Discontinuation of Tyrosine Kinase Inhibitors in Chronic ...sites.utexas.edu/pharmacotherapy-rounds/files/2019/01/PhamD_Res-Rounds... · pathway IV. Epidemiology2,3,4 A. Constitutes

Pham | 1

Discontinuation of Tyrosine Kinase

Inhibitors in Chronic Myeloid Leukemia:

What’s Stopping us from Stopping?

David Pham, PharmD PGY2 Hematology/Oncology Pharmacy Resident

South Texas VA Health Care System

Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center, UT Health San Antonio

San Antonio, Texas

January 11, 2019

Learning Objectives:

1. Describe the disease state, diagnosis, and management of chronic myeloid leukemia (CML)

2. Compare and contrast tyrosine kinase inhibitors and other agents used in the management of CML

3. Evaluate the available literature regarding potential discontinuation of tyrosine kinase inhibitor therapy in

CML

4. Evaluate the available literature regarding potential second discontinuation of tyrosine kinase inhibitor

therapy in CML

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Figure 1. Stem Cell Differentiation Pathway

Chronic Myeloid Leukemia

I. Definition1

A. Myeloproliferative neoplasm that affects the myeloid lineage of the hematopoietic stem cell

differentiation pathway

B. Results in the overproduction of immature myeloid blast cells

C. Affects the production and maturation of red blood cells, white blood cells, and platelets

Table 1. Phases of CML2,F10

Chronic Phase (CP) Accelerated Phase (AP) Blast Phase (BP)

• Majority of

patients are

diagnosed during

chronic phase

• May or may not

be symptomatic

but typically

responsive to

standard

treatments

• Can progress to

accelerated or

blast phase if left

untreated

• Characterized by symptoms and increasing blast

count

• Can progress to blast phase if left untreated

• Worse prognosis

• Presents and behaves like an

acute leukemia

• Patients symptomatic with

high blast count

• Behaves like acute leukemia

• Worst prognosis

Modified criteria per MD Anderson Cancer Center

Criteria

• Peripheral blood myeloblasts between 15-30%

• Peripheral blood myeloblasts and promyelocytes

combined 30%

• Peripheral blood basophils 20%

• Platelets 100 x 109/L unrelated to therapy

• Additional clonal cytogenetic abnormalities in Ph+

cells

Criteria per International Bone

Marrow Transplant Registry

• 30% blasts in blood, bone

marrow, or both

• Extramedullary infiltrates of

leukemic cells

II. Background2

A. 1960 – BCR-ABL1 first identified by Drs. Nowell and Hungerford in Philadelphia, PA and CML

becomes first leukemia with chromosomal abnormality linked to pathophysiology

B. Historically, interferon was a standard therapy for the treatment of CML

i. Poor outcomes – 10-year survival of approximately 20%

ii. Toxic regimen – flu-like symptoms, depression, pancytopenia

C. Identified driver mutation found in 95% of CML cases

i. Target mutation treatment – tyrosine kinase inhibitors

ii. TKIs improve outcomes – 10-year survival of approximately 84-90%

a. Good efficacy with lifelong treatment

b. Tolerable adverse effect profile

https://www.medscape.com/viewarticle/500691_1

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Figure 3. BCR-ABL Tyrosine Kinase Pathway

III. Pathophysiology2,5

A. Abelson murine leukemia (ABL1) gene on

chromosome 9

B. Breakpoint cluster region (BCR) gene on

chromosome 22

C. Translocation (9;22)

i. Oncogene constitutively active

ii. Philadelphia chromosome

iii. Driver mutation for CML

iv. Utilizes a downstream signaling

pathway

IV. Epidemiology2,3,4

A. Constitutes approximately 15% of all new leukemia diagnoses in adults

B. Lifetime risk

i. Approximately 1 in 526 Americans will develop CML in their lifetime ii. About 50% of individuals with newly diagnosed CML are age 65 or older at the time of

diagnosis

C. Incidence

i. Affects approximately 1-2 individuals per 100,000 adults

ii. An estimated 8,430 individuals will be diagnosed with CML in 2018 with approximately

1,090 deaths

D. Survival

Figure 2. Philadelphia Chromosome

http://clincancerres.aacrjournals.org/content/17/2/212

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i. 10-year overall survival increased from ~20% to ~80-90% after 2001

V. Clinical Presentation2,5,10

A. Signs and symptoms

i. ~50% of patients asymptomatic diagnosis made after incidental findings

ii. Symptomatic patients may have fatigue, weight loss, splenomegaly, night sweats, easy

bleeding, malaise, loss of appetite

B. Laboratory findings

i. WBC >25,000 cells/mm3

ii. Megakaryocytosis, basophilia, eosinophilia

iii. May have hyperkalemia, hyperuricemia, increased lactate dehydrogenase

C. Bone marrow findings

i. Hypercellular (~75-90%), increased erythropoiesis, increased megakaryocytes, minimal

dysplasia, blasts <10%

VI. Diagnosis2,5,10

A. Bone marrow aspiration/biopsy

i. Can be utilized to confirm the diagnosis of CML

ii. Provides additional information regarding hypercellularity and blast and basophil

percentages iii. Able to detect chromosomal abnormalities other than the Philadelphia chromosome

B. Reverse transcriptase-polymerase chain reaction (RT-PCR) to evaluate BCR-ABL1 transcripts

i. Used to detect presence of residual disease while on treatment

ii. Can detect for presence (qualitative) or amount (quantitative) of BCR-ABL1 transcripts

VII. Risk Stratification5

A. Risk factors

i. Older age

ii. Being male

iii. Radiation exposure

B. Scoring systems used in CML6-10

i. Provides information regarding prognosis

ii. Types

• Sokal score – 1984

• Hasford (Euro) score – 1998

• European Treatment and Outcome Study (EUTOS) score – 2011

a. Shown to have stronger prognostic capabilities compared to Sokal score

b. Has not been validated yet in a subsequent study

iii. Only Sokal and Hasford scores currently recommended for use by National Comprehensive

