Donor Lymphocyte Infusions (DLI) for the Treatment of Disease Relapse in Hematological Malignancies Following Allogeneic Transplantation: Similar Efficacy Following RIC or Myeloablative Regimen
Authors: Guillaume Thierry , Chevallier Patrice , Ayari Sameh , Delaunay Jacques , Lode Laurence , Mechinaud Francoise , Avet-Loiseau Hervé , Moreau Philippe , Harousseau Jean Luc , Mohty Mohamad 
Published: April 2020

Abstract
DLI have been shown to have a potent GVL effect in relapsing chronic phase CML while for reasons that remain unclear, they appear less effective in treating relapsing diseases other than CML. A lack of tumor-specific antigens, the absence of co-stimulatory molecules on tumor cells, or inhibition of effector cells may account for the lower therapeutic effect. Given the sub-optimal results of DLI in non-CML diseases, predictive factors of DLI efficacy such as type and stage of the disease and levels of chimerism would serve to better guide the use of leukocytes infusions.
We analyzed a series of 73 patients (pts) who received DLI for various indications (disease relapse or progression, n=66; persistent mixed chimerism (less than 90% donor cells) without evidence of relapse, n=4; EBV lymphoproliferation, n=3). Diagnosis included: CML (n=9), MDS or AML (n=21), LAL (n=5), myeloma (n=18), NHL (n=10), Hodgkin’s disease (n=5), CLL (n=2), and other (n=3). Median age at transplantation was 46 (1–62) years. Eigthy-six percent of donors were HLA-matched siblings, while 12% were MUD, one donor was a haplo-identical sibling, and two had one class I mismatch. Reduced intensity conditioning was used in 39 patients (52%; fludarabine, busulfan and ATG), and 35 pts (48%) received a standard myeloablative TBI/cyclophosphamide-based regimen. The graft was T-cell depleted in 14 cases. GHVD prophylaxis consisted of CsA alone in RIC patients, and CsA+Mtx in the myeloablative group. DLI was given at a median of 247 (19–3163) days after transplantation. Escalating dose were given if no response or GVHD were observed: one DLI n=36, 2 infusions (n=36), 3 infusions (n=5), 4 infusions (n=1). The median pre-DLI lymphocyte count was 0.95×109/L (0.05–4.38). In addition to DLI, 22 pts (47%) received prior (n=9, 19%) or subsequent chemotherapy to enhance disease control. In those who received DLI for mixed chimerism alone, all four returned to full donor chimerism. In those who received DLI for relapsing/progressive disease, CR was achieved in 21 pts (28%), including 15 with non-CML diseases (23%): 6/21 AML, 5/18 MM, 2/10 NHL, 1/5 HD, 1/5 ALL. In 16 pts, CR was obtained with DLI only. Two of the three patients who received DLI for EBV lymphoproliferation responded. Response to DLI was comparable between pts receiving RIC regimen and myeloablative regimen (p=ns). The rate of acute GVHD II-IV and chronic GVHD was 27% and 23%. The incidence of acute GVHD II-IV did not differ whether the conditioning was myeloablative or RIC while the rate of GVHD was higher in recipient of DLI from unrelated donor (60%, although the number is small). Chimerism was performed on unselected WBC and available prior DLI for 7/9 of CML pts, and 54/65 non-CML pts. For non-CML disease donor chimerism was &lt;90% for 17 pts (including 6 pts with &lt;50%) and ≥90% for 37 pts with an incidence of acute grade II-III GVHD of 52% and 32% respectively (p=ns). Correlation was observed between GVHD and graft versus malignancy in non-CML diseases (.015). The median overall survival was 28.3 months. The overall probability of survival following DLI at 2 and 4 years was 50.7% and 40.5% (95% CI, 27.7–53.3) for the whole group; the survival at 4 years according to the disease was 38.8% for AML/MDS, 40% for NHL, 35.7% for myeloma. With a median follow-up of 1662 days from the time of the initial DLI, 33/73 pts of the whole group (45%) are alive, while in the non CML group 26/64 (37.5%) pts are alive and 18/64 (28%) alive in CR. These results indicate that DLI combined with chemotherapy for disease relapse or mixed chimerism is similarly effective in non-CML diseases following RIC or standard allografting and works in one case out of four in AML and myeloma. Its efficacy can be further improved with the use of more tumor-specific DLI and reduction of the suppressing activity of regulatory T cells.