New Tyrosine Kinase Inhibitors and Other Agents to Treat CML Post Imatinib Failure
Leukemia Insights - Fall 2008
More potent Bcr-Abl and dual Src/Abl kinase inhibitors are being developed. At least four of them are already in phase II trials or have been approved: nilotinib (AMN107; Tasigna), dasatinib (BMS-354825; Sprycel), bosutinib (SKI-606), and INNO-406.
Nilotinib was developed following a rational drug design with nilotinib as the lead compound. Imatinib fits into the canonical ATP-binding site of the kinase domain and captures a specific inactive conformation of the activation loop of Abl. This close interaction made changes in the core of imatinib prohibitive. However, the N-methylpiperazine group of imatinib was more amenable to modifications. Nilotinib was developed through replacements of this ring and proved to be approximately 30 times more potent than imatinib in vitro against BCR-ABL, while maintaining similar activity against other kinases.13 Nilotinib inhibits the kinase activity of most BCR-ABL mutants tested, except T315I. A phase I study of nilotinib in patients with CML in all phases of the disease who had failed prior imatinib therapy showed efficacy.14 The phase II dose selected was 400 mg twice daily with dose limiting toxicities being myelosuppression, and transient bilirubin elevations.15
Phase II studies have confirmed the high response rates and favorable toxicity profile of nilotinib after imatinib failure (Table 1).15,16
|Table 1. Response in Phase 2 studies of nilotinib after imanitib failure|
In the phase II study in chronic phase CML post imatinib failure, 321 patients received nilotinib 400 mg P.O. BID. The CHR rate was 77%, the major cytogenetic response rate was 58%, the complete cytogenetic response rate was 42%. The estimated 18-month survival rate was 91%. This resulted in the FDA approval of nilotinib for CML post imatinib failure in chronic and accelerated phases.
Based on this experience, we have initiated a study of nilotinib as first line therapy for patients with CML in early chronic phase with the objective to improve the overall molecular response and to achieve responses earlier, since early achievement of response has been correlated with improved long-term outcome. The preliminary data in the first 50 patients suggest that indeed nilotinib may be better than imatinib: 97% of patients were in complete cytogenetic response after only 3 months of therapy, and 100% at 6 months. This compares favorably with rates at 6 months of 82% and 54% with high- and standard-dose imatinib, respectively (p=.0001). This study continues accrual.
In addition, we are exploring earlier intervention with nilotinib in patients who have not met the criteria for failure but have a suboptimal response as defined by the recommendations of a panel of CML experts. (Baccarani. Blood 2004). Ongoing studies with nilotinib in CML at our institution include:
- Single-arm, phase II study of nilotinib in patients with newly diagnosed Ph-positive CML in chronic phase – protocol 2005-0048.
- Randomized trial of Nilotinib versus standard dose imatinib in patients with newly diagnosed Ph-positive CML in chronic phase – protocol 2007-0545.
Dasatinib is an ATP-competitive, dual-specific Src- and Abl-kinase inhibitor. Src activation may play a role in the development and progression of many tumors. Dasatinib is structurally unrelated to imatinib and is 300 times more potent inhibitor of Bcr-Abl kinase activity. It induces significant inhibition of the kinase activity of cells transfected with the wild-type Bcr-Abl as well as all mutants of Bcr-Abl, the exception being T315I. Phase II studies of dasatinib in CML post imatinib failure were very encouraging and led to the FDA approval of dasatinib post imatinib failure in all CML phases.17,18 In chronic phase, 91% achieved CHR and 62% achieved a major cytogenetic response, which was complete in 53%. The estimated 2-year survival rate was 94%. Responses were observed in patients with a wide variety of mutations. DLTs are myelosuppression (in approximately 50%) and pleural effusions (severe in 10%). The summary of phase II studies is shown in Table 2.
|Table 2. Response in Phase 2 studies of dasatinib after imanitib failure|
Based on these favorable results we have initiated a trial of dasatinib in newly diagnosed CML in chronic phase. Preliminary results in the first 50 patients suggest that approximately 80% of patients achieve a complete cytogenetic response after 3 months of therapy and 94% after 6 months of therapy; results compare favorably to those achieved with imatinib at standard- or high-dose.
Ongoing studies with dasatinib are as follows:
- Dasatinib as front-line therapy in patients with newly diagnosed Ph-positive CML in chronic phase – protocol 2005-0422.
- Dasatinib in combination with chemotherapy (Hyper-CVAD) for patients with Ph-positive ALL – protocol 2006-0478.
Bosutinib is another orally available, potent dual Src/Abl kinase inhibitor. Bosutinib is 100-fold more potent than imatinib as an inhibitor of Bcr-Abl phosphorylation, and is active against mutant lines except T315I. Unlike imatinib, nilotinib and dasatinib, bosutinib exhibits no significant inhibition of c-kit and PDGFR. This could reduce problems of myelosupression and pleural effusions. Phase I-II studies of bosutinib have shown high efficacy and minimal side effects (rash 7%, diarrhea 9%, myelosuppression 19%). No pleural effusions were seen.
Ongoing studies with bosutinib include:
- A phase II study of bosutinib for patients with CML resistant to prior therapy with imatinib – protocol 2005-0813.
- A randomized phase III study of bosutinib versus imatinib as frontline therapy for for newly-diagnosed CML – protocol 2007-0709.
T315I mutations represent approximately 20% of all mutations. Patients with T315I mutations do not respond to imatinib, dasatinib, nilotinib or bosutinib. New “T315I inhibitors” are available to treat such patients with favorable responses being observed. Studies at MD Anderson ongoing include XL228 (IV once or twice weekly; protocol 2007-0502), PHA739358 (IV daily x 7 every 2 weeks; protocol 2007-0939), and AP 24534 (orally daily; protocol 2008-0046). A study with DCC-2036 will open soon. These agents are also under study for patients with resistance to 2 or more TKIs.
HHT is active in patients with CML as a single agent or in combinations.19,20 HHT may be additive or synergistic with imatinib. In addition, there is in vitro evidence of activity of HHT in CML cells carrying the T315I obtained from patients who have failed imatinib therapy. A study by Marin et al included 10 patients with CML who had achieved at least a cytogenetic response with imatinib but had reached a plateau in transcript levels. In addition to continuing imatinib, SQ HHT 1.25 mg/m2 twice daily for 5 days was given every 28 days. Seven patients had a decline in Bcr-Abl transcript levels which was greater than 1-log in 5. Two patients not in complete cytogenetic remission at the start of therapy became 100% Ph-negative.21 Recent studies investigated an easier subcutaneous (SQ) HHT schedule. Two studies at MD Anderson are studying SQ HHT in patients with CML and 1) T315I mutations, or 2) failure on 2 or more TKIs. The preliminary data (multi-institutional) are shown in Table 3.
|Table 3. Homoharringtonine results|
|CML Chronic Phase||No.||Complete Hematologic||Cytogenetic||T315I Suppression|
|Failure >/= 2 TKIs|
There is evidence of synergy between imatinib and HHT and this is currently being explored in the clinic. Patients with CML in any stage of the disease who have failed imatinib (or imatinib-naïve if they are in blastic phase) receive therapy with HHT intravenously combined with imatinib. Over 60% of patients treated achieve a hematologic response in all phases of the disease even in the presence of T315I, and complete cytogenetic responses have been observed in some patients. In addition, the T315I clone is eliminated in approximately half of the patients.
The following ongoing studies with HHT are available:
- Intravenous HHT plus imatinib in patients who have failed imatinib therapy. Patients in any phase of the disease (chronic, accelerated or blastic) are eligible, and patients in blast phase can be imatinib-naïve – protocol 2005-0067.
- Subcutaneous HHT for patients with CML in any stage who have failed imatinib therapy and carry the T315I mutation – protocol 2006-0192.
- Subcutaneous HHT for patient with CML in any stage who have failed 2 or more TKIs – protocol 2006-0926.
Immune modulation may be partially responsible for the favorable results with IFN-a. Immunomodulation is an attractive way to try to eliminate the leukemic stem cell which is insensitive to all available tyrosine kinase inhibitors. If successful, this strategy could lead to a safe permanent discontinuation of therapy in patients with a good response. Different types of antigens may be used in CML vaccines. One approach is to use tumor-specific antigens. The Bcr-Abl fusion creates a new sequence of amino acids only expressed in leukemic cells. Short peptides containing 8 to 12 amino acids, derived from the fusion region, have been tested.22,23
A different peptide used for immune stimulation is PR1, a nona-peptide derived from proteinase 3 and presented through HLA-A2.1. Proteinase 3 is expressed in myeloid cells during normal neutrophil maturation and is overexpressed in myeloid malignancies. Cytotoxic T-lymphocytes (CTL) specific for PR1 inhibit colony formation in an HLA-restricted manner. PR1-specific CTL is identified in most patients with CML who responded to IFN-a or allogeneic SCT, but not in non-responding patients or in patients treated with chemotherapy. In one study, 10 patients with CML were treated with PR1: 1 achieved a complete cytogenetic response, and 3 had cytogenetic improvement.24
Other approaches can also be used to stimulate an immune response against the leukemic clone. One approach is to use anti-CTLA-4 monoclonal antibodies. These have been shown to stimulate an anti-tumor immune response in patients with melanoma and other solid tumors.
Studies with vaccines and other immunomodulatory approaches for patients with CML at M.D. Anderson, some in collaboration with many other centers in the USA, include:
- Phase II study of PR1 vaccine in patients with Ph-positive CML who are HLA-A2 positive who have received at least 12 months of therapy with imatinib and are in complete cytogenetic remission but have stable or increasing levels of BCR-ABL as determined by real-time PCR – protocol 2006-0360.
- A phase II study of ipilimumab (an anti-CTLA4 monoclonal antibody) in combination with dasatinib for patients with CML in any stage that have minimal residual disease (molecular in chronic phase, cytogenetic or molecular in advanced stages) while on treatment with dasatinib– protocol 2008-0157.