Post ASH 2014 - ActualitésLMC - hematologie-dz.com M LMC.… · ENESTnd: Mise à jour à 6 ans...

Post ASH 2014 - Actualités LMC

Actualités de première ligne LMC PC

• ENESTnd (6 ans)

• Dasision (5 ans)

• EPIC

• Spirit France (5 ans)

• Spirit 2 UK (5 ans)

ENESTnd: Mise à jour à 6 ans

Imatinib 400 mg QD (n = 283)

Nilotinib 300 mg BID (n = 282)RANDOMIZE

RANDOMIZE

Nilotinib 400 mg BID (n = 281)

Planned follow-up: 10 yearsa,b

N = 846

Adults with

newly

diagnosed

≤ 6 months)

Ph+ CML-CP1:1:1

Stratified by

Sokal risk

score

Larson RA, et al. Blood. 2014:[abstract 4541].

Design



a On core or extension treatment or in posttreatment follow-up. b Per the 2009 European LeukemiaNet criteria (Baccarani M, et al. J Clin Oncol. 2009;27:6041-6051) or investigator assessment. c Included abnormal test procedure results (n = 0 [nilotinib 300 mg BID], 1 [nilotinib 400 mg BID], and 1 [imatinib]), condition no longer required study drug (n = 1, 0, and 0, respectively), lost to follow-up (n = 4, 2, and 3, respectively), administrative problems (n = 7, 6, and 7, respectively), treatment duration completed per protocol (n = 3, 1, and 2, respectively), and protocol deviation (n = 14, 11, and 6, respectively).

Patient Status, n (%)Nilotinib

300 mg BID(n = 282)

Nilotinib 400 mg BID

(n = 281)

Imatinib 400 mg QD

(n = 283)

Still on studya 231 (81.9) 238 (84.7) 224 (79.2)

Still on core treatment 151 (53.5) 155 (55.2) 127 (44.9)

Discontinued core treatment and entered extension study 24 (8.5) 3 (1.1) 45 (15.9)

Discontinued core treatment without entering extension study 107 (37.9) 123 (43.8) 111 (39.2)

Adverse event/laboratory abnormalities 39 (13.8) 64 (22.8) 39 (13.8)

Withdrawal of consent 19 (6.7) 22 (7.8) 22 (7.8)

Suboptimal response/treatment failureb 11 (3.9) 10 (3.6) 19 (6.7)

Death 7 (2.5) 2 (0.7) 2 (0.7)

Disease progression 2 (0.7) 4 (1.4) 10 (3.5)

Other reasonc 29 (10.3) 21 (7.5) 19 (6.7)

Patients’ disposition



0 6 12 18 24 30 36 42 48 54 60

0

20

40

60

80

100

Months Since Randomization

Cu

mu

lati

ve

In

cid

en

ce

of

MR4.5

, %

Nilotinib 300 mg BID (n = 282)Nilotinib 400 mg BID (n = 281)

Imatinib 400 mg QD (n = 283)

10

30

50

70

90

66 72 78

11%; P < .0001a

7%; P < .0001a

1%

∆ 6% to 10%

By 1 Year

56%; P < .0001a

55%; P < .0001a

33%

∆ 22% to 23%

By 6 Years

31%

By 5 Years

54%; P < .0001a

52%; P < .0001a

∆ 21% to 23%

Cumulative incidence of MR4.5

Nilotinib

300 mg BID

(n = 282)

Nilotinib

400 mg BID

(n = 281)

Imatinib

400 mg QD

(n = 283)

Progression to AP/BC on core treatment, n 2 3 12

KM-estimated 6-year freedom from

progression to AP/BC (95% CI), % 99.3

(98.2-100)

98.7

(97.2-100)

95.2

(92.6-97.9)

Hazard ratio vs imatinib (95% CI)0.1599

(0.0358-0.7143)

0.2457

(0.0693-0.8713)–

Nominal P value vs imatinib .0059 .0185 –

Progression to AP/BC on study, n 11 6 21


progression to AP/BC (95% CI), %

95.8

(93.3-98.2)

97.8

(96.0-99.5)

92.2

(89.1-95.4)


(0.2464-1.0600)

0.2773

(0.1119-0.6870)–




Freedom from progression to AP/BC at 6 years



Overall survival and deathsNilotinib

300 mg BID

(n = 282)

