As John Goldman, DM, FRCP, FRCPath, FMedSci, discussed earlier, a substantial minority of patients with chronic myeloid leukemia (CML) experience treatment failure. Jorge Cortes, MD, of The University of Texas MD Anderson Cancer Center, introduced this session with two patient cases to illustrate how subsequent therapy must be tailored to the individual experiencing treatment failure. The first patient had been treated with imatinib (Gleevec) after having becoming intolerant of interferon. Her best response was a major cytogenetic response, and after 26 months, she lost her complete hematologic response. At that time her only option was an increased dose of imatinib, which seems primarily to help those who have developed cytogenetic resistance, but is less likely to be effective in patients losing a hematologic response, which was exactly what happened in this case. No mutations were detected, and the patient was started on dasatinib (Sprycel).
The patient rapidly achieved a complete cytogenetic response and a 2-log reduction in transcript levels, but she lost her complete cytogenetic response (20% Philadelphia chromosome–positive metaphases) 19 months later. Despite dose escalation of dasatinib, Philadelphia chromosome–positive metaphases increased to 100% with loss of complete hematologic response. Direct sequencing revealed the presence of F486S and V299L mutations. Subsequent failure of bosutinib (Bosulif) (mutation sensitivity data for this agent were not available at the time), followed by a rapid response with nilotinib (Tasigna), which is effective against this mutation, highlights the need to tailor therapy based on mutations present and their tyrosine kinase inhibitor sensitivity pattern.
“In chronic-phase CML, patients with mutations with a low half maximal inhibitory concentration [IC50] for a specific drug have a very good outcome, whereas those with mutations with an intermediate IC50 do worse, and those with mutations with a high IC50, particularly T315I, do not do well at all,” noted Dr. Cortes. In accelerated-phase CML, it is not as clear; the correlation with response is there, but there is no correlation with event-free survival, likely due to additional molecular events characteristic of transformation.
Dr. Cortes pointed out that the investigational agent ponatinib has been shown to be effective against all of the mutations commonly seen in the clinic in which it has been tested including the T315I mutation.1 More importantly, mutagenesis assays have demonstrated that this agent suppresses mutant outgrowth (resistant clones) at pharmacologic doses.
Early Intervention Stressed
The patient introduced in the second case experienced treatment failure with front-line imatinib despite a dose increase. Although still in complete hematologic response, the G250E and F317L mutations were detected. At this point, the audience respondents were about equally divided between choosing dasatinib or nilotinib as second-line therapy. Dr. Cortes stressed the need to intervene early once it is clear that a patient has lost a response, and certainly for loss of a cytogenetic response. Some physicians will wait until a patient has lost a complete hematologic response before referring, but the probability of achieving a good response with a second-line agent drops significantly at that point. Likewise, if a patient has not achieved a complete hematologic response by 3 months, a change in therapy should be considered.
The patient received nilotinib and achieved a complete cytogenetic response after 6 months. Follow-up sequencing analysis showed persistence of the two preexisting mutations, with the appearance of T315I. The patient had no sibling donors, so a registry search was undertaken while nilotinib was continued, since no other options were available at the time. The patient remained in complete cytogenetic response, but after 15 months of therapy, the two original mutations were no longer detectable, T315I remained, and Y253H appeared. Despite the presence of T315I, the patient continued to be stable for over 1 year before receiving a transplant.
“One of the important things that we need to recognize about T315I is that it is not necessarily the most aggressive mutation,” noted Dr. Cortes. For example, Y253F is a much more efficient mutation in terms of transformation capacity.2 Although relapses may not necessarily happen immediately, they will occur, so new agents are needed to address them.
Agents Targeting T315I Mutation
The third-generation tyrosine kinase inhibitor ponatinib has been shown to be effective in patients harboring the T315I mutation as well as patients who are resistant or intolerant to previous tyrosine kinase inhibitor therapy. In the phase II PACE (Ponatinib Ph+ ALL and CML Evaluation) study, major cytogenetic response (the primary endpoint for chronic-phase patients) was achieved by 54% of chronic-phase patients, including 49% of patients who were refractory or intolerant to dasatinib or nilotinib and 70% of patients with the T315I mutation (Table 1, page 12).3 The rates of major hematologic response (the primary endpoint in accelerated- or blast-phase patients) in patients with advanced disease who were refractory or intolerant to previous tyrosine kinase inhibitor therapy or who had the T315I mutation were also substantial (60% and 50%, respectively, in accelerated-phase CML and 35% and 33%, respectively, in blast-phase CML).
