Burkitt lymphoma is a rare and extremely aggressive subtype of B cell non-Hodgkin’s lymphoma (B-NHL). It is characterized by the dysregulation of the proto-oncogene MYC, which is commonly caused by a typical chromosomal translocation [t(8;14)] (1, 2). Burkitt lymphoma is highly sensitive to short-term intensive chemotherapy, and most patients can be treated using a multiagent regimen that includes rituximab (3). A large multicenter study including 30 cancer centers of the United States has shown that adult patients with Burkitt lymphoma have relatively favorable outcomes, with 3-year progression-free survival (PFS) and overall survival (OS) rates of 64% and 70%, respectively (4). However, relapsed and refractory (r/r) cases remain ineluctable, especially in patients with adverse prognostic factors or high-risk genetic abnormalities (5). Patients with Burkitt lymphoma who are refractory to initial therapy or who relapse after an intensive regimen and autologous stem cell transplantation (ASCT) usually have an extremely poor clinical prognosis (6, 7). Therefore, the early initiation of salvage therapies is essential for these patients owing to the invasive nature of the disease.

Treatment of patients with r/r Burkitt lymphoma via traditional or targeted chemotherapy produces poor outcomes. In a previous study, only two-fifths of patients with r/r Burkitt lymphoma or high-grade B cell lymphoma responded to second-line salvage chemotherapy, and even fewer patients achieved sustained remission (6). While ASCT shows therapeutic effects in some patients with r/r Burkitt lymphoma, chemotherapy-resistant patients obtain no significant benefit from further consolidative ASCT. Thus, combination with other innovative strategies may prove to be more effective for r/r high-risk subtypes (8). Recently, there has been considerable progress in the use of chimeric antigen receptor-modified (CAR) T cell immunotherapy for r/r malignancy treatment. Representative hematological diseases are r/r B cell acute lymphoblastic leukemia (B-ALL) and diffuse large B cell lymphoma (DLBCL) (9–11). Several case reports have demonstrated positive results for patients with r/r Burkitt lymphoma receiving CAR T cell immunotherapy (12–15); however, explicit data on CAR T cell immunotherapy alone or in combination with ASCT are still lacking.

In this study, we aimed to systematically evaluate the outcomes of adult patients with r/r Burkitt lymphoma treated with CAR T cell immunotherapy. We conducted two single-arm clinical trials to explore the clinical efficacy and related toxicity of CD19/CD22 CAR T cell immunotherapy alone and in combination with ASCT in adult patients with r/r Burkitt lymphoma.

CAR T cell immunotherapy can be beneficial to patients with r/r hematological tumors and r/r Burkitt lymphoma (13, 14). However, a systematic assessment has not been conducted previously. In the current study, adult patients with r/r Burkitt lymphoma receiving CD19/CD22 CAR T cell immunotherapy or its combination with ASCT achieved objective response. In total, 19 of the 28 adult patients (67.9%) with r/r Burkitt lymphoma included in our trials responded to the therapy. After a median follow-up of 12.5 months, 16 patients finally survived. The estimated 1-year PFS and OS rates were both 55.6%. Hence, our preliminary results suggest that some adult patients with r/r Burkitt lymphoma can benefit from novel treatment strategies involving CD19/CD22 CAR T cell immunotherapy or its combination with ASCT.

In trial A, 46.7% of the participants eventually achieved objective response, and 33.3% achieved long-term survival. Previously, in the ZUMA-1 study, 83.2% of patients with large B cell lymphoma achieved objective response to CD19 CAR T cell therapy (22). Additionally, in our previous study, we found the ORRs of patients with B-ALL and DLBCL treated with CD19/CD22 CAR T cell infusions in our department to be 96.0% and 72.2%, respectively (18). Thus, CAR T cell immunotherapy alone is thought to be less effective against r/r Burkitt lymphoma than other B cell malignancies in adults. Previous studies in the literature have speculated that this phenomenon might be caused by the tumor immunosuppressive microenvironment (TIME) and reduced antigen exposure, which impedes the effective proliferation of CAR T cells in vivo (23). The mechanism underlying the poor outcomes observed in adult patients with r/r Burkitt lymphoma should be further investigated. Recently, Liu et al. found that 65.4% of their pediatric r/r Burkitt lymphoma cases benefited from mouse-derived CD19 CAR T cell infusions; this rate is significantly higher than the rate observed in adult patients in the present study (24). Greater tumor homogeneity and different baseline characteristics could partially explain this discrepancy. That study also found that some pediatric patients who failed to respond or relapsed after receiving mouse-derived CD19 CAR T cell infusions subsequently responded to human-derived CAR T cell infusions; however, further research is required to determine whether this strategy is suitable for adults. Generally, CD19/CD22 CAR T cell infusions alone appear to be a viable treatment option for adult patients with r/r Burkitt lymphoma without enough HSCs, but the clinical efficacy was relatively limited.

