Donor Lymphocyte Infusion for Mixed Chimerism or Residual Disease after Reduced-Intensity T Cell Depleted Stem Cell Transplantation Results in Conversion to Full Donor Chimerism Combined with Graft Versus Tumor Responses and Limited GVHD.
Authors: von dem Borne Peter A. , Starrenburg Ingrid , Marijt Erik W.A. , Halkes Stijn , Falkenburg J.H. Frederik , Willemze Roel 
Published: April 2020

Abstract
We perform reduced intensity allogeneic stem cell transplantation (SCT) with HLA identical sibling and matched unrelated donors using a conditioning regimen consisting of fludarabine, busulphan and ATG combined with alemtuzumab added to the stem cell graft for extensive donor T cell depletion. With this regimen hardly any acute and chronic graft versus host disease (GVHD) are observed after SCT and mixed chimerism is induced in most patients (Barge et al, Exp Hematol 2003). In patients transplanted for malignant disease, donor lymphocytes (DLI) are administered in escalating doses from 6 to 9 months to convert mixed into complete donor chimerism and to induce graft versus tumor (GVT) responses. We report results of chimerism analysis, clinical antitumor response and GVHD after DLI. 41 patients (median age 54 years, range 37–65) transplanted with stem cells from sibling donors (29) or matched unrelated donors (12) for various malignancies received DLI with a median dose of 5 × 106 CD3+ cells/kg (range 1–5) at a median time point of 7 months after SCT (range 5.1–15). After DLI administration 35 of 38 evaluable patients (92%) developed an immune response as defined as a major decrease in patient chimerism. In 26 patients full donor chimerism was achieved, in 9 patients a low patient signal remained present (1–2%). Patient chimerism decreased from median 12% (range 1 to 86%) to 0% (range 0–2%). In most patients conversion occurred after the first DLI, in 4 patients after the second and in 1 patient after the third DLI. In 31 of 38 patients measurable disease was present before DLI. In 22 of these patients conversion from mixed to full donor chimerism coincided with clinical GVT responses. Seven patients with active myeloid disease all achieved complete remission (4 AML/MDS patients with 8–65% blasts, 2 patients with progressive CML and 1 with active CMMOL). All these patients are still in CR after a median time of 22 months. In 8 myeloma patients with measurable disease 5 complete and 1 partial response were observed. However, most responding myeloma patients subsequently developed bone or extramedullary relapses without evidence of bone marrow involvement. In 13 patients with lymphoid disease 9 responses were observed. One patient with an immunocytoma and one with T-PLL achieved CR. In 7 CLL patients 3 CR and 1 PR were observed, notably two CR occurred in patients with massive bone marrow involvement. Two of four patients with aggressive NHL showed a CR to DLI in combination with rituximab and one patient a PR to DLI. Although no regression of tumor was observed in three patients with renal cell carcinoma after DLI, disease progression was halted for several years. Grade 3–4 acute GVHD developed in 22% of patients, grade 1–2 in 39%. Limited or extensive chronic GVHD was observed in 30 and 23% of patients, respectively. GVHD responded to therapy in most patients, only in 9% of patients chronic GVHD did not resolve. Mortality due to acute and chronic GVHD was 10%. In conclusion, after T cell depleted reduced intensity SCT a state of mixed chimerism is induced in most patients, which can be converted into full donor chimerism with DLI in more than 90% of patients. Conversion to full donor chimerism is accompanied with clinical GVT responses in a high percentage of patients with acceptable GVHD.