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CML: What's New at EHA? Tim Brümmendorf, EHA Capacity Building Session, EHA congress June 2017
1. Chronic myeloid leukemia (CML) 2017:
What’s new at EHA ?
Prof. Dr. med. Tim H Brümmendorf
Klinik für Hämatologie und Onkologie
Universitätsklinikum Aachen
2. Challenges in Treatment of CML in 2017
Background: Most patients with newly diagnosed CML are
assumed to have a normal life-expectancy !
The challenges in CML treatment are focussed on
1.Offer the perspective of a treatment-free remission (cure ?) to
as many as possible patients
2.Prevention of and (in case it happens) improved treatment of
– disease progression to AP/BC and
– development of resistance to TKI
1.Improvement of tolerability and adherence to TKI
2.Eradiaction of leukemic stem cells as a continued source of
relapse/disease progression
3. Evolution of targeted therapy of CML:
A simplified view
reviewed in: Balabanov, Braig and Brümmendorf Drug Discovery Today 2014; 11:89-99
Inhibition: +++ (+) –
(bcr-)abl c-KIT PDGF-R
Resistance
Imatinib 1 x Proof-of-principle, Role model of TKIs
2nd Generation
Nilotinib 30 x T315I Modulation of resistance
src
Dasatinib 325 x
T315I
Escalation to
synergistic pathways
Bosutinib 100 x
T315I
De-escalation of
“off-target“ kinases
Rationale behind compound
Ponatinib 250 x
“3rd Generation”
T315I
Coverage of T315I
FGFR
RET
4. 4
Imatinib
(retrospective)
N=252
Nilotinib
(prospective)
N=408
Dasatinib
(prospective)
N=418
Imatinib
(prospective)
N=416
Primary Objective
•Better understand use of TKIs in
1st
-line treatment of CP-CML in
routine clinical practice
Secondary Objectives
•Evaluate patient benefit of
CML treatment
•Determine healthcare resource
utilization
SIMPLICITY: An Ongoing Observational Study1,2
Eligibility:
•Newly-diagnosed
CP-CML pts
•Receiving 1st
-line
imatinib, dasatinib
or nilotinib
•≥18 years at time
of diagnosis
•Not participating in
CML clinical trial
CP-CML, chronic phase chronic myeloid leukemia; TKI, tyrosine kinase inhibitor
1.Clinical Trials.gov. Study record: NCT01244750
2.Zyczynski T et al. Presented at ISPOR 7th Asia-Pacific Conference (Singapore), Poster PCN63.
SIMPLICITY
Recruitment targets: 200 patients (retrospective imatinib cohort)
400 patients (each prospective cohort)
6. 6
Reason to Switch TKI Early vs. Late
Dasatinib
Nilotinib
Imatinib
SIMPLICITY
*†
*Reasons for discontinuation according to clinician judgement; chosen from electronic case report form or entered manually
†
Includes insurance/financial reasons, unrelated medical conditions, pt and/or physician choice
* * *
Across TKIs, intolerance is most common reason for switching, both early and late
TKI, tyrosine kinase inhibitor
7. BOSUTINIB VS IMATINIB FOR NEWLY DIAGNOSED CHRONIC
MYELOID LEUKEMIA: INITIAL RESULTS FROM THE BFORE TRIAL
Author(s): Tim H. Brümmendorf
Abstract: S425
Type: Oral Presentation
Presentation during EHA22:
On Saturday, June 24, 2017 from 12:15 - 12:30
8. Bosutinib: A Dual Inhibitor of SrcBosutinib: A Dual Inhibitor of Src
and Abl Kinasesand Abl Kinases
Src enzyme (ELISA) IC50 = 1.2 nM
Src enzyme (Lance) IC50 = 3.8 nM
Abl enzyme IC50 = 1.4 nM
K562 cell IC50 = 20 nM
KU812 cell IC50 = 4.3 nM
Once daily oral application !
independent of food !
Boschelli DH, et al. J Med Chem. 2005;48(11):3891-3902.
Golas JM, et al. Cancer Res. 2003;63(2):375-381.
