NEW YORK CITY—Suboptimal response in chronic myelogenous leukemia (CML) patients is not a response to “be all that impressed with,” and switching off first-line imatinib treatment should be considered. That was the message from Neil P. Shah, MD, PhD, a member of the National Comprehensive Cancer Network Guidelines CML Panel, speaking here at the organization's 7th Annual Congress on Hematologic Malignancies.
In discussing an update to the guidelines, released the day before, Shah noted that what in the past may have been considered a suboptimal response to first-line imatinib therapy should now be considered a justifiable cause for changing treatment course to increase the chance that patients can achieve an earlier deep response to a tyrosine-kinase inhibitor (www.nccn.org/professionals/physician_gls/f_guidelines.asp).
“There is a bigger emphasis on achieving rapid deep response,” said Shah, the Edward S. Ageno Distinguished Professor of Hematology/Oncology at the University of California San Francisco and the Leader of the Hematopoietic Malignancies Program at UCSF Helen Diller Family Comprehensive Cancer Center.
The new NCCN guidelines recommend that patients treated with first-line imatinib therapy be switched to a second-generation TKI (rather than continuing on or having an escalating dose of imatinib) if the patient has not achieved a deep molecular or cytogenetic response by three months or a complete cytogenetic response by 12 months. Both are defined as suboptimal responses in the European LeukemiaNet (ELN) 2009 recommendations for the management of CML (JCO 2009;27:6041–6051), that the patient may have a substantial long-term benefit from continuing a specific treatment, but that the chances of an optimal outcome are reduced—and therefore these patients should be considered eligible for alternative approaches.
“It is important to realize that several studies are showing that suboptimal-responding patients at six and 12 months have outcomes similar to those for patients with imatinib failure,” Shah said. Even though some such patients may achieve long-term benefits, “suboptimal is [only] the ‘silver medal’ of responses.”
He cited data from ASH's 2009 Annual Meeting (Abstract 1126) showing that 37 percent of patients on first-line imatinib therapy have unacceptable outcomes—either patients don't have or lose a complete cytogenetic response (CCyR), or have adverse effects from the drug (which in that study included cardiac events, vomiting, chest pain, inclusion body myositis, and dyspnea).
He also cited research showing that patients with a suboptimal response tend to have worse outcomes overall:
- For 224 chronic-phase CML patients treated with imatinib, the cytogenetic criteria used to define suboptimal response at both six and 12 months better identified patients with a bad prognosis than the cytogenetic criteria did used to define treatment failure (Blood 2008;112:4437–4444).
- For 204 chronic-phase CML patients, those who failed to achieve CCyR at three months or at six months after first-line imatinib therapy had a low probability of achieving CCyR during subsequent follow-up, and the major predictor for overall survival and progression-free survival was the cytogenetic response at one year (JCO 2008;26:3358–3363). The takeaway, Shah said, is that failure to achieve CCyR by 12 months puts patients at risk of disease progression or death.
- For 949 chronic-phase CML patients treated with imatinib, a BCR-ABL level of more than 10% was associated with a higher incidence of treatment failure at 12 and 18 months and disease progression compared with patients whose BCR-ABL level was less than 10%, which showed that hitting the 10% BCR-ABL level landmark was a highly significant predictor of treatment failure. That study, reported at the 2010 ASH Annual Meeting (Abstract 360), concluded early assessment of molecular response after three months of imatinib allows identification of a patient cohort with an increased risk of treatment failure and disease progression.
“In general,” Shah summed up, “the deeper the response to imatinib, the better the outcome for the patient.”
NCCN CML Guidelines Update in Brief
- “Failure” on imatinib and cause for change of therapy is:
- At three months, greater than 10% BCR-ABL transcript level (International Scale) or less than partial cytogenetic response; and
- At 12 months, lack of complete cytogenetic response (0% Ph+ bone marrow metaphases).
- At 18 months, regardless of which TKI the patient had started on or been switched to, less than complete cytogenetic response is defined as failure—the guidelines recommend switching to an alternate second-generation TKI.
- There is no longer a six-month intervention time point.
- When “failure” is recognized, as defined above:
- Patients should be evaluated for patient compliance and drug interactions.
- Mutational analysis should be considered.
- If prior therapy has been imatinib, switching to dasatinib or nilotinib is recommended (rather than continuation or escalation of imatinib). And, if prior therapy is either dasatinib or nilotinib, the alternative agent is recommended.
- Patients should be evaluated for allogeneic hematopoietic stem cell transplant, depending on response to TKI therapy, and also considered for participation in clinical trials.
- Patients who meet the ELN criteria for suboptimal response at six and 12 months—minor cytogenetic response at six months and partial cytogenetic response at 12 months—should be monitored closely, and may benefit from alternate treatment options, although the Guidelines make no specific treatment recommendation.