Interleukin-2 and Granulocyte-Macrophage Colony Stimulating Factor Is an Alternative to Donor Lymphocyte Infusion for Relapse after Allogeneic Stem Cell Transplantation and Is Associated with Increase Immune Effector Cells and Polarization to Type 2 Dendritic Cells.
Authors: Bachier Carlos R. , Shaughnessy Paul , Smith2 Brad , Salinas Richard , LeMaistre Charles F. 
Published: April 2020

Donor lymphocyte infusion (DLI) is use for relapse after allogeneic stem cell transplant (ASCT). Immune activation with cytokines maybe an alternative to DLI. We administered Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and Interleukin-2 (IL-2) at the time of relapse after ASCT in patients (pts) with hematologic malignancies. Pts. received subcutaneous GM-CSF at 500 mcg/day on days 1–14 and IL-2 at 1 × 106 units/m2/day on days 8–14. Pts. were off immunosuppressive therapy and had no prior history of graft versus host disease (GVHD) at the start of treatment. Twelve pts. received IL-2/GM-CSF for treatment of relapse AML (7), ALL (2), CML (1), MDS (2). Median age was 55 (range 8–66). Stem cell sources included: peripheral blood = 9, bone marrow = 2, umbilical cord blood (UCB) = 1. Donor sources were: match-related sibling = 4 and match-unrelated donor = 8 (UCB=1). Nine pts. had resistant relapse or primary resistant disease at time of ASCT. Median time from transplant to relapse was 4 months (range = 1–14). Two pts. had failed DLI and 5 pts. had received reinduction chemotherapy prior to IL-2/GM-CSF. Eight pts. responded to IL-2/GM-CSF (CR = 7, PR = 1). Two pts. remain disease free at 18 and 26 months post IL-2/ GM-CSF. Six pts. developed GVHD and of these 4 were responders. Two pts. had GM-CSF discontinued due to increase in peripheral blood blasts. No other toxicities related to IL-2/GM-CSF except for mild flu-like symptoms. The table below summarizes quantitative analysis of immune activation. Values represent means +/− standard error at day 0 (first day of GM-CSF), day 8 (prior to start of IL-2) and day 14 (last day of IL-2 and GM-CSF). P-values are based on paired t-test analysis of day 8 versus day 0 and day 14 versus day 0, respectively. Flow cytometric analysis showed an increase in the numbers of T-lymphocytes (CD3) and T-cell subsets (CD3/CD8 and CD3/CD4) as well as an increase in natural killer cells (CD16/56). Although no differences were seen in the number of dendritic cell subsets, DC1/DC2 ratios decreased with the administration of GM-CSF/IL-2. Limited (n= 4) CD4/FoxP3 analysis did not show change in absolute numbers with administration of GM-CSF/IL-2 (data not shown). In conclusion, cytokine therapy with IL-2/GM-CSF is well tolerated and is an alternative to DLI for relapse after ASCT. Flow cytometry analysis demonstrated a quantitative increase in immune effector cells and polarization to DC2.

IMMUNE ACTIVATION FLOW CYTOMETRY ASSAYS D0 (Mean +/− SE) D8 (Mean +/− SE) D14 (Mean +/− SE) P-Value (Day7–0) P-Value (Day 14–0) SE=Standard Error; DC = dendritic cells CD3 (K/uL) 309 +/− 117 535 +/− 103 1306 +/− 403 0.034 0.027 CD3/CD8 (K/uL) 94 +/− 42 174 +/− 33 325 +/− 90 0.021 0.029 CD3/CD4 (K/uL) 309 +/− 117 404 +/− 102 977 +/− 310 0.249 0.045 CD16/CD56 (K/uL) 124 +/− 60 404 +/− 110 496 +/− 162 0.029 0.044 CD19 K/uL) 68 +/−39 89 +/− 36 116 +/− 31 0.183 0.044 Total Lymphs (K/uL 488 +/− 167 942 +/− 160 2353 +/− 532 0.016 0.013 CD11(DC1) (K/uL) 97.1 +/− 60.7 46.3 +/− 32.5 32.6 +/− 27.5 0.108 0.101 CD123(DC2) (K/uL) 32.1 +/− 7.3 39.7 +/− 15.9 45.4 +/− 35.8 0.694 0.628 DC1/DC2 2.77 +/− 1.26 0.68 +/− 0.35 0.61 +/− 0.07