Cancer Network (NCCN) guidelines

Figure 4. CML Survival Over Time https://seer.cancer.gov/statfacts/html/cmyl.html

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Table 2. Prognostic Score Equations6-10 Study Calculation Risk Definition

Sokal et al,

1984

Exp 0.0116 x (age in years – 43.4) + (spleen –

7.51) + 0.188 x [(platelet count ÷ 700)2 – 0.563]

+ 0.0887 x (blast cells – 2.10)

Low: <0.8

Intermediate: 0.8 – 1.2

High: >1.2

Hasford et

al, 1998

0.666 when age ≥50 years + (0.042 x spleen) +

1.0956 when platelet count > 1500 x 109/L +

(0.0584 x blast cells) + 0.20399 when basophils

> 3% + (0.0413 x eosinophils) x 100

Low: ≤780

Intermediate: 781 – 1480

High: >1480

iv. Categorizing CML as low, moderate, or high risk helps dictate choice of initial TKI used

• Low risk imatinib

• Intermediate or high risk dasatinib, nilotinib, bosutinib

Management I. Historical treatment timeline2,5

A. 1994 – Italian Cooperative Study Group: interferon vs. chemotherapy11

i. OS: 72 months vs. 52 months, p < 0.002

ii. Time to progression to AP/BP: 72 months vs. 45 months (p < 0.001)

iii. Patients undergoing allogeneic transplant: 36/322 patients (11%) data censored

iv. Patients stopping treatment due to toxic effects: 16% vs. 0% (p<0.001)

v. Adverse effects of interferon :

a. Usually multiple: Flu-like symptoms (asthenia, fever, headache, arthralgia,

myalgia), nausea, anorexia, diarrhea, weight loss

b. Stopping treatment: polyneuropathy; a syndrome of confusion, dizziness,

drowsiness, and depression

B. 2001 – Tyrosine kinase inhibitor therapy

i. In 2001, results from the IRIS trial introduced a new era of targeted therapy that has since

replaced interferon as the standard treatment for CML12

ii. TKIs have improved life expectancies, offered a more tolerable adverse effect profile, and

precluded the need for allogeneic transplant and its complications such as infections and graft

versus host disease

iii. Agents

a. First generation: imatinib

b. Second generation: dasatinib, nilotinib, bosutinib

c. Third generation: ponatinib

Table 3. First-line TKI Therapy for CP-CML: Long-term follow-up data10

Trial

Study

arms

No. of

patients

Median

follow-

up

CCyR

MMR

Disease

progression

n (%)

PFS

OS

IRIS12

Imatinib

400 mg

553

11

years

83%

---

38 (7%)

92%

83%

IFN- +

cytarabine

553 --- --- 71 (13%) --- 79%

DASISION13

Dasatinib

100 mg

259

5 years

--- 76%

(p=0.002)

12 (5%) 85% 91%

Imatinib

400 mg

260 --- 64% 19 (7%) 86% 90%

ENESTnd14

Nilotinib

300 mg

282 5 years --- 77%

(p<0.0001)

10 (4%) 92% 94%

Nilotinib

400 mg

281 --- 77%

(p<0.0001)

6 (2%) 96% 96%

Imatinib

400 mg

283 --- 60% 21 (7%) 91% 92%

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BFORE16 Bosutinib

400 mg

268 12

months

77%

(p=0.0075)

47%

(p=0.02)

4 (2%) --- ---

Imatinib

400 mg

268 66% 37% 6 (3%) --- ---

CCyR: complete cytogenetic response; MMR: major molecular response; PFS: progression free survival; OS: overall survival

iv. Initial TKI selection for CP-CML is based on risk score, TKI toxicities, age, comorbidities,

and ability to tolerate therapy

C. Protein synthesis inhibitor therapy: omacetaxine18

i. Reserved for after failure of 2 or more TKIs

ii. Reserved for T315I mutation

II. Monitoring Response to TKI Therapy and Mutational Analysis2,10,19

A. Goals of Therapy

i. If in CP remain in CP and prevent progression to AP/BP

a. Long life expectancies for patients who remain in CP while on treatment

b. Lower life expectancies even if patients in AP/BP are able to achieve CP again

ii. If in AP achieve CP and proceed to allogeneic stem cell transplantation

a. Prognosis is significantly worse in patients who progress to AP

iii. If in BP achieve CP and proceed to allogeneic stem cell transplantation

a. Prognosis is significantly worse in patients who progress to BP

b. Acquisition of additional genetic mutations such as trisomy 8, isochromosome 17,

trisomy 21 and deletion 7 causes CML to progress from CP to either myeloid BP

(~2/3 of patients) or lymphoid BP (~1/3 of patients)

B. Monitoring Response to TKI Therapy2,10 i. Types of responses

a. Hematologic response: improvement of blood counts and signs/symptoms b. Cytogenetic response: amount of Philadelphia chromosomes in metaphase c. Molecular response: number of BCR-ABL1 transcripts present

Table 4. Response Criteria for TKI Therapy10 Response Type Criteria

Hematologic

• Normal peripheral blood count

• WBC <10,000 cells/mm3

• Platelets < 450,000 cells/mm3

• No immature cells in the peripheral blood

• No signs or symptoms of disease

Cytogenetic

• Complete (CCyR): 0% Ph+ metaphases

• Major (MCyR): 0-35% Ph+ metaphases

• Partial (PCyR): 1-35% Ph+ metaphases

• Minor: >35-65% Ph+ metaphases

Molecular

• Early: BCR-ABL1 ≤ 10% at 3 and 6 months

• Major (MMR): BCR-ABL1 <0.1% or ≥ 3 log reduction in BCR-ABL1

mRNA from the standardized baseline, if qPCR (IS) is not available

• Complete (CMR): no detectable BCR-ABL mRNA by qPCR (IS)

o BCR-ABL1 ≤ 0.0032% yields a 4.5-log reduction (MR4.5)

ii. Tests for monitoring response a. Types of tests

Table 5. Tests for Monitoring Response5,10 Test Recommendation for Monitoring

Bone marrow

aspiration/

biopsy

• At diagnosis

• Failure to reach response milestones

• Any sign of molecular or cytogenetic relapse

RT-qPCR (IS) • At diagnosis

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• Every 3 months after starting treatment. After BCR-ABL1 (IS) between