Nilotinib

400 mg BID

(n = 281)

Imatinib

400 mg QD

(n = 283)

Total deaths on study, na 21 11 23

KM-estimated 6-year OS on study

(95% CI), %91.6 (88.0-95.1) 95.8 (93.4-98.2) 91.4 (88.0-94.7)

Hazard ratio vs imatinib (95% CI) 0.8934

(0.4944-1.6143)

0.4632

(0.2258-0.9503)–


Deaths due to advanced CML, n 6 4 16


death due to advanced CML (95% CI),

%

97.7 (96.0-99.5) 98.5 (97.1-100) 93.9 (91.0-96.8)


(0.1445-0.9440)

0.2433

(0.0813-0.7279)–


Dasision: Mise à jour à 5 ans

Cortes J, et al. Blood. 2014:[abstract 152].

Design

Database lock of 24-Mar-2014

Primary end point: confirmed CCyR by 12 months

• 77% dasatinib vs. 66% imatinib (P=0.007)1

5-year

final resultsRandomized a

Imatinib 400 mg QD (n=260)Imatinib 400 mg QD (n=260)

Dasatinib 100 mg QD (n=259)Dasatinib 100 mg QD (n=259)

�Treatment-naïve

CML-CP patients

(N=519)

�108 centers

�26 countries

�Enrollment:

September 2007–

December 2008

�Treatment-naïve

CML-CP patients

(N=519)

�108 centers

�26 countries

�Enrollment:

September 2007–

December 2008

a Stratified by EURO (Hasford) risk score.

1. Kantarjian H et al. N Engl J Med 2010;362:2260

Dasision : Mise à jour à 5 ans



Treated Patients, n (%)

Dasatinib 100 mg QD

(n=258)

Imatinib 400 mg QD

(n=258)

On initial therapy at study end 158 (61) 162 (63)

Discontinued

Progression or treatment failure 28 (11) 36 (14)

AE related to study treatment a 42 (16) 17 (7)

AE unrelated to study treatment a 12 (5) 4 (2)

Poor/nonadherence 1 (<1) 7 (3)

Other 17 (7) b 31 (12) c

a As defined by investigator.b Includes withdrawal of consent and patient request (4 each), insufficient molecular response (3), pregnancy (2), and lost to follow-up, loss of CCyR, increased BCR-ABL,

and relocation to the US (1 each).c Includes patient request (10), no molecular response/loss of molecular response (4), withdrawal of consent and suboptimal response (3 each), lost to

follow-up, insufficient cytogenetic response, and investigator request (2 each), and pregnancy, recurrence of blasts in bone marrow, no CMR, no MMR,

and appearance of mutation (1 each).



CI MR4.5

0 6 12 18 24 30 36 42 48 54 60

100

90

80

70

60

50

40

30

20

10

0

By 1 year

By 2 years

By 3 years

By 4 years

By 5 years

3%

8%

13%

23%

33%

5%

19%

24%

34%

42%

p=0.0251

Months Since Randomization

% W

ith

MR4.5

Dasatinib 100 mg QD

N

Imatinib 400 mg QD 260259

One imatinib patient and no dasatinib patients transformed between 4 and 5 yearsOne imatinib patient and no dasatinib patients transformed between 4 and 5 years

Dasatinib 100 mg QD

(n=259)

Imatinib 400 mg QD

(n=260)

BCR-ABL at 3 Months a≤10%

n=198

>10%

n=37

≤10%

n=154

>10%

n=85

Transformation to AP/BP b, n (%) 6 (3) 5 (14) 5 (3) 13 (15)

Pa

tie

nts

, n

Pa

tie

nts

, n

4.6%4.6%

7.3%7.3%

Dasatinib n=259Dasatinib n=259 Imatinib n=260Imatinib n=260

On studyOn study During follow-up beyond discontinuationDuring follow-up beyond discontinuationOn study During follow-up beyond discontinuation

a One dasatinib and one imatinib patient transformed but did not have 3-month molecular assessments.

b Including follow-up beyond discontinuation (intent to treat).



