Optimizing Dasatinib Therapy for Patients with Chronic-phase CML

Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome (Ph), which is formed by genetic exchange between chromosomes 9 and 22 and codes for the pathogenic tyrosine kinase BCR-ABL.^1-3 Historically, therapeutic interventions for CML have included busulfan, hydroxyurea, interferon-a, and stem cell transplantation.⁴ These therapies vary greatly in tolerability, toxicity, and efficacy. Current treatment options primarily comprise the tyrosine kinase inhibitors that target BCR-ABL, which have revolutionized the treatment of this disease. Imatinib was the first BCR-ABL inhibitor to be approved by the US Food and Drug Administration (FDA) for CML. It is currently the standard first-line treatment, although its use is limited by resistance and/or intolerance. In the International Randomized Interferon and STI-571 (IRIS) trial, 31% (171/553) of patients randomized to imatinib discontinued the study within 5 years of follow-up because of unsatisfactory therapeutic effect, adverse events (AEs), switching to alternative treatment, or other reasons.⁵

Subsequent BCR-ABL–targeted agents have been developed and ap proved: dasatinib and nilotinib. Preclinical studies have indicated that dasatinib was the most potent inhibitor of native (unmutated) BCR-ABL. Indeed, both dasatinib and nilotinib were shown to be more potent than imatinib (dasatinib, ~325-fold; nilotinib, ~20-fold).⁶
Dasatinib was initially approved in June 2006 based on data from the phase 2 SRC/ABL Tyrosine Kinase Inhibition Activity: Research Trials of Dasatinib (START) study. START consisted of a series of multicenter, open-label studies of dasatinib 70 mg twice daily in chronic-phase (CP), accelerated-phase (AP), or myeloid or lymphoid blast crisis (BC) CML with resistance or intolerance to prior therapy, including imatinib.^7-10 Results from a recent dose-optimization study (CA180-034) have led to a newly approved starting dose for dasatinib in patients with CP CML: 100 mg administered orally once daily in the morning or in the evening. For patients with AP CML, BC CML, or Ph+ acute lymphoblastic leukemia (ALL), the dose has also recently changed to a once daily schedule of 140 mg.

Pharmacokinetic information
Pharmacokinetic analysis demonstrated that dasatinib reaches maximum plasma concentration between 0.5 and 6 hours after oral administration. At a dose range of 15 mg/day to 240 mg/day, elimination is linear, and increase in area under the curve is proportional to the dose. The overall mean terminal half-life is 3 to 5 hours. These results were, in part, the rationale for twicedaily dosing. Once-daily dosing has proved to be at least as effective as twice-daily dosing, with an improved tolerability profile.^11,12 Binding of dasatinib and its active metabolite to human plasma proteins in vitro was approximately 96% and 93%, respectively, with no concentration dependence within the range of 100 ng/mL to 500 ng/mL.¹²

Dasatinib is metabolized primarily to its active metabolite by the cytochrome P450 enzyme 3A4 (CYP3A4). The active metabolite is unlikely to play a major role in the observed pharmacology of the drug, because it represents only 5% of the dasatinib area under the curve. In the human liver, dasatinib is a time-dependent inhibitor of CYP3A4 but does not induce human CYP enzymes. Elimination is primarily via the feces (85%) and urine (4%).¹²

Drug interactions

Because dasatinib is a CYP3A4 substrate, the use of CYP3A4 inhibitors may increase exposure to dasatinib and should be avoided. If CYP3A4 inhibitors must be used, toxicity should be monitored closely and dosages decreased as needed (Table 1). Caution is warranted any time azole antifungals, marcrolides, or antiretrovirals are used concurrently with dasatinib.

Concurrent use of CYP3A4 inducers, such as rifampin, may decrease dasatinib plasma concentrations. Agents with less enzyme-induction potential would be preferable in patients who require CYP3A4 inducers; dasatinib dose escalation in 20-mg increments is recommended if it is necessary to use CYP3A4 inducers. Use of St. John's wort should be avoided, because it may also decrease the dasatinib plasma concentrations.

