Outcomes in Routine Clinical Practice with Methotrexate-Temozolomide-Rituximab Induction and Modified Etoposide-Cytarabine Consolidation in Newly Diagnosed Primary CNS Lymphoma

Background:

Recent studies have reported improved outcomes for patients with Primary CNS lymphoma (PCNSL) with addition of agents in induction (for e.g. cytarabine, thiotepa and rituximab in IELSG studies), intense consolidation (Autologous stem cell transplant (ASCT) as in IELSG 43) and intense non-myeloablative chemotherapy with etoposide/cytarabine (EA) as in CALGB 50202). Delivery of such an intense therapy is often difficult in clinical practice due to advanced age, comorbidities, poor performance status and resource constraints. We started using induction with methotrexate, temozolomide and rituximab (MTR) as per CALGB 50202 study however the intense non-myeloablative EA consolidation was not feasible. We used a strategy of reduced dose EA consolidation for 2 cycles with etoposide at 100 mg/m² over 2 hours and cytarabine 2 gm/m² twice daily for 2 or 3 days based on clinical judgement of the treating physician. Here we report outcomes with this approach in newly diagnosed PCNSL patients treated at our centre.

Method:

We did a retrospective analysis of patients with newly diagnosed PCNSL treated with MTR induction followed by modified EA consolidation. Kaplan-Meier was used to estimate progression free (PFS) and overall survival (OS). Variables influencing the outcomes with P less than 0.05 were considered significant.

Results:

Between January 2015 to December 2022, 72 patients were treated with above protocol with a median age of 46.5 years (range, 17 to 68 years) and 50 (69.4%) were males. Median ECOG performance score at presentation was 1 with 16 (22%) patients having ECOG performance score of 3 or more. IELSG scores were high and intermediate risk in 26 (36.1%) and 27 (37.5%) respectively while only 7 (9.7%) were in the low risk (data was not available for remaining 12 (17%) patients). MSKCC scores were available for all patients with 43 (59%) patients in class 1, 14 (19%) patients in class 2 and 15 (20%) patients in class 3.

MTR induction with a dose of 8 gm/m2 could be delivered for all 4 cycles in 64 (88%) patients. Dose reduction was required in 14 (19.4%) patients; reasons were renal dysfunction in 8 (11%), infections in 3 (4%), liver dysfunction in 2 (3%). Nine patients (12.5%) had disease progression during induction.

Total of 54 patients received consolidation with systemic therapy. Dose reduced EA consolidation was delivered in 46 (63%) patients while 8 patients received single agent high dose cytarabine consolidation and only 3 patients underwent ASCT. Seven patients received WBRT consolidation. EA consolidation was given for 2 days in 30 (65%) patients while 16 (35%) patients received 3 days of EA consolidation. Twenty six patients received maintenance lenalidomide.

With a median follow up of 39.2 months (range, 2.1 to 91), median PFS is 46.9 months and median overall OS has not reached. Three years PFS & OS for all patients is 59.5% and 78% respectively (Fig 1A &B). Median PFS and OS of patients receiving EA consolidation has not been reached with a 3-year PFS and OS of 77% and 79% respectively.

MSKCC score was predictive of OS with 3 year OS in class 1, 2 and 3 of 89.5%, 68% and 58% respectively. Consolidation with split dose EA was associated with better OS and PFS as compared to single agent cytarabine alone. None of the 3 patients receiving ASCT have relapsed. Patients receiving full dose methotrexate had better OS compared to patients requiring dose reduction. Two versus 3 day EA consolidation had no impact on OS.

MTR induction was well tolerated with grade 3 or more toxicity as follows: renal dysfunction in 8 (11%) patients, transaminitis in 4 and febrile neutropenia in 4 patients with no treatment related deaths. EA consolidation resulted in 18 episodes of febrile neutropenia with two deaths. Grade 3 or more hematologic toxicities were common with grade 3 or more anaemia, neutropenia and thrombocytopenia in 15 (32%), 40 (86%), 33 (71%) patients respectively. There were two deaths in the consolidation phase, one due to intracranial bleeding and another due to febrile neutropenia.

Conclusion:
MTR induction with modified EA consolidation is feasible and results in optimal outcomes in real world setting. Higher cumulative methotrexate dose and use of EA consolidation were associated with better OS. These outcomes compare favourably to CALGB 50202 study and represent a feasible option in resource limited setting.