Page 31 - 2019_05-HaematologicaMondo-web

Evolutionary trajectory of AML
diagnosed by the presence of their typical chromosomal aberrations, regardless of actual blast count.45,46 These chromosomal abnormalities, which result in novel fusion RNA transcripts, are being used for monitoring minimal residual disease following therapy and dictate pre-emptive treatment upon detection.47,48 While this implies that these chromosomal aberrations should be regarded as leukemic events, some of the chromosomal abnormalities of CBF- AML were retrospectively detected in blood samples taken more than 10 years before the patients were diag- nosed with AML,49 as well as up to 7 years following allo- geneic transplantation in patients without evidence of dis- ease.50 In fact, when stem cells and cells from various line- ages were sorted from BM of CBF-AML patients in remis- sion, t(8;21) translocations were identified in B cells as well as in myeloid cells. This suggests that this event occurred at the stem cell level, still capable of differentia- tion.51
A debate continues over the cell of origin of APL. It was shown that APL blasts have a gene expression profile with T-cell lymphoid features52 and that they can engraft immune-deficient mice.53 This raises the possibility that APL blasts (especially blasts of the hypogranular variant) originate in early multipotent progenitors prior to lineage commitment.54 Nevertheless, t(15;17) translocation was identified only in CD34 positive (CD34+) precursor cells of the myeloid lineage and not in B or T lymphocytes.55 Thus, it is generally accepted that the APL transforming event occurs at a more committed progenitor cell.56 In contrast to the aforementioned pre-leukemic HSPCs (e.g. DNMT3A mutated), these cells do not maintain multilineage hematopoiesis.
Leukemic cells that harbor APL and CBF-AML translo- cations acquire additional mutations as they evolve. Similarly to other AML subtypes, additional somatic mutations that were identified in these clones involved tyrosine kinase receptor genes (e.g. RAS, FLT3 and KIT).
Clinical implications and future challenges
Pre-leukemic stage: prediction and screening
A reliable screening strategy for a rare disease, such as AML with an estimated incidence of 4:100,000,57 should have a high positive predictive value. In order to improve current models, specific variants that were described in hematologic malignancies, rather than specific genes, should be used for screening. In addition, a better under- standing of the selective pressures and the germline back- ground, under which pre-AML clones evolve, is required. While such an understanding still remains elusive, the term “fitness” encompasses both clonal intrinsic factors and environmental selective pressures. Thus, exposing a detrimental, malignant, clonal evolution requires a dynamic, longitudinal follow up of healthy individuals, rather than relying on a single blood test that depicts a static picture of the hematopoietic clonal structure (as sug- gested by the term CHIP). Therefore, AML screening pro- grams should use a 2% VAF threshold as well as a docu- mentation of clonal temporal evolution (by having at least two assessments of the clonal mutational profile 6-12 months apart). This should be incorporated into a refined definition of ARCH.58 Documenting ARCH-defining events in two consecutive tests will allow a better charac- terization of the clones and increase the confidence in
their status, thus facilitating patient risk stratification. Screening for therapy-related AML can be performed by detecting pre-leukemic clones at the time of initial chemotherapy treatment (administered for a non-AML tumor), and patients should be monitored at least once
again to define ARCH.59
Additional improvement in the positive predictive value
of such a model might also require inclusion of yet unde- scribed non-genomic, evolutionary events that manifest in the epigenome or in post-transcriptional or post-transla- tional landscapes of the pre-malignant clone. It is still not known what influences these events: whether there are cause-and-effect relations between specific mutations and these non-genomic events, or whether they are influenced by the environment itself. As an example of the latter, p53 (wild-type at the genomic level) was shown to acquire a mutant-like post-translational conformation following stimulation by growth factors in AML cells.60
Incorporating clinical data into prediction models is expected to improve their accuracy and enable risk strati- fication for individuals carrying ARCH.9 However, pre- AML individuals were shown to have only subtle abnor- malities in their blood count measures, often within the normal limits, with a large overlap with values document- ed in controls.9,13,21
Pre-leukemic stage: prevention
Once prediction tools become more reliable, prospec- tive, intervening clinical trials can be initiated. When plan- ning such clinical trials two major challenges arise: 1) the low incidence of AML in the general population; and 2) its prolonged latency. The former can be mitigated by regis- tering a large cohort of participants and by patient selec- tion based on risk stratified according to clonal temporal progression (using the refined ARCH definition) and on their clinical data.8,9,13 Overcoming its prolonged latency requires a long follow up of the participants and might require a prolonged or indefinite treatment period to sup- press pre-leukemic clones.
Targeting pre-leukemic clones as a means to prevent AML needs to be performed with caution. This might cause aplasia when the entire hematopoietic system is comprised by this clone (e.g. as is the case with a high VAF TET2 clone). This can also give a selective advantage to a different pre-leukemic clone that resides in the shared microenvironment. An effective intervention must target both the clone with its driver genes and the environment that enabled it to flourish.
Leukemic stage
Targeting leukemic mutations might be an effective way to eliminate the malignant clone,38 thus preventing relapse. This is particularly true in AML because most relapses arise during the first 2 years and stem from the original clone detected at diagnosis.34,61,62
Can pre-leukemic mutations serve as a target for thera- py as well? On the one hand, all leukemic cells share these mutations. Targeting IDH1 using a specific inhibitor resulted in a 30% complete remission rate among 125 IDH1-mutated relapsed/refractory AML patients. These responses lasted a median of 8 months. Remission was accompanied by a decrease in IDH1 VAF values.63
Similar results were obtained when using an IDH2 spe- cific inhibitor, with an overall response rate of 40.3% and a median response duration of 5.8 months.64 These results
haematologica | 2019; 104(5)
877