US Pharm. 2011;36(5)(Oncology suppl):3-7.

ABSTRACT: Imatinib mesylate has had a significant impact on the survival of patients with chronic myeloid leukemia (CML), particularly chronic-phase (CP) disease. However, a proportion of patients lose their response, fail to respond, or are intolerant to imatinib. The second-generation tyrosine kinase inhibitors, dasatinib and nilotinib, are more potent than imatinib and are effective against imatinib-resistant mutations. Initially approved for CML patients who are resistant or intolerant to imatinib, both dasatinib and nilotinib recently received approval for front-line treatment of patients with CP-CML. These approvals occurred after each agent demonstrated greater and faster response rates compared with imatinib in large phase III trials. Imatinib, dasatinib, and nilotinib are generally well tolerated.

Chronic myeloid leukemia (CML) accounts for approximately 15% of adult leukemias, and an estimated 4,870 new cases were diagnosed in the United States in 2010. The median age at diagnosis is 45 to 55 years; however, CML affects people of all ages. In 2010, an estimated 440 CML-related deaths occurred in the U.S.1,2

CML is a clonal myeloproliferative disorder of hematopoietic stem cells that results in uncontrolled proliferation of predominately mature granulocytes. The disease is characterized by the presence of the Philadelphia chromosome, which results from the reciprocal translocation between chromosomes 9 and 22, t(9;22). This occurs when part of the BCR gene from chromosome 22 is fused with the ABL gene on chromosome 9. The resulting fusion protein (BCR-ABL) is a constitutively active tyrosine kinase (TK) that causes increased cell proliferation and survival of CML cells.1

CML may be classified as chronic-phase (CP), accelerated-phase (AP), or blast-phase (BP) disease. The vast majority of patients are diagnosed in CP, which behaves more like an indolent disease. Patients with CP-CML are often asymptomatic or have mild symptoms such as fatigue, malaise, weight loss, or early satiety or abdominal pain due to an enlarged spleen. Left untreated, CP progresses to advanced disease (AP or BP) within 3 to 5 years.1 Blast phase, which is the most advanced, behaves like an acute leukemia and confers a poor prognosis.

CML was the first malignancy whose exact molecular abnormality (BCR-ABL gene) was identified. This led to the development of several targeted therapies against BCR-ABL. This review will focus on the three TK inhibitors (TKIs) approved for front-line therapy of CP-CML: imatinib mesylate (Gleevec, Novartis), dasatinib (Sprycel, Bristol-Myers Squibb), and nilotinib (Tasigna, Novartis) (TABLE 1).

Goals of Therapy and Response Criteria

CML is considered incurable outside of stem cell transplantation (SCT); however, complete and durable responses are possible with imatinib therapy. The European LeukemiaNet established criteria for the definitions of optimal and suboptimal responses to front-line imatinib, as well as for treatment failure.3 These criteria play an important role in therapeutic decision-making and in determining long-term outcomes in patients with CP-CML. The ultimate treatment goals for CP-CML patients are to achieve a complete cytogenetic response (CCyR) by 12 months (optimal) or 18 months and to prevent progression to AP or BP. CCyR is defined as having no Philadelphia chromosome–positive (Ph+) cells. Additionally, achieving a major molecular response (MMR)—defined as a ratio of BCR-ABL to ABL of <0.1% (or a >3-log reduction)—by 18 months is considered optimal. Meanwhile, meeting milestones for response at 3, 6, 12, and 18 months is essential for continuing current therapy.3

Front-Line Treatment

Before imatinib was introduced, standard therapy for CML consisted of interferon alfa plus low-dose cytarabine. Although this combination could produce CCyR, few patients were able to maintain response, and interferon toxicity limited treatment.4 FDA approval of imatinib in 2001 dramatically changed the treatment of CML and led to remarkably improved outcomes. Imatinib was the first drug to target the molecular abnormality responsible for CML. Recently, nilotinib and dasatinib—two second-generation TKIs—have been approved for the treatment of CML. TKIs target the constitutively active TK that causes the disease. Although SCT is the only curative treatment for CML, its use is limited because of the high potential for toxicity and mortality, especially in the era of TKIs.

