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10th Biennial Meeting of the Canadian Blood and Marrow Transplant Group

Edmonton, Alberta / April 21-24, 2006

Targeting the defect in the bcr-abl kinase domain that gives rise to chronic myeloid leukemia (CML) has considerably improved the prognosis for patients with CML. Today, those receiving first-line imatinib in chronic-phase (CP) CML and who achieve a good early response to treatment can expect to do exceedingly well out to and likely beyond 54 months, according to long-term results from the original IRIS (International Randomized Trial of Interferon vs STI571). Indeed, at 54 months, 98% of patients treated with first-line imatinib in IRIS had achieved a complete hematological response (CHR), while 92% had achieved a major cytogenetic response (MCyR). Moreover, 86% of patients receiving first-line imatinib had also achieved a complete cytogenetic response (CCyR), again at 54 months.

Nevertheless, resistance to imatinib does develop, especially in more advanced disease, as pointed out by Nicholas Donato, PhD, Associate Professor of Medicine, Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, Texas.

When resistance develops, patients may lose their response to treatment even when the dose of imatinib is increased to 600 or 800 mg/day. Once response is lost, patients then may relatively quickly progress to either accelerated-phase (AP) or blast crisis (BC). In fact, approximately three-quarters of patients in AP CML and 95% of patients in BC are resistant to imatinib. As explained by Dr. Donato, acquired resistance—which occurs in between 40 and 80% of CML patients—usually arises from kinase domain mutations in bcr-abl but there also appear to be bcr-abl-independent mechanisms behind some of the resistance, most notably Src-family kinase activation.

Because imatinib binds only to the inactive conformation of bcr-abl, “a mutation that occurs in the bcr-abl kinase distorts the ability of the kinase to interact with imatinib,” Dr. Donato explained. Over-expression of the bcr-abl gene may also be associated with resistance but this occurs in no more than 10% of patients. As Dr. Donato pointed out, mutations in the bcr-abl kinase domain can confer varying degrees of resistance to imatinib and in some patients, increasing the dose of imatinib may overcome resistance, although not when it is caused by the T315I mutation.

Exploring Kinase Mutations

Ongoing research at the M.D. Anderson Cancer Center has targeted mechanisms other than bcr-abl that may contribute to resistance, especially those mediated by Src kinase activation. These mechanisms may be either independent of resistance mechanisms mediated by bcr-abl or they may simply amplify resistance caused by mutations in bcr-abl kinase.

One of the key mutations on which the M.D. Anderson Cancer Center group has focused is Lyn, a Src-family kinase that is insensitive to imatinib. Both Lyn and Hck, another Src-family kinase, are activated by bcr-abl in leukemia cells and likely serve as essential mediators of bcr-abl signal transduction and transformation. In imatinib-resistant cells, Dr. Donato and colleagues have demonstrated that Lyn kinase is over-expressed and that this over-expression is not dependent upon or regulated by bcr-abl. This suggests that independent regulation of Src may contribute to the development of imatinib resistance. A series of studies undertaken by the Houston researchers showed that imatinib could still reduce bcr-abl kinase activation but not Src-family kinase activation in specimens taken from patients who had developed resistance to imatinib.

In contrast, dasatinib, a dual bcr-abl/Src-family kinase inhibitor, blocked activation of both bcr-abl and Src-family kinases expressed in leukemic cells and this action correlated with clinical response to dasatinib. Dr. Donato and colleagues have also observed that dasatinib is able to overcome resistance conferred by Src-family kinase activation. Thus, dual or multi-targeted kinase inhibitors that affect Lyn and other Src-family kinases suggest that multiple kinase inhibition may successfully overcome resistance to imatinib, as Dr. Donato suggested.

