CML and Future Perspective Hani Al-Hashmi, MD
Objectives Learning from CML history Outcome of interest to clinician Patient and community interest!!
Learning from CML history
Survival Probability (All Ph+ CML Disease Phases) Imatinib Changed the Therapeutic Landscape for Patients With Ph+ CML 1.0 0.9 0.8 0.7 0.6 0.5 0.4 1995-2008, IFN- or SCT 0.3 0.2 0.1 0 2002-2008, imatinib* Best available therapy 5-Yr OS, % Imatinib* 93 IFN- or SCT + second-line imatinib 71 IFN- or SCT 63 IFN- 53 Hydroxyurea 46 Busulfan 38 1997-2008, IFN- or SCT plus second-line imatinib 1986-2003, IFN- 1983-1994, hydroxyurea 1983-1994, busulfan 0 2 4 6 8 10 12 14 16 18 20 22 Yrs After Diagnosis 2010 2000 1990 1980 1970 1960 Leitner AA, et al. Internist (Berl). 2011;52:209-217.
Diagnosis of CML Hematologic Sensitivity Cytogenetic Molecular Karyotype (Ph chromosome) FISH PCR (BCR-ABL fusion) Peripheral blood (with myeloid cells) Bone marrow (with myeloid hyperplasia) Chromosomal translocation t(9;22)(q34;q11) Abnormal BCR-ABL Red: BCR Green: ABL Yellow: fusion Abnormal BCR-ABL Lane 1: BCR-ABL+ Lane 2: BCR-ABL-
Evolution of Treatment Goals 1960 1970 1980 1990 2000 2010 Busulfan IFN Imatinib 2GTKI Best achievable response Complete Hematologic Response (CHR) Major Cytogenetic Response (CCyR) Major Molecular Response (MMR) Deeper Molecular Responses Tumor Reduction a 10% 1-log 1% 2-log Tumor Burden a Compared with baseline levels. CMR, complete molecular response; IFN, interferon; IS, international scale. CMR 4 and beyond 0.1% IS 3-log 0.01% IS 4-log 0.0032% IS 4.5-log 0.0001% IS 5-log Discontinuation?
Probability of Survival BCR-ABL/ABL Cutoff ~ 10% IS at 3 Mos Predicts Survival 1.0 0.8 0.6 BCR-ABL/ABL > 9.84% 8-yr OS: 56.9% BCR-ABL/ABL 9.84% 8-yr OS: 93.3% 0.4 P <.001 0.2 0 0 1 2 3 4 5 6 7 8 Yrs From Onset of Imatinib Therapy Marin D, et al. J Clin Oncol. 2012;30:232-238.
First-line Treatment Milestones Have Evolved The European LeukemiaNet (ELN) recommendations for optimal responses have shifted to deeper responses 3 to 6 months earlier in treatment 2 Similarly, failure criteria occur 3 months earlier vs 2009 ELN recommendations 3 months 6 months 12 months 18 months Log reduction 2009 ELN 1 CHR a, mcyr b 1 BCR-ABL IS = 10% 2013 ELN 2 PCyR c and/or BCR-ABL IS 10% PCyR c CCyR d and/or BCR-ABL IS < 1% CCyR d 2 BCR-ABL IS = 1% MMR e MMR e Stable or improving MMR f 3 BCR-ABL IS = 0.1% a Platelet count < 450 10 9 /L, WBC < 10 10 9 /L, differential count without immature granulocytes, and < 5% basophils b 36% to 65% Ph+ metaphases c 1% to 35% Ph+ metaphases d No Ph+ metaphases e BCR-ABL IS 0.1% f BCR-ABL to ABL (or other housekeeping gene) ratio 0.1%. 4.5 BCR-ABL IS = 0.0032% Baccarani M, et al. J Clin Oncol. 2009;27:6041-6051. Baccarani M, et al. Blood. 2013;122(6):872-884
Baccarani et al, Blood 2013;122:872-884
Patients with EMR at 3 months had improved OS and PFS and a higher probability of subsequent deeper response vs patients without EMR 5-Year OS 5-Year PFS MR4.5 by 5 Years Patients with EMR had improved OS at 5 years Patients with EMR had improved PFS at 5 years Patients with EMR had a higher probability of achieving MR4.5 by 5 years 96% 100% 82% 95% 100% 78% 100% 63% n = 233 n = 24 n = 234 n = 24 n = 234 n = 24 EMR EMR failure EMR EMR failure EMR EMR failure 8% Hochhaus A, et al. Leukemia. 2016; 30(5):1044-1054 (Suppl).
