APL meeting, Rome, Italy. Sept. 25 2009

Salvage Therapy with Chemotherapy- or Arsenic Trioxide-based Regimens for Acute Promyelocytic Leukemia in

First Relapse.

P. Montesinos, J. Esteve, E. Vellenga, C. Rivas, S. Brunet, P. Montesinos, J. Esteve, E. Vellenga, C. Rivas, S. Brunet, M. Arnan, J. D. González, P. Sánchez, J. Díaz-mediavilla, M. Arnan, J. D. González, P. Sánchez, J. Díaz-mediavilla, A. Verdeguer, L. Escoda, E. Amutio, V. Rubio, I. Pérez, R. A. Verdeguer, L. Escoda, E. Amutio, V. Rubio, I. Pérez, R.

Guàrdia, J. Bueno, B. Lowenberg, and M.A. Sanz. On Guàrdia, J. Bueno, B. Lowenberg, and M.A. Sanz. On behalf behalf of the PETHEMAof the PETHEMA, HOVON and GATLA Groups, HOVON and GATLA Groups

Background

• Arsenic trioxide (ATO) is currently regarded as the best treatment option in relapsed acute promyelocytic leukemia (APL).

• The efficacy and safety of salvage therapy using ATO-based approaches compared with chemotherapy-based regimens is not well established.

Objectives

• We analyze the clinical outcome of 110 APL patients in first relapse who received salvage therapy with chemotherapy- or ATO-based regimens.

Patients and Methods

• From June 1997 to May 2009, 110 of 1,225 patients included in three subsequent PETHEMA trials (LPA96, LPA99 & LPA2005) relapsed after front-line therapy.

• Salvage therapy:

• 67 patients (61%) CT-based regimens.

• 43 patients (49%) ATO-based regimens.

Salvage therapy: CT-based regimens

• Induction with ATRA plus mitoxantrone plus cytarabine (n=46), plus etoposide (n=7), or other anthracycline-based regimens (n=14).

• Consolidation with one cycle of chemotherapy followed by SCT.

• Patients not eligible for SCT received one additional consolidation cycle with or without maintenance therapy.

Salvage therapy: ATO-based regimens

• Induction with ATO (0.15 mg/kg) ± ATRA (45mg/sqm) until CR.

• Consolidation with one cycle of ATO (5d x 5w) plus ATRA (15d), followed by SCT.

• Patients not eligible for SCT received maintenance therapy with ATO plus ATRA with or without gemtuzumab ozogamicin or other agents.

Patient characteristics (1)

CharacteristicTotal

(n=110)

CT-based(n=67)

ATO-based (n=43)

P

Age, median (range) 40 (2-81) 37 (2-73) 42 (10-81) NS

Gender, % Male 63 63 63 NS

FAB, % M3V 33 (30) 19 (28) 14 (33) NS

BCR3 isoform, % 58 (54) 23 (53) 23 (55) NS

Secondary APL, % 6 (5) 3 (4) 3 (7) NS

ATO-Based group (n=43)

42%

49%

9%

CT-Based group (n=67)53%44%

3%

High-riskIntermediate-riskLow-risk

Relapse-risk group at APL diagnosis

ATO-Based group (n=43)

33%

55%

12%

CT-Based group (n=67)

34%

53%

13%

Molecular RelapseClinical RelapseCNS Relapse

Type of relapse

Patient characteristics (2)

CharacteristicTotal

(n=110)

CT-based(n=67)

ATO-based (n=43) P

Early relapse

(<18 months), N (%)54 (49) 40 (60) 14 (33) 0.01

Follow-up in months,

median (range)

38

(2-134)

62

(6-134)

18

(2-53)<0.01

Results: Induction therapy

7% 5%

88%

12%4%

84% DeathResistanceCR2

ATO-Based group (n=43)

CT-Based group (n=67)

P = 0.49

Results: Molecular Remission

9%

91%

21%

79%PCR positivePCR negative

ATO-Based group (n=38)

CT-Based group (n=56)

P = 0.13

ATO-Based group (n=38)

50%11%

39%

CT-Based group (n=56)36%

25%

39%

Auto-SCTAllo-SCTNon-SCT

Post-remission therapy

*4 mobilization failures, 7 early relapses before planned SCT

*No mobilization failures, 6 early relapses before planned SCT

0

0,2

0,4

0,6

0,8

1

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

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

Months

Pro

babi

lity

Results in the overall seriesaccording to

salvage therapyOS

RFS

0

0,2

0,4

0,6

0,8

1

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

Months

Prob

abili

ty

0

0,2

0,4

0,6

0,8

1

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

Months

Prob

abili

ty

63%

44%

P = 0.05

ATO-based (n=43)

CT-based (n=67)

0

0,2

0,4

0,6

0,8

1

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

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

Months

Pro

babi

lity

DFS

34%

33%

P = 0.51

ATO-basedCT-based

37%

34%

P = 0.61

ATO-based (n=38)CT-based (n=56)

OS after Auto-SCTaccording to salvage therapy

0

0,2

0,4

0,6

0,8

1

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

Months

Pro

ba

bili

ty

0

0,2

0,4

0,6

0,8

1

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

Months

Pro

ba

bili

ty

87%

60%

P = 0.03ATO-based (n=19)

CT-based (n=20)

OS after Allo-SCTaccording to salvage therapy

0

0,2

0,4

0,6

0,8

1

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

Months

Pro

ba

bili

ty

0

0,2

0,4

0,6

0,8

1

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

Months

Pro

ba

bili

ty

100%

56%

P = 0.15ATO-based (n=4)

CT-based (n=14)

OS in patients not receiving SCTaccording to salvage therapy

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120

Months

Pro

ba

bili

ty

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120

Months

Pro

ba

bili

ty

38%

26%

P = 0.98

ATO-based (n=15)

CT-based (n=22)

Concluding remarks

• High rates of second CR with either ATO (88%) or chemotherapy regimens (84%).

• The 2-year DFS and RFS were similar with both approaches.

• An apparent benefit in terms of OS was observed in the ATO-based group (P=0.05), especially in patients undergoing SCT.

• A longer follow-up is required in the ATO-based group to confirm these results.

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)