Golas JM, et al. Cancer Res. 2005;65(12):5358-5364.
Puttini M, et al. Cancer Res. 2006;66(23):11314-11322.
Courtesy of Scapozza L and Shaheen A, University
of Geneva, Switzerland.
N
C N
H N
C l C l
O
O
ON
N
9. 9
Bosutinib Efficacy and Safely in NewlyBosutinib Efficacy and Safely in Newly
Diagnosed CML (BELA): Study DesignDiagnosed CML (BELA): Study Design
● Primary endpoint: complete cytogenetic response (CCyR) rate at 12 mo
● Secondary endpoints:
– Major molecular response (MMR) rate at 12 mo
– Time to CCyR and MMR
– Time to and rate of transformation to accelerated phase (AP) or blast
phase (BP) CML
– Safety and tolerability
Phase 3 open-lapel
trial in newly
diagnosed chronic
phase CML
N = 502
139 sites
31 countries
Bosutinib
500 mg/day
n = 250
Imatinib
400 mg/day
n = 252
5-year follow-up
5-year follow-up
R
A
N
D
O
M
I
Z
E
1-year analysis
10. BELA Study (3000): CCyR and MCyR
Jorge E. Cortes et al. J. Clin. Oncol. 2012;30:3486-3492
Primary study endpoint
11. AV001 Study Design
• Key eligibility criteria: Chronic Phase - CP CML ≤6 months prior, no prior
therapy (other than hydroxyurea or anagrelide)
• Primary endpoint: Major molecular response at 12 months (48 weeks)
• Key secondary endpoints
− MMR by 18 months, duration of MMR, CCyR by 12 months, duration of CCyR, event-free
survival (EFS), and overall survival (OS)
R
A
N
D
O
M
I
Z
E
Randomization is stratified based on Sokal
risk score and geographical regions
Bosutinib
400 mg/day
n = 250
Imatinib
400 mg/day
n = 250
5-year study
Phase 3 open-label trial in
newly
diagnosed CP CML
N = 500 Ph+ (approx. 530Ph+
and Ph-)
195 sites
up to 28 countries
Phase 3 open-label trial in
newly
diagnosed CP CML
N = 500 Ph+ (approx. 530Ph+
and Ph-)
195 sites
up to 28 countries
4-year follow-up
1-year core
Treatment Phase
Lead investigators: Jorge Cortes, Houston (North America)
Tim Brümmendorf, Aachen (Europe)
first presentation of
the data at
ASCO (Chicago)
and EHA (Madrid)
in June 2017
12. BFORE: BOS vs IM in Frontline CML
Introduction
• Bosutinib (BOS): dual SRC/ABL TKI approved for adults with
Ph+ CML resistant or intolerant to prior TKIs
• Potent activity and manageable toxicity in all phases of CML
– Ph+ leukemias resistant/intolerant to previous TKIs (phase 1/2)1-4
– Newly diagnosed CP CML (phase 3; BELA)5-7
• CCyR rate at 12 mo (primary objective) higher with BOS vs imatinib (IM)
but not statistically significant
• Improved 12-mo MMR rate and shorter time to response with bosutinib
• Objective: further assess the efficacy and safety of BOS vs IM
for first-line treatment of CP CML
1. Cortes JE, et al. Blood. 2011;118:4567-76. 2. Khoury HJ, et al. Blood. 2012;119:3403-12. 3. Kantarjian HM, et al. Blood. 2014;123:1309-18. 4. Gambacorti-Passerini C, et al. Am J Hematol.
2014;89:732-42. 5. Cortes JE, et al. J Clin Oncol. 2012;30:3486-92. 6. Brümmendorf TH, et al. Br J Haematol. 2015;168:69-81. 7. Gambacorti-Passerini C, et al. Am J Hematol. 2014;89(10):947-53.
Cortes et al. ASCO 2017
13. BFORE: BOS vs IM In Frontline CML
Molecular Response Over Time (mITT)
BOS IM
(n=246) (n=241) P=0.02
P=0.01
P=0.02
MR4
MR4.5
MMR MR4
MR4.5
MMR MR4
MR4.5
MMR MR4
MR4.5
MMR
P=0.12
P<0.0001
P<0.01
Cortes et al. ASCO 2017
14. BFORE: BOS vs IM in Frontline CML
Cumulative Incidence of CCyR (mITT)
Results are subject to change after 12 mo due to incomplete follow-up.
