10/25/14 CML: Overview, Controversies, and Management Through - - PDF document

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Elias Jabbour, MD MD Anderson Cancer Center Phyllis McKiernan, APN, MSN, OCN John Theurer Cancer Center Hackensack University Medical Center

CML: Overview, Controversies, and Management Through Collaborative Practice

Elias Jabbour, MD MD Anderson Cancer Center Phyllis McKiernan, APN, MSN, OCN John Theurer Cancer Center Hackensack University Medical Center § 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.

Disclosure

§ 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

• ral therapeutic options for CML

Learning Objectives

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Interferon TKI

Survival in Early Chronic-Phase CML

Kantarjian H. Blood. 2012;119:1981–1987.

Chemotherapy

Parameter Historical Modern Course Fatal Indolent Prognosis Poor Excellent 10-yr survival 10% 84%–90% Front-line Rx Allo-SCT; IFN-α Imatinib; nilotinib; dasatinib Second-line Rx ? New TKIs; allo-SCT

CML: Historical vs. Modern Perspective

IFN = interferon; SCT = stem cell transplant.

§ 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

CML Therapy in 2014

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§ 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%; MR4.0 66%

• MR4.0 intent-to-treat (ITT) at 60 mo = 33%
• Stable MR4.0 (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%)

Imatinib Front-Line Therapy for CML Long-Term Follow-Up: GIMEMA

MR4.0 = deep molecular response Castagnetti F, et al. Blood. 2013;122, Abstract 258.

Nilotinib vs. Imatinib in Newly Diagnosed Chronic-Phase (CP) CML

Outcome Nil 300 Nil 400 IM 400 % complete cytogenetic response (CCyR)* 87 85 77 % MMR** 77 77 60 % BCR-ABL ≤ 0.0032%** 54 52 31 % Transformed accelerated phase/blast crisis (AP/BP) 3.5 2.1 7.1 % 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.

§ 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 ¡

Dasatinib vs. Imatinib in Newly Diagnosed Chronic-Phase CML

Cortes JE, et al. Blood. 2013;122, Abstract 653.

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)

§ 519 patients randomized to dasatinib 100 mg qd (n = 259) or imatinib 400 mg qd (n = 260) § Minimum follow-up 48 mo ¡

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Imatinib Relative risk Dasatinib Relative risk Nilotinib Relative risk Marrow/ tumor bleed 14–27 Pleural effusion 17–60 Femoral artery necrosis 409 Bleeding 9.4 Pericardial effusion 10 Peripheral arterial

• cclusive disease

191 Effusion- ascites 4.5–5.6 Pulmonary arterial hypertension 4.0 Coronary stenosis 185 Angina 7.2 Myocardial infarction 4.9 Arterial ischemia 4.0

CML: Relative Risks of Uncommon Events

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 MMR Modest improvement in EFS; possible longer duration CCyR; no survival benefit Complete molecular response (CMR) Possibility of Rx discontinuation (clinical trials only)

§ 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

Case 1

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§ Therapy is well tolerated by the patient § At 3 mo, BCR-ABL is 20% IS What would you do?

Timeline: Patient Monitoring and Treatment

Initiate imatinib 400 mg qd 3 mo BCR- ABL 20% IS

NCCN Response Milestones

3 mo BCR-ABL/ABL ≤ 10% (IS) or PCyR

Milestone Not Reached IS = International Scale; NCCN = National Comprehensive Cancer Network.

Probability of survival Time from onset of imatinib therapy (yr) BCR-ABL/ABL < 9.8% OS = 93.3% BCR-ABL/ABL > 9.8% OS = 54%

p<0.0001

Optimal PCR value determined by receiver operating characteristic (ROC) curve

Survival After Imatinib Therapy by Molecular Response Achieved at 3 Months

PCR = polymerase chain reaction Marin D, et al. ASCO 2012, Abstract 232.

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%

% Survival/TFS by Early Molecular Response

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.

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The Problem With the 3 Months Response

Transcripts ¡ Time ¡

3 ¡mo ¡

10% ¡

Are ¡these ¡the ¡same? ¡ Are ¡these ¡the ¡same? ¡ Myelosuppression ¡ Rash ¡ Nonadherence ¡

Response No. % at 4 yr 3 mo 6 mo 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

Outcome by Response at 3 and 6 Months

Branford S, et al. Blood. 2013;122, Abstract 254.

