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Along with cure and avoidance of disease progression, molecular response is one of the primary goals of therapy for chronic myelogenous leukemia (CML), reported Harry P. Erba, MD, PhD, of the University of Michigan Comprehensive Cancer Center in Ann Arbor. This molecular response is defined as a reduction in Bcr-Abl transcripts as measured by the polymerase chain reaction (PCR). The Bcr-Abl fusion protein affects a variety of signaling pathways controlling adhesion, differentiation, and mitosis. With its enhanced tyrosine kinase activity, this molecular pathway has become a target for tyrosine kinase inhibitors (TKIs) in the treatment of chronic-phase CML. “Certainly, the TKIs have changed the complete treatment approach to this disease,” stated Jerald P. Radich, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
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| Dr. Erba |
The introduction of the first TKI, imatinib (Gleevec), dramatically altered the management of patients with CML. The recent report of the 5-year data of the IRIS (International Randomized Study of Interferon vs STI571) trial helps to put the success of imatinib in perspective (Druker BJ et al. J Clin Oncol 2006;24[18]:6506). With 1,106 patients treated at 117 centers in 16 countries, the data confirm imatinib as the standard of first-line therapy for all patients with CML, Dr. Erba said. According to the study investigators, high overall survival, increasing response, and decreasing disease progression validate the use of imatinib in this setting. Furthermore, toxicities were found to decrease over time: de novo side effects declined sharply after 2 years and were reduced to 2% after 4 years. “The 89% rate of overall survival at 5 years with imatinib exceeds that of all other CML therapies,” Dr. Erba noted.
Regarding the molecular response of patients enrolled in the IRIS trial, Hughes et al (N Engl J Med 2003;349:1421–1430) reported that an estimated 40% of those receiving imatinib, versus only 2% of interferon-treated patients, who were in complete cytogenetic remission had a more than a 1,000-fold reduction in Bcr-Abl transcripts. “In most cases, the Bcr-Abl was still detectable using quantitative PCR assays, and the level of response had an effect on progression-free survival,” said Dr. Erba. The investigators indicated that the level of molecular response at 12 months was confirmed to predict long-term clinical outcomes.
Patients in advanced phases of CML may not be sensitive to imatinib, and patients in any phase of the disease may develop resistance to imatinib. According to Dr. Erba, resistance to imatinib therapy is generally defined as no complete hematologic response (CHR) by 3 months, no cytogenetic response by 6 months, no major cytogenetic response (MCyR) by 12 months, loss of CHR, or loss of MCyR.
One of the first options when confronted with a patient with
CML who has become resistant to imatinib is to increase the dose of imatinib.
In a study out of The University of Texas M. D. Anderson Cancer Center in
Houston, investigators assessed patient response to escalating doses of
imatinib (from 400 to 800 mg/d or from 300 to 600 mg/d) in patients with
Philadelphia chromosome-positive (Ph+) CML in chronic phase without CHR or MCyR
(Kantarjian H et al. Blood 2003;101:473). In 34 patients with
cytogenetic resistance/relapse, 56% had a MCyR, and in 20 patients with
hematologic resistance/relapse, 65% responded to a higher dose of imatinib.
Another therapeutic option is to switch to one of the newer TKIs, and according to many investigators, the second generation of TKIs may prove to be superior to imatinib (Hughes T et al. Blood 2006;108:28–37). Two of these oral Abl inhibitors—dasatinib (Sprycel) and nilotinib (AMN107)—have produced encouraging results in patients with imatinib-resistant and/or refractory CML and Ph+ ALL. Reportedly 325-fold more potent than imatinib, dasatinib is directed at a variety of Bcr-Abl mutations associated with resistance, except T315I.
Several recent studies have demonstrated the significant hematologic and cytogenetic efficacy of dasatinib in patients who had imatinib-resistant CML in chronic phase or who were intolerant of imatinib. These studies reported that dasatinib shows significant hematologic and cytogenetic efficacy in imatinib-resistant and -intolerant patients in chronic phase. Responses are durable; 86% of patients remain on treatment after 6 months and none of the patients with a complete cytogenetic response had progressed. Dasatinib is also associated with hematologic and cytogenetic responses in patients with accelerated phase CML or CML in blast crisis. Furthermore, dasatinib was generally well tolerated, and toxicities such as reversible myelosuppression and diarrhea were usually mild to moderate; however, the occurrence of pleural and pericardial effusions in some patients in the trial is receiving additional attention, revealed Dr. Erba.
Like dasatinib, nilotinib is another next-generation TKI that inhibits 32 of the 33 imatinib-resistant Bcr-Abl mutations (but not T315I). Nearly 20- to 50-fold more potent than imatinib, nilotinib has achieved high hematologic and cytogenetic response rates in patients with Ph+ CML in advanced and chronic phases as well as ALL in phase I trials and offers a favorable pharmacokinetic profile for oral administration.
