Therapeutic options for chronic myeloid leukemia: focus on imatinib (Glivec^®, Gleevec™)

Figures & data

Figure 1 Molecular structures of imatinib, nilotinib, dasatinib, and ON012380. The respective H-bond interactions with the Abl kinase domain are indicated in red. Derived from Weisberg et al (2006).

Figure 2 Position of relevant AA substitutions within the Abl kinase causing resistance to imatinib. The structure of Abl is shown in its inactive status bound to imatinib. Relevant AA are highlighted in yellow. Derived from Nagar et al (2002).

Figure 3 Structure of the Abl kinase in complex with imatinib (red, left panel), dasatinib (red, middle panel), and MK-0457 (red, right panel). The positions of the P-loop and the activation loop are indicated in yellow. Imatinib binds and stabilizes the inactive conformation of Abl (left panel) whereas dasatinib binds to the active conformation of the Abl kinase which is similar for Src and Abl (middle panel). MK-0457 (left panel) is not fully buried in the kinase domain and is anchored to this domain by 4 hydrogen bonds to sequence-invariant elements within the active form of Abl. Derived from Nagar et al (2002), Tokarski et al (2006), and Young et al (2006).

Table 1 Efficacy of imatinib in early phase II trials

	CML-CP, IFN failure	CML-AP	CML-BC
Hematological response	88%	63%	26%
Major cytogenetic response	49%	21%	13.5%
Complete cytogenetic response	30%	14%	5%

Adapted with permission from Cohen et al (2002)

Abbreviations: CML-CP, CML in chronic phase; IFN, interferon; CML-AP, CML in accelerated phase; CML-BC, CML in blast crisis.

Table 2 Mechanisms, frequencies, and functional consequences on proliferation of relevant bcr-abl mutations

Mutation	Mechanism of resistance		Frequency in patients		in vitro proliferation IC50 [nM]
	direct	indirect	high	low or medium	Imatinib	Nilotinib	Dasatinib
wt					260	13	0.8
Met244Val		+		+	2000	38	1.3
Leu248Val	+		+			675
Gly250Ala			+		1350	48	1.8
Gly250Glu (P-loop)		+		+
Gln252His (P-loop)		+		+	1325	70	3.4
Gln252Arg (P-loop)		+		+
Tyr253His (P-loop)	+	+	+		>6400	450	1.3
Tyr253Phe (P-loop)		+	+		3475	125	1.4
Glu255Lys (P-loop)		+		+	5200	200	5.6
Glu255Val (P-loop)		+		+	>6400	430	11
Glu292Lys				+
Phe311Ile		+		+
Phe311Leu		+		+	480	23	1.3
Thr315Ile	+		+		>6400	>2000	>200
Phe317Leu	+		+		1050	50	7.4
Phe317Val	+			+	350		53
Met343Thr		+		+
Met351Thr		+	+		880	15	1.1
Glu355Gly			+		2300		1.8
Phe359Ala	+			+
Phe359Val	+		+		1825	175	2.2
Val379Ile		+		+	1630	51	0.8
Met388Leu (A-loop)		+		+
His396Arg (A-loop)		+	+
His396Pro (A-loop)		+		+	850	41	0.6
Phe486Ser		+		+

Adapted from Ray et al (2007), Weisberg et al (2007), O’Hare et al (2005), and O’Hare et al (2007).

The IC₅₀ value is the concentration of inhibitor resulting in a 50% reduction of BaF3 cellular proliferation

Table 3 Definition of failure and suboptimal response in first-line imatinib treatment (400 mg)

	Failure	Suboptimal response	Warning signs
at diagnoses	NA	NA	High risk, del9q ACAs in Ph^+ cells
3 months after diagnosis	No HR	Less than complete HR
6 months after diagnosis	Less than complete HR No CgR (Ph^+ >95%)	Less than partial CgR (Ph^+ >35%)
12 months after diagnosis	Less than partial CgR (Ph^+ >35%)	Less than complete CgR	Less than major MolR
18 months after diagnosis	Less than complete CgR	Less than major MolR
Anytime	Loss of complete HR1 Loss of complete CgR2 Mutation3	ACA in Ph^+ cells4 Loss of major MolR4 Mutation4 Mutation5	Any rise in transcript level OCA in Ph^− cells

Adapted with permission from Baccarani M, Saglio G, Goldman J, et al. 2006. Evolving concepts in the management of chronic myeloid leukemia:recommendations from an expert panel on behalf of the European LeukemiaNet. Blood, 108:1809–20. Copyright © 2006 American Society of Hematology.

1 to be confirmed on 2 occasions unless associated with progression to AP/BC.

2 to be confirmed on 2 occasions unless associated with loss of complete hematologic remission or progression to AP/BC.

3 high level of insensitivity to imatinib (eg, Thr315Ile).

4 to be confirmed on 2 occasions unless associated with loss of complete hematologic remission or complete cytogenetic remission.

5 low level of insensitivity to imatinib.

Abbreviations: NA, not applicable; ACA, additional cytogenetic aberrations in Ph+ cells; OCA, other chromosomal abnormalities in Ph- cells; HR, hematologic remission; CgR, cytogenetic remission; MolR, molecular remission.

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