Azienda Ospedaliera S. Maria di TerniAzienda Ospedaliera S. Maria di TerniS.C. Oncoematologia-autotrapianto,

Direttore Prof. A.M. Liberati

Terapia della malattia fludarabina-resistente:ruolo delle mutazioni di TP53

Università degli studi di PerugiaUniversità degli studi di PerugiaFacoltà di Medicina e Chirurgia

Marco Gunnellini

CLL outcome

Doner et Al. N Engl J Med, 2000; 343: 1910-6

Del (17p) patients outcome is worse than others cytogentic abnormalities

Abnormalities N(%) Median TTF Median OS

Del(17p) 7 9 32

Del(11q) 18 13 79

12q Trisomy 16 33 114

Normal 18 92 111

Del(13q) 55 49 133

p<0,001

CLL guidelines

Multidrug-resistent CLL

Grever et Al; J Clin Oncol, 2007; 25:799-804

Prospective clinical studies

Fludarabine

Fludarabine plus Cyclophosphamide

235 pts.

PFSp=0,0006

CLL guidelines

Median PFS = 30,3 mesi3-ys OS = 96%

Role of Steroids

Castro et Al, Leukemia, 2009; 23: 1779-89Castro et Al, Leukemia, 2008; 22: 2048-53

28 chemotherapy-naive pts

ORR= 96% (27/28)CR= 32% (9/28)

MRD negative = 22% (2/9)MRD positive = 78% (7/9)30 mg

3 times weekly

RR = 83%

CLL guidelines

Role of Alemtuzumab

Hillmen et Al, J Clin Oncol, 2007; 25: 5616-23

CAM 307: Alemtuzumab vs Chlorambucil

Role of Alemtuzumab

Cortelezzi et Al; Leukemia, 2009; 1-7

Reduced-dose Alemtuzumab

Relapse in 61,5% of CR

Combination therapy

Pettitt et Al, Leukemia, 2006; 20: 1441–5

CAM-PRED

3 pre-treated pts(3-6, median 3 previous agents)

2 untreated pts

substantial lymphadenopathy p53 abnormalities

ORR= 100%CR= 60% (3/5 pts)

(40% MDR negative)→ 1 relapsed after 1 year

PR= 40% (2/5 pts)(20% nPR)

→ early relapse (4-6 months)

CAM-PRED regimen appears to be a highly effective treatment option for CLL patients with p53 defects

HDMP → regression of bulky lymphadenopathy

Alemtuzumab → eradication from the blood and bone marrow.

Role of Alemtuzumab

Stilgenbauer et Al, J Clin Oncol, 2009; 27: 3994-4001

31 (30%) → del(17p)20 (19%) → del(11q)

Alemtuzumab SC in heavily pre-treated 106 pts

(1-10, median 3 previous agents)

CLL2H Study - GCLLSG

ORR = 34% (only 4% of CR)PFS = 7,7 monthsOS = 19,1 months

del(11q)ORR = 30%

PFS = 9 monthsOS = 22,7 months

del(17p)ORR = 39%

PFS = 5,8 monthsOS = 18,3 months

“Altough Alemtuzumab is efficacious in inducing remissions in fludarabine-refractory CLL, the disease will eventually relapse and progress. Currently the only potentially

curative therapy for fludarabine-refractory CLL is allo-SCT”

CLL guidelines

R-CHOPCFARR-Hyper-CVADOFARAlemtuzumab + Rituximab

Role of Allo-SCT

Schetelig et Al; J Clin Oncol, 2008; 26: 5094-100

43 (98%) → Fludarabine19 (43%) → Alemtuzumab

13 (30%) → Auto-SCT

Median 3 pre-treatment(range 2-7)

ORR = 84%PFS 3ys = 44%OS 3ys = 37%

Early death in 2/44 (5%)

Allogenic SCT in pre-treated 44 del(17p) pts

Graft-versus-leukemia effects may overcome the

negative prognostic impact of 17p deletions in CLL

Novel therapy

Byrd et Al; Blood, 2007; 109: 399-404

Flavopiridol in refractory, high-risk CLL

PR= 40%

PR= 52%

PR= 33%

Hyperacute Tumor Lysis Syndrome

→ 6 pts (14%)

30 mg/m2

+30 mg/m2

40 mg/m2

+40 mg/m2

30 mg/m2

+50 mg/m2

n= 20

n= 3

n= 19

PRtot= 45%PR17p-= 42%

No CR

Median PFS for responders

→ 13 months

Basso Rischio:assenza delle caratteristiche

dell’alto rischio

FLU 30mg/mq/ev+ Cy 250 mg/mq/evgg 1,2,3 (4 cicli)

RC,RP

FLU+Cy (2 cicli)

Alemtuzumab30mg/w (6+6 w)

RP,RC, RC-cy, RC-mol

MS-PM

Watch&Wait Off-Study

MS-PM

Alto Rischio: del17p in >20%,

del11q + IgVH germline o ZAP70+ >10% o CD38+ >7% IgVH germline (o mutated VH3-21) + (almeno 2) ZAP70+

>10%, CD38+ >7%, del6q o tri12.

