A new prognostic index (CLIPI) stratifies risk in advanced cutaneous lymphomas: Associations with treatment pathways, quality of life and survival

Abstract Advanced-stage mycosis fungoides (MF) and Sézary Syndrome (SS) are primary cutaneous T-cell lymphomas (CTCL) have a high symptom and emotional burden and a poor prognosis with overall survival <5 years. Treatment selection is particularly challenging in these patients who have high clinical needs. Studies have also found the current clinical staging (IA-IVB) inadequate for risk stratification with worse survival in IIB than stage III. Developing a prognostic index in MF/SS will identify patients with poor outcomes and may allow better management decisions, improve HRQoL and ultimately survival. The PROCLIPI (PROspective Cutaneous Lymphoma International Prognostic Index) Study was launched in 2015 at 46 international expert CTCL Centers, prospectively collecting pre-defined datasets in newly diagnosed MF/SS patients to determine a cutaneous lymphoma IPI (CLIPI), which included treatment selection and HRQoL measures using Skindex-29 at diagnosis. 552 advanced-stage MF/SS patients were recruited. The 5-year overall survival (OS) is IIB=50.0%, IIIA=64.8%, IIIB=43.9%, IVA1=50.8%, IVA2=25.9%, IVB=36.9%. Factors at diagnosis associated with a significantly worse survival were lymphomatous nodes (N3 status) (p<0.001); age>60years (p<0.001), raised serum lactate dehydrogenase (p=0.005); and large-cell transformation in skin (p=0.006). These 4 independent prognostic factors were modelled into prognostic index (CLIPI) risk groups, where patients with 0-1 prognostic factors were low-risk, 2 were intermediate-risk, and 3-4 factors were high-risk. CLIPI stratification by risk group found there was a significantly worse OS in high versus low-risk (p<0.001), high-versus intermediate-risk (p=0.002), as well as intermediate-versus low-risk (p=0.010) with 5-Year OS in low-risk=63.3%, intermediate-risk=44.7% and high-risk=18.3%. Analysis of first-line treatment selection in these risk-groups found that most received systemic therapies however 23.5% of low-risk patients, 25.0% of intermediate-risk and 13.2% of high-risk patients received skin-directed therapies (SDTs) only, with no significant difference between groups (low-versus intermediate-risk p=0.121, intermediate-versus high-risk p=0.10, low vs high-risk p=0.799). In all patients given subsequent systemic treatments, the median time to next systemic treatment (TTNT) trended downward; low-risk=6.3mnths (Interquartile range (IQR):4.3,14.5), intermediate-risk patient=5.7mnths (IQR:3.5,8.1), and high-risk=4.7 months (IQR:3.3-7). The median number of total treatment lines was 4 (IQR:2,5) in low-risk, 2 (IQR:2,5) in intermediate-risk and 3 (IQR:2,5) in high-risk patients, with a significant difference between intermediate-versus low-risk patients (p=0.0211). HRQoL measured using Skindex-29 found median global scores (symptom+emotion+function domains) were low-risk=36.6 (23.0,50.8), intermediate-risk=42 (29.5,62.3) and high-risk=45.6 (34.9,58.1) with a trend towards worse HRQoL in high-risk which didn't reach statistical significance. The median symptom domain scores were low-risk=42.9 (25,58.9), intermediate-risk=53.6 (39.3,67.9) and high-risk=58.9 (51.8,69.6) respectively, with a significant difference between low versus high-risk (p=0.003) and low versus intermediate-risk (p=0.008) groups. Median functioning scores also trended downward at low-risk=21.9 (8.3,52.1), intermediate-risk=33.3 (14.6,54.2) and high-risk=41.7 (20.8,59.4) whilst median emotions domain scores were similar across the groups with low-risk=43.8 (26.3,63.4), intermediate-risk=42.5 (25,62.5) and high-risk=41.3 (33.8,50). The CLIPI stratifies advanced-stage MF/SS into low, intermediate and high-risk groups with significantly worse 5-year survival rate. Most MF/SS treatments are associated with low response rates and duration of response. Treatment patterns emerged between the risk-groups with SDTs more commonly used in low and intermediate-risk and shorter TTNT in the high-risk group. HRQoL using Sindex-29 found significantly worse symptom burden in intermediate and high-risk groups. Emotional scores were similar in risk groups reflecting the negative effect of MF/SS on patients well-being. Our data shows that CLIPI can stratify patients into precise low, intermediate, and high-risk prognostic groups and emphasizes the potential to be utilized in optimizing treatment selection to improve patient quality of life and outcomes.