixty-teen patients (3.6%) had a secondary primary malignancy, and the 5-year incidence was 2.3% for hematological malignancies, and 15.2% for solid tumor. Overall, one case of T cell lymphoma was observed, suggesting a very low risk of this disease after CAR T.

Tisa-cel is approved for adults with R/R FL in the ≥3 rd-line setting (43). The primary analysis of the Phase II ELARA trial reported high response rates and excellent safety profile in extensively pretreated patients with r/r FL (44). Findings from a longer-term update of the ELARA trial continue to demonstrate high response rates and durable remissions with a favorable safety profile (45). No new safety signals were reported. Two patients experienced a secondary malignancy during this longer-term follow-up (squamous cell carcinoma and bladder transitional cell carcinoma). Additionally, 3 new deaths occurred during this updated 2-year follow-up period (progressive disease, n=1; serious adverse events, n=2 (urothelial bladder carcinoma and graft-vs-host disease following allogeneic SCT). None of the malignancies or deaths were considered related to study treatment.

Beyond the potential efficacy of CAR-T in FL, axi-cel results in a high number of durable responses in the third and higher treatment line in a non-comparative clinical trial (46). Axi−cel was tested on the ZUMA−5 multicenter, single−arm, Phase 2 study, in patients with R/R indolent non−Hodgkin lymphoma (NHL), including FL and marginal zone lymphoma (MZL) (47). After a median follow−up of ≥3 years, median PFS was 40.2 months in patients with FL and not reached in those with MZL (25). After ≥4 years median follow−up in ZUMA−5, axi−cel demonstrated continued durable responses and long−term survival in patients with RR iNHL (47). After the 3-year data cutoff date, 1 patient with FL developed a myelodysplastic syndrome, and 1 patient with MZL an acute myeloid leukemia.

Brexu-cel is an autologous anti-CD19 CAR T-cell therapy approved in adults with R/R MCL following ≥2 prior therapies, including ibrutinib a BTKi (48). After three years in ZUMA-2, brexu-cel demonstrated an ORR of 91%, and a CR rate of 68%. ZUMA-18 is an expanded access study of brexu-cel for the treatment of patients with R/R MCL, including BTKi-naive patients who received ≥ 1 prior therapy following ZUMA-2 enrollment completion. Goy et al. reported the primary analysis of ZUMA-18 and the 4-year follow-up of ZUMA-2 (49). Consistent with ZUMA-2 findings, brexu-cel demonstrated a high level of efficacy, with an ORR of 87%.

Newer treatment options for patients with triple-class RRMM include classes of drugs targeting BCMA, among which are the CAR-T cells idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) (50).

The first commercially available CAR-T therapy was ide-cel, approved for patients with RR disease after at ‗three lines of therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody (51, 52). In the phase 2 KarMMa trial, at a median follow-up of 24.8 months, patients who received ide-cel showed an ORR of 73% and a CR or better rate of 33% (53). The phase III KarMMa-3 randomized controlled trial results were published comparing ide-cel with SOC (54). No second cancers have been reported.

Cilta-cel was the second CAR-T cell therapy to enter the market for MM and was approved by the FDA and the EMA for the same indications as ide-cel (54–57). At the 28-month median follow-up, a total of 20 secondary tumors had occurred in CARTITUDE-1 and were all considered unrelated to cilta-cel. Six cases of skin cancers were reported, including squamous cell carcinoma (n = 4) and basal cell carcinoma (n = 2). Ten cases of hematologic secondary tumors were reported in ten patients, including low-grade B-cell lymphoma (n = 1), myelodysplastic syndrome (n = 6), and l acute myeloid leukemia (n = 3). One case each of prostate cancer, malignant melanoma, adenocarcinoma, and myxofibrosarcoma also occurred. The accumulation of late-onset malignancies is not unexpected with long-term follow-up of patients with RR MM, many of whom have received subsequent anti-myeloma therapy. Initially referred to as LCAR-B38M, this construct was first studied in humans in a phase I trial (58). Four-year follow-up results were recently published, representing the most extended follow-up to date of any CAR-T therapy for MM. Second primary malignancies occurred in 4 patients [lung cancer (n = 2) and 1 case each of esophageal and cervical cancer].

The use of retroviral and lentiviral vectors for lymphocyte transduction results in the so-called risk of insertional mutagenesis (59–61).

Although this risk, no genotoxicity of gene transfer into differentiated cells, including T cells, has been reported, and. no vectors-related transformational events in more than 500 cumulative follow-up years of patients treated with engineered T cells have been observed (62). Pre-existing mutations in patients receiving CAR-T cell therapies can result in secondary malignancies in some cases (63). A recently published study showed a clonal hematopoiesis before treatment in 86% of patients receiving CAR-T cells, among those with prolonged cytopenias (64).

The risk of second malignancies in the context of CAR-T therapies needs to be evaluated against other available therapeutic approaches (65). The development of secondary malignancies is demonstrated after radiotherapy and/or chemotherapy treatment. The genotoxicity of these treatments is a well-known long-term side that results in a predisposition to the development of neoplasms (66).

Increased risk of second cancer after stem cell transplantation (SCT) ranges from 8 to 28% (67). Incidence correlates with the type of therapy given before and after SCT, the age of the patient, and the type of transplantation. Most of these secondary malignancies are myeloid-derived.