Clinical Development Of Dasatinib In Chronic Myeloid Leukemia

Dasatinib was first investigated in a phase I dose-escalating study involving patients with CML in all phases who had failed or developed intolerance to imati-nib therapy (Table 1). Initially, dasatinib was administered only to patients with CP on a once-daily schedule for five consecutive days, followed by two days without treatment every week, and later a twice-daily administration was also investigated as well as a continuous daily administration. After clinical activity was observed in CP, patients with accelerated phase (AP) or BP and patients with Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) were included, all of them treated with the twice-daily schedule. Within two hours of oral administration of the higher doses, plasma concentrations in the range of 100 to 200 nM were achieved and a terminal half-life of about five hours was reported (28). A total of

TABLE 1 Response to Dasatinib in Patients with Chronic Myeloid Leukemia Who Have Developed Resistance or Intolerance to Imatinib

Response (%) Hematologic Cytogenetic

Study Agent CML phase No. Overall Complete Overall Complete

Phase I Dasatinib CP 40 93 93 63 35

AP 11 81 45 36 18

MyBP 23 61 35 52 26

LyBP 10 80 70 90 30

Phase II Dasatinib CP 387 90 90 51 40

AP 174 59 34 39 25

MyBP 109 49 25 44 25

Abbreviations: AP, accelerated phase; CE, clonal evolution; CML, chronic myeloid leukemia; CP, chronic phase; LyBP, lymphoid blast phase; Ph+ ALL, Philadelphia chromosome-positive acute lymphoblastic leukemia; MyBP, myeloid blast phase.

84 patients (40 in CP, 11 in AP, 23 in myeloid BP, and 10 with Ph+ ALL) received dasatinib 15 to 240 mg daily (29). A CHR was achieved in 37 (93%) patients in CP and a major cytogenetic response (MCyR) in 18 (45%), including a CCyR in 14 (35%). Major hematologic responses were observed in 31 (70%) of 44 patients with AP, BP, or Ph+ ALL, and MCyR were achieved in 27%, 35%, and 80% of patients in AP, BP, and Ph+ ALL, respectively. Responses were maintained in 95% of patients with CP and in 82% of patients with AP after a median follow-up of more than 12 and 5 months, respectively. However, only one (10%) patient with Ph+ ALL remained relapse-free after a median follow-up of four months (29). Overall, therapy with dasatinib therapy was well tolerated. The most frequently described toxicities were myelosuppression, gastrointestinal, and fluid retention syndromes. Grade 3-4 neutropenia or thrombocytopenia was observed in 45% and 35% of patients treated in CP and in 89% and 80% of those with AP, BP, or Ph+ ALL, respectively. Diarrhea occurred in 23% of patients, but was grade 1-2 in all but one patient. Fifteen (18%) patients had nonmalignant pleural effusions likely related to dasatinib therapy, usually grade 1 or 2 and grade 1-2 peripheral edema was observed in 16 (19%) patients. In this phase I study, 60 (71%) of 84 patients presented BCR-ABL mutations at baseline. CHR and cytogenetic responses were observed across all mutations, except in the four patients who had the T315I mutation, including one patient who developed this mutation while receiving dasatinib (29).

Results from a series of open-label phase II studies of dasatinib in patients with CML in all phases who had failed or become intolerant to imatinib, have been recently reported (Table 1). In these studies, dasatinib was administered at a dose of 70 mg twice daily based on pharmacokinetic data and optimal inhibition of Bcr-Abl and Src activity (28). In one study, involving exclusively patients in CP, 387 patients resistant (75%) or intolerant (25%) to imatinib with a median age of 58 years (range, 21 -85 years) were treated (30). Dose escalation to 90 mg twice daily was permitted in patients achieving suboptimal response, and dose reductions down to 40 mg twice daily were allowed in those who developed intolerance. A CHR was observed in 90% of patients, and MCyR was reported in 78% of imatinib-intolerant (68% CCyR and 10% PCyR) and in 42% of imatinib-resistant (30% CCyR and 12% PCyR) patients. BCR-ABL mutations were detected in 160 (44%) of 363 assessable patients, with G250E (n = 23) being the most frequent. T315I was present in only three patients. Significant molecular responses were not observed until after six months of dasatinib therapy, with a median Bcr-Abl/Abl ratio of 0.3% at nine months (30). The 10-months progression-free survival was 88%. The most common nonhematologic toxicity was diarrhea (32%), headache (30%), rash (22%), superficial edema (20%), and pleural effusion (17%), but most of these were grade 1 or 2. Grade 3 or 4 nonhematologic toxicity included pleural effusion in 3%, and diarrhea and liver toxicity in 2% each. Neutropenia or thrombocytopenia grade 3 or 4 were reported in 47% of patients each (30).

