Yittrium 90 Ibritumomab Tiuxetan (Zevalin®) in the Treatment of Relapsed or Refractory Indolent B-Cell Non-Hodgkin Lymphoma; Integrated Analysis of Three Japanese Institution’s Experience with Improvement Trend of the Long-Term Responses over a 10 Year Study Period

Background

This study investigated all cases treated by Yittrium 90 Ibritumomab Tiuxetan (90Y-IT, Zevalin®) for relapsed or refractory indolent B-cell non-Hodgkin lymphoma at the three Japanese institutions between 2008/10/14 and 2018/5/15. 90Y-IT is the only radioimmunoconjugate agent available on the Japanese market since August 2008. J3Zi study (UMIN-CTR: 000037105) created integrated dataset of 90Y-IT treatment, and subjects were requiring at least two years follow-up period.

Methods

A total of 347 cases were registered and 316 patients of the per-protocol set were analyzed creating the integrated dataset. Overall response rate (ORR) and complete response rate (CR) were evaluated using positron emission tomography (PET, 84%), computed tomography (CT, 8%) or other methods (8%) at 8-12 weeks after 90Y-IT treatment. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. The prognostic factors of PFS and OS were analyzed using Cox regression analysis.

Results

All patients had previously been administered with median of 2 (mean 3.9) chemotherapeutic regimens at a mean age of 65 years. The majority of cases were follicular lymphoma (FL) patients (75%) followed by mucosa-associated lymphoid tissue lymphoma/marginal zone lymphoma (MALT/MZL) patients (13%). The ORR was 89% and CR was 66%. The Kaplan-Meier survival curves of PFS and OS extending over the 10 year study period were shown in Figure 1A. The progression free 2-year cumulative survival rate (PFS 2-years) was 61%. The PFS 2-years of the early phase (2008/10/14-2013/7/9) defined as the cut-off date of the previous report, and the late phase (2013/7/10-2018/5/15) were 51% and 73%, respectively (p<0.0001). The overall 5-year cumulative survival rate (OS 5-years) was 77%. The OS 5-years of the early phase and the late phase were 73% and 83% respectively (p=0.0565). The evident improvement trend of the long-term responses during the 10 year study period was demonstrated (Figure 1B).

Among several prognostic factors, treatment response (CR/non-CR), number of prior treatments (≦2/≧3), sIL-2R (≦500/>500 U/ml) and progression of disease within 24 months after the first-line treatment initiation (POD24, no/yes), were the significant factors (univariate analysis, p<0.05) for both PFS and OS. The number of prior treatment and POD24 showed correlation with each other, but also showed a significant different between the early phase and the late phase of the study, thus the factors resulting in the improvement trend shown in figure 1 have to be carefully discussed.

In 316 cases, 26 (8.2%) of second primary malignancy (SPM) including 9 (2.8%) haematological malignancy (7 myelodysplastic syndrome, 1 acute myeloid leukemia and 1 chronic myeloid leukemia) were observed and 1 death (treatment related Sepsis) in 15 infection cases recorded. All the long-term follow-up safety reports were consistent with the previous studies of the relapsed/refractory low-grade follicular lymphoma, and there was no obvious trend associated with radioimmunoconjugate therapy.

Conclusions

The study represents the largest reported cohort for therapeutic use of 90Y-IT in Japan. The improvement trend of the long-term responses (PFS and OS) during the 10 year study period was demonstrated. The response and survival data in this large real-world cohort is superior to the previously published 90Y-IT trial data including the US phase-3 trial conducted 20 years ago. The factors resulting in this improvement trend have to be carefully assessed in attempt to achieve better outcomes for 90Y-IT treatment in future.

Figure-1 Legend

(A) Overall survival (OS, black line) and progression-free survival (PFS, gray line) with 95% confidence intervals (n=316), Kaplan-Meier method.

(B) Improvement trend of the long-term (2-year) treatment responses (PFS and OS) over the 4 periods of 90Y ibritumomab tiuxetan treatment (n=316) dated; 2008/10/14-2011/7/9 (n=91), 2011/7/10-2013/7/9 (n=86), 2013/7/10-2015/7/10 (n=60), 2015/7/10-2018/5/15 (n=79).

Disclosures

This study was sponsored by Mundipharma. Data management and statistical analysis under the direction of investigators Ilseung Choi, Masaya Okada and Tomoki Ito was provided by L Data Science, Co., Ltd. and was funded by Mundipharma.