A phase II trial designed to evaluate ponatinib as front-line therapy in patients with early chronic-phase Philadelphia chromosome–positive CML is currently enrolling patients (ClinicalTrials.gov identifier NCT01570868), as is a randomized, open-label, phase III trial comparing ponatinib and imatinib in adult patients with newly diagnosed chronic-phase CML (ClinicalTrials.gov identifier NCT01650805). A New Drug Application for use of ponatinib in patients with resistant or intolerant CML and Philadelphia chromosome–positive acute lymphoblastic leukemia was submitted to the FDA in July 2012.
Omacetaxine mepesuccinate (Synribo) is a recently approved agent that has demonstrated efficacy in patients with T315I mutation. In a phase II/III study in imatinib-resistant disease, a major cytogenetic response rate of 27% was seen in patients with chronic-phase CML, and two-thirds of these were complete cytogenetic responses.4 In a separate study of patients not harboring T315I who were resistant to two or more tyrosine kinase inhibitors, including imatinib, 10% of patients with chronic-phase CML achieved a complete cytogenetic response, and 24% of patients with accelerated-phase CML achieved complete hematologic response.5
New Agent Approved for Ph+ CML
Patients without the T315I mutation have a new option available to them, the tyrosine kinase inhibitor bosutinib, which was recently approved for use in the United States in adult patients with all phases of Philadelphia chromosome–positive CML with resistance or intolerance to prior therapy. Among patients experiencing failure of imatinib and a second-generation tyrosine kinase inhibitor, between 30% and 35% achieved a major cytogenetic response with bosutinib, with many being complete cytogenetic responses.6 Patients who were resistant to imatinib and dasatinib were less likely to achieve complete cytogenetic response (14%) than patients who were resistant to imatinib and nilotinib (27%) and those who were imatinib-resistant/dasatinib-intolerant (28%). Responses also varied according to baseline mutation, with lower levels of responses in patients who harbored F317L, which also confers resistance to dasatinib.7 Thus, it is essential to obtain mutational status. ■
References
1. O’Hare T, Shakespeare WC, Zhu X, et al: AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16:410-412, 2009.
2. Griswold IJ, MacPartlin M, Bumm T, et al: Kinase domain mutants of Bcr-Abl exhibit altered transformation potency, kinase activity, and substrate utilization, irrespective of sensitivity of imatinib. Mol Cell Biol 26:6082-6093, 2006.
3. Cortes JE, Kim D, Pinilla-Ibarz J, et al: PACE: A pivotal phase II trial of ponatinib in patients with CML and Ph+ ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. J Clin Oncol 30(suppl 15):Abstract 6503, 2012.
4. Cortes-Franco J, Khoury HJ, Nicolini FE, et al: Safety and efficacy of subcutaneous-administered omacetaxine mepesuccinate in imatinib-resistant chronic myeloid leukemia (CML) patients who harbour the Bcr-Abl T315I mutation-results of an ongoing multicenter phase 2/3 study. Blood 114(suppl 22):Abstract 644, 2009.
5. Cortes JE, Nicolini FE, Wetzler M, et al: Subcutaneous omacetaxine in chronic or accelerated chronic myeloid leukemia resistant to two or more tyrosine-kinase inhibitors including imatinib. Blood 118(suppl 21):Abstract 3761, 2011.
6. Khoury HJ, Cortes JE, Kantarjian HM, et al: Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 119:3403-3412, 2012.
7. Khoury HJ, Cortes JE, Gambacorti-Passerini C, et al: Activity of bosutinib by baseline and emergent mutation status in Philadelphia chromosome-positive leukemia patients with resistance or intolerance to other tyrosine kinase inhibitors. Blood 118(suppl 21):Abstract 110, 2011.
