Abstracts of 4th Annual UKMF Scientific Meeting on 07-Feb-2003
Allogeneic transplantation and graft versus myeloma
N H Russell, Department of Haematology, Nottingham City Hospital, Nottingham UK
Allogeneic SCT for myeloma may be curative for patients with myeloma but its role remains controversial because of a reported high procedural mortality in some series. Recent data from the EBMT demonstrates an improving outcome for this approach using conventional conditioning regimens for the year 1994-1998 mainly due to a reduction in transplant related mortality. Factors predicting for a lower TRM include age (<50 years) and early rather than late transplant. Although a high CR rate may occur following conventional conditioning there is a risk of relapse with late relapses (>5 years) occurring in some patients either as generalised or localised disease without overt BM involvement.
There is evidence however that, patients who achieve durable molecular remissions are at a significantly lower risk, of disease relapse that patients who remain PCR positive. Several reports have supported the existence of a graft versus myeloma effect most notably supported by the reports of remissions induced following donor leucocyte infusions (DLI). Lokhorst et al (2000) reported a 52% response rate to DLI, with 22% of patients achieving a CR and the majority of these were sustained. Most responses were only achieved with a CD3 cell dose of >1 x 108/kg and there was a strong association of response with the development of acute and / or chronic GvHD.
However some patients had clear GvM responses without GvHD suggesting that some responding patients had GvM directed towards either minor histocompatibility antigens or to tumour specific antigens. Disappointingly patients with disease refractory to BMT had a poor response to DLI therapy. Strategies to improve the response to and reduce the toxicity of DLI are needed. With others we have been exploring the role of infusion of DLI from sibling donors previously vaccinated with idiotypic DNA vaccines. The aim being to enhance the GvM effect whilst reducing the risks of developing GvHD by reducing the total number of T-cells infused. Alternative approaches that have been explored include the use of CD8-depleted DLI (Alyea et al 2001).
More recently there has been a move towards exploring the role of non-myeloblative conditioning in myeloma with a view to reduce the procedure-related mortality. A variety of conditioning regimens have been utilised either with or without T-cell depletion using Alemtuzumab. The optimal timing for this approach is almost certainly when the patient has achieved a maximal response to conventional therapy including a high dose melphalan autograft procedure. This approach is being prospectively explored by a number of groups including the EBMT using fractionated TBI plus Fludarabine as conditioning and the UKMF using Fludarabine, Melphalan and Alemtuzamab. The use of DLI to augment graft versus myeloma responses is an integral part of this strategy.
Lokhorst HM, Schattenberg A, Cornelissen JJ, van Oers MH, Fibbe W, Russell I, Donk NW, Verdonck LF. Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. J. Clin Oncol. 2000: 18; 3031.
Alyea E, Weller E, Schlossman R, Canning C, Webb I, Doss D, Mauch P, Marcus K, Fisher D, Freeman A, Parikh B, Gribben J, Soiffer R, Ritz J, Anderson K. T-cell-depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect. Blood 2001: 98; 934