Novel Therapies vs. AML and Impact on AlloHCT: My Money is...
Transcript of Novel Therapies vs. AML and Impact on AlloHCT: My Money is...
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Novel Therapies vs. AML and Impact on AlloHCT: My Money is on AML & AlloHCT
ISTANBUL APRIL 2017
Christopher Bredeson MD MSc FRCPC
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▶ Very brief examples existing targeted therapies
▶ Why even if beneficial unlikely to solve AML
▶ Caveats RE MRD
▶ How to move forward?
TOPICS
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AML IS NOT ONE DISEASE
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DAVID VERSUS MEDUSA!
Circos Diagram: Gene Mutations in
Newly Diagnosed AML in ECOG E1900 trial
Vs.
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▶ FMS-like tyrosine kinase 3 (FLT3) mutation
▶ Recpetor tyrosine kinase family
▶ 1/3 of AML mutated flt3
▶ Mediate growth and differentiation via several pathways
▶ Flt3 ITD important RE relapse: mutation load important
▶ Flt3 TDK: not clear if important
▶ First inhibitors (sorafenib, midostaurin, lestauratinib)
• Not very specific (also target JAK2, PDGFR, VEGFR, KIT)
• Sorafenib: Not very useful beyond getting some patients to transplant
- Only one available off study
• Midostaurin: prolonged survival in age <60 with chemo
FLT3 INHIBITORS?
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▶ Quizartinib
▶ More selective, still some KIT targets (side effects, benefit?)
▶ 40 to 50% CR in rel/ref AML
▶ Resistance via TDK mutations
▶ In phase 3
▶ Crenolanib, Gileritinib
▶ ITD and TDK inhibition
▶ 40% CR/Cri in rel/ref AML with flt3 prior flt3 inhibitor patients
▶ They seem to work in flt3 wild type as well: what is the mechanism of action?
▶ May have a role in getting patients to alloHCT
NEWER FLT3 INHIBITORS
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▶ AlloHCT still standard of care for flt3 AML
▶ Sorafinib
• Promising retrospective studies
• Promising phase 1 data post alloHCT
- Started 1.5 to 4 months post alloHCT
▶ Phase 2 trials open
BMTCTN 1506 (Gilteritinib)
▶ Phase 3 vs. placebo x 2 years
▶ flt3 mutated AML
▶ Primary outcome LFS
▶ MRD lab validation, MRD and outcomes
FLT3 INHIBITORS AFTER ALLO HCT
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▶ Enthusiasm not in keeping with data: believers believe
▶ Some efficacy in MDS and AML; reasonably well tolerated as primary therapy
▶ Post alloHCT relapse +/- DLI (retro data)
• Usual results: some responses, better if MRD, long time since relapse, CR preAlloHCT
▶ Prophylactic Maintenance / Consolidation
• Buy time for immune reconstitution
• Early studies: can‟t give early enough, too toxic, high drop out
- Still Ph3 accruing!
▶ “Pre-emptive”
• Based on MRD
• Data is poor as are results
HYPOMETHYLATING AGENTS (AZACITIDINE > 5AZA)
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▶ Some Lessons from Cytogenetic and Molecular Biology that highlight the
challenge of the magic bullet for AML
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• Molecular Definition of Disease Entities
• Tumour Heterogeneity and Clonal Evolution
• Clonal Hematopoiesis of Indeterminate
Potential (CHIP)/ Preleukemia
MOLECULAR PROFILING AND AML
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Blood 2015; 125:1367-1376
▶ Target mutational NGS (89 genes) analysis
• 194 rigorously-defined
• sAML (prior MDS; 93)
• tAML (101 [18 prior tMDS])
• 105 de novo AML patients
• (81 sites, 22 countries)
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• 3 traditional clinical AML ontogeny groups (sAML, tAML, de novo
AML) are defined by the ability to identify an antecedent MDS
(sAML) or leukemogenic exposure (tAML), or the absence of both
(de novo AML)
• Inexact, and depends on availability of prior clinical data rather that
objective criteria at time of diagnosis
• Characterized molecularly a carefully-defined sAML group, then
applied those molecular data to tAML group, and finally to de novo
AML group
CLINICAL CATEGORIZATION OF AML
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MOLECULAR VS CLINICAL DEFINITION OF AML DISEASE ENTITIES
4 distinct groups
sAML (post MDS)
* *
*>95% specificity for sAML
Lindsley, R.C et al. Blood 2015; 125:1367-1376
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▶ 3 genetic ontogenic groups
• Secondary-type mutations (similar to MDS)
• De novo-type or pan AML mutations
• TP53 mutations
• The 3 groups have distinct clinical and biological features
• We will come back to how this highlights the problem with our
targeted therapies
RECLASSIFIED BASED ON MOLECULAR FINGERPRINT
Lindsley, R.C et al. Blood 2015; 125:1367-1376
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TAML ALSO HAS DISTINCT GENETIC GROUPINGS
N=105
tAML patients
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▶ de novo AML (n=105) ▶
contained sAML, TP53, de novo, and pan-
AML type patients, each with distinct
characteristics
MOLECULAR DEFINITION OF DISEASE ENTITIES
Lindsley, R.C et al. Blood 2015; 125:1367-1376
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DE NOVO AML ALSO
Lindsley, R.C et al. Blood 2015; 125:1367-1376
Genetically-defined sAML, TP53, and de novo/pan-AML type ‘de novo’
AMLs differ in number of driver mutations, number of cytogenetic
abnormalities, and in age
