Illerhaus et al first described results from a pilot multicentre phase II trial evaluating the feasibility and efficacy of high dose therapy (HDT) and autologous stem cell transplantation (ASCT) as first line treatment for patients with PCNSL in 2006.r
The rationale underlying this approach was that sequential application of high doses of blood brain barrier penetrating water soluble cytostatic agents (MTX and Ara-C) followed by high doses of lipophilic alkylating agents (thiotepa and carmustine) would improve outcomes in patients with PCNSL. In this initial trial whole brain radiation therapy (WBRT) was administered as consolidation to all patients to a total of 45 Gy.
The results from initial 30 patients (9 patients in initial pilot, 21 in phase II trial) less than 65 years, median age 54 (27-64) were reported. Initial therapy consisted of 3 cycles of methotrexate (8 gm/m2), one cycle of Ara-C (3 gm/m2 x 2 and thiotepa 40 mg/m2) followed by stem cell collection and HDT with carmustine (400 mg/m2) and thiotepa (5 mg/kg X 2 doses) and ASCT. 23 patients completed HDT and ASCT with 8 pts achieving PR and 15 pts achieving CR. All patients achieved CR following WBRT. Intent to treat analysis for all 30 patients revealed OS of 68.9% at both 3 and 5 years, with probability of death due to relapse 21%. Of those completing HDT and ASCT, estimated 3 and 5 year OS was 87% at 3 and 5 years with probability of death due to relapse of 8.7%. With a median follow up of 63 months, leukoencephalopathy rate was 16.7% and 24% in those completing all therapy.
In an attempt to reduce rates of leukoencephalopathy, but maintain the efficacy of the polychemotherapy regimen, Illerhaus et al presented the results from a second pilot with intensified Ara-C and thiotepa dosing prior to HDT and ASCT while restricting WBRT to only those patients not achieving CR after completing all scheduled therapy including ASCT.r Furthermore, the thiotepa dosing schedule in the ASCT was increased to twice-daily dosing, for a total of 4 doses. The pilot was conducted on all consecutive PCNSL patients, age less than 70 years. The intensified schedule consisted of 3 sequential steps (1) 2-4 cycles of methotrexate (8 gm/m2) given over 4 hours at 10 day intervals, (2) two 21 day cycles of Ara-C (1 x 3 gm/m2 days 1 and 2) together with thiotepa (40 mg/m2) given on day 2 followed by stem cell collection after the first cycle and (3) conditioning with carmustine (400 mg/m2 given on day -6) and thiotepa (2 X 5 mg/kg) day -5 and -4 with PBSC infusion day 0. All patients were planned to proceed to HDT and ASCT irrespective of response to HD-MTX.
13 pts, median age 54 were treated. With a median follow up of 25 months, 3 year DFS and OS was 76.9%. 3 pts required WBRT after HDT and ASCT. Treatment was well tolerated with no TRM. No severe neurotoxicity was observed with median mini Mental State Examination score 29/30 (26-30) and median KPS 90 (70-100).
The same group published the long-term follow up of the pooled data from these two studies.r At a median follow-up of 140 months, 10/30 patients in study I were still alive. Median survival was reached after 104 months, with 5 to 10 year estimates of OS of 67% (95% CI 52 to 86%) and 42% (95% CI 28% to 65%) respectively. In study II, at a median follow-up of 72 months, 9/13 patients remain alive. The median OS was not reached at the time of publication, and the 2 to 5 year estimate of overall survival were both 77% (95% CI 57 - 100%). In the pooled anaylsis of all 43 patients, at a median follow-up of 101 months, the median OS was 104 months. 2 and 5 year OS was 81% (95% CI 71 - 94%) and 70% (95% CI 57 - 85%) respectively. Of those patients achieving CR in the entire cohort, 12/34 relapsed, with 6 relapses occurring beyond 5 years post-ASCT. The 5 year cumulative risk of death from PCNSL was 15%.