Transformation to AP/BC

Dasatinib100 mg QD

(n=259)

Imatinib400 mg QD

(n=260)

Hazard ratio

(95% CI)

Total number of deaths, n 26 26 –

Estimated 5-year OS, % (95% CI)

91(87–94)

90(85–93)

1.01 (0.58–1.73)

Estimated 5-year PFS, % (95% CI)

85(80–89)

86(80–89)

1.06 (0.68–1.66)

Causes of death were cardiovascular disease (2 dasatinib, 1 imatinib); disease progression

(9 dasatinib, 17 imatinib); infection (11 dasatinib, 1 imatinib); other malignancy, septic shock and cardiac failure,

multi-organ failure, and whole body swelling (1 each dasatinib); stem cell transplantation complications and

unknown (2 each imatinib); severe chest pain, clinical deterioration and decrease in performance status, and fatal

bleeding (1 each imatinib)

On-study treatment and in follow-up after discontinuation of randomized treatment.



Overall and Progression-free survival

EPIC

Lipton JH, et al. Blood. 2014:[abstract 519].

Design

EPIC


Molecular results at 3, 6, 9 and 12 months (Evaluable patients)

EPIC


Treatment-emergent vascular events = 14% emergent CV events in total= 14% emergent CV events in total

SPIRIT France

F, et al. Blood. 2014:[abstract 1793].

Survie à 5 ans

Survie globaleSurvie globale Survie sans progressionSurvie sans progression

SPIRIT 2 : Study Design

Chronic phase CML

within 3 months of diagnosis R

Arm AImatinib 400

Arm BDasatinib 100

Randomised, open labelPrimary endpoint: 5 year EFSSecondary: cytogenetic, PCR response, toxicity

n=814

N=407

N=407

EndpointsPrimary� 5 year event free survival (EFS)

– Assessed for all patients March 2018

Secondary� Rate of complete cytogenetic response (CCR)� Rate of Major Molecular Response

– (MMR, MR3, BCR-ABL1/ABL1 ratio<0.1%)

� Toxicity� Treatment failure rates (TFR) after 5 years� Rates of complete haematologic response (CHR)� Overall survival at 2 and 5 years

Patients Who Stopped Study Drug

Reason for stopping study drug (exc. death)Imatinib406 (%)

Dasatinib406 (%)

Total812 (%)

Consent withdrawn 7 (1.7) 9 (2.2) 16 (2.0)Disease progression - accelerated phase 1 (0.2) 2 (0.5) 3 (0.4)Disease progression - blast crisis 7 (1.7) 4 (1.0) 11 (1.4)Failure to achieve CCR after 24 months 4 (1.0) 1 (0.2) 5 (0.6)Failure to achieve MCR after 12 months 23 (5.7) 3 (0.7) 26 (3.2)Intolerance - non haem tox 53 (13.1) 80 (19.7) 133 (16.4)Intolerance - haem/lab tox 10 (2.5) 10 (2.5) 20 (2.5)Loss of CHR 5 (1.2) 0 5 (0.6)Loss of MCR 5 (1.2) 2 (0.5) 7 (0.9)Other reason 4 (1.0) 11 (2.7) 29 (3.6)Reason unknown - Lost to follow up 2 (0.5) 0 2 (0.2)

‘Inadequate response’ (cytogenetic, haematological, molecular, mutation detected) 42 (10.3) 3 (0.7) 45 (5.5)

Total 163 (40.1) 125 (30.8) 288 (35.5)

Cause of Death

CML related 6/18 (33%)

Non – CML related 9/18 (50%)

Total Deaths38/812 (4.7%)

Imatinib18/406 (2.2%)

Dasatinib20/406 (2.5%)

CML related 5/20 (25%)

Non – CML related 10/20 (50%)

Unknown3/18 (17%)

Unknown5/20 (25%)

Other cancer4/9 (44%)

Non cancer5/9 (56%)

BronchogenicEndometrialRectalGastric

• Left ventricular failure• Bronchopneumonia secondary to

emphysema• Myocardial infarction • Ruptured aortic aneurysm• Bronchopneumonia

Other cancer3/10 (30%)

Non cancer7/10 (70%)

• Colon ca• Lung ca• Metastatic breast ca

• Ischaemic heart disease, COPD, CCF

• Chest Infection, CCF, renal failure, diabetes

• Bowel perforation• Cardiac failure and

bronchopneumonia• Liver disease• COPD• Chronic cardiac failure

11

Comparative AEsFluid retention

Oedema

Pleural effusion

Myalgia

Nausea

Vomiting

Diarrhoea

Fatigue

Headache

Rash

Pulmonary (arterial) hypertension

Dyspnoea (exertional) with no pleural effusion

Favours dasatinib Favours imatinib

Difference

95% CIs

November 2014

Cytogenetics at 12 Months

Imatinib (%) Dasatinib (%) Difference (%) p value

Major cytogenetic response (MCR)