HR=1.38 (95% CI: 1.13‒1.69); P<0.001
Cortes et al. ASCO 2017
15. BFORE: BOS vs IM in Frontline CML
Transformation to AP/BP (mITT)
• 4 (1.6%) BOS and 6 (2.5%) IM
patients progressed to AP/BP
during treatment
• 5 of these patients (3 BOS and 2
IM) met AP criteria within 2
weeks based on basophil count
─ All 5 continued on study
drug, and 4 achieved MMR
Cortes et al. ASCO 2017
16. BFORE: BOS vs IM in Frontline CML
Conclusions
• BFORE met its primary endpoint with a significantly higher rate of
MMR at 12 mo with BOS vs IM (47% vs 37%; P=0.02)
─ Rate of CCyR by 12 months significantly higher with BOS (77%
vs 66%; P<0.01)
• Responses occurred earlier with BOS
• Results suggest lower dose (400 mg) is associated with better
tolerability and improved outcomes
• Safety data consistent with known profiles; no new safety signals
─ BOS associated with higher incidence of GI events and
transaminase elevations; rarely leading to discontinuation
─ Lower incidence of musculoskeletal events
• BOS could become a welcome new frontline treatment option
Cortes et al. ASCO 2017
17. ASSESSMENT OF IMATINIB 400MG AS FIRST LINE TREATMENT
OF CHRONIC MYELOID LEUKEMIA: 10 -YEAR SURVIVAL
RESULTS OF THE RANDOMIZED CML STUDY IV
Author(s): Ruediger Hehlmann
Abstract: S424
Type: Oral Presentation
Presentation during EHA22:
On Saturday, June 24, 2017 from 12:00 - 12:15
18. Methods
•1551 newly diagnosed patients in chronic phase (CP)
were randomized into a 5-arm study.
•1536 patients were evaluable:
• 400 for IM400mg,
• 430 for IM + IFN,
• 420 for IM800mg,
• 158 for IM + cytarabine* and
• 128 for IM-after-IFN-failure*
*recruitment to the latter two arms was stopped after a pilot-phase.
19. Results
•10-year overall survival (OS) was 82%,
•10-year progression free survival (PFS) was 80%
•In the treatment arms, 10-year OS was
• 80% with IM400mg,
• 84% with IM + IFN,
• 79% with IM800mg,
• 84% with IM + cytarabine and
• 79% with IM after IFN
•In a multivariate analysis, risk factors for survival were:
• Clinical risk group,
• comorbidities,
• major route chromosomal aberrations,
• smoking and
• type of treatment center (academic vs other) !
21. CONCLUSION
• Monotherapy with IM400mg provides a close to
normal life expectancy.
• Faster response does not necessarily translate
into better survival.
• Outcome of CML is currently more determined by
disease biology and demographics than by
treatment optimization.
22. INITIAL REDUCTION OF THERAPY BEFORE COMPLETE
WITHDRAWAL IMPROVES THE CHANCE OF SUCCESSFUL
TREATMENT DISCONTINUATION IN CHRONIC MYELOID
LEUKAEMIA (CML): YEAR 2 RESULTS IN THE BRITISH DESTINY
STUDY
Author(s): Richard Clark
Abstract: S423
Type: Oral Presentation
Presentation during EHA22:
On Saturday, June 24, 2017 from 11:45 - 12:00
23. Methods
•Trial entry required first chronic phase of CML, TKI treatment for ≥
3 years, and either the same TKI (imatinib, dasatinib or nilotinib)
since diagnosis or only one switch for intolerance.
•All PCR tests (minimum of 3) in the 12 months before trial entry
must have been ≤0.1% (i.e. MMR), each with ≥ 10,000 ABL1 control
transcripts;
•those with all results ≤ 0.01% were allocated to the ‘stable MR4’
group; the remainder to the ‘MMR but not MR4’ group.
