IELSG 42 - Marietta
Research type
Research Study
Full title
An international phase II trial assessing tolerability and efficacy of sequential Methotrexate-Aracytin-based combination and R-ICE combination, followed by high-dose chemotherapy supported by autologous stem cell transplant, in patients with systemic B-cell lymphoma with central nervous system involvement at diagnosis or relapse (MARIETTA regimen)
IRAS ID
174392
Contact name
Kate Cwynarski
Contact email
Sponsor organisation
International Extranodal Lymphoma Study Group
Eudract number
2014-003031-19
Clinicaltrials.gov Identifier
Duration of Study in the UK
8 years, 0 months, 1 days
Research summary
Research Summary:
When there is CNS involvement in diffuse large B cell lymphoma the outcome is often fatal. CNS involvement usually arises where there are risk factors such as raised LDH levels, sites of disease outside of the lymphatic system and where the cancer is quite advanced and involving other high risk organs (such as testes, orbit and para-nasal cavities). In these instances, central nervous system (CNS) relapse would usually happen within the first year of diagnosis. Often in these patients the disease spreads around the body (systemic dissemination) and as such, treatments need to be able to tackle both systemic and CNS areas of disease. The treatment regimens (MATRIX & R-ICE) that have been selected in this trial have been shown to be able to cross the blood brain barrier and are absorbed well within the CNS (CNS bioavailability). They have been used in various other phase II trials supported by stem cell transplant or whole brain radiotherapy to consolidate the treatment. This trial aims to combine those treatments found effective in other trials into a complete regimen and to evaluate the feasibility and efficacy of this sequential, combination chemotherapy and consolidation treatment.
Patients involved in the Marietta trial will potentially receive up to 3 courses of the MATRIX treatment regimen followed by three courses of R-ICE. They will then go on to receive a stem cell transplant to consolidate their treatment. Patients may also have whole brain radiotherapy if they do not have a complete response to the chemotherapy.
All patients who respond to treatment will be followed up in clinic for 5 years. Patients who progress during this time will be assessed every two months or according to standard care, for survival status.Lay Summary of Results:
• Who carried out the research?
The trial was conducted by the International Extranodal Lymphoma Study Group (IELSG), a not-for-profit organisation dedicated to advancing the understanding of the biology and improving the outcomes of lymphoma. The trial was also supported in the UK by a grant from Cancer Research UK and managed by Southampton Clinical Trials Unit.
• Where and when the trial took place?
The trial took place in five countries: United Kingdom, Switzerland, Italy, The Netherlands and Czech Republic, from March 30th, 2015 to March 22nd, 2024.
• Why was the research needed?
Secondary Central Nervous System Lymphoma (SCNSL) is a rare complication in patients with diffuse large B-Cell Lymphoma. There is no standard treatment approach for SCNSL in the UK or internationally. The rarity of this cancer means there is not much information on outcomes although historical data suggests that most people don’t survive more than a year. As this disease can affect both the central nervous system (CNS) and the body outside the brain (systemic), there is a need to develop effective treatments that are equally effective at treating both sites of disease.
This trial investigated the effectiveness of a new combination of different treatment regimens for SCNSL. Individually, these regimens have been shown to be effective in other types of lymphoma. However, it has not yet been clearly shown that the sequential combination of these regimens is tolerable and effective in patients with SCNSL.
• What was the main question studied?
The trial was designed to evaluate whether a new sequential combination of chemoimmunotherapy is effective and safe in participants with SCNSL.
Who participated in the trial?
Researchers sought participation from people who had lymphoma involving the CNS at the time of the initial diagnosis or relapse, were aged between 18 and 70, and were in good general health.
The study involved 79 patients, 20 of them in the UK, aged 23-70 when they were enrolled. Seventy-five of them were deemed suitable to receive the study treatments. Participants voluntarily agreed to participate in this trial after receiving appropriate explanations and signing the Informed Consent.
Median age (the middle value in a list of ages) of the trial participants was 58 years. Thirty-eight participants were male and 37 were female.
What treatments and interventions did the participants receive?