Because the solubility of dasatinib is dependent on pH, concomitant administration of dasatinib and antacids can decrease the absorption of dasatinib; therefore, it is recommended that antacids be taken at least 2 hours before or after dasatinib administration. Concomitant use of proton pump in hibitors may reduce bioavailability of dasatinib and thus, ideally, should be avoided. Antacids would be the preferred therapy to use in place of proton pump in hibitors. Although not studied, the use of H2 antagonists could also be a cause for concern, because their mechanisms of action indirectly impact acid secretion in the gastrointestinal tract.

AEs and monitoring

In clinical studies, the most frequently reported adverse reactions to dasatinib (reported in ≥20% of patients) are presented in Table 2. The most frequently reported serious adverse reactions with clinical implications included pleural effusion (11%), pneumonia (3%), infection (2%), febrile neutropenia (4%), gastrointestinal bleeding (4%), dyspnea (3%), sepsis (1%), congestive heart failure (2%), and pericardial effusion (1%).12 Of these, the incidence of pleural effusion is particularly concerning. Patients who may develop symptoms suggestive of pleural effusion, such as dyspnea or dry cough, should be evaluated by chest radiograph because early intervention is desirable. Fluid-retention events can usually be managed by supportive care mea sures that include diuretics or short courses of steroids. Severe pleural effusion (occurring in 2% of patients) may require thoracentesis and oxygen therapy. Fluid retention events were reported less frequently in patients treated with 100 mg/day than in patients treated with 70 mg twice daily, thus providing more than just convenience or compliance as an incentive for the newly approved dosing schema.

Treatment with dasatinib is also associated with cytopenias. Nearly half the patients treated experienced neutropenia and thrombocytopenia; 18% demonstrated anemia. With this in mind, complete blood counts should be performed weekly for the first 2 months then monthly thereafter (or as clinically indicated). Myelosuppression is generally reversible and usually managed by dose reductions or interruptions (Table 3).¹² Myeloid growth factors and/or platelet transfusions may help lessen the risks of complications associated with neutropenia and thrombocytopenia, respectively, and reduce the need for dose modification.^13,14 Similar to fluid-retention events, thrombocytopenia was reported less frequently in patients treated with 100 mg/day than with 70 mg twice daily.

Cardiotoxicity has been described infrequently in patients receiving dasatinib, with an incidence of 3% in 911 patients reported in the prescribing information.¹² There is also in vitro evidence of prolonged cardiac ventricular repolarization (QT interval) in patients receiving dasatinib. In clinical studies, these QTc interval changes from baseline were 3 millisecond to 6 millisecond. Nine patients had QTc prolongation reported as an AE, and three patients (<1%) experienced a QTc greater than 500 millisecond. Cardio toxicity has also been reported with imatinib¹⁵ and most recently with nilotinib, which has a black box warning included in the prescribing information highlighting the risk of QT prolongation and sudden death.¹⁶ Although the incidence of cardiotoxicity differs between agents, these AEs may be related to BCR-ABL inhibition and, therefore, may be genuine class effects. Further research is needed to clarify the mechanisms underlying these effects, and the use of tyrosine kinase inhibitors in general may benefit from closer monitoring of cardiac function.¹⁷

Clinical data supporting change to dasatinib prescribing information
The dasatinib 70-mg twice-daily regimen used in phase 2 studies and subsequently FDA-approved was selected based on phase 1 study data, which showed that BCR-ABL kinase inhibition was more sustained across a 24-hour period with the twice-daily schedule than with the once-daily schedule.¹⁸ However, major cytogenetic response (MCyR) was achieved regardless of treatment schedule in this phase 1 study, even in patients receiving the once-daily schedule who achieved intermittent BCR-ABL inhibition. 18 The updated label for dasatinib includes results from a phase 3 dose-optimization study11 and from a phase 2 study of dasatinib versus high-dose imatinib.¹⁹

Phase 2 study of dasatinib versus highdose imatinib in patients resistant to imatinib 400 mg/day to 600 mg/day. High-dose imatinib has commonly been used as a treatment option for patients who experience resistance to standard doses (400 mg/day-600 mg/day) of imatinib in CML. Previous studies have shown that escalating the dose of imatinib to 800 mg/day can induce responses in some of these patients but that responses tend to be short in duration and increased drug intolerance may be an issue.^20-23 Hence, a phase 2 head-to-head randomized study of dasatinib versus high-dose imat inib (START-R) was undertaken.¹⁹