>0.1%-1% is reached, can monitor every 3 months for 2 years, then

every 3-6 months thereafter

• If there is 1-log increase in BCR-ABL transcript levels with MMR,

qPCR should be repeated in 1-3 months

BCR-ABL

kinase domain

mutation

analysis

• Chronic phase

o Failure to reach response milestones

o Any sign of molecular or cytogenetic relapse

o 1-log increase in BCR-ABL transcript levels with loss of MMR

• Disease progression to accelerated or blast phase

b. Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) blood test

conducted periodically throughout treatment a) Monitors for presence and quantity of BCR-ABL1 transcripts b) Conducted every 3 months for two years as long as patient is responding to

treatment, followed by every 3-6 months thereafter

c) Helps determine if early treatment milestones are being achieved

iii. Early Treatment Milestones

a. Gold standard: Complete cytogenetic response at 12 months

Table 6. Early Treatment Milestones10 BCR-ABL1 (IS) 3 months 6 months 12 months >15 months

>10% Possible TKI

resistance

TKI resistance

>1% - 10% TKI sensitive disease Possible TKI

resistance

TKI

resistance

≤ 1 % TKI sensitive disease

iv. IRIS trial: 8-year follow-up20

a. Results

a) Event-free survival at 8 years: 81%

b) Freedom from progression to AP/BP: 92%

b. Take home:

a) Patients on long-term imatinib maintain their responses

b) Progression to AP/BP occurred early and risk for progression was minimal

after year 3

v. Resistance to imatinib?10,21

a. Evaluate adherence to TKI therapy and screen for drug interactions

a) Poor adherence to therapy leads to worse outcomes

i. Reasons for non-adherence

1. Intolerable adverse effects

2. High cost

Table 7. Cost of Therapy22 Drug Cost per month (AWP) Cost per year (AWP)

Gleevec

Imatinib

$12,147.00

$11,839.80

$145,764.00

$142,077.60

Sprycel $15,494.40 $185,932.80

Tasigna $16,372.80 $196,473.60

Bosulif $17,058.90 $204,706.80

Iclusig $19,873.20 $238,478.40

Omacetaxine $10,201.02 $122,412.24

b) Drug-drug interactions

i. TKIs are substrates of cytochrome P450 (CYP) enzymes

1. CYP3A4 inducers decreased TKI concentration

decreased efficacy and increased potential for relapse

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2. CYP3A4 inhibitors increase TKI concentration

increased toxicities which may decrease adherence

ii. Consider dose modifications if co-administration cannot be avoided

b. Conduct kinase domain mutational analysis in patients who are intolerant to

imatinib or in patients who progress to AP/BP

a) If resistant mutation(s) present, consider second line treatment with 2nd

generation TKIs which have higher binding affinity for the ABL1 kinase

i. Y253H, E255K/V, or F359V/C/I: dasatinib

ii. F317L/V/I/C, T315A, or V299L: nilotinib

iii. E255K/V, F317L/V/I/C, F359V/C/I, T315A, or Y253H: bosutinib

iv. T315I: ponatinib, omacetaxine, allogeneic HS

III. Controversy with TKI Discontinuation24

A. Since the introduction of TKIs, chronic myeloid leukemia has evolved from an incurable and fatal

disease to a manageable, chronic illness2,5

i. Patients receiving long-term TKIs can achieve undetectable molecular BCR-ABL transcript

levels

ii. Optimal responders to therapy can have life expectancies similar to those of the general

population

iii. Potential long-term implications on quality of life resulting from lifelong TKI use may cause

patients to want to stop their therapy

B. Risks of TKI discontinuation include possible progression of leukemia and increased morbidity

i. Significant risk for relapse of CML

a. Untreated CP-CML can also progress to AP or BP

ii. Development of TKI withdrawal syndrome23

a. Reported in ~25-30% of patients who discontinue their TKI

b. Characterized by low-grade, diffuse musculoskeletal pain

a) Treated with NSAIDs or steroids

b) Resolves with TKI resumption

c. Appears within 1-2 months following TKI discontinuation and can last up to 6

months

C. Benefits of TKI discontinuation include improved overall quality of life

i. No longer taking medications that cause side effects like fatigue, edema, malaise, etc.

ii. Reduced pill burden

iii. Decreased medication costs

iv. Women of childbearing age may now consider pregnancy following TKI discontinuation

a. TKIs can cross through placenta

b. Teratogenic toxicities

Clinical Question #1

Is it appropriate to stop tyrosine kinase inhibitor therapy in patients who have

chronic myeloid leukemia?

Table 8. STIM trial25

Mahon, et al. Lancet Oncol 2010; 11: 1029–35.

Study Aim

• To assess whether imatinib can be discontinued without occurrence of molecular relapse in patients in

complete molecular remission while on imatinib

Methods

Study Design • Prospective, multi-center, non-randomized

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Patient Population Inclusion Exclusion

• Age 18 years old

• Diagnosis of CML-CP or CML-AP

• Ongoing treatment with imatinib for at least 3

years

• Sustained complete molecular response for at

least 2 years

• Previous treatment with

immunomodulatory agents

except interferon

• Treatment for other

malignancies

• Previous hematopoietic stem

cell transplant

Intervention • Molecular biology follow-up of BCR-ABL transcripts using quantitative RT-PCR from

peripheral blood was performed:

o Every month for the first year

o Every 2 months for the second year

o Every three months for the third year and beyond

• Karyotype of bone marrow cells was assessed in all patients to show complete

cytogenetic remission before discontinuation of therapy

• Molecular relapse was defined as positivity in BCR-ABL transcripts in quantitative