§ Mutation analysis revealed no detectable BCR-ABL kinase domain mutations

Timeline: Patient Monitoring and Treatment

Initiate imatinib 400 mg qd 3 mo BCR- ABL 20% IS NCCN Response Milestones 3 mo BCR-ABL/ABL ≤ 10% (IS) or PCyR Milestone Not Reached

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§ Therapy is well tolerated by the patient § At 3 mo, BCR-ABL is 20% IS We decided to continue therapy and monitor by QPCR at 6 mo

Timeline: Patient Monitoring and Treatment

Initiate imatinib 400 mg qd 3 mo BCR- ABL 20% IS NCCN Response Milestones 3 mo BCR-ABL/ABL ≤ 10% (IS) or PCyR No mutations detected

§ Therapy continued to be well tolerated by the patient with minor supportive interventions § QPCR at 6 mo showed BCR-ABL levels of 14% IS

Timeline: Patient Monitoring and Treatment

Initiate imatinib 400 mg qd 3 mo BCR- ABL 20% IS

NCCN Response Milestones

3 mo BCR-ABL/ABL ≤ 10% (IS) or PCyR 6 mo BCR- ABL 14% IS

Molecular Monitoring in a Community Setting in the US

CGCR = complete cytogenetic response Chen L, et al. ASCO 2013, Abstract 7093.

% 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 § Newly diagnosed pts initiating TKI from 6/07 to 3/11 § 189 pts with ≥ 18 mo follow-up § 15% no CGCR or PCR 1,226 PCRs: 25% IS, 69% non-IS, 9% unknown

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§ 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

CML Monitoring

BM = bone marrow; FISH = fluorescence in situ hybridization.

Criteria for Response/Failure and Change of Therapy ELN 2013

CCA = clonal chromosome abnormalities; CHR = complete hematologic response. Baccarani M, et al. Blood. 2013;122:872–884

Time Optimal Warning Failure Diagnosis _ High risk CCA in Ph+ _ 3 mo PCGR and/or < 10% Ph+ 36%–95% and/or > 10% No CHR and/or 95% Ph+ 6 mo CCyR and/or < 1% Ph+ 1%–35% and/or 1%‒10% Ph+ > 35% and/or > 10% 12 mo MMR < 0.1%‒1% > 0% Ph+ and/or > 1% Then at any time Less than MMR CCA/Ph- (-7 or 7q-) Loss of CHR, loss of CCyR, confirmed loss

• f MMR, mutations,

CCA/Ph+

ELN2013: Definitions of response to TKIs first line

Criteria for Response/Failure and Change of Rx

Time (mo) Imatinib Second TKIs 3–6 mo Major CG; QPCR ≤ 10% CG CR; QPCR ≤ 1% 12 mo CGCR CGCR Later CGCR CGCR § CG ≤ 35% ≈ QPCR ≤ 10% § CGCR ≈ QPCR ≤ 1%

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Clinical condition % Positive Failure 27 No CHR at 3 mo 19 No CyR at 6 mo 11 No PCyR at 12 mo 17 No CCyR at 18 mo 17 Loss CCyR 31 Loss CHR 50 Suboptimal 5 No CyR at 3 mo 7 No PCyR at 6 mo 5 No CCyR at 12 mo 8 No MMR at 18 mo Loss MMR 4

When to Look for Mutations?

Soverini S, et al. Blood. 2011;118:1208–1215 and Abstract 112

Mutation analysis in 1,301 pts receiving imatinib or second-generation TKI (GIMEMA) ¡

5 10 15 20 G250E Y253F/H E255G/K V299L F311I/L T315I F317L/V M351T E355G/A F359C/V H396P/R BCR/ABL Mutation % Imatinib Dasatinib Nilotinib

Spectrum and Frequency of BCR-ABL KD Mutations Recovered After TKI Therapy

%

10 G250E Y253F/H E255G/K V299L F311I/L T315I F317L/V M351T E355G/A F359C/V H396P/R

BCR/ABL Mutation

Imatinib Nilotinib Dasatinib

5 15 20

KD = kinase domain Cortes J, et al. Blood. 2007;110:4005–4011.