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GENETICALLY DEFINED GROUPS HAVE DIFFERENT CLINICAL OUTCOMES
Lindsley, R.C et al. Blood 2015; 125:1367-1376
Patient stratification by ‘genetic ontogeny’ is much more predictive
than is stratification by ‘clinical ontogeny’
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▶ With disease progression
• 59% new driver mutation
• All new genetic lesions were pan-AML
- Late lesions e.g. RUNX1, flt3
• Secondary type mutations + TET2, DNMT3A persist
in CR, while driver ones (flt3, CEPBA, RUNX1) clear
- Targeted therapies hitting late events
• Similar to driver mutations found in healthy older
people
IT GETS WORSE
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Welch, J.S. Seminars in Hematology 2014; 51: 273–281
MULTISTEP DEVELOPMENT OF AML
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JCO 2013 31:3898-905
We don‟t all have gene panels: cytogenetics is a good start
AML DIAGNOSTICS
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Subclones found,
• 418/2639 (15.8%) overall
• 418/1274 (32.8%) with aberrant karyotype
• Found in all cytogenetic risk groups, but
especially in high risk (51.2%)
• Development of subclones is an adverse
prognostic marker
• AlloHCT improved the prognosis of these
patients
Bochtler, T. et al., JCO 2013 31:3898-905
TUMOR HETEROGENEITY AND CLONAL EVOLUTION
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Nature 2012, 481: 506-510
WHAT ABOUT RELAPSE
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• The leukemia „founding clone‟ can acquire additional
cooperating mutations over time that can contribute to
disease progression and relapse, with increasing clonal
complexity
• Mutations can be lost or gained at relapse, consistent
with the existence of multiple subclones
• Relapse can arise from the predominant clone at
diagnosis, from a pre-existing subclone, or from a
preleukemic stem cell
AML IS GENETICALLY UNSTABLE
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Welch, J.S. Seminars in Hematology, Vol 51, No 4, October 2014, pp 273–281
MUTATIONS COME AND GO IN CLONES
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Where do these early preleukemic mutations come from?
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Where do these early initiating mutations come from?
…Arise in normal HSCs with aging
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Nature Med 2014; 20:1472
N Engl J Med 2014; 371: 2477
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N Engl J Med 2014;371:2488-98.
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WITH AGE COMES INITIATING LESIONS
Genovese, G. et. al., N Engl J Med 2014; 371: 2477
Whole exome sequencing of
12,380 Swedes in national
registry, unselected
for blood or cancer
phenotypes ‘Hematopoietic’ mutations
detected; ease of detection
(allelic fraction) indicated
clonal advantage of mutated
cells - ‘clonal hematopoiesis’
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Genovese, G. et. al., N Engl J Med 2014; 371: 2477
• Clonal hematopoiesis with somatic mutations observed in 10% >
65 years, but in only 1% of those <50 years
• Clonal hematopoiesis was a strong risk factor for subsequent
hematologic cancer (1% incidence per year)
CLONAL HEMATOPOIESIS OF UNDETERMINED POTENTIAL (CHIP)
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Steensma, DP., et al. Blood (2015) 126:9-16
COULD WE THINK ABOUT CHIP LIKE MGUS?
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Affiliated with • Affilié à Welch, J.S., et al., Cell 2012; 150: 264-278
Welch, J.S. Seminars in Hematology 2014; 51: 273–281
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▶ AML cells apoptose ex vivo
▶ Relapse is from MRD in BM niches
▶ Various factors support and protect
the leukemic “stem” cell
• Induce chemo resistance
• Prevent apoptosis
▶ Target LSC? (the seed)
• CD123
▶ Target the BMSC / microenvironment? (the soil)
• Various ideas
YOUR NEIGHBOURHOOD MATTERS
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POTENTIAL TARGETS
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▶ MRD = minimal or measurable residual disease
▶ What tissue? How big is the sample? How much disease is present?
▶ How sensitive and specific is the “MRD test”
▶ Are you measuring the right population (subclones, late clones etc)
▶ Is MRD validated as a biomarker of the clinical outcomes of interest?
▶ It is always better to be negative than positive
▶ Some MRD NEG relapse; some MRD POS don‟t!
• Mutation does not equal malignancy (clonal hematopoiesis in elderly, t(14:18) in normal people
▶ Almost no data that intervening changes things
• Need MRD POS RCT to observation vs. intervention
MRD CAVEATS: THE EMPEROR MAY OR MAY NOT HAVE CLOTHES
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▶ Targeted therapy in AML so far is overly optimistic
• Limited role in alloHCT for AML
▶ Novel genetic and molecular investigations (mutation analysis)
• Define AML subgoups better than clinicians and traditional methods
• Help explain the development of AML as a multistep process
• Demonstrate why targeted therapy is a challenge in AML
▶ The microenvironment
• Facilitates development and sustenance of AML
• Needs to be targeted
▶ MRD in AML can‟t do what it is asked to do (yet)
▶ Well designed RCT evaluating promising agents required
• (e.g. BMCTN 1
SUMMARY
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