Increasing the Imatinib Dose
In case of a suboptimal response to imatinib, the dose may be increased (53,54). Treatment guidelines have been proposed to identify patients who may benefit from a dose escalation (12,55). When resistance to imatinib emerges, the BCR-ABL kinase domain should be sequenced. If a mutation mediating moderate imatinib resistance is identified, increasing the dose to 600 or 800 mg is one therapeutic option. The degree of resistance for most mutations is known from in vitro studies, and the published IC50 values for different BCR-ABL mutations can be used as a guideline (Table 1). In the case of mutations other than P-loop or T315I, increasing the imatinib dose was reported to improve or stabilize the disease in a proportion of patients (56). This benefit was of shorter duration in P-loop mutant cases, and patients expressing T315I did not benefit from increasing the dose of imatinib.
Recently, additional compounds have been developed that inhibit BCR-ABL more potently than imatinib, and display activity against the majority of known imatinib resistance mutants. Results of ongoing clinical studies indicate that these theoretical advantages, indeed, might translate into clinical activity. However, whether the use of novel agents like AMN107 (nilotinib) or BMS-354825 (dasatinib) also generate superior response rates and long-term results in early chronic phase CML, remains to be shown. During the past years, several strategies have been employed to identify drugs with improved antileukemic activity that could be used in CML and Ph+ ALL. Agents may be subdivided into several subcategories:
1. Compounds that are similar to imatinib binding BCR-ABL in an inactive conformation but achieving a higher potency by an optimized fit to the ATP-binding site. An example is nilotinib (AMN107), which has been demonstrated to inhibit many of the known imatinib-resistant mutations, except T315I (57-59). Nilotinib has entered phase 2 clinical trials, and phase 1 data show promising activity in imatinib resistant, intolerant CML, or Ph + ALL (60).
2. Compounds that bind to both the inactive and active conformation irrespective of the A-loop conformation (closed versus open). Dasatinib (BMS-354825, Sprycel™) constitutes an example of this class (61,62). Dasatinib, similar to nilotinib, inhibits many of the known imatinib-resistant forms of BCR-ABL, except T315I (63). Dasatinib displayed significant activity in phase 1 studies of CML and Ph+ ALL (64) and is currently being evaluated in phase 2 clinical studies. Dasatinib was recently approved by the FDA for the treatment of adults in all phases of CML with resistance or intolerance to prior therapy, including imatinib. Pyrido-pyrimidines analogues also belong to this class of compounds (65 -69). However, there are currently no plans for clinical evaluation of these compounds.
3. Dual SRC/ABL kinase inhibitors, in addition to BCR-ABL, inhibit other target kinases that may be important for the survival of the malignant clone. Examples for this group of compounds are dasatinib (BMS-354825, Sprycel™, see earlier), pyrido-pyrimidines analogues (mentioned earlier), SKI-606 (70), which recently entered phase 1 clinical evaluation, and INN0-406 [former NS-187 (72)].
4. Compounds that do not act as ATP-competitors but are thought to act as allosteric inhibitors binding to sites different from the ATP-binding pocket.
An example is 0N012380, which is thought to act as a substrate competitor (73). The compound might be operational against imatinib-resistant BCR-ABL mutations, including T315I, and is currently in preclinical development. The allosteric inhibitor GNF-2 also belongs to this category (74). Inhibition by this agent may be attained by binding to the myristate binding moiety, thereby, capturing the kinase in an inactive state. The compound displayed activity against some of the tested imatinib resistant mutant forms of BCR-ABL (74). 5. Agents that show activity against the T315I mutation. A high throughput screen identified the aurora-kinase inhibitor VX-680 (MK-0457) to inhibit BCR-ABL T315I (75,21). A phase 1 clinical study with this compound has been launched. Also the non-ATP-competitive inhibitor 0N012380 described earlier was reported to suppress T315I (72).
Thus, a large number of alternative BCR-ABL kinase inhibitors with divergent mode of actions are currently in preclinical or clinical development. Phase 1 clinical studies already demonstrated that AMN107 (nilotinib) and BMS-354825 (dasatinib) display activity in imatinib resistant cases, with and without the presence of BCR-ABL mutations (59,62). A large number of in vitro studies showed that novel ABL-kinase inhibitors like PD166326 (65,68), PD180970 (66), AMN107 (nilotinib) (57), BMS354825 (dasatinib) (64), AP23464 (71), SK1-606 (70) NS-187 (currently INNO-406) (72), 0N012380 (73), or VX-680 (75) are capable of suppressing known imatinib resistant mutant forms of BCR-ABL. This well agrees with comparative crystal structure analysis indicating that different compounds display distinct binding modes to the ABL kinase domain (59,61,62,67), suggesting that different scaffolds may display specific patterns of resistance mutations. Knowing these scaffold specific resistance patterns may allow tailoring treatment strategies with respect to drug combinations in the future, which might reduce the frequency of resistance. In vitro screening strategies for imatinib resistance mutations in BCR-ABL have been developed that revealed specific mutation profiles for various ABL kinase inhibitors (22,76-80). These studies indicated that alternative ABL kinase inhibitors in comparison to imatinib indeed might display a limited, albeit overlapping, pattern of mutations. Indeed, the use of drug combinations narrowed the spectrum of BCR-ABL mutations emerging in vitro (77-79). Thus, specific mutation profiles for ABL kinase inhibitors can be generated in vitro, and this information may be translated into treatment strategies in the future that hopefully will minimize the emergence of drug resistance.
However, as mentioned earlier, it is important to keep in mind that most novel compounds do not overcome resistance to the T315I mutant. Therefore, patients with T315I should not be treated within these trials, unless studies are available where drug candidates with documented T315I activity are examined. One compound with reported T315I activity that has entered a phase 1 study is VX-680 (MK-0457) (Vertex Pharmaceuticals/Merck).
Allogenic stem cell transplantation in the era of specific ABL kinase inhibitors is becoming increasingly infrequent and always constitutes an individual decision. Allogeneic transplant should be considered in case of imatinib resistant relapse preferentially after achieving a remission with an alternative ABL kinase inhibitor.
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