•TKI treatment was reduced to half the standard dose (imatinib
200mg daily, dasatinib 50mg daily or nilotinib 200mg twice daily)
for the first 12 months, then stopped completely.
•Molecular recurrence was timed as the first of 2 consecutive
samples with loss of MMR (>0.1%) and mandated resumption of
full TKI dose.
24. BRITISH DESTINY STUDY - design
174 Patienten mit CML, TKI-Behandlung ≥ 3 Jahre mit dem gleichen TKI (oder Tausch
bei Intoleranz), PCR-Tests in den letzten 12 Monaten ≤0,1%
Stable MR4
PCR-Tests in den letzten 12
Monaten ≤ 0,01%
MMR, aber nicht MR4
PCR-Tests in den letzten 12
Monaten 0,01% ≤ x ≤ 0,1%
Behandlung
1.Reduktion auf Hälfte der jeweiligen TKI-Standarddosis in den ersten 12 Monaten
2.Danach komplettes Absetzen
3. Monatliches PCR-Monitoring
4.TKI-Re-Therapie im Falle eines molekularen Rückfalles (MMR >0,1% in zwei
aufeinander folgenden Proben)
25. Results
•174 patients (male 98; female 76) were recruited after giving informed consent
from 20 UK centres.
•At entry, 148 patients were receiving imatinib, 16 nilotinib and 10 dasatinib,
for a median duration of 6.8 years.
•after 12 months of half-dose therapy, molecular recurrence was lower in
patients with stable MR4 at entry (3 of 125 patients; 2.4%) than in those in
“MMR but not MR4” (9 of 49 patients; 18.4%) (p < 0.001).
•during the subsequent 12 months of complete treatment cessation in 117
stable MR4 patients, only 26 further recurrences and 4 withdrawals occurred,
giving a recurrence free survival (RFS) of 77% (90% CI: 71-83%) for the overall
24 months for this patient group.
•The recurrence rate on cessation is higher in the “MMR but not MR4 group”
(20 recurrences and 4 withdrawals among 36 patients during cessation;
39% RFS overall (90% CI: 29-52%); p = < 0.001).
•duration of TKI treatment was an additional predictive factor (p = 0.058; HR
0.93), in line with recent data from EUROSKI.
•The probability of RFS remains unrelated to age, gender, performance status
or prior TKI (imatinib vs second generation). No progression to advanced
phase was seen; one case lost haematological response.
26. Sex Imatinib Nilotinib Dasatinib
Median
duration
98 m, 76 w 148 16 10 6,8 Jahre
MR4
(n=117)
90% CI-
Intervall
MMR, but no MR4
(n=57)
90% CI-
Intervall
relapse 26 - 20 -
withdrawal 4 - 4 -
24-Months-
RFS
77% 71-83% 39% 29-52%
Results
28. CONCLUSION
• The present 24 month RFS of 77% for the overall
24 months in patients in stable MR4 appears better
than in any comparable study to date !
• This implies that the initial 12 months of dose
reduction may be responsible, perhaps via
improved compliance in the few months prior to
stopping or through an as yet undefined
mechanism.
29. DURABLE TREATMENT-FREE REMISSION (TFR) FOLLOWING
FRONTLINE NILOTINIB (NIL) IN PATIENTS (PTS) WITH CHRONIC
MYELOID LEUKEMIA IN CHRONIC PHASE (CML-CP):
ENESTFREEDOM 96-WK UPDATE
Author(s): David Ross
Abstract: P601
Type: Poster Presentation
Presentation during EHA22:
On Saturday, June 24, 2017 from 17:30 - 19:00
30. Methods
•ENESTfreedom (NCT01784068) is evaluating the ability to stop NIL
and remain in TFR in pts with a sustained deep molecular
response (DMR) on frontline NIL.
•Previous results from ENESTfreedom showed that 51.6% of pts
(98/190) who attempted TFR remained off treatment and in major
MR (MMR; BCR-ABL1 ≤ 0.1% on the International Scale [IS]) at 48
wk.