RT-PCR with a ratio of BCR-ABL to ABL of 10-5 or more

o Re-introduction of imatinib was recommended in instances of molecular relapse

Outcomes • Primary: Molecular relapse-free survival

Methods • Time to molecular relapse was measured from date of imatinib discontinuation to date

of molecular relapse or date of last molecular examination for patients who did not

relapse

• Relapse-free survival was estimated using Kaplan-Meier method

• Patients who received follow-up for at least 12 months after discontinuation were

further analyzed to determine potential factors associated with CMR persistence

o Patients with factors that were identified by univariate analyses as potential

predictive factors were entered into a Cox regression model

• All patients in molecular relapse were treated again with imatinib 400 mg PO daily

Results

Baseline

Characteristics • N=100 patients; 69 patients with minimum 12-months follow-up after discontinuation

of imatinib

• Age: 29-80 years (median 62 years)

• Low Sokal risk score: 35 (50.7%)

• Female: 43 (62.3%)

• Previous therapy with interferon : 34 (49.2%)

• Imatinib therapy duration 50 months: 51 (73.9%)

• Time to CMR: 2-56 months (median 19 months)

• CMR duration before discontinuation: 24-85 months (median 35.5 months)

Outcomes • Relapse-free survival was 41% at 12 months & 38% at 24 months

• Forty-six patients remained free of molecular relapse at median follow up of 14 months

o Interim analysis: 39% in CMR (median follow-up 55 months)

Potential factors for predicting molecular relapse by multivariate Cox regression model:

Hazard ratio (95% CI) p-value

Sokal score (low vs. intermediate vs. high) 2.012 (1.252-3.234) 0.004

Imatinib duration (<50 months vs. 50 months) 0.421 (0.217-0.815) 0.010

Sex (male vs. female) 2.023 (1.004-4.007) 0.049

Discussion

Authors’

Conclusions • Imatinib can be safely discontinued in patients who obtain a stable complete molecular

remission (CMR)

Reviewer’s

Interpretation

Strengths Limitations

• Prospective, multicenter study • Small sample size

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• BCR-ABL1 values by international scale (IS)

• 31% had follow-up less than 12

months

Take-Home Points

• Imatinib discontinuation may be feasible and safe in ~40% patients

• Patients need to be re-introduced to imatinib therapy after molecular relapse • Sokal risk score, gender, imatinib duration may affect prognosis of relapse

Abbreviations: CMR: complete molecular response

Table 9. STOP 2G-TKI trial26

Rea, et al. Blood 2017; 129(7):846-854.

Study Aim

• To evaluate outcomes of first-line subsequent dasatinib or nilotinib discontinuation in CML patients with

long-lasting and deep molecular responses

Methods

Study Design • Prospective, multi-center, observational study

Patient

Population

Inclusion Exclusion


• Diagnosis of CML-CP or CML-AP

• Treated with dasatinib or nilotinib either first-

line or after imatinib intolerance, suboptimal

response, or resistance

• 3 or more years duration on TKI therapy

• 2 years or more of molecular response 4.5

• Previous allogeneic hematopoietic

stem cell transplant

• Nonmajor BCR-ABL transcripts

• History of progression to AP or BP

CML while on therapy

• Received chemotherapy or

radiotherapy for other malignancies

• Failure of prior TKI discontinuation

Intervention • Molecular biology follow-up of BCR-ABL transcripts using quantitative RT-PCR from

peripheral blood was performed:

o Every month for the first year

o Every 2 months for the second year

o Every three months for the third year and beyond

• Molecular relapse was defined as loss of MMR on any single test

o Re-initiation of previously prescribed TKI was recommended in instances of

molecular relapse

• Bone marrow cytogenetic analyses and BCR-ABL1 kinase domain mutation assessments

recommended in patients with BCR-ABL1 1% and those failing to regain MMR after

therapy resumption

Outcomes • Primary: Treatment-free remission (TFR) at 12 months

Methods • TFR was defined as time from second generation TKI discontinuation to date of first major

molecular response (MMR) loss or re-initiation of therapy and calculated using Kaplan-

Meier method

• Changes in BCR-ABL transcript levels between date of molecular relapse and date of

treatment resumption calculated using Wilcoxon-matched pairs signed rank test

• Comparison of quantitative variables from 2 independent groups: Mann Whitney U test

• Two tailed p-values of <0.05 were considered statistically significant

Results

Baseline

Characteristics • N=60 patients that completed at least 12 months of follow-up after TKI cessation

• All patients in chronic phase at diagnosis

• Female: 38/60 (63.3%)

• Low Sokal score: 32/60 (53.3%)

• Second line dasatinib or nilotinib as TKI type before discontinuation: 40/60 (66.7%)

• History of intolerance to imatinib: 39/60 (65%)

• Median duration of TKI treatment: 76 months

Pham | 11

Outcomes

Discussion

Authors’

Conclusions • First-line or subsequent dasatinib or nilotinib can be safely stopped in CML patients with

deep and long-lasting molecular responses

• A suboptimal response or resistance prior to dasatinib or nilotinib is associated with

significantly worse treatment-free remission

Reviewer’s

Interpretation


• Prospective, multicenter study

• Similar study criteria as previous imatinib

discontinuation studies such as MR4.5 and

relapse defined as loss of MMR

• Small sample size

• Mostly nilotinib/dasatinib for 2nd line

• Included patients with history of

progression to AP-CML

Take-Home Points

• Dasatinib or nilotinib may be stopped after achieving deep molecular responses

• Prompt re-introduction of TKI after relapse is important in disease control

• Resistance or suboptimal response to prior therapy worsens treatment free remission

Table 10. EURO-SKI trial27

Saussele, et al. Lancet Oncol 2018; 19: 747–57.