209/406(51.5)

228/406(56.2)

(4.7) 0.181*

Complete cytogenetic response (CCR)

169/406 (41.6)217/406(53.4)

(11.8) <0.001*

Missing analyses181/406 (44.6)

166/406(40.9)

*caution required, missing analyses included in denominator

12 Month PCR

Dasatinibn=406

Achieved MR4.5 Response

24/406(5.9%)

Achieved MR4.5Response

54/406(13.3%)

On treatment320/406 (78.8%)

Off treatment 80/406 (19.7%)

Unknown6/406 (1.5%)

On treatment344/406 (84.7%)

Off treatment59/406 (14.5%)

Unknown3/406 (0.7%)

Achieved MR3Response

175/406(43.1%)

Achieved MR3Response

237/406(58.4%)

Total Cohortn=812

∆ = 7.4% P=0.001

∆ = 15.3% p<0.001

November 2014

Imatinibn=406

Partial PCR Responses

Imatinib Dasatinib Totals

3 month PCR samples available 317 100% 319 100% 636 100%

PCR > 10% (MR1) at 3 months 66 20.8% 20 6.3% 86 13.5%

PCR < 10% (MR1) at 3 months 251 79.2% 299 93.7% 550 86.5%

12 month PCR samples available 210 100% 267 100% 477 100%

PCR > 1% (MR2) at 12 months* 20 9.5% 10 3.7% 30 6.3%

PCR < 1% (MR2) at 12 months* 190 90.5% 257 96.3% 447 93.7%

Total with 'less than ideal' progress 86/317 27.1% 30/319 9.4% 116/636 18.2%

PCR Data: All Patients, Both Arms

PC

R R

atio

(B

CR

-AB

L1/A

BL1

Rat

io)

IS

7,431 data points, IS

Months From Randomisation

11 Patients Who ‘Died From CML’

No follow up data 3 overt blast crisis• 10.6 month interval to death• 12.6 months• 14.2 months1 equivocal accelerated phase• 42.4 months

PC

R R

atio

(B

CR

-AB

L1/A

BL1

Rat

io)

IS

Months From Randomisation

Actualités de première ligne LMC PC

Prognostic Significance of Early Predictors

Comparing the Prognostic Significance of Early Predictors of Survival in Chronic Myeloid Leukemia (CML) Treated with Imatinib - an

Analysis of the Randomized CML-Study IV

�BackgroundEarly prediction of outcome using response-related predictive landmarks has become a major paradigm in the clinical management of chronic myeloid leukemia (CML)

�Aims• Compare the prognostic significance of early predictors of survival according

to sensitivity and specificity of 3 Mo and 6 Mo landmarks

• Apply landmarks in patients with disease progression (AP, BP, deaths) within the CML study IV

A156

Hanfstein B, et al. Comparing the Prognostic Significance of Early Predictors of Survival in Chronic Myeloid

Leukemia (CML) Treated with Imatinib - an Analysis of the Randomized CML-Study IV.

Comparing the Prognostic Significance of Early Predictors of Survival in Chronic Myeloid Leukemia (CML) Treated with Imatinib - an

Analysis of the Randomized CML-Study IV

� A total of 967 newly diagnosed patients were assigned to an imatinib-based treatment arm of CML-Study IV Median follow-up: 7.1 years

� The number of molecular assessments:

n= 789 (at 6 months)

n= 692 (at 3 months)

n= 301 (at 3 months and at diagnosis, without pretreatment)

� At 3 and 6 months, a BCR-ABL ratio was calculated using ABL as reference gene and standardized. At +3 mo a standardization was also made by GUS as a reference gene in order to ensure the linearity of the data

A156



Applying early landmarks on patients with disease

progression in CML-study IV

� Patient sample

3-month and 6-month molecular assessment: n=513

� Events defined by disease progression (accelerated phase, blastic phase or death) later than 7.5 months:

• Total: n= 45

• Accelerated phase: n= 4

• Blastic phase: n= 11

• Death from any reason: n= 30

• 2nd TKI: n= 21

• SCT: n= 13

A156

How could patients at risk be identified early and more precisely?

