Int J Clin Oncol DOI 10.1007/s10147-013-0641-7
REVIEW ARTICLE
Ever-advancing chronic myeloid leukemia treatment Shinya Kimura • Toshihiko Ando • Kensuke Kojima
Received: 30 October 2013 Ó Japan Society of Clinical Oncology 2013
Abstract Treatment of chronic myeloid leukemia (CML) has been drastically changed by the emergence of the ABL tyrosine kinase inhibitor (TKI), imatinib mesylate. However, resistance and intolerance have frequently been reported, particularly in patients with advanced-stage disease. Point mutations within the ABL kinase domain that interfere with imatinib binding are the most critical cause of imatinib resistance. To overcome this resistance, four second-generation ATP competitive ABL TKIs, dasatinib, nilotinib, bosutinib and bafetinib, have been developed. Dasatinib and nilotinib also demonstrated higher efficacy than imatinib in previously untreated CML patients in chronic phase. Despite promising clinical results, the frequently observed mutant T315I is not effectively targeted by any of the second-generation ABL TKIs. Thus, a thirdgeneration ABL TKI, ponatinib, was developed to inhibit all mutated BCR-ABL and showed clinical efficacy in CML cells harbouring T315I. CML treatment is rapidly progressing and further evolution is surely expected. Moreover, it was recently reported that some CML patients who achieved sustained complete molecular response could stop TKI. CML may become the first human cancer to be conquered solely with oral medicines. Keywords Chronic myeloid leukemia Imatinib Dasatinib Nilotinib Tyrosine kinase
Introduction Chronic myeloid leukemia (CML) is a malignant hematological disorder that causes marked increases in white blood cells and platelets, progresses through chronic, accelerated, and blastic phases, and results in death within a few years after diagnosis without appropriate treatments. CML is caused by the appearance of Philadelphia (Ph) chromosome due to reciprocal translocation between chromosomes 9 and 22, fusion of the abl gene on chromosome 9 with the bcr gene on chromosome 22, and the consequent development of the bcr-abl chimeric gene, which produces BCR-ABL chimeric protein with a kinase activity stronger than that of normal ABL (Fig. 1a). Imatinib mesylate (GlivecÒ), a potent ABL tyrosine kinase inhibitor (TKI), was approved in 2001 and became the first choice for CML in chronic phase (CML-CP) due to its significant efficacy. Binding of ABL with adenosine triphosphate (ATP) is necessary for the activation of BCRABL protein. Imatinib was developed as an ATP competitive type ABL TKI (Fig. 1b). According to the International Randomized Study of Interferon ? Ara-C vs. STI571 in CML (IRIS Study), no progression of the disease was observed in 92 % of patients in whom oral imatinib therapy could be continued for 8 years, and the overall survival (OS) with restriction of deaths to those related to CML was excellent, at 93 % [1, 2].
Imatinib resistance and intolerance S. Kimura (&) T. Ando K. Kojima Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan e-mail: [email protected]
Efficacy of imatinib is evaluated according to hematological, cytogenetic, and molecular responses. The hematological response is evaluated according to the normalization of blood cell counts including the white
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Int J Clin Oncol Table 1 Definition of the response to TKIs (any TKI) as first-line treatment
Baseline
Optimal
Warning
Failure
NA
High risk
NA
or
3 months
BCR-ABL1 B10 % and/or Ph? B35 %
CCA/Ph?, major route BCR-ABL1 [10 % and/or Ph? 36–95 %
6 months
BCR-ABL1 \1 % and/or Ph? 0
BCR-ABL1 1–10 % and/or Ph? 1–35 %
BCR-ABL1 [10 % and/or Ph? [35 %
12 months
BCR-ABL1 B0.1 %
BCR-ABL1 [0.1–1 %
BCR-ABL1 [1 % and/or Ph? [0
Then, and at any time
BCR-ABL1 B0.1 %
CCA/Ph- (-7 or 7q-)
Loss of CHR
Non-CHR and/ or Ph? [95 %
Loss of CCyR Confirmed loss of MMR Mutations CCA/Ph?
NA not applicable, CCA clonal chromosome abnormalities, CHR complete hematologic response, CCyR complete cytogenetic response, MMR major molecular response
Fig. 1 Philadelphia chromosome and the action of imatinib. a Reciprocal translocation between chromosome 9 and chromosome 22 forms an extra-long chromosome 9 and the Philadelphia chromosome containing the fused bcr-abl gene. The fused bcr-abl gene is translated to BCR-ABL chimera protein that causes CML and Ph?ALL. b BCR-ABL tyrosine kinase (TK) is a constitutively active kinase that functions by binding ATP and transferring phosphate (PO4) from ATP to tyrosine residues on various substrates. This causes excess proliferation of leukemia cells characteristic of CML and Ph?ALL. Imatinib functions by blocking the binding of ATP to the BCR-ABL TK, inhibiting its activity. In the absence of TK activity, substrates required for BCR-ABL function cannot be phosphorylated, and subsequent cellular events are abrogated
blood cell count, cytogenetic response according to the frequency of Ph chromosome, and molecular response according to the transcript number of bcr-abl genes in peripheral blood or bone marrow (quantitative PCR or AmpCML). If the response is insufficient, the disease is judged to be resistant to imatinib. The efficacy evaluation of imatinib against CML is generally performed according to the criteria of the European LeukemiaNet (ELN) (Table 1) [3] or National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) [4]. In Japan, the ELN criteria are currently used more frequently. The definition of intolerance has not been clearly established. Generally, however, the patient may be
123
considered intolerant if the response is not greater than the major cytogenetic response (MCyR), in which the percentage of Ph-positive cells is reduced to 35 % or less, and a grade 3/4 side effect has occurred, or if a grade 2 side effect has persisted for 1 month or longer or recurred more than 3 times despite supportive therapies.
Mechanisms of imatinib resistance Imatinib shows excellent efficacy against CML-CP but is less effective against exacerbated CML in the accelerated or blastic phase or Ph chromosome-positive acute lymphoblastic leukemia (Ph?ALL), with many patients exhibiting resistance from the beginning or an early phase of treatment. Also, according to the results in the 8th year of the IRIS study, the administration of imatinib could not be continued over a long period in about 1/3 of patients with CML-CP, similarly due to resistance or intolerance [5]. Reported causes of imatinib resistance are point mutation of the ATP-binding region in the abl kinase domain (KD), which is the binding site of imatinib (Fig. 1b) [6], amplification of the bcr-abl gene and an increase in the number of mRNA copies [6], emergence of multi-drug resistance genes [7], activation of other oncogenes (LYN,
Int J Clin Oncol Fig. 2 The structures of threonine and isoleucine. When the amino acid (aa) at 315, threonine, is replaced by isoleucine, hydrogen bonding between threonine at aa 315 and imatinib is lost. Moreover, the bigger side chain of isoleucine becomes an obstacle for the binding of imatinib to the ATP binding pocket
etc.) [8], and low expression of the drug transporter Oct-1 [9]. Also, BIM has already been reported to be important for the induction of apoptosis by imatinib [10], but it has recently been reported that deletion-type polymorphism in an intron of a gene coding for BIM is involved in the poor response to TKIs [11]. Among these mechanisms of resistance that pose clinical problems, point mutation of abl KD is the most frequent and important problem. Since T315I, the change of the 315th amino acid of abl KD from threonine (T) to isoleucine (I), was reported in an imatinib-resistant patient [6], more than 100 mutations have been reported to date. However, less than 20 of these mutations are frequently encountered in clinical practice [12]. For an ABL TKI to bind to the ATP-binding site of ABL, the hydrogen bond is important, and the presence of a nitrogen or oxygen molecule in the side chain of the amino acid is essential for the hydrogen bond. In wild-type BCR-ABL protein, the 315th amino acid is threonine (T) with nitrogen in the side chain, and a hydrogen bond is formed between the nitrogen molecule in the side chain of this T315 and imatinib. With its replacement by isoleucine (I), with no oxygen or nitrogen molecule in the side chain, I315 loses the hydrogen bond with imatinib. In addition, isoleucine has larger molecules in the side chain compared with threonine and conformational characteristics that physically interfere with binding of various drugs. Thus, the T315I mutation, in particular, causes marked resistance to ABL TKIs (Fig. 2). Among other mutations, Y253H, E255K, T315I, and M315T are frequently observed. Multiple mutations causing imatinib resistance may be also detected simultaneously. When multiple mutations are detected, mutations may be present in different BCR-ABL molecules (polyclonal mutation) or in a single BCR-ABL molecule (compound mutation) (Fig. 3). Compound mutation has been reported to often cause stronger resistance to TKIs [13]. Other than the ATP-binding site, mutation of the
Fig. 3 Polyclonal versus compound mutations. In a subset of patients who develop clinical resistance to ABL1 TKIs, two or more point mutations in the kinase domain of BCR-ABL1 are detectable by direct sequencing. In the case of polyclonal mutations, these BCR-ABL1 mutations (open circle and open triangle; top panel) exist separately in different clones. In contrast, BCR-ABL1 compound mutants exhibit 2 mutations within the same BCR-ABL1 molecule (open circle and open square; bottom panel)
SH3-SH2 domain of BCR-ABL (T212R) has been reported to be involved in resistance [14].
Overriding imatinib resistance When a CML patient exhibits resistance or intolerance to imatinib, the treatment is changed to second-generation ABL TKIs or hematopoietic stem cell transplantation. Four second-generation ABL TKIs have been developed, and dasatinib (SprycelÒ) and nilotinib (TasignaÒ) have already
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been approved in Japan as first-line drugs to be used immediately after the diagnosis of CML, and additionally as second-line drugs to be used for imatinib-resistant or intolerant patients. Each novel drug is briefly profiled.