As a multi-kinase inhibitor, dasatinib binds to both inactive and active conformations of bcr-abl. “It is also 325-fold more potent at inhibiting bcr-abl kinase activity than imatinib and it is active against all bcr-abl mutants tested, the one exception being the T315I mutation,” he added. In phase I study results reviewed by Dr. Donato, investigators concluded that dasatinib had “significant efficacy” in all phases of imatinib-resistant and imatinib-intolerant CML, and that responses were durable at 19 months in CP CML patients and at 13 months in AP CML patients. Responses have also been durable in a subset of myeloid BC CML patients as well. “Responses have also been observed in patients with all types of mutations except T315I,” Dr. Donato indicated.

“Significant efficacy” was again observed when dasatinib was used in Philadelphia-positive (Ph+) acute lymphoid leukemia (ALL). Importantly, “very little cross-tolerance was noted between imatinib and dasatinib,” Dr. Donato reported, suggesting that multi-targeted Src/abl inhibitors hold significant promise for CML patients who become resistant to or who cannot tolerate imatinib.

Another emerging bcr-abl kinase inhibitor that is derived from imatinib but which appears more potent is AMN 107 (nilotinib). As does imatinib, nilotinib binds to the inactive conformation of bcr-abl but is approximately 20-fold more potent than imatinib and it inhibits kinase activity of most bcr-abl mutants except for T315I. In a phase I study, various dosing strategies were evaluated in imatinib-resistant CML patients in all phases of the disease, as well as in relapsed or refractory Ph+ ALL patients. The objectives of the study were to determine the safety, biologic activity and pharmacokinetic profile of nilotinib, Dr. Donato reported. Investigators also sought to define the maximum tolerated dose (MTD) of the new agent, defined as that dose at which 33% or greater grade 3 to 4 toxicities were reached after the first treatment cycle.

Results as cited by Dr. Donato and presented by Dr. Hagop Kantarjian, Chair, Department of Leukemia, M.D. Anderson Cancer Center, at the American Society of Hematology meeting in December 2005 showed that response rates to nilotinib were generally high, with the exception of Ph+ ALL patients, where response was poor. Again, responses were seen in patients with known bcr-abl mutations and treatment was generally well tolerated, the MTD being 400 mg b.i.d. based on efficacy, safety and pharmacokinetic data.

Corroborative Data

Dr. Pierre Laneuville, Director, Hematology/Oncology Program, MUHC-Royal Victoria Hospital, and Associate Professor of Medicine, McGill University, Montreal, Quebec, reviewed the available data for dasatinib in CML patients as well as in those with Ph+ ALL. Eight trials either have been or are in the process of being completed and results from more recent trials are expected to be presented at ASCO and ASH this year. In study CA180001, patients in all phases of CML (CP, AP, BC, myeloid and lymphoid) as well as Ph+ ALL patients were all resistant to or intolerant of imatinib. The primary end point of the study was the rate of CHR, and the doses used ranged from dasatinib 15 to 180 mg q.d. or b.i.d. in CP disease, and the total daily doses were 70 to 240 mg (i.e. 35 mg b.i.d. to 120 mg b.i.d.) in advanced disease. Following is a summary of results from this study which were updated at last year’s ASH meeting and which were reviewed by Dr. Laneuville.

Table 1. CA180001 Study: Responses

Again, cytogenetic responses were seen in patients with a wide spectrum of bcr-abl mutations, as well as in patients with minimal or no prior cytogenetic response with imatinib. Reversible grades 3 to 4 toxicity was observed in all patient groups, especially those with advanced disease. Following are hematologic toxicity rates. It should be noted, however, that grade 3 to 4 myelosuppression was already present in two-thirds of advanced-disease patients before initiating treatment with dasatinib.

Table 2. CA180001 St
rates (grade 3 to 4)

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Five patients in CP CML developed grade 1 to 4 pleural effusions, as did 10 patients with advanced disease. As Dr. Laneuville told delegates, pleural effusions were managed without having to discontinue treatment and no patient has gone off study agent for reasons of toxicity. Other non-hematologic adverse events include gastrointestinal symptoms (diarrhea, nausea, vomiting) and edema.

