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Genomics in Acute Myeloid Leukemia - A Dynamic Landscape with Elegant Vista


By PAVAN KUMAR BHAMIDIPATI, MD

Acute Myeloid Leukemia (AML) is a fatal hematological malignancy commonly occurring in relatively older population with limited progress in the last 4 decades. Anthracycline and cytarabine based combo (7+3) is still the standard in first line in younger patients, while hypomethylating agents (e.g., decitabine and azacitidine) are tolerable alternatives in older patients. However, the response rates with HMAs is in the order of 40% with no long-term disease control and no effective second line options exist. Five-year survival rate for AML is approximately 20-25% with allogeneic stem-cell transplantation still being the most curative option.

Unlike many solid cancers where new targeted therapies that are coming out every day, progress in AML has been extremely sluggish, until recently.

Genomic alterations in leukemogenesis:

Advent of Next Generation Sequencing (NGS) aided in understanding the biology of AML better in the recent years. Initial whole genome sequencing of AML tumor came from Washington University that shed light on the frequency of various mutations. Further deeper analyses of whole genome (WGS - includes both coding and non-coding regions), whole exome (WES- functional region- constitutes 1% of whole genome) and targeted sequencing of genes led to the identification of these critical mutations that can be fit into individual pathways. These pathways play an important role ranging from transcription function, DNA methylation, cellular differentiation, apoptosis and metabolism. Despite the rapid increase in our understanding of genomic alteration, it is fascinating that the frequency of mutational burden in AML is relatively low with only 1.6 mutation per patient. As few as 1 critical genomic alteration (e.g., RUNX1, DNMT3A) per functional pathway can lead to leukemic transformation.

Certain mutations that occur initially in leukemogenesis are considered as foundation or driver mutations (e.g., DNMT3A, ASXL) that can themselves or through acquisition of additional mutations lead to AML. These founder mutations are often present at a low frequency in normal healthy populations (at increasing frequency with age) without any co-existent CBC abnormalities known as clonal hematopoiesis of indeterminate potential or CHIP. Currently no strategy exists to screen for or treat CHIP as the rate of progression to full blown AML is very low. Initial TCGA analyses showed that these mutations are often in the DNA methylation machinery that leads to DNA instability (through transcriptional repression or activation of oncogenes).

AML is an oligoclonal disease with co-existence of multiple clones that harbor various mutational combinations at the same time. The prognostic interpretation of co-occurring mutations is hard. As more mutations are identified, the permutations and combinations can be become infinity and would be difficult to fit any patient into set category. However, recent attempts tried to compartmentalize the mutations that often co-occur or are mutually exclusive. For example, NPM1 mutations are often associated with mutations in DNMT3A, FLT3, while mutations in DNMT3A often co-occur with FLT3-ITD, IDH1, IDH2 mutations. Bioinformatics aid in identifying the prognostic groups based on mutual exclusivity. As such, mutations in NPM1, FLT3, CEBPA, TP53, and, in patients <60 years, DNMT3A and RUNX1, are the most important molecular risk factors in AML.

Targeting genomic alterations:

Since the initial discovery of BCR-ABL mutation in 1985 in CML, 111 pathogenic genomic alterations were identified in AML. This has provided us with opportunity to find the "holy grail" at genomic level and development of novel therapeutic options. Drugs that inhibit FLT3 (quizartinib, midostaurin, crenolanib and gilteritinib), IDH (Enasidenib- AG120 and ivosidenib -AG220), BCL2 (venetoclax), TP53 (MDM2 inhibitors), MLL (DOT1L- inhibitors) are being actively investigated more than ever. Hypomethylating agents probably act through reversal of dysfunctional methylation machinery. Novel HMAs with additional DNMT inhibitor activity (e.g., guadecitabine) are being investigated in older AML patients.

Failures:

In contrast to acute lymphoblastic leukemia or multiple myeloma where therapeutic targets such as CD19 or CD38 exist, no such targets exist on AML. CD33, a myeloid differentiation antigen that is exclusively present on leukemic blasts although appeared to be a potential target, attempts to target CD33 (gemtuzumab ozogamicin and most recently vadastuximab) have been unsuccessful owing to increased deaths. This led to withdrawal of gemtuzumab from market and premature stoppage of a phase III trial with vadastuximab. Further, due to low mutational burden and limited immune repertoire in AML made immunotherapies a relatively less attractive therapeutic option unlike in several other hard to treat solid cancers.

Recent successes:

Since the FDA approval of Arsenic trioxide (Trisenox) in 2000 for AML, one agent was just approved and another two agents is placed under priority review in April and July of this year. Midostaurin, a novel oral small molecule tyrosine kinase inhibitor of FLT mutation was approved for first line AML in combination with anthracycline based induction and cytarabine consolidation. Enasidenib a first in class oral IDH 2 inhibitor was granted priority review for relapse refractory AML in April of this year based on phase III results of IDHENTIFY trial. Isocitrate dehydrogenase or IDH is a key enzyme in citric acid cycle that gains neomorphic activity due to mutations that leads a differentiation and maturation arrest. IDH mutations that are commonly seen in high grade gliomas are noted to occur in up to 20-30% of AML with normal karyotype. These novel IDH inhibitors appear to remove the differentiation block and thus reconstitute marrow with recovery of counts unlike cytotoxic chemotherapy that usually leads to cytopenias. CPX-351 (Vyxeos), a novel liposomal formulation with daunorubicin and cytarabine in combination has shown higher response rates in older AML patients was placed under fast-track review by FDA just this week.

Improving outcomes further:

Apart from therapeutics, novel genomic diagnostic panels are being developed to rapidly identify and categorize AML patients into risk groups. This will aid in selecting appropriate treatment strategies including allogeneic stem cell transplantation. Minimal residual disease (MRD) testing either using a multi-parametric flow cytometry prior to allogeneic transplantation has taken hot seat similar to other diseases. Although achieving MRD negativity is clearly shown to improve outcomes after allotransplant, it isn't clear how to achieve MRD negativity in a patient who is in complete remission and this work is still in progress.

To answer many of these questions in diagnosis, prognosis and management of AML, Washington University is conducting multiple clinical trials in collaboration with other groups. These are exciting times for AML where rapid developments altering the course of this fatal disease and are pacing towards cure.

Dr. Bhamidipati is an expert in hematological malignancies with specialized experience in bone-marrow transplantation. He published extensively on improving outcomes in CML, AML, particularly in older people. He is known for his ground-breaking research in identifying the protective effect of CMV reactivation on AML relapse and being one of the earliest researchers to demonstrate the feasibility of peripheral blood for haplo-identical transplantation. He laid the ground work for haplo-identical stem cell transplantation at Washington University in St Louis, where he is currently a fellow in Oncology. He is pioneering novel approaches in this relatively new field that extends hope to ethnic minorities who lack matched donors. He is a principal investigator in clinical trials aimed at reducing GVHD in transplantation and Granix trial to reduce the costs of stem cell mobilization. He can be reached at pbhamidipati@wustl.edu



 
 
 
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