Allogeneic Stem Cell Transplantation with Intermediate Conditioning Is Effective in High Risk Relapse and Progressive Disease of Aggressive Non-Hodgkin-Lymphoma.

Allogeneic stem cell transplantation ( SCT ) is increasingly being used to treat relapsed lymphoma. We reasoned that patients with high – risk ( chemorefractory disease, short time interval between first – line therapy and relapse ) aggressive lymphoma need vigorous debulking ( myeloablative conditioning ) and a strong GvLymphoma effect (early T–cells transferred with the graft: Glass et al., BMT 2004 ) ) in order to obtain optimal results

Younger patients ( 18 to 65 yrs ) with aggressive NHL and primary progressive disease, early relapse with at least one IPI risk factor, or relapse after HDT /ASCT were included into the study. They received myeloablative conditioning (Fludarabine 125 mg/m2, Busulfan 12 mg/kg and cyclophosphamide 120 mg/kg) followed by GVHD prophylaxis with short term mycophenolat mofetil plus tacrolimus. After an amendment in July 2008 anti-thymocyte globulin (ATG) was given to all patients prior to transplantation. Patients were randomized to receive two courses of rituximab ( 4 × 375 mg/ m2) post transplant starting on day +21 and day +175 or no additional GVHD prophylaxis. From June 2004 to July 2009, 84 patients with aggressive NHL were enrolled and 81 were eligible for toxicity analysis (median age 49 years). 71 patients had follow up allowing for a meaningful survival analysis. Forty - one pts had diffuse large B cell NHL, 6 patients follicular lymphoma grade 3, 8 pts blastic mantle cell lymphoma, 2 pts aggressive marginal zone lymphoma, 4 patients lymphoblastic B cell lymphoma, and 20 pts suffered from T cell lymphoma. Forty-five (54%) pts received at least one cycle of HDT and autologous SCT prior to alloSCT; 75% had early relapse (< 12 months) or primary progressive disease, 59% chemo-refractory disease and 24% had progressive disease with high or high intermediate age adjusted IPI immediately prior to conditioning. Mobilized blood was obtained from HLA-identical siblings in 24 pts, from matched unrelated donors in 40 pts and from one locus mismatched unrelated donors in 17 pts. Fifty – five patients did receive ATG. Median observation time of surviving patients is 1.9 years. Forty – one pts died, in 26 patients death was treatment related. After one year, estimated overall survival is 52% (95% CI 39% to 63%), progression free survival is 46% (95% CI 33% to 57%), relapse rate is 29% (95% CI 43% to 10%), non relapse mortality is 37% (95% CI 26% to 50%). The incidence of acute GVHD > grade 1 is 66% (95% CI 49% to 82%). The last documented lymphoma progress occurred at day 288 after alloSCT. Patients with high-intermediate or high IPI at transplant did not differ significantly in PFS from patients with low and low-intermediate IPI (PFS at 2 years 34% vs 41%, p=0.144). There are no significant differences in OS, PFS and GvHD for pts receiving Rituximab or not.

This alternative myeloablative conditioning followed by T - replete allogeneic SCT is an effective treatment option in patients with high risk features like active disease at transplantation and high – tumor burden. Although the incidences of GVHD ( uninfluenced by the administration of Rituximab ) and non-relapse mortality were relatively high, relapse rates were low and OS and EFS are promising While further optimization of conditioning by using lymphoma – specific drugs in high doses and improvement of GvHD – prophylaxis by adding optimal doses of ATG are certainly possible we do not believe that minimal conditioning and in vivo T – cell depletion will cure patients with high – risk aggressive lymphoma.

Glass:Roche: Honoraria, Research Funding. Off Label Use: Rituximab will be used as prophylaxis for graft-versus-host-disease. Schmitz:Roche: Honoraria, Research Funding.