Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients Age 60 Years and Younger: Long-Term Results of the Randomized Phase II PRECIS Study

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We previously reported the results of a randomized phase II study in patients with newly diagnosed primary CNS lymphoma (age 18-60 years). Patients were treated with high-dose methotrexate-based induction chemotherapy followed by whole-brain radiotherapy (WBRT) or high-dose chemotherapy (thiotepa-busulfan-cyclophosphamide) with autologous stem-cell transplantation (ASCT). The median follow-up was 33 months. In this report, we provide long-term data (median follow-up, 8 years) regarding the outcomes and toxicities. Fifty-three and 44 patients received induction chemotherapy followed by WBRT or ASCT, respectively. Their 8-year event-free survival from random assignment was 67% and 39% in the ASCT and WBRT arms, respectively ( P = .03), with a significantly lower risk of relapse after ASCT (hazard ratio = 0.13, P < .001). One third of patients who relapsed after WBRT were alive after salvage treatment. Five and four patients died of ASCT and WBRT-related toxicities, respectively. The 8-year overall survival was 69% and 65% in the ASCT and WBRT arms, respectively (not significant). Balance (52% v 10%, P ≤ 0.001) and neurocognition (64% v 13%, P < .001) significantly deteriorated after WBRT compared with ASCT during the follow-up. This study shows that 40 Gy WBRT should be avoided in first-line treatment because of its neurotoxicity and suboptimal efficacy in reducing relapses while ASCT appears to be highly efficient in preventing relapses.

Primary central nervous system lymphoma - an overview

“…Long-term follow-up of randomized phase 2 PRECIS study demonstrated advantage in 8-y event-free survival in ASCT arm over WBRT with 40 Gy (67% and 39%, respectively, p = 0.03), but without OS benefit (69% and 65%, respectively). Conversely, a significant deterioration in balances (52% vs. 10%, P ≤ 0.001) and neurocognition (64% vs. 13%, P < .001) was observed in WBRT over ASCT arm, suggesting avoidance of 40 Gy WBRT in consolidation within the first line treatment [35]. A systematic review and meta-analysis of 13 prospective trials encompassing 348 PCNSL patients treated with ASCT revealed a pooled overall response rate (ORR) of 95%,a CR rate of 80%, and a relapse rate of 19%.…”

“…First-line treatment regimens in PCNSL (adapted from Schaff et al, Blood 2021)(10,35) Tabela 2. Protokoli u prvoj liniji terapije u PCNSL (adaptirano iz Schaff et al, Blood 2021)(10,35) .…”

“…First-line treatment regimens in PCNSL (adapted from Schaff et al, Blood 2021)(10,35) Tabela 2. Protokoli u prvoj liniji terapije u PCNSL (adaptirano iz Schaff et al, Blood 2021)(10,35) . ORR overall response rate (complete response + partial response), PFS progression free survival, AraC cytarabine, IT M intrathecal methotrexate, MVP: methotrexate, vincristine, procarbazine, WBRT whole brain radiotherapy, M methotrexate, MT-R rituximab, methotrexate, temozolomide, R-MVP rituximab, methotrexate, vincristine, procarbazine, ASCT high dose chemotherapy with autologous stem cell transplantation MT methotrexate, temozolomide, MA methotrexate, cytarabine, MARix methotrexate, cytarabine, rituximab, MATRix…”

Prevention and management of secondary central nervous system lymphoma

“…Compared with whole-brain radiation therapy (WBRT) there is reduced neurotoxicity in the long-term in patients with PCNSL. 57 A dynamic review of a patient’s performance status and overall fitness is recommended to assess transplant eligibility accurately as this may improve significantly after treatment initiation. Four phase II prospective trials support this approach in both treatment-naïve SCNSL and relapsed presentations ( Table 4 ).…”

Primary CNS Lymphoma: Progress With Dose-Intensive Consolidation

“…In the companion to this article, 23 long-term outcomes and toxicity data of the PRECIS study are provided, with a median follow-up of 8 years, the longest follow-up to date of the survival and delayed toxicities of any cohort of patients with PCNSL prospectively treated with dose-intensive chemotherapy consolidation in comparison with WBRT (Table 1 A key question in comparing the IELSG-32 and PRECIS studies is as follows: why was there improved survival with ASCT compared with WBRT in the PRECIS study but not in the IELSG32 trial? One potential explanation is that the quality and depth of response to induction might have been significantly different between the two studies.…”