Neha Vapiwala, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 12, 2003
Presenter: Edwin P. Alyea III, MD
Affiliation: Dana Farber Institute
Patients with low-grade lymphoma and chronic lymphocytic leukemia (CLL) typically have relatively prolonged disease-free survival, but this does not hold true for more advanced and chemotherapy-refractory cases. These diseases are still considered "incurable", and although the use of autogeneic stem cell transplantation (SCT) following high-dose therapy has resulted in prolongation of remission periods for some patients, relapse remains common.
The replacement of autologous SCT with allogeneic techniques offers theoretical advantages of infusing a tumor-free graft and of exploiting a possible graft vs. disease effect. Evidence suggesting improved results with allogeneic techniques stems from observations of increased relapse rates following autogeneic compared to allogeneic SCT and disease remissions following flares of graft vs. host disease (GVHD)(Khouri et al). Furthermore, direct evidence demonstrating the graft vs. leukemia effect has been collected using quantitative PCR analysis following allogeneic SCT and donor lymphocyte infusions (DLI) for CLL patients, which demonstrated conversion of patients from PCR (+) to PCR (-) status. However, the use of allogeneic SCT remains limited by the significant treatment-related toxicity profile.
In an effort to reduce these complications, a technique of nonmyeloablative allogeneic SCT (NST)--aka "mini allo transplant"-- is being studied. The regimen consists of a conditioning regimen given to either a related or unrelated donor (eg: fludarabine-based, total body irradiation-based), followed by growth factor-based mobilization and pheresis of peripheral donor cells, and finally stem cell infusion into the patient using GVHD prophylaxis (+/- DLI). The role of any chemotherapy given at the time of transplant is solely to facilitate donor cell engrafment, NOT to provide anti-tumor effect. Thus far, encouraging overall survival (OS) and progression-free survival (PFS) have been observed using NST in both indolent lymphoma and CLL patients. Indications for NST using lower intensity conditioning regimens include: advanced age, comorbid disease, history of prior transplant and specific diseases (ie: CLL, low-grade Lymphomas, multiple myeloma).
Although randomized data are still needed comparing high-dose conventional SCT to NST, preliminary data with small patient numbers was presented, and showed 1-yr OS rates of 67% with NST vs. 23% with a conventional regimen (Bertz et al. Ann Oncol 2002). Although the toxicity observed was less in the NST group, it was still associated with complications such as acute and chronic GVHD, infectious complications (eg: CMV, PCP), and graft failure.
The future of NST will depend on further reducing relapse rates through various techniques: treating at earlier stages of disease, performing autologous SCT followed by mini-allogeneic SCT later, pre-emptively treating patients with DLI. Attempts to further reduce toxicity with NST are also crucial and ongoing, including the use of agents like rapamycin to decrease rates of GVHD, and the search for methods to reconstitute patient immunity. Thus far, there are encouraging preliminary results seen in patients with CLL and indolent lymphomas. Larger, randomized trials comparing NST to both conventional allogeneic and autologous SCT techniques will be needed.