APL meeting 2009, Rome, Italy. Sept. 25 2009 All-trans Retinoic Acid and Anthracycline Monochemotherapy for the Treatment of Elderly Patients with Acute

APL meeting 2009, Rome, Italy. Sept. 25 2009

All-trans Retinoic Acid and Anthracycline Monochemotherapy

for the Treatment of Elderly Patients with Acute Promyelocytic

Leukaemia

P. Montesinos, E. Vellenga, C. Rayón, V. Rubio, S. P. Montesinos, E. Vellenga, C. Rayón, V. Rubio, S. Brunet, J. Díaz-Mediavilla, C. Rivas, J. Bueno, J. de la Brunet, J. Díaz-Mediavilla, C. Rivas, J. Bueno, J. de la

Serna, E. Amutio, S. Negri, G. Milone, A. Holowiecka, J. Serna, E. Amutio, S. Negri, G. Milone, A. Holowiecka, J. Bergua, A. Novo, E. de Lisa, J. Mayer, B. Lowenberg, Bergua, A. Novo, E. de Lisa, J. Mayer, B. Lowenberg,

and M.A. Sanz on behalf of the PETHEMA Groupand M.A. Sanz on behalf of the PETHEMA Group

Background

Therapeutic results in elderly patients with acute promyelocytic leukemia (APL) have been generally reported as less effective than for younger patients.

Results of the GIMEMA, European APL Group, and PETHEMA studies

GIMEMA1

(n = 134)

European APL932

(n = 129)

PETHEMA3

(n = 104)

CR, (%) 86 86 84

Death in CR 13 19 8

Overall survival 82 (3 y)* 56 (4 y) --

Disease-free survival 72 (3 y)* -- 79 (6 y)

CI of relapse -- 16 (4 y) 9 (6 y)

1- Leukemia 2003; 2- Leukemia 2005; 3- Blood 2004

More low-risk among elderly

Sanz et al., Blood 2004

Study Aims

Update the analysis of the LPA96 and LPA99 Update the analysis of the LPA96 and LPA99 trials including a significantly higher number of trials including a significantly higher number of

elderly patients and longer follow-up.elderly patients and longer follow-up.

Previous report

Presentreport

Analysis updated on June 15, 2004 July 15, 2009

No. of patients 104 195

Follow up (months) median range

366 – 87

715 – 151

PETHEMA LPA96 TrialAll patients

CONSOLIDATIONCONSOLIDATION

INDUCTIONINDUCTION

AIDAAIDA

All patientsAll patients

MTZ 10 mg/m²/dMTZ 10 mg/m²/d × 5× 5

IDA 5 mg/m²/d × 4IDA 5 mg/m²/d × 4

IDA 12 mg/m²/dIDA 12 mg/m²/d × 1 × 1

#1#1

#2#2

#3#3

MAINTENANCE MAINTENANCE

2 year2 year

ATRA + MP + MTXATRA + MP + MTX

ATRA 45 mg/m²/d until CRATRA 45 mg/m²/d until CR IDA 12 mg/m² d2, 4, 6, 8IDA 12 mg/m² d2, 4, 6, 8

PETHEMA LPA99 TrialPatients >60 years


INDUCTIONINDUCTION

AIDAAIDA


2 year2 year


(Risk-adapted)(Risk-adapted)