Timeline: Patient Monitoring and Treatment

§ Dasatinib therapy was initiated at 100 mg qd

Initiate imatinib 400 mg qd 3 mo BCR- ABL 20% IS NCCN Response Milestones 3 mo BCR-ABL/ABL ≤10% (IS) or PCyR 6 mo BCR- ABL 14% IS Initiate dasatinib 100 mg qd

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Timeline: Patient Monitoring and Treatment

§ At 12 mo, QPCR revealed BCR-ABL levels of 1% IS § Treatment continued to be well tolerated

Initiate imatinib 400 mg qd 3 mo BCR- ABL 20% IS NCCN Response Milestones 3 mo BCR-ABL/ABL ≤10% (IS) or PCyR 6 mo BCR- ABL 14% IS Initiate dasatinib 100 mg qd 12 mo BCR- ABL 1% IS 12 mo CCyR

Timeline: Patient Monitoring and Treatment

§ At 24 mo, QPCR revealed BCR-ABL levels of 0.4% IS § Treatment continued to be well tolerated What would you do next?

Initiate imatinib 400 mg qd 3 mo BCR- ABL 20% IS NCCN Response Milestones 3 mo BCR-ABL/ABL ≤10% (IS) or PCyR 6 mo BCR- ABL 14% IS Initiate dasatinib 100 mg qd 12 mo BCR- ABL 1% IS 12 mo CCyR 24 mo BCR- ABL 0.4% IS

EFS and Survival by 12-mo Response: CCyR vs. Others With TKI Frontline Rx

Jabbour E. Blood. 2011;118:4541–4546.

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EFS and Survival by 12-mo Response: CCyR With

• vs. Without MMR With TKI Frontline Rx

Jabbour E. Blood. 2011;118:4541–4546.

OS According to Response at 12 Months

Jabbour E, et al. EHA 2012.

Dasatinib 100 mg qd Imatinib 400 mg qd

MMR, N=95 CCyR (no MMR), N=86 <CCyR, N=28 < CCyR, N=52 MMR, N=64 CCyR (no MMR), N=89

Months Months

100 80 60 40 20 6 12 24 36 42 100 80 60 40 20 6 12 24 36 42

% Alive MMR and/or CCyR <CCyR p = .0503 MMR and/or CCyR <CCyR p = .0041

Outcome (%) Nilotinib n = 104 Imatinib n = 103 Confirmed CMR 12 mo 13 6 Confirmed CMR 24 mo 22 9 CMR 32 17 MR4.5 43 21 MR4 49 26 Discontinued Rx, % 23 9 Adverse event(s) 12 3 Withdrawal of consent 6 3 Death 1 Other† 5 3

ENESTcmr: Results

Hughes TP, et al. ASH 2012, Abstract 694.

†Includes toxicity, noncompliance pregnancy, protocol violation, and transient loss of MMR.

13 ¡

14 ¡

§ 207 pts with CML CP treated with imatinib ≥ 2 yr, in CCyR with persistent disease by PCR § Randomized to continue imatinib 400–600 mg or change to nilotinib.

Net change

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Criteria for Response/Failure and Change of Rx

Time (mo) Imatinib Second TKIs 3–6 mo Major CG; QPCR ≤ 10% CG CR; QPCR ≤ 1% 12 mo CG CR CG CR Later CG CR CG CR § CG ≤ 35% ≈ QPCR ≤ 10% § CGCR ≈ QPCR ≤ 1%

Criteria for Response/Failure and Change of Therapy ELN 2013

Baccarani M, et al. Blood. 2013;122:872–884

Time Optimal Warning Failure Diagnosis – High risk CCA in Ph+ – 3 mo PCgR and/or < 10% Ph+ 36%–95% and/or > 10% No CHR and/or 95% Ph+ 6 mo CCyR and/or < 1% Ph+ 1-35% and/or 1%‒10% Ph+ >35% and/or > 10% 12 mo MMR < 0.1%‒1% > 0% Ph+ and/or > 1% Then at any time Less than MMR CCA/Ph- (-7 or 7q-) Loss of CHR, loss of CCyR, confirmed loss

• f MMR, mutations,

CCA/Ph+

ELN2013: Definitions of response to TKIs first line

Adherence to Imatinib

Response % Response at 6 yr by Adherence Rate p value > 90% N = 64 ≤ 90% N = 23 MMR 94 14 <.0001 CMR 44 .002 § 87 pts on imatinib for ≥ 2 yr § Compliance measured by: self-reporting, pill count, and microelectronic monitoring system (MEMS) ¡

§ Poor correlation between 3 methods § MVA for molecular response: adherence (MMR and CMR) and OCT1

(CMR)

Marin D, et al. J Clin Oncol. 2010;28(14):2381–2388.

