Dendritic Cell Reconstitution Following Autologous Stem Cell Transplant with GM-CSF Support for Multiple Myeloma.
Authors: Schlueter Annette J. , Glasgow Judith K. , Wilke Werner , Marietta Jacquie R. , Hohl Raymond J. , Carter Thomas H. , Gingrich Roger D. , Magalhaes-Silverman Margarida D. 
Published: October 2019

Abstract
High dose therapy followed by autologous stem cell rescue for the treatment of multiple myeloma has been shown to be associated with improved outcome including increased complete response rates and survival. It is unclear what role, if any, autologous dendritic cell (DC) reconstitution patterns play in determining outcome. DC in peripheral blood (PB) can be divided into two subsets: DC1, which favor Th1 responses and DC2, which favor Th2 responses and in some cases appear to be immunosuppressive. In this companion study to a tandem stem cell transplant research protocol, PB DC subsets were studied just prior to the administration of mobilizing chemotherapy (baseline), at the time of stem cell collection, and on transplant d. 0, 15, 30, 60, and 90 following the first and second transplants. DC were identified as lineage (CD3/14/16/19) negative, HLA-DR+. Of these cells, DC1 = CD11c+CD123− or CD33hiCD4lo, and DC2 = CD11c−CD123+ or CD33lo/−CD4+. Precursor DC numbers (Pre-DC1 = CD45loCD34+HLA-DR+CD86+; Pre-DC2 = CD45loCD34+HLA-DR+CD10+) were also assessed in the stem cell products. GM-CSF (sargramostim) was used as part of the mobilization regimen as well as to enhance neutrophil recovery post-transplant. Twenty patients were enrolled and all are >90 d. post transplant #1. Six patients received a 2nd transplant. Median followup time is 25 months (range 3–56 months). Seven patients are in complete remission (CR), 7 have had a partial response, 4 have progressive disease, and 2 died of recurrent disease. In most cases, DC1 counts were higher than DC2 counts at all time points examined. At baseline, this was true for 70% of patients, indicating that immediately prior to transplant most patients maintain the DC1>DC2 ratio found in healthy humans. DC subset numbers generally increased over baseline in mobilized PB, and correlated well with the patients’ baseline DC counts. Similarly, baseline DC subset numbers were highly correlated (R>0.7) with the number of pre-DC1 or pre-DC2 found in the stem cell products. No patients with pre-DC1<pre-DC2 achieved a CR. Post-transplant, DC1 recovery to baseline levels occurred in most patients by d. 60. DC2 recovery was often more rapid, with baseline levels reached in many patients at d. 30. Patients who had high (>10/ul) PB DC1 numbers at d. 90 consistently remain in CR. This study is the first to systematically examine DC subset reconstitution following autologous transplant for multiple myeloma. Our results provide preliminary evidence that the presence of high numbers of PB DC1 at d. 90 may predict a good long term prognosis, perhaps by promoting an effective endogenous immune response against residual disease. Furthermore, pre-DC1<pre-DC2 in the stem cell product might predict a poor outcome, and increase early consideration of post-transplant adjunctive therapy. As GM-CSF is known to mobilize proportionately more DC1 (relative to DC2) than G-CSF (Vela-Ojeda 2006, Ann Hematol 85:308–14), use of GM-CSF may provide a long-term disease free benefit in addition to facilitating stem cell collection and limiting post-transplant neutropenia in patients with multiple myeloma.