Study Aim

• To define precise conditions for TKI discontinuation

Methods

Study Design • Prospective, single-arm, open label, non-randomized

Patient

Population

Inclusion Exclusion


• Confirmed diagnosis of BCR-ABL1 positive CML in chronic

phase

• Receiving first-line or second-line treatment with any TKI

or taking a TKI as part of a combination treatment

• Needed 3 PCR results showing deep molecular response

within the year +/- 2 months

• Previous allogeneic

stem cell transplant

• Previous TKI treatment

failure

• Active concomitant

malignancies

Intervention • Molecular response was assessed using RT-qPCR

• Molecular response monitoring was done once monthly during the first 6 months after TKI

discontinuation, every 6 weeks until month 12, and then every 3 months for at least 3 years

• Patients with confirmed deep molecular response could stop TKI treatment immediately

Outcomes Primary: molecular relapse-free survival

Secondary: factors affecting MMR maintenance at 6 months, cost impact of TKI

discontinuation

Methods • Molecular response assessed using RT-PCR and occurred monthly during first 6 months

after TKI discontinuation, every 6 weeks until month 12, and then every 3 months for at

least 3 years

Pham | 12

• Molecular recurrence defined as loss of MMR corresponding with >0.1% BCR-ABL

transcripts

Results

Baseline

Characteristics • 821 patients were enrolled in the study

• Descriptive characteristics available only for 758 patients at time of analysis due to

exclusion criteria

Characteristic Patients

Age at diagnosis, years 52 (41-60)

Duration of TKI therapy, years 7.5 (5.0-9.9)

Sokal score

Low

Intermediate

High

259/584 (44%)

197/584 (34%)

128/584 (22%)

Hasford/Euro score

Low

Intermediate

High

239/547 (44%)

256/547 (47%)

52/547 (10%)

EUTOS score

Low

High

536/588 (91%)

52/588 (9%)

Treatment before TKI

Hydroxycarbamide

396 (52%)

273 (36%)

First-line TKI:

Imatinib

710 (94%)

Second-line TKI:

Nilotinib

Dasatinib

47/116 (41%)

62/116 (53%)

Outcomes Outcomes Patients

Molecular relapse free survival:

6 months

24 months

61%

50%

MMR or better at 6 months 123 (62%)

Loss of MMR after TKI discontinuation

Loss of MMR within 6 months

371/755 (49%)

297/373 (80%)

Discussion

Authors’

Conclusions • If following certain procedures, such as standardized molecular monitoring of BCR-ABL,

TKI discontinuation is safe and predictable

Reviewer’s

Interpretation


• Prospective, multicenter, international study

• Largest sample size

• Less stringent criteria for TKI

discontinuation

• Date of 1st deep molecular response

retrieved retrospectively

• Only 6% of patients on 2nd gen. TKI

Take-Home Points

• Less deep MR (MR4.0) and loss of MMR are acceptable criteria

• Sokal and EUTOS risk scores not predictive of keeping MMR

• Previous IFN α, TKI duration, & DMR duration affects relapse-free survival at 6 months

IV. NCCN Guideline Recommendations for First TKI Discontinuation10

A. TKIs may be safely discontinued in select patients

B. Outside of a clinical trial, all of the following criteria must be met for TKI discontinuation:

i. Age 18 or older

ii. CP-CML only. No history of AP- or BP-CML

Pham | 13

iii. On TKI therapy for at least 3 years

iv. Prior evidence of quantifiable BCR-ABL1 transcripts

v. Stable molecular response (MR4; BCR-ABL1 < 0.01% IS) for 2 years, as documented on

at least 4 tests performed at least 3 months apart

vi. Molecular monitoring monthly for 1 year, then every 6 weeks for the second year, then every

12 weeks thereafter indefinitely

vii. Prompt resumption of TKI within 4 weeks of a loss of MMR with molecular monitoring

every 4 weeks until MMR is re-established

Clinical Question #2

Is it appropriate to stop tyrosine kinase inhibitor therapy in patients who have

failed to achieve a treatment-free remission (TFR) after first discontinuation failure?

Table 11. RE-STIM Trial28

Legros, et al. Cancer 2017; 123(22):4403-4410.

Study Aim

• To evaluate TFR after a second TKI discontinuation attempt

Methods

Study Design • Observational, multicenter study

Patient

Population

Inclusion Exclusion


• Confirmed diagnosis of BCR-ABL1

positive CML in CP

• Failed a first TKI discontinuation attempt,

regained deep molecular response with

MR4.5, and discontinued TKI again

• Previously included in trials like STIM, A-

STIM, or EURO-SKI

• Previous autologous or allogeneic stem

cell transplant

• Patients with non-major BCR-ABL1

transcripts

• History of progression to AP-CML or

BP-CML

Intervention • Molecular response was assessed using RT-qPCR

• Molecular response monitoring was done monthly during the first 12 months after TKI

discontinuation, every 2-3 months during the second year, and then every 3-6 months for

up to 5 years

Outcomes Primary: Treatment-free remission (TFR)

Secondary: Lack of progression to advanced phase CML, efficacy of treatment resumption

Methods • Molecular recurrence defined as loss of MMR corresponding with >0.1% BCR-ABL

transcripts

Results

Baseline

Characteristics • 70 patients were enrolled in the study

Baseline characteristics at second TKI discontinuation:

Characteristic Patients

Age at diagnosis, years 60 (36-93)

Duration of TKI therapy before 2nd

discontinuation, months

32 (6.0-72)

Duration of uMR4.5 before 2nd

discontinuation, months

25 (4.0-68)

First-line TKI

Imatinib

50/70 (71%)

Second-line TKI

Nilotinib

Dasatinib

13/70 (19%)

7/70 (10%)

Pham | 14

Outcomes Outcomes Patients

Number of patients that lost an MMR 45 (64%)

Median time off therapy (months) 5.3 (2.0-42.0)

Molecular relapses occurring in first year after

TKI discontinuation

54%

TFR probability at:

6 months

12 months

24 months

36 months

66%

48%

42%

35%

Same TKI restarted 27 (60%)

TKI change due to past tolerance issues:

Dasatinib

Nilotinib

5

4

TKI change from 2nd generation TKI to:

Different 2nd generation TKI

Imatinib

5

3

Progression to advanced phase CML 0 (0%)

Discussion

Authors’