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Adherence Is the Most Important Factor Contributing to Molecular Responses

Marin D, et al. J Clin Oncol. 2010;28(14);2381–2388.

Adherence monitored over a period of 3 months using a microelectronic monitoring device in the imatinib bottle cap. Patients were not aware of the device.

0.1 12 Time Since Start of Imatinib Therapy (mo) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 6 18 24 30 36 42 48 54 60 66 72 Probability of MMR

Adherence > 90% (n = 64) Adherence ≤ 90% (n = 23) p < .001

ATP binding T315I-active Non-kinase Inhibition Bcr-Abl Abl + Src Imatinib Dasatinib Ponatinib Omacetaxine Nilotinib Bosutinib DCC-2036 Decitabine INNO-406 XL228 AZD 0530 PHA-739358 KW-2449

Inhibition of Bcr-Abl

Parameter Dasatinib Nilotinib Bosutinib Potency (fold vs. IM) 325 30 20–50 Target Src + Abl Abl Src + ABL BCR-ABL binding Active + Inactive Inactive Intermediate Resistant mutations T315I T315I T315I Mutations with intermediate sensitivity E255K/V, V299L, F317L E255K/V, Y253F/H, Q252H, F359V E255V/K, V299L, F317L Standard dose (CP) 100 mg qd 400 mg bid 500 mg qd Grade 3/4 neutropenia + thrombocytopenia 33% / 22% 31% / 33% 12% / 21% Other notable toxicities Pleural effusion, bleeding Bilirubin, lipase elevation Diarrhea, rash C-kit inhibition (vs. imatinib) Increased Similar None PDGFR inhibition (vs. imatinib) Increased Similar None Clinical activity Highly active Highly active Highly active

Second-Generation TKI in CML

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Second-Generation TKI in CML CP Post-Imatinib Resistance

Shah NP, et al. Haematologica. 2010;95:232–240; Kantarjian H, et al. Blood. 2011;117:1141–1145; Cortes JE, et al. Blood. 2011;118:4567–4576.

Response Percentage Dasatinib Nilotinib Bosutinib Follow-up > 24 mo > 24 mo 24 mo* CHR 89 77 86 MCyR 59 56 54 CCyR 44 41 41 24-mo PFS** 80% 64% 79% 24-mo OS** 91% 87% 92%

Second-Generation TKI in CML CP Post-Imatinib Failure

Toxicity Dasatinib Nilotinib Bosutinib Pleural effusion ++

• Liver

+ + + Transaminases + + ++ Bilirubin

• ++
• Rash

+ + ++ Diarrhea

• ++

Lipase

• (+)

++

• Glucose
• ++
• Hypophosphatemia

++ ++ + Bleeding +

• QTc

++ ++

• Second-Generation TKI in CML CP

Post-Imatinib Failure (cont)

Shah NP, et al. Haematologica. 2010;95:232–240; Kantarjian H, et al. Blood. 2011;117:1141–1145; Cortes JE, et al. Blood. 2011;118:4567–4576.

Toxicity Dasatinib Nilotinib Bosutinib Anemia 13 11 13 Neutropenia 35 31 18 Thrombocytopenia 23 30 24

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§ 123 pts treated with dasatinib (n = 78) or nilotinib (n = 45) after imatinib failure § Multivariate analysis for predictors of outcome § Adverse factors: PS ≥ 1 and lack of CG response to imatinib

Predictive Factors of Outcome With Second-Generation TKI

Jabbour E, et al. Blood. 2011;117:1822–1827.

Risk factors N (%) Percentage 24 mo 12 mo EFS OS MCyR 59 (48) 78 95 64 1 48 (39) 49 85 36 2 5 (4) 20 40 20 p value .001 .002 .007

Predictors of Outcome to Second-Line TKI in CML

Jabbour E, et al. Blood. 2010;116, Abstract 2289; Jabbour E, et al. Clin Lymphoma Myeloma Leuk. 2013 Jan 11. [Epub ahead of print]

§ 123 pts treated with dasatinib (n = 78) or nilotinib (n = 45) after imatinib failure § Median follow-up 76 mo (range, 25–109 mo) § MCyR 63%, CCyR 59%, 3-yr EFS 53%, 3-yr OS 84% § 3-mo CCyR 33% MVA: 3-mo CCyR only factor independently associated with EFS (p < .001) and OS (p = .03)

§ Dual Src & Abl inhibitor, no effect over c-kit or PDGFR § 114 pts who failed imatinib (600 mg) and dasatinib or nilotinib

Response to Bosutinib Third-Line Therapy

Khoury HJ, et al. Blood. 2010;116, Abstract 892.

