April 2024 ONCOLOGY CARTOON by DR KANHU CHARAN PATRO
Addressing Imatinib-resistant CML
1. Oncology Journal Club Addressing Imatinib-resistant CML Frank Giles, MD, FRCPI, FRCPath Chief, Division of Hematology and Medical Oncology Director, Institute for Drug Development Deputy Director, CTRC at University of Texas Health Science Center San Antonio, TX
7. ASH 2007, Abstract 25 Hochhaus A. et al IRIS 6-Year Follow-Up: Sustained Survival and Declining Annual Rate of Transformation in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib
8. IRIS 6-Year Update: Overall Survival (ITT Principle) 6 year OS is 88% (95% considering only CML-related deaths) (incl. 3% after BMT, 4% non-CML related) Hochhaus A. et al, Blood. 110, 11. Abstract 25. ASH 2007 38 (7%) patients lost to follow-up by 5 years
9. IRIS 6-Year Update: Annual Event Rates 3.3 7.5 4.8 1.5 0.8 0.4 1.5 2.8 1.6 0.9 0.5 0 0 1 2 3 4 5 6 7 8 1st 2nd 3rd 4th 5th 6th % Annual Rates Year Event Loss of CHR, Loss of MCyR, AP/BC, Death during treatment AP/BC Hochhaus A. et al, Blood. 110, 11. Abstract 25. ASH 2007
22. ASCO 2007, Abstract 7004 Shah NP. et al. Dasatinib 50 Mg Or 70 Mg BID Compared To 100 Mg Or 140 Mg QD In Patients With CML In Chronic Phase (CP) Who Are Resistant Or Intolerant To Imatinib: One-year Results Of CA180034
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24. Dasatinib Phase III in CP-CML Failing Imatinib (N = 662) + 100 QD vs 70 BID Shah, JCO. 2007;25: Abstract 7004 Parameter (%) 100mg QD N = 165 50mg BID N = 167 140mg QD N = 163 70mg BID N = 167 P value MCyR 64 58 62 58 NS CCyR 46 46 47 50 NS Interruption 58 66 69 71 0.047 Reduction 33 45 54 57 <0.001 Neutropenia 34 46 43 43 0.123 Thrombocytopenia 22 34 40 38 0.003 Pleural effusion 10 16 20 18 0.058 +
34. Nilotinib: Phase I Study Grade 3/4 Possibly Related Laboratory AEs Kantarjian*, Giles* et al. N Engl J Med. 354:2542, 2006 * Indicates co-first author Overall (N=119) 400 BID (N=32) 600 BID (N=18) 0% 0% 11% 11% 5% 3% 9% 3% 5% 3% 5% 3% Amylase ALT/AST Lipase Bilirubin
35. ASH 2007, Abstract 471 and 735 Le Coutre P. et al. (471) Kantarjian HM. et al. (735) Nilotinib Is Highly Active and Safe in Chronic Phase Chronic Myelogenous Leukemia (CML-CP) Patients with Imatinib-Resistance or Intolerance
36. Nilotinib: Phase II Baseline Demographics and Disease Characteristics Kantarjian HM et al. ASH abstract 735, Blood 2007: 110 (11). Le Coutre P et al. ASH abstract 471, Blood 2007: 110 (11). CML-CP (N = 321) CML-AP (N = 127) Median age, years 58 (21-85) 58 (22-82) Additional chromosomal abnormalities, % 24.4 31 Median duration of CML, months 58 (5-75) 71 (2-298) Median duration of prior imatinib use, months 33 29 Imatinib-resistant/intolerant, % 71/29 80/20
37. Nilotinib Phase II Studies: Dose Intensity (mg/day) le Coutre et al. ASH 2006; Abst #165 Kantarjian et al. ASH 2006; Abst #2169 800 797 787 Planned Delivered (CP) N = 316 Delivered (AP) N = 64
38. Nilotinib Phase II CML-CP Study Response Rates Hematologic Response Cytogenetic Response ASH'06 Patients with ≥ 6 months of follow-up (N = 279) ASCO'07 Patients with ≥ 6 months of treatment (N = 320) ASH'07 Patients with ≥ 11 months of treatment (N = 321) CHR at baseline / *No CHR at baseline, N 115 / 206 Time to first CHR* 1 month Time to first MCyR (N=178) 2.8 months Median duration of MCyR has not been reached at the time of data cutoff
