CD34+ Selected ASCT for Aggressive Lymphomas

Background and rationale: Autologous stem cell transplantation (ASCT): High-dose chemotherapy (HDCT) followed by ASCT is considered the treatment of choice for relapsed/refractory lymphomas. On the basis of the results of the PARMA study group trial, high-dose chemotherapy followed by ASCT has become the standard of care for patients with relapsed, chemo-sensitive aggressive lymphoma , and it is the treatment of choice in patients relapsing with diffuse large B-cell lymphomas (DLBCL), mantle cell lymphomas (MCL), follicular lymphoma (FL) or Hodgkin's disease (HD). Worldwide, about 11'000 patients are treated with ASCT per year because of relapsing lymphoma. The BEAM chemotherapy regimen is the most frequently used conditioning regimen before ASCT since more than thirty years.

Although HDCT with ASCT is a curative strategy for some patients with aggressive non-Hodgkin lymphoma (NHL), relapse or progression after ASCT is the major limitation of this procedure. Together with previously described factors that affect outcome after ASCT - such as prognostic score index, clinical response to induction or salvage chemotherapy, and the number of chemotherapy regimens received before ASCT - graft contamination with residual lymphoma cells is a major factor for disease relapse.

Graft contamination: Contamination of autologous graft by residual lymphoma cells has been demonstrated using several techniques including flow cytometry, immunohistochemistry or molecular methods. Subsequent studies have suggested that contamination with lymphoma cells contributes to relapse after ASCT using mobilized stem cells. A better outcome in syngenic transplantation in NHL compared with ASCT suggested the potential clinical benefit of purging the stem cell graft used for SCT.

Graft purging: The strategies implemented to remove lymphoma cells from harvested peripheral stem cells include complement-mediated use of lymphoma-directed antibodies, immunomagnetic beads, immunotoxins, or chemotherapeutic agents, as well as oncolytic viruses. Among them, CD34+ cell selection is an alternative and theoretically attractive strategy for tumor cell removal in lymphomas that do not express the CD34+ antigen. Various technologies have been used for positive selection of CD34+ cells, including immunomagnetic bead separation, avidin-biotin immunoaffinity systems, fluorescence-activated cell sorting, and magnetic-activated cell sorting (MACS). The feasibility and safety of CD34+ purified progenitor cell reinfusion after high-dose chemotherapy have also been demonstrated.

Clinical use of purged autologous grafts: Despite the theoretical advantage of using a purged graft in the ASCT setting, the standard procedure for ASCT involves the use of non-selected grafts. Whether the use of ex vivo purged grafts with CD34+ cell selection translates into improved long-term treatment outcome remains controversial. Noteworthy, not a single randomized study has been reported so far directly comparing in a prospective manner purged and unpurged grafts in ASCT. Thus, a randomized prospective direct comparison between these two procedures is long awaited and an unmet clinical need with presumably immediate impact on daily practice of ASCT.

Own experience with purged grafts: the investigator's institution has a long-standing experience with CD34+ cell selection applying the CliniMACS device (Miltenyi Biotec, Bergisch Gladbach, Germany). The investigator recently summarized the data in a retrospective analysis of advanced stage lymphoma patients comparing 31 patients with CD34+ cell selection versus 31 patients without selection (including 32 MCL and 30 DLBCL patients). Remarkably, the investigator found that the 5-year OS for selected versus not selected ASCT patients was 87% and 53% (p=0.004), and the 5-year PFS was 62% and 38% (p=0.031), respectively. These retrospective data suggest that using selected autografts for ASCT in advanced stage MCL and DLBCL is associated with significantly longer OS and PFS without increased toxicity, infectious complications or impaired engraftment. Finally, the investigator propose that these data provide the rationale for initiating a prospective randomized study on the use of CD34+ cell selection of grafts used for ASCT in patients with advanced-stage aggressive lymphomas.