Fewer Progressions Menu Fewer patients progressed with Nilotinib vs imatinib in ENESTnd Six times as many patients progressed to AP/BC on imatinib than on Nilotinib Progressions On Core Treatment (6-year follow-up) a 2 (0.7%) TASIGNA PATIENTS PROGRESSED vs P =.0059 12 (4.2%) 6 Months 12 Months 18 Months 24 Months 3 Years 4 Years 5 Years 6 Years IMATINIB PATIENTS PROGRESSED a Progression to AP/BC events included progressions to AP/BC (excluding clonal evolution) or CML-related deaths occurring on core treatment. Kantarjian HM, et al. Lancet Oncol. 2011;12(9):841-851; Hochhaus A, et al. Leukemia. 2016; 30(5):1044-1054
Fewer Progressions Menu Fewer patients progressed with Dasatinib vs Imatinib in DASISION No P-value was provided for the difference in progression rates with dasatinib vs imatinib in DASISION Progressions During Treatment (5-year follow-up) a 12 Months 24 Months 3 Years 4 Years 5 Years 8 (3%) DASATINIB PATIENTS PROGRESSED (n = 259) 15 (5.8%) IMATINIB PATIENTS PROGRESSED (n = 260) a Progression events included increasing white blood cells despite appropriate therapeutic management, loss of CHR, partial CyR or CCyR, progression to AP/BC, or death. vs Kantarjian HM, et al. New Engl J Med. 2010;362(24):2260-2270; Kantarjian HM, et al. Blood. 2012;119(5):1123-1129; Jabbour E, et al. Blood. 2014;123(4):112494-500; Cortes J, et al. J Clin Oncol. 2016 Jul 10;34(20):2333-40.
Fewer Progressions Menu Progressions on imatinib in ENESTnd and DASISION Approximately 7% of patients progressed to AP/BC with imatinib in both studies ENESTnd: On-Study Progressions With Imatinib 1-4 21/283 (7%) PATIENTS PROGRESSED DASISION: On-Study Progressions With Imatinib 5-9 19/260 (7%) PATIENTS PROGRESSED 1 year 2 years 3 years 4 years 5 years 6 years 1 year 2 years 3 years 4 years 5 years Limitations: On-study Progressions with imatinib data come from different trials with different durations of follow-up. Progression was defined differently in each trial. No cross trial comparison can be made. Kantarjian HM, et al. Lancet Oncol. 2011;12(9):841-851; Hochhaus A, et al. Leukemia. 2016; 30(5):1044-1054 5. Kantarjian HM, et al. New Engl J Med. 2010;362(24):2260-2270; Kantarjian HM, et al. Blood. 2012;119(5):1123-1129; Jabbour E, et al. Blood. 2014;123(4):112494-500; Cortes J, et al. J Clin Oncol. 2016 Jul 10;34(20):2333-40.
Goals of Therapy Prolong survival Prevent progression Time at Risk Quality of Life Reduce toxicities Cost smart Treatment Free Remission 1. Baccarani M, et al. Blood. 2013;122(6):872-884; 2. Hughes T, et al. Blood. 2016; 128 (1):17-23; 3. 3. Steegmann JL, et al. Leukemia (2016) 30, 1648 1671
Outcome of interest to clinician
Evidence based medicine More potent TKIs: Faster response Deeper response Lower risk for: Progression and transformation Mutations Signals toward better PFS and OS
Making the decision According to: Disease risk assessment Side Effect profile FDA and Saudi FDA approved.
Earlier Menu
Patient and community interest!!
Life long TKIs Therapy!!! Occurrence of chronic low-grade adverse events Impaired Quality of Life Risk of inadequate drug compliance and poorer clinical outcome Eliasson L et al., Leuk Res, 2011;35(5):626-30 Noens L et al., Blood, 2009;13:5401 5411 Marin DJ et al.,clin Oncol, 2010;28:2381 2388 Akker M van den et al., J Clin Epidemiol, 1998;51:367 375 Akker M van den et al.,eurj GenPract, 1996;14:65 70 Tasigna Prescription information; September 2015.Novartis Pharma GmbH Glivec Prescription information; May 2016.Novartis Pharma GmbH Bansal D et al.,pediatr Blood Cancer, 2012;59(3):481-4
Life long TKIs Therapy!!! Occurrence of chronic low-grade adverse events Impaired Quality of Life Risk of inadequate drug compliance and poorer clinical outcome Age-increasing incidence of multi-morbidity requires intake of several drugs, leading to a higher risk for medication interaction Eliasson L et al., Leuk Res, 2011;35(5):626-30 Noens L et al., Blood, 2009;13:5401 5411 Marin DJ et al.,clin Oncol, 2010;28:2381 2388 Akker M van den et al., J Clin Epidemiol, 1998;51:367 375 Akker M van den et al.,eurj GenPract, 1996;14:65 70 Tasigna Prescription information; September 2015.Novartis Pharma GmbH Glivec Prescription information; May 2016.Novartis Pharma GmbH Bansal D et al.,pediatr Blood Cancer, 2012;59(3):481-4