Interestingly, in our study, CD19/CD22 CAR T cell infusions combined with ASCT appeared to lead to more favorable long-term outcomes in adult patients with r/r Burkitt lymphoma. The efficacy of this approach has previously been observed in patients with r/r B-NH and double-hit lymphoma (16, 25). A previous clinical trial conducted by our center reported an estimated 1-year PFS rate of 85.7% for patients with r/r B-NHL treated with CD19/CD22 CAR T cells and ASCT (25). For double-hit lymphoma, the estimated 2-year PFS rate reached 83.3% (16). In the current study, the estimated 1-year PFS rate for adult patients with r/r Burkitt lymphoma in trial B was 83.3%. This is roughly equivalent to the rates observed in the contemporary literature for other B cell hematological diseases. These robust results appear to be due to the synergistic effects of ASCT and CAR T cells. Relapse due to product contamination or residual disease is an urgent challenge in ASCT (26, 27). Targeted tumor-specific antigen-modified T cells can purify grafts and eradicate residual lesions after transplantation, effectively preventing recurrence. In addition, the standard BEAM conditioning regimen can considerably deplete lymphocytes and reduce tumor burden, and HSC infusion may modulate complex and heterogeneous TIME, enhancing the function and persistence of CAR T cells in vivo (17, 25, 28). For intermediate- or high-risk patients who fail to respond or relapse after initial therapy, HSC stimulation and CAR T cell therapy alongside the initiation of salvage chemoradiotherapy is recommended. This can guarantee a low tumor burden, thereby contributing to satisfactory curative effects (29, 30). However, whether this synergistic strategy is an appropriate second-line treatment option for adult patients with r/r Burkitt lymphoma remains to be confirmed. Meanwhile, further studies comparing ASCT in combination with CAR T cell immunotherapy with ASCT or CAR T cell immunotherapy alone should be conducted.

Subgroup analyses showed objective responses to be associated with ECOG PS score ≥ 2, LDH levels of >400 u/L, lesions ≥ 7.0 cm, the presence of a TP53 mutation, and limited CD19 CAR T cell proliferation in vivo. Large lesions, which are common in Burkitt lymphoma, prevent CAR T cells from infiltrating tumors, fully contacting and recognizing cognate antigens, and performing their antitumor functions (23, 24). Besides, as shown in previous studies, the peak level of CAR T cell expansion is a significant predictor of clinical objective response (24, 31). Burkitt lymphoma has similarities to both leukemia and solid tumors. Therapeutic failure in some patients may be partly attributable to the limited increase in CAR T cell levels induced by complex and heterogeneous TIME (32). In our study, three partially responsive patients eventually experienced disease progression and died. Target antigen loss is an important mechanism of relapse or progression after CAR T cell immunotherapy (33, 34). Liu et al. assessed a pediatric patient with r/r Burkitt lymphoma who achieved CR status following mouse-derived CD19 CAR T cell infusion and eventually relapsed due to a loss of CD19 expression (24). Unfortunately, the three abovementioned patients did not undergo secondary biopsies at the time of progression.

CRS and ICANS are the two main toxicities observed in association with cellular therapy, and these were monitored and graded in this study. In a previous report on adult patients with r/r DLBCL who received tisagenlecleucel therapy, 22% experienced grade 3–4 CRS and 12% experienced neurological events (35). In a study on pediatric r/r Burkitt lymphoma cases, the incidence of grade 3–4 CRS and ICANS after treatment with mouse-derived CD19 CAR T cells were 34.8% and 24.1%, respectively (24). In another study, one of six (16.7%) adult patients with refractory Burkitt lymphomas was found to develop high-grade CRS after CD19/CD22 CAR T cell infusions (23). We observed no obvious differences in the incidence of severe CRS and ICANS compared to those previously reported. Our analysis also indicated that the levels of the major cytokine, IL-6, were significantly higher in patients with grades 2–4 CRS than in those with 0–1 CRS (36). However, the relatively lower incidence rate of grade 2–4 CRS seen in previous studies was not observed among patients in trial B of our study (17, 25). This might be because patients with r/r Burkitt lymphoma commonly present with large lesions and a high tumor burden and these factors are significantly associated with CRS severity after cellular therapy (36–38). Overall, adult patients with r/r Burkitt lymphoma were able to tolerate the toxicities associated with CAR T cell infusion.

To the best of our knowledge, this is the first systematic evaluation of CAR T cell immunotherapy outcomes in adult patients with r/r Burkitt lymphoma. We found that salvage therapy with CD19/CD22 CAR T cell infusions or CD19/CD22 CAR T cell infusions combined with ASCT is effective in some adult patients with r/r Burkitt lymphoma. Early initiation of CD19/CD22 CAR T cell therapy combined with ASCT appeared to be more beneficial. However, a randomized controlled cohort study is required to further validate our findings due to differences in some of the baseline characteristics of enrolled patients.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Chinese Clinical Trial Registry. The patients/participants provided their written informed consent to participate in this study.

JZ conceived and designed the study. YX revised the manuscript for submission. SZ and TZ supervised CAR T cell production and quality control. JiW and YC collected and analyzed data and wrote the paper. All authors conducted the clinical trials. All authors contributed to the article and approved the submitted version.

This work was supported by the National Natural Science Foundation of China (grant numbers: 81873444 and 82070213).

SZ and TZ were employees of Wuhan Bio-Raid Biotechnology Co. Ltd.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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