PCNSL

Phase II results for the use of rituximab and chemotherapy combo for PCNSL

Results from a phase II trial on the combined use of rituximab and chemotherapy for the treatment of primary central nervous system lymphoma (PCNSL), were published online in the Oncotarget journal in an article by Lode J Swinnen, Johns Hopkins University, Baltimore, MD, and colleagues from the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network (ECOG-ACRIN) cancer research group.

PCNSL is a rare aggressive non-Hodgkin lymphomas (NHL), typically of B-cell nature. If left untreated, PCNSL patients have a median survival between 1–3 months. Despite high response rates, radiotherapy alone leads to short survival rates, due to disease relapse. Although the addition of the traditional chemotherapy combination (CHOP) does not improve survival, results from phase II studies (DeAngelis et al. 1992, 2002; RTOG/SWOG-9310) have confirmed that pharmaceutical agents able to cross the blood–brain barrier (BBB), like high-dose methotrexate (HD-MTX), significantly prolong PCNSL patients’ survival, with or without radiotherapy. Nevertheless, late neurological toxicity remains a critical issue for such combination treatments.

In this prospective ECOG-ACRIN phase II multicenter trial (E1F05; NCT00335140), the toxicity and efficacy of rituximab and chemotherapy combination treatment – without radiation.– was investigated, as a potentially safer alternative PCNSL regimen. Although rituximab cannot cross the intact BBB, it has been detected in cerebrospinal fluid (CSF; Rubenstein et al., 2003) and rituximab monotherapy has demonstrated remission sustainability in PCNSL patients (Batchelor et al., 2011). The primary endpoints of this study were response rates (overall response rate [ORR] and complete response [CR]) and toxicity. Secondary endpoints included overall survival (OS) and progression-free survival (PFS).

Patient characteristics and study plan
  • N = 25 immunocompetent newly diagnosed with PCNSL (40% males, 60% females)
  • Median age (range) = 57 (30–76) years
  • N = 9/25 (36%) patients with ECOG score 2 or 3
  • Only patients with histologically documented NHL in the CNS were enrolled
  • Patients had not received previous radiotherapy or chemotherapy for PCNSL
  • Treatment plan:
    • HD-MTX (3.5 g/m2) with leucovorin rescue and vincristine (1.4 mg/m2) IV in Weeks 1, 3, 5, 7, 9 (x5 doses)
    • Rituximab (375 mg/m2) IV 3 times per week in Weeks 1—4
    • Procarbazine (100 mg/m2) PO daily for 7 days in Weeks 1, 5, 9
    • Cytarabine (3 g/m2) IV daily for 2 days in Weeks 11, 14
    • Dexamethasone (16 mg) daily in week 1 and tapered 4 mg/week in Weeks 2, 3 and tapered to 2 mg/week in Weeks 4–6
    • Patients with CSF involvement received intrathecal MTX (12 mg) every 2 weeks in Weeks 2, 4, 6, 8, 10 with leucovorin rescue
  • Median treatment duration (range) = 14 (4–19) weeks
  • N= 16/25 (64%) completed the treatment mainly due to adverse events (AEs) or disease progression (see below [Toxicity])
Key findings
  • CR + unconfirmed CR (CRu): 64% (16/25) (95% CI [42.5–82%])
  • ORR: 80% (20/25) (95% CI [59.2–93.2%])
  • Disease progression(PD) as best outcome: 16% (4/25)
  • Median PFS (60 months follow-up): 34.1 months (95% CI [12.2–60.1%])
  • Median OS (60 months follow-up): not reached
  • Two-year PFS: 63%
  • Post-hoc exploratory analysis: similar PFS for ≥ 60 year-olds and < 60-year-olds
  • Rituximab was detected in CSF from all assayed patients:
    • Rituximab CSF concentration: 0.1-1% of serum levels
Toxicity
  • No treatment-related deaths
  • Grade 3 AEs: N = 5/25 (20%)
  • Grade 4 AEs: N = 19/25 (76%)
  • N = 4/25 (16%) stopped treatment due to AEs (1, bowel perforation; 1, acute renal failure and 2, other reasons)
  • N = 2/25 (8%) stopped treatment due to PD
  • Most common grade 3–4 AEs were hematologic:
    • Neutropenia (n = 16/25; 64%)
    • Lymphopenia (n = 13/25; 52%)
    • Hypokalemia (n = 8/25; 32%)
    • Anemia (n = 5/25; 20%)

The results of this phase II trial demonstrated the potential use of rituximab and conventional chemotherapy, as a treatment modality for PCNSL. Main limitations included the single-arm design of the study, along with the lack of long-term follow-up neuropsychological and comparative data, to address late treatment safety. According to the authors, the outcomes of this trial are comparable to those seen in HD-MTX and radiotherapy combination studies (SWOG/RTOG-93-10) but without neurotoxicological AEs, and thus they recommend the combined use of rituximab and chemotherapy as a potentially safer PCNSL regimen.

References
  1. Swinnen L.J, et al. Phase II study of rituximab given in conjunction with standard chemotherapy in primary central nervous system lymphoma (PCNSL): a trial of the ECOG-ACRIN cancer research group (E1F05). Oncotarget. 2017 Nov 6;9(1):766-773. doi: 10.18632/oncotarget.22332. eCollection 2018 Jan 2.