Life long TKIs Therapy!!! Occurrence of chronic low-grade adverse events Impaired Quality of Life Risk of inadequate drug compliance and poorer clinical outcome Age-increasing incidence of multi-morbidity requires intake of several drugs, leading to a higher risk for medication interaction No TKI during pregnancy and nursing Eliasson L et al., Leuk Res, 2011;35(5):626-30 Noens L et al., Blood, 2009;13:5401 5411 Marin DJ et al.,clin Oncol, 2010;28:2381 2388 Akker M van den et al., J Clin Epidemiol, 1998;51:367 375 Akker M van den et al.,eurj GenPract, 1996;14:65 70 Tasigna Prescription information; September 2015.Novartis Pharma GmbH Glivec Prescription information; May 2016.Novartis Pharma GmbH Bansal D et al.,pediatr Blood Cancer, 2012;59(3):481-4
Life long TKIs Therapy!!! Occurrence of chronic low-grade adverse events Impaired Quality of Life Risk of inadequate drug compliance and poorer clinical outcome Age-increasing incidence of multi-morbidity requires intake of several drugs, leading to a higher risk for medication interaction No TKI during pregnancy and nursing Negative impact on growth and development in children and adolescents Eliasson L et al., Leuk Res, 2011;35(5):626-30 Noens L et al., Blood, 2009;13:5401 5411 Marin DJ et al.,clin Oncol, 2010;28:2381 2388 Akker M van den et al., J Clin Epidemiol, 1998;51:367 375 Akker M van den et al.,eurj GenPract, 1996;14:65 70 Tasigna Prescription information; September 2015.Novartis Pharma GmbH Glivec Prescription information; May 2016.Novartis Pharma GmbH Bansal D et al.,pediatr Blood Cancer, 2012;59(3):481-4
Life long TKIs Therapy!!! Occurrence of chronic low-grade adverse events Impaired Quality of Life Risk of inadequate drug compliance and poorer clinical outcome Age-increasing incidence of multi-morbidity requires intake of several drugs, leading to a higher risk for medication interaction No TKI during pregnancy and nursing Negative impact on growth and development in children and adolescents Lifelong CML-therapy; Cost implications on the patient and the community Eliasson L et al., Leuk Res, 2011;35(5):626-30 Noens L et al., Blood, 2009;13:5401 5411 Marin DJ et al.,clin Oncol, 2010;28:2381 2388 Akker M van den et al., J Clin Epidemiol, 1998;51:367 375 Akker M van den et al.,eurj GenPract, 1996;14:65 70 Tasigna Prescription information; September 2015.Novartis Pharma GmbH Glivec Prescription information; May 2016.Novartis Pharma GmbH Bansal D et al.,pediatr Blood Cancer, 2012;59(3):481-4
TFR and QoL
Probability of MMR Probability of CMR Achieving Molecular Response Long-term Adherence to Imatinib Is Critical for Achieving Molecular Response 1.0 MMR Adherence > 90% (n = 64) Adherence 90% (n = 23) 1.0 CMR Adherence > 90% (n = 64) Adherence 90% (n = 23) 0.8 P <.001 0.8 P =.002 0.6 0.6 0.4 0.4 0.2 0.2 0 0 6 12 18 24 30 36 42 48 54 60 66 72 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Mos Since Start of Imatinib Therapy Mos Since Start of Imatinib Therapy Marin D, et al. J Clin Oncol. 2010;28:2381-2388.
STIM1: Patients With Sustained Deep Molecular Responses on Imatinib Can Maintain TFR
Cost Saving Taking into account the cost of imatinib and the number of months without treatment. The Saving in STIM (1 & 2) = 8.6 millions
Patients included between May 2012 and December 2014
EURO-SKI: Molecular Relapse Free Survival (n= 750)
Univariate analysis for relapse free survival at 6 months Significant association Treatment duration with imatinib MR4 duration Duration of IFN pre-treatment No significant association Age Gender Depth of molecular response (MR4.5vs. not in MR4.5) any variable part of the Sokal, EURO, EUTOS or ELTS scores
ENEST freedom: Study Design
ENEST freedom: Kaplan-Meier Estimated Treatment-Free Survival
Nilotinib Results in Higher Rates of MR4.5 vs Imatinib
ENESTfreedom: Response to Nilotinib Re-initiation
Leukemia(2016)30,1638 1647; doi:10.1038/leu.2016.115 Hematology-2017-Mahon-102-9
TKI Discontinuation/TFR A Novel Treatment Milestone Multiple studies have consistently demonstrated the safety and feasibility of stopping treatment TKI discontinuation is an emerging goal of CML management and is happening right now Patient awareness of TFR has resulted in increasing need for who can appropriately discontinue TKI A sustained DMR and long-term TKI therapy seem to be necessary prior to attempting TFR
Are we ready for routine discontinuation? Treatment discontinuation may be considered in individual patients, if proper, high-quality, and certified monitoring can be ensured. Pre-requisites for safe stopping are: 1. Institutional requirements for safe supervision 2. Identification of typical BCR-ABL1 transcripts at diagnosis 3. At least 5 years of TKI therapy 4. Achievement of DMR (MR4 - MR4.5) 5. Stability of DMR (at least MR4) for at least 2 years
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