Hanfstein B, et al. Comparing the Prognostic Significance of Early Predictors of Survival in Chronic Myeloid Leukemia (CML) Treated with Imatinib - an Analysis of the Randomized CML-Study IV.



Conclusions� The 3-month 10% BCR-ABLIS landmark identifies patients at risk of

progression with a sensitivity of 41% and a specificity of 75%

� The 6-month 10% BCR-ABLIS landmark is less sensitive (18%) and more specific (94%)

� The most precise identification of patients at risk is allowed by a comparison of BCR-ABLIS at diagnosis and at 3 months



A half-log reduction of BCR-ABL transcripts at 3 mo nths is associated with an 8-year PFS of 94% vs 75% (43%

sensitivity, 87% specificity)



A156Progression-free survival (PFS) according to 0.5-lo g

reduction of BCR-ABL at 3 months



Essais d’arrêt de traitement

• Euroski (3 ans)

• Stop TKI2G (7 ans)

Relapse defined as BCR-ABL > 0.1% (loss of MMR) on the IS at one time point

Mahon FX, et al. Blood 2014:[abstract 151].

Molecular Relapse-free survival

At 6 months : 63 % (95% CI : 55% - 69%)At 12 months: 56 % (95% CI : 49 % - 63 %)At 18 months : 55 % (95% CI : 47 % - 61 %)

Relapses within 6 months , n=77

FX, et al. Blood. 2014:[abstract #151]

Molecular Relapse-free survival200 interim patients by TKI duration

Pts treated > 8 y N = 86, loss MMR = 29Pts treated < 8 y N = 114, loss MMR = 60

Overall p=0.007

At 18 months : > 8 y : 65 % (95% CI : 53 % - 74%)< 8 y : 47 % (95% CI : 38 % - 56%)


Molecular Relapse-free survival200 interim patients by MR4 duration

> 5 y : N = 92, loss MMR = 32< 5 y : N = 108, loss MMR = 57

Overall p=0.0122

At 18 months : > 5 y : 65 % (95% CI : 54 % - 74%)< 5 y: 46 % (95% CI : 38 % - 56%)


Study design and objectives

Rea D. et al. Blood 2014; Abstract #811.

- Adult CP-CML patients (n=100 planned)

- TKI therapy for at least 3 years

- 2G-TKI frontline or after intolerance/resistance to imatinib

- Undetectable BCR-ABL* (CMR4.5) for at least 2 years

*Major BCR. Molecular monitoring performed in local laboratories filling international standardization requirements. At least20000x2 copies of ABL control gene until 2012 then at least 32000 copies (Cross et al. Leukemia 2012; 26: 2172-2175.)

→ Primary objective: treatment-free survival in MMR

M12 M60STOP

RQ-PCRmonthly

RQ-PCRq3-6 months

RQ-PCRq2-3 months

M24 M36 M48

Year 1 Year 2 Year 3-5

Treatment-free survival in MMR

24 patients lost MMR after a median time of 3.7 months (1.5-37.6)

Rea D. et al. Blood 2014; Abstract 811.

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60

At 12 months: 59.6% (95% CI: 46.2-72.9)

At 24 months: 57.4% (95% CI: 43.9-70.9)

Months after 2G TKI discontinuation

% T

rea

tme

nt-

fre

e s

urv

iva

l in

MM

R

KM analysis

Treatment-free survival in MMR according to

baseline factors� No association between treatment-free survival without MMR loss and the following factors was found:

age, gender, Sokal risk group, exposure to IFN, treatment/CMR duration and type of 2G-TKI.

� Only prior history of suboptimal response or resistance to imatinib was found to have a significant impact:

Rea et al. Blood (ASH) 2014; Abstract 811.

KM analysis

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60


% T

rea

tme

nt-

fre

e s

urv

iva

l in

MM

R

P=0.048

First line/imatinib intolerant: 65.6% (95% CI: 50,2-79.7).

Suboptimal/resistant to imatinib: 41.6% (95% CI: 13.7-65.5).

At 12 months:


Treatment-free survival in MMR according to BCR-ABL

levels at 3 months

Landmark analysis among 40 patients who remained treatment-free in MMR at 3 months.