A small retrospective series of 5 patients further evaluated the role of BCNU-thiotepa as part of first-line therapy for PCNSL.r All patients received, and were responsive to, high-dose methotrexate as induction prior to ASCT. In addition to the chemotherapy backbone (which included 2 doses of thiotepa), 3 patients also received a single dose of rituximab at D-7.After a short median follow-up of 8 months, 4 of the 5 patients remain alive.Two patients relapsed at 3 and 5 months post ASCT. No neurocognitive effects were reported, with 3 patients alive and in remission at 4, 43 and 52 months post ASCT.
The IELSG32 study seeks to determine the role of ASCT in patients with newly diagnosed PCNSL. In this study, patients are stratified according to IELSG score, and randomised to one of 3 primary chemotherapy arms. Patients who achieve SD or better, are stratified according to primary chemotherapy arm and response to primary chemotherapy, and randomised to receive either WBRT, or BCNU-thiotepa ASCT (incorporating 4 doses of thiotepa). This study has ceased recruitment, with estimated data completion date of December 2016.
At this time, there is no published data of the outcomes from this conditioning regimen for relapsed PCNSL. Two studies have evaluated its role in relapsed secondary CNS lymphoma (SCNSL).rr A multicentre German study evaluated the addition of etoposide 150 mg/m2 x 3 doses to a BCNU-thiotepa (2 doses of thiotepa). In the follow-up of the 24 (of 30 total) patients who proceeded to ASCT, 17 patients achieved an objective response with 15 attaining a CR. A 2 year time to treatment failure of 58% plus or minus 22% was demonstrated.
An Italian study evaluated an induction/intensification regimen, consolidated by ASCT conditioned by BCNU-thiotepa (2 doses of thiotepa). Of the 40 patients entering the study, 20 proceeded to ASCT, all in CR at the time of transplant. For these patients, 5 year OS was 68% plus or minus 11% and EFS was 63% plus or minus 16%. Toxicity was reported as acceptable.
Note that the trials have varied between 2 (once-daily dosing) and 4 (twice-daily dosing) doses of thiotepa, with no head to head comparison of the efficacy or toxicity profile.
Kaplan-Meier plot: disease- free survival (- - ) and overall survival (-) from time of initial diagnosis of all patients:r
© Haematologica 2008
Detailed acute toxicity data was outlined in the initial 2006 report.r 5/30 patients developed rise in serum creatinine following high dose methotrexate (2 pts grade 1, 3 pts grade 2). One patient with a history of alcohol abuse died due to severe liver toxicity following second round of high dose methotrexate.
One patient developed cognitive impairment during WBRT which resolved spontaneously after completion of radiotherapy.
All 23 pts proceeding to HDT and ASCT developed grade 4 neutropenia and thrombocytopenia. Neutropenic fever was observed in 13/23 pts. All patients engrafted by day 11. Mucositis with maximum WHO grade 1 or 2 was seen in 5 pts and one pt respectively. Overall TRM was 1 of 30 pts (3%). TRM associated with HDT and ASCT was 0%.
At a median follow up of 63 months, 5 of 30 pts (16.7%) had developed leukoencephalopathy following the initial phase II trial. All patients developing leukoencephalopathy had completed therapy according to protocol with consolidating WBRT in doses of 45 Gy. Median KPS at diagnosis of pts developing was 60 (range 30-70) vs. 80 (range 40-100) for those not developing this complication.
In the report of the second pilot trial follow up rates of leukoencephalopathy in those proceeding to HDT and ASCT from the initial phase II trial were reported as 24%. With a median follow up of 25 months, no severe neurotoxicity has been reported from the second pilot trial where consolidating WBRT was not planned for patients achieving CR post ASCT.1r
In the long-term follow-up, of those 8 patients who developed neurotoxicity, all were irradiated (7 in study 1, and 1 patient in study II who achieved only a PR post ASCT). None of these patients who solely underwent an ASCT developed neurotoxicity. Patients not receiving WBRT appeared to have excellent outcomes with 100% achieving a response of PR or greater.rr