Precision medicine is a rapidly growing field of medicine that proposes individually customized diagnostics and therapeutics based upon molecular and genetic profile of individual patients. The main goal of precision medicine is to minimize harmful side effects and maximize benefits. In particular, hematological malignancies were seen as the most direct candidates of the most promising applications of precision medicine. However, Precision medicine approaches face multiple challenges. Despite these challenges and limitations, continuous effort is carried out to use these molecular findings as disease biomarkers and targets for therapeutic intervention. In the last decade the hemato-oncology witnessed a major revolution in the understanding of the molecular pathogenesis of hematological malignancies. While the therapeutic research for hematologic malignancies is continuously expanding, some medicines have been approved in hematological malignancies patients’ therapeutic algorithm and many are still under investigation.
2. OUTLINES
Definition of Precision Medicine.
Introduction on AML.
Therapeutic impact of precision medicine on AML.
Immunotherapy in AML.
Challenges of applying precision medicine in AML.
3. Definitions
1. Precision Medicine:
An approach in medicine that uses interactions between molecules and cells aiming to improve
diagnosis, prognosis, prevention and treatment.
2. Personalized Medicine:
An approach in medicine that uses interactions between molecular and cellular levels as well as
several other related patient-related factors aiming to optimize diagnosis, prognosis, prevention
and treatment for the individual patient at the right time.
3. Evidence-based Medicine:
An approach based on generally accepted published evidences, in recognized peer-reviewed
journals, and consequences in certain patient cohorts without knowing the reasons behind some
patients responding and some not responding to that approach.
4. Molecular Genomics Revolution
During the past few years, the genomic revolution relevant to
hematologic malignancies has improved substantially.
This offers the potential for deeper and more precise insight into the
cause, classification, treatment and response to particular treatments
in a patient.
As a result, precision medicine is rapidly growing and support the
clinician in making the correct diagnosis, in predicting outcomes,
and in optimally selecting patients for interventional therapies.
5.
6. AML
• Acute Myeloid Leukemia (AML) comprises a clonal hemopoietic stem cell neoplastic
disorders where ≥20% blast cells in the blood or bone marrow.
• AML is heterogenous with respect to morphology, immunophenotyping, cytogenetics and
response to treatment.
• Despite attaining CR in 80% of patients, the relapse rates are high. The 5-year survival rate
is 40% in younger patients and <20% in the elderly.
• Major advances in the molecular genetic features of hematologic malignancies have led to a
revolution in the diagnosis and clinical management of AML. Therefore, the WHO revised
4th edition has been released in 2017 in order to incorporate the continuing major advances
in molecular genetics.
7. ● The standard therapy of AML, like the 7+3 regimen, is accompanied by
very severe side effects, mostly related to deep immunosuppression with
serious bacterial and fungal infections.
● In contrast to conventional induction cytoreduction in AML, treatment
approaches are becoming more personalised.
● Much focus has been put on genetic and epigenetic mapping of AML in
each patient.
● Consequently, the information of somatic mutations and specific antigens
expressed on leukemic cells have been included to improve outcomes.
Therapeutic impact of precision medicine
on AML
8. Therapeutic impact of precision medicine
on AML
1. Therapeutic Targeting of mutated proteins
FLT3 (fms-related tyrosine kinase 3)
IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2)
KMT2A and NPM1
TP53
2. Targeting apoptosis
BCL-2 inhibitors
3. Epigenetic targets
4. Targeting Hedgehog pathway
9. ● FLT3 mutations are found in 30% of AML patients.
● They encode for a tyrosine kinase receptor.
● They are either ITDs or mutated TKD. Both lead to activation of the tyrosine kinase
receptor.
● Patients with FLT3 mutations have significantly lower OS.
1) Targeting of mutated proteins
I. fms-like tyrosine Kinase 3 (FLT3)
10. FLT3 inhibitors
• First-generation agents as midostaurin. They are less specific
tyrosine kinase inhibitors (TKIs), as they act on wild and
mutated FLT3 cells (ITD or mutated TKD).
• Second-generation FLT3 inhibitors as giltertinib and
quizartinib. These are more selective and more potent than the
first-generation agents.
11. FLT3 inhibitors
FLT3-TKIs are classified according to the mechanism of action into :
1. Type I (midostaurin, gilteritinib and crenolanib), that target all
FLT3-mutated cells
2. Type II (sorafenib, quizartinib and ponatinib), targeting ITD+ cells
but not TKD+.
12. ● Midostaurin use in combination with standard induction and consolidation
therapy in newly diagnosed AML with FLT3 mutations.
● Giltertinib that has been approved for relapsed/refractory AML with FLT3
mutations.
FDA approved:
13. II. Isocitrate Dehydrogenase (IDH1 and IDH2)
• Both enzymes convert isocitrate to α-ketoglutarate to produce
NADPH.
• Gain of function mutations in IDH1 and IDH2 in AML affect
the enzymes leading to production of 2-OH glutarate (an
oncometabolite) that leads to uncontrolled proliferation of
immature blood cells .
14. ● IDH inhibitors, enasidenib and ivosidenib
prevent the conversion of ᾳ-Ketoglutarate .
● Enasidenib was FDA approved for AML with
IDH2 mutations.
