Lymphoma encompasses an array of heterogeneous neoplasms that originate in lymphoid tissues but may arise in almost any tissue. The 2016 classification of the World Health Organization distinguishes, among others, mature B-cell neoplasms 1, which account for the vast majority of non-Hodgkin lymphomas (NHL) 2. Based on data from the Surveillance, Epidemiology, and End Results Program (SEER), NHLs' age-adjusted incidence was 18.6/100,000 persons with a death rate of 5.3/100,000 persons in the United States in 2017, and NHLs are estimated to be responsible for 4.3% of all cancer cases and 3.3% of cancer-related deaths by 2020. Although 5-year survival has prolonged to 72.7% (2010–2016), one-third of the patients are diagnosed in an advanced stage 3.
Among NHLs, diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the two most common subtypes, representing about 30 and 20% of the cases, respectively 2. In the native Arab population, “Anonymized for Review”, 59 and 7% of the cases had DLBCL and FL, respectively 4. DLBCL has an expected 5-year survival of 63.8%, whereas that of FL is 89.0% in the United States 3.
In B-cell NHLs, conventional chemotherapy combined with rituximab, a monoclonal antibody targeting CD20 molecules on the cell surface, radiation therapy, high-dose chemotherapy with autologous stem cell transplantation (ASCT), and other target therapies offer a wide range of therapeutic options 2,5. Despite the inherent sensitivity of most NHLs to initial chemo-immunotherapy, a high percentage of cases eventually relapse, and patients die of their disease 6. In many cases, radioimmunotherapy (RIT) is a promising therapeutic option. The most commonly used 90Y-labelled ibritumomab tiuxetan (90YIT) consists of an anti-CD20 murine monoclonal antibody conjugated with a radioactive isotope (90yttrium) purely emitting beta particle (2.293 MeV, 2.6 days isotope half-life). The molecule specifically binds to CD20 positive cells, expressed in 98–99% of B-cell NHLs 7, minimizing the drug's uptake on normal tissues 8.
In 2002, a randomized controlled trial (RCT) was released, in which 90YIT proved to be superior over rituximab regarding overall response rate and complete response in relapsed or refractory low-grade, follicular, or transformed CD20 positive NHLs 9. That year, 90YIT became the first RIT modality approved by the Food and Drug Administration (FDA) in the US 10. According to the drug label, 90YIT is indicated (1) 'for the treatment of relapsed or refractory, low-grade or follicular B-cell NHLs'; and (2) 'for the treatment of previously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy.' 11. Since then, RCTs proved that 90YIT is effective as consolidation after induction of remission 12,13 and as pre-treatment before ASCT in NHLs 14. The current guidelines of the European Society for Medical Oncology (ESMO) do not mention RIT as a therapeutic option regarding DLBCL 15 and MZL 16, and do not recommend RIT as stand-alone therapy for induction (III, B) but propose it as a potential therapeutic option in patients after multiple relapses in the elderly (>65 years) in MCL 17. In FL, ESMO preserves RIT mainly for selected, advanced (stage III-IV) cases. As a first-line therapy, RIT can be given for induction in low-risk FL if conventional chemotherapy is contraindicated (III, C), and may be considered for consolidation as an alternative for rituximab (II, B). In relapsing/progressing FL, RIT may be an option for those patients with comorbidities not eligible for chemotherapy (IV, B) 20.
In this study, we aimed to examine the efficacy and safety of 90YIT in a unique hospital setting in “Anonymized for Review”, where the indication of RIT was far broader than that approved by the FDA or the ESMO guidelines.
This study aimed to examine B-cell NHL patients' outcomes, who were treated with 90YIT. The unique setting of our study is ensured by the facts (1) that ASCT was not available in our center, (2) that many patients did not afford to move to remote centers for ASCT treatment, (3) that 90YIT-eligible patients were offered to receive the treatment in the first line, and (4) that 90YIT was well-funded, so that is available for all eligible patients. Consequently, the indication of 90YIT was far broader than that described in the drug's labels and extended the application of this treatment modality beyond the guidelines. In our study population comprising indolent and aggressive B-cell NHL cases, patients treated with 90YIT showed good EFS both in first and later lines, while the safety profile of the therapy was acceptable.
