PREDICTORS OF IMATINIB FAILURE IN CML

Esther Musyoka Dindi, N.A.Othieno-Abinya, Grace W Kitonyi.

Department of Clinical Medicine and Therapeutics, University of Nairobi.

CML: Massive splenomegaly

The history of CML

1845

First description of CML

1865

Fowlers’s solution -1% arsenic trioxide

2001

Imatinib

1879

Staining methods for blood

1903 1953 19831965

Radiotherapy

Busulfan

Hydroxyurea

Interferon

1968

BMT

2006

Dasatinib,Nilotinib

2012

BosutinibPonatinib

1960:Nowell & Hungerford describe the Philadelphia Chromosome

1973:Janet Rowley describes the9:22 translocation

1999: After seminal preclinical work first clinical trials commence with STI571 (imatinib)

1845:John Hughes Bennett reported a “Case of Hypertrophy of the Spleen and Liver in which Death Took Place from Suppuration of the Blood” in the Edinburgh Medical Journal

Today:5 kinase

Inhibitorsdeveloped

What is Philadelphia process?

• Co-habitation between a man with a rich woman goes sore and leaves a very bitter man, even poorer than before.• He becomes violent

Watson and Crick

Background

Imatinib mesylate: A small molecule tyrosine kinase inihibitor Targets BCR-ABL,KIT, PDGFR, and stem cell

factor. Revolutionized the treatment of chronic

myeloid leukaemia (CML). Treatment failure with imatinib has been

demonstrated in approximately 10% to 15% of CML patients.

Imatinib---abl kinase interaction

Importance of monitoring

Early identification of patients at risk of failures is important so that they can be put on alternative treatments.

Predictors of failure in CML are yet to be fully established

Sokal, Hasford and EUTOS scores are being used to predict cytogenetic response in some centres.

No study had been carried out locally to determine response to imatinib,the magnitude of failure, and its possible predictors.

 

Objectives

• To determine the haematological response of CML patients receiving imatinib, the proportion of patients with hematological failure

• To describe the clinical and haematological characteristics of patients with hematological failure and compare them with those with optimal response.

Methodology

Study design:  A cross-sectional descriptive study. Setting: The Nairobi Hospital GIPAP clinic.

Subjects: Philadelphia chromosome positive (Ph+ve) CML patients on imatinib therapy for at least 3 months

Information sought

• Socio-demographic parameters including age and sex

• Clinical parameters including presence of splenomegaly or hepatomegaly

• Laboratory parameters.• History of prior leukemia-targetted therapy• Duration between CML diagnosis and start of

imatinib

• Duration of CML from diagnosis• Duration on imatinib • Time taken to achieve complete

haematological response• Results of haematologic, cytogenetic or

molecular studies• Evidence of haematological treatment failure.

• Characteristics of patients with haematological failure were recorded and compared with those of patients with good response.

RESULTS

• 206 patients were included.• The mean age was 38.6years with a range of

14-85 years. There was slight male preponderance; 115(55.8%) and 91(44.2%) females.

Bone marrow findings at diagnosis

• Phase Number Percentage• Chronic 182 92.2• Accelerated 10 4.9• Blastic 2 1• Dry tap 1 0.5• Inconclusive 2 1

Results

• Complete hematologic response was attained within 3 months of imatinib therapy and sustained in 79.1%.

• 20.9% were found to have hematologic failure, and of these, 21% had primary failure with the rest having secondary failure.

Predictors of failure

Missed doses (60.5% vs 37.4%) Higher BCR-ABL concentration(mean of 81%

vs 68.2%) at diagnosis Longer durations between diagnosis and start

of therapy with imatinib. On logistic regression, only prolonged

duration between diagnosis and commencement of imatinib was an independent predictor of failure (OR 2.69(1.03-7.03 95%CI, p = 0.043).

• The Sokal and Hasford risk scores did not significantly predict for treatment outcome.

• EUTOS score was not applied in the majority

DISCUSSION

Estimated Annual Rate of Treatment Failure IRIS Estimated Annual Rate of Treatment Failure IRIS StudyStudy

General PopulationGeneral Population Complete Cytogenetic Complete Cytogenetic ResponseResponse

Year 1Year 1 3.3%3.3% 5.5%5.5%

Year 2Year 2 7.5%7.5% 2.3%2.3%

Year 3Year 3 4.8%4.8% 1.1%1.1%

Year 4Year 4 1.5%1.5% 0.4%0.4%

Year 5Year 5 0.9%0.9%

Perhaps the most important observation from IRIS: clinical resistance is an early event

Deininger M et al. Blood. 2009;114(22):462, # 1126.

CCyR expected @ 12mo for progression protection, MMR at 18mo for protection against any event

Hughes T et al Blood 116:3758-65, 2010Marin D, et al. Blood. 2008;112:4437-4444.

IRIS: Impact of transcript levels(CCyR equivalent

and MMR):

12 mo response: AP/BC progression

18 mo response: all events

Response at 12 months n Loss of CCyR

CCyR without MMR 95 24%

CCyR plus MMR 32 3%

Months Since Start of Imatinib Therapy

Loss

of C

CyR

(%

)

P = 0.04

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60

Single-institution analysis of patients with CP CML (n = 224) showed significant loss of response in cases lacking MMR at 12mo

Early molecular response brings success and safety:

Branford S, et al, Leukemia 17(12), 2401-9, 2003Marin D, et al, J Clin Oncol 30(3) 232-8, 2012Hanfstein B, et al, Leukemia 26(9):2096-102, 2012

25

Months on Imatinib

% a

chie

ving

MM

R

50

60

70

80

90

100

20

30

40

10

0

P<0.00169%

100%

3 6 9 12 15 18 24 3021 27

13%

>2 log reduction

1-2 log reduction

0-1 log reduction

0.0

0 1 2 3 4 5 6 7 8

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Prob

abili

ty o

f PFS

>10%1-10%≤1%

BCR-ABLIS

≤1%

1-10%

>10%

n

218281189

5Y-PFS

96%92%87%

p-value

n.s.

0.037

Years since diagnosisPFS as a function of BCR-ABLIS

@ 3 months, imatinib-based therapy German CML IV (2012)

MMR as a function of BCR-ABLIS

@ 3 months, imatinibIRIS (2003)

Tyrosine kinase inhibitors are capable of inducing molecular and cytogenetic response but not hydroxyurea

Those on other therapies including hydroxyurea likely to have accumulated other cytogenetic/molecular abnormalities that could influence downstream signalling.Likely to have accumulated drug resistant mutants in line with Goldie-Coldman hypothesis

• Norton-Simon resistance could have applied to some extent

ACKNOWLEDGEMENTS

Esther Musyoka Dindi

Grace w. Kitonyi

Walter O Mwanda

The Nairobi Hospital CEO

Mary Kisingu and Mary Kiarie

Staff at Anderson Centre.