Imatinib Mesylate (Gleevec): Imatinib, a selective BCR-ABL TKI, works by competitively binding to the ATP-binding site on BCR-ABL, thereby inhibiting downstream signaling and ultimately causing apoptosis of cancer cells.5 It also inhibits other kinases, such as c-Kit and PDGFR. Imatinib was first approved for second-line treatment of Ph+ CML and gained an indication for front-line therapy shortly afterward.6 The pivotal study that led to its approval for front-line therapy was the IRIS trial, which randomized 1,106 patients with newly diagnosed CP-CML to treatment with imatinib 400 mg daily or interferon plus cytarabine.4 Patients treated with imatinib achieved significantly higher response rates (RRs) (CCyR 76.2% vs. 14.5%, P <.001) at 18 months. Shortly after this notable finding emerged, imatinib became the standard of care for CML. After 8 years of follow-up, imatinib continues to produce durable responses, with a projected overall survival (OS) of 85% and a low rate of progression to AP/BP.7

In an effort to improve RRs, the safety and efficacy of high-dose (HD) imatinib (800 mg daily) were evaluated in several studies. Although HD imatinib induced more rapid responses compared with the standard dose, it did not result in improved response rates at 12 months.8 Additionally, HD imatinib was associated with more side effects. At present, the precise significance of achieving early response and the impact this has on long-term outcomes are unclear. However, from the IRIS data, it is known that attaining CCyR and MMR by 18 months is important, as this was associated with higher event-free survival at 72 months.9 Thus, imatinib 400 mg daily remains the standard for front-line CP-CML.

Imatinib is generally well tolerated; however, many patients experience grade 1/2 adverse events (AEs). Common nonhematologic AEs are fluid retention (peripheral and papillary edema), nausea, vomiting, diarrhea, rash, myalgias, and elevated liver-function tests (LFTs). If grade 3/4 hematologic toxicity occurs, it is generally early in the treatment course.4,6,7

Although many patients treated with imatinib have a durable response, about one-third of patients develop resistance, fail to achieve an optimal response, or are intolerant to imatinib.7 For this reason, more potent BCR-ABL TKIs that are effective against imatinib-resistant mutations were developed.

Dasatinib (Sprycel): Dasatinib is approximately 325 times more potent in vitro than imatinib for inhibiting BCR-ABL kinase.10 Dasatinib’s chemical structure differs from that of imatinib; unlike imatinib, dasatinib binds to both the active and inactive ABL kinase domains. It is also a strong inhibitor of the Src kinase. Dasatinib was first approved in 2006 for the treatment of patients with CML resistant or intolerant to imatinib.11 Approval was based on results of phase II trials in which dasatinib produced CCyR in approximately 50% of patients resistant or intolerant to imatinib.12 Dasatinib was also associated with high 3-year progression-free survival and OS rates (73% and 87%, respectively).13 Additionally, dasatinib was superior to HD imatinib in a similar patient population.14 The approved dosing of dasatinib for CP-CML is 100 mg once daily. This dose was recently shown to be as effective as and better tolerated than the originally approved dose of 70 mg twice daily.13 These results, along with a favorable safety profile, led to the evaluation of dasatinib as front-line therapy for CP-CML.

In October 2010, dasatinib was approved for the treatment of adults with newly diagnosed Ph+ CP-CML.11 Approval was given based on results of phase II and phase III trials.15,16 The single-arm phase II trial suggested that dasatinib safely and rapidly induced high rates of CCyR and MMR in 50 patients with newly diagnosed CP-CML.15 In the pivotal international, multicenter, open-label, phase III DASISION study (TABLE 2), 519 patients with newly diagnosed CP-CML were randomized to dasatinib 100 mg daily or imatinib 400 mg daily.16 Dasatinib demonstrated superior efficacy and higher RRs compared with imatinib; additionally, responses were achieved faster with dasatinib. Compared with imatinib patients, fewer dasatinib patients had disease progression to AP or BP, and none of the patients who achieved MMR experienced disease progression. After 18 months of follow-up, dasatinib has continued to show superior efficacy.17


Dasatinib is generally well tolerated, with most AEs being grade 1/2. The most commonly reported nonhematologic AEs were fluid retention (including pleural effusions), nausea, vomiting, diarrhea, myalgia, rash, and headache. With the exception of pleural effusions, these AEs occurred less frequently with dasatinib than with imatinib. The majority of dasatinib-treated patients experienced some degree of myelosuppression. While rates of grade 3/4 neutropenia and anemia were similar to rates with imatinib, more grade 3/4 thrombocytopenia occurred with dasatinib.11,16 Dasatinib has continued to be well tolerated at 18-month follow-up.17

