P. Montesinos Disclosures

4949thth ASH Annual Meeting–Atlanta, Georgia ASH Annual Meeting–Atlanta, Georgia

Research Support/P.I. No conflict of interest to disclose

Employee No conflict of interest to disclose

Consultant No conflict of interest to disclose

Major Stockholder No conflict of interest to disclose

Speakers Bureau No conflict of interest to disclose

Honoraria No conflict of interest to disclose

Scientific Advisory Board No conflict of interest to disclose

2007 ASH Meeting, Atlanta, GO

Central Nervous System Relapse in Patients with Acute

Promyelocytic Leukemia Treated with All-trans Retinoic Acid and

Reinforced Anthracycline Monochemotherapy

P Montesinos, J.D Gonzalez, E Vellenga, C Rayon, R P Montesinos, J.D Gonzalez, E Vellenga, C Rayon, R Parody, A Leon, J Esteve, J Bergua, G Milone and MA Parody, A Leon, J Esteve, J Bergua, G Milone and MA Sanz on behalf of the PETHEMA, HOVON and GATLA Sanz on behalf of the PETHEMA, HOVON and GATLA

Groups

Background

• CNS relapse can complicate the course of APL in first CR.

• Incidence of CNS relapse is still not well established (from 0.6% to 5%1,2).

• WBC count (>10 x 109/L) is the only well established independent risk factor for CNS relapse1.

• Other factors with less or no evidence: age <45 year1, BCR31,2,3, RA syndrome4, adhesion molecules (CD11b, CD56).

1. de Botton S, Leukemia 2006; 20: 35-41 2. Liso V, Cancer 1998, 83: 1522-28; 3. Specchia G, JCO 2001, 19: 4023-28; 4. Ko BS, Leukemia 1999, 13: 1406-8

Background

• ATRA and anthracyclines do not cross the cerebrospinal barrier use of intrathecal prophylaxis or high-dose cytarabine.

• The advantage of CNS prophylaxis in APL patients is still controversial.

Study Aims

1. Analyze the incidence and characteristics of CNS involvement at first relapse in APL patients treated with risk-adapted consolidation, without CNS prophylaxis (PETHEMA LPA99 trial).

2. Compare LPA99 and LPA96 trials, with or without risk-adapted consolidation including ATRA.

3. Identify risk-factors for CNS relapse in APL.

CONSOLIDATION

PETHEMA LPA99 Trials

addition of ATRA 45 mg/m2/d for intermediate- and high-risk patients

INDUCTION

AIDA

low risk

MTZ 10 mg/m²/d × 5

IDA 5 mg/m²/d × 4

IDA 12 mg/m²/d × 1

#1#2

#3

MAINTENANCE

intermediate and high risk

MTZ 10 mg/m²/d × 5 + ATRA × 15

IDA 7 mg/m²/d × 4 + ATRA × 15

IDA 12 mg/m²/d × 2 + ATRA × 15

#1#2

#3

2 yearATRA + MP + MTX

(Risk-adapted)

Patient Characteristics

PETHEMA LPA 96

PETHEMA LPA99

No. of patients 172 560

Age, median (range) 39 (2-78) 40 (2-83)

WBC, median (range) 2.0 (0.3-210) 2.2 (0.2-460)

Patients achieving CR 156 (91%) 510 (91%)

Follow up (months) median range

11396 – 133

6328 – 98

Results updated on Nov. 30, 2007.

Diagnosis of CNS Relapse

• Neurological signs and symptoms (clinical or radiological).

• Positive lumbar puncture (compatible cytology + genetic diagnosis).

• Positive biopsy of CNS granulocytic sarcoma.

End-points and Statistical Methods

• Cumulative incidence (CI) of CNS involvement at first relapse.

• Risk competing events:

• Isolated bone marrow molecular relapse.

• Isolated bone marrow clinical relapse.

• Death in CR.

• Secondary MDS/AML.

