The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the Kasenda et al. studyr
Evidence Level
(NHRMC)
|
Study |
Study Design |
Disease |
Is the conditioning regimen
consistent with the protocol?
|
Comments |
II |
Kasenda et al. 2017r |
Prospective, multicentre, phase 2 trial |
Relapsed or refractory (R/R) primary CNS lymphoma (PCNSL)
|
Yes |
2 cohorts (newly diagnosed PCNSL and R/R PCNSL) - only data from the R/R cohort reported |
II |
Illerhaus et al. 2016r |
Prospective, single-arm, phase 2 trial |
Newly diagnosed PCNSL |
No |
Sequential induction with rituximab/high-dose methotrexate and rituximab/cytarabine/thiotepa followed by rituximab/carmustine/thiotepa conditioning and ASCT; 5-year OS 79% |
II |
Illerhaus et al. 2006r |
Multicentre, phase 2 trial |
Newly diagnosed PCNSL |
No |
Sequential high-dose methotrexate/cytarabine/thiotepa followed by carmustine/thiotepa ASCT; WBRT for consolidation |
ASCT = autologous stem cell transplant; OS = overall survival; WBRT = whole brain radiotherapy
The evidence supporting this protocol is provided by a German prospective multicentre single-arm phase II trial in patients with relapsed/refractory (R/R) primary CNS lymphoma (PCNSL) after failure with at least one high-dose methotrexate-based systemic chemotherapy.r The study comprised of two separate cohorts including patients with newly diagnosed PCNSL and R/R PCNSL with only the data from the R/R cohort reported in the study by Kasenda et al. The rationale underlying this protocol was administration of maximum tolerable doses of cytostatics to overcome drug resistance and to reach therapeutic CNS concentrations.rr
Immunocompetent adult patients aged 18-65 years with histologically confirmed PCNSL at primary diagnosis with R/R disease were included without limitation on clinical performance status. The median age was 57 years. A total of 39 patients commenced induction treatment, of which 32 patients received autologous stem cell transplant (ASCT). Relapse was defined as radiologically confirmed lymphoma regrowth after achieving complete remission (CR), and refractory was defined as lymphoma progression during high-dose methotrexate-based chemotherapy. Patients received a 21-day cycle induction protocol as follows: rituximab 375 mg/m2 IV on day 1; high-dose cytarabine 3000 mg/m2 IV on days 2 and 3; and thiotepa 40 mg/m2 IV on day 3 plus prophylactic filgrastim. In case of cerebrospinal fluid lymphoma involvement, no additional intrathecal therapy was given.
Disease response evaluation with contrast-enhanced MRI brain was performed after the first and second cycle, before conditioning treatment, and 30 days after the completion of autologous stem cell transplant (ASCT). Patients with progressive disease (PD) or stable disease (SD) without clinical improvement after 1 cycle of induction treatment were directly deferred to ASCT after autologous stem cell collection. Patients with complete remission (CR), partial response (PR) or SD with clinical improvement proceeded to ASCT after cycle 2 of induction treatment. Peripheral blood stem cell harvesting was performed in between induction cycle 1 and 2. Conditioning treatment for ASCT was started 21 days after cycle 2 and consisted of rituximab 375 mg/m2 IV (day -7), carmustine 400 mg/m2 (day -6) and thiotepa 5 mg/kg BD (day -5 and -4), followed by reinfusion of autologous stem cells on day 0 and pegfilgrastim 6 mg on day 4. After ASCT, patients not achieving CR received whole-brain radiotherapy (WBRT) at 40 days after ASCT (45 Gy in total). The primary endpoint was the rate of CR 30 days after completing ASCT. Secondary endpoints included safety, overall survival (OS, time from registration until death of any cause), and neurological side effects.
In patients with R/R PCNSL after failing high-dose methotrexate-based chemotherapy, salvage treatment with cytarabine, rituximab and thiotepa followed by thiotepa-based consolidation with ASCT may be a feasible treatment, with this protocol demonstrating durable remissions and stable survival prognosis of over 50%. Of note, none of the patients in the trial received induction treatment with MATRix (rituximab, high-dose methotrexate, cytarabine, thiotepa), and hence, the remission rates and their durability reported in the trial may vary in patients relapsing after receiving MATRix as first-line treatment.
Efficacy
A summary of the evidence supporting the effectiveness of this protocol is below:
Study |
Number of
Patients
|
NRM/TRM |
Response* |
Relapse Rate |
OS (1yr/2yr) |
DFS |
Comments |
Kasenda et al.r |
39
Pts who completed ASCT = 32 (82.1%)
|
1 yr NRM 10.3% (95% CI 4.1–26.0%) at 1 yr |
Before ASCT:
Remission = 22 (56.4%) - CR = 4 (10.3%), PR = 18 (46.2%)
SD = 5 (12.8%)
PD = 9 (23.1%)
Number of scans = 3 (7.7%)
After ASCT:
CR = 56.4% (95% CI 39.6 – 72.2%)
|
33.3% (95% CI 21.4–52.0%) at 2 yrs |
1 yr: 61.5% (95% CI 46.3–76.8%)
2 yr: 56.4% (95% CI 40.8–72.0%)
|
1 yr PFS: 51.3 (95% CI 35.6–67.0%)
2 yr PFS: 46.0% (95% CI 30.3–61.7%)
|
26 pts (66.6%) received 2 induction cycles - 24 undertook ASCT
13 pts (33.3%) received just 1 induction cycle:
- 7 achieved SD without clinical improvement
- 4 - PD
- 1 - death due to sepsis
- 1 - study withdrawal
- 8/13 received ASCT
6 pts in PR received WBRT after ASCT- 4 achieved CR, 1 maintained PR and 1 progressed
|
* OR = overall response; CR = complete response; PR = partial response; SD = stable disease; VGPR = very good partial response; R = refractory; Pts = patients
After a median follow-up of 45.2 months, the median progression-free survival (PFS) was 12.4 months. The median overall survival (OS) was not reached.
Figure 1. Progression-free survival and overall survival curves
© Leukemia 2017
Toxicity
A summary of the toxicities associated with this protocol are included in the table below:
Study |
Mucositis |
VOD/SOS |
Lung/IPS |
Infection * |
Comment |
Kasenda et al. 2017r |
Induction: 0
ASCT: 13 (40.6%)
|
Not reported |
Not reported |
Induction: 5 (12.8%)
ASCT: 21 (65.6%)
|
Induction: n = 39
ASCT: n = 32
|
*Infection : include neutropenic sepsis, invasive fungal infection (IFI) and viral reactivation/disease where reported
There were four treatment-related deaths reported; three patients with fatal sepsis (one during induction and two after ASCT), and one case of treatment-associated CNS toxicity (after ASCT without WBRT).
Table 2. Incidence of grade 3 or higher adverse event during induction or transplant
© Leukemia 2017