A total of 174 patients with CML AP were treated with dasatinib in another phase II study (31). Ninety-one (52%) patients had failed imatinib therapy at doses equal or higher than 600 mg daily. Dose escalation up to 100 mg twice daily or reductions down to 40 mg twice daily were allowed for poor initial response or dasatinib-related toxicity, respectively. The median duration of dasati-nib therapy was seven months (range, 0.13-13), and the average daily dasatinib dose was 113 mg (range, 24-192). Dasatinib dose was reduced in 53% and escalated in 46% of patients, respectively, and 63 (36%) patients eventually discontinued dasatinib, mainly due to disease progression (n = 27), toxicity (n = 10), or death (n = 10). A major hematologic response was reported in 102 (59%) patients, including 59 (34%) who achieved a CHR and 43 (25%) with no evidence of leukemia (NEL). A MCyR was attained by 60 (34%), including 43 (25%) and 17 (10%) patients who had CCyR and PCyR, respectively. MCyR occurred in 34 (36%) of 94 patients harboring Bcr-Abl mutations. The majority of patients (97%) experienced some degree of cytopenias, although 18% and 45% of patients entered the study with baseline neutropenia and thrombocytopenia, respectively. The most common nonhematologic toxicities were diarrhea (61%) and rash (27%), mostly grade 1 and 2. Grade 3 or 4 diarrhea occurred in 10%, but could be managed with proper therapy. Pleural effusion was observed in 43 (25%) patients, but it was grade 3 or 4 in only 5 (3%) and was manageable with diuretics and/or pulse steroids (31).

Preliminary data after a minimum follow-up of six months were reported in 109 patients with CML myeloid BP (32) and in 94 patients with either CML lym-phoid BP (n = 48) or Ph+ ALL (n = 46) (33). Ninety-one percent of patients were resistant to imatinib in each group and the proportion of patients who had failed imatinib therapy at doses equal or higher than 600 mg daily were 50%, 52%, and 46% for patients with myeloid BP, lymphoid BP, and Ph+ ALL, respectively. Dose escalation to 100 mg twice daily or reduction to 50 and 40 mg twice daily was permitted. The overall hematologic and cytogenetic response rates among patients with myeloid BP were 49% (50% for imatinib-resistant and 40% for imati-nib-intolerant) and 44% (CCyR 25%, PCyR 6%, and minor/minimal cytogenetic response 13%), respectively. Major hematologic responses were observed in 33% (CHR 29% and NEL 4%) patients with lymphoid BP and in 39% (CHR 33% and NEL 7%) among those with Ph+ ALL and MCyR were reported in 44% (CCyR 38%) of patients with lymphoid BP and in 46% (CCyR 44%) of those with Ph+ ALL. Dasatinib therapy was associated with rapid and profound myelosuppression in all groups of patients, although this was pre-existing in a substantial proportion of patients. Grade 3-4 neutropenia or thrombocytopenia was observed in 64% (18% at baseline) and 64% (43% at baseline) of patients with CML in myeloid BP and in 81%/74% (48%/20% at baseline) and 88%/78% (67%/48% at baseline) in those with lymphoid BP/Ph+ ALL, respectively. The most frequent nonhematologic toxicities included diarrhea (30-37%), nausea (18-22%), and vomiting (17-20%), which were generally grade 1 -2 and manageable. Pleural effusion was observed in 30% (grade 3 -4 in 13%) of patients receiving dasatinib in myeloid BP and in 16% (grade 3-4 in 4%) of patients with lymphoid BP/Ph+ ALL (32,33).

