CAR-T therapy demonstrated safety and efficacy in relapsed/refractory diffuse large B-cell lymphoma patients complicated with hepatitis B related cirrhosis

doi:10.21203/rs.3.rs-4713165/v1

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CAR-T therapy demonstrated safety and efficacy in relapsed/refractory diffuse large B-cell lymphoma patients complicated with hepatitis B related cirrhosis

https://doi.org/10.21203/rs.3.rs-4713165/v1

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Chimeric antigen receptor T cell (CAR-T) therapy has demonstrated both efficacy and safety in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients infected with hepatitis B virus (HBV). However, its applicability in individuals with liver cirrhosis remains largely unexplored due to the potential for unpredictable complications. Here, we report three cases (P1, P2, P3) of relapsed/refractory DLBCL with HBV-related cirrhosis treated with CAR-T cells infusion. P1 and P2 received CAR-T cells infusion following a conditioning regimen of fludarabine and cyclophosphamide (FC) for lymphodepletion; while P3 received SEAM (CCNU, etoposide, cytarabine, and melphalan) regimen and autologous stem cell transplantation bridging CAR-T cells infusion. P1 and P2 achieved rapid complete remission (CR), whereas P3 initially exhibited stable disease a month post-CAR-T infusion and subsequently achieved CR after local radiation salvage therapy and lenalidomide maintenance. With a median follow-up of 42 months after CAR-T, the progression free survival rate was 100%. Notably, during follow-up, these patients experienced complications associated with cirrhosis, including endoscopic variceal bleeding, HBV reactivation, or the diagnosis of hepatic malignancy. Our findings suggest that CAR-T therapy is highly effective for the treatment of DLBCL patients with HBV-related cirrhosis, albeit necessitating monitoring for potential hepatic complications.

diffuse large B-cell lymphoma

cirrhosis

chimeric antigen receptor T cell therapy

hepatitis B virus

Hepatitis B virus (HBV) infection represents a significant global public health concern, precipitating a cascade of hepatic complications including cirrhosis and hepatocellular carcinoma, often culminating in fatal outcomes in the absence of timely intervention. Concurrently, diffuse large B-cell lymphoma (DLBCL) stands as one of the predominant B cell malignancies, characterized by its aggressive nature and challenging treatment landscape. The prevalence of HBV infection in DLBCL patients is higher than that in the general population and often leads to worse clinical outcomes[1, 2]. But there is limited information on treatment recommendations and a lack of appropriate clinical trials for DLBCL patients facing disease progression.

Chimeric antigen receptor T cell (CAR-T) therapy has been reported as safe and effective in treating relapsed/refractory(R/R) DLBCL and about 40% even achieved sustained response[3]. For patients with chronic HBV infection, one big concern is hepatitis B virus (HBV) reactivation due to the prolonged immunosuppressive state induced by CAR-T therapy. Recent reports have shown that HBV reactivation occurred in about 5.3–20% of HBsAg-positive patients receiving antiviral prophylaxis after CAR-T therapy[4–6]. Nevertheless, it appears that viral infection does not adversely affect the clinical safety and efficacy of CAR-T therapy [5, 6].

In 2021, the World Health Organization (WHO) disclosed that among individuals afflicted with chronic hepatitis B virus (HBV) infection, up to 40% may progress to cirrhosis if left untreated, with a subset of patients facing the dire consequences of liver malignancy, hepatic failure, or mortality. Notably, within the subset of patients diagnosed with DLBCL complicated by HBV related cirrhosis, the utilization of chimeric antigen receptor T cell (CAR-T) therapy is frequently cautioned against due to the dearth of documented data on potential adverse events during and post-infusion. Herein, we presented a single-center case series of R/R DLBCL patients with cirrhosis, who underwent CAR-T cells infusion, delineating both the therapeutic efficacy and associated adverse outcomes.

Patients

We retrospectively reviewed R/R DLBCL patients who received CAR-T therapy at the First Affiliated Hospital of Soochow University from Jan 2018 to Jan 2023. Three DLBCL patients (P1, P2, P3) complicated with hepatitis B related cirrhosis were drawn out and analyzed. The follow-up visit was conducted until the last visit time June, 2024. The study was conducted in accordance with Declaration of Helsinki principles and approved by the Ethics Review Board of the First Affiliated Hospital of Soochow University. All patients provided written informed consent.

