Based on a 6-year update of the landmark IRIS (International Randomized Study of Interferon vs ST1571) trial, the benefits of treatment with imatinib (Gleevec) for patients with chronic myelogenous leukemia (CML) continue to accrue with time. However, for those who become resistant to or intolerant of imatinib-based therapy, the tyrosine kinase inhibitor nilotinib (Tasigna) has joined the ranks of dasatinib (Sprycel) as an effective alternative in the revised 2008 National Comprehensive Cancer Network (NCCN) guidelines.
The benefits of treatment with imatinib appear to continue well into the sixth year of treatment, according to the most recent IRIS data (Hochhaus A et al. Blood 2007;110:25). The annual rate of events, such as the loss of complete hematologic response, loss of molecular cytogenetic response, disease progression, or death during treatment, declined over the years. “In 6 years, not a single patient has developed accelerated or blast crisis,” reported Susan O’Brien, MD, from the M. D. Anderson Cancer Center in Houston. Before the use of imatinib, the median event-free survival in these patients was historically around 60%, whereas in the IRIS trial, the estimated event-free survival at 72 months was 83%, she added.
“In the early days of imatinib, there was a feeling that maybe because this was a targeted therapy and because we could potentially get resistance through a mutation that, as time went on, more and more people would become resistant. In fact, almost the opposite is what we are seeing,” Dr. O’Brien revealed.
Nilotinib, which was recently approved for the treatment of chronic- or accelerated-phase Ph+ (Philadelphia chromosome-positive) CML in adult patients who are resistant to or intolerant of prior therapy with imatinib, is recommended for the following chronic-phase settings after imatinib therapy: no hematologic remission at 3 months; no cytogenetic response at 6 months; minor or no cytogenetic response at 12 months; and partial, minor, or no cytogenetic response at 18 months.
Furthermore, nilotinib was added as a treatment option for
patients who are not in remission or relapse with graft-versus-host disease
after hematopoietic stem cell transplantation. Finally, nilotinib is also
recommended for imatinib-treated patients with disease progression to
accelerated-phase CML, but not for blast crisis.
Dr. O’Brien summarized the results of a pivotal phase II study that led to the approval of nilotinib (Kantarjian HM et al. Blood 2007;110:735). In this study of 320 patients with imatinib resistance (71%) or intolerance (29%), the use of nilotinib (at the approved dose of 400 mg orally twice daily) resulted in “good cytogenetic response, good hematologic response, and excellent survival.” Although use of nilotinib resulted in anemia, neutropenia, and thrombocytopenia in more than half of treated patients (Rosti G et al. J Clin Oncol 2007;25[18S]:7007), she explained that this myelosuppression, which is a common side effect of all tyrosine kinase inhibitors, was “significantly less than that seen with imatinib or dasatinib.” Moreover, Dr. O’Brien said that the nonhematologic side effects that caused patients to stop taking imatinib did not arise with nilotinib therapy.
With the addition of nilotinib, the 2008 NCCN guidelines have also included a section on the management of nilotinib toxicity, especially QT-interval prolongation, consistent with the black-box warning issued by the US Food and Drug Administration (FDA) for this drug. Electrocardiograms should be obtained at baseline and 7 days after any dose adjustment to monitor QTc. “It is very important to make sure that the patients have normal electrolytes when they go on study with nilotinib,” Dr. O’Brien added.
The guidelines also address the use of erythropoietin for the management of grade 3/4 anemia. “Although it works…, the recent guidelines from the Centers for Medicaid and Medicare Services (CMS) and the FDA do not support the use of these drugs in myeloid malignancies. So it may be an issue with reimbursement,” admitted Dr. O’Brien.
In a recent randomized trial (Kantarjian et al. Blood 2007;110:736), patients who had failed to respond to standard-dose imatinib (400–600 mg/d) showed better response rates and progression-free survival (PFS) with dasatinib (70 mg twice daily) than with high-dose imatinib (800 mg/d). However, according to Dr. O’Brien, “dasatinib at 70 mg twice daily was even more myelosuppressive than high-dose imatinib.” In addition, she suggested that if patients did not respond to 400 mg/d of imatinib, increasing the dose of imatinib to 800 mg/d is still a “viable alternative.” However, “if they failed [to respond to] 600 mg/d, you are much better off switching to dasatinib,” Dr. O’Brien recommended. Higher-dose imatinib is one of the treatment options included in the current NCCN guidelines for patients who fail to respond to standard-dose imatinib (400–600 mg/d).
In a recent dose-optimization study (Shah NP et al. J Clin Oncol 2007;25[18S]:7004), patients were randomized to receive four dose levels of dasatinib (100 mg once daily, 50 mg twice daily, 140 mg once daily, and the standard dose of 70 mg twice daily). Dasatinib at 100 mg/d was associated with significantly less toxicity than standard-dose dasatinib, with comparable response rates, event-free survival, and PFS. “Myelosuppression and pleural effusion were significantly reduced [with the 100 mg/d dose],” Dr. O’Brien revealed. Based upon these results and the FDA approval, the NCCN guidelines now recommend dosing dasatinib at 100 mg/d for chronic-phase CML; the original dosing schedule (70 mg twice daily) remains in effect for managing blast crisis.
Dr. O’Brien briefly discussed the options for monitoring response in CML. Because treatment of accelerated-phase and blast-crisis CML produces only a transient response, “everything we do in CML is geared to the chronic phase,” she said.
Dr. O’Brien stressed the importance of using bone marrow studies. “Although patients understandably do not like bone marrow [biopsies],” she admitted, a bone marrow study is the only current modality that shows the blast count. This diagnostic study is also of value, she said, because “a small cohort of patients may present with CML in accelerated phase, and you won’t know that without bone marrows to do a blast count.”
“NCCN guidelines are based on standard cytogenetics,” Dr. O’Brien explained. Cytogenetic studies evaluate chromosomal abnormalities other than the Philadelphia chromosome. The use of other options for monitoring response in CML, such as fluorescence in situ hybridization (FISH) and reverse transcriptase-polymerase chain reaction (RT-PCR), was a controversial topic for the NCCN panel. Although FISH can establish a CML diagnosis, it does not replace cytogenetics because it cannot detect additional cytogenetic abnormalities. However, Dr. O’Brien did admit that “FISH is useful to look for early relapse.” As for RT-PCR, its clinical significance centers on its ability to establish a baseline BCR-ABL transcript level for monitoring molecular response after the patient has achieved a complete cytogenetic response.
Cytogenetic responses are indicative of treatment effectiveness. In the IRIS study, PFS was significantly better for patients who achieved any cytogenetic response at 6 months after initiation of therapy and a major cytogenetic response at 12 months, compared with those who had no cytogenetic response at 6 and 12 months. “Do we have any molecular endpoints so far we can use?” Dr. O’Brien inquired. Such endpoints have been the focus of an investigational study (Hughes TP et al. N Engl J Med 2003;349:1423−1432). The estimated PFS rate at 54 months was 97% for patients with a complete cytogenetic response (CCyR) and at least a 3-log reduction in the BCR-ABL transcript level at 12 months, compared with 89% for those with a CCyR and < 3-log reduction in BCR-ABL at 12 months. “This [difference in PFS] is only of borderline significance,” Dr. O’Brien observed. “One could use PCR to potentially change therapy at 12 months, and this isn’t in the guidelines yet, if you have a 3-log reduction or don’t have a 3-log reduction,” suggested Dr. O’Brien. However, there are no specific guidelines yet for changing therapy based on PCR results.
“Approximately 50% of people treated with imatinib develop resistance,” Dr. O’Brien said. A common cause is the presence of kinase domain mutations in BCR-ABL gene pair. Amplification of BCR-ABL or a BCR-ABL–independent mechanism may also result in imatinib resistance. Although the data are still emerging, Dr. O’Brien stated that, in general, all tyrosine kinase domain mutations except T315I appear to be sensitive to both dasatinib and nilotinib.
Dr. O’Brien concluded that all therapies discussed work best in patients who are still in chronic-phase CML, and molecular monitoring can predict response. Several questions remain to be answered by further studies. Will second-generation tyrosine kinase inhibitors (TKIs) prove to be better than imatinib for treatment of early chronic-phase CML? “There are trials now looking at up-front usage of second-generation TKIs,” Dr. O’Brien revealed. Should therapies be changed based on molecular testing? “We don’t have very firm guidelines yet for changing therapies based on molecular testing, but they may emerge with time,” she indicated.