Abstract
Background
Recently, chimeric antigen receptor-modified (CAR) T cell therapy for hematological malignancies has shown clinical efficacy. Hundreds of clinical trials have been registered and lots of studies have shown hematologic toxic effects were very common. The main purpose of this review is to systematically analyze hematologic toxicity in hematologic malignancies treated with CAR-T cell therapy.
Methods
We searched databases including PubMed, Web of Science, Embase and Cochrane up to January 2021. For safety analysis of overall hematologic toxicity, the rate of neutrophil, thrombocytopenia and anemia were calculated. Subgroup analysis was performed for age, pathological type, target antigen, co-stimulatory molecule, history of hematopoietic stem cell transplantation (HSCT) and prior therapy lines. The incidence rate of aspartate transferase (AST) increased, alanine transaminase (ALT) increased, serum creatine increased, APTT prolonged and fibrinogen decreased were also calculated.
Results
Overall, 52 studies involving 2004 patients were included in this meta-analysis. The incidence of any grade neutropenia, thrombocytopenia and anemia was 80% (95% CI: 68–89%), 61% (95% CI: 49–73%), and 68% (95%CI: 54–80%) respectively. The incidences of grade ≥ 3 neutropenia, thrombocytopenia and anemia were 60% (95% CI: 49–70%), 33% (95% CI: 27–40%), and 32% (95%CI: 25–40%) respectively. According to subgroup analysis and the corresponding Z test, hematological toxicity was more frequent in younger patients, in patients with ≥4 median lines of prior therapy and in anti-CD19 cases. The subgroup analysis of CD19 CAR-T cell constructs showed that 41BB resulted in less hematological toxicity than CD28.
Conclusion
CAR-T cell therapy has dramatical efficacy in hematological malignancies, but the relevant adverse effects remain its obstacle. The most common ≥3 grade side effect is hematological toxicity, and some cases die from infections or severe hemorrhage in early period. In long-term follow-up, hematological toxicity is less life-threatening generally and most suffered patients recover to adequate levels after 3 months. To prevent life-threatening infections or bleeding events, clinicians should pay attention to intervention of hematological toxicity in the early process of CAR-T cell therapy.
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Background
Hematological malignancies accounted for 1.2 million, that was around 7%, newly diagnosed cancer cases every year worldwide [1]. Among them, lymphocytic leukemia, lymphoma and multiple myeloma (MM) represent a large part. Chemotherapy, as a traditional and common treatment for them, is being replaced gradually by some novel therapies, like chimeric antigen receptor-modified (CAR-T) cell therapy.
CAR-T cells are produced strictly ex-vivo and then infused to patients by intravenous injection. The CARs, recognizing their targets by a specific mechanism distinct from classic TCRs, are comprised of an antigen-specific single-chain variable fragment (scFv) that is fused to an internal T-cell signaling domain and costimulatory molecules like CD28 or 41BB [2]. The development of CAR-T cell therapy was a wave of optimism for selected hematological malignancies in the past decades. Meanwhile, cytokine release triggered by CAR-T cell activation, expansion and cytotoxicity, leads to CRS, immune effector cell-associated neurotoxicity syndrome (ICANS) and even hematological toxicities [3, 4]. Adverse effects related to CAR-T cell therapy should be paid attention to, and there are already some reviews reporting the overall rate of CRS and ICANS. And hematological toxicity is the most common grade ≥ 3 AE in CAR-T cell therapy [63,64,65], our pooled results indicated that the most common grade ≥ 3 AEs were hematological toxic effects. Based on I2 statistic, the results from random-effect model were used to represent overall hematological toxicity. At the same time, subgroup analysis did not reduce heterogeneity. According to subgroup analysis and the corresponding Z test, hematological toxicity is more frequent in younger patients, in patients with ≥4 median lines of prior therapy and in cases targeting CD19. With specific regards to anti-CD19 CAR-T cell constructs, we focused on lymphoma to explore the difference of hematological toxicity between CD28 and 41BB, as two main co-stimulatory molecules in CAR-T therapy. Consistent with our expectations and similar with other AEs, hematological toxicity was more likely to occur in CD28 cases [62]. Some studies reported that patients with severe neutropenia died from severe infections, and some patients with severe thrombocytopenia died because of intracranial hemorrhage or other life-threatening bleeding events [11, 21, 28, 43, 44, 66]. In long-term follow-up after CAR-T therapy, most delayed hematological toxicities were not life-threatening and would ameliorate 3 months after treatment [28, 46]. This reminds us of paying attention to hematological toxicities in the early process of CAR-T therapy. Hepatotoxicity, nephrotoxicity and coagulation disorder are less frequent, compared with hematological toxicity, CRS and ICANS. All of these AEs can reflect the levels of inflammation in patients treated with CAR-T cell, and this meta-analysis provided the pooled results to clinicians for reference.
Cytopenia was common after CAR-T cell infusion. Meanwhile, some studies reported that myelodysplastic syndrome (MDS), characterized as cytopenia, occurred 4–39 months after infusion [27, 28, 46, 67,68,69]. The mechanism of cytopenia is unclear currently, and it was important to rule out the process of CAR-T therapy or MDS as the cause of cytopenia [68]. However, Strati P et al. reported that cytopenia at day 30 after infusion was not associated with the later diagnosed MDS statistically [27]. The conclusion denied the association between cytopenia and MDS to some extent. Meanwhile, Jain T et al. deemed that inflammation factors remained significantly associated with hematopoietic recovery at 1 month [46]. In other words, the viewpoints about cytopenia were not consistent. Besides, whether MDS is secondary to CAR-T therapy also remains unclear, although some researchers held the standpoints that MDS were attributed to previous chemotherapies [27, 28]. To figure out the potential mechanism of cytopenia or MDS, more work exploring its etiology is needed.
