The sorafenib anti-relapse effect after alloHSCT is associated with heightened alloreactivity and accumulation of CD8+PD-1+ (CD279+) lymphocytes in marrow.

Andrzej Lange,Grzegorz Dworacki,Monika Mordak-Domagala,Aleksandra Simiczyjew,Janusz Lange,Emilia Jaskula,Dorota Nowak,Mariola Sedzimirska,Graca D Almeida-Porada

doi:10.1371/journal.pone.0190525

Abstract

We studied three FLT3 ITD acute myeloid leukemia (AML) patients who relapsed after allogeneic haematopoietic stem cell transplantation (alloHSCT) and received multikinase inhibitor (MKI) sorafenib as part of salvage therapy. MKI was given to block the effect of FLT3 ITD mutation which powers proliferation of blast cells. However, the known facts that sorafenib is more effective in patents post alloHSCT suggested that this MKI can augment the immune system surveillance on leukaemia. In the present study, we investigated in depth the effect of sorafenib on the alloreactivity seen post-transplant including that on leukaemia. The patients (i) responded to the treatment with cessation of blasts which lasted 1, 17 and 42+ months, (ii) developed skin lesions with CD3+ cell invasion of the epidermis, (iii) had marrow infiltrated with CD8+ lymphocytes which co-expressed PD-1 (programmed cell death protein 1 receptor, CD279) in higher proportions than those in the blood (163±32 x103 cells/μl vs 38±8 x103 cells/μl, p<0.001). The Lymphoprep fraction of marrow cells investigated for the expression of genes involved in lymphocyte activation showed in the patients with long lasting complete remission (CR) a similar pattern characterized by (i) a low expression of nitric oxide synthase 2 (NOS2) and colony stimulating factor 2 (CSF2) as well as that of angiopoietin-like 4 (ANGPTL4) (supporting the immune response and anti-angiogenic) genes, and (ii) higher expression of fibroblast growth factor 1 (FGF1) and collagen type IV alpha 3 chain (COL4A3) as well as toll like receptor 9 (TLR9) and interleukin-12 (IL-12) (pro-inflammatory expression profile) genes as compared with the normal individual. The positive effect in one patient hardly justified the presence of unwanted effects (progressive chronic graft-versus-host disease (cGvHD) and avascular necrosis of the femur), which were in contrast negligible in the other patient. The anti-leukemic and unwanted effects of sorafenib do not rely on each other.

Highlights

The successful use of kinase tyrosine inhibitors in the treatment of acute myeloid leukaemia (AML) patients has promoted interest in this field, and a number of similar drugs have entered the market
While sorafenib is used with the aim of slowing the signal transduction originating from the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families [3,4,5], it efficiently blocks constitutive activation of Fms-related tyrosine kinase 3 mutated via internal tandem duplication (FLT3 ITD) [3,6,7]
A similar pattern of expression was found in two cases with a long lasting response, with higher expression levels of toll like receptor 9 (TLR9), PRLR and IL12A and lower expression of nitric oxide synthase 2 (NOS2) and colony stimulating factor 2 (CSF2) (GM-CSF, Fig 2A) as compared to the expression levels seen in the marrow of a normal individual

Summary

Introduction

The successful use of kinase tyrosine inhibitors in the treatment of acute myeloid leukaemia (AML) patients has promoted interest in this field, and a number of similar drugs have entered the market Most of these drugs broadly inhibit kinases that conduct signals from different receptors but share targeted molecular characteristics [1,2]. The present study provides an analysis of the effect of sorafenib at the molecular and cellular level which documented prompt cessation of blasts and a long lasting effect associated with skewing of the gene expression profile toward gene-activated immune responsiveness and prolonged inflammation at the expense of genes involved in CD8 lymphocyte suppression and angiogenesis It is reflected by an elevated blood level of von Willebrand factor and significant accumulation of CD8+CD279+ (PD-1 – programmed cell death protein 1 receptor) lymphocytes resembling phenotypically those described as tumor-infiltrating lymphocytes (TILs) in the marrow and GvHD in the skin and in a case-dependent manner in other organs. This information is over great clinical value in the area of Nivolumab (anti-PD-1 (CD279) monoclonal antibody) therapy opening a new avenue for treatment of AML patients having over dismal prognosis FLT3 ITD mutation and relapsing post HSCT [17]

Methods

Results

Conclusion