The Short-Term Efficacy and Safety of Brentuximab Vedotin Plus Cyclophosphamide, Epirubicin and Prednisone in Untreated PTCL: A Real-World, Retrospective Study

An observational retrospective study was performed to assess the safety and effectiveness of BV in previously untreated patients with PTCL who received ≥ 1 cycles of BV-CEP treatment from May 2020 onwards. Data from patients with a pathological diagnosis of PTCL with positive expression of CD30 were extracted from the hospital registry database. We also included patients with PTCL who were treated with CHOEP at the same time as a control group to compare the safety and efficacy of the two programs. The study was approved by the ethics committee of the First Hospital of Jilin University 2021-468, and the need for informed consent was waived by the ethics committee since only anonymized patient data were used for the study. The study was performed in accordance with the Declaration of Helsinki.

All the patients were subjected to bone marrow biopsy to ascertain the involvement of bone marrow, and positron emission tomography-computed tomography (PET-CT) evaluation was performed at the time of diagnosis. PET CT was also performed after the course of treatment to evaluate the effectiveness of treatment. The patients included in the study were treated with BV (1.8 mg/kg) in combination with CEP (cyclophosphamide 750 mg/m², epirubicin 75 mg/m², prednisone 60 mg/m², every 3 weeks) based on the clinical judgment of the treating physician. Treatment with chemotherapy was temporarily terminated in patients with agranulocytosis with severe infection [grade 4 related adverse events (AEs)], and the treatment was resumed only after the clinical improvement in agranulocytosis and infection. The clinical data extracted from the database include basic demographic details and clinical data including previous treatment.

The primary endpoint assessed in this study was the ORR achieved during the treatment with BV, and secondary endpoints were duration of response and incidence of adverse events (AEs). Exploratory endpoints such as progression-free survival (PFS) are discussed even though after such a short period.

Basic statistical analysis was performed, and the categorical variables were expressed as frequencies and continuous variables were expressed as mean and standard deviation (SD) or median and interquartile range (IQR) depending on the distribution. ORRs were calculated based on the number of patients with complete response (CR) and partial response (PR) and were provided as percentage. We did formal statistical tests for PFS for the secondary endpoints. For the primary efficacy analysis, we used the stratified log-rank test to compare the difference in PFS between the two treatment groups. All the statistical analyses were performed with SPSS statistics 22 software and Graphpad prism 6.0 software.

Nineteen patients, who had completed ≥ 1 cycles of BV-CEP treatment, including both males and females [7 ALCL (6 ALK-positive and 1 ALK-negative), 8 AITL and 1 PTCL-TFH, 2 NK/T, 1 Mycosis fungoides (MF)], featured by untreated, advanced clinical stage and high international prognostic index (IPI) score, were included for the study. (Please refer to the table in the Supplementary Material for more details.) Eighteen patients (94.7%) were identified with Ann Arbor stage III/IV, 14 (73.7%) patients had B symptoms (fever, drenching night sweats and loss of > 10% of body weight over 6 months), and 15 (78.9%) patients had extranodal infiltration. Further 13 patients (68.4%) had an International Prognostic Index (IPI) score ≥ 3, and 14 patients (71.4%) had higher lactate dehydrogenase (LDH) values (Table 1). All the patients had higher than normal β2-MG values (100%), which suggests that the patients may not derive benefits from monotherapy with chemotherapeutic agents.

Nineteen patients completed ≥ 1 cycles of BV-CEP treatment (16 cases completed ≥ 4 cycles, 3 cases only completed 1 cycle). At a median follow-up of 6.7 months (range 1.3–9.7) for the entire cohort, all patients were evaluated for response. Among them, the ORR reached 89.5% (CR 52.7%; PR 36.8%) (Table 2). In the ALCL group, CR reached 100%, with a median duration of response of up to 8 months (Table S1 Supplementary Material). In the AITL group, the ORR was 75% (CR 25%; PR 50%) (Figs. 1, 2) and the median duration of response up to 6 months, while 2 patients experienced progression after BV + CEP. The remaining 25% of the patients had disease progression. One subject developed a new target lesion, and another subject developed an increase in the size of the primary lesion. In the PTCL-TFH group, one elderly female patient with poor functional status at baseline (ECOG > 2 points) who received BV + CEP treatment had CR after four courses of treatment and then received chidamide for maintenance with a subsequent duration of response of up to 6 months. Two other high-risk ENKTLs and one case of MF patients’ lesions reduced by > 50% after only one cycle of BV-CEP, but still needed long-term observation of later efficacy and safety.

Compared to the CHOEP treatment during the same period (n = 14, Table 3), BV-CEP may improve response rates and delay disease progression (ORR 50%, PD 50% in CHOEP, Fig. 3). During the follow-up period, no deaths occurred in the BV-CEP group, while four patients (28.5%) died in the CHOEP group. The median PFS was not reached in the BV-CEP group, while 6.5 months in the CHOEP group, which may indicate that BV-CEP may extend the PFS of PTCL patients [HR 0.21 (95%CI 0.06–0.71); p = 0.026] (Fig. 4).

We also explored the relationship between CD30 expression and efficacy (Table 4). The results showed that, among these patients, the CD30 expression level of ALCL is relatively high, and 80% of them have expression levels > 80%. The use of BV has achieved very significant curative effects. However, in AITL, we found that the overall expression level is low, ranging from 2% to 40%, and there is no obvious correlation with the therapeutic effect.

For the safety assessment patients who have received at least one cycle of BV treatment were included (Table 5). In general, the AEs of BV combined with chemotherapy were mostly tolerable. The most common adverse effects occurring in patients were peripheral neuropathy, but no patients had neuropathy of grade 3 or above; the second most common adverse reaction was gastrointestinal reactions, including vomiting and diarrhea, especially in the AITL group. In addition, grade > 3 neutropenia occurred in almost 26.3% of the patients (Table 5), which is similar to the CHOEP group in our center (30%). One patient with ALCL had a severe respiratory infection and the pathologic testing showed Pneumocystis pneumonia (PCP). After anti-infective treatment, the respiratory function was restored and treatment was continued. All patients recovered after management and treatment according to the guidelines. There were no incidences of AEs leading to treatment withdrawal or death.