Interleukin-2 and Granulocyte-Macrophage Colony Stimulating Factor for Relapse After Allogeneic Stem Cell Transplantation

Strategies for treatment of relapse after allogeneic stem cell transplant (SCT) include withdrawal of immunosuppressive therapy and donor lymphocyte infusions (DLI). Trials using cytokines (CK) have also demonstrated allo-immune responses after allogeneic SCT.  We evaluated the role of interleukin-2 (IL-2) and granulocyte-macrophage colony stimulating factor (GM-CSF) on patients (pts) relapsing after allogeneic SCT. 

Twenty three pts (median age=50, range 7 months to 66 years) received IL-2 at 1 million units/m2 subcutaneously (days 8-14) without (n=13) or with (n=10) GM-CSF at 500 mcg subcutaneously (days 1-14).  Pts received a median of 2 cycles (range 1-4) of IL-2/GM-CSF.  SCT sources included:  peripheral blood matched-related (n=9), or unrelated (n=7), bone marrow matched related (n=1), or unrelated (n=2) or umbilical cord blood (n=4) SCT.  Diagnosis included AML (n=12), MDS (n=3), ALL (n=2), non-Hodgkin's lymphoma (n=2) and Hodgkin's disease (n=1), Chronic Lymphocytic Leukemia (n=1).  Disease status at SCT included CR1= 3, CR2= 1; all other pts underwent SCT for primary induction failure or resistant relapse.  Median time from SCT to relapse was 5 months.  Pts had received DLI (n=13) or chemotherapy (n=19) prior to CK therapy.  Response rate after CK therapy  was 57 % (13/23, all CR's). Median overall survival (see figure) after CK therapy was 9 months (range= 1-47 months).   Acute or chronic graft versus host disease occurred in 13 pts after CK therapy. The table below summarizes 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 analysis of day 7 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, CK therapy with IL-2 ± GM-CSF post SCT is associated with alloimmune responses.  Relapse rate remains high with most pts relapsing after initial responses.

	D0 (Mean ± SE)	D7 (Mean ± SE)	D14 (Mean ± SE)	P-Value (Day 7-0)	P-Value (Day 14-0)
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