This protocol has been superseded as liposomal cytarabine has been removed from the TGA register and is no longer available in Australia.
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 study by Korfel et al.r
Evidence Level
(NHRMC)
|
Study |
Study Design |
Disease |
Is the conditioning regimen
consistent with the protocol?
|
Comments |
II |
Korfel et al. 2013r |
Prospective, multicentre, phase 2 trial |
CNS relapse of aggressive lymphoma. |
Yes |
Induction chemotherapy with methotrexate, ifosfamide, liposomal cytarabine (MTX/IFO/DEP) and cytarabine, thiotepa, liposomal cytarabine (AraC/TT/DEP) followed by high-dose chemotherapy conditioning(carmustine, thiotepa, etoposide) and autologous stem-cell transplant (ASCT). |
II |
Doorduijn et al. 2017r |
Multicentre, phase 2 trial |
CNS relapse of systemic non-Hodgkin lymphoma. |
No |
Two cycles of R-DHAP alternating with high-dose methotrexate (MTX); combined with intrathecal rituximab. Responding patients received a third R-DHAP-MTX cycle followed by busulfan, cyclophosphamide and ASCT. |
II |
Ferreri et al. 2021r |
International, single-arm, phase 2 trial |
Diffuse large B-cell lymphoma with secondary CNS involvement |
No |
Three courses of MATRix followed by three courses of RICE and carmustine, thiotepa and ASCT. |
II |
Ferreri et al. 2015r |
Multicentre, phase 2 trial |
Systemic B-cell lymphoma and secondary CNS involvement. |
No |
High doses of methotrexate and cytarabine, followed by rituximab combined with high doses of cyclophosphamide, cytarabine, etoposide and ASCT. |
CNS = Central nervous system; ASCT = autologous stem cell transplant
Central nervous system relapse occurs in 2-5% of patients with aggressive systemic non-Hodgkin lymphoma, occurring in the parenchyma in approximately 50% of patients, leptomeninges in 40%, and both in 10%.rrr Data on the treatment of secondary CNS lymphoma is limited. A small number of prospective single-arm trials incorporating consolidation ASCT report 1 to 2-year overall survival (OS) between 25% and 80% (HOVON,r MARIETTA,r Ferrerir). A recent Center for International Blood and Marrow Transplant Research (CIBMTR) study reports superior survival for ASCT conditioning regimens incorporating thiotepa.r
The evidence supporting this protocol is provided by an open-label phase II multicentre, international, single-arm trial published by Korfel et alr involving 30 patients with systemic high-grade lymphoma relapsing in the central nervous system. The majority of patients had relapsed diffuse large B-cell lymphoma. A small number of patients with relapsed peripheral T-cell lymphoma were included. Concurrent systemic relapse was present in a minority of patients.
Patients were aged 18 to 65 with an Eastern Cooperative Oncology Group (ECOG) performance status less than 3. Patients with HIV or other immunodeficient states were excluded, as were patients who had received prior whole-brain radiation therapy. CNS relapse was identified by either cerebrospinal fluid (CSF) evidence or magnetic resonance imaging (MRI) features in keeping with leptomeningeal or parenchymal involvement.r
30 patients with a median age of 58 (range 29 to 65) were treated as per the intended protocol. All patients received the first cycle of high-dose methotrexate, ifosfamide, dexamethasone, and intrathecal liposomal cytarabine (MTX/IFO/DEP) followed by response assessment by MRI and/or CSF analysis. Patients without progression received a second cycle of this therapy, followed by a third induction cycle of high-dose cytarabine, thiotepa, dexamethasone and liposomal intrathecal cytarabine (AraC/TT/DEP). Patients progressing after the first cycle proceeded to two cycles of AraC/TT/DEP. All responding patients were consolidated with ASCT, as well as 4 radiologically progressing patients at the physician discretion.r
Prior to autologous stem cell mobilisation, filgrastim 10 microgram/kg/day was given subcutaneously starting on Day 7 after the second induction course. A minimum of 2x106 CD34+ cells per kg of body weight were required.r
The primary endpoint was time to treatment failure. Secondary endpoints were response, toxicity, and overall survival. Patients not responding to induction chemotherapy without clinical deterioration were allowed to proceed to ASCT at the discretion of the physician.r
Figure 1: Patient characteristicsr
*In this patient, HDMTX/ifosfamide was the only pre-treatment.
