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Imatinib resistance: a role for dasatinib
Although imatinib changed the landscape dramatically, resistance has created a new set of challenges.
Chronic myelogenous leukemia is a rare disease accounting for fewer than 5,000 new cancer diagnoses each year in the United States. However, chronic myelogenous leukemia is notorious for being the first malignant disease in which a causative genetic abnormality was found and targeted.
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The Philadelphia chromosome is the result of a translocation between the ABL proto-oncogene on chromosome 9 and the BCR gene on chromosome 22. The product of this translocation is a tyrosine kinase that activates many signal transduction pathways, leading to uncontrolled cell proliferation and reduced apoptosis. The Philadelphia chromosome is found in about 95% of patients diagnosed with CML. It is also present in a small percentage of patients with acute lymphoblastic leukemia.
Imatinib (Gleevec, Novartis) was the first drug developed and marketed in the United States that targets the BCR-ABL (Philadelphia chromosome) tyrosine kinase. Compared with the previous standard of care for CML — interferon-alpha — imatinib produced higher percentages of complete hematologic responses, as well as major and complete cytogenetic responses.
Cytogenetic responses are necessary to alter the natural history of the disease. Despite the impressive activity of imatinib in Philadelphia chromosome–positive (Ph+) leukemias, patients may be inherently resistant or develop resistance to imatinib.
The clinical trials story
Based on the promising results of a phase-1 trial, a phase-2 development program was initiated for dasatinib, known as the START program (Src-ABL Tyrosine Kinase Inhibition Activity Research Trials). Four trials were initiated in adult patients with imatinib-resistant or imatinib-intolerant leukemias: START-C (CML–chronic phase), START-A (CML–accelerated phase), START-B (CML–myeloid blast crisis) and START-L (CML–lymphoid blast crisis and Ph+ ALL).
In addition, a randomized phase-2 trial was conducted in patients with chronic-phase CML who failed first-line imatinib comparing high-dose imatinib to dasatinib.
The starting dose of dasatinib in all of these phase-2 trials was 70 mg orally twice daily. Dose escalation was allowed for lack or loss of response. Dose adjustments were recommended for toxicity. Hematologic and cytogenetic responses were defined based on standard criteria used in all of the dasatinib trials (see Table 2).
The results of the single agent dasatinib phase-2 trials are shown in Table 3. Despite the majority of patients being resistant to imatinib therapy, dasatinib produced a significant number of hematologic and cytogenetic responses. Many of these responses were durable. As expected, response rates diminished with more advanced stages of the disease.
In the randomized phase-2 trial, 150 patients were randomly assigned in a 2-to-1 fashion to either dasatinib (70 mg twice daily) or high-dose imatinib (800 mg/day). The patient groups were balanced with one exception: twice as many patients in the dasatinib arm had a BCR-ABL mutation. With a median follow-up of 15 months, 93% of dasatinib patients (n=101) had achieved a complete hematologic response compared with 82% of patients treated with high-dose imatinib (n=49).
Major cytogenetic responses were obtained in 52% of patients treated with dasatinib compared with 33% of patients treated with high-dose imatinib. Time to treatment failure and progression-free survival were longer with dasatinib, marking the first treatment to show activity in the setting of imatinib resistance. Confirmatory trials and other trials in which imatinib and dasatinib as first-line therapy for Ph+ leukemias will be compared are underway.
Dasatinib toxicity profile
Dasatinib is associated with a greater degree of myelosuppression compared with imatinib. In advanced stages of CML and Ph+ ALL, it is important to distinguish between myelosuppression due to persistent leukemia vs. toxicity from therapy. See Table 4 for dasatinib dose adjustment recommendations for myelosuppression.
Similar to imatinib, dasatinib may also cause fluid retention. Although the fluid retention with imatinib tends to be more superficial, dasatinib may cause fluid collections around vital organs such as pleural or pericardial effusions. These effusions respond to withholding dasatinib in addition to diuretics with or without pulse corticosteroids. Dose reduction of dasatinib is recommended if effusions occur.
Dasatinib may also cause rash, diarrhea, stomach upset, headache and fatigue. These symptoms are seldom dose limiting and are manageable with usual supportive measures. Changing dosing and/or administration of dasatinib are strategies being investigated to alleviate some toxicities. Pasquini and colleagues reported preliminary results of a study at the 2007 ASCO Annual Meeting comparing the standard 70 mg twice daily dosing against once daily dosing at 140 mg/day. The daily dosing regimen appeared to result in comparable hematologic and cytogenetic responses and a trend toward improved tolerability (less fluid retention and dose reductions) compared with the twice daily regimen. Final results from this study are eagerly anticipated and may help to improve the quality of life for these patients.
Dasatinib drug interactions
Dasatinib has a number of clinically significant drug interactions that clinicians should keep in mind. Dasatinib is a substrate for cytochrome p450 (CYP) 3A4. Inhibitors and inducers of CYP 3A4 may alter the drug levels of dasatinib. Common inhibitors of CYP 3A4 include ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, indinavir and nefazodone. Common inducers of CYP 3A4 include dexamethasone, phenytoin, rifampin, phenobarbital, carbamazepine and St. John’s wort. Dasatinib is also an inhibitor of CYP 3A4. Drugs with a narrow therapeutic window that are metabolized by CYP 3A4 (eg, fentanyl, cyclosporine, tacrolimus, sirolimus, quinidine and ergot alkaloids) should be administered with caution in patients taking dasatinib.
Dasatinib absorption from the gastrointestinal tract is pH dependent. Increases in pH will decrease the bioavailability of dasatinib. Ideally, the coadministration of long-acting acid blockers (H2 blockers, proton pump inhibitors) and dasatinib should be avoided. Short-acting antacids should be used instead and separated by two hours from any dasatinib dose.
Dasatinib is a new multitargeted tyrosine kinase inhibitor that has demonstrated ability to overcome imatinib resistance and produce clinical responses. Future studies will help define the role of dasatinib — and other novel targeted therapies — in the management of Ph+ leukemias. Clinicians should be aware of the toxicity and drug interaction profile of dasatinib to help optimize patient care.
For more information:
- American Cancer Society. Cancer facts & figures 2007. 2007 ASCO Annual Meeting; June 1-5, 2007; Atlanta.
- O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly-diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004.
- National Comprehensive Cancer Network Chronic Myelogenous Leukemia Clinical Practice Guidelines in Oncology, v.1.2008. www.nccn.org/professionals/physician_gls/PDF/cml.pdf. Accessed July 31, 2007.
- Dasatinib (Sprycel, Bristol Myers Squibb) prescribing information; July 2006.
- Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome–positive leukemias. N Engl J Med. 2006;354:2531-2541.
- Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109:2303-2309.
- Guilhot F, Apperley J, Kim DW, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood. 2007;109:4143-4150.
- Cortes J, Rousselot P, Kim DW, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. 2007;109:3207-3213.
- Ottmann O, Dombret H, Martinelli G, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a Phase II study. Blood. 2007;doi:10.1182/blood-2007-02-073528. Accessed August 8, 2007.
- Kantarjian H, Pasquini R, Hamerschlak N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007;109:5143-5150.
- Pasquini R, Ottmann OG, Goh YT, et al. Dasatinib 140 mg QD compared to 70 mg BID in advanced-phase CML or Ph(+) ALL resistant or intolerant to imatinib: One-year results of CA 180-035. J Clin Oncol, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition). 2007;25(Suppl 18S, June 20):7025.