11%11%

12 24 36 48 60 72 84

0

0,01

0,02

0,03

0,04

0,05

0,06

0,07

0,08

0,09

0,1

0 12 24 36 48 60 72 84 96 108 120 132 144

Months after CR

Pro

bab

ility

0

0,01

0,02

0,03

0,04

0,05

0,06

0,07

0,08

0,09

0,1

0 12 24 36 48 60 72 84 96 108 120 132 144

Months after CR

Pro

bab

ility

1. 6%1. 6%

CI of CNS Relapse: LPA96 and LPA99 TrialsCI of CNS Relapse: LPA96 and LPA99 Trials

n = 10 / 666

Relative Frequency of CNS Relapses

LPA99 (n=5/53)

30%61%

9%

LPA96 (n=5/28)

39%

43%

18%

Molecular relapse/persistence

Clinical bone marrow relapseCNS relapse

Characteristics and Outcome of CNS Relapses: LPA96 Trial

Sex/Age

WBC (x109/L)

Relapse risk BCR DS

Time to CNS relapse (months)

Bone marrow relapse

Survival from CNS relapse (months)

F/6 13.6 High 3 No 49 No 54+

M/33 67.9 High 1 No 16 No 14

F/43 162 High 3 No 7 Yes 5

F/57 7.7 Interm. 1 No 32 Yes 2

M/16 26.7 High 3 No 6 Yes 0.5

Characteristics and Outcome of CNS Relapses: LPA99 Trial

Sex/Age

WBC (x109/L)

Relapse risk BCR DS

Time to CNS relapse (months)

Bone marrow relapse

Survival from CNS relapse (months)

M/32 6.2 Interm. 3 No 10 No 47+

F/22 66.5 High 3 No 29 No 45+

M/29 34.5 High 3 No 13 No 42+

F/50 1.9 Interm. 3 No 41 No 13

F/70 68.8 High 1 No 14 No 3

11%11%

12 24 36 48 60 72 84

0

0,01

0,02

0,03

0,04

0,05

0,06

0,07

0,08

0,09

0,1

0 12 24 36 48 60 72 84 96 108 120 132 144

Months after CR

Pro

bab

ility

0

0,01

0,02

0,03

0,04

0,05

0,06

0,07

0,08

0,09

0,1

0 12 24 36 48 60 72 84 96 108 120 132 144

Months after CR

Pro

bab

ility

3.2%3.2%

1.0%1.0%

P = 0.07P = 0.07

CI of CNS Relapse: LPA96 Trial vs LPA99 TrialCI of CNS Relapse: LPA96 Trial vs LPA99 Trial

LPA99 (n = 5 / 510) LPA96 (n = 5 / 156)

11%11%

12 24 36 48 60 72 84

0

0,01

0,02

0,03

0,04

0,05

0,06

0,07

0,08

0,09

0,1

0 12 24 36 48 60 72 84 96 108 120 132 144

Months after CR

Pro

bab

ility

0

0,01

0,02

0,03

0,04

0,05

0,06

0,07

0,08

0,09

0,1

0 12 24 36 48 60 72 84 96 108 120 132 144

Months after CR

Pro

bab

ility

4.9%4.9%

0.8%0.8%

P = 0.004P = 0.004

Intermediate (n = 3 / 380) Low (n = 0 / 136)

CI of CNS Relapse According to Risk GroupCI of CNS Relapse According to Risk Group

High (n = 7 / 149)

0%0%

Multivariate Analysis (LPA96 and LPA99)

Prognostic factor Hazard Ratio

P value

Risk group 7.4 0.003

PETHEMA trial 0.07

N=596, variables included: age, sex, protocol, WBC, risk, BCR and FAB subtype.

