Carlson, Robert H.
NEW YORK—Outcomes for patients with chronic myeloid leukemia in chronic phase (CML-CP) have improved dramatically since the introduction of imatinib and the start of the era of targeted therapy for CML. The challenge now, says Harry Erba, MD, PhD, Professor of Medicine and Director of the University of Alabama at Birmingham's Hematologic Malignancy Program, is to improve on the overall survival rate of approximately 95 percent.
“I doubt there's going to be a trial large enough to actually show a statistically significant benefit of some other therapy over what we use now,” he said here at the International Congress on Hematologic Malignancies.
But improvements might be made if surrogate molecular markers of early response could predict which patients are going to enjoy a longer progression-free and overall survival, and which might require early intervention.
Erba addressed what is now known about using the BCR-Abl marker.
It is apparent that failure to achieve BCR-Abl levels of less than 10 percent at three months after initiation of imatinib is associated with inferior overall survival in CML-CP patients in multiple studies, he noted.
The first reference he cited was a study of 282 patients treated with imatinib at Hammerhill Hospital in London between 2000 and 2010 (Marin et al: JCO 2012;30:232-238). In that study, analysis of BCR-Abl transcript levels to predict overall survival showed optimal cutoff points of 9.84 percent at three months, 1.67 percent at six months, and 0.53 percent at 12 months. Patients with higher levels had significantly lower probabilities of eight-year survival, with the three-month mark being the strongest predictor.
The authors concluded that a single measurement of BCR-Abl transcripts performed at three months is the best way to identify patients destined to fare poorly, thereby allowing early clinical intervention.
Another study (Neelankatan P et al. Blood. 2013 Apr 4;121(14):2739-42), also from the U.K., asked whether the prognostic value of the three-month transcript level for patients treated with imatinib or dasatinib could be improved by combining the three- and six-month results.
The combined results did not improve the prognostic value, Erba said. The study showed that patients who met the three-month landmark but not the six-month one had outcomes identical to those of patients who met both landmarks, whereas patients who met the second but not the first one had prognoses similar to those who did not meet both landmarks.
The authors concluded that “early intervention strategies can be based robustly just on the transcript level at three months.”
Having a BCR-Abl ratio of more than 10 percent is a poor risk category, but not all patients with a high ratio at three months have a high ongoing risk of treatment failure. “Any reduction below 10 percent at six months may improve outcome,” Erba said, citing a study presented at the 2013 American Society of Hematology Annual Meeting by Susan Branford (Abstract 254).
Nevertheless, patients with a ratio greater than 10 percent at both three and six months have inferior outcomes and are undoubtedly in need of a therapy change, he said.
That study also suggested that the rate of reduction over the first three months is an important factor for outcome and could be considered in therapeutic decisions.
Erba said the National Comprehensive Cancer Network CML Practice Guidelines for patients with a BCR-Abl ratio of above 10 percent at three months offer what is probably the most important advice for clinicians:
- Assess for compliance: Consider barriers in drug scheduling, adverse events, and patient finances;
- Assess for drug-drug interactions: Erba said all five of the tyrosine-kinase inhibitors (TKIs) for CML are metabolized by the CYP 3A4 enzyme and their efficacy reduced, so discontinue CYP 3A4 inducers if possible, or consider TKI dose escalations;
- Assess for Abl kinase domain mutation;
- Consider a clinical trial (“I know, the NCCN always says this,” Erba interjected);
- Increase the imatinib dose;
- Evaluate for allogeneic hematopoetic stem cell transplant, depending on response;
- Assess for interference with the oral absorption of the TKIs: “Second-generation TKIs