low risklow risk

MTZ 10 mg/m²/dMTZ 10 mg/m²/d × 5× 5

IDA 5 mg/m²/d × 4IDA 5 mg/m²/d × 4

IDA 12 mg/m²/dIDA 12 mg/m²/d × 1 × 1

#1#1

#2#2

#3#3

intermediate and high riskintermediate and high risk

MTZ 10 mg/m²/dMTZ 10 mg/m²/d × 5 + ATRA × 15 d × 5 + ATRA × 15 d

IDA 7 mg/m²/d × 4 IDA 7 mg/m²/d × 4 ++ ATRA ATRA × 15 d× 15 d

IDA 12 mg/m²/dIDA 12 mg/m²/d × 2 + ATRA × 15 d × 2 + ATRA × 15 d

#1#1

#2#2

#3#3

PETHEMA LPA 2005 TrialPatients >60 years

INDUCTIONINDUCTION

AIDAAIDA


2 year2 year




MTZ 10 mg/m²/dMTZ 10 mg/m²/d × 3× 3 + ATRA x15d + ATRA x15d

IDA 7 mg/m²/d × 4 + ATRA x15dIDA 7 mg/m²/d × 4 + ATRA x15d

IDA 12 mg/m²/dIDA 12 mg/m²/d ×× 2 + ATRA x15d 2 + ATRA x15d

#1#1

#2#2

#3#3

Intermediate and high riskIntermediate and high risk

MTZ 10 mg/m²/dMTZ 10 mg/m²/d × 3 + ATRA x15d× 3 + ATRA x15d

IDA 5 mg/m²/d × 4 IDA 5 mg/m²/d × 4 + ATRA x15d+ ATRA x15d

IDA 12 mg/m²/dIDA 12 mg/m²/d × 1 × 1 + ATRA x15d+ ATRA x15d

low risklow risk

#1#1

#2#2

#3#3

(Dose reduction)(Dose reduction)

PETHEMA LPA96, 99 & 2005 TrialsAccrual

• Study period: November 1996 – July 2009

Accrual270

Ineligible 69 (25.5%) Eligible

201 Non evaluable 6 (2.9%) Evaluable 195

• 195 elderly (17.3%) of 1130 patients included

PETHEMA LPA96, 99 & 2005 TrialsDemographic and baseline characteristics

Characteristic Median (range) N (%)

Age 67 (60-83)

Gender

Female 103 (52)

PETHEMA trial

LPA96 30 (15)

LPA99 106 (55)

LPA2005 59 (30)

ECOG

Grade 2-3 63 (36)

PETHEMA LPA96, 99 & 2005 TrialsDemographic and baseline characteristics

Characteristic N (%)

Relapse-risk score

Low 55 (28)

Intermediate 96 (49)

High 44 (23)

FAB subtype

Microgranular (M3v) 35 (18)

BCR isoform

BCR3 66 (44)

Induction Outcome with AIDA Regimen

LPA96(n = 30)

LPA99(n = 106)

LPA2005(n = 59)

P

CR, (%) 80.0 78.3 88.1 0.12

Causes of failure (%)

Hemorrhage 10.0 8.5 5.1 NS

Infection 6.7 8.5 3.4 NS

Diff. Syndrome 3.3 2.8 1.7 NS

Myocardial Infarct. 0 1.9 1.7 NS

Resistance 0 0 0 NS

PETHEMA LPA96, 99 & 2005 TrialsPost-remission events (154 of 159 completed the consolidation therapy)

4

10

67 8

0

5

10

15

Nº o

f Pat

ient

s

MolecularRelapse

ClinicalRelapse

t-MDS/AML SolidNeoplasia

Toxic Deathin CR

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Months

Pro

bab

ility

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Months

Pro

bab

ility

PETHEMA LPA96, 99 & 2005 Trials

Overall survival

OS

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Months

Pro

bab

ility

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Months

Pro

bab

ility

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Months

Prob

abilit

y

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Months

Prob

abilit

y

OS by LPA trial

67%

72%

P = 0.13

LPA 99LPA96

63%

LPA 2005 75%

OS by Relapse Risk

63%

51%

P = 0.003IntermediateHigh

Low

73%

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Months

Pro

babi

lity

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Months

Pro

babi

lity

OS by Age

49%

P = 0.06Age >70

69%

Age <70

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Months

Pro

bab

ility

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Months

Pro

bab

ility

PETHEMA LPA96, 99 & 2005 Trials Relapse-free survival

Overall RFS

RFS by Relapse Risk

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Months

Pro

bab

ility

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Months

Pro

bab

ility

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Months

Prob

abilit

y

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Months

Prob

abilit

y

RFS by LPA trial

89%

89%

87%

P = 0.90

LPA 99LPA96

LPA 2005

91%

87%

82%

P = 0.21IntermediateHigh

Low

95%

PETHEMA Trials in Elderly PatientsConcluding remarks

• This study confirms the high antileukemic efficacy and high degree of compliance of protocols using ATRA and anthracycline monochemotherapy for induction and consolidation therapy in elderly patients.

• Induction death remains the most challenging cause of therapeutic failure, especially in patients with WBC >10.000xµL.

• Consolidation and maintenance chemotherapy was relatively well tolerated in low-risk patients and in younger than 70 years.

• “Age-adapted” strategies focusing on decreasing the intensity of chemotherapy, while maintaining the antileukemic efficacy, should be a major objective in future studies.

PETHEMA Trials in Elderly PatientsConcluding remarks

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)

Documents

APL meeting 2009, Rome, Italy. Sept. 25 2009 All-trans Retinoic Acid and Anthracycline Monochemotherapy for the Treatment of Elderly Patients with Acute