Conclusions • A second attempt to discontinue TKI therapy in patients who failed a first discontinuation

and subsequently regained undetectable MR4.5 after TKI re-challenge is safe

Reviewer’s

Interpretation


• Prospective, multicenter study

• Used TFR as treatment goal

• Same PCR testing frequency as STIM trial


• Only had patients with 1st line TKI

• Time to loss of MR4.5 = 3 months, but

time to TKI re-start = 5 months

Take-Home Points

• May be feasible if strict MR4.5 requirement met

• Second discontinuation is more successful in patients who relapse later than 3 months

during a TKI discontinuation attempt

• Close and prolonged molecular monitoring is necessary

Summary and Recommendations

I. Discontinuation of TKI therapy is a potentially feasible and safe option for CML patients

II. Achieving a deep molecular response prior to discontinuation of TKI may help achieve longer TFR

A. Duration of TKI therapy for at least 3 years

B. Stable molecular response (MR4; BCR-ABL1 < 0.01% IS) for at least 2 years

III. Continuous molecular monitoring is important in CML

A. BCR-ABL transcript levels detected by RT-PCR can fluctuate

B. Therefore, routine monitoring is recommended to ensure sustained TFR

i. Monthly for one year

ii. Every 6 weeks for second year

iii. Every 12 weeks indefinitely

IV. Prompt resumption of TKI within 4 weeks of loss of MMR with molecular monitoring every 4 weeks until

MMR is re-established

V. A second TKI discontinuation attempt in patients who have previously failed a first TKI discontinuation

attempt may be safe and feasible

VI. Future Directions

A. Utilizing TFR as an endpoint in future studies and comparing TFR rates between imatinib and second

generation TKIs

B. Larger, prospective studies evaluating the long-term safety and efficacy of a second TKI

discontinuation

Pham | 15

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Leukemia: Results From the BELA Trial. Journal of Clinical Oncology. 2012;30(28):3486-3492.

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phase CML with T315I mutation. Blood. 2012 Sep 27;120(13):2573-80.

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Pham | 16

Appendix A: Review of Landmark Trials for Therapies in CML

Table 1. IRIS Trial (2001) – Imatinib

Purpose • To compare the efficacy of imatinib with that of interferon alfa plus low dose cytarabine in the treatment of CP-

CML

Population Inclusion Exclusion

• 18-70 years old

• Diagnosed with Ph+

CP-CML within six

months of study entry

• LFTs, total bilirubin,

and serum creatinine

≤ 1.5x ULN

• Women who were breastfeeding, pregnant, or child-bearing potential

• ECOG 3 or higher

• Presence of other uncontrolled serious medical conditions

• Received prior chemotherapy or any investigational agent

• Had undergone hematopoietic stem cell transplant

• Had undergone major surgery within the preceding 4 weeks

• Were known to be seropositive for HIV

• Had a history of cancer within the previous 5 years excluding basal cell carcinoma

or cervical carcinoma in situ

Design/

Methods

Prospective, multi-center, open-label, phase 3, randomized trial; 1106 patients were randomized: 553 pts received

imatinib vs. 553 pts received interferon alfa and cytarabine.

Results CCyR, 18 mo: 87.1% imatinib vs. 34.7% interferon/cytarabine

Conclusion • Imatinib superior to interferon alfa plus low-dose cytarabine as 1st line for newly diagnosed CP-CML

Critique Strengths Limitations

• Prospective, multicenter, open-label randomized phase 3 study

• Large sample size

• Balanced baseline characteristics

• Intention to treat

• Early cross-over of many

patients to imatinib group

may cloud differences in

survival

Take-Home

Points • Imatinib produced better hematologic and cytogenetic responses compared to interferon alpha and cytarabine

Table 2. DASISION Trial (2012) – Dasatinib

Purpose • To compare the efficacy of dasatinib with that of imatinib in the treatment of CP-CML


• Diagnosed with Ph+ CP-CML

within 3 months of study entry

• No previous treatment for CML

except for anagrelide or

hydroxyurea

• ECOG 0-2

• Total bilirubin ≤ 2x ULN

• AST/ALT ≤ 2.5x ULN

• Serum creatinine ≤ 3x ULN

• Women who were breastfeeding, pregnant, or child-bearing age without

negative pregnancy test

• Serious, uncontrolled medical disorders or infections

• Uncontrolled or serious cardiovascular disease

• QTc interval >450 msec

• History or serious bleeding disorder unrelated to CML

• Previous or concurrent cancer other than basal-cell skin cancer

• Previous chemotherapy for peripheral stem-cell mobilization

• Pleural effusion at baseline

Design/

Methods

Multinational, open-label, phase 3, randomized trial;

259 pts Dasatinib vs. 260 pts Imatinib

Results CCyR, 24 mo: 86% dasatinib vs. 82% imatinib

Conclusion • Dasatinib shows deeper and faster responses compared to imatinib


• Multinational, open-label

randomized, phase 3 study


Follow-up period not long enough to detect long-term effects

Take-Home

Points • Dasatinib produced a faster and deeper complete cytogenetic response and major molecular response within 12

months after initiating therapy compared to imatinib

Table 3. ENESTnd Trial (2010) – Nilotinib

Purpose • To compare the efficacy of nilotinib with that of imatinib in the treatment of CP-CML


• Diagnosed with Ph+, CP-

CML within 6 months of

study entry

• ECOG 0-2

• Adequate organ function

• Previously treated with a TKI before study entry (except imatinib for ≤ 2

weeks) or any medical treatment for CML for > 2 weeks (except anagrelide

or hydroxyurea)

• Patients with impaired cardiac function

• Use of coumadin

• Drugs that block or stimulate the activity of the liver enzyme cytochrome

P450 3A4 or with potential to prolong QTc interval

Design/ Multinational, open-label, phase 3, randomized trial

Pham | 17

Methods

282 pts nilotinib 300mg, 281 pts nilotinib 400mg, and 283 pts imatinib

Results MMR, 12 mo: 44% nilotinib 300mg, 43% nilotinib 400mg, vs. 22% imatinib (p<0.001)

Conclusion • Nilotinib either at 300mg or 400mg was superior to imatinib for newly diagnosed CP-CML