Response, % IM + D resistant (n = 36) IM + D intolerant (n = 51) IM + NI resistant (n = 27) CHR 61 80 78 MCyR 29 37 29 CCyR 9 34 17 PCyR 21 3 13 MMR 8 36 6

IM = imatinib; D = dasatinib; NI = nilotinib

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§ 93% failed ≥ 2 TKI, 58% failed ≥ 3 TKI

Ponatinib Phase II Study – PACE Response Characteristics CP-CML

Cortes J, et al. Blood. 2012;120, Abstract 163.

Response rate, n (%) N = 267 Any cytogenetic response 180 (67) MCyR 149 (56) CCyR 124 (46) MMR 91 (34) MR4.5 39 (15) BCR-ABL ≤10% at 3 mo, n/N(%) 142/240 (59) 1 prior approved TKI 14/16 (88) Median time to response* (range) MCyR 2.8 mo (1.6–11.3 mo) MMR 5.5 mo (1.8–19.2 mo)

*91% MCyR sustained at 12 mo (K-M) ¡

§ 122 pts with CML CP (n = 81) or AP (n = 41) with ≥ 2 prior TKI § Omacetaxine 1.25 mg/m2 bid × 14d, then × 7d

Omacetaxine for CML CP After Failure to ≥ 2 TKI

Kantarjian H, et al. Blood. 2012;120, Abstract 2767.

Response, % CP N = 81 AP N = 41 Primary endpoint MCyR 20% MaHR 27% CCyR 10% CHR 24% Median duration 17.7 mo 9 mo Median PFS 9.6 mo 4.7 mo Median OS 33.9 mo 16 mo

§ 11 pts (9 CP, 2 AP) ongoing response § Median 35 cycles over median 39 mo § Median response duration: 14 mo CP, 24 mo AP

§ ≥ 12 mo: Less than/loss of CCyR, and/or PCR > 1% (IS)

• Switch based on mutations and comorbidities

§ At 6 mo

• PCyR and PCR ≤ 10% (IS): Good
• PCyR and PCR > 10% (IS)

§ If imatinib, then switch to second TKI § If 2nd TKI:

– Check for adherence and comorbidities – Mutation profile – Concern: Maybe waiting and reassess at 12 mo, 10-yr OS of 85%

§ Loss of CyR: Confirm PCR increase by karyotype § Do not react to isolated PCR changes

When to Switch, and to What?

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§ Disease characteristics

• AP/BP: Favor dasatinib (?) and combinations
• Chronic: See below

§ Mutations

• T315I → ponatinib
• Nilotinib IC50 > 150 nM → avoid
• Dasatinib IC50 > 3 nM → avoid

§ Patient history

• Hypertension, CHF, lung problems, COPD → avoid dasatinib
• Severe diabetes, pancreatitis history, atherosclerosis → avoid nilotinib
• QTc problems → be cautious with all (?)

How Do You Choose the Second-Generation TKIs?

CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease.

CML: Role and Timing of Allo-SCT

Status TKIs Allo SCT AP-BP Interim Rx to MRD ASAP IM failure in CP, T315I Ponatinib interim Rx to MRD ASAP IM failure in CP: no CE, no mutations, good initial response Long-term second-line TKIs Third-line post second TKI failure IM failure in CP: CE, bad mutations, no CG response Interim Rx to MRD Second line Older ≥ 65–70 post IM failure Long term May forgo allo-SCT for many years of QOL

MRD = minimal residual disease; QOL = quality of life.

Timeline: Patient Monitoring and Treatment

§ At 36, 48, and 54 months, QPCR revealed undetectable BCR-ABL levels Can we stop therapy?

