OCTOBER 2010, VOL. 3, NO. 7 by The Oncology Pharmacist

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ASCO 2010 Update on Chronic Myelogenous Leukemia: Payers’ and Providers’ Perspectives Figure 4 The DASISION Trial: Confirmed CCyR and MMR, by 12 Months (n = 258 in each group)

Patients responding to therapy, %

100

Dasatinib 100 mg/day Imatinib 400 mg/day

P = .067

90 77

80 70

P <.001

60 50

40 28

30 20 10 0

MMRb

Confirmed CCyRa a

Confirmed on 2 consecutive assessments at least 28 days apart. Patients who had a first assessment of CCyR at 12 months that was confirmed on a second assessment thereafter were considered to have had a confirmed CCyR by 12 months. b BCR-ABL transcript level ≤0.1% in peripheral blood on RQ-PCR assay, as expressed on the International Scale. CCyR indicates complete cytogenetic response; MMR, major molecular response; RQ-PCR, real-time quantitative polymerase chain reaction. Source: Reference 17.

Figure 5 The DASISION Trial: Grade 3/4 Hematologic Toxicities Dasatinib 100 mg/day Imatinib 400 mg/day

Patients with hematologic toxicities, %

25 21 20

15 10

7 5

Anemia

Neutropenia

Thrombocytopenia

Source: Reference 17.

Figure 6 Common Adverse Events Associated with Bosutinib

Patients with adverse events, %

100 90

Any grade Grade 3/4 84

80 70 60 50

30 20 10

Diarrhea

Abdominal pain

Fatigue

9 2

Nausea

Vomiting

Rash

Source: Reference 21.

MMR receiving imatinib, hazard ratio = 2.01; P <.001). Rates of MMR at 12 months among patients receiving dasatinib by Hasford risk score were 56% (low risk), 45% (intermediate risk), and 31% (high risk)

who achieved an MMR has progressed to advanced phase or blast crisis. The rates of grade 3/4 cytopenias are shown in Figure 5.17 In particular, the rate of grade 3/4 neutropenia (21%) was comparable to that observed in patients receiving imatinib (20%) and lower than that observed in patients receiving dasatinib second-line after imatinib resistance or intolerance (36%).17,20 The rate of thrombocytopenia was 19% among patients receiving dasatinib compared with 10% among those receiving imatinib. This, too, is lower than that experienced by patients receiving dasatinib second-line. Grade 3/4 nonhematologic adverse events were rare for both treatment arms.17 Several events of any grade occurred less frequently among patients receiving dasatinib than among those receiving imatinib, including nausea (8% vs 20%, respectively), vomiting (5% vs 10%, respectively), rash (11% vs 17%, respectively), muscle inflammation (4% vs 17%, respectively), and fluid retention (19% vs 42%, respectively). Similar rates were seen with both agents for any grade diarrhea (17% for both), fatigue (8% vs 10%), and headache (12% vs 10%). Pleural effusion was reported only in the dasatinib arm (10%), with all being grade 1/2.17 Three patients in the dasatinib arm discontinued treatment because of grade 2 pleural effusion.

OcTOber 2010 I VOL 3, NO 7

compared with patients receiving imatinib (36%, 28%, and 16%, respectively). Fewer patients receiving dasatinib have progressed to advanced phase or blast crisis compared with those receiving imatinib (1.9% vs 3.5%). No patient

Several events of any grade occurred less frequently among patients receiving dasatinib than among those receiving imatinib, including nausea. Laboratory abnormalities, including lipase and amylase elevations and abnormal liver function tests, were rare on both arms, as was clinically relevant prolongation in QT interval. On July 12, 2010, the FDA granted a priority review designation to the application for dasatinib for the treatment of adult patients with newly diagnosed chronic-phase Ph+ CML. A decision is expected by late October 2010. Following resistance or intolerance to first-line therapy: bosutinib Bosutinib is an orally bioavailable dual SRC/ABL TKI that is active against the vast majority of imatinib-resistant BCR-ABL mutations, excluding T315I. Jorge Cortes, MD, Chair, CML Section of the Department of Leukemia, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center,

Houston, reported preliminary results from a phase 1/2 study that is investigating the efficacy and safety of bosutinib in patients with chronic-phase CML who failed treatment with imatinib. A total of 294 patients are enrolled in this study— 18 from the phase 1 portion (bosutinib 400, 500, or 600 mg/day) and 276 in the phase 2 portion (bosutinib 500 mg/day).21 Patients with complete hematologic response (CHR), CCyR, or MMR at baseline and patients lacking either a baseline or a postbaseline assessment were considered nonevaluable for the respective response. After a median treatment duration of 13.7 months and a median follow-up of 23.8 months, 91% of evaluable patients had achieved a CHR, 50% of patients had achieved CCyR, and 52% had achieved MMR. Median time to CCyR was 12.3 months. Median progression-free survival has not been reached, and 94% of patients are still alive at month 24. Treatment with bosutinib was generally well tolerated (Figure 6).21 Diarrhea was the most common nonhematologic toxicity, reported in 84% of patients (9%, grade 3/4). It was most frequently observed within the first few weeks of treatment, and was manageable and subsided quickly. Twenty-five percent of patients required a dose reduction and 2% of patients had to discontinue bosutinib because of diarrhea. Rash of any grade was observed in 34% of patients, with 9% of patients experiencing rash of grade 3/4. Rash responded favorably to symptomatic management strategies and seldom required dose reductions, interruptions, or therapy discontinuation. Fluid retention was minimal. The most common grade 3/4 toxicity was myelosuppression. Grade 3/4 thrombocytopenia was observed in 24% of patients, grade 3/4 neutropenia in 16%, and grade 3/4 anemia in 12%. As with other TKIs, myelosuppression most often occurred within the first few months of therapy and did not require dose reductions or interruptions in most patients. Grade 3/4 laboratory abnormalities, including hypermagnesemia (12%), hypophosphatemia (8%), lipase elevations (7%), and abnormal liver function tests (10% elevated alanine aminotransferase and 5% elevated aspartate aminotransferase) were also observed.21 These results demonstrate that bosutinib has clinical efficacy in patients with chronic-phase CML who are resistant or intolerant to imatinib. A phase 3 randomized clinical trial comparing the efficacy of bosutinib with that of imatinib in newly diagnosed, previously untreated patients with chronic phase CML has finished accrual. Results should be available by the end of 2010.