The Achievement of An Early Complete Cytogenetic Response (CCyR) Is A Major Determinant for Outcome In Patients (pts) with Early Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Treated with Tyrosine Kinase Inhibitors (TKIs).
Authors: Jabbour Elias , Kantarjian Hagop M. , Shan Jenny , O'Brien, MD Susan , Kadia Tapan , Borthakur Gautam , Quintas-Cardama Alfonso , Garcia-Manero Guillermo , Ravandi Farhad , Cortes Jorge 
Published: October 2019

Abstract
Abstract 3429
The achievement of a CCyR is a known major surrogate endpoint in the treatment of pts with CML that has shown correlation with survival improvement. Second generation TKIs (2nd TKI) have shown significant activity in pts with CML post imatinib (IM) failure and have recently shown superiority when compared to IM 400 mg standard of care in pts with newly diagnosed CML –CP. We assessed the correlation between the achievement of an early CCyR and event-free survival (EFS as defined by the IRIS trial) and overall survival (OS) in sequential phase II trials run at our institution in pts with newly diagnosed CML in CP treated with IM 400 mg daily (n=73), IM 400 mg BID (n=208), and 2nd TKI (n=154). Patient and disease characteristics at start of treatment were listed in Table 1. The overall rates of CCyR were 87 %, 91%, and 96% for pts receiving IM 400 mg/d, 400 mg BID, and 2nd TKI (p = 0.06). The rates of major molecular response (MMR) were 77%, 87%, and 89%, respectively (p = 0.05). Their 3-year EFS and OS rates were 85%, 92%, and 97% (p=0.01), and 93%, 97%, and 100% (p = 0.18), for pts receiving IM 400 mg daily, IM 400 mg BID, and 2nd TKI, respectively. The rates of 3-, 6-, and 12-month (mo) CCyR of the total group were 65%, 83%, and 89%, respectively. Pts with 3-, 6-, and 12-mo CCyR had statistically a significantly better outcome with 3-year EFS and OS rates of 98%, 97%, and 98% and 99%, 99%, and 99%, respectively compared to 83%, 72%, and 67% and 95%, 90%, and 94%, in pts who did not achieve a CCyR. There was no difference in EFS and OS in pts who achieved a CCyR whether they received IM 400 mg daily, IM 400 mg BID, or 2nd TKI (Table 2.). In conclusion, 2nd TKI induced higher rates of CCyR and MMR than IM. The achievement of an early CCyR remains a major determinant for outcome of pts with early CP-CML regardless of the TKI.
Table 1. Patients characteristics Parameter 400mg 800mg 2nd TKI No. patient treated 73 208 154 Age (years) Median (range) 48 (15–78) 48 (17–84) 47 (18–85) Splenomegaly Yes (%) 16 (22) 59 (28) 41 (27) Hemoglobin (g/dl) Median (range) 12.7 (7.9–15.7) 12.4 (6.2–16.7) 12.2 (6.7–15.8) WBC (× 109/L) Median (range) 20.5 (1.6–277) 27.9 (2.2–283) 31.8 (0.8–342.5) Platelets (× 109/L) Median (range) 367 (103–1043) 353 (58–1476) 299 (73–2000) Peripheral blast % Median (range) 0 (0–2) 0 (0–12) 0 (0–7) baso % Median (range) 3 (0–16) 3 (0–19) 3 (0–19) Marrow blast % Median (range) 1 (0–6) 2 (0–14) 2 (0–8) baso % Median (range) 2 (0–9) 3 (0–15) 2 (0–12) Sokal risk, no (%) Low 50 (68) 132 (63) 118 (77) Intermediate 22 (30) 57 (27) 27 (18) High 1 (2) 19 (9) 9 (6) Ph + > 90 % yes (%) 67/72 (93) 195 (94) 133 (86) Clonal evolution (%) Yes (%) 2 (3) 7 (3) 11/151 (7)
Table 2. Outcome Total group 3mo-CCyR 6mo-CCyR 12mo-CCyR y n p y n P Y n P 3-yr EFS 98 83 <0.001 97 72 <0.001 98 67 <0.001 3-yr OS 99 95 0.07 99 90 <0.001 99 94 0.001 IM 400mg 3-yr EFS 92 81 0.12 97 74 0.001 98 72 <0.001 3-yr OS 100 88 0.046 100 87 0.09 100 88 0.046 IM 800 mg 3-yr EFS 97 84 0.005 97 68 <0.001 98 58 <0.001 3-yr OS 98 97 0.93 99 92 0.001 99 100 0.03 2nd TKI 3-yr EFS 100 80 <0.001 99 67 <0.001 99 NA (no patient) NA 3-yr OS 100 100 NA (no death) 100 100 na 100 NA (no patient) NA p-value (PFS/OS) 0.13/0.24 0.41/0.92 0.9/0.6

Disclosures:
Jabbour: Novartis: Honoraria; BMS: Honoraria. Kantarjian:Novartis: Research Funding. Cortes:Novartis: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding.