Page 210 - Essential Haematology

196 / Chapter 14 Chronic myeloid leukaemia

Patients with optimal responses continue imat-
inib whereas those with treatment failure are treated
with second generation tyrosine kinase inhibitor
ATP
BCR-ABL1 (TKI) therapy or stem cell transplantation (SCT).
protein
kinase Patients with suboptimal responses can be treated
Substrate with an increase in the dose of imatinib to 600 or
800 mg/day, change in TKI therapy or early alloge-
(a)
neic SCT.

Protein BCR - ABL 1 m utation s creening
kinase One mechanism of disease resistance to imatinib
inhibitor
treatment is the development of mutations within

the BCR - ABL1 fusion gene. These mutations may
Substrate
be detected by sequencing the BCR - ABL1 gene and
(b) this is performed in many centres for patients who
fail to respond adequately to imatinib treatment.

The pattern of mutation can be useful for determin-
Figure 14.4 Mode of action of the tyrosine kinase

ing which treatment to choose as second - line
inhibitor imatinib. It blocks the adenosine triphosphate
(ATP) binding site. therapy.
marrow analysis to assess marrow metaphase cytoge-
Second g eneration t yrokinase k inase
netics. A complete cytogenetic response (CCyR) is
i nhibitors
defined as the absence of Ph - positive metaphases

Dasatinib is a broad multikinase inhibitor that is
within bone marrow and once CCyR is achieved
effective in many cases in which BCR - ABL1 has

monitoring continues with PCR quantifi cation
acquired mutations that render it resistant to imat-
of BCR - ABL1 transcripts within blood at regular
inib. It is widely used in this setting although fl uid
intervals.
retention can be a troublesome side eff ect.

The response of CML to imatinib can be defi ned
Nilotinib has a mechanism of action similar to
as optimal , suboptimal or treatment failure .
imatinib but has a higher affinity for the BCR -

An optimal response to is defi ned by:

ABL1 kinase and can be effective in cases with
• Complete haematological response (normal imatinib - resistant mutations. Both nilotinib and
blood count) and at least minimal cytogenetic dasatinib are currently being assessed in comparison
response (CyR) (Ph + < 95%) at 3 months; with imatinib for first - line treatment of CML and

• At least partial CyR (Ph + < 35%) at 6 months; early results suggest they may be superior.
• Complete CyR at 12 months; and
• Major molecular response with at least a 3 - log Overall r esponse to i matinib t herapy

reduction in BCR - ABL1 transcripts at 18 months The IRIS study recruited 553 patients to study effi -
(i.e. to 0.1% or less of pre - treatment level). cacy of imatinib therapy in chronic phase CML and
reported 7 - year clinical follow - up in 2008. Th is
Failure of response is defi ned by:
showed that 60% of patients remained on treatment
• Incomplete haematological response at 3 months;
with imatinib whereas 40% has discontinued treat-
• No CyR (Ph + > 95%) at 6 months;
ment because of disease progression or intolerance
• Less than partial CyR (Ph + > 35%) at 12 months;
of therapy. Overall survival was excellent with 84%
• Less than complete CyR at 18 months; and
of patients still alive at 7 years (Fig. 14.6 ).
• Loss of a previous complete haematological or
If patients become negative for BCR - ABL1 tran-
cytogenetic response.
scripts and imatinib is discontinued, some patients
In any other situation, the response is defi ned as remain negative. For those who become positive
suboptimal . again, imatinib will usually produce a further