Nilotinib (Tasigna): Nilotinib is approximately 20 times more potent than imatinib for inhibiting BCR-ABL in vitro.10 Nilotinib structurally resembles imatinib; similarly, it binds to the inactive conformation of the ABL kinase domain. However, nilotinib has an increased binding affinity for ABL kinase and a better topographic fit to the ATP binding site compared with imatinib. It also inhibits c-Kit and PDGFR.18 Nilotinib was originally investigated for second-line treatment of Ph+ CML resistant or intolerant to imatinib. Nilotinib produced RRs similar to those for dasatinib in the second-line setting and had a favorable safety profile.19 This led to the drug’s approval in 2006 for the treatment of Ph+ CML in patients resistant or intolerant to prior therapy with imatinib.18

In June 2010, based on results of two phase II trials and one phase III trial, the FDA added an indication for the treatment of patients with newly diagnosed CP-CML.18,20-22 In the single-arm phase II trials, nilotinib 400 mg twice daily produced high rates of CCyR and MMR, with almost all patients achieving CCyR by 6 months.20,21 These results supported the multicenter, open-label, randomized, phase III ENESTnd trial (TABLE 3), which evaluated the safety and efficacy of nilotinib in the first-line treatment of patients with newly diagnosed CP-CML.22 In this trial, 846 patients were randomized to receive nilotinib 300 mg or 400 mg twice daily or imatinib 400 mg daily. Nilotinib patients achieved significantly higher and faster RRs. Treatment failure and progression to AP or BP were significantly lower in the nilotinib arms versus the imatinib arm. As with dasatinib, none of the patients who achieved MMR experienced disease progression. RRs were similar for both nilotinib arms. An update at 18-month follow-up found that nilotinib maintains superior RRs and has lower rates of suboptimal response or treatment failure compared with imatinib. Notably, at 18 months, nilotinib 400 mg twice daily yielded significantly improved OS compared with imatinib (99.3% vs. 96.9%).23


Nilotinib was generally well tolerated at both dose levels. The most frequent grade 1/2 nonhematologic AEs were rash, headache, nausea, pruritus, myalgias, and biochemical laboratory abnormalities (increased LFTs, amylase, lipase, glucose, and alkaline phosphatase; decreased phosphate). Six percent of patients experienced grade 3/4 increases in glucose. About 50% of patients had nilotinib-induced myelosuppression, but this was predominately grade 1/2. Compared with imatinib, nilotinib was associated with less nausea, diarrhea, vomiting, muscle spasm, and edema, but more rash, headache, pruritus, and alopecia.18,22

Toxicity of TKIs

For most patients with CP disease, CML has become more of a chronic illness—comparable to diabetes or heart disease—and requires long-term treatment with a TKI. Hence, adherence has become an important issue so that patients can achieve and maintain optimal outcomes. Although imatinib, dasatinib, and nilotinib share common toxicities, each drug has its own caveats. Toxicity appears to be lower in the front-line setting for CP-CML compared with second-line treatment of CML. Because of the similar RRs between the three TKIs, the decision about which agent to start often comes down to the AE profile, especially in the absence of mutations. Although the majority of AEs are grade 1/2, each drug has the potential for more serious AEs to occur, such as bleeding or cardiotoxicity. Most AEs can be managed with supportive care and/or dose reduction or interruption. The DASISION and ENESTnd trials include helpful tables comparing the rates of AEs between nilotinib or dasatinib and imatinib.16,22 The AE profile and the need for chronic therapy highlight the importance of patient education and close monitoring by clinicians.

Conclusion

Imatinib revolutionized the treatment of CML and changed the natural course of the disease. The IRIS study provides long-term data showing durable RRs with standard-dose imatinib. However, about one-third of patients fail to benefit or lose their benefit from imatinib. The second-generation TKIs are more potent and effective against most imatinib-resistant mutations. Dasatinib and nilotinib were recently approved for first-line treatment of CP-CML based on results of two large, randomized phase III trials comparing each drug against imatinib. To date, these trials have shown the superiority of dasatinib and nilotinib to imatinib in producing and achieving faster responses. Both studies have planned 5-year follow-up, which is eagerly awaited, as it is not known how nilotinib and dasatinib will compare with imatinib in the long term. For this reason, the precise role of dasatinib and nilotinib in the first-line setting remains debatable. Furthermore, when imatinib becomes available in generic form, questions will arise regarding the cost benefit of initiating treatment with a second-generation TKI.

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