Responses have proved to be durable in both CP (19 months) and AP (13 months) patients, and in a subset of myeloid BC patients, but responses in lymphoid BC and Ph+ ALL patients were short-lived. As Dr. Laneuville also noted, responses to dasatinib correlated with bcr-abl genotype prior to initiation of therapy.

Ongoing Trials

The phase II START (SRC/ABL Tyrosine Kinase Inhibition Activity: Research Trials of Dasatinib) program consists of four studies described by Dr. Laneuville, including CA180005, CA180006, CA180013 and CA180015. The dose of dasatinib being explored in these studies is uniformly set at 70 mg b.i.d. The populations being studied in these four trials are largely more advanced patients, with one exception (CA180013). As he also reported, 31% of imatinib-resistant patients in CP CML enrolled in CA180013 have achieved a MCyR, while 22% have achieved a CCyR. (Response rates are much higher in imatinib-intolerant patients)

In AP patients enrolled in CA180005, 31% have achieved a MCyR, while 21% have achieved a CCyR. Among myeloid BC patients enrolled in CA180006, a MCyR was achieved in 30% of resistant patients and 27% also achieved a CCyR. MCyR rates in lymphoid BC and Ph+ ALL patients enrolled in CA180015 have reached 50% in BC patients and 58% in Ph+ ALL patients. Progression-free survival in the CP CML study group has also been impressive, with 86% of patients remaining on dasatinib therapy and only three deaths over a 10-month follow-up.

As Dr. Laneuville explained, the proportion of responders increases over time, such that over half of AP patients randomized to the CA180005 study have achieved a major hematologic response (MHR) five months after initiation of therapy. “Responses in AP patients are also durable,” Dr. Laneuville noted, with only one patient losing their response to dasatinib out of a total of 63 patients who achieved a MHR in response to dasatinib.

At 10 months’ follow-up, only 15 patients had progressed out of a total of 107 patients who received treatment for AP disease in CA180005. Time to MCyR and MHR in myeloid BC patients (CA180006) has also been similar to that for AP patients (CA180005), peaking between month 4 and 5 after initiation of dasatinib. At eight months of follow-up, no patient in the myeloid BC study who responded to dasatinib had lost their response, although 35 out of a total of 74 patients in this particular cohort had progressed at 10 months of follow-up.

In the CA180015 trial involving lymphoid BC and Ph+ ALL patients, approximately 60% had responded to dasatinib by approximately 60 days. Twenty-one out of 42 lymphoid BC patients achieved a MCyR, as did 21 out of 36 Ph+ ALL patients. However, progression-free survival rates dropped off steeply in both cohorts, such that between months 4 and 6, over half of patients had progressed. The same hematologic toxicity profile observed in the phase I study was again recorded in the phase II trials, while the incidence of grade 3 to 4 pleural effusion ranged from a low of 2% to a high of 11%.

As Dr. Laneuville indicated, the mean dose delivered in the CP CML trial was 119 mg/day out of an intended dose of 140 mg/day, with a similar mean dose being delivered in the myeloid BC trial. In the AP trial, as well as in the trial in which lymphoid BC and Ph+ ALL patients were treated, the mean daily dose was either very close to or reached the intended dose. That said, 49% of CP patients required a reduction in dose at some point during the study, as did 30% of AP patients, 96% of myeloid BC patients, 14% of lymphoid BC patients and 28% of Ph+ ALL patients. Only a minority of patients required discontinuation of treatment during any of the four trials.

Dr. Laneuville concluded, “Dasatinib induces significant hematological and cytogenetic responses in imatinib-resistant and imatinib-intolerant patients in all phases of CML. Responses are durable in nearly all CP and AP patients and in myeloid BC patients who achieve a MHR.”

Note: At the time of printing, dasatinib is not available in Canada.