10/25/14 ¡ CML: Overview, Controversies, and Management Through Elias Jabbour, MD Collaborative Practice MD Anderson Cancer Center Elias Jabbour, MD MD Anderson Cancer Center Phyllis McKiernan, APN, MSN, OCN John Theurer Cancer Center Phyllis McKiernan, APN, MSN, OCN Hackensack University Medical Center John Theurer Cancer Center Hackensack University Medical Center Disclosure § Dr. Jabbour has acted as a consultant for ARIAD, Bristol-Myers Squibb, Novartis, Pfizer, and Teva. § Ms. McKiernan has acted as a consultant/advisor for and received honoraria from Novartis Oncology. Learning Objectives § Define the current efficacy and safety profiles of first-, second-, and third-generation tyrosine kinase inhibitors (TKIs) in the treatment of patients with chronic myelogenous leukemia (CML) § Describe genetic and molecular profiling and newly approved therapies for the treatment of CML § Identify common adverse effects of TKIs § Discuss the role of the advanced practitioner in the multidisciplinary management of patients with CML § Implement effective strategies to optimize patient adherence to oral therapeutic options for CML 1 ¡
10/25/14 ¡ Survival in Early Chronic-Phase CML TKI Interferon Chemotherapy Kantarjian H. Blood . 2012;119:1981–1987. CML: Historical vs. Modern Perspective Parameter Historical Modern Course Fatal Indolent Prognosis Poor Excellent 10-yr survival 10% 84%–90% Allo-SCT; Imatinib; nilotinib; Front-line Rx IFN- α dasatinib Second-line Rx ? New TKIs; allo-SCT IFN = interferon; SCT = stem cell transplant. CML Therapy in 2014 § Front line • Imatinib 400 mg daily • Nilotinib 300 mg bid • Dasatinib 100 mg daily § Second and third line • Nilotinib, dasatinib, bosutinib, ponatinib • Allogeneic SCT § Other • Omacetaxine, decitabine, peginterferon alfa-2a • Hydroxyurea, cytarabine, combos of TKIs and with TKIs • Investigational: Hedgehog inhibitors, JAK2 inhibitors, IL-3-DT 2 ¡
10/25/14 ¡ Imatinib Front-Line Therapy for CML Long-Term Follow-Up: GIMEMA § 559 patients from 3 separate studies (24% imatinib 800) • Median age 52 yr (range, 18–84 yr) § Median follow-up 76 mo (range, 37–99 mo) § Cumulative rate major molecular response (MMR) 86%; MR 4.0 66% • MR 4.0 intent-to-treat (ITT) at 60 mo = 33% • Stable MR 4.0 (i.e., ≥ 18 mo, ≥ 3 samples) = 19% § Discontinued imatinib, 35% § 96 months: Progression-free survival (PFS) 84%; failure-free survival (FFS) 66%; overall survival (OS) 85% • Worse survival for high Sokal score (88% vs. 94%–97%) MR 4.0 = deep molecular response Castagnetti F, et al. Blood . 2013;122, Abstract 258. Nilotinib vs. Imatinib in Newly Diagnosed Chronic-Phase (CP) CML § 846 patients randomized to nilotinib 300 mg bid (n = 282), nilotinib 400 mg bid (n = 281), or imatinib 400 mg qd (n = 283) § Minimum follow-up 5 yr ¡ Outcome Nil 300 Nil 400 IM 400 % complete cytogenetic 87 85 77 response (CCyR)* % MMR** 77 77 60 % BCR-ABL ≤ 0.0032%** 54 52 31 % Transformed accelerated phase/blast 3.5 2.1 7.1 crisis (AP/BP) % 5-yr event-free survival (EFS) 92 95 91 % 5-yr OS 94 96 92 *By 24 months. **By 60 months (Kaplan-Meier). Saglio G, et al. Blood. 2013;122, Abstract 92. Dasatinib vs. Imatinib in Newly Diagnosed Chronic-Phase CML § 519 patients randomized to dasatinib 100 mg qd (n = 259) or imatinib 400 mg qd (n = 260) § Minimum follow-up 48 mo ¡ Outcome DAS 100 IM 400 % CCyR* 86 82 % MMR** 74 60 % BCR-ABL ≤ 0.0032%** 34 21 % Transformed AP/BP 5 7 % 4-year PFS 90 90 % 4-year OS 93 92 *By 24 months **By 48 months (Kaplan-Meier) Cortes JE, et al. Blood . 2013;122, Abstract 653. 3 ¡
10/25/14 ¡ CML: Relative Risks of Uncommon Events Relative Relative Relative Imatinib risk Dasatinib risk Nilotinib risk Marrow/ Pleural Femoral artery 14–27 17–60 409 tumor bleed effusion necrosis Pericardial Peripheral arterial Bleeding 9.4 10 191 effusion occlusive disease Pulmonary Effusion- 4.5–5.6 arterial 4.0 Coronary stenosis 185 ascites hypertension Angina 7.2 Myocardial 4.9 infarction Arterial ischemia 4.0 Saglio G, et al. Blood . 2013;122, Abstract 92; Cortes J, et al. Blood . 2013;122, Abstract 653. Important Response Categories in CML Response Translates into … CCyR Significantly improved survival Modest improvement in EFS; possible longer MMR duration CCyR; no survival benefit Complete molecular Possibility of Rx discontinuation response (CMR) (clinical trials only) Case 1 § 35-year-old male diagnosed with CP-CML following a regular checkup § No significant comorbidities or medical history; not currently on any medications § Initiated on imatinib 4 ¡