Initiate imatinib 400 mg qd 3 mo BCR- ABL 20% IS NCCN Response Milestones 3 mo BCR-ABL/ABL ≤10% (IS) or PCyR 6 mo BCR- ABL 14% IS Initiate dasatinib 100 mg qd 12 mo BCR- ABL 1% IS 12 mo CCyR 24 mo BCR- ABL 0.4% IS 54 mo BCR- ABL UND

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The overall probability of maintenance of CMR at 24 and 36 months was 39% (95% CI, 29%–48%) Molecular relapse occurred in 61 pts, with 58 relapses occurring during the first 7 months; 3 late relapses at months 19, 20, and 22, respectively

STIM: Duration of CMR

Mahon FX, et al. Blood. 2011;118, Abstract 603

§ ~ 45% of patients achieve sustained undetectable transcriptsa § ~ 39% sustained CMR 24 mo after discontinuationb .45 × .39 = .17

~ 18% of patients may discontinue therapy and maintain CMR

How Many Patients Can Stop Therapy?

aFalchi F, et al. ASH 2012, Abstract 164; bMahon FX, et al. ASH 2011, Abstract 603.

Pros § QOL issues with TKIs § Long-term toxicities: renal, cardiac, CNS, PNS, POD § Pregnancy in women § Concept of molecular cure § Economic factors Cons § Misinterpretation of message § Potential long-term harm in a minority (e.g., sudden BP)

Discontinuation of TKIs: Pros and Cons

CNS = central nervous system; PNS = peripheral nervous system; POD = progression of disease.

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§ Older agents: Peginterferon alfa-2a, decitabine, omacetaxine § Sexy agents: Hedgehog inhibitors, JAK2 inhibitors, IL3-DT toxins

CML: Eradication of MRD

§ Rare syndrome of fetal malformations (exomphalos, kidneys, bones) in 3/125 § Stop imatinib if pregnancy § Female partners of males on TKIs → no problems § If pregnancy/children highly desired: Achieve durable CMR on TKIs then hold TKI and proceed with pregnancy/delivery under closer monitoring (e.g., FISH/QPCR every 2–3 mo)

Imatinib and Pregnancy Take-Home Message – CML 2014

§ Great therapy for CML § CGCR is endpoint of Rx = improves survival § Early response (3 mo) predictive

• Should not change at 3 mo
• Monitor at 6 mo and decide

§ Deeper molecular responses improve event-free survival

• No impact on transformation or survival
• No clear benefit for CMR (except discontinuation?)

§ Excellent new drugs: ponatinib, bosutinib, omacetaxine

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Leukemia Questions? Pager 713-606-1307 ejabbour@mdanderson.org

Elias Jabbour, MD “Born to Treat Leukemia—No Plan B”

(Courtesy of Van Morrison)

Management of CML Through Collaborative Practice

CML: Patient Experience

§ Diagnosis

• Disease education
• Treatment options

§ Treatment initiation

• Insurance approval
• Drug access
• Administration instructions
• Potential side effects
• Drug/food interactions

§ Monitoring

• Defined schedule for follow-up
• Guidelines

§ Ongoing management

• Adherence
• Side effect management
• Drug interactions
• Lifestyle changes
• Quality of life

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§ Hematologist § Advanced practitioner (AP) § Registered nurse coordinator § Other health professionals

• Pharmacist
• Social worker
• Research coordinator

CML Treatment Team

Holloway S, et al. Clin Lymphoma Myeloma Leuk. 2012;12:88–93

§ Provide education at diagnosis and ongoing

• Written and oral
• CML and treatment
• Medication administration

§ Establish monitoring schedule § Perform procedures § Drug interactions § Manage side effects § Evaluate adherence § Empower the patient to assist in management of their disease

Role of the AP

Coleman M. Clin J Oncol Nurs. 2014;18:E12–E18; Holloway S, et al. Clin Lymphoma Myeloma Leuk. 2012;12:88–93.

§ Tim, a 62-year-old small business owner, presents with fatigue to his primary MD § Past medical history: Hypercholesterolemia, otherwise healthy § Current medications: Atorvastatin 10 mg daily, MVI § Physical exam: Mild left upper quadrant tenderness, otherwise unremarkable § CBC

• WBC 56,000
• Hgb 9.2
• Hct 26.8
• MCV 109
• Platelets 275,000

§ Bone marrow biopsy: CML chronic phase § Referred to hematologist

Case Study

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§ NCCN Guidelines

• H&P
• CBC, chem
• HLA typing
• Bone marrow biopsy

§ Morphology § Blasts % § Basophils % § Cytogenetics

• FISH
• qRT-PCR (blood or bone marrow)
• Risk score

Diagnosis

NCCN Guidelines CML, Version 3.2014

§ Initial meeting with MD and AP

• Disease education, treatment options, monitoring guidelines, and

follow-up schedule discussed

• Labs/tests

§ CBC, chemistry, EKG, baseline qRT-PCR (IS)

• Comorbidities/past medical history
• Current medications
• Lifestyle
• Social barriers to care

§ Initiates therapy TKI

Case Study

• A. Drug access/cost
• B. Side-effect management
• C. Lifestyle changes
• D. Drug interactions
• E. All of the above

What are some potential issues Tim faces during his treatment for CML?