Diagnostic criteria

The diagnosis of DLBCL was made based on the fifth edition of World Health Organization classification. Chronic HBV infection was defined by the detection of hepatitis B surface antigen (HBsAg) for more than 6 months.

The diagnosis of hepatitis B related cirrhosis requires a comprehensive approach, involving: (1) HBV infection medical history and symptoms such as fatigue or jaundice et al; (2) laboratory tests including HBV serological tests, HBV-DNA and liver function; (3) imaging studies by ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI) of the liver to detect the signs of cirrhosis and evaluate the complications. Child-Pugh score system was used to assess the severity of liver disease and predict prognosis. HBV reactivation was defined as at least one of the followings: (1) newly detectable HBV-DNA; (2) ≥ 2 log HBV-DNA increase compared to baseline; (3) reappearance of HBsAg. The hepatitis flare was defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increased to ≥ 3 upper limit of normal. The lower reference limit of HBV-DNA was 60 international units (IU)/milliliter(mL) based on our laboratory standards.

CAR-T or ASCT bridging CAR-T therapy procedures

CAR-T products were provided by the Unicar-Therapy Bio-Medicine Technology Co. (Shanghai, China), and quality tests were performed before infusion to patients as previously described [7, 8], the detailed procedures were described in supplementary data S1.

FC (fludarabine 30mg/m²/d, day − 5, -4, -3; cyclophosphamide 300mg/m²/d, day − 5, -4, -3) conditioning regimen was used for lymphodepletion prior to CAR-T infusion in both P1 and P2. Then P1 received scheduled infusion of anti-CD19 and anti-CD22 CAR-T cells at total doses of 1.5×10⁷/kg and 2×10⁷/kg, respectively; P2 received infusion of tandem CD19/CD22 CAR-T cells at total dose of 1×10⁷/kg by dose escalation in 3 days (10%, 30% and 60%). P3 underwent ASCT bridging CAR-T therapy. The transplant conditioning was SEAM (Me-CCNU 250mg/m²/d day − 8; etoposide 200mg/m²/d day − 7, -6, -5, -4; cytarabine 400mg/m²/d day − 7, -6, -5, -4; melphalan 140mg/m²/d day − 3) regimen, then autologous stem cells were infused at day 0, the CD34⁺ cell count was 4.12×10⁷/kg. CAR-T cells were infused from day1 to day3 at a total dose of 1×10⁷/kg (10%, 30% and 60%).

The evaluation included complete blood count (CBC), coagulation routine, organ function, expansion of CAR-T cells in peripheral blood, cytokines and other inflammatory markers such as ferritin et al.

Outcomes assessments and measurements

Response criteria was defined in accordance with the National Comprehensive Cancer Network (NCCN) guidelines. All adverse events were assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0).Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were evaluated based on the widely accepted scoring system[9].Progression-free survival (PFS) was calculated from the day of remission after CAR-T therapy to progression, relapse, death from any cause, or the last follow-up.

Statistics analysis

Patient characteristics were summarized using the median and range for continuous variables, and frequency and percentage for categorical variables. Statistical analysis was performed using GraphPad Prism 8.

Patient characteristics and prior immunochemotherapy

All three DLBCL patients had a known history of contaminant HBV infection for years characterized by positive results for HBsAg, but did not receive proper attention. HBV related cirrhosis was diagnosed through a combination of clinical assessment, laboratory tests, and imaging studies by ultrasonography or computed tomography (CT). (see details in Table 1). For P1 and P2, cirrhosis was diagnosed at the presentation of DLBCL, however, P3 was diagnosed with cirrhosis only when the disease relapsed 5 years after the onset of DLBCL, despite receiving short-term antiviral therapy over the past few years.

Table 1

Characteristics of the three patients at the diagnosis of DLBCL complicated with HBV related cirrhosis
variable	P1	P2	P3
sex	male	male	female
age(years)	62	53	46
DLBCL subtype	non-GCB	non-GCB	non-GCB
Ann Arbor Stage	IV B	II A	IV B
IPI score	5	1	4
other high-risks	-	double expression	double expression relapsed disease
history of chronic HBV infection	yes	yes	yes
HBV-DNA (range, <60 IU/ml)	3.59×10⁷	<60	<60
HBV serology	HBsAg+ HBeAg+ HBcAb+	HBsAg+ HBeAb+ HBcAb+	HBsAg+ HBeAb+ HBcAb+
hepatic complications besides cirrhosis	severe ascites; splenomegaly; esophageal varices	splenomegaly	esophageal and gastric varices
Child-Pugh grade	Grade B	Grade A	Grade A
Note DLBCL, diffuse large B-cell lymphoma; HBV, hepatitis B virus; GCB, germinal center B-cell-like; IPI, International Prognostic Index

