General AML,   RUNX1

Phase I/II study of NK cell immunotherapy for high-risk MDS and AML

Andreas T. Björklund, Mattias Carlsten and Ebba Sohlberg from Karolinska University Hospital, Stockholm, Sweden, and colleagues published in the April 2018 Issue of Clinical Cancer Research, data from a phase I/II adoptive immunotherapy trial (EudraCT number: 2011-003181-32), which evaluated the safety, efficacy and immunobiological functions of allogeneic natural killer (NK) cell-based therapy for patients with primary chemotherapy-refractory or relapsed high-risk myelodysplastic syndrome (MDS), secondary and de novo acute myeloid leukemia (AML). 

Sixteen patients (median age = 64 years, range 40–70) with high-risk MDS (n = 5), secondary MDS/AML (n = 8) and de novo AML (n = 3) who were refractory to first-line chemotherapy and were considered ineligible for hematopoietic stem cell transplantation were enrolled in this study. Patients were administered lymphodepleting chemotherapy (fludarabine [25 mg/m2/day on Days -7 to -4]/cyclophosphamide [25 mg/kg/day on Days -3 to -2] conditioning combined with total lymphoid irradiation [at Day -1] prior to infusion with haploidentical NK cells (median NK cell dose infused was 6.7 x 106 cells/kg, range 1.3–1.7 x 106 cells/kg). Evaluation of clinical responses was done on Day 28, with weekly immunological assessment from week 1 until week 4 from NK cell infusion. Patients with response were followed monthly thereafter.

NK cell infusions were well tolerated with transient (<6 hours) grade 3–4 toxicities including chills and nausea seen in two of the sixteen patients. Two patients presented with grade 3 and 5 cytokine release syndrome respectively with one dying six weeks after cell infusion due to relapse, hemophagocytic lymphohistiocytosis and human herpesvirus 6.

Six (38%) patients achieved an objective response (OR) with complete remission (CR) or partial remission (PR). Two patients achieved stable disease and one patient fulfilled the criteria of morphological leukemia-free state (MLFS), with a short-lasting reduction in blast cells without hematological recovery at day 14. Five of the six responders proceeded to HSCT and three remain disease free > 3 years after treatment. The authors noted that these results suggest that the “infusion of haploidentical NK cells without post-NK cell infusion IL-2 can induce ORs and, as such, may serve as a bridge to HSCT for patients with high-risk MDS, MDS/AML and de novo AML”.

Using real-time polymerase chain reaction, it was observed that patients with OR had detectable donor NK cells 7 and/or 14 days after infusion and showed a reduced number of chromosomal aberrations and more complex cytogenetics than non-responders. Interestingly, responders displayed a significant reduction of total allelic burden following therapy with NK infusion. Four of the responders had mutations (RUNX1, ASXL1) associated with poor prognosis which became undetectable after therapy.

It was observed that responders had low frequencies of myeloblasts (lin-CD34+CD45RA+CD123+ cells) post-NK cell infusions and demonstrated significantly higher levels of total HLA class 1 as well as HLA-E compared to blasts in the non-responders. Responding patients also showed a reduced activation of CD8+T cells and lower levels of inflammatory cytokines following NK cell infusion.

The authors concluded by stating that their “study suggests that MDS, MDS/AML and de novo AML are susceptible to NK cell-based cancer immunotherapy” and “supports the use of haploidentical NK cell infusions as a bridge to HSCT in refractory patients”. Additionally, “objective clinical responses and reduction of high-risk clones was associated with detectable donor-derived NK cells, immunoediting of residual blast cells, and less pronounced host immune activation”.

References
  1. Björklund A. T., Carlsten M., Sohlberg E. et al. Complete Remission with Reduction of High-Risk Clones following Haploidentical NK-Cell Therapy against MDS and AML. Clin Cancer Res. 2018 Apr 15; 24(8): 1834–1844. DOI: 10.1158/1078-0432.CCR-17-3196. Epub 2018 Feb 14.
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