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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.