Overcoming Imatinib Resistance

The understanding of mechanisms of IM resistance and of the overall biology of the BCR-ABL1 gene and protein has stimulated interest in developing therapeutic strategies to overcome resistance. Because it remains difficult to define the precise mechanism of resistance in the vast majority of patients on a routine clinical basis, the choice of alternative therapy in patients who are failing IM remains empirical. The commonly used strategy is to escalate the dose of IM since no dose-limiting toxicity was seen in the phase 1 trial of IM (18).

A strategy of dose-escalating IM was also based on the efficacy of higher doses of IM in patients with accelerated and blast phase of CML, as previously described (21,22). In a trial of twice-daily administration of an IM dose of 400 mg (800 mg total), a complete hematologic response was seen in 65% of patients with cytogenetic remission, and patients with cytogenetic resistance achieved a complete cytogenetic response 56% of the time (80). The same group reported the outcome of 114 patients with newly diagnosed chronic-phase CML who were given 400 mg of IM twice daily. A MCR was achieved in 96% of patients with 90% of patients having a CCR. After a median follow-up of 15 months, no patient had progressed to accelerated or blastic phase, and the estimated 2-year survival rate was 94%. In 63% of patients, a MMR was achieved; and in 28%, a CMR was achieved. These responses were significantly better than those seen in a retrospective cohort of patients given 400 mg of IM daily. More frequent myelosuppres-sion was seen with the high-dose regimen, but 82% of patients were able to continue to received 600 mg or more of IM daily (81).

Different approaches have been considered to overcome some of the resistance mechanisms outlined earlier in this chapter. Many of these have not been tested clinically but could include blockage of ^-glycoprotein-mediated drug efflux or administering agents such as erythromycin that compete for a-1 acid glycoprotein binding of IM (82). There is an anecdotal report of a patient who went into blast crisis of CML while taking IM and then reverted to chronic phase when IM was withdrawn (83). The rationale behind this approach is thought to be that withdrawal of IM might allow the re-emergence of unmutated leukemic clones that suppress the mutant clone by removing the competitive advantage the mutant clone has. A patient with CML resistance with a Y253H P-loop mutation discontinued IM and a reduction in a number of clones bearing the Y253H mutation was noted (84).

Another approach to the management of IM resistance is to combine agents that are individually active against CML but have differing mechanisms of action that may allow either additive or synergistic effects in a non-cross-resistant manner. This approach has been extensively studied in the literature and will not be reviewed in detail here. An excellent discussion of combination therapy is found in the reviews by Hochhaus and La Rosee (52,85). Some combination approaches have utilized farnesyl transferase inhibition such as lonafarnib in combination with IM, inhibitors of the mammalian target of rapamycin (mTOR) in combination with IM and combining mycophenolic acid, an inhibitor of the JAK-STAT pathway.

Because the dominant mechanism of IM resistance is the development of mutations, this area has attracted the most interest in developing therapeutic strategies. The focus has been to develop small molecules that can inhibit the BCR-ABL1 kinase protein in alternate ways compared to IM. The new class of compounds, pyridopyrimidines, which are inhibitors of SRC, have been shown to inhibit wild-type ABL1 at nanomolar concentrations (86).

Several of these compounds were tested for activity against IM-resistant BCR-ABL1 mutants and demonstrated activity (87,88,89). However, these derivatives of pyridopy-rimidine were predicted to have unsatisfactory pharmacokinetic profiles and further clinical development was aborted. Fortunately, an alternative compound was found to be efficacious (90).

The two compounds in the most advanced stages of development included dasa-tinib (BMS354825, Sprycel®) and nilotinib (AMN107, Tasigna®) (Fig. 5). Dasatinib

Fig. 5. Chemical formula of imatinib, the second-generation ABL kinase inhibitor, nilotinib, and the dual SRC/ABL kinase inhibitors. (Reprinted with permission from Ref. (52)).

is a synthetic, small-molecule carboxamide derivative that inhibits the SRC family of kinases. It is orally bio-available, and was recently reported to inhibit 14 of 15 IM-resistant BCR-ABL1 mutants and had a two-log increased potency relative to IM (91).

The T315I mutation has been consistently shown to retain resistance to both dasatinib and nilotinib, and to the other pyridopyrimidine derivatives previously described. These recently developed small-molecule inhibitors have a differential activity compared to IM that relates to several key structural elements of ABL1. The ABL1 kinase domain is bound by IM only in its inactive confirmation (with the activation loop in the closed position) (55). Because the inactive confirmations of ABL1 and SRC are distinct, IM is able to inhibit ABL1 but not SRC.

As discussed previously, the activation loop can also flip into an active state, and the pyridopyrimidine derivatives and dasatinib are able to bind ABL1 whether the activation loop is in the closed or open position (inactivated or activated) (92). Thus, binding is not affected by the activation state. Dasatinib and related compounds are also smaller in size than IM, so the P-loop must undergo major conformational changes on binding with IM, whereas only minimal changes occur with dasatinib and related compounds. This dual activity of dasatinib also raises the question as to whether its broader activity may have broader effects, including potentially adverse effects in the treatment of patients.

A phase I trial of dasatinib in IM-resistant Ph+ leukemias was reported last year and dosed over a range of 15-240 mg per day in once- or twice-daily doses. Complete hematologic responses were seen in 37 of 40 patients with chronic phase CML while major hematologic responses were noted in 31 of 44 patients with Ph+ ALL and blast crisis or accelerated-phase CML.

Rates of MCR were 45% in chronic phase CML and 25% in the more advanced phase group. Ninety-five percent of the patients with chronic phase and 82% of the patients with accelerated phase disease had their responses maintained for a median of 12 and 5 months, respectively; whereas, virtually all patients with Ph+ ALL or lymphoid blast crisis had relapsed within 6 months.

Only patients with the T315I mutation were resistant to dasatinib. The most common toxicity was myelosuppression, but this was not dose-limiting (93). Subsequent phase II trials in different phases and types of Ph+ disease are being reported. A phase II study of 186 patients with IM-resistant or -intolerant chronic phase CML with the standard dose of 70 mg orally BID has been reported. A CHR was achieved in 90% of these patients, and 52% achieved an MCR. Only 2% of patients achieving MCR progressed or died. Molecular responses were also seen with reductions in BCR-ABL1/ABL1 transcript ratios declining from 66% at baseline to 2.6% by 9 months of therapy (94).

In accelerated-phase CML patients who are IM resistant or intolerant, a major hema-tologic response was found in 63% of patients with 43% of patients achieving a CHR and 20% showing no evidence of leukemia. An MCR was documented in 37% of patients and was a CCR in 28% and partial in 9%. The estimated progression-free survival at 9 months was 70%. Up to 80% of patients experienced grade 3 to 4 cytopenias, but non-hematologic toxicities are generally mild or moderate including diarrhea, headache, fatigue, fever, and pleural effusions (95).

In IM-resistant or intolerant blast phase CML, a phase II trial demonstrated major hematologic responses in 34% of myeloid blast crisis and 31% of lymphoid blast crisis with MCR in 31% and 50% of these patients, respectively. Of the MCR achieved, 86%

were CCR, and the responses were durable in 88% and 46% of myeloid blast crisis and lymphoid blast crisis patients, respectively (96). In patients with chronic phase CML who are resistant to IM in doses of 400-600 mg per day, a randomized comparison of dasatinib 70 mg orally BID to 800 mg per day of IM demonstrated a CHR of 92% for dasatinib vs. 82% for IM and MCR of 48% with dasatinib vs. 33% with IM.

The CCR was 35% with dasatinib and 16% with IM suggesting that dasatinib may be more effective in achieving MCR than high-dose imatinib (97). Dasatinib is also active in patients who have failed both IM and nilotinib where in a small trial of 23 patients who were mostly in accelerated or blastic phase achieved a CHR in 43% with some form of cytogenetic response in 32% (98).

Nilotinib was developed by scientists at Novartis by altering the N-methylpiperazine group and thus substantially increasing the selectivity and binding affinity of nilotinib for the ABL1 kinase compared with IM (99). In vitro nilotinib was found to be 20-fold more potent than IM against cells expressing wild-type or mutated BCR-ABL1 (dasatinib is 325-fold more potent than IM in the same system) (100). Similar to dasatinib, nilotinib also lacks activity against CML cells expressing the T315I mutation.

In phase I testing of nilotinib against IM-resistant CML or ALL in doses ranging from 50 to 1200 mg once daily or 400 to 600 mg orally BID, 39% of blast phase CML patients had a hematologic response with 18% achieving an MCR. In 17 patients with chronic phase of CML, CHR was seen in 11 of 12 with active disease. Six of 17 CCR were seen (101).

Phase II studies of nilotinib in different phases of Ph+ leukemias are also being reported. In 132 patients with IM-resistant or intolerant chronic phase CML, 69% of patients achieved a CHR. An MCR was observed in 42% of patients, and in 25% of patients a CCR was obtained. Cytopenias and elevated lipase were some of the most common toxicities. The median time to MCR was 2.6 months (102). In accelerated-phase disease, hematologic responses were observed in 44% of patients. Of these, 17% were complete. An MCR occurred in 31% of patients, and in 17% was complete (103). Patients resistant to IM and dasatinib can also respond to nilotinib with a CHR rate of 45% in chronic phase patients. An MCR was seen in 31% of patients (104).

The results with dasatinib were impressive enough that the U.S. Food and Drug Administration (FDA) approved dasatinib for IM-resistant or intolerant CML in June 2006.

The rapidity with which dasatinib and nilotinib were developed is striking because IM was approved by the FDA only in 2001. As Druker has pointed out, the understanding of the crystal structure of ABL1 when complexed with IM and the rapid understanding of mechanisms of relapse allowed development of modifications of IM or alternate agents (105). The development of multiple drugs that inhibit ABL1 raised the specter of utilizing drug combinations, and, indeed, in vitro studies have suggested that combining any of these three agents in pairs leads to maximal suppression of the outgrowth of resistant clones and that this can be achieved with lower concentrations of drug compared to any of the single agents (106,107,108,109).

An additional concern has been whether any of the BCR-ABL1 tyrosine kinase inhibitors in development can inhibit or eliminate the leukemic stem cell. Dasatinib does appear to be active against an earlier progenitor population in the CD34+ CD38- population compared to IM, but is still not capable of eliminating the most primitive quiescent CML cells (110).

The development of these drugs has fueled an explosion of research into the discovery of alternate CML inhibitors, particularly those that may be active against the T315I mutation. The inhibitor ON012380 blocks the substrate-binding site rather than the ATP-binding site of ABL1, and in vitro studies have shown inhibition of multiple IM-resistant mutations including the T315I. This compound also demonstrates a 10-fold stronger inhibition of wild-type BCR-ABL1 compared to IM (HI). Similarly, adaphostin is a tyrphostin that also alters the binding site of peptide substrates rather than that of ATP. However, adaphostin-mediated cytotoxicity is actually dependent on oxygen production and does not require BCR-ABL1, indicating—not surprisingly—that it may interact with multiple targets (112). Some examples of other agents active against BCR-ABL1 include INNO-406 and NS-187, a novel BCR-ABL1/LYN dual tyrosine kinase inhibitors (113, 114), and SKI-606, another dual inhibitor of SRC and ABL kinases (115).

The aurora kinases are important in the regulation of mitotic chromosome segregation and cytokinesis. They show aberrant activity in a variant of human tumors. Their attractiveness in CML lies in their ability to inhibit the T315I mutation. Two of these agents, MK-0457 (formally VX-680) and VE-465, are in pre-clinical or early clinical development and show activity against the T315I mutation (116,117,118). Targeting BCR-ABL1-dependent signaling pathways required for transformation including RAS or the PI3 K pathway may also be important avenues of drug development. They are reviewed by Walz and Sattler (119).

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