Complete Clinical and Molecular Remissions Due to Very Effective GVL Reactions after Allogeneic Blood Stem Cell Transplantation for Mantle Cell Lymphoma in First or Second Remission.

High-dose chemotherapy followed by allogeneic blood stem cell transplantation (allo-BSCT) from HLA-matched related or unrelated donors has been shown to induce durable remissions in patients with relapsed/refractory mantle cell lymphoma (MCL). Two clinical phase III-studies were initiated by the East-German Study Group Haematology and Oncology (OSHO) to investigate allo-BSCT as consolidation treatment in MCL patients after successful first line treatment with R-CHOP or R-CHOP/R-DHAP (OSHO #74 - study carried out in collaboration with the European MCL/GLSG study) or after successful R-DHAP treatment of relapsed MCL (OSHO #60 study). From February 2001 to January 2007, 13 patients with MCL, 10 males and 3 females, with a median age of 58 years (range 38 to 69) were enrolled in both studies (OSHO#60: 5 pats.; OSHO#74: 8 pats.). 10 patients received an allo-BSCT (MUD=6; sibling donor=4), two are still on first line chemotherapy. Reduced intensity conditioning (RIC) with treosulfan/fludarabin was used in the case of 9 patients (age range 38 to 69 years), Bu/Cy in one 45 year old male. After initial chemotherapy complete clinical remissions were observed in 9 patients, a partial remission in one and progressive disease with fatal outcome in another one. 9 of 10 patients transplanted are alive in complete clinical remission, 1 patient died because of intracerebral bleeding due to aspergillosis on day 18 after transplant. Median follow up of all patients is 7.6 months (range 3.9–72.3). Here we report our data on the molecular monitoring of minimal residual disease in these patients. Residual lymphoma cells were detected by real-time quantitative PCR in blood and bone marrow samples before and after transplant with t(11;14) or clone-specific VDJ-CDR-3 rearrangements serving as targets. Prospective molecular monitoring has been carried out on 5 patients (median follow up 21 months, range 4 to 72 months), retrospective molecular monitoring has been started on stored samples from further 4 patients (median follow up 7.5 months) after the identification of their lymphoma clone-specific VDJ-rearrangements. All pre-therapeutic peripheral blood samples tested contained 5 – 90% lymphoma cells. A 2 – 4 log reduction of circulating lymphoma cells was achieved by chemotherapy alone. In 2/5 patients monitored prospectively an intermediate increase of circulating lymphoma cells of >2 log was observed within the first 100 days after transplant. Immunosuppressive therapy was promptly reduced in both cases, one patient received rituximab in addition. Circulating lymphoma cells disappeared within 3 months after allogeneic transplantation and could not further be detected in all 5 patients at a sensitivity of 1/10^5–6. These results strongly favour the idea of potent graft versus lymphoma effects in patients with MCL given an allogeneic transplant. In conclusion, allogeneic blood stem cell transplantation after RIC seems to be an attractive treatment for patients with MCL responding to first or second line chemoimmunotherapy and leading to a higher rate of complete clinical as well as molecular remissions.