They received antiviral treatment with entecavir at a daily dose of 0.5 mg along with supportive measures, when HBV-DNA was undetectable and liver function improved to Child-Pugh grade A, they initiated standard immunochemotherapy. However, the optimal therapeutic outcomes were not realized, prompting the recommendation for salvage treatment with CAR-T or ASCT bridging CAR-T therapy as salvage treatment. The treatment course and corresponding responses of the patients were summarized in Fig. 1.

Clinical efficacy and follow-up of CAR-T therapy or ASCT bridging CAR-T therapy

Post-CAR-T infusion, positron emission tomography-computed tomography (PET-CT) assessments confirmed complete remission (CR) in P1 and P2. Both individuals received comprehensive clinical oversight from hepatologists and hematologists for concurrent cirrhosis and DLBCL management, resulting in sustained DLBCL remission. P3 exhibited stable disease (SD) one month after ASCT bridging CAR-T, subsequently undergoing salvage local radiotherapy, but with minimal effect. Following this, lenalidomide maintenance therapy was initiated six months post-ASCT bridging CAR-T, remarkably achieving complete disease control, she finally achieved CR at one year after ASCT bridging CAR-T and maintained thereafter. Comprehensive radiological evaluations via PET-CT scans of three patients were detailed in supplementary data S2.

As of June 2024, these three patients had been followed up for a median of 42 months (range, 26.5 to 73 months) after CAR-T infusion, they all achieved progression free survival (PFS) and the median PFS duration was 37.5 months (range, 15 to 72 months).

Short-term toxicities

The short-term toxicities associated with CAR-T infusion within a month were mild and reversible in three patients (detailed in Table 2). In particular, all showed grade 4 hematologic toxicity, but no CRS ≥ grade 3 or ICANS was observed. CD19⁺ B cell deletion persisted post CAR-T infusion for a longest 6 months (range, 4–6 months).

Table 2

Short-term toxicities of CAR-T infusion
variable	P1	P2	P3
treatment	CAR-T therapy	CAR-T therapy	ASCT bridging CAR-T therapy
CRS	1	0	2
ICANS	0	0	0
fever	yes	none	yes
hypotension	none	none	none
hypoxemia	none	none	low flow oxygen
ALT/AST ≥ 3 ULT	none	none	yes
total bilirubin ≥ 2 ULT	none	none	none
albumin<30g/L	none	none	none
prolonged coagulation	none	none	none
hematologic toxicity	Grade 4	Grade 4	Grade 4
IL-6 max/baseline	20.6	2.2	150.7
other short-term toxicities	none	none	gastrointestinal mucositis; upper gastrointestinal hemorrhage
Note CAR-T, chimeric antigen receptor T cell; ASCT, autologous stem cell transplantation; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; ALT, alanine transaminase; AST, aspartate transaminase; ULN, upper limit of normal.

Long-term hepatic complications

P1 was diagnosed as hepatic malignancy based on typical radiographic signs that both enhanced CT and MRI scans revealed newly detected nodules with a maximum diameter exceeding 2 cm 14 months after CAR-T therapy (Fig. 2). Laboratory assessments indicated HBV reactivation, with an HBV-DNA level of 94.4 IU/mL, and elevated serum bilirubin levels of 36.4 µmol/L, suggestive of liver function impairment. Serum alpha-fetoprotein (AFP), AST, ALT, platelet counts, coagulation tests remained within normal range while Child-Pugh grade remained A classification. The patient refused surgical intervention or chemotherapy/radiotherapy options due to concerns about adverse reactions, he opted for continuous antiviral therapy with entecavir and short term adefovir, coupled with several sessions of transcatheter arterial chemoembolization (TACE), ablation therapy, and three cycles of anti-PD-1 inhibitor camrelizumab administration. Throughout his last visit, the patient remained alive with liver neoplasm under good control, and undetectable HBV-DNA.

