Response-adapted treatment with upfront high-dose chemotherapy followed by autologous stem-cell transplantation rescue or consolidation phase high-dose methotrexate for primary central nervous system lymphoma: a long-term mono-center study

Abstract

Treatment regimens for primary central nervous system lymphoma (PCNSL) include high-dose methotrexate (HD-MTX)-based chemotherapy, with or without radiotherapy and are based on studies of selected patient groups. This retrospective study assessed a consistent strategy of response-adapted protocol applied for patients including age >65 years in a cancer center for 10 years longitudinally. Case notes were studied of 61 consecutively treated patients with PCNSL histologically diagnosed between 2003 and 2013. Clinical follow-up during and after treatment included neurologic examination and magnetic resonance imaging. Of the patients studied, 14.8 % (9/61) were clinically unfit for chemotherapy; the remaining 85.2 % (52/61) of patients were treated with HD-MTX. Of these patients, 58 % (30/52) achieved an initial complete response, with a median survival of 100.1 months. Of these response-adapted patients, 33 % (10/30) were <65 years and were treated with upfront high-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT). The remaining response-adapted patients included 53 % (16/30) who were ≥65 years underwent consolidation with HD-MTX, and 14 % (4/30) who chose radiotherapy. The median survival of patients with HDC-ASCT had not yet been reached compared with 67.6 months for patients with HD-MTX consolidation treatment (p = 0.26). At the end of the study, 75 % (39/52) of patients had died mainly owing to progression or relapse of PCNSL. Multivariate analysis showed that age younger than 65 years (p = 0.02) and complete response for up-front HD-MTX (p = 0.001) were independent prognostic indicators of overall survival. In conclusion, this single-center retrospective clinical study has shown that treatment of PCNSL with upfront HDC-ASCT and consolidation phase HD-MTX monotherapy may be feasible, even for elderly patients in a routine clinical setting, using the three-step selection by eligibility and response to initial HD-MTX, and age threshold of 65 years for ASCT.

Keywords: Autologous stem-cell transplant; Chemotherapy; Methotrexate; Primary central nervous system lymphoma; Radiotherapy; Rituximab.

Fig. 1

Treatment schema and distribution of patients. AE adverse events, CR complete response, HD-MTX high-dose methotrexate, HDC high-dose chemotherapy, ASCT autologous stem-cell transplantation, PD progressive disease, PR partial response, RTX rituximab, WBR whole brain radiotherapy

Fig. 2

Kaplan–Meier curves of all patients. a Kaplan–Meier curve shows the median overall survival (OS) of all patients is 41.6 months (95 % CI 21.1–67.6 months). b Kaplan–Meier curve shows the median progression-free survival (PFS) of 27.9 months (95 % CI 14.7–38 months)

Fig. 3

Eligibility and responses for HD-MTX. a Age distribution of patients and eligibility for HD-MTX. For initial HD-MTX therapy, 85.2 % patients were eligible (white), and nine were unfit for treatment (black). b In total, 57.7 % patients achieved a complete response (light gray), and 22 other responses (dark gray) for initial HD-MTX. c Kaplan–Meier estimate of overall survival by eligibility for initial HD-MTX. Median survival for patients eligible for treatment was 54.1 months (95 % CI 30.7–100.1 months) compared with 13.3 months (95 % CI 1.2–27.5 months) for those not eligible (Log rank p < 0.0001). d Kaplan–Meier estimate of overall survival by the response to the initial HT-MTX. Median survival for patients with complete response was 100.1 months (95 % CI 55.4 months to upper limit not available), compared with those with other responses 15.2 months (95 % CI 4.5–41.6 months (Log rank p < 0.0001). HD-MTX high-dose methotrexate, CR complete response, PR partial response, PD progressive disease, OS overall survival

Fig. 4

Kaplan–Meier estimate of overall survival according to initial treatment groups. a Patients treated with chemotherapy alone had a median overall survival 80.6 months (95 % CI 54.1 months to upper limit not available) compared with patients received HD-MTX + WBR 38.7 months (95 % CI 9.1–59.3 months) (Log rank p = 0.0037). b Of 26 patients treated with chemotherapy alone, ten patients underwent HDC-ASCT and 16 received HD-MTX consolidation. Patients treated with HDC-ASCT showed a survival curve that did not reach the median; patients treated with HD-MTX consolidation had a median overall survival 67.6 months (95 % CI 30.2 months to upper limit not available) (Log rank p = 0.2618). c Karnofsky Performance Score of the patients at the last follow-up. More than half of the patients treated with HDC-ASCT presented with 80–100 % KPS (red). d Distribution of KPS by age groups. Twenty-two patients were alive longer than 2 years, and 10 (45.5 %) of 22 patients had returned to their normal lives with a KPS of 80–100 %. WBR whole brain radiotherapy, OS overall survival, KPS Karnofsky performance status, HD-MTX high-dose methotrexate, HDC-ASCT high-dose chemotherapy with autologous stem-cell transplant, MTX methotrexate