Donor-Derived CIK Cell Infusion As Consolidative Therapy after Non-Myeloablative Allogeneic Transplant in Patients with Myeloid Neoplasms

Introduction: Non-myeloablative conditioning combining total lymphoid irradiation (TLI) with rabbit anti-thymocyte globulin (ATG) has been shown to have a low incidence of non-relapse mortality (NRM) for patients with myeloid neoplasms (Benjamin Biol Blood Marrow Transplant 2014). As with other reduced intensity conditioning regimens, relapse remains the primary cause of treatment failure following allo-HCT using TLI-ATG conditioning. Cytokine induced killer (CIK) cells derived from peripheral blood culture with interferon (IFN)-γ, interleukin (IL)-2, and anti-CD3, have demonstrated anti-tumor effects in vitro, and have been safely administered in a phase I/II study of patients with post-transplant relapse with low incidence of acute GVHD (Laport Biol of Blood and Marrow Transplantation 2011). In an effort to promote conversion to full donor chimerism and reduce the risk of relapse following TLI/ATG conditioning for patients with myeloid neoplasms, we evaluated the addition of donor derived cytokine induced killer (CIK) cells post-HCT. 

Methods: Here we report interim results for 37 patients enrolled to date in an unplanned analysis. Day+90 full donor chimerism (FDC) was the primary endpoint. Secondary endpoints include overall survival and incidence of acute GVHD. Median age is 64 years (range 37-74) with primary disease of de novo MDS (19, 51.3%), secondary AML (6, 16.2%), MPN (2, 5.4%), and therapy (t-) related myeloid neoplasm (10, 27%; including 4, t-MDS; 4, t-AML; 2, t-MDS/MPN overlap). Of patients with MDS or MDS/MPN overlap, 54% had intermediate-2 IPSS risk classification. Fifteen (40.5%) patients had a morphological complete remission at the time of HCT. Twenty-three (62%) donors were unrelated.

Results: Median CD34+ dose was 7.2e6/kg (range 2.3-17e6/kg). Ten patients (27%) did not receive CIK cells; causes included CD34+ cell dose below the threshold for culture inoculation (n=4), acute graft versus host disease (n=2), fever with concern for active infection at the time of scheduled infusion (n=1), or logistical reasons (n=3, including lack of donor consent for CIK infusion, transplant delay, and reagent unavailability). Of the 27 patients receiving CIK cells, 23 received the target dose of 1e8/kg CD3+ CIK product, at a median time of 26 days (range 24-31) post peripheral blood stem cell (PBSC) infusion. The median CD3+, CD3+CD56+, CD3+CD8+NKG2D+, CD8+CD45RO+ cell culture content was 97%, 13%, 51%, and 41%, respectively. Median followup time for living patients is 420 days. Day+90 FDC, defined by 95% or greater donor-type peripheral blood CD3+ cells, was 29%. The incidence of acute GVHD grade II-IV and grade III-IV in the total cohort is 21.6% and 5.4%, respectively. The incidence of chronic GVHD is 19%. Of the 27 patients receiving CIK product, the incidence of acute GVHD grade II-IV is 7.4% with no acute grade III or IV events to date and 22% chronic GVHD.

On an intention to treat analysis of enrolled patients, one year NRM 10.5% (95% CI: 0.8%-22.1%) and one year cumulative incidence of relapse 46.3% (95% CI: 28.4%-64.1%) are not significantly different compared to our historical cohort (5.2%, 95%CI: 2.0%-8.4% and 53%, 95%CI: 45.9%-60.1%) respectively. The 1-year OS by intention to treat of 68.6% (95%CI: 54%-87%) is similar to our historical control, 60.8% (95%CI: 54.3%-68.2%, p=0.76). The 1-year OS in the 27 CIK recipients is 75% (95%CI: 59.3%-94.7%).

Conclusion: CIK infusion was found to be safe and feasible. There was no increase in grade III-IV acute GVHD or chronic GVHD risk. There was a statistically non-significant trend towards increased one-year survival in our cohort. The potential benefit on overall survival remains to be further evaluated with additional patient enrollment and longer followup. However, given the favorable safety profile of CIK cells, future strategies to enhance efficacy such as repeat dosing or modification of CIK cells are worth potential exploration.