Aims
To analyze updated TFR data and predictive factors for remaining
in TFR in ENESTfreedom.
33. CONCLUSION
• The majority of pts in TFR at 48 wk remained in TFR
at 96 wk, and they reported fewer AEs during the
second 48 wk of TFR than in the first 48 wks
• No strong predictors for remaining in TFR were
identified.
• the biological explanation for an association between
Sokal risk score at diagnosis and a subsequent
ability to remain in TFR is unknown. These results
support TFR as a valuable option for pts in sustained
DMR on frontline NIL.
34. LONG-TERM FOLLOW-UP IN VERY ELDERLY PATIENTS WITH
CHRONIC MYELOID LEUKEMIA TREATED WITH IMATINIB
FRONTLINE
Author(s): Monica Crugnola
Abstract: P604
Type: Poster Presentation
Presentation during EHA22:
On Saturday, June 24, 2017 from 17:30 - 19:00
35. Background
Very elderly (>75 yrs) people are a substantial proportion of
chronic myeloid leukemia (CML) patients that sometimes receive
Imatinib (IM) at reduced doses based on physicians’ judgment.
However, data on long-term follow-up of these patients are still
lacking.
Aims
To investigate the treatment response and outcome in a cohort of
very elderly patients with newly diagnosed CML in chronic phase.
Method
We revised in a retrospective database 263 CML patients aged ≥ 75
years and diagnosed from 2/2002 to 1/2016 and treated with IM
frontline; among these, 121 patients (46%) were older than 80 yrs.
36. Results I
•Median age at diagnosis was 78.5 yrs
•Sokal Risk at diagnosis was
• low in 1 patient (0.4%),
• intermediate in 171 (68.4%),
• high in 78 (31.2%) and
• not evaluable in 13 patients.
•As regards comorbidities,
• 63 patients had no or 1 concomitant disease,
• 147 patients 2 or 3 and
• 53 patients (20.1%) 4 or more.
•initial IM dose was
• 400 mg/day in 180 (68.4%),
• 300 mg/day in 67 (25.5%) and
• <300 mg/day in 16 (6.1%) patients.
37. Results II
•250 patients (92.8%) achieved a complete haematological response
(CHR).
•Among these, 208 (79% of all 263 patients) achieved a cytogenetic
response (CyR), which was partial in 18 patients and complete (CCyR)
in 190 (72.2% )
•Among the 190 patients in CCyR, 148 (56.2%) achieved a molecular
response (MMolR) (ratio < 0.1).
•Eleven patients (4.2%) developed a blastic phase (myeloid in 8 and
lymphoid in 3 cases). After a median follow-up of 45.0 months from IM
start (IQR 22.3– 72.0),
• 93 patients have died (9 from disease progression and 84 from
unrelated causes),
• 144 are alive and 104 of them are still in treatment with IM, while
8 discontinued for prolonged deep molecular response and 22
switched to 2nd
generation TKI.
• Five-years event-free survival (EFS) and overall survival (OS)
were 51.2% (CI95% 44.8-57.6) and 70.9% (CI95% 64.6-77.2),
respectively.
38. Results III
Multivariate analysis for OS OR 95% CI P
MMolR achievement 0.363 0.236 - 0.560 <0,001
Age < 80 years 0.622 0.397 - 0.975 0.038
Male gender 1.589 1.048 - 2.410 0.029
Multivariate analysis for EFS OR 95% CI P
400 mg IM initial dose 0.656 0.459 - 0.938 0,021
PLTS < 500 x 109
/l 1.517 1.064 - 2.161 0.021
Concomitant diseases ≤ 3 0.597 0.398 - 0.896 0.013
39. CONCLUSION
• The long term follow-up of very elderly CML patients
treated with IM suggests that any effort to treat
these patients with standard doses should be made,
in order to achieve cytogenetic and molecular
responses as in younger subjects.