Dasatinib (70 mg twice daily) or highdose imatinib (800 mg/day) was administered to patients with CP CML who were resistant to standard imatinib dosing. Crossover to the alternate treatment was permitted after confirmed progression (ie, progression to AP or BC CML, loss of complete hematologic response [CHR] or MCyR, or increasing white blood cell count), lack of MCyR at the week 12 cytogenetic evaluation, or intolerance (grade 3/4 nonhematologic toxicity or hematologic toxicity requiring multiple dose modifications).

With a 15-month follow-up, patients treated with dasatinib experienced significantly increased response rates compared with patients treated with high-dose imat inib (93% vs 82%, P = .034). Patients in the dasatinib arm also had significantly greater MCyR (52% vs 33%; P = .023) and complete cytogenetic response (CCyR; 40% vs 16%; P = .004) compared with the high-dose imat inib arm. MCyR rates were higher with dasatinib compared with the high-dose imatinib arm in those who had no prior cytogenetic response and those who received prior imatinib doses of 600 mg/day. Molec ular response rates were also significantly higher in the dasatinib arm versus the highdose imatinib arm (16% vs 4%; P = .038). Responses were generally achieved in patients with imatinib-resistant BCRABL kinase domain mutations.

Dasatinib was also associated with a significant prolongation in the time-totreatment failure compared with highdose imatinib (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.10-0.26; P <.001).¹⁹ Rates of progression-free survival showed a statistical difference in erfrcoa-vor of the dasatinib arm, with a sponding risk reduction of 86% compared with high-dose imatinib (HR, 0.14; 95% CI, 0.05-0.40; P <.001).¹⁹ These results suggest that when patients do not respond, or experience loss of response to imatinib, treatment with dasatinib is more effective than escalating the imatinib dose.¹⁹

Phase 3 dose-optimization study. A randomized, phase 3, open-label study was conducted to optimize the dose and schedule of dasatinib in patients with CP CML. Dasatinib was administered in once-daily and twice-daily schedules at two total daily doses (100 mg and 140 mg) in patients with CP CML after imatinib resistance or intolerance. The 100-mg daily dose was selected as the median total daily dose across the phase 2 program in CP CML.¹¹

Similar, marked hematologic and cytogenetic efficacy was seen across all four treatment arms. Rates of CHR, MCyR, and CCyR were 90%, 59%, and 41% for patients receiving 100 mg/day and 87%, 55%, and 45% for patients receiving 70 mg twice daily.¹² In this noninferiority trial design, the once-daily schedule demonstrated comparable efficacy with the twice-daily schedule on the primary efficacy end point (difference in MCyR, 2.8%; 95% CI, 6.0-11.6). The main secondary end point of the study also showed comparable efficacy between the 100-mg total daily dose and the 140-mg total daily dose (difference in MCyR, -0.8%; 95% CI, 9.6-8.0). Because the minimum follow-up was only 6 months, too few progressions were available to estimate the duration of MCyR. Compared with the 70-mg twice-daily arm, 100 mg/day was associated with a reduced incidence of cytopenia and pleural effusions.^11,12

Severe AEs (grades 3/4) included superficial localized edema (0%-1%), congestive heart failure (0%-2%), pericardial effusion (1%), pleural effusion (2%-3%), diarrhea (1%-4%), hemorrhage (1%-2%), and gastrointestinal bleeding (0%-2%).¹² The incidence of all AEs (including grades 3/4) was lower in the 100-mg/day arm compared with the 70-mg twice-daily arm. The reduced rate of pleural effusions in the 100-mg/day arm is particularly en couraging. Grade 3/4 cytopenias occurred in all arms, but were less frequent in the 100-mg/day arm compared with the 70-mg twice-daily arm.