Rea et al. Blood (ASH) 2014; Abstract 811.

CMR at 3 months n=23

No CMR at 3 months n=17

MR4.5 at 3 months n=30

No MR4.5 at 3 months n=10

KM analysis

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60


% T

reat

men

t-fr

ee s

urvi

val i

n M

MR

P=0.019

At 12 months: 91.3% (95%CI: 79.7-100)

At 12 months: 58.8% (95%CI: 35.4-82.2)

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60% T

reat

men

t-fr

ee s

urvi

val i

n M

MR


P=0.000007

At 12 months: 93.3% (95%CI: 84.4-100)

At 12 months: 30% (95%CI: 15.9-58.4)


Early Disease Relapse after Tyrosine Kinase Inhibitor Treatment Discontinuation in CML Is Related Both

to Low Number and Impaired Function of NK-Cells

� Aim of the study:

To identify predictive biomarkers for relapse/non relapse after TKI discontinuation

� CML-CP Nordic patients included in the EURO-SKI study (n=119)

� Basic lymphocyte immunophenotyping (number of NK-, T-, and B-cells) performed at baseline and 1, 6 and 12 months after TKI discontinuation

� Functional analyses (cytotoxicity of NK-cells, Th1 cytokines) were performed in some patients

Patients with at least 6 months of follow-up after imatinib discontinuation (n=58)

Baseline variables Patients without loss of MMR(n=36)

Patients with loss of MMR(n=22)

p

NK-cells count (109cells/L) 0.26 0.15 0.01

NK-cells proportion (%) 18 11 0.005

NK-cells cytotoxic phenotype 1 19.2 13 0.02

Ilander MM, et al. Early Disease Relapse after Tyrosine Kinase Inhibitor Treatment Discontinuation in CML Is Related Both to Low Number and

Impaired Function of NK-Cells.

A812

(1) Based on levels of expression of CD57, CD16, CD 62L and IFN-ϒ/TNF-α secretion.

Early relapsing patients have lower proportion and number of Nkcells compared to non-relapsing or late-relapsing patients1) Based on levels of expression of CD57, CD16, CD62 L and IFN-ϒ/TNF-α secretion.

MM, et al. Early Disease Relapse after Tyrosine Kinase Inhibitor Treatment Discontinuation in CML Is Related Both to Low Number and Impaired Function of NK-Cells.

Early Disease Relapse after Tyrosine Kinase Inhibitor

Treatment Discontinuation in CML Is Related Both

to Low Number and Impaired Function of NK-Cells

Actualités de ≥ 2° ligne LMC PC

• PACE (3 ans)• BMS 034 (7 ans)

Essai PACE



Essai PACE


Survival for CP CML

Median follow-up: 38 months

Essai PACE


Survival

Median follow-up: 34 months

Essai PACE


Adverse Events = 49% emergent CV events in total= 49% emergent CV events in total

CA180-034 Study Design

� After 2 years, protocol allowed switching from BID to QD dosing

� Primary endpoint: To compare the MCyR rates of dasat inib when administered QD vs BID after a minimum follow-up of 6 months

N=662 treated

100 mg QD (n=167)

140 mg QD (n=167)

50 mg BID ( n=168)

70 mg BID ( n=168)

CP-CML pts ≥18 years with• Resistance• Suboptimal

response• Intolerance

to imatinib

N=670 randomized a

7-year

final results

Enrollment period: July 13, 2005 – March 13, 2006.

Patients were stratified by imatinib resistance vs. imatinib intolerance.

Duration of TherapyPatients in the 100 mg QD arm:� Remained on assigned therapy longer compared to oth er

dose groups� Maintained their assigned dose in a greater proport ion of

patients (38%) After 2 years:� The majority of patients on BID dosing arms were sw itched to

QD dosing� 19% of patients in the 140 mg QD arm treated after amendment switched to 100 mg QD

dosing by last recorded dose

100 mq QD(n=165)

140 mg QD(n=163)

50 mg BID(n=167)

70 mg BID(n=167)

Total(n=662)

Median duration, m 37 27 28 29 30

≥7 years dasatinib, % 22 15 19 21 19

Data are reported according to dose assigned at study entry.