10/25/14 ¡ Timeline: Patient Monitoring and Treatment Initiate imatinib § Therapy is well tolerated by the patient 400 mg qd § At 3 mo, BCR-ABL is 20% IS 3 mo What would you do? BCR- ABL 20% IS Milestone Not Reached NCCN 3 mo Response BCR-ABL/ABL ≤ 10% Milestones (IS) or PCyR IS = International Scale; NCCN = National Comprehensive Cancer Network. Survival After Imatinib Therapy by Molecular Response Achieved at 3 Months Optimal PCR value determined by r eceiver operating characteristic (ROC) curve BCR-ABL/ABL < 9.8% OS = 93.3% � Probability of survival � BCR-ABL/ABL > 9.8% OS = 54% � p<0.0001 � Time from onset of imatinib therapy (yr) � PCR = polymerase chain reaction Marin D, et al. ASCO 2012, Abstract 232. % Survival/TFS by Early Molecular Response Study QPCR < 10% QPCR > 10% Marin (8 yr) 93% 54% MD Anderson (10 yr) 98% 94% ENEST-nd 97% 87% DASISION 97% 86% BELA 98% 88% TFS = transformation-free survival; QPCR = quantitative PCR Marin D, et al. J Clin Oncol . 2012;30:232–238; Jain P, et al. Blood . 2012;120, Abstract 70; Hochhaus A, et al. Blood . 2012;120, Abstract 167; Saglio G, et al. Blood . 2012;120, Abstract 1675; Brummendorf TH, et al. Blood . 2012;120, Abstract 69. 5 ¡
10/25/14 ¡ The Problem With the 3 Months Response Are ¡these ¡the ¡same? ¡ Are ¡these ¡the ¡same? ¡ Transcripts ¡ 10% ¡ Myelosuppression ¡ Rash ¡ Nonadherence ¡ 3 ¡mo ¡ Time ¡ Outcome by Response at 3 and 6 Months Response % at 4 yr 3 mo 6 mo No. Survival PFS FFS MMR ≤ 10% < 1 342 97 97 87 88 ≤ 10% 1–10 42 100 97 79 71 ≤ 10% > 10 10 89 90 51 56 > 10% < 1 18 100 100 76 88 > 10% 1–10 36 100 94 79 69 > 10% > 10 35 74 69 11 3.3 Branford S, et al. Blood . 2013;122, Abstract 254. Timeline: Patient Monitoring and Treatment Initiate imatinib § Mutation analysis revealed no 400 mg qd detectable BCR-ABL kinase domain 3 mo mutations BCR- ABL 20% IS Milestone Not Reached 3 mo NCCN BCR-ABL/ABL ≤ 10% Response (IS) or PCyR Milestones 6 ¡
10/25/14 ¡ Timeline: Patient Monitoring and Treatment Initiate imatinib § Therapy is well tolerated by the patient 400 mg qd § At 3 mo, BCR-ABL is 20% IS 3 mo We decided to continue therapy and BCR- ABL monitor by QPCR at 6 mo 20% IS No mutations detected NCCN 3 mo BCR-ABL/ABL ≤ 10% Response (IS) or PCyR Milestones Timeline: Patient Monitoring and Treatment Initiate imatinib § Therapy continued to be well tolerated 400 mg qd by the patient with minor supportive 3 mo 6 mo interventions BCR- BCR- § QPCR at 6 mo showed BCR-ABL ABL ABL 20% IS 14% IS levels of 14% IS NCCN 3 mo Response BCR-ABL/ABL ≤ 10% Milestones (IS) or PCyR Molecular Monitoring in a Community Setting in the US § Newly diagnosed pts initiating TKI from 6/07 to 3/11 § 189 pts with ≥ 18 mo follow-up § 15% no CGCR or PCR % with assessment by months on therapy 0–3 mo 3–6 mo 6–9 mo 9–12 mo 12–15 mo 15–18 mo CG 24 21 24 22 10 7 PCR 34 47 54 47 51 55 1,226 PCRs: 25% IS, 69% non-IS, 9% unknown CGCR = complete cytogenetic response Chen L, et al. ASCO 2013, Abstract 7093. 7 ¡
10/25/14 ¡ CML Monitoring § Establish confirmed CGCR in first year (BM at 6-12 mo) § In CGCR • FISH and QPCR every 6 mo • If MMR (QPCR < 0.1%), may monitor with QPCR only (watch for false results) • If QPCR ↑ by 0.5–1 log and/or loss of MMR (PCR > 0.1%) → monitor more frequently § Mutation studies if resistance/need to change TKIs § Change TKI only for loss of CGCR, not based on MMR/QPCR BM = bone marrow; FISH = fluorescence in situ hybridization. Criteria for Response/Failure and Change of Therapy ELN 2013 ELN2013: Definitions of response to TKIs first line Time Optimal Warning Failure High risk Diagnosis _ _ CCA in Ph+ PCGR Ph+ 36%–95% No CHR 3 mo and/or > 10% and/or 95% Ph+ and/or < 10% CCyR Ph+ 1%–35% Ph+ > 35% 6 mo and/or < 1% and/or 1% ‒ 10% and/or > 10% > 0% Ph+ 12 mo MMR < 0.1% ‒ 1% and/or > 1% Loss of CHR, loss of Then at any CCyR, confirmed loss Less than MMR CCA/Ph- (-7 or 7q-) time of MMR, mutations, CCA/Ph+ CCA = clonal chromosome abnormalities; CHR = complete hematologic response. Baccarani M, et al. Blood. 2013;122:872–884 Criteria for Response/Failure and Change of Rx Time (mo) Imatinib Second TKIs Major CG; CG CR; 3–6 mo QPCR ≤ 10% QPCR ≤ 1% 12 mo CGCR CGCR Later CGCR CGCR § CG ≤ 35% ≈ QPCR ≤ 10% § CGCR ≈ QPCR ≤ 1% 8 ¡
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