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§ Cost

• TKI prices range from $92,000 to $132,000 annually in the US
• Insurance coverage

§ High co-pays § Lack of reimbursement

• Patient assistance programs

§ Glivec International Patient Assistance Program § Pharmaceutical company programs § Other organizations/private funding

§ Time spent by providers assisting with access

Drug Access

Experts in CML. Blood. 2013; Simoneau CA. Clin J Oncol Nurs. 2013;17:E13–E20.

§ Every 1–2 wk after initial therapy until stable then every 3 mo

• CBC
• Chemistry
• Side-effect management

§ Proactive § Reactive

• Drug interactions
• Adherence

Monitoring

§ 3 mo: qRT-PCR (IS)

• BCR-ABL 1 < 10% continue current TKI and

monitor every 3 mo

• BCR-ABL 1 > 10%

§ Check drug interactions § Adherence § Mutation analysis § Switch to alternate TKI

Monitoring

NCCN Guidelines CML, Version 3.2014.

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§ 12 months

• Bone marrow biopsy

§ CCyRL: continue current therapy § Less than CCyR – Check drug interactions – Adherence – Mutation analysis – Switch to alternate TKI/increase dose imatinib – Consider allogeneic transplantation – Consider clinical trial

Monitoring

National Comprehensive Cancer Network. NCCN Clinical Guidelines in Oncology. CML, Version 3.2014

Case Study (cont)

During Tim’s first few weeks of treatment, he complains of daily diarrhea that interferes with his work and social functioning.

The AP should do all of the following except:

A. Attempt to manage Tim’s diarrhea through supportive care B. Determine if Tim has missed any doses of medication C. Insist that Tim stay on his current TKI due to efficacy data D. If no improvement in symptoms, discuss alternate TKI therapy with the hematologist and provide education to Tim

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Management of TKI Side Effects

Hochhaus A. Hematology, 2011; NCCN Guidelines, CML Version 3.2014; Pinilla-Ibarz J, et al. Cancer. 2011;117:688–697; Simoneau CA. Clin J Oncol Nurs, 2013;17:E13–E20.

Adverse Event Recommended Management Grade 3/4 neutropenia or thrombocytopenia Dose interruption/reduction; transfusions; colony stimulating agent Diarrhea Supportive care; avoid sugar substitutes, anti-diarrheals Nausea/vomiting Supportive care; antiemetics; take with large meal and fluid (except nilotinib) Rash/pruritus Topical steroids; dose interruption/reduction Muscle cramps/myalgia Calcium; tonic water; magnesium; NSAIDs Weight gain/fluid retention Diuretics; decrease sodium intake; check thyroid function Pleural effusion Diuretics; dose interruption/adjustment; steroids Hepatic Dose interruption/adjustment Lipase/amylase increase Dose interruption/adjustment Fatigue Correct anemia; check thyroid function; depression

§ Tim is referred to dietician for dietary modifications to control diarrhea § Prescribed antidiarrheal agents to use as needed § Reports improvement in symptoms § Evaluation at 3 mo shows BCR-ABL 1 transcript level 8.4% (IS) by qRT-PCR § Evaluation at 6 mo shows BCR-ABL 1 transcripts at undetectable levels § Bone marrow biopsy at 12 mo revealed a normal male karyotype

Case Study (cont)

§ Hematologic

• CBC with differential
• Diagnosis
• Monitor for myelosuppression or loss of response

Monitoring

Shah J. J Community Support Oncol. 2014;12:179–187; NCCN Guidelines CML, Version 3.2014.

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§ Cytogenetic

• Karyotyping
• FISH
• Diagnosis
• During TKI therapy

§ At 3 mo if qRT-PCR (IS) not available § At 12 mo if neither CCyR nor MMR achieved § At 18 mo if not in MMR and lack of CCyR at 12 mo § If > 1 log increase in BCR-ABL 1 transcript level without MMR

Monitoring

Armed Forces Institute of Pathology; NCCN Guidelines CML, Version 3.2014.