• Multicenter, open-label


• Balanced baseline

characteristics

• Did not review complete cytogenetic response as a primary endpoint

• Follow-up period not long enough to detect durability of responses

Take-Home

Points • Nilotinib produced significantly better major molecular responses and complete cytogenetic responses compared

to imatinib

Table 4. BELA Trial (2012) – Bosutinib

Purpose • To compare the efficacy of bosutinib with that of imatinib in the treatment of CP-CML


• Adults diagnosed

with Ph+, CP-CML

within 6 months of

study entry

• Total bilirubin ≤ 2x

ULN; AST/ALT

≤ 2.5x ULN

• Serum creatinine

≤ 1.5x ULN

• ECOG 0-1

• Previous treatment received for leukemia (except anagrelide or hydroxyurea)

• Prior stem cell transplant

• CNS leukemia

• Extramedullary disease only

• History of accelerated or blast phase CML

• Major surgery or radiotherapy within 14 days of randomization

• Use of medications that prolong QTc interval

• History of uncontrolled heart disease

• Prolonged QTc interval

• History of another malignancy except basal-cell carcinoma in past 5 years

• Congenital or acquired cytopenias

Design/

Methods

Phase 3, randomized trial

250 pts bosutinib 500mg vs. 252 pts imatinib

Results CCyR, 12 mo: 70% bosutinib vs. 68% imatinib (p=0.601);

MMR, 12 mo: 41% bosutinib vs. 27% imatinib (p<0.001)

Conclusion • The primary endpoint of CCyR was not met and not significantly different between bosutinib and imatinib


• Multicenter, open-label




• Did not review complete cytogenetic response as a primary endpoint


• Early discontinuation of bosutinib due to toxicities

Take-Home

Points • Bosutinib 500 mg did not demonstrate superior complete cytogenetic response at 12 months compared to imatinib

Table 5. BFORE Trial (2018) – Bosutinib

Purpose • To compare the efficacy of bosutinib with that of imatinib in the treatment of CP-CML


• Adults diagnosed

with Ph+, CP-

CML within 6

months of study

entry

• Total bilirubin

≤ 2x ULN

• AST/ALT

≤ 2.5x ULN

• Serum creatinine

≤ 1.5x ULN

• ECOG 0-1

• Previous treatment received for leukemia (except anagrelide or hydroxyurea)

• Past CNS involvement

• Extramedullary disease only

• Major surgery or radiotherapy within 14 days of randomization


• History of uncontrolled heart disease

• Known seropositivity to HIV, acute or chonic hepatitis B or C, cirrhosis

• Recent or ongoing GI disorder

• History of another malignancy except basal-cell carcinoma or cervical carcinoma in situ

in past 5 years

• Uncontrolled hypomagnesemia or uncorrected hypokalemia

• Current or recent participation in clinical trials of investigational agents

• Women who were breastfeeding, pregnant, or child-bearing age without negative

pregnancy test

Design/

Methods

Open-label, phase 3, randomized trial

268 pts bosutinib 400mg vs. 268 pts imatinib

Pham | 18

Results MMR, 12 mo: 47.2% bosutinib vs. 36.9% imatinib (p=0.02)

CCyR, 12 mo: 77.2% bosutinib vs. 66.4% imatinib (p=0.0075)

Conclusion • Patients who received bosutinib had significantly better and faster results than imatinib


• Multinational, open-label randomized,

phase 3 study



• Did not review complete cytogenetic response as a primary

endpoint

• Follow-up period not long enough to detect durability of

responses

Take-Home

Points • Bosutinib had significantly higher rates of major molecular response and complete cytogenetic response and

achieved faster responses than those who received imatinib

• This difference in result was seen with bosutinib 400 mg compared to the 500 mg dose that was used in the BELA

trial

Table 6. PACE Trial (2013) - Ponatinib

Purpose To compare the efficacy of ponatinib with that of imatinib in the treatment of CP-CML


• Adults diagnosed with CML in

any phase or Ph+ ALL

• Previously treated with dasatinib

or nilotinib

• Developed the T315I mutation

after any TKI therapy

• ECOG 0-2

• Total bilirubin ≤ 1.5x ULN

• AST/ALT ≤ 2.5x ULN

• Prothrombin time ≤ 1.5x ULN

• Lipase ≤ 1.5x ULN

• Amylase ≤ 1.5x ULN

• Serum creatinine ≤ 1.5x ULN

• QTc ≤450 msec in males and <470

msec in females

• Subjects of child-bearing age must

agree to use effective

contraception

• Received TKI in previous 7 days

• For CP or AP, received hydroxyurea or anagrelide within 24 hrs of

receiving ponatinib

• For BP, received chemotherapy within 14 days prior to first dose of

ponatinib

• For Ph+ ALL patients, received corticosteroids within 24 hrs prior to

first dose ponatinib

• Previous stem cell transplant with past 60 days


• Require treatment with immunosuppressive agents other than

corticosteroids

• Have active CNS disease

• Significant cardiovascular disease

• History of significant bleeding

• History of pancreatitis or alcohol abuse

• Triglycerides ≥450 mg/dL

• History of GI or malabsorption syndrome

• Women who were breastfeeding, pregnant, or child-bearing age

without negative pregnancy test

• Major surgery in past 14 days

• Known seropositivity to HIV, acute or chronic hepatitis B or C,

cirrhosis

Design/

Methods

Multinational, multicenter, open-label Phase 2 trial

449 pts with CML, Ph+ ALL with resistance to dasatinib or nilotinib, or pts with BCR-ABL T315I mutation treated

with ponatinib 45mg PO daily and followed at 15 months

Results Hematologic response lasting >8 weeks: 67% of pts

MCyR: 22% of pts

Conclusion Ponatinib had activity against CML across various stages of disease and mutational status


• Multinational, multicenter, open-label

phase 2 study

• Relevant primary endpoint with

complete cytogenetic response

• Unbalanced baseline characteristics between groups


• Included patients previously treated with cytarabine and interferon

alpha

Take-Home

Points

Ponatinib was associated with antileukemic activity in heavily pre-treated patients with CML