39. Nilotinib Phase II CML-AP Study: Response Rates Hematologic Response Cytogenetic Response ASH'06 Patients with ≥ 8 months of treatment (N = 64) ASCO'07 Patients with ≥ 6 months of treatment (N = 119) ASH'07 Patients with ≥ 6 months of treatment (N = 129)
40. Nilotinib Phase II Study: CML-CP Overall Survival Post Imatinib Failure Kantarjian et al. ASH 2007 abstract 735 95% 91% Months Since Start of Treatment Alive, % Total = 321 Failed = 25 lll = Censored observations
41. Phase II CML-AP Study Overall Survival Post Imatinib Failure Le Coutre et al . ASH 2007 abstract 471 Patients = 129 Number deaths = 27 92% 81% Alive, % Months Since Start of Treatment
42. Phase II CML-CP Study Grades 3/4 Biochemical Laboratory Abnormalities Kantarjian et al . ASH 2007 abstract 735 N = 321 Grades 3/4 (%) AST 2 ALT 4 Bilirubin (total) 8 Bilirubin (direct) 5 Creatinine 1 Hypocalcemia 1 Hypomagnesemia <1 Hypophosphatemia 14 Lipase elevation 15 Hyperglycemia 13
43. Phase II CML-CP Study Possibly Related Non-hematologic AEs (frequency >10%) Kantarjian et al , ASH 2007 abstract 735 N = 321 All Grades (%) Grades 3/4 (%) Rash 30 2 Pruritus 25 <1 Nausea 24 <1 Fatigue 20 1 Headache 18 2 Vomiting 12 <1 Constipation 12 0 Diarrhea 12 2
44. Cross-intolerance Between Imatinib and Nilotinib Cortes et al . ASH abstract 29, Blood 2007:110 (11) CML-CP (N=94) / CML-AP (N=23) Patients enrolled in nilotinib study 2101 with grade 3/4 imatinib intolerance Patients with cross-intolerance (grade 3/4) after switching to nilotinib Rash / skin toxicity Fluid retention GI intolerance Liver toxicity Myalgias / Arthralgias
45. Nilotinib Cross Intolerance in Patients with Imatinib Intolerance Nonhematologic AEs Reason for Imatinib Intolerance Imatinib Intolerant* Grade 3/4 AE or persistent Grade 2 AE on nilotinib** Gr. 3/4 AE on Nilotinib*** AE that led to dose reduction of nilotinib D/C nilotinib due to AE N N N N CML-CP N = 95 Non-hematologic 57 4 1 0 0 Rash/Skin 26 0 0 0 0 Fluid Retention 17 0 0 0 0 GI - diarrhea 17 3 1 0 0 Liver Toxicity - ALT - AST 12 3 1 0 0 Myalgia/arthralgia 9 1 0 0 0
46. Nilotinib Phase II Study CML-CP Myelosuppresion All Grades Grade 3/4 ASH'06 Patients with ≥ 6 months of follow-up (N = 316) ASCO'07 Patients with ≥ 6 months of treatment (N = 320) ASH'07 Patients with ≥ 11 months of treatment (N = 321) Grade 3/4 Median Duration (days) 9 15 23 Median Onset (days) 61 55 42 Most Frequent Newly Occurring or Worsening Hematologic Lab Abnormalities Regardless of Causality
47. Nilotinib Phase II Study CML-AP Myelosuppresion All Grades Grade 3/4 ASH'06 Patients with ≥ 8 months of treatment (N = 64) ASCO'07 Patients with ≥ 6 months of treatment (N = 127) ASH'07 Patients with ≥ 11 months of treatment (N = 136) Grade 3/4 Median Duration (days) 8 15 27 Median Onset (days) 14 21 21 Most Frequent Newly Occurring or Worsening Hematologic Lab Abnormalities Regardless of Causality
53. ASCO 2007, Abstract 7023 Hochhaus A. et al. Efficacy Of Dasatinib In Chronic Phase Chronic Myelogenous Leukemia Patients After Imatinib Failure According To Baseline BCR-ABL Mutations
55. ASCO 2007, Abstract 7024 Mueller MC. et al. Response Dynamics To Nilotinib Depend On The Type Of Bcr-abl Mutations In Patients With Chronic Myelogenous Leukemia (CML) After Imatinib Failure