SIMPLICITY is an ongoing observational study of CP-CML patients receiving first-line imatinib, dasatinib or nilotinib in the United States and Europe outside of clinical trials (NCT01244750)
The primary objective of SIMPLICITY is to understand tyrosine kinase inhibitor (TKI) use and management patterns in clinical practice
The study includes:
Three ‘prospective’ cohorts of patients enrolled into SIMPLICITY at the time they initiated first-line IM, DAS or NIL during or after 2010
A ‘retrospective’ cohort that includes patients treated with first-line IM since 2008, before their enrollment in SIMPLICITY
Observational Study Protocol CA180330. STUDYING INTERVENTIONS FOR MANAGING PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE: THE 5-YEAR PROSPECTIVE COHORT STUDY (SIMPLICITY), Protocol Version 2, 01-Aug-2011.
Zyczynski T, Khoury HJ, Goldberg S, Mauro M, Michallet M, Paquette R, Foreman A, Turner M, Subar M, Manley Daumont M, Hehlmann R, Simonsson B. Imatinib discontinuation and TKI switching patterns in the retrospective and prospective cohorts in SIMPLICITY, a study of chronic phase-chronic myeloid leukemia (CP-CML) patients in routine clinical practice. Presented at ISPOR 7th Asia-Pacific Conference (Singapore), Poster PCN63.
The 1st-line imatinib cohort had the greatest proportion of early and late switchers
The 1st-line dasatinib cohort had the smallest proportion of early switchers
The 1st-line nilotinib cohort had the smallest proportion of late switchers
In the EHA 2014 poster It was reported that:
1st-line IM patients – Das (45%), Nil (32%)
1st-line Nil patients – Im (33%), Das (29%)
1st-line Das patients – Im (40%), Nil (17%)
All patients – Im (16%), Das (35%), Nil (27%)
US – more common to go to Das; EU more common to go to Nil
For patients on 1st-line imatinib, resistance was an important reason to switch TKI
For the overall population, 71% of patients switched TKI due to intolerance and 12% of patients switched TKI due to resistance
In late switchers, primary resistance was a more common reason for discontinuation in imatinib patients pts vs. dasatinib or nilotinib patients
Acquired resistance was only reported as a reason for discontinuation in imatinib-treated patients
Cortes et al_Submitted BFORE MS, p24 Fig 1; T14_02_02_03_01_mmr_comp_mitt_sce
Could not verify P values; otherwise verified per original verfications on source BAB 5.1.17
Verified p-values –JVS 5.2.17
Cortes et al_Submitted BFORE MS, p35, Fig S3
Otherwise all (except HR, CI, P value, and footnote) verified per original verification. 5.1.17
T14_02_03_06_ccyr_mtime_sce for embedded data
Verified JVS 5.2.17
BOS Pts:
All 4 bosutinib patients had intermediate Sokal risk
Pts were aged 45, 47, 62, and 64 (median = 55) years
1 pt achieved an MR1 and 2 pts achieved an MR2 at 3 months; 1 pt (who transformed to BP) did not achieve a molecular response
IM Pts:
3 IM patients had high Sokal risk, 2 had intermediate, and 1 had low risk
Pts were aged 28, 32, 33, 55, 57, and 80 (median = 44) years
2 pts achieved an MR1 and 1 pt achieved an MR2 at 3 months; 3 pts did not achieve an MR (1 of whom transformed to BP)
RE: 5 Pts Meeting AP Criteria Based on Basophils:
1 pt in the bosutinib arm did not achieve MMR. This pt’s best overall response was MR1
Basophil count at screening:
BOS:InO:
120-03-06 = 22.0110-35-02 = 9.04
490-02-03 = 22.0120-03-03 = 16.99
650-01-01 = 9.0 (did not achieve MMR)
AV001_BFORE_CSR_Final_V1.0_30_Jan_2017, p135/A for figure
Aside from breakout of BP and AP, verified BAB 5.1.17; breakout Verified JVS 5.2.17
Cortes et al_Submitted BFORE MS, p10/B for bullets
Aside from breakout of BP and AP, verified BAB 5.1.17; breakout Verified JVS 5.2.17
For notes, see L16_02_06_05_02_apbp_study (Sokal from L16_02_04_02_char; Age from L16_02_04_01_dm; Response from L16_02_06_01_resp)
verified with edits BAB 5.1.17