Page 345 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR
Elderly long-term survivors in the Nordic phase II study with first-line maintenance temozolomide for primary central nervous system lymphoma: a 10-year follow-up
Primary central nervous system lymphoma (PCNSL) is a sep- arate group of lymphomas confined to the central nervous system (CNS) including the eyes. More than 95% of the cases represent aggressive CD20+ diffuse large B-cell lymphoma (DLBCL) with distinct clinical and biological features and poor prognosis.1
The outcome of PCNSL is particularly poor among elderly patients, and the improvements achieved in survival during recent decades appear to be restricted to younger PCNSL patients.2,3 The main feature of our Nordic phase II PCNSL study was its focus on elderly patients. The treatment for the elderly subgroup in our study consisted of de-escalated induction immunochemotherapy followed by maintenance temozolomide. We have previously reported the 22-month results with 2-year overall survival (OS) rates of 60.7% and 55.6% (P=0.40) and progression-free survival (PFS) rates of 33.1% and 44.4% (P=0.74), among younger and elderly pa- tients, respectively.4 In our study, we found an astonishing good result for the elderly patients with a median duration of response (DOR) not reached among elderly patients, compared to a median DOR of 10 months among younger patients treated with more intensive immunochemother- apy but without maintenance temozolomide. One of our hypotheses is that the improved results among the elderly subgroup were due to maintenance temozolomide therapy. In PCNSL, late relapses occur but long-term follow-up da- ta is scarce. Herein, we present long-term outcomes and neurocognitive performance at 10 years after diagnosis in the Nordic phase II first-line PCNSL study (clinicaltrials gov. Identifier: 01458730).
In this prospective multicenter phase ll study, immunocom- petent, newly diagnosed, and histologically confirmed PCNSL patients up to 75 years of age at diagnosis were treated with an age-adjusted multi-agent immunochemotherapy regimen. The induction regimen for the younger subgroup (18-65 years at diagnosis) included high-dose methotrexate (HD-MTX) and HD-cytarabine combined with rituximab, if- osfamide, cyclophosphamide, dexamethasone, intrathecally administered liposomal cytarabine, vindesine, and vincris- tine. In the de-escalated induction regimen for the elderly subgroup (66-75 years at diagnosis), cyclophosphamide and vincristine were replaced with temozolomide, followed by temozolomide maintenance in patients responding to in- duction therapy.4
For baseline evaluation, response assessment, and statistical design, see the original article.4 All patients were intended to be followed for 120 months after the end of treatment, which
in the younger subgroup was the end of induction therapy and, in the elderly subgroup, was the end of maintenance therapy. Patients with refractory disease, progressive dis- ease (PD), and patients not achieving a complete response (CR) at the end of planned therapy went off-study and were followed for OS only. OS, PFS, and DOR were estimated by using the Kaplan-Meier method. Crude differences between the groups of patients were tested using the log-rank test. Median follow-up was calculated using the reverse Ka- plan-Meier method.
The study was approved by the local ethics committees and conducted in agreement with the Declaration of Helsinki and Good Clinical Practice Guidelines.
Sixty-six patients (35 males and 31 females) from 12 centers in Denmark, Norway, Sweden, and Finland were enrolled between May 2007 and October 2010. Baseline character- istics, treatment, responses, and adverse events have been previously reported.4 The overall response rate was 73.8% for the entire cohort, 69.9% in the younger and 80.8% in the elderly subgroup. Myelosuppression after HD-cytarabine cycles was the most common grade 3-4 adverse event. After a median follow-up of 10 years, the 10-year OS rate was 29.8% (95% confidence interval [CI]: 20.5-43.4), the 10-year PFS rate was 13.3% (95% CI: 6.6-26.8), and median DOR was 13.2 months (95% CI: 7.7-72.4) for the entire cohort. Among the younger patients, the 10-year OS rate was 30.4% (95% CI: 18.8-49.1), and the 10-year PFS rate was 8.5% (95% CI: 2.6-27.8). Likewise, the 10-year OS rate was 29.6% (95% CI: 16.6-53.0), and the 10-year PFS rate was 21.3% (95% CI: 8.6- 46.9), for the elderly patients. Median PFS was 13 months for the entire cohort (range, 1,2-162,8 months), 11 months in the younger (range, 1.8-168.5 months), and 57 months (range, 0-140 months) in the elderly subgroups (Figure 1).. Seventeen of 66 patients (25.8%) were known to be alive at 10 years after diagnosis. Long-term survivors were three younger male patients, eight younger female patients, two elderly male patients, and four elderly female patients. Seven patients had primary refractory disease, six younger patients, and one elderly patient. Early relapses less than 1 year af- ter the end of treatment were observed in 21 patients. Of these, 13 patients belonged to the younger subgroup. Later relapse occurred in 14 patients, at 15-168 months after the completion of therapy.
The number of deaths at the end of the study was 46 (69.7% of the 66 patients enrolled), and three patients were lost to follow-up at around 8 years. The cause of death was PCNSL in 25 patients. Four patients (6%) aged 64, 66, 73, and 74
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