P3 underwent indefinite lenalidomide maintenance therapy to manage DLBCL, maintaining platelet levels between 50–100×10⁹/L. However, the patient experienced two episodes of esophagogastric variceal bleeding. She underwent endoscopic tissue glue injection and variceal ligation surgeries successively, additionally with supporting treatments such as fasting, proton pump inhibitors (PPIs), pancreatic secretion inhibition, and nutritional support. Her condition remained stable and under control until the last follow-up assessment.

DLBCL patients with chronic HBV infection revealed distinct clinical features of a younger age, more advanced disease stage and even poorer outcomes[1, 2]. The role of HBV in the mechanism of DLBCL has not been fully elucidated, one hypothesis was, like hepatitis C, an protracted antigenic stimulation of B cells that produce virus-specific antibodies; another hypothesis was based on genome-wide analysis, which revealed enhanced gene mutation load possibly mediated by apolipoprotein B mRNA-editing enzyme catalytic polypeptide (APOBEC) enzyme activity and the activity of the B-cell specific activation induced cytidine deaminase (AID)[1, 10].

Currently, there are no specific guidelines or sufficient clinical trials available for treating relapsed or refractory DLBCL with HBV infection. As hepatitis B virus X protein (HBX) overexpression can be detected in DLBCL, DLBCL cells expressing HBX potentiated resistance to S-phase arrest-inducing chemotherapeutics like methotrexate (MTX) and cytarabine (Ara-C) in vitro[11, 12], suggesting that neither MTX nor Ara-C are suitable as second-line treatments. CAR-T therapy has been attempted in this disease entity under prophylactic antiviral therapy[4–6]. In a study of 15 R/R DLBCL patients with HBV infection, overall response (OR) and CR rate of CAR-T therapy was 66.7% and 60%, respectively, accompanying controllable CRS. HBV reactivation was seen in 3 patients[5].

However, DLBCL patients with HBV-related cirrhosis have received scant attention in medical literature. A retrospective case series of 8 patients assessed the administration of rituximab in DLBCL patients with HBV-related cirrhosis, all of whom were undergoing standardized antiviral therapy. Among them, one patient experienced HBV reactivation, yet neither hepatitis flares nor abnormal liver function were observed. The median overall survival was 39 months (range, 7–82 months), indicating that rituximab is a safe option for these patients [13].In our study, the CR rate was 66.7%, P3 did not achieve the expected efficacy despite receiving more intensive treatment with ASCT bridging CAR-T. HBV reactivation occurred in P1 despite whole-course combination of entecavir prophylaxis. The crucial risk factors for HBV reactivation can be broadly classified into three categories: host-related factors, virus-related factors, and immunosuppressive therapy. Immunosuppressive therapy is the major risk and quite common applied in DLBCL patients. In oncological practice, it is recommended to initiate antiviral prophylaxis with nucleoside analogs (NA) before immunosuppressive therapies. Compared to first approved NA lamivudine, next-generation NA entecavir is less likely to cause drug resistance, more effective in viral suppression and preventing HBV reactivation among HBsAg-positive lymphoma patients undergoing chemotherapy[14]. It is reported tenofovir may be more effective than entecavir in patients with HBeAg-positive[15]. Entecavir or tenofovir is now recommended standard agent for prevention and treatment of HBV reactivation in patients under immunosuppressive therapy. In our P1 case, entecavir was quite effective, but in consideration of transient detectable HBV-DNA presented without drug withdrawal, entecavir wasn’t guarantee for avoiding HBV reactivation.

CRS is a major concern since chronic HBV infection may induce higher IL-6 production[16]. Neither our cases nor other reported patients with HBV infection observed increase in the frequency or severity of CRS or ICANS. However, due to the constraint of a small sample size, the relationship between HBV infection and CRS warrants further investigation.

The clinical presentation of HBV reactivation or HBV related mortality varied, ranging from unnoticed elevated HBV-DNA levels and/or ALT to life-threatening fulminant hepatitis, hepatic encephalopathy and liver failure[5, 6, 17]. However, the occurrence of newly developed hepatic malignancy was rare. In chronic viral hepatitis-related cirrhosis patients, the estimated cumulative incidence of HCC over a 10-year period was only about 4.0%[18]. HBV plays a direct role in HCC transformation by triggering specific oncogenic pathways as well as stimulating host immune response and driving liver chronic necro-inflammation[19]. Furthermore, complex immune imbalance may promote HCC transformation[20]. In P1, despite the potential for CAR-T therapy to induce immune dysregulation characterized by cytokine elevation and B lymphocyte abnormalities, the likelihood of it significantly contributing to hepatocellular carcinoma (HCC) transformation appears low. This conclusion is supported by the relatively modest and transient elevation in cytokine levels post-therapy, as well as the restoration of B lymphocyte counts within six months. Overall, it is preferable to believe that CAR-T therapy was not primarily responsible for hepatic malignancy development. The occurrence of cirrhosis cancerization following CAR-T therapy in this case may be coincidental; however, caution should still be exercised regarding this issue.