The trial's treatment involved combining different chemotherapy regimens over several cycles. Participants received up to six cycles of chemotherapy, split into two regimens: MATRIX (methotrexate, rituximab, cytarabine, thiotepa) for the first three cycles and R-ICE (rituximab, etoposide, ifosfamide, carboplatin, cytarabine) for the remaining three. Intrathecal chemotherapy (IT CHT) which is given through a lumbar puncture to ensure that the chemotherapy gets into the cerebrospinal fluid, was administered during every cycle.
Initially, participants underwent two cycles of MATRIX with IT CHT, followed by an evaluation to check for improvement. If the disease improved, they received a third MATRIX cycle and IT CHT, then transitioned to R-ICE with IT CHT for the fourth cycle. If no improvement was observed, the third MATRIX cycle was skipped, and participants proceeded directly to R-ICE with IT CHT.
After the fourth cycle, participants were evaluated again. If the treatment was still working, the participants received two additional R-ICE cycles (cycles 5 and 6) with IT CHT. Once treatment finished, the participants were assessed. Participants with continued positive responses to treatment proceeded to a stem cell transplant. If the disease had stopped responding to the treatment, radiotherapy could be administered before the transplant.
Following the transplant, participants who achieved complete remission did not require further treatment and were monitored in the clinic for five years. After this, their health status was recorded annually.
What happened during this trial?
Thirty-seven participants stayed in the trial until it ended, and 38 participants discontinued the trial for various reasons.
The main aspect evaluated in this trial, (primary endpoint) is how long patients went without their lymphoma getting worse (progression-free survival). The researchers monitored this endpoint over a 1-year period. If at least 41 patients were progression -free after one year, the trial would be considered effective.
The doctors also analyzed how many patients had a response after treatment. A lymphoma is considered to respond to treatment if it:
a) Disappears completely, known as a Complete Response OR
b) Shrinks by at least 50 %, known as a Partial Response Together these measurements are known as the Objective Response During the trial, side effects that occurred during treatment (safety endpoints) were monitored and recorded.
What were the results of the study
This is a summary of the main results of this trial as a whole. Individual results for each participant may be different and are not shown in this summary.
The primary endpoint of the trial was met with 42 participants who were progression-free at 1 year representing 58% of all participants.
After completing the MATRIX–R-ICE regimen, 49 participants (65%) achieved an objective response, including 29 participants (39%) with a complete response. Of the responders, 37 went on to transplant.
At the end of the treatment program, 46 participants (61%) had an objective response which lasted for a median of 26 months.
At a median follow-up of 29 months, 35 participants remained free from progression.
What medical problems (adverse reactions) did the participants have?
During this trial participants experienced medical problems that the doctors reported as possibly being related to the trial treatments. These medical problems are called adverse reactions. An adverse reaction is considered serious when it is life-threatening, causes persistent problems, or requires hospital care.
Seventy-two participants (96 %) had at least one adverse reaction and 35 participants (47%) had at least one serious adverse reaction.
The most common serious adverse reactions were:
• Fever associated with a low number of neutrophils, a type of blood cell (febrile neutropenia) reported in 18 participants (24%)
• A potentially life-threatening condition that occurs when the body's response to infection causes damage to its own tissues and organs (sepsis) occurred in 10 participants (13%).
The most common side effects were predominantly blood toxicity. The chemotherapy regimens caused a reduction in neutrophils (60% of participants), which means that participants were more susceptible to infection; a reduction in platelets (60% of participants) which caused bleeding or bruising; and a reduction in red blood cells (19 % of participants), which meant participants felt tired because they could become anaemic. Serious infections occurred in 14 (19%) participants.What did researchers learn from this trial?
The results of this trial have helped researchers to learn more about the treatment of Secondary Central Nervous System Lymphoma.
The MARIETTA trial offers encouraging results and could serve as a reference for future clinical trials in this disease.REC name
Yorkshire & The Humber - Leeds West Research Ethics Committee
REC reference
15/YH/0349
Date of REC Opinion
1 Sep 2015
REC opinion
Further Information Favourable Opinion