In summary, the results from the phase I and II studies demonstrate significant clinical activity of dasatinib in all stages of CML. Responses have been durable to the extent of the follow-up available to date, particularly among patients treated in CP and AP and less so in the BP. In addition, responses have been observed across a wide range of mutations, except T315I, confirming the results obtained in vitro. Dasatinib has been overall well tolerated. Myelosuppression occurs in many patients, particularly those treated in AP and BP, who start therapy with an already compromised marrow reserve. In most instances, myelosuppression is transient and rapidly reversible. Among nonhematologic adverse events, most are mild and manageable. Fluid retention has received significant attention, particularly in the form of pleural effusion. This is more common (20-30%) in BP than in earlier stages (10-15% in CP) and is frequently mild, with grade 3-4 cases present in only 3% to 5% in CP and 10% to 15% in BP. This can usually be managed with transient treatment interruptions and use of diuretics and corticosteroids. Only occasionally does it require thoracentesis, and it rarely results in permanent treatment discontinuation. Other adverse events have been usually mild and manageable.

Recently, results from a randomized, multinational, open-label phase II study comparing the activity of dasatinib and high-dose imatinib have been reported (34). The analysis was based on data from 150 imatinib-resistant patients randomized 2:1 to receive dasatinib 70 mg twice daily or imatinib 400 mg twice daily. Crossover was allowed for progression, lack of response, or intolerance. After a follow-up of three months, MCyR was achieved in 35% (CCyR 21% and PCyR 14%) of patients in the dasatinib arm and in 29% (CCyR 8% and PCyR 21%) in the high-dose imatinib arm. In addition, 15% of patients in the dasatinib arm and 76% in the imatinib arm had progression or crossover. Interestingly, among 19 patients who crossed over to dasatinib therapy, 42% achieved a MCyR while none of the four who crossed over to imatinib achieved MCyR. There were no significant differences in the toxicities between both arms, except for the occurrence of pleural effusion in 11% of patients treated with dasatinib (34).

A molecular analysis of imatinib resistant/intolerant patients (19 in CP and 14 with advanced disease (AP, BP, and Ph+ ALL) treated at UCLA in the phase I dose escalation trial of dasatinib showed that 6 (43%) of 14 patients in advanced phase and 7 (37%) of 19 in CP achieved >2-log reductions, including four patients in each group who had a major molecular response (MMR) as measured by quantitative polymerase chain reaction (PCR). More important, responses were maintained in two of six patients with advanced disease, and six of seven in CP achieving > 2 log reductions. Mutations were detected at last analysis in all 23 patients with baseline mutations. The same mutation that was present at baseline was present in 21 patients and five of them had an additional mutation. Mutations were present in all patients who progressed (1 CP, 7 AP/BC) and it was T315I in six of them. T315I evolved in three other patients who have not progressed (1CP, 2 AP/BC), making this mutant the most frequently detected during dasatinib therapy, and it was accompanied by significant increase in Bcr-Abl transcripts in all patients (35).

Another analysis of the dynamics of molecular response to dasatinib has been recently reported (36). Fifty-four patients [CP = 29 (55%), AP = 14 (26%), and BP = 10 (19%)] received dasatinib at 140 mg daily (n = 49) or at 100 mg daily (n = 4) in phase II studies for a median of 36 weeks (range, 11-73). Patients in CP had a baseline median BCR-ABL/ABL ratio of 68.99%. After two months of therapy a significant decrease in the BCR-ABL transcript level was observed, with a median value of 11.64%. By nine months the median value had decreased to 0.12%. In contrast, patients with advanced phase CML (baseline BCR-ABL/ABL ratio of 100%) experienced a steady decline in transcript levels from the start of dasatinib therapy, but the decline was slower and less pronounced than that observed in CP. The lowest median PCR value achieved by this group of patients was observed at nine months (0.94%). At this time point, the median BCR-ABL transcript level reached by these patients was similar to that achieved by patients in CP at six months (0.99%). Ten patients achieved at least an MMR (BCR-ABL/ ABL ratio below 0.05%) by quantitative real-time PCR, with three of them having undetectable BCR-ABL levels. All 10 patients who achieved a MMR were in CP at the start of dasatinib therapy, and three of five evaluated had an Abl kinase domain mutation at the start of the therapy. No T315I mutations were observed in this study (36).

0 0

Post a comment