Second-generation ABL TKIs: dasatinib (SprycelÒ) The affinity of dasatinib for ABL is about 325 times stronger than that of imatinib. It inhibits more than 50 kinases including eight Src family kinases (SFKs) as well as BCR-ABLs, resulting in its specificity being relatively low. Also, while it is effective for most mutant BCR-ABLs, its effects on T315I/A, F317L/V, V299L, Q252H, etc., are limited [15, 16]. A phase II clinical trial (P-II) of 70 mg dasatinib b.i.d. (140 mg/day) was performed in 387 imatinib-resistant/intolerant patients with CML-CP, and a complete cytogenetic response (CCyR, a state in which no Ph chromosome is detected) was achieved in 49 %. Pleural effusion was frequently noted as an adverse event [17]. In another study, similar effects were observed at 100 mg q.d. and 70 mg b.i.d [18]. At present, dasatinib is usually administered at 100 mg q.d. to CML-CP adult patients. A clinical trial of first-line dasatinib using the drug immediately after the diagnosis of CML (DASISION) was carried out. Dasatinib was administered at 100 mg q.d. or imatinib at 400 mg b.i.d. to previously untreated patients with CML-CP, and CCyR was observed in 77 and 66 % of patients in the dasatinib and imatinib groups, respectively, after 12 months. Also, a major molecular response (MMR: a decrease of bcr-abl mRNA by 3 log or more on quantitative PCR) was observed in 46 and 28 %, respectively, and the time until MMR was also significantly shorter in
the dasatinib group (Table 2a). As for safety, pleural effusion and thrombocytopenia were observed slightly more frequently, and edema, gastrointestinal symptoms, muscle-related symptoms, and rash were observed less frequently, in the dasatinib than imatinib group [19]. Large granular lymphocytes (LGLs) were increased in part of the patients administered dasatinib, and the outcome was reported to be more favorable in such patients [20]. This is speculated to be due to the direct stimulation of LGL proliferation or inhibition of LGL-suppressing regulatory T cells by dasatinib, but the details are still unclear.
Second-generation ABL TKIs: nilotinib (TasignaÒ) With structural modification of imatinib, nilotinib acquired about a 30-fold stronger anti-CML activity. It is effective against many mutant BCR-ABLs except T315I. Nilotinib suppresses ABL, PDGFR, and c-KIT activities but does not suppress SFKs, indicating higher specificity than dasatinib [21]. In a P-II trial against imatinib resistant/intolerantCML-CP, CCyR was achieved in 48 %. As for grade 3 or severer side effects, thrombocytopenia, neutropenia, and increases in bilirubin and lipase were observed. Cross-tolerance with imatinib was rare [22]. The ENESTnd study was performed in patients with previously untreated CML-CP, and nilotinib was administered at 300 or 400 mg b.i.d., or imatinib was administered at 400 mg q.d. After 12 months, the MMR rate was 44 % in the nilotinib 300 mg b.i.d. group, 43 % in the nilotinib 400 mg b.i.d. group, and 22 % in the imatinib group (Table 2b). No significant difference was noted in safety between the two drugs. Rash, headache, and mild increases
Table 2 Second-generation TKIs compared to imatinib in patients with newly diagnosed CML-CP A. DASSISION (dasatinib) Imatinib 400 mg q.d. (%)
B. ENESTnd (nilotinib) Dasatinib 100 mg q.d. (%)
CCyR
Imatinib 400 mg q.d. (%)
Nilotinib 300 mg b.i.d. (%)
Nilotinib 400 mg b.i.d. (%)
6 months
45
67
63
12 months
65
80
78
CCyR
3 months
31
54
6 months
59
73
9 months
67
78
12 months
72
83
MMR
MMR
3 months
0.40
8
3 months
1.00
9
5
6 months
8
27
6 months
12
33
30
9 months
18
39
9 months
18
43
38
12 months
28
46
12 months
22
44
43
3.50
1.90
4
\1
\1
Progression to AP/BP
Progression to AP/BP
CCyR complete cytogenetic response, MMR major molecular response, AP accelerated phase, BP blastic phase, q.d. once a day, b.i.d. twice a day
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about 55 times stronger than imatinib. While it is also effective against most mutants, it has no effect on T315I [16, 25]. In a P-I trial, it had few serious side effects and was effective in some dasatinib-resistant patients [26]. Interestingly, we recently reported the possibility that bafetinib is effective not only in CML but also Parkinson’s disease [27].
Third-generation ABL TKIs: ponatinib (IclusigÒ) Ponatinib is an epoch-making drug called a third-generation BCR-ABL TKI. It is effective against most mutant BCR-ABLs including T315I. Therefore, ponatinib is often called a pan-BCR-ABL TKI. It can avoid the conformational effect of T315I because of a long and flexible carbon–carbon triple bond [28]. Ponatinib is currently the only ABL TKI effective against T315I. However, caution is needed as it may be ineffective against compound mutations [13]. The FDA approved ponatinib in December 2012. Its P-II trial is also progressing in Japan. Fig. 4 Treatment approach for patients with chronic myeloid leukemia in chronic phase (CML-CP). Imatinib-resistant/intolerant patients are treated with either dasatinib or nilotinib selectively according to the mutation type and patients’ backgrounds. HSCT hematopoietic stem cell transplantation
in liver and pancreatic enzyme levels were observed slightly more frequently in the nilotinib group, but edema, muscle convulsion, and neutropenia were observed less frequently [23]. Based on the clinical trials, imatinib-resistant/intolerant patients are treated with either dasatinib or nilotinib selectively according to the mutation type and patients’ backgrounds (Fig. 4).
Second-generation ABL TKIs: bosutinib (BosulifÒ) Bosutinib has about a 50-fold stronger activity against ABL compared with imatinib and a characteristically weak inhibitory activity against c-KIT or PDGFR, which is a cause of side effects in imatinib. Although bosutinib is also effective against most mutant BCR-ABLs, it is not effective against T315I [24]. Among the side effects, attention is needed regarding severe diarrhea. Bosutinib was approved by the FDA in September 2012.
Second-generation ABL TKIs: bafetinib (formerly INNO-406) Bafetinib was developed in Japan as a drug that simultaneously inhibits ABL and LYN with an activity against ABL
Other novel agents [29] Omacetaxine mepesuccinate is a cephalotaxine alkaloid and is classified as an anticancer agent. It is also effective against T315I-positive CML-CP, and was approved by the FDA in October 2012. The above agents, other than ponatinib and omacetaxine mepesuccinate, are ineffective against CML cells and CML stem cells with T315I, and efforts to develop novel agents are being made to overcome this weakness. Aurora kinase is a serine/threonine kinase closely involved in cell division. Danusertib (PHA-739358), AT9283, and XL228 are its variations with inhibitory activities against wild and various mutant BCR-ABLs. Also, drugs called switch pocket inhibitors are being developed and undergoing clinical trials. Drugs that act directly on CML stem cells include hedgehog inhibitors, histone deacetylase inhibitors, heat shock protein 90, and vaccines such as WT1 peptide and K562/GM-CSF vaccines.
Hematopoietic stem cell transplantation at present If the response to second-generation TKIs is still insufficient, and if T315I is observed, in particular, hematopoietic stem cell transplantation is effective and should be considered positively with the fulfillment of conditions including age and donor (until ponatinib is approved in Japan) [30]. Conventional IFN-a and hydroxyurea may be used if the patient is resistant/intolerant to TKIs and has no indication for hematopoietic stem cell transplantation.
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Progress towards a cure for CML A complete molecular response (CMR) has been maintained over a long period even after the discontinuation of imatinib therapy in about 40 % of patients who had achieved CMR for at least 2 years on imatinib [31]. With the control of imatinib resistance and advent of second- and third-generation ABL TKIs and other novel drugs that more rapidly achieve higher-level remission, treatment of CML aiming at cure is expected to be advanced. Currently, several TKI stop trials are ongoing in Japan. Under these circumstances, to ensure safe and effective treatment, it is important to sufficiently understand the characteristics of various drugs and use them selectively for individual patients. Conflict of interest S.K. received research grants and lecture fees from Bristol-Myers Squibb and Novartis Pharmaceuticals.
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11. Ng KP, Hillmer AM, Chuah CT et al (2012) A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat Med 18:521–528 12. Tanaka R, Kimura S, Ashihara E et al (2011) Rapid automated detection of ABL kinase domain mutations in imatinib-resistant patients. Cancer Lett 312:228–234 13. Khorashad JS, Kelley TW, Szankasi P et al (2013) BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: frequency and clonal relationships. Blood 121:489–498 14. Sherbenou DW, Hantschel O, Kaupe I et al (2010) BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib. Blood 116:3278–3285 15. Shah NP, Tran C, Lee FY et al (2004) Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305:399–401 16. Deguchi Y, Kimura S, Ashihara E et al (2008) Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines. Leuk Res 32:980–983 17. Hochhaus A, Baccarani M, Deininger M et al (2008) Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 22:1200–1206 18. Shah NP, Kantarjian HM, Kim DW et al (2008) Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 26:3204–3212 19. Kantarjian H, Shah NP, Hochhaus A et al (2010) Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 362:2260–2270 20. Kim DH, Kamel-Reid S, Chang H et al (2009) Natural killer or natural killer/T cell lineage large granular lymphocytosis associated with dasatinib therapy for Philadelphia chromosome positive leukemia. Haematologica 94:135–139 21. Weisberg E, Manley PW, Breitenstein W et al (2005) Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7:129–141 22. Kantarjian HM, Giles F, Gattermann N et al (2007) Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 110:3540–3546 23. Saglio G, Kim DW, Issaragrisil S et al (2010) Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362:2251–2259 24. Golas JM, Arndt K, Etienne D et al (2003) SKI-606, a 4-anilino3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res 3:375–381 25. Kimura S, Naito H, Segawa H et al (2005) NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood 106:3948–3954 26. Kantarjian H, le Coutre P, Cortes J et al (2010) Phase I study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias post-imatinib resistance or intolerance. Cancer 16:2665–2672 27. Imam SZ, Trickler W, Kimura S et al (2013) Neuroprotective efficacy of a new brain-penetrating C-Abl inhibitor in a murine Parkinson’s disease model. PLoS One 8:e65129 28. O’Hare T, Shakespeare WC, Zhu X et al (2009) AP24534, a panBCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16:401–412
Int J Clin Oncol 29. Kimura S (2010) Second generation Abl kinase inhibitors and novel compounds to eliminate the Bcr-Abl/T315I clone (Second Edition). Recent Pat Anticancer Drug Discov 2010:116–131 30. Saussele S, Lauseker M, Gratwohl A et al (2010) Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV. Blood 115:1880–1885
31. Mahon FX, Re´a D, Guilhot J et al (2010) Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 11:1029–1035
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REVIEW ARTICLE
Ever-advancing chronic myeloid leukemia treatment Shinya Kimura • Toshihiko Ando • Kensuke Kojima
Received: 30 October 2013 Ó Japan Society of Clinical Oncology 2013
Abstract Treatment of chronic myeloid leukemia (CML) has been drastically changed by the emergence of the ABL tyrosine kinase inhibitor (TKI), imatinib mesylate. However, resistance and intolerance have frequently been reported, particularly in patients with advanced-stage disease. Point mutations within the ABL kinase domain that interfere with imatinib binding are the most critical cause of imatinib resistance. To overcome this resistance, four second-generation ATP competitive ABL TKIs, dasatinib, nilotinib, bosutinib and bafetinib, have been developed. Dasatinib and nilotinib also demonstrated higher efficacy than imatinib in previously untreated CML patients in chronic phase. Despite promising clinical results, the frequently observed mutant T315I is not effectively targeted by any of the second-generation ABL TKIs. Thus, a thirdgeneration ABL TKI, ponatinib, was developed to inhibit all mutated BCR-ABL and showed clinical efficacy in CML cells harbouring T315I. CML treatment is rapidly progressing and further evolution is surely expected. Moreover, it was recently reported that some CML patients who achieved sustained complete molecular response could stop TKI. CML may become the first human cancer to be conquered solely with oral medicines. Keywords Chronic myeloid leukemia Imatinib Dasatinib Nilotinib Tyrosine kinase
Introduction Chronic myeloid leukemia (CML) is a malignant hematological disorder that causes marked increases in white blood cells and platelets, progresses through chronic, accelerated, and blastic phases, and results in death within a few years after diagnosis without appropriate treatments. CML is caused by the appearance of Philadelphia (Ph) chromosome due to reciprocal translocation between chromosomes 9 and 22, fusion of the abl gene on chromosome 9 with the bcr gene on chromosome 22, and the consequent development of the bcr-abl chimeric gene, which produces BCR-ABL chimeric protein with a kinase activity stronger than that of normal ABL (Fig. 1a). Imatinib mesylate (GlivecÒ), a potent ABL tyrosine kinase inhibitor (TKI), was approved in 2001 and became the first choice for CML in chronic phase (CML-CP) due to its significant efficacy. Binding of ABL with adenosine triphosphate (ATP) is necessary for the activation of BCRABL protein. Imatinib was developed as an ATP competitive type ABL TKI (Fig. 1b). According to the International Randomized Study of Interferon ? Ara-C vs. STI571 in CML (IRIS Study), no progression of the disease was observed in 92 % of patients in whom oral imatinib therapy could be continued for 8 years, and the overall survival (OS) with restriction of deaths to those related to CML was excellent, at 93 % [1, 2].
Imatinib resistance and intolerance S. Kimura (&) T. Ando K. Kojima Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan e-mail: [email protected]
Efficacy of imatinib is evaluated according to hematological, cytogenetic, and molecular responses. The hematological response is evaluated according to the normalization of blood cell counts including the white
123
Int J Clin Oncol Table 1 Definition of the response to TKIs (any TKI) as first-line treatment
Baseline
Optimal
Warning
Failure
NA
High risk
NA
or
3 months
BCR-ABL1 B10 % and/or Ph? B35 %
CCA/Ph?, major route BCR-ABL1 [10 % and/or Ph? 36–95 %
6 months
BCR-ABL1 \1 % and/or Ph? 0
BCR-ABL1 1–10 % and/or Ph? 1–35 %
BCR-ABL1 [10 % and/or Ph? [35 %
12 months
BCR-ABL1 B0.1 %
BCR-ABL1 [0.1–1 %
BCR-ABL1 [1 % and/or Ph? [0
Then, and at any time
BCR-ABL1 B0.1 %
CCA/Ph- (-7 or 7q-)
Loss of CHR
Non-CHR and/ or Ph? [95 %
Loss of CCyR Confirmed loss of MMR Mutations CCA/Ph?
NA not applicable, CCA clonal chromosome abnormalities, CHR complete hematologic response, CCyR complete cytogenetic response, MMR major molecular response
Fig. 1 Philadelphia chromosome and the action of imatinib. a Reciprocal translocation between chromosome 9 and chromosome 22 forms an extra-long chromosome 9 and the Philadelphia chromosome containing the fused bcr-abl gene. The fused bcr-abl gene is translated to BCR-ABL chimera protein that causes CML and Ph?ALL. b BCR-ABL tyrosine kinase (TK) is a constitutively active kinase that functions by binding ATP and transferring phosphate (PO4) from ATP to tyrosine residues on various substrates. This causes excess proliferation of leukemia cells characteristic of CML and Ph?ALL. Imatinib functions by blocking the binding of ATP to the BCR-ABL TK, inhibiting its activity. In the absence of TK activity, substrates required for BCR-ABL function cannot be phosphorylated, and subsequent cellular events are abrogated
blood cell count, cytogenetic response according to the frequency of Ph chromosome, and molecular response according to the transcript number of bcr-abl genes in peripheral blood or bone marrow (quantitative PCR or AmpCML). If the response is insufficient, the disease is judged to be resistant to imatinib. The efficacy evaluation of imatinib against CML is generally performed according to the criteria of the European LeukemiaNet (ELN) (Table 1) [3] or National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) [4]. In Japan, the ELN criteria are currently used more frequently. The definition of intolerance has not been clearly established. Generally, however, the patient may be
123
considered intolerant if the response is not greater than the major cytogenetic response (MCyR), in which the percentage of Ph-positive cells is reduced to 35 % or less, and a grade 3/4 side effect has occurred, or if a grade 2 side effect has persisted for 1 month or longer or recurred more than 3 times despite supportive therapies.
Mechanisms of imatinib resistance Imatinib shows excellent efficacy against CML-CP but is less effective against exacerbated CML in the accelerated or blastic phase or Ph chromosome-positive acute lymphoblastic leukemia (Ph?ALL), with many patients exhibiting resistance from the beginning or an early phase of treatment. Also, according to the results in the 8th year of the IRIS study, the administration of imatinib could not be continued over a long period in about 1/3 of patients with CML-CP, similarly due to resistance or intolerance [5]. Reported causes of imatinib resistance are point mutation of the ATP-binding region in the abl kinase domain (KD), which is the binding site of imatinib (Fig. 1b) [6], amplification of the bcr-abl gene and an increase in the number of mRNA copies [6], emergence of multi-drug resistance genes [7], activation of other oncogenes (LYN,
Int J Clin Oncol Fig. 2 The structures of threonine and isoleucine. When the amino acid (aa) at 315, threonine, is replaced by isoleucine, hydrogen bonding between threonine at aa 315 and imatinib is lost. Moreover, the bigger side chain of isoleucine becomes an obstacle for the binding of imatinib to the ATP binding pocket
etc.) [8], and low expression of the drug transporter Oct-1 [9]. Also, BIM has already been reported to be important for the induction of apoptosis by imatinib [10], but it has recently been reported that deletion-type polymorphism in an intron of a gene coding for BIM is involved in the poor response to TKIs [11]. Among these mechanisms of resistance that pose clinical problems, point mutation of abl KD is the most frequent and important problem. Since T315I, the change of the 315th amino acid of abl KD from threonine (T) to isoleucine (I), was reported in an imatinib-resistant patient [6], more than 100 mutations have been reported to date. However, less than 20 of these mutations are frequently encountered in clinical practice [12]. For an ABL TKI to bind to the ATP-binding site of ABL, the hydrogen bond is important, and the presence of a nitrogen or oxygen molecule in the side chain of the amino acid is essential for the hydrogen bond. In wild-type BCR-ABL protein, the 315th amino acid is threonine (T) with nitrogen in the side chain, and a hydrogen bond is formed between the nitrogen molecule in the side chain of this T315 and imatinib. With its replacement by isoleucine (I), with no oxygen or nitrogen molecule in the side chain, I315 loses the hydrogen bond with imatinib. In addition, isoleucine has larger molecules in the side chain compared with threonine and conformational characteristics that physically interfere with binding of various drugs. Thus, the T315I mutation, in particular, causes marked resistance to ABL TKIs (Fig. 2). Among other mutations, Y253H, E255K, T315I, and M315T are frequently observed. Multiple mutations causing imatinib resistance may be also detected simultaneously. When multiple mutations are detected, mutations may be present in different BCR-ABL molecules (polyclonal mutation) or in a single BCR-ABL molecule (compound mutation) (Fig. 3). Compound mutation has been reported to often cause stronger resistance to TKIs [13]. Other than the ATP-binding site, mutation of the
Fig. 3 Polyclonal versus compound mutations. In a subset of patients who develop clinical resistance to ABL1 TKIs, two or more point mutations in the kinase domain of BCR-ABL1 are detectable by direct sequencing. In the case of polyclonal mutations, these BCR-ABL1 mutations (open circle and open triangle; top panel) exist separately in different clones. In contrast, BCR-ABL1 compound mutants exhibit 2 mutations within the same BCR-ABL1 molecule (open circle and open square; bottom panel)
SH3-SH2 domain of BCR-ABL (T212R) has been reported to be involved in resistance [14].