Recent studies have focused on the evaluation of ASCT bridging CAR-T therapy vs CAR-T therapy for R/R DLBCL. One single-arm prospective clinical study[21] explored the efficacy and safety of ASCT bridging CD19/CD22 CAR-T therapy in 42 R/R aggressive B cell non-Hodgkin lymphoma (B-NHL) patients, at a median follow-up of 24.3 months, the OR rate was 90.5%, the 2-year PFS rate was 83.3%, the median PFS and overall survival were not reached. All cases of CRS and ICANS were reversible. Another retrospective cohort study[22] compared ASCT-CART to ASCT in 67 R/R DLBCL patients. The ASCT-CART group showed higher CR rate (71% vs. 33%; p = 0.003), superior 3-year PFS (80% vs. 44%; p = 0.036) and lower 3-year relapse/progression rate (15% vs. 56%; p = 0.015) than ASCT group. Although P3 in our study failed this combined therapy, the prospect of future trials to explore the efficacy and safety of ASCT bridging CAR-T therapy in a larger patient cohort is still promising.

P3 achieved CR under lenalidomide maintenance six months after ASCT bridging CAR-T. Lenalidomide, an oral immunomodulatory drug, exerts its effects primarily through direct anti-tumor activity, immune modulation, and regulation of the tumor microenvironment.[23]. We conducted a study[24] evaluating lenalidomide maintenance after CAR-T therapy in R/R DLBCL patients, we found that OS was significantly prolonged in the lenalidomide maintenance group, also in vitro test showed the delayed exhaustion of CAR-T cells may contribute to the OS benefit. The remission observed in patient P3 cannot be attributed to delayed exhaustion of CAR-T cells, as these cells were undetectable prior to maintenance therapy. Nonetheless, the early introduction of lenalidomide maintenance therapy following CAR-T treatment may enhance efficacy and promote sustained peripheral blood levels of CAR-T cells.

Looking back retrospectively, gene next generation sequencing (NGS) could not be performed and many novel targeting drugs were not available, otherwise, genetic guided targeting treatment might have been an alternative choice for these patients.

CAR-T therapy demonstrated high effectiveness with tolerable treatment-related toxicities in treating refractory DLBCL patients with HBV-related cirrhosis. However, concerns persist regarding HBV reactivation and other long-term complications, despite the use of antiviral prophylaxis. Close monitoring of HBV-DNA levels, liver imaging, and liver function post-CAR-T therapy is imperative. Further data collection is warranted to ascertain whether CAR-T therapy is a suitable strategy for this unique patient population.

Acknowledgements

The authors gratefully acknowledge all the members in Department of Hematology, the First Affiliated Hospital of Soochow University for their help in treating the patients.

Author contributions

DQK, NNP and RZ collected, analyzed data and wrote the manuscript. QZ, XZ and JHL provided major clinical care to the patients. CJQ, ZMJ and DPW identified, consented and treated the patients as principal investigator. All authors contributed to writing the paper by providing guidance and comments on its content.

Funding

This work was supported by research grants from National Natural Science Foundation of China (81400155, 81600114), Jiangsu Natural Science Foundation of China (BK20140374), Top-notch young health talents, 5th Suzhou health professionals’ program (GSWS2019035).

Data availability

Data of this study are available from the corresponding author by request.

Competing interests

The authors declare no competing financial interests.

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CAR-T therapy demonstrated safety and efficacy in relapsed/refractory diffuse large B-cell lymphoma patients complicated with hepatitis B related cirrhosis

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Abstract

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Introduction

Patients and methods

Patients

Diagnostic criteria

CAR-T or ASCT bridging CAR-T therapy procedures

Outcomes assessments and measurements

Statistics analysis

Results

Patient characteristics and prior immunochemotherapy

Clinical efficacy and follow-up of CAR-T therapy or ASCT bridging CAR-T therapy

Short-term toxicities

Long-term hepatic complications

Discussion

Declarations

References

Additional Declarations

Supplementary Files

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