The preliminary findings of a phase II, open-label, multicenter clinical trial have also been positive in patients with imatinib-resistant/refractory CML and Ph+ ALL (le Coutre PD et al. J Clin Oncol 2006;24[18S]:6531; Kantarjian HM et al: J Clin Oncol 2006;24[18S]:6534; Giles FJ et al. J Clin Oncol 2006;24[18S]:6536). Among the 81 patients with chronic phase imatinib resistant disease, 46% had major cytogenetic remissions and 32% had complete cytogenetic remissions. Among 25 patients with accelerated-phase CML, 16% had a complete cytogenetic response. Benefit from treatment was also seen in some patients with blast-crisis imatinib-resistant/refractory CML and Ph+ ALL. Investigators urged long-term follow-up for these patients to assess for additional response and durability.
A critical issue in managing these patients is to monitor their response to treatment, agreed both Drs. Erba and Radich. “Obviously, these patients should be shown to go into a hematologic response, so physical exams and complete blood counts are crucial,” said Dr. Erba. Detecting myelosuppression early in therapy can be accomplished with weekly blood counts, which can be spaced farther apart as patients become stable. In addition, bone marrow examination is critical at the time of diagnosis. “There are morphologic clues to acceleration of the disease in the marrow, like extensive fibrosis or islands of blast [cells], but also clonal evolution in the bone marrow can be seen,” Dr. Erba revealed. Cytogenetic analysis should be performed at baseline, at 6 months, and every 3 to 6 months thereafter until a complete cytogenetic remission by bone marrow examination is achieved. After the critical outcome of complete cytogenetic remission is achieved, quantitative measures of Bcr-Abl transcripts using PCR techniques may be helpful, said Dr. Erba.
According to Dr. Erba, there are several criteria for determining which patients with chronic-phase CML might benefit from a change in therapy (see table). In patients with imatinib-resistant disease, increasing the dose of imatinib and considering allogeneic hematopoietic stem cell transplantation (HSCT) are viable options. A trial with one of the newer TKIs (dasatinib or nilotinib) is another alternative, but mutational analysis should guide such a decision; referral for HSCT would be indicated in patients with the T315I mutation, since these two newer agents are not effective against this mutation.
In light of the emergence of potent TKIs such as imatinib, dasatinib, and nilotinib, all of which are effective in chronic-phase CML, the role of HSCT has been curtailed. With TKI therapy now serving as a reasonable option in all phases of CML, transplantation represents a curative alternative, with current survival rates in chronic-phase disease of about 85%, revealed Dr. Radich. However, the cost of not monitoring patients carefully or waiting until disease advances or patients reach blast crisis is a “huge drop-off” in the success of transplantation. For patients who are diagnosed in accelerated-phase CML or blast crisis after initial therapy with TKIs, transplantation is indicated if a donor option is available.
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| Dr. Radich |
“All these therapies we have work great in chronic phase, including transplant, but they really lose their efficacy as you go into advanced-phase disease,” Dr. Radich clarified. In addition to phase of disease, age is a consideration for unrelated donor transplants. Although the results of unrelated and related donors are similar for younger patients, for patients in their 40s and 50s, results for unrelated donors are significantly poorer than those for transplants from related donors.
Monitoring patients’ response to initial treatment is a critical issue when determining the opportune time to consider transplantation. “Cytogenetic responses at 6 and 12 months are particularly good milestones to determine which patients need to go to ‘plan B,’” stated Dr. Radich. Potential transplant candidates in chronic-phase disease are those with no hematologic response at 3 months, less than a CHR or no cytogenetic response at 6 months, and less than a MCyR at 12 months, he added.
Assessment of probability of progressing to blast crisis after the detection of mutation is another tool for evaluating the timing of transplantation. “It is critical to identify the presence and type of mutations to predict disease progression,” Dr. Radich asserted. For instance, P-loop mutations, he said, are a predictor of poor response and survival rates, even in chronic-phase disease.
Although the impact of pre-transplantation TKI therapy on the outcome of transplantation is unclear, early, soon-to-be-published findings indicate that the use of imatinib may not have a harmful effect on such results, according to Dr. Radich. Moreover, imatinib given after HSCT may be effective in treating and preventing relapse. “In patients who relapse after a transplant, imatinib is remarkably effective in getting them back into remission,” Dr. Radich reported.
Final recommendations regarding HSCT include considering HLA typing early in the treatment process, even simultaneously with the administration of TKIs. “If you wait for treatment failure and/or disease progression, it is often too late,” Dr. Radich warned. “If someone is a potential transplant candidate, I start the HLA typing at the same time I start imatinib, and then when a donor comes up, an assessment can be performed; if things look good, fine, stay on the drug. If things don’t, you’re ready to go to transplantation,” he concluded.