Overriding imatinib resistance When a CML patient exhibits resistance or intolerance to imatinib, the treatment is changed to second-generation ABL TKIs or hematopoietic stem cell transplantation. Four second-generation ABL TKIs have been developed, and dasatinib (SprycelÒ) and nilotinib (TasignaÒ) have already
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been approved in Japan as first-line drugs to be used immediately after the diagnosis of CML, and additionally as second-line drugs to be used for imatinib-resistant or intolerant patients. Each novel drug is briefly profiled.
Second-generation ABL TKIs: dasatinib (SprycelÒ) The affinity of dasatinib for ABL is about 325 times stronger than that of imatinib. It inhibits more than 50 kinases including eight Src family kinases (SFKs) as well as BCR-ABLs, resulting in its specificity being relatively low. Also, while it is effective for most mutant BCR-ABLs, its effects on T315I/A, F317L/V, V299L, Q252H, etc., are limited [15, 16]. A phase II clinical trial (P-II) of 70 mg dasatinib b.i.d. (140 mg/day) was performed in 387 imatinib-resistant/intolerant patients with CML-CP, and a complete cytogenetic response (CCyR, a state in which no Ph chromosome is detected) was achieved in 49 %. Pleural effusion was frequently noted as an adverse event [17]. In another study, similar effects were observed at 100 mg q.d. and 70 mg b.i.d [18]. At present, dasatinib is usually administered at 100 mg q.d. to CML-CP adult patients. A clinical trial of first-line dasatinib using the drug immediately after the diagnosis of CML (DASISION) was carried out. Dasatinib was administered at 100 mg q.d. or imatinib at 400 mg b.i.d. to previously untreated patients with CML-CP, and CCyR was observed in 77 and 66 % of patients in the dasatinib and imatinib groups, respectively, after 12 months. Also, a major molecular response (MMR: a decrease of bcr-abl mRNA by 3 log or more on quantitative PCR) was observed in 46 and 28 %, respectively, and the time until MMR was also significantly shorter in
the dasatinib group (Table 2a). As for safety, pleural effusion and thrombocytopenia were observed slightly more frequently, and edema, gastrointestinal symptoms, muscle-related symptoms, and rash were observed less frequently, in the dasatinib than imatinib group [19]. Large granular lymphocytes (LGLs) were increased in part of the patients administered dasatinib, and the outcome was reported to be more favorable in such patients [20]. This is speculated to be due to the direct stimulation of LGL proliferation or inhibition of LGL-suppressing regulatory T cells by dasatinib, but the details are still unclear.
Second-generation ABL TKIs: nilotinib (TasignaÒ) With structural modification of imatinib, nilotinib acquired about a 30-fold stronger anti-CML activity. It is effective against many mutant BCR-ABLs except T315I. Nilotinib suppresses ABL, PDGFR, and c-KIT activities but does not suppress SFKs, indicating higher specificity than dasatinib [21]. In a P-II trial against imatinib resistant/intolerantCML-CP, CCyR was achieved in 48 %. As for grade 3 or severer side effects, thrombocytopenia, neutropenia, and increases in bilirubin and lipase were observed. Cross-tolerance with imatinib was rare [22]. The ENESTnd study was performed in patients with previously untreated CML-CP, and nilotinib was administered at 300 or 400 mg b.i.d., or imatinib was administered at 400 mg q.d. After 12 months, the MMR rate was 44 % in the nilotinib 300 mg b.i.d. group, 43 % in the nilotinib 400 mg b.i.d. group, and 22 % in the imatinib group (Table 2b). No significant difference was noted in safety between the two drugs. Rash, headache, and mild increases
Table 2 Second-generation TKIs compared to imatinib in patients with newly diagnosed CML-CP A. DASSISION (dasatinib) Imatinib 400 mg q.d. (%)
B. ENESTnd (nilotinib) Dasatinib 100 mg q.d. (%)
CCyR
Imatinib 400 mg q.d. (%)
Nilotinib 300 mg b.i.d. (%)
Nilotinib 400 mg b.i.d. (%)
6 months
45
67
63
12 months
65
80
78
CCyR
3 months
31
54
6 months
59
73
9 months
67
78
12 months
72
83
MMR
MMR
3 months
0.40
8
3 months
1.00
9
5
6 months
8
27
6 months
12
33
30
9 months
18
39
9 months
18
43
38
12 months
28
46
12 months
22
44
43
3.50
1.90
4
\1
\1
Progression to AP/BP
Progression to AP/BP
CCyR complete cytogenetic response, MMR major molecular response, AP accelerated phase, BP blastic phase, q.d. once a day, b.i.d. twice a day
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about 55 times stronger than imatinib. While it is also effective against most mutants, it has no effect on T315I [16, 25]. In a P-I trial, it had few serious side effects and was effective in some dasatinib-resistant patients [26]. Interestingly, we recently reported the possibility that bafetinib is effective not only in CML but also Parkinson’s disease [27].
