Primary CNS Lymphoma: Trial Confirms Optimal Treatment Strategy

A randomised, multicentre phase 3 trial, the largest ever conducted for primary CNS lymphoma, has confirmed that high-dose chemotherapy followed by autologous blood stem cell transplant is the most effective consolidation strategy for prolonging survival in patients who respond to induction therapy. The study, published in The Lancet, lists Professor Andrés J.M. Ferreri, Full Professor of Haematology at Vita-Salute San Raffaele University (UniSR) and Director of the Lymphoma Strategic Programme at IRCCS Ospedale San Raffaele, and Dr Gerald Illerhaus, Head of the Department of Haematology, Oncology, Stem Cell Transplantation and Palliative Care at the Stuttgart Cancer Centre, Germany, as joint first authors. Co-authors include Professor Maurilio Ponzoni, Director of the Postgraduate School in Pathological Anatomy at UniSR and Head of the hospital's Pathological Anatomy laboratory, and Dr Teresa Calimeri, senior researcher at the Lymphoma Strategic Programme of IRCCS Ospedale San Raffaele. 

Primary CNS lymphoma (PCNSL) is a rare and aggressive form of lymphoma that originates in, and stays confined to, the central nervous system. Because the disease is so rare, identifying the most effective therapy requires large, international, multicentre clinical trials capable of guiding treatment choices. Treatment for PCNSL starts with induction therapy based on conventional chemotherapy drugs, chiefly methotrexate, which significantly reduces the tumour mass. This is followed by consolidation therapy, which eliminates residual tumour cells and lowers the risk of relapse. 

Consolidation therapy for PCNSL includes several options: a non-myeloablative chemo-immunotherapy regimen, which does not eliminate the bone marrow, or myeloablative chemotherapy based on the alkylating agent thiotepa, followed by autologous blood stem cell transplant, the reinfusion of the patient's own bone marrow progenitor cells collected during induction. 

Earlier phase 2 trials, conducted in small patient cohorts, had already suggested that consolidation with autologous stem cell transplant outperformed the available alternatives, in particular whole-brain radiotherapy. Autologous transplant is markedly less toxic to higher neurocognitive function than radiotherapy. The newly published study confirms and extends these findings in the largest cohort of untreated PCNSL patients to date, involving 56 hospital centres across Germany, Italy, Denmark, Norway and Switzerland, coordinated by Freiburg Hospital in Germany. 

Between 2014 and 2019, the trial enrolled 368 adult patients, all of whom first received induction with a four-drug chemo-immunotherapy regimen called MATRix, developed 17 years ago at IRCCS Ospedale San Raffaele and Freiburg Hospital. The 229 patients who responded to MATRix were then randomised to one of two consolidation treatments: two cycles of chemotherapy plus immunotherapy with rituximab, dexamethasone, etoposide, ifosfamide and carboplatin (R-DeVIC), or myeloablative chemotherapy with thiotepa and carmustine followed by autologous stem cell transplant. 

With a median follow-up of almost four years, patients who received the autologous transplant had significantly better outcomes. At three years, 78% of transplanted patients had shown no tumour progression, compared with half of those treated with the R-DeVIC combination. More strikingly, 86% of transplanted patients were alive at three years, against 71% in the R-DeVIC group. 

As expected, the more intensive autologous transplant was associated with a higher rate of toxic events than non-myeloablative consolidation, but without an increase in mortality, which remained below 5%. 

These findings extend and build on earlier work that helped define the international treatment standard for PCNSL. Professor Ferreri has coordinated international clinical research on extranodal lymphomas, cancers affecting organs other than the lymph nodes, for years with the I.E.L.S.G. (International Extranodal Lymphoma Study Group). This includes the earlier IELSG20 and IELSG32 trials, also published in Lancet-group journals, which laid the groundwork step by step for the induction therapy used in this study. 

The transplant strategy originates from the conditioning regimen designed at Freiburg Hospital, later refined within the Stem Cell Programme of the Haematology Unit at IRCCS Ospedale San Raffaele, led by Professor Fabio Ciceri, who also directs UniSR's Postgraduate School in Haematology. «This new study represents a further step in defining evidence-based treatment pathways for a rare and complex disease such as PCNSL, and confirms the role of the San Raffaele campus in international onco-haematological clinical research», Ferreri concludes. 

Read the study here.