A.M. Carella U.O.C. Ematologia
IRCCS AOU San Martino – IST, Genova
LEUCEMIA MIELOIDE ACUTA
Impact of mutational analysis in AML
C. Thiede
Optimal acute myeloid leukemia therapy in
2012
H. Dombret
• Acquired mutations and epigenetic
alterations accumulate in progressive way.
• Subclones of cells acquire new properties,
giving cells advantages such as the ability
to resist chemotherapy.
ü MDS clones contain hundreds of
acquired mutations.
ü Leukemias arose from at least one
subclone that had gained new mutations.
ü Sequential development of leukemia.
Walter et al. NEJM 2012; 366:1979
Do they have prognostic value?
Poor Survival:
FLT3+ or MLL and in those with point mutations
of ASXL1 or PHF6.
Favorable Survival:
CEBPA or IDH2 mutations; NPM1 mutations
with concurrent IDH1 or IDH2 mutations.
In a recent comprehensive analysis of
mutations in a cohort of almost 400 pts with
AML treated in the ECOG, reported for the first
time a simultaneous mutational analysis of 18
genes, covering most abnormalities currently
discussed as relevant for AML prognosis.
(Patel et al., NEJM 2012)
ü These data indicate:
a. more detailed genetic analysis may lead to improved risk stratification and identification of patients who can benefit from more intensive induction chemotherapy.
b. the challenge is to provide genetic information in a timely and affordable way and show that this information could prospectively influence treatment decisions.
AML Therapy in 2012 Younger AML
ELN Guidelines 2010 - Induction 18-60 years
ü Standard - 7 + 3
- AraC 100-200 + Dauno 60+, Ida 10-12, Mtx 10-12
- HiDAC too toxic - Phase 3 studies: SWOG 2 g x12, ALSG 3 g x 8 - Phase 2 studies: ECOG 3 g x 6, SWOG 7+3 fw by 2 g x 6 (7+3+3)
ü Promising options
- CSF priming - G-CSF: HOVON-SAKK study - GM-CSF: ALFA study
- Gemtuzumab ozogamicin (GO) - British AML15 study
Inhibition of constitutively activated FLT3,
lestaurtinib in relapsed AML and sorafenib
in newly diagnosed older AML, have failed
to demonstrated significant benefit when
combined to intensive chemotherapy.
Lestaurtinib / Sorafenib
• Phase III randomized study of midostaurin restricted to FLT3 mutated pts younger than 60 yrs is ongoing.
• Phase II study of quizartinib or AC220, the most selective FLT3 inhibitor available, in relapsed AML have confirmed that clonal responses could be observed with monotherapy.
Midostaurin /Quizartinib
• KIT mutation, associated with unfavorable prognosis in CBF-AML, may be targeted with dasatinib.
• A frontline study of dasatinib combined to intensive chemotherapy is ongoing by the AMLSG.
• No responses were observed with dasatinib alone in the French DASA-CBF study.
Dasatinib
Plerixafor, a CXCR4 antagonist blocking the
CXCR4/SDF-1 interaction has been
developed as an agent capable to mobilize
hematopoietic progenitors from the
hematopoietic niche to the peripheral blood.
Evaluating its safety and potential when used
alone or combined with G-CSF as a chemo-
sensitizing agent in AML pts are ongoing.
ALLOGRAFTING
ü Intent to treat donor versus no-donor comparisons is not well suited to evaluate the real effect of HSCT in very high-risk pts.
ü Transplant versus no-transplant comparison should be preferred (as a significant proportion of these pts will never be transplanted in 1st CR despite an identified donor).
ü The value of allogeneic HSCT needs to be reassessed based on:
- the identification of AML genetic heterogeneity. - the availability of different transplant sources and donor types. - The use of reduced-intensity conditioning (RIC).
It is important to consider TRM that may vary between less than 15% and up to 50%. It is essential to assess whether the benefit of the reduced relapse rate outweighs TRM or will be offset by a high TRM.
AML Therapy in 2012 Older AML
• Older age per se, however, should not be a reason to withhold intensive therapy.
• Remission induction chemotherapy provides better quality of life and longer survival than supportive care only.
• Intensive chemotherapy should thus remain the standard in pts capable to tolerate it.
• The 3+7 remains the most frequently used chemotherapy induction regimen.
Standard therapy in older AML pts
Azacitidine and Decitabine:
significant benefit in HR-MDS (and pts
with 20-30% marrow blasts), compared
with conventional care including LDAC.
Hypomethylating Agents
Azacitidine has also shown interesting
results in retrospective AML studies.
Azaci&dine followed by lenalidomide in pa&ents with higher-‐risk MDS or AML; ongoing AZALE study: results
• Median 2 cycles (range 1–6) administered within all dose cohorts
• To date, 20 pa=ents enrolled: – cohort 1 and 2: 4 pa=ents each – cohort 3 and 4: 6 pa=ents each
Platzbecker U, et al. Poster presentation at ASH 2011. Abstract 3799
Patients
Safety • MTD of lenalidomide: 20mg • Therapy-induced grade 3/4 neutropenia or
thrombocytopenia, n (%): 12 (60) • DLTs, n:
• infectious complications: 2 • thrombosis: 1 • incomplete haematological recovery: 1
Response (n=19)
CR PR 0
2
Pat
ient
s, n
Overall = 7 (37%)
3 4
CR CRi HI 0
1
2
3
Pat
ient
s, n
Overall = 6 (32%)
PR
Cytogenetic response (n=19)
4
Sequential azacitidine and lenalidomide is feasible and appears effective in patients with higher-risk MDS/AML and del(5q)
• ORR in previously untreated patients: 5/9 (56%) • Response in patients with p53 mutations: 5/7 (71%)
• 13 (68%) patients had SD
Ulz Krug et al., Blood. 2010;[ASH 2010 Abstract 2180]
Addic&on of AZA to standard induc&on therapy in older pa&ents with AML
Pollyea , et al. abstract 3288 ASH 2010
Novel Agents which may have role in trea&ng elderly AML
• Hedgehog inhibitors.
• PARP inhibitors.
• Aminopep=dase inhibitors: Tosedostat
• Rigoser=b: ON 01910
• HDM2 inhibitors
ü In 2012, the ELN guidelines published in 2010 by an international expert panel remain valid.
ü Addition of GO might become a new standard, at least in some patient subsets.
ü Most recent and current investigations concern: • conventional drug dose intensification • new agent incorporation • allograft stratification on patient-, AML- and stem cell
source-related factors.
CONCLUSIONS
It is exciting to think that the goal of personalized medicine is quickly approaching, but it will require careful thought to implement genomic-based clinical evaluation in a way that is meaninful for patients.
Lucy A. Godley. Profiles in Leukemia. NEJM 2012:366;1152
§ Rilevanza prognostica del profilo genetico integrato.
§ Associazione di target therapy e chemioterapia nei pazienti FLT3 mutati.
§ Trapianto autologo: nuovi protocolli ad alte dosi.