FLU 30mg/mq/ev+ Campath1H 30 mg ev

gg 1,2,3 (4 cicli)

RC, RC-cy, b-RP

nb-RP, MS, PM

no donor donor RC-mol

W&W

alemtuzumab AutoBEAMMini Allo Fam

Off-Study

No CS Si CS

(Thio/CTX/Flu)

Mobilizzazione CSP

Ara-C(800 mg/mq/12h x 3 gg)+G-CSF

(multicenter, < 60 years, advanced/progressive CLL)

GIMEMA LLC0405

Ongoing Study

Identification

Drugs Phase

State

NCT00022880 Iodine-131 Anti-B1 Antibody I not recruiting

NCT00829647 Dasatinib plus Lenalidomide I/II recruiting

NCT00002838 Allo-SCT I/II not recruiting

NCT00292760 Alemtuzumab plus HDMP II not yet recruiting

NCT00558181 HDMP plus Rituximab II not recruiting

NCT00562328 Alemtuzumab plus Rituximab plus GM-CSF

II recruiting

NCT00343447 RC plus vaccine therapy II not recruiting

NCT00436904 Alemtuzumab plus Rituximab II not recruiting

NCT00525603 CFAR II not recruiting

NCT00513747 Rituximab plus Fludarabine (early vs delayed treatment)

III recruiting

http://www.clinicaltrial.gov

Take-home message

An optimal treatment of del(17p) B-CLL still awaits to be defined

Del(17p) B-CLL results in poor response to fludarabine and rituximab

Alemtuzumab with or without HDMP can partially overcome p53-dependent resistance but duration of responses is short

New agents and more effective regimens are in pre-clinical or early clinical study in del(17p) CLL patients

Allogeneic HCT has the potential to induce long term disease-free survival in patients with 17p– CLL but prospective confirmation is needed

Grazie per l’attenzione

Terapia della malattia fludarabina-resistente:ruolo delle mutazioni di TP53

Marco Gunnellini

Multidrug-resistent CLL

Pettitt et Al, Br J Haematol 1999:;106: 1049-51Sturm et Al, Cell Death Differ 2003; 10: 477-84

In-vitro studies

P= 0.03 P<0.0001

Fludarabineγ-radiation

p53 mutated cases conserve response to steroids,

anthracyclines and vincristine

P= 0.0001

Multidrug-resistent CLL

Byrd et Al, J Clin Oncol 2006; 24: 437-43Valganon et Al, Br J Haematol 2005; 129: 53-9

Retrospective clinical studies

Fludarabine plus Rituximab

88 pts

Fludarabine

Significant correlation between non-response to treatment and the

presence of p53 aberrations (P=0.0065)

54 pts

Multidrug-resistent CLL

Tam et Al; Blood, 2009; 114: 957-64

Retrospective clinical studies

p=0,001

Role of Steroids

Thornton et Al, Ann Hematol, 2003; 82: 759-65

25 pre-treated pts(1-6, median 3 previous

agents)

HDMP can induce regression of bulky

lymphadenopathy in CLL patients with p53 abnormalities

Pts with p53 losses still fared worse than those

with normal p53

Role of Alemtuzumab

Stilgenbauer et Al, Blood, 2004;104: a478

13 (29%) → del(17p)13 (29%) → del(11q)27 (59%) → VH um

Heavily pre-treated(1-7, median 4 previous agents)

Alemtuzumab SC in heavily pre-treated 46 pts

Early stop of treatment for toxicity in 13/46 (28%) pts

del(17p)

del(11q)ORR = 36%

PFS = 9,7 monthsOS = 13,1 months

PD in 9/46 (20%)

Role of Alemtuzumab

Lozanski et Al; Blood , 2004; 103: 3278-81

15 (42%) →p53 mutation or del(17p)

Heavily pre-treated(1-12, median 3 previous agents)

81% → Fludarabine

Cytogenetic screening of allB-CLL patients at diagnosis can

avoid administration of ineffective therapy for this disease

Alemtuzumab in heavily pre-treated 36 pts

ORR →11 (31%)

Role of Alemtuzumab

Osuji et Al; Blood, 2004; a2510

7 (30%) → del(17p)

Heavily pre-treated(1-11, median 4 previous agents)

92% → Fludarabine8% → ASCT

Alemtuzumab in heavily pre-treated 23 pts

Toxicity in 10/23 (43%) pts:4 asymptomatic CMV reactivation

4 cytopenias with infection 1 anorexia

1 death for pulmonary CMV

Novel therapy

Drugs Phase References

OFAR I/II Tsimberidou et Al., J Clin Oncol, 2008; 26:196-203

Lenalidomide II Ferrajoli et Al.; Blood, 2008; 111: 5291-7.

Gossypol Pre-clinic Balakrishnan et A.; Blood, 2008; 112: 1971-80.

ABT-737 Pre-clinic Paoluzzi et Al.; Blood, 2008; 112: 2906-16.

microRNA106b activators

Pre-clinic Sampath et Al.; Blood, 2008; PMID 19096009

CD40L gene-therapy

Pre-clinic Kato et Al.; J Clin Invest, 1998; 101: 1133-41.

Kipps; ASCO EDUCATIONAL BOOK.2009; 2009: 385-93