Pham | 19

Table 7. Omacetaxine Trial (2013)

Purpose • To evaluate the efficacy and safety of subcutaneous omacetaxine in CML patients with resistance or intolerance

to two or more TKIs


• Adults diagnosed with

Ph+, CP-CML within 6

months of study entry

• NYHA Class III or IV heart disease, active ischemia, or any other uncontrolled

heart condition

• Active malignancy other than CML

• Uncontrolled active infection

• HIV positive status

• Patients eligible for stem cell transplant at time of screening

• Patients in lymphoid blast crisis

Design/

Methods

Multicenter, noncomparative, open-label phase 2 trial

46 pts enrolled with CP-CML, with 85% having received treatment with 2 or more TKIs, treated with omacetaxine

induction (1.25 mg/m2 SQ bid x14 days, q28d) and maintenance (1.25 mg/m2 SQ x7 days, q28d for up to 24 months)

Results Hematologic response lasting >8 weeks: 67% of pts

MCyR: 22% of pts

Conclusion • Omacetaxine can produce clinically meaningful hematologic and cytogenetic responses with an acceptable safety

profile for pts with CP-CML who have previously failed multiple TKIs


• Prospective, multicenter, single

arm, open-label phase 2 study


• No comparator


• Included patients previously treated with cytarabine and interferon alpha

Take-Home

Points

There is a favorable risk-benefit profile in patients with T315I mutation who have failed prior TKI therapy

Appendix B: Summary of TKI Discontinuation Trials

Study Treatment prior to

discontinuation

No. of

patients

Depth and duration of MR

required for

discontinuation

Trigger to

resume TKI

therapy

Median follow-

up

Treatment-free

remission rate

STIM1 Imatinib ±

interferon

100 MR5.0 for at least 2 years Loss of MR5.0 77 months 38% at 60

months

TWISTER Imatinib ±

interferon


months

HOVON Imatinib +

cytarabine


months

A-STIM Imatinib ±

interferon

80 MR5.0 for at least 2 years Loss of MMR 31 months 61% at 36

months

ISAV study Imatinib (after

failure of

interferon or

hydroxyurea)

108 CMR for at least 18

months

Loss of MMR 36 months 52% at 96

months

KID study Imatinib ±

interferon

90 MR4.5 for at least 2 years Loss of MMR 27 months 59% at 24

months

Stop 2G-TKI Dasatinib/nilotinib

(1st or 2nd line)

60 MR4.5 for at least 24

months


months

ENESTFreedom Nilotinib (1st line) 190 MR4.5 for at least 12

months


weeks

ENEStop study Nilotinib (2nd line) 126 MR4.5 for at least 12

months


weeks

DADI Dasatinib (2nd

line)

63 MR4.0 for at least 12

months

Loss of MR4.0 44 months 44% at 36

months

EURO-SKI Any TKI 758 MR4.0 for at least 1 year Loss of MMR 27 months 50% at 24

months

Pham | 20

Appendix C: Overview of therapies for CML

Table 1. Overview of Therapies for CML Imatinib

(Gleevec)

Dasatinib

(Sprycel)

Nilotinib

(Tasigna)

Bosutinib

(Bosulif)

Ponatinib

(Iclusig)

Omacetaxine

(Synribo)

FDA

Approval

May 10, 2001 June 28, 2006 October 29, 2007 September 4, 2012 December 14,

2012

October 26, 2012

MOA Inhibits BCR-

ABL tyrosine

kinase,

inducing

apoptosis; also

inhibits PDGF,

c-kit

Inhibits most

BCR-ABL

tyrosine

kinase

mutations that

are resistant to

imatinib

(except T315I

and F317V),

inducing

apoptosis; also

inhibits SRC

family, c-kit,

EPHA2, and

PDGF

Inhibits most

BCR-ABL

tyrosine kinase

mutations that

are resistant to

imatinib (except

T315I and

F317V), inducing

apoptosis; also

inhibits c-kit,

EPHA2, and

PDGF, but not

SRC family

Inhibits most BCR-

ABL tyrosine

kinase mutations

that are resistant to

imatinib (except

T315I and V229L),

inducing apoptosis;

also inhibits SRC

family; minimal

activity on c-kit and

PDGF

Inhibits most

BCR-ABL

tyrosine kinase

mutations that are

resistant to

imatinib, inducing

apoptosis; also

inhibits SRC

family, c-kit,

EPHA2, and

PDGF

Reversibly binds to

the A-site cleft of the

ribosomal subunit to

interfere with chain

elongation and inhibit

protein synthesis;

Acts independently

of BCR-ABL1

tyrosine kinase

activity

Dose

CP

400

mg PO

daily

100 mg PO

daily

300 mg PO twice

daily (400 mg if

resistant)

400 mg PO once

daily

45 mg PO once

daily

Induction: 1.25

mg/m2 SQ twice daily

x 14 days of a 28-day

cycle; maintenance:

1.25 mg/m2 SQ twice

daily x 7 days of a

28-day cycle

AP,

BP

600-

800

mg PO

daily

140 mg PO

daily

400 mg PO twice

daily

500 mg PO once

daily

Adverse

Effects

Edema,

fatigue, skin

rash, nausea,

diarrhea,

vomiting,

muscle cramps

Fluid

retention,

pleural

effusions,

diarrhea,

thrombo-

cytopenia,

neutropenia,

anemia

Hyperglycemia,

skin rash, nausea,

QTc interval

prolongation,

occlusive arterial

disease,

arthralgia

Diarrhea, nausea,

vomiting,

hyperphosphatemia,

skin rash, fatigue,

headache,

cytopenias, fever

Arterial

occlusions, heart

failure,

hepatotoxicity,

VTE,

hypertension,

arterial ischemia,

skin rash,

constipation,

cytopenias

Thrombocytopenia,

neutropenia,

infection, increased

uric acid, diarrhea,

nausea, abdominal

pain, fever, injection

site reaction, fatigue,

weakness, alopecia

Notes Take on empty

stomach

Dose adjustment

for CYP 3A

inhibitors

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