NCI first International Workshop on the biology, prevention, and treatment of relapse after allogeneic hematopoietic stem cell transplantation: report from the committee on the biological considerations of hematological relapse following allogeneic stem cell transplantation unrelated to graft-versus-tumor effects: state of the science

Abstract

Hematopoietic malignant relapse still remains the major cause of death following allogeneic hematopoietic stem cell transplantation (HSCT). Although there has been a large focus on the immunologic mechanisms responsible for the graft-versus-tumor (GVT) effect or lack thereof, there has been little attention paid to investigating the biologic basis of hematologic malignant disease relapse following allogeneic HSCT. There are a large number of factors that are responsible for the biologic resistance of hematopoietic tumors following allogeneic HSCT. We have focused on 5 major areas including clonal evolution of cancer drug resistance, cancer radiation resistance, genomic basis of leukemia resistance, cancer epigenetics, and resistant leukemia stem cells. We recommend increased funding to pursue 3 broad areas that will significantly enhance our understanding of the biologic basis of malignant relapse after allogeneic HSCT, including: (1) genomic and epigenetic alterations, (2) cancer stem cell biology, and (3) clonal cancer drug and radiation resistance.

Figure 1

The neoplastic cells in an allogenic stem cell transplant patient go through 3 regimes of selection. During neoplastic progression, clones with evolutionary neutral mutations (in gray), which have no effect on survival or reproduction of the clone, expand and contract randomly. Inactivation of tumor suppressor genes and activation of oncogenes often drive clonal expansions (clones in shades of yellow, red, and blue). Ablation introduces a new selective pressure on the neoplastic cells, which may kill most of them, but some clones may survive (blue clone) and continue to generate subclones (shades of purple and green). The allogenic immune cells then introduce a third selective regime in the graft-versus-tumor reaction. If there is a clone that can escape the allogenic immune response (the green clone), minimal residual disease may remain, which can eventually lead to relapse, possibly through additional somatic evolution. Thus, relapse derives from clones that have survived the different selective pressures of both ablation and the graft-versus-tumor immune response.

Figure 2

Proposed model of the developmental hierarchy in the development of acute myelogenous leukemia, similar to normal hematopoiesis.

Figure 3

Proposed model of progression from committed hematopoietic stem cell progenitor cells transformed by an oncogene MLL-AF9 into a leukemia stem cell (LSC).

Figure 4

Proposed model of the balance of genetic and epigenetic content in the progression of tumor stem cells to a malignant phenotype.