IELSG 32

• Research type

  Research Study

• Full title

  Randomized phase II trial on primary chemotherapy woth high-dose methotrexate and high-dose cytarabine with or without thiotepa, and with or wothout rituximab, followed by brain irradiation vs high-dose chemotherapy supported by autologous stem cells transplantation for immunocompetent patients with newly diagnosed primary CNS lymphoma.

• IRAS ID

  68403

• Contact name

• Sponsor organisation

  Southampton University Hospitals NHS Trust

• Eudract number

  2009-012432-32

• ISRCTN Number

  not sent

• Research summary

  Primary central nervous system (PCNS) lymphoma is a cancer of the lymphatic system that's located in the brain. The most effective treatment is chemotherapy but high dose chemotherapy which can penetrate into the brain is required. Currently the treatment usually consists of high dose chemotherapy followed by radiotherapy to the brain. A new treatment programme for patients with PCNS may be a more effective combination for the condition and also incur less toxicity (unpleasant side-effects). Therefore we have devised a protocol that contains other anti-lymphoma drugs that have been shown in several studies to have a beneficial effect in patients with Non-Hodgkin's lymphoma.The best combination of currently available chemotherapy includes the administration of two agents, high dose methotrexate and cytarabine. The combination of these two drugs has been shown to be more effective than high-dose methotrexate alone. A third drug, thiotepa, is also effective in the brain when given separately and the addition of this agent to methotrexate and cytarabine may further improve the overall effectiveness of the treatment.Rituximab, a monoclonal antibody directed against lymphocytes, is directed against a protein expressed on the surface of the lymphoma cells, causing them to die and also sensitising them to the effects of chemotherapy drugs. The addition of Rituximab to chemotherapy has been shown to improve the survival of patients treated for some types of B-cell non-Hodgkin lymphoma outside the brain. The combination of rituximab to high dose methotrexate and cytarabine could also bring an additional benefit in treating PCNSL.After high-dose chemotherapy, whole brain radiotherapy is routinely offered to patients but the combination has been associated with problems (particularly ??neurotoxicity) later. We are also asking if high-dose chemotherapy followed by autologous peripheral stem cell transplantation is more effective or better tolerated than radiotherapy.

  Lay summary of study results:
  Who participated in the trial?
  Researchers sought participation from people who had lymphoma involving the CNS at the time of the initial diagnosis, were aged between 18 and 70, and were in good general health.
  The study involved 227 participants, 39 of them in the UK, aged 18-70 when they were enrolled. Two hundreds nineteen 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 57 years. One hundred thirty-six participants were male and 83 were female.
  What treatments and interventions did the participants receive?
  The trial's treatment involved combining different chemotherapy regimens over 4 cycles. Participants were randomly assigned to receive the chemotherapy regimens as follows:
  • 75 participants received methotrexate–cytarabine (Arm A)
  • 69 participants received methotrexate, cytarabine plus rituximab (arm B)
  • 75 participants received methotrexate–cytarabine plus rituximab and thiotepa (arm C)
  Once treatment with chemotherapy finished, the participants were assessed. Participants with positive response to treatment or with a stable disease proceeded to “consolidation” treatment as follows:
  • 55 participants received whole brain radiotherapy (Arm D)
  • 58 participants received autologous peripheral stem cell transplantation (Arm E)
  Following the consolidation treatment, participants who achieved complete remission did not require further treatment and were monitored periodically in the clinic for five years. After this, their health status was recorded annually.
  If participant’s disease progressed at any time during the primary chemotherapy or after it, participants were offered alternative treatments.

  What happened during this trial?
  The main aspects evaluated in this trial, (primary endpoints) are
  • How many participants had a Complete Remission i.e. the lymphoma disappeared completely, after chemotherapy.
  • How many participants went without their lymphoma getting worse (progression-free survival). The researchers monitored this endpoint in participants who received consolidation therapy, over a 2-year period.
  The doctors also analyzed the Progression Free Survival in participants who received the chemotherapy and the survival of all participants after 2 years from study entry.
  During the trial, adverse side effects that occurred during treatment (safety endpoints) were monitored and recorded. Participants’ quality of life was also evaluated.

  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.
  After completing the chemoimmunotherapy, 17 participants (23%) in Arm A, 21 participants (30%) in Arm B and 37 participants (49%) in Arm C achieved a complete response showing that participants in Arm C obtained a better response rate.
  The 2 years Progression Free Survival of participants who received the consolidation therapy produced similar results between the two Arms, 76% of participant in Arm D and 75% in Arm E had no worsening of the disease after two years from study entry.

  What did researchers learn from this trial?
  The results of this trial have helped researchers to learn more about the treatment of Primary Central Nervous System Lymphoma.
  The IELSG32 trial confirms that high-dose methotrexate and cytarabine plus rituximab and thiotepa followed by consolidation therapy is an effective therapy for PCNS.
  Regarding consolidation therapy, both conventional whole-brain radiotherapy and autologous stem cell transplantation were feasible and effective. Doctors should choose the most appropriate treatment to patient considering the effects of treatment on cognitive abilities and quality of life.

• REC name

  London - Bloomsbury Research Ethics Committee

• REC reference

  11/LO/0420

• Date of REC Opinion

  29 Jun 2011

• REC opinion

  Further Information Favourable Opinion