Long-term Outcome after hyper-CVAD and Imatinib for De Novo or Minimally Treated Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph-ALL) Deborah A. Thomas, Susan O’Brien, Stefan Faderl, Farhad Ravandi, William Wierda, Michael Andreeff, Rebecca Garris, Richard Champlin, Jorge Cortes, Hagop Kantarjian The University of Texas M. D. Anderson Cancer Center

Treatment of Adults with Philadelphia positive (Ph)-ALL in Pre-Imatinib Era CR rates similar to Ph negative ALL Outcome with chemotherapy – Short relapse-free survival (RFS) – 3-year survival (OS) rates 10% – 20% – No single regimen superior Allogeneic stem cell transplant (aSCT) – Improved OS rates 27% – 65% (1 st CR)

aSCT in 1st CR for Ph-ALL: Pre-Imatinib Era StudyNo. %OS %TRM aSCTChemo Dombret et al — Laport et al 7954—31 Goldstone et al — Fielding et al*26744 (MRS) 36 (MUD) *Only RFS significant for aSCT after accounting for age, leukocyte count

Imatinib + Hyper-CVAD in Ph-ALL: Rationale Single agent activity of imatinib – CR rate ~20%; marrow CR 10% – 55% – Median time to progression 2 – 4 mos Synergy in vitro with chemotherapy – Cytarabine, anthracyclines, vincristine Hyper-CVAD regimen in de novo Ph-ALL – CR rate 90% – Median CR duration 16 mos – Historical rate aSCT in 1st CR 15% Druker et al, NEJM 345:1038, 2001; Ottmann et al, Blood 100:1965, 2002 Hofmann et al, Leuk Lymph 45:655, 2004; Kantarjian et al, JCO 18:547, 2000

Imatinib + Hyper-CVAD in Ph-ALL Hyper-CVAD MTX-cytarabine Imatinib (400 mg then 600 mg) Vincristine + prednisone Intensive phase Maintenance phase 12 mos Thomas et al, Blood 103:4396, 2004 Imatinib (600 mg then 800 mg)

Imatinib + Hyper-CVAD in Ph-ALL: Eligibility Ph chromosome or BCR-ABL + ALL – De novo untreated – Primary refractory: failure 1 induction – CR after 1 cycle of induction (CR at start) Residual disease by FISH or RT-PCR Imatinib naive Age 15 years or older Adequate hepatorenal function Adequate cardiac function

Imatinib + Hyper-CVAD in Ph-ALL: Induction Response (n=54) Category No. CR/Total %CR De Novo 36/39 92 Primary refractory 6/6 100 CR at start 9 — De novo failures: 1 CRp, 1 PR, 1 early death (sepsis) Molecular CR (nested PCR for BCR-ABL) in 52%

Imatinib + Hyper-CVAD in Ph-ALL Characteristics of de novo groups Parameter Percent Imatinib + HCVAD HCVAD (n=39) (n=50) Age > 60 yrs26 30 WBC > 30 x 10 9 /L Hgb < 10 g/dL Albumin < 3 g/dL Zubrod PS > 2 — 4 LDH > 620 U/L CNS disease 13 2 B2 microglobulin >

Imatinib + Hyper-CVAD in de novo Ph-ALL Parameter Percent Imatinib + HCVAD HCVAD (n=39) (n=50) Response CR Courses to CR > 2 — 11 Median days to CR 21 20

Imatinib + Hyper-CVAD in Ph-ALL: Outcome After CR CR (n=51) Chemo (n=35) [14] SCT (n=16) [2] CCR (n=10) [8] Deaths in CR (n=10) [3] Relapse (n=15) [3] CCR (n=10) [2] Deaths in CR (n=4) [0] Relapse (n=2) [0] 7 infection; 1 pancreatitis, 1 CNS hemorrhage; 1 unknown 2 infection; 2 GVHD [No. with molecular CR]

Thomas et al, ASH 2006

Thomas et al, ASH 2007

Imatinib + Hyper-CVAD in Ph-ALL: Relapses 6 relapses on program – Most between 8 – 21 mos, 1 at 42 mos 5 relapses after change in TKI therapy – Persistent Ph or ↑ BCR-ABL by PCR 2 after aSCT without imatinib maintenance ABL sequencing in 5 of 10 relapses – 5 with ABL KD mutations (none T315I) – Y253H, Y253F, V338G, F359V, E459K Salvageable with hyper-CVAD + dasatinib

Improvements in outcome with continuous imatinib simultaneously with hyper-CVAD Durable remissions – aSCT in 1st CR appears beneficial JALSG ALL202, GRAAPH-2003 Elderly group may benefit from RIC SCT – PCR for BCR-ABL not predictive relapse – ABL KD mutations relatively less common Second or later generation tyrosine kinase inhibitors may further improve outcome Imatinib + Hyper-CVAD in Ph-ALL: Conclusions