Third-generation ABL TKIs: ponatinib (IclusigÒ) Ponatinib is an epoch-making drug called a third-generation BCR-ABL TKI. It is effective against most mutant BCR-ABLs including T315I. Therefore, ponatinib is often called a pan-BCR-ABL TKI. It can avoid the conformational effect of T315I because of a long and flexible carbon–carbon triple bond [28]. Ponatinib is currently the only ABL TKI effective against T315I. However, caution is needed as it may be ineffective against compound mutations [13]. The FDA approved ponatinib in December 2012. Its P-II trial is also progressing in Japan. Fig. 4 Treatment approach for patients with chronic myeloid leukemia in chronic phase (CML-CP). Imatinib-resistant/intolerant patients are treated with either dasatinib or nilotinib selectively according to the mutation type and patients’ backgrounds. HSCT hematopoietic stem cell transplantation
in liver and pancreatic enzyme levels were observed slightly more frequently in the nilotinib group, but edema, muscle convulsion, and neutropenia were observed less frequently [23]. Based on the clinical trials, imatinib-resistant/intolerant patients are treated with either dasatinib or nilotinib selectively according to the mutation type and patients’ backgrounds (Fig. 4).
Second-generation ABL TKIs: bosutinib (BosulifÒ) Bosutinib has about a 50-fold stronger activity against ABL compared with imatinib and a characteristically weak inhibitory activity against c-KIT or PDGFR, which is a cause of side effects in imatinib. Although bosutinib is also effective against most mutant BCR-ABLs, it is not effective against T315I [24]. Among the side effects, attention is needed regarding severe diarrhea. Bosutinib was approved by the FDA in September 2012.
Second-generation ABL TKIs: bafetinib (formerly INNO-406) Bafetinib was developed in Japan as a drug that simultaneously inhibits ABL and LYN with an activity against ABL
Other novel agents [29] Omacetaxine mepesuccinate is a cephalotaxine alkaloid and is classified as an anticancer agent. It is also effective against T315I-positive CML-CP, and was approved by the FDA in October 2012. The above agents, other than ponatinib and omacetaxine mepesuccinate, are ineffective against CML cells and CML stem cells with T315I, and efforts to develop novel agents are being made to overcome this weakness. Aurora kinase is a serine/threonine kinase closely involved in cell division. Danusertib (PHA-739358), AT9283, and XL228 are its variations with inhibitory activities against wild and various mutant BCR-ABLs. Also, drugs called switch pocket inhibitors are being developed and undergoing clinical trials. Drugs that act directly on CML stem cells include hedgehog inhibitors, histone deacetylase inhibitors, heat shock protein 90, and vaccines such as WT1 peptide and K562/GM-CSF vaccines.
Hematopoietic stem cell transplantation at present If the response to second-generation TKIs is still insufficient, and if T315I is observed, in particular, hematopoietic stem cell transplantation is effective and should be considered positively with the fulfillment of conditions including age and donor (until ponatinib is approved in Japan) [30]. Conventional IFN-a and hydroxyurea may be used if the patient is resistant/intolerant to TKIs and has no indication for hematopoietic stem cell transplantation.
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Progress towards a cure for CML A complete molecular response (CMR) has been maintained over a long period even after the discontinuation of imatinib therapy in about 40 % of patients who had achieved CMR for at least 2 years on imatinib [31]. With the control of imatinib resistance and advent of second- and third-generation ABL TKIs and other novel drugs that more rapidly achieve higher-level remission, treatment of CML aiming at cure is expected to be advanced. Currently, several TKI stop trials are ongoing in Japan. Under these circumstances, to ensure safe and effective treatment, it is important to sufficiently understand the characteristics of various drugs and use them selectively for individual patients. Conflict of interest S.K. received research grants and lecture fees from Bristol-Myers Squibb and Novartis Pharmaceuticals.
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