The efficacy of radioimmunotherapy was investigated by many studies in the rituximab era 26
. 90YIT, as first-line monotherapy, was proven effective in a phase II trial in FL (overall response rate was 87%; in patients aged >50 years with stage II–IV disease) 27
as well as in bulky, advanced FL 28
. According to recent, long-term follow-up data from the international RIT Network, patients receiving 90YIT in first line had a higher 8-year OS and PFS compared to those treated with the drug after relapse (78.1 vs. 54.5% and 53.6 vs. 29.6%, respectively) 29
. In refractory or relapsing FL cases, 90YIT proved to be effective on the long-term (≥5 years of follow-up with mean estimated OS of 82.3 months), with acceptable health-related quality of life 30
. In our study, the length of follow-up was a median 3 years for the 90YIT group (median OS and PFS were not being reached) but no FL cases treated with 90YIT relapsed during follow-up. With this regard, PFS may be more informative about the efficacy of the treatment than OS due to the crossover and sequential treatments after relapse 31
. Our results on efficacy of treatment are comparable to that observed in the literature. Note that we did not use the treatment in bulky cases (as per the drug's label), and most patients refused to receive external beam radiotherapy. Besides, the proportion of patients receiving 90YIT in first-line (33%) was higher than that observed in the literature (19%) 29
, which is probably the consequence of our unique setting (easy-to-access RIT vs. difficult-to-access ASCT, Fig. 1
In DLBCL, 90YIT proved to be effective as first-line treatment, following R-CHOP, in patients >60 years of age (estimated 2-year PFS was 75%) 32, in high-risk elderly patients on the short-term (estimated 2-year PFS was 85%) 33 as well as on the long-term (estimated 7-year PFS and OS were 36.1 and 38.9%, respectively) 34. These studies included exclusively (or dominantly) ASCT-ineligible DLBCL cases. In our study involving patients treated with 90YIT both in the first and later lines, OS and EFS were comparable to that reported in the literature.
While being effective, 90YIT treatment has an acceptable short-term safety profile 35. The most informative controlled study is a phase III RCT comparing 90YIT to no treatment as consolidation therapy in 409 FL cases. In this study, grade 3 or 4 non-hematological toxicities affected only 5.4% of the treated cases (of which infections accounted for 1%), compared to 5.9% in the no-treatment arm 13. In general, thrombocytopenia (<25–50 G/L) is expected to develop 4–6 weeks after treatment, whereas less apparent decline in hemoglobin level (15–25% compared to baseline) is expected a few weeks later 27,32,33. Another minor concern is the deteriorating quality of life with 90YIT 30; however, in a study, the treated elderly NHL patients (in an FL-dominant population) scored similarly for global health and social functioning compared to that in the healthy population 36. Long-term follow-up data of 90YIT-treated cases are scarce. In the report of the RIT Network (285 FL cases), secondary neoplasms developed in 12.5% (22 solid and 13 hematological neoplasms, most commonly acute myeloid leukemia and myelodysplastic syndrome), and histological transformation occurred in 5.7% of the cases with a median follow-up of 8.2 years 29. In our study, the treatment's short-term safety profile was similar to that reported earlier: 13.0% of the cases developed grade 3 or 4 hematological toxicity, of which none urged therapy cessation. Although we had one case of acute myeloid leukemia, the follow-up length does not allow us to draw firm conclusions about long-term safety (the carcinogenic effects of radiation may manifest 5–10 years later than the exposure).
Our study has several strengths and limitations. The main strength of our study is its unique setting: many ASCT-eligible patients were treated with 90YIT due to the unavailability and unaffordability of ASCT. Our study's major limitation is the single-arm design and the retrospective nature, with their inherent limitations (vulnerability to selection and information bias). Besides, the median length of follow-up was shorter than that required to analyze the treatment's long-term safety. Finally, we did not investigate cost-effectiveness of 90YIT 37.
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