LEUCEMIA MIELOIDE ACUTA

REPORT  del  Gruppo  di  Lavoro  

Giorgina  Specchia    

§  Rilevanza prognostica del profilo genetico integrato……..

ü  The  proto-­‐oncogene  EVI1  (ecotropic  viral  integra;on  site-­‐1),  located  on  chromosome  band  3q26,  is  aberrantly  expressed  in  human  acute  myeloid  leukemia  (AML)  with  3q26  rearrangements.    

ü  Aberrant  expression  of  EVI1  occurs  in    8%-­‐10%  of  human  adult  AML  pa;ents  and  is  associated  with  a  poor  outcome.  

ü  High  expression  of  EVI1  was  also  found  in  leukemias  with  chromosomal  abnormali;es,  other  than  the  ones  affec;ng  the  EVI1  locus.  

Aim:  to  inves;gate  the  frequency  and  the  prevalence  of  EVI1  overexpression  in  a  large  cohort  of  MLLrearranged  human  AMLs.  

GIMEMA  ………   GIMEMA  ,Pia.aforme  macroregionali  ?RETI  …    

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

3  RCT  

ALFA  0701  

NCRI    AML  16  

E/G  AML  17  

AddiEon  of  gemtuzumab  (GO)  

Treatment  Schedules  

MICE    Mito  7  mg/m2  d1,3,5;  Ara-­‐C  100  mg/m2  d1-­‐7;  Eto  100  mg/m2  d1-­‐3  

GO  inducEon    6  mg/m2  d  1,  15  

GO  consolid    3  mg/m2  d  0  

ICE    Ida  8  mg/m2  d1,3,5;  Ara-­‐C  100  mg/m2  d1-­‐5;  Eto  100  mg/m2  d1-­‐3  

GOx2   MICE   CR/CRp   GO+          ICEx2  

MICE   CR/CRp   ICEx2  R  

Amadori et al, EHA 2012

EORTC/GIMEMA  AML-­‐17  study  

No  GO   GO   No  GO   GO  CR+CRp  (%)   47,4   52,3   52,4   32,5  No  resp  (%)   40,8   29,4   29,8   31,3  Ind  death  (%)   9,9   11,8   15,5   26,5  Inev/unkn  (%)   2   6,6   2,4   9,6  

0  

10  

20  

30  

40  

50  

60  

PaEe

nts  %

 

Age  61-­‐69   Age  70-­‐75  

P=0.01  

Induction results by age

(years)0 1 2 3 4 5 6

0102030405060708090

100

O N Number of patients at risk : Treatment 204 236 102 61 42 30 13210 236 78 41 32 27 17

No GOGO

Logrank test: p=0.07

(years)0 1 2 3 4 5 6

0102030405060708090

100

O N Number of patients at risk : Treatment 76 84 35 21 15 9 277 83 16 5 5 4 2

No GOGO

Logrank test: p=0.002

(years)0 1 2 3 4 5 6

0102030405060708090

100

O N Number of patients at risk : Treatment 33 34 12 4 1 1 036 44 21 14 10 8 7

No GOGO

Logrank test: p=0.02

OS  (all  pts)   OS  (age  70-­‐75y)  

OS    

sAML  61-­‐69y  

Survival

•  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

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.

Trials  ongoing…………………………  

Purine  analogues  

FLUDARABINE…………    CLADRIBINE………..    CLOFARABINE…………  

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).

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  

Poor  risk:  Novel  agents  to  watch…  

CPX-­‐351  

CR/CRi  67%  

ED  3%  

LaromusEne  

CR/CRp  32%  

ED  14%  

Clofarabine  

CR/CRp  46%  

ED  10%  

Decitabine  

CR/CRi  64%  

ED  2%  

HD-­‐LEN  

CR/CRi  30%  

ED  24%  

Myelosuppressive  regimens  

Responses  in  all  poor  risk  groups  

Randomized  trials  (vs  3+7)      

Azacitidine and Decitabine:

significant benefit in HR-MDS (and pts

with 20-30% marrow blasts), compared

with conventional care including LDAC.

Hypomethylating Agents

•  Intensive  Rx  (even  at  high  age)  •  Define  op;mal  therapy,  consider  RIC-­‐SCT  

Fit  (Low  Risk)    

TreaEng  elderly  AML  in  2012  

•  Inves;ga;onal  Rx  •  Consider  RIC-­‐SCT  

Fit  (Poor  Risk)    

•  Less  intensive  Rx  (LDAC)  •  Suppor;ve  care  (HU)  Unfit/Frail    

Novel  Agents  which  may  have  role  in  treaEng  AML  

•  Hedgehog  inhibitors.  

•  PARP  inhibitors.  

•  Aminopep;dase  inhibitors:  Tosedostat  

•  Rigoser;b:  ON  01910  

•  HDM2  inhibitors  

•  .........................