11%11%

12 24 36 48 60 72 84

0

0,01

0,02

0,03

0,04

0,05

0,06

0,07

0,08

0,09

0,1

0 12 24 36 48 60 72 84 96 108

Months after CR

Pro

bab

ility

0

0,01

0,02

0,03

0,04

0,05

0,06

0,07

0,08

0,09

0,1

0 12 24 36 48 60 72 84 96 108

Months after CR

Pro

bab

ility

P = 0.11P = 0.11

CI of CNS Relapse in LPA99 Trial According CI of CNS Relapse in LPA99 Trial According to Relapse Risk Groupto Relapse Risk Group

Intermediate (n = 2 / 294) Low (n = 0 / 103)

High (n = 3 / 112)

2.7%2.7%

0.7%0.7%

0%0%

Conclusions

1. The relapse risk score is the main risk factor for CNS relapse in patients with APL.

2. The LPA99 risk-adapted protocol has proved effective in reducing CNS relapses.

3. Despite the lack of intrathecal prophylaxis or high-dose cytarabine in the LPA99 trial, the overall 5 year CI of CNS relapse was 0%, 0.8% and 2.7% in the low-, intermediate- and high-risk groups, respectively.

4. Our results do not support the systematic use of CNS prophylaxis in APL patients.

Participating Institutions

H.U. La Fe, ValenciaH. Central, AsturiasH.J. Canalejo, CoruñaH. General, Jerez H. Clinic, BarcelonaH.C. S. Carlos, MadridH. Clínico, ValenciaH. Cruces, BaracaldoH. 12 Octubre, MadridH.C.U. SalamancaH. Son Dureta, MallorcaH.U. P. del Mar, CádizH. Insular, Las PalmasC.H. Xeral-Calde, LugoH. General, AlicanteH.S.P.Alcántara, Cáceres

H. Carlos Haya, MálagaH.C.U. SantiagoH. Reina Sofia, CórdobaH. Dr. Peset, ValenciaH. San Pau, BarcelonaH. Joan XXIII, TarragonaH.U. V. D'Hebron, BarcelonaC.H. LeónH. Navarra, PamplonaH.C. ValladolidH. G. AlbaceteH. M. Valdecilla, SantanderH.U. V. D'Hebron (Inf), BarnaH. La Princesa, Madrid

H.U. G. Trias i Pujol, Barna

H. Dr. Negrin, Las PalmasH. M-Infantil, Las PalmasH. Basurto, BilbaoH. R. Hortega, ValladolidH.C.U. ZaragozaH.G.E. Ciudad de JaénH.U. V. Victoria, MálagaH.General, CastellónH.U. V. Arrixaca, MurciaH. Montecelo, PontevedraF. Jiménez Díaz, MadridC.H. de SegoviaH. Meixoeiro, VigoH. Severo Ochoa, LeganésH.G. Murcia

H. San Jorge, HuescaH. Ramón y Cajal, Madrid

Participating Institutions

Fundaleu, Buenos Aires

H. Rossi, La PlataH. General San Martín, La Plata

H. General San Martín, ParanáI. Trasplante de Médula Ósea, La Plata

H. Clemente Álvarez, Rosario

GATLA (Argentina)

I. P. de Hematología, ParanáH. de Clínicas, Buenos Aires

H.U. del Aire, MadridH. del Mar, Barcelona H. Dr. Trueta, GeronaH. Niño Jesús, Madrid

H.G. Valencia

F. Hospital, Brno (Czec Rep.)

H.U. Arrixaca (Inf), Murcia

H. Xeral-Cies, Vigo

H. Txagorritxu, VitoriaH. General (Inf), AlicanteH. Río Carrión, PalenciaH. C. Haya (Inf), MálagaH. P. Asturias, A. HenaresH. Mutua, Terrasa

H. N.S. Sonsoles, Ávila

H. Sta María Rosell, CartagenaH. San Rafael, MadridH. Virgen de la Cinta, TortosaH. C. Haya (Inf), Málaga

H. Virgen del Rocío, Sevilla

H. Maciel, Montevideo (Uruguay)

HOVON (The Netherlands)

H. La Paz (Inf), Madrid

H.C. San Carlos (Inf), MadridI.C.O., Hospitalet de Llobregat

H.U. La Fe (Inf), ValenciaSHOP (Spain)