In this real-world observational study based on the use of Sintilimab, Sintilimab demonstrated superior efficacy and safety. The ORR, DCR and CBR of the 19 patients were 63.2%, 84.2% and 73.7% respectively. This result is lower than the results of The Phase II study of Sintilimab [5] (ORR = 78.7%, DCR = 94.7%, CBR = 82.4%), considering that it is related to the pathological type of included patients. Only patients with relapsed or refractory classic Hodgkin's lymphoma were included in the phase II clinical trial. In our subgroup analysis of lymphoma types, ORR and DCR of Hodgkin's lymphoma were 77.8% and 100%, which were close to the results of the phase II clinical trial with Sintilimab. In the peripheral T/NK cell lymphoma subgroup, ORR and CBR were 66.7% and 83.3% respectively. This has not been reported in previous literature, but in the 2019 ASCO meeting, the pathologic diagnosis of failure in asparaginase based regimen was extranodal NK/T cell lymphoma, nasal type (ENKTL). This result is similar to our observation.
The results of this observation suggest that Sintilimab has different curative effects in different pathological types. Efficacy was best in relapsed refractory Hodgkin's lymphoma (CBR = 100%), followed by peripheral T/NK cell lymphoma (CBR = 83.3%) and worst in diffuse large B cell lymphoma (CBR = 0%). This is similar to the efficacy reported by other anti-PD-1 [8–11]. The efficacy of Sintilimab in non-Hodgkin's disease needs to be confirmed in large cohort studies. A high response rate to anti-PD-1 in classic Hodgkin's lymphoma was associated with stronger expression of PD-L1 / PD-L2, which was due to amplification of 9p24.1(sites of PD-L1, PD-L2 and JAK2 genes on chromosome 9) [12]. Genetic alterations in 9p24.1 are rare in DLBCL, and the incidence and severity of 9p24.1 alterations in DLBCL are significantly lower than those in cHL, as confirmed in a single-arm phase II study of Nivolumab for recurrent/refractory diffuse large B-cell lymphoma in patients who are not suitable or have failed autologous transplantation[9]. A retrospective analysis of 1253 biopsy samples from patients with DLBCL has proved that only 11% of them are PD-L1 positive [13]. Han et al. found that PD-L1 and PD-L2 showed higher expression levels in T cell lymphoma than in B cell lymphoma[14]. Jo et al. performed PD-1 and PD-L1 immunostaining on 79 ENKTL biopsy samples, and the expression rate of PD-L1 in ENKTL was as high as 79.7% [15].
Interestingly, it was observed in this study that the efficacy of Sintilimab was correlated with the number of previous chemotherapy lines (P = 0.029), and the lower the number of previous chemotherapy lines, the better the efficacy of Sintilimab. This is different from the results in the Phase II trial of Orient-1 Sintilimab[5], in which all included patients benefited to a similar degree from Sintilimab regardless of their previous chemotherapy regimen. It is worth noting that the refractory patients did not progress faster or worse even after receiving Sintilimab treatment [16].It is different from the previous research results may be the reason; Sintilimab previous studies were limited to patients with cHL and this study included not only cHL but also NHL. Current studies have found that the expression level of PD-1 is weakened by chemotherapy, and chemotherapy may change the tumor antigen-specific response.
In the subgroup analysis of the choice of regimen for Sintilimab, there was no statistical difference between regimen and efficacy. This may be due to the small sample size, or it may be the case. This needs to be verified in future clinical trials of Sintilimab. Although some basic experimental studies suggest that chemotherapy [17] or radiotherapy [18, 19] can induce the up-regulation of PD-L1 expression in tumor cells, the percentage of PD-L1 expression in NSCLC cells after radiotherapy is significantly lower than that before radiotherapy[20]. Radiotherapy can induce tumor microenvironment sensitivity to immune checkpoint inhibitors[21]. Preclinical evidence [22, 23] shows that combining radiotherapy with anti-PD-1 therapy can improve the anti-tumor activity and long-term survival rate of the two treatments. In refractory Hodgkin's lymphoma, local irradiation combined with anti-PD-1 checkpoint blocking therapy has a synergistic effect [24]. Many other retrospective case series support a combined strategy of radiotherapy and anti-PD-1 / PD-L1 antibody therapy, including concurrent and sequential use, although the exact mechanisms that contribute to improved outcomes are unclear. The synergetic effect of chemotherapy drugs and PD-1 antibody was also tested in a single-center, two-arm, open-label phase II clinical trial recently conducted by the PLA General Hospital [25]. The 6-month sustained response rate was 76% for Camrelizumab monotherapy, and 100% for Decitabine combined treatment with Camrelizumab.
In the analysis of influencing factors affecting the efficacy of PD-1 inhibitors, a retrospective study showed that PFS and OS of patients with BMI ≥ 25 were significantly longer than those with BMI 25 in continuous use of PD-1/PD-L1 inhibitors [26]. The reason may be that white adipose tissue also participates in the induction and/or coordination of host defense and is a source of cytokines and chemokines [27]. However, in this study, there was no statistical difference between BMI and efficacy, which may be related to the small sample size.
In this study, the most common adverse reactions were hypothyroidism (40%) and anemia (40%), and the adverse reactions were controllable. In this study, patients with grade 2 or 3 anemia had anemia prior to treatment, or were associated with combination of Sintilimab with radiotherapy or chemotherapy or targeted therapy. Our study found that the duration of hypothyroidism was within 5 cycles of treatment. Barroso et al recommend monitoring thyroid stimulating hormone and free thyroxine levels before each infusion of checkpoint inhibitors for at least the first five cycles of treatment [28]. The most common adverse reactions in the phase II clinical trial of Sintilimab were fever (41%) and hypothyroidism (22%). The overall tolerance of PD-1/PD-L1 inhibitors was superior to chemotherapy.PD-1 /PD-L1 inhibitors are associated with a lower risk of treatment-related symptoms (fatigue, anorexia, nausea, diarrhea, constipation, and sensory neuropathy), but a higher risk of immune-related adverse events [29]. It is worth noting that anti-PD-1 drugs can achieve long-term tumor control by prolonging immune activation, so immune-related adverse events requiring treatment may persist, develop or even occur over time [30]. As the use of anti-PD-1 drugs increases, there is a growing need for non-oncologists to manage rare but clinically significant organ-specific immune-related adverse events and more common general adverse events related to immune activation. A multidisciplinary clinical team may better meet the long-term needs of these patients.