discontinuation of tyrosine kinase inhibitors in chronic...
TRANSCRIPT
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%
Pham | 6
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
Pham | 10
• 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
• Age 18 years old
• 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
Strengths Limitations
• 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
• Age 18 years old
• 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
Strengths Limitations
• 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
• Age 18 years old
• 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
Strengths Limitations
• Prospective, multicenter study
• Used TFR as treatment goal
• Same PCR testing frequency as STIM trial
• Small sample size
• 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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757.
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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
Population Inclusion Exclusion
• 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
Critique Strengths Limitations
• Multinational, open-label
randomized, phase 3 study
• Balanced baseline characteristics
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
Population Inclusion Exclusion
• 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
Critique Strengths Limitations
• Multicenter, open-label
randomized, phase 3 study
• 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
Population Inclusion Exclusion
• 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
Critique Strengths Limitations
• Multicenter, open-label
randomized, phase 3 study
• Balanced baseline characteristics
• Intention to treat
• Did not review complete cytogenetic response as a primary endpoint
• Follow-up period not long enough to detect durability of responses
• 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
Population Inclusion Exclusion
• 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
• Use of medications that prolong QTc interval
• 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
Critique Strengths Limitations
• Multinational, open-label randomized,
phase 3 study
• Balanced baseline characteristics
• Intention to treat
• 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
Population Inclusion Exclusion
• 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
• Use of medications that prolong QTc interval
• 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
Critique Strengths Limitations
• Multinational, multicenter, open-label
phase 2 study
• Relevant primary endpoint with
complete cytogenetic response
• Unbalanced baseline characteristics between groups
• Follow-up period not long enough to detect durability of responses
• 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
Population Inclusion Exclusion
• 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
Critique Strengths Limitations
• Prospective, multicenter, single
arm, open-label phase 2 study
• Intention to treat
• No comparator
• Small sample size
• 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
40 MR4.5 for at least 2 years Loss of MR4.5 42 months 47% at 24
months
HOVON Imatinib +
cytarabine
15 MR4.5 for at least 2 years Loss of MR5.0 36 months 33% at 24
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
Loss of MMR 47 months 54% at 48
months
ENESTFreedom Nilotinib (1st line) 190 MR4.5 for at least 12
months
Loss of MMR 96 months 49% at 96
weeks
ENEStop study Nilotinib (2nd line) 126 MR4.5 for at least 12
months
Loss of MMR 96 months 53% at 96
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