§ Molecular

• qRT-PCR (IS)

§ Quantitative real-time PCR using the International Scale

• Diagnosis
• During TKI therapy

§ Every 3 mo § After CCyR, every 3 mo for 3 yr, then every 3–6 mo § If > 1 log increase in BCR-ABL 1 level with MMR, repeat in 1–3 mo

Monitoring

NCCN Guidelines CML, Version 3.2014

§ BCR-ABL kinase domain mutation analysis

• During TKI

§ Lack of PCyR or BCR-ABL 1 > 10% (IS) at 3 mo § < PCyR at 12 months or < CCyR at 18 mo § Loss of response

– Hematologic or cytogenetic relapse – > 1 log increase in BCR-ABL 1 (IS) and loss of MMR

§ Progression to accelerated or blast phase

Monitoring

NCCN Guidelines CML, Version 3.2014.

10/25/14 ¡ 27 ¡

§ Tim has qRT-PCR testing done every 3 mo since his CCyR

• At 27 mo, he has a rise in his BCR-ABL 1 transcripts to 0.1%
• At 30 mo, the level was 0.02%
• At 33 mo, the level was 10%

§ Mutation analysis is negative and bone marrow cytogenetics show 2/20 Ph+ cells

Case Study (cont)

• A. Switch Tim to another TKI
• B. Refer Tim to the transplant team for immediate transplant
• C. Do nothing and repeat testing in 3 months
• D. Have a discussion with Tim about his adherence to taking his

medication

What should the AP do?

§ Critical for achieving MMR § Poor adherence

• Loss of CCyR
• More prevalent than clinicians believe
• Increased with poor side-effect management
• Increased inpatient treatment
• Increased cost
• Multifactorial

§ Should be assessed routinely

Adherence

Jabbour E, et al. Clin Lymphoma Myeloma Leuk. 2012;12:223–229; Marin D, et al. J Clin Oncol. 2010;28:2381–2388; Noens L, et al. Blood. 2009;113:5401–5411; Wu EQ, et al. Curr Med Res Opin. 2010;26:2861–2869.

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§ Age § Psychological/emotional factors § Expectations of treatment § Patient beliefs § Socioeconomic factors § Poor understanding of benefits of treatment § Cognitive impairment

Barriers to Adherence: Patient Variables

Accordino MK, et al. ASCO Educational Book, 2013; Jabbour E, et al. Clin Lymphoma Myeloma Leuk. 2012;12:223–229; Noens L, et al. Blood. 2009;113:5401–5411.

§ Complexity of regimen/multiple prescriptions § Toxicity/side effects § Cost § Time between diagnosis and treatment initiation § Length of therapy

Barriers to Adherence: Treatment Variables

Accordino MK, et al. ASCO Educational Book, 2013; Jabbour E, et al. Clin Lymphoma Myeloma Leuk. 2012;12:223–229; Noens L, et al. Blood. 2009;113:5401–5411.

§ Poor communication/relationship with patient § Minimal patient education § Poor consideration of patient lifestyle or beliefs § Limited experience in CML § Minimal time spent with patient

Barriers to Adherence: Provider Variables

Accordino MK, et al. ASCO Educational Book, 2013; Jabbour E, et al. Clin Lymphoma Myeloma Leuk. 2012;12:223–229; Noens L, et al. Blood. 2009;113:5401–5411.

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§ Patient/family education § Obtain help from family/community § Prompt initiation of therapy § Management of side effects proactively and reactively § Assistance with drug access § Encourage use of technology as reminders to take medication § Simplify regimens § Regular follow-up care

Strategies to Improve Adherence

Jabbour E, et al. Clin Lymphoma Myeloma Leuk. 2012;12:223–229; Osterberg L, et al. N Engl J Med. 2005;353:487–497.

§ Tim admits to not taking his medication while on vacation several months ago. He thought he was on the medication long enough that he could miss a few doses without harm. § The AP provides additional counseling, and Tim is restarted on his TKI. § BCR-ABL 1 transcript level fell to nondetectable in 3 months.

Case Study (cont)

§ Management of CML should be a multidisciplinary approach § Advanced practitioner plays a role in education, monitoring, and side-effect management § Empowering the patient with information can increase adherence § Recognize and address barriers to adherence § Employ strategies to improve adherence to maximize outcomes

Summary