The 100-mg/day arm was associated with fewer treatment interruptions and discontinuations compared with the 70-mg twice-daily arm. The rate of discontinuation for adverse reaction was 4% versus 12% in patients in the 70-mg twice-daily arm.¹² Conclusions
Dasatinib has become a treatment option for patients with all phases of CML or Ph+ ALL who have failed on or are intolerant to imatinib. The newly recommended dose of 100 mg once daily in patients with CP CML offers improved safety and compliance profiles— as evidenced by fewer treatment delays and discontinuations—while main taining efficacy compared with the previous 70-mg twice-daily dose. The 70-mg twice-daily dose remains the recommended regimen for patients with advanced CML and Ph+ ALL. New clinical data demonstrate greater efficacy with dasatinib compared with high-dose imatinib in CP CML patients resistant to standard-dose imatinib.

From a practicing pharmacist's standpoint, although clinical trial designs employ logical dosing choices, it is inevitable that these original "calculated guesses" (using preclinical and early clinical data) on dosing will, on occasion, require further investigation. Less than optimal dosing probably exists for multiple agents in cancer care, and is more likely with drugs whose clinical availability was accelerated because of unmet medical need. Clinicians wish to have the best available treatments for their patients, but all parties, including the pharmaceutical manufacturers, must be vigilant in the management of these new agents. It is desirable for new published data to be rapidly incorporated into labeling approval, as seen with the recent package change on dasatinib. Rapidly informing clinicians about dosage changes ultimately benefits patients, not only in improved safety and tolerability, but also potentially for improved clinical efficacy.

Acknowledgments
Writing and editorial support was provided by Kerrie Allen-O'Rourke, Johnathan Maher, and Josh Collis and was funded by Bristol-Myers Squibb.

References

1. Lugo TG, Pendergast AM, Muller AJ, Witte ON. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 1990;247:1079-1082.
2. Nowell PC, Hungerford DA. Chromosome studies in human leukemia. II. Chronic granulocytic leukemia. J Natl Cancer Inst. 1961; 27: 1013-1035.
3. Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining [letter]. Nature. 1973;243:290-293.
4. Savona M, Talpaz M. Chronic myeloid leukemia: changing the treatment paradigms. Oncology (Williston Park). 2006;20:707-711.
5. Druker BJ, Guilhot F, O'Brien SG, et al; for the IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.
6. O'Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinibresistant Abl kinase domain mutants. Cancer Res. 2005;65:4500-4505.
7. 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.
8. 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.
9. 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.
10. 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 2 study. Blood. 2007;110:2309-2315.
11. Hochhaus A, Kim DW, Rousselot P, et al. Dasatinib dose and schedule optimization in chronic-phase CML resistant or intolerant to imatinib: results from a randomized Phase-III trial (CA180034).Haematologica. 2007;92 (suppl 2):128. Abstract 0359.
12. Sprycel (dasatinib) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2009.
13. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia. V.3.2008. www.nccn.org/professionals/physician_gls/PDF/cml.pdf. Accessed March 4, 2008.
14. Quintas-Cardama A, Kantarjian H, O'Brien S, et al. Granulocyte-colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia.Cancer. 2004;100:2592-2597.
15. Kerkelä R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate.Nat Med. 2006;12:908-916.
16. Tasigna (nilotinib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2007.
17. Xu Z, Cang Z, Yang T, Liu D. Cardiotoxicity of tyrosine kinase inhibitors in chronic myelogenous leukemia therapy. Haematol Revs. 2009;1(1):e4.
18. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531-2541.
19. 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.
20. Kantarjian H, Talpaz M, O'Brien S, et al. Highdose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood. 2004; 103:2873-2878.
21. Kantarjian HM, Talpaz M, O'Brien S, et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood. 2003;101:473-475.
22. Marin D, Goldman JM, Olavarria E, Apperley JF. Transient benefit only from increasing the imatinib dose in CML patients who do not achieve complete cytogenetic remissions on conventional doses. Blood. 2003;102:2702-2703.
23. Zonder JA, Pemberton P, Brandt H, et al. The effect of dose increase of imatinib mesylate in patients with chronic or accelerated phase chronic myelogenous leukemia with inadequate hematologic or cytogenetic response to initial treatment. Clin Cancer Res. 2003;9:2092-2097.