● Ivosidenib was approved for IDH1 mutated
AML.
IDH1 and IDH2
15. ● KMT2A-rearranged AML leads to recruitment of
chromatin complex enzymes including menin
and DOT1L that leads, in turn, to deregulated
expression of HOXA and MEIS genes, leading to
proliferation of MLL-rearranged leukemias.
• DOT1L/menin inhibition induces differentiation
of MLL-rearranged HOXA leukemias.
• DOT1L inhibitors are in clinical trials.
III. A) KMT2A (MLL)
16. ● DOT1L inhibitor pinometostat induced leukemic cells
differentiation but showed only moderate antileukemic activity in
KMT2A-rearranged AML patients.
● Menin inhibitors, such as KO-539 can reduce tumor growth and
increase survival in KMT2A-MLLT3-driven mouse model.
17. ● AMLs with NPM1 mutations lead to deregulated expression
of HOXA and MEIS1 genes.
● Therefore, NPM1-mutated AMLs are also sensitive to
chromatin complex inhibitors including DOT1L and menin
inhibitors.
III. B) NPM1
18. ● TP53 is the most frequently mutated gene in human cancers.
● It is present in 10% of AML patients.
● TP53 mutatins exert an inhibitory effect on P53 leading to loss of
function.
● P53 is the guradian of the genome. It herlps in regulating cell cycle and is
tumor suppressor.
● TP53 mutations have poor response to treatment and resistance to
chemotherapy.
IV. TP53
19. IV. TP53
● Eprenetapopt (APR-246 or PRIMA-1) is one of the recently
developed substances reported to restore normal function of
the mutated P53 protein, thus helping cell cycle arrest and
tumor cell apoptosis.
● It binds to cysteine residues Cys124 and Cys277 in the mutant
P53, restoring its wild functions.
● Adverse effects of eprenetapopt include reversible
neurological adverse events in around 40% of patients,
therefore its use is questionable with intensive chemotherapy.
20. 2) BCL-2 inhibitors
● BCL-2 is overexpressed in hematologic malignancies
and implicated in AML cell survival, chemoresistance,
and is linked to poor OS in AML patients.
● Venetoclax is an oral selective inhibitor of BCL-2
leading to cell apoptosis.
21. ● Venetoclax inhibitory action is directed towards the IDH-mutated
AML cells, correlating with good response. Therefore, its use with
IDH inhibitors is still to be tested.
● Combination of venetoclax with LDAC or HMAs in elderly, newly
diagnosed AML patients showed 76% CR and OS of 17.5 months.
These impressive results led to recent FDA approval of combining
venetoclax with low-intensity chemotherapy in elderly patients unfit of
intensive chemotherapy.
22. 3) Epigenetic targets
● Epigenetic alterations lead to variations in gene expression in the
absence of modifications of the relevant DNA sequence.
● DNA methyltransferase inhibitors (DNMTis), such as azacitidine
and decitabine, have been widely adopted as first-line therapies for
patients who are unfit to receive intensive chemotherapy.
● An orally administered azacitidine derivative (CC-486) has been
shown to alter the natural history of AML by prolonging both RFS and
OS when administered as ‘maintenance therapy’ to patients older than
55 years entering disease remission after induction chemotherapy.
23. 4) Targeting Hedgehog pathway
● The Hedgehog–glioma (HH–GLI) signalling pathway has been
implicated in the maintenance and expansion of leukaemic stem
cells.
● Targeting this pathway in patients with AML has the potential to
suppress the chemoresistant stem cell population, thus delaying
disease relapse.
● Glasdegib is a potent, selective, oral inhibitor of the Hedgehog
signalling pathway in leukemic stem cells.
● Glasdegib was FDA approved in combination with LDAC for the
treatment of patients with newly diagnosed AML patients who are
unfit for intensive chemotherapy.
24. ● Various antigens widely expressed in AML (such as CD33,
CD123, CD70, CD47, CLL1, CD44v6 and TIM3) have been
intensely studied for their usefulness as targets in both antibody-
mediated and cell-based immunotherapeutic approaches.
● Examples:
1. Cusatuzumab, an anti-CD70 antibody.
2. Magrolimab, an anti-CD47 antibody.
3. Gemtuzumab Ozogamicin (GO), a selective anti-CD33
antibody.
5) Immunotherapy in AML
25. Gemtuzumab ozogamycin (GO)
● CD 33 antigen is a transmembrane receptor and myeloid differentiation
marker variably expressed on AML cells in almost all patients.
● GO is a CD33 antibody-toxin conjugate toxic to CD33-expressing
leukemic cells. After binding to the antigen on the surface of leukemic
blasts, the Ab is internalized and binds to DNA leading to cell death.
26.
27.
28. Challenges
1. Numerous disease subtypes
2. Clonal Heterogeneity
3. Clonal evolution and rapid emergence of therapeutic resistance in single-agent
settings
4. Shared expression of epitopes on AML and non-malignant haematopoietic
progenitors implies a risk of serious myelotoxic effects following
immunotherapies
5. Increased myelosuppression and non-haematological toxic effects when precision
medicines are combined with intensive chemotherapy or other AML therapies
6. Limited number of AML patients with specific molecular subsets are available
for research trials in precision medicine.
29. CREDITS: This presentation template was
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