Cytokine release is a double-edged sword as high cytokine levels can result in severe AEs [70]. CRS, the most common toxicity of CAR-T cell therapy, is triggered by engagement of their CARs with the antigen expressed on tumor cells [3]. Hematological toxicities potentially leading to additional complications such as infection or hemorrhage are also associated with cytokine release after CAR-T cell infusion. The study published recently proposed that improved CRS management may improve hematopoietic recovery following CD19 CAR T-cell therapy [4]. Management for CRS and ICANS has been specialized and the related guideline is being constantly being optimized. As hematological toxicities often occur after lymphodepleting chemotherapy, antiviral prophylaxis, i.e. acyclovir, should be started with pretreatment. Antimicrobial and antifungal prophylaxis may be considered when severe or persistent neutropenia happened [71]. Additionally, extended growth factors and transfusional support are needed for hematopoietic recovery [4, 72]. Meanwhile, symptomatic treatment, such as antibiotics and rehydration therapy, and professional nursing are important as well.
CAR-T cell therapy has achieved dramatical efficacy in ALL, B cell lymphoma and MM, but not in acute myeloid leukemia (AML). What limited the use of CAR-T cell in AML is the absence of specific antigen, as many myeloid antigens also expressed on hematopoietic stem cells which would lead to myelosuppression [3, 73]. Therapeutic approach still needs to be optimize to improve the efficacy and safety of CAR-T cell therapy, such as questing more specific antigens, improving CAR structure, professional management during the CAR-T therapy and application of combination of CAR-T cell and other therapies [71, 72, 74]. Recently, the clinical study showed that CD19-directed CAR-T cell with concurrent ibrutinib for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) led to high rates of MRD-negative with low CRS severity [75].
Compared with previous meta-analysis about CAR-T treatment, the study holds some advantages. We included more studies and targeted not only a single pathological type. Besides, we aimed to analyze hematological toxicity during CAR-T therapy, which was not reported by other systematical reviews. Thirdly, we performed subgroup analysis by age, pathological type, targeting antigen, co-stimulatory molecule, proportion of HSCT and median lines of prior lines. In addition, we also analyzed hepatotoxicity, nephrotoxicity and coagulation disorder, all of which should be paid attention to but have not been explored previously.
This meta-analysis has some limitations as well. Firstly, we defined all kinds of lymphoma (DLBCL, MCL, HL, etc.) as “lymphoma”, and we set all kinds of leukemia into the “leukemia” subgroup. Some studies pooled all patients with different pathological types together and analyzed the efficacy and safety of CAR-T therapy. When extracting the data in this situation, we deemed the subgroup as the pathological type in majority of the patients included in the study. For example, the study by Shah N. N. et al. [14] included 11 DLBCL patients, 7 MCL patients, 1 FCL patient and 3 CLL patients, so we categorized them as “lymphoma”. This method of classification biased the pooled results. Secondly, some articles provided mean lines but not median lines of prior therapy. According to the statistics principle that both mean and median stand for the central tendency of the relevant data, we deemed the mean lines as the corresponding median lines roughly. Additionally, we included some conference proceedings to extract data for analyzing. The data was not detailed as those published in journals, and it might bring bias.
Conclusions
In conclusion, the CAR-T therapy is associated with hematological toxic effects. And some cases died from infections or severe hemorrhage in early period. In long-term follow-up, the majority of hematological toxicity is less life-threatening and most patients will ameliorate after 3 months. However, more work is needed to explore its mechanism. The significance of this study is to provide the pooled results to clinicians for reference, and to remind them of paying attention to prevention and intervention for hematological toxicity in the early process of CAR-T therapy.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Abbreviations
- CAR:
-
Chimeric antigen receptor-modified
- HSCT:
-
Hematopoietic stem cell transplantation
- AST:
-
Aspartate transferase
- ALT:
-
Alanine transaminase
- APTT:
-
Activated partial thromboplastin time
- CI:
-
Confidence interval
- MM:
-
Multiple myeloma
- scFv:
-
Single-chain variable fragment
- ICANS:
-
Immune effector cell-associated neurotoxicity syndrome AE: adverse effect
- CRS:
-
Cytokine release syndrome
- SCE:
-
Serum creatine elevated
- MDS:
-
Myelodysplastic syndrome
- DLBCL:
-
Diffuse large B cell lymphoma
- MCL:
-
Mantle cell lymphoma
- HL:
-
Hodgkin lymphoma
- FCL:
-
Follicular cell lymphoma
- CLL:
-
Chronic lymphocytic leukemia
- R/R:
-
Relapsed/refractory
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This work was supported by grants from the Key Special Project of “Research on Prevention and Control of Major Chronic Non-infectious Diseases” (No. 2019YFC1316203), the National Natural Science Foundation of China (No. 81873434) and Natural Science Foundation of Hubei Province (No. 2020CFA065).
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Conception and design of study: HY, MH, LWJ. Acquisition of data: LWJ, LCG, KHM. Analysis and/or interpretation of data: LWJ, ZYQ, DMY. Drafting and revision of manuscript: LWJ, LC. All authors have read and approved the manuscript.
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Luo, W., Li, C., Zhang, Y. et al. Adverse effects in hematologic malignancies treated with chimeric antigen receptor (CAR) T cell therapy: a systematic review and Meta-analysis. BMC Cancer 22, 98 (2022). https://doi.org/10.1186/s12885-021-09102-x
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DOI: https://doi.org/10.1186/s12885-021-09102-x