© Haematologica 2013
Efficacy
A summary of the evidence supporting the effectiveness of this protocol is shown below.
Study |
No. of
Patients
|
NRM / TRM |
Response* |
Relapse Rate |
OS (1yr/2yr) |
DFS |
Comments |
Korfel et al. 2013r |
30
Patients who completed ASCT = 24 (80%)
|
1 patient died of neutropenic sepsis |
At the end of induction chemotherapy:
CR = 7 (26%), PR = 13 (48%), SD = 2 (7%) and PD = 4 (15%); no response evaluation in 1 patient (4%).
After ASCT:
CR = 15 (63%), PR = 2 (8%), PD = 7 (29%).
|
2-year TTF was 49% ± 19% for all patients and 58% ± 22% for patients completing ASCT. Median TTF was 12 months (95% CI: 0-34.9) and 24.3 months (95% CI: 5.9-42.8), respectively.
|
2-year OS
All pts: 63% ± 19%
After ASCT: 68% ± 20%
|
Median follow up of 21 months: (95% CI: 10-32) 17 (57%) patients were alive
|
29 (97%) patients proceeded to the second induction cycle, and 24 (80%) patients proceeded to ASCT with no patients failing to mobilise stem cells.
Of 4 patients with PD after induction, 3 died without further treatment at 2, 6 & 8 months due to lymphoma, and one patient received salvage WBRT but relapsed and died 14 months after study entry.
The median number of CD34+ cells collected was 5.3x106/kg.
17 (57%) patients were in remission after ASCT: 15 (50%) had CR, and 2 (6.6%) had PR.
|
NRM = Non-relapse mortality; OS = overall survival; OR = overall response; CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; TTF = time to treatment failure; WBRT = whole brain radiation therapy
Figure 1: Course of therapy and responser
© Haematologica 2013
After the first induction course of MTX/IFO/DEP, CNS CR was achieved in 17%, PR in 47% and SD in 20% of patients. 29 (of 30) patients proceeded to the second induction course, with 2 switched to AraC/TT/DEP due to PD. After median follow up of 21 months (95% CI 10-32) 17 patients were alive by ITT analysis. An ECOG of 2 versus 1 (hazard ratio (HR) 2.9) and parenchymal versus leptomeningeal involvement (HR 2.17) were both adverse risk factors for OS. Most deaths were due to progressive or relapsed lymphoma. Quality of life was not reported.
Figure 2: Time to treatment failure and overall survivalr
© Haematologica 2013
Toxicity
A summary of the toxicities associated with this protocol are included in the table below.
Study |
Mucositis |
VOD/SOS |
Lung/IPS |
Infection * |
Comment |
Korfel et al. 2013r |
Grade 3:
Induction: 4 of 24 (17%)
Grade 4:
ASCT: 3 of 24 (13%)
|
Not specifically reported.
Grade 3 bilirubin elevation: 1 patient on MTX/IFO/DEP
Grade 3 transaminase elevation: 9 of 30 (30%) patients on MTX/IFO/DEP
|
Pneumonitis grade 4: 1 patient on MTX/IFO/DEP |
Grade 3:
MTX/IFO/DEP induction: 5 of 58 (9%) courses.
AraC/TT/DEP induction: 6 of 28 (21%) courses.
ASCT: 10 of 24 (42%) courses.
Grade 4: 2 of 58 (3%), 0 and 1 of 24 (4%) courses, respectively
|
One death on therapy; patient developed diverticulitis during the first course of MTX/IFO/DEP and later died due to neutropenic septicaemia.
|
*Infection: includes neutropenic sepsis, invasive fungal infection (IFI) and viral reactivation/disease if reported
Figure 1: Evaluation of toxicitiesr
© Haematologica 2013