Number of Treated Patients (%)

Dasatinib Dose100 mg QD

(n=166)140 mg QD

(n=163)50 mg BID a

(n=166)70 mg BID

(n=167)

Protocol -definedprogression b 35 (21) 42 (26) 29 (17) 27 (16)

Study drug toxicity 39 (24) 45 (28) 45 (27) 51 (31)

AE unrelated to study drug 10 (6) 4 (3) 10 (6) 8 (5)

Investigator request 12 (7) 6 (4) 7 (4) 5 (3)

Patient request 14 (9) 19 (12) 18 (11) 16 (10)

Other 16 (10) 15 (9) 19 (11) 22 (13)

Reason for DiscontinuationPrior to Study Closure

� The majority of patients classified as “other” cont inued to receive dasatinib

Reason for discontinuation was not reported in one patient in the 50 mg BID arm.Protocol-defined progression included increasing WBC count, loss of CHR or MCyR, ≥30% increase in Ph+ metaphases, or transformation

to AP/BP.

Safety

Number of Patients (%)

Dasatinib Dose100 mg QD

(n=165)

Other Dose Groups(n=497)

Total(n=662)

Drug -related AE 150 (91) 471 (95) 621 (94)

Grade ≥3 drug -related AE 75 (46) 281 (57) 356 (54)

Serious drug -related AE 43 (26) 173 (35) 216 (33)

Drug -related AE leading to discontinuation 34 (21) 130 (26) 164 (25)

Death 51 (31) 133 (27) 184 (28)

Study drug toxicity a 1 (1) 2 (<1) 3 (<1)

Disease progression 28 (17) 54 (11) 82 (12)

Safety and tolerability were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0.

Deaths due to study drug toxicity include 1 due to sepsis; 1 due to pulmonary edema, congestive heart failure, neck pain, and pleural effusion; due to necrosis of the colon.

Cumulative Incidence Rate of All-Cause Nonhematologic AEs of Special Interest

� For 100 mg QD, most nonhematologic AEs (all grades) first occurred within 24 months of treatment

0 5 10 15 20 25 30 35 40 45 50

Rash

Myalgias/arthralgias

Fatigue

Nausea/vomiting

Diarrhea

Pleural effusion

Hemorrhage

Patients, %

100 mg QD (Any grade)

Other Dose Groups (Any grade)

100 mg QD (Grade ≥3)

Other Dose Groups (Grade ≥3)

Efficacy Results:Cumulative Incidence of MMR

� Over 7 years of follow -up, cumulative incidence of MMR was similar across dose groups

100 mg QD(n=167)

140 mg QD(n=167)

50 mg BID(n=168)

70 mg BID(n=168)

Assessed treated patients, n (%) 160 (96) 153 (92) 160 (95) 151 (90)

MMR in assessed treated patients, n (%)

73 (46) 68 (44) 70 (44) 69 (46)

OS is Similar Across Dose Groups

162154158157

154150153150

147147147142

143141140136

141132129129

137126124123

130120120113

120118114106

112114105104

1061069995

991019692

94979289

89948983

73767974

100 mg QD140 mg QD50 mg BID70 mg BID

167167168168

100

90

80

70

60

50

40

30

20

10

0

% A

live

100 mg QD140 mg QD50 mg BID70 mg BID

Months

65%

73%

68%70%

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

Imatinib-resistant Patients Imatinib-intolerant Pati ents Overall

OS, % (95% CI) 63 (53–71) 70 (52–82) 65 (56–72)

PFS, % (95% CI) 39 (29–49) 51 (32–67) 42 (33–51)

OS by 3-Month BCR -ABL Level: 100 mg QD

8658

8658

8657

8455

8255

8253

8051

7950

7849

7848

7748

7548

7547

7446

7244

7043

6741

6540

6239

6039

5938

5936

5635

5544

5333

5232

5130

4927

4521

Patients at Risk

%>10%

Unstratified Log Rank P-Value = 0.0374

≤10%>10%

72%

56%

BCR-ABL ≤10% at 3 months (60%) BCR-ABL >10% at 3 months (40%)

OS, % (95% CI) 72 (60–81) 56 (42–68)

PFS, % (95% CI) 56 (43–67) 21 (10–34)

100

90

80

70

60

50

40

30

20

10

0

3 9 15 21 27 33 39 45 51 57 63 69 75 810 6 12 18 24 30 36 42 48 54 60 66 72 78 84

% A

live

Months

Other results….

The Experience of the International Registry for CML in Children and Adolescents

(I-CML-Ped Study): Pronostic Consideration

A521 Results-1 N=278

Age, Median (yrs)< 4 yrs (%)

12.4 (9-17.5)6

Sex - Female (%) 43

Phase at diagnosis (%)ChronicAcceleratedBlastique

9281

Sokal risk score (%)LowIntermediateHigh

183151

Splenomegaly (%)Median spleen size (below costal margin) (cm)

7611 (1-25)

Median leucocyte count (x109/L) 235 (5-1038)

Additional chromosomal abnormalities in Ph+ cells (% pts.) 6

Median follow-up (mo) 39 (0.5 – 161)

F, et al. The Experience of the International Registry for Chronic Myeloid Leukemia (CML) in Children and Adolescents (I-CML-Ped Study):

Pronostic Consideration.

The Experience of the International Registry for CML in Children and Adolescents

(I-CML-Ped Study): Pronostic Consideration

1) 169 pts. with available evaluation, CCyR in 124. 2) In univariate analysis. 3) Multivariate analysis.

A521

N=278

Estimated overall survival at 60 months (%) 95% (95%CI 89-97)

Cumulative incidence of CCyR 1 73%

CCyR Predictive factors 2 Eutos scoreSpleen sizeHematocrit levelLymphocyte countImmature cells in peripheral blood

CCyR Predictive factors 3 Sokal and medullary blast count

Children and adolescents with CML presented with clinical and biological differences compared to adult patients

F, et al. The Experience of the International Registry for Chronic Myeloid Leukemia (CML) in Children and Adolescents (I-CML-Ped Study):

Pronostic Consideration.

CP-CML pediatric cohort – Imatinib upfront

N=102

Age, Median (yrs) at imatinib initiation 12 (1-18)

Prepubertal (< 10 yrs), n (%) 27 (26.4)

Pubertal (age:10-14 yrs), n (%) 46 (45)

Postpubertal (age > 14 yrs), n (%) 29 (28.4)

Sex - Female (%) 47

Median duration of imatinib exposure (mo) 9 (0-98)

Change of SDS height on therapy

All cohort Decrease of 0.48 SDS per year during the first 3 years of therapy

Pubertal (age:10-14 yrs), n (%) 0.75 SDS per year during the first 3 years of therapy

Impairment of Longitudinal Growth By Tyrosine Kinase Inhibitor (TKI) Treatment – Data from a Large Pediatric Cohort with Chronic Myeloid Leukemia (CML)

� Aim:

To determine the impact of sex, age, and pubertal stage on impaired growth in a

pediatric cohort CP-CML treated with imatinib up-front

� Retrospective German study

JT, et al. Impairment of Longitudinal Growth By Tyrosine Kinase Inhibitor (TKI) Treatment – Data from a Large Pediatric

Cohort with Chronic Myeloid Leukemia (CML).

A522

SDS: Standard deviation scores

60

Impairment of Longitudinal Growth By Tyrosine Kinase Inhibitor (TKI) Treatment – Data from a Large Pediatric Cohort with Chronic Myeloid Leukemia (CML)

Changes in SDS body height analyzed at 3 months intervals during TKI therapy n=102 pts(age at diagnosis: 12 years, range: 1-18 years; 54 male, 48 female)

JT, et al. Impairment of Longitudinal Growth By Tyrosine Kinase Inhibitor (TKI) Treatment – Data from

a Large Pediatric Cohort with Chronic Myeloid Leukemia (CML).

Growth retardation is a significant adverse effect of IMA in children with CML affecting predominantly prepubertal children

KCL-22 CML Xenograft

Combination of ABL001 and Nilotinib prevents the emergence of resistance

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180 180

Nilotinib (75mg/kg) BIDNilotinib (75mg/kg) BID

ABL001 (30mg/kg) BIDABL001 (30mg/kg) BID

Nilotinib (75mg/kg) BID + ABL001 (30mg/kg) BIDNilotinib (75mg/kg) BID + ABL001 (30mg/kg) BID

Dosing stopped on day 77, all mice remain disease f ree >176 daysDosing stopped on day 77, all mice remain disease f ree >176 days

T315I detected

A337V detected

Each line represents individual animals

* *

*Wylie A, et al. Blood. 2014:[abstract 398].

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