Transcript 0930 AML research developments – Prof Mary Cahill

HAI Nurses Forum 2016
AML (Research Developments)
Prof Mary Cahill
UCC
AML
Morphology
and function
Concepts AML
• Clonality….its more complex than we thought.
• Genetics- what goes on in the nucleus of the
cell matters and when it alters it can be
bad!..or not so bad.
• Cure….maybe making cells differentiate ( grow
up and behave) is a viable alternative to
eradication.
• Treatment..somethings old and somethings
new
Haematopoiesis and clonality
Concept of clonality and cancer
• Diagnosis emphasises clonality
• The ability to characterise large amounts of
DNA has led to a redefinition of this concept
Clonal –founding clone and sub-clones
Clonal Haematopoiesis of
indeterminate potential (CHIP)
• So we all know Chips are bad for you….
• Or are they?
• Clonal haematopoiesis up to 10% of healthy
individuals age >65 years
Significance of CHIPs
Epigenetics
Eight Functional Categories of Genes That Are
Commonly Mutated in Acute Myeloid
Leukaemia.
Abbreviations…we love them
• IMHO
• ??
What happens in the nucleus maters
• NPM1 nucleophosphmin 1
• ASXL1
Additional sex combs like transcriptional
regulator 1
• DNMT3A DNA methyltransferase 3 alpha
• RUNX1 Runt-related transcription factor 1
• TET2 Tet-methylcytosine dioxygenase 2
• FLT3
FMS*-related tyrosine kinase 3
• FLT3 ITD…internal tandem duplications
• HDACi
Histone deacetylase inhibitor
• SF3B1 splicing factor 3B subunit 1
• BRD4 Bromodomain containing protein 4
ASXL1
Photo from Wikipedia
Practical issues
• We don’t need to see the clones and
characterise them to provide a working
diagnosis
• Additional diagnostics…
Current eradication of disease
model
Minimal Residual Disease (MRD)
1 x 1012
Number of leukaemia Cells
At diagnosis
CR 2 log reduction
1x1010
CR (immunofixation negative)
Nonquantitative PCR of bone marrow
1 x 108
1 x 106
1 x 104
MRD+
Quantitative PCR of bone marrow
High-quality flow cytometry of bone marrow
Deep sequencing of bone marrow
MRD0
Cure
Adapted from Mailankody S, et al. Nat Rev Clin Oncol. 2015. [Epub ahead of print]
Early phase clinical trials
• Advantages
• Offer options when all available
lines of therapy have been tried
• Offer patients with poor
prognosis hope
• Early access to new therapy with
ability to become familiar before
licensing – advantages future
patients in that centre
• Exposure to protocol driven
excellence and attention to detail
which ‘rubs off’ on other work in
the unit
• Enhances the experience and
standing of the early phase trial
centre
• Disadvantages
• Possible unknown hazards and
risks
• Cost saving on drugs for
institution but increased spend
on laboratory and radiology
• Time consuming for PI and
ancillary staff
• May sometimes offer false hope
to patients
Blood Cancer Research Network
Ireland
• Clinical trials
• Biobanking
• Enhanced registration of blood cancer by NCRI
What happens in the nucleus maters
• NPM1 nucleophosphmin 1
• ASXL1
Additional sex combs like transcriptional
regulator 1
• DNMT3A DNA methyltransferase 3 alpha
• RUNX1 Runt-related transcription factor 1
• TET2 Tet-methylcytosine dioxygenase 2
• FLT3
FMS*-related tyrosine kinase 3
• FLT3 ITD…internal tandem duplications
• HDACi
Histone deacetylase inhibitor
• SF3B1 splicing factor 3B subunit 1
• BRD4 Bromodomain containing protein 4
• In AML, RATIFY trial of the tyrosine kinase
inhibitor midostaurin combined with standard
chemotherapy in the initial treatment of patients
with FLT3-mutated AML.
• New, potentially more-potent FLT3 inhibitors such
as quizartinib and gilteritinib are being
investigated in clinical trials and may provide
even better outcomes.
Home grown research UCC
• Autophagy and differentiation ( in
collaboration with Weill Cornell)
• Delivering small clever drugs right into the
nucleus
BRD4
• BRD 4 is mutated or upregulated in AML
• BRD4 inhibitors are in use in 5 early phase
trials – JQ1
• ‘Knockdown’ of BRD4 is possible
Short Interfering RNA (siRNA) –
-a New Class of Drugs
1)
siRNA targeted to a specific gene.
2)
siRNA unwinds and is incorporated into
RISC, a stable protein-RNA pathway.
3)
siRNA directed to targeted mRNA.
4)
mRNA undergoes degradation interrupting
the protein synthesis of the target gene.
siRNA
Anti CD123
attached
here
Cyclodextrin cyclovector
Patented by Prof Caitriona O Driscoll –School of
Pharmacy
AUTOPHAGY
Next-Generation
gene Sequencing
Pre-ATRA
(Vitamin A)
Post-ATRA
Autophagy can be manipulated to
promote differentiation
• Use of ATRA in non-APML leukaemia
• Use of HDACi – sodium valproate as
synergistic
Combinations of older and novel
agents
• Demethylating Agents
• Advances in treatment for the elderly
population include demethylating agents decitabine and azacitidine,
• may prove effective in combination with
molecularly targeted agents such as
venetoclax and pracinostat as well as
antibody-based drugs.
Venetoclax + Low-Dose Cytarabine in
Untreated AML: Efficacy
• Majority of pts had blast count reduction
– > 50% decrease in bone marrow: 79%
– > 50% decrease in peripheral blast count: 88%
Response, %
Ven 600 mg
(n = 16)
Ven 800 mg
(n = 10)
All Pts
(N = 26)
ORR (CR + CRi + PR)
 CR
 CRi
 PR
75
31
38
6
30
10
20
0
58
23
31
4
Resistant/progressive disease
19
60
35
•Bone
ORR
highlyblast
correlated
marrow
count <with
5% OS: median
81OS ~ 4 mos among
80 nonresponders
81 (n
= 11) vs not reached among responders
(n = 15)
Lin TL, et al. ASCO 2016. Abstract 7007.
Slide credit: clinicaloptions.com
Venetoclax + Low-Dose Cytarabine in
Untreated AML: Other Outcomes
• Recommended phase II dose: 600 mg, based on
dose-limiting toxicity of thrombocytopenia
• Coadministration with low-dose cytarabine
shows no apparent effect on venetoclax
exposure
• P12-mo OS: 57.6%
– Non-MPN pts: 70.5%
Lin TL, et al. ASCO 2016. Abstract 7007.
Slide credit: clinicaloptions.com
Venetoclax + Low-Dose Cytarabine in
Untreated AML: Conclusions
• Coadministration of venetoclax 600 mg + lowdose cytarabine is active and well tolerated
according to investigators
– Majority of pts had significant reduction in blast
counts
– CR/CRi 54% overall; 64% if no history of MPN
• Investigators suggest venetoclax + low-dose
cytarabine combination promising option for
older, treatment-naive AML pts
Lin TL, et al. ASCO 2016. Abstract 7007.
Slide credit: clinicaloptions.com
CAR T cells?
•
•
•
•
•
20 years in development and still not ‘there’
Three generations of development
Use in Leukaemia, Myeloma, other cancers
A bespoke therapy for each patient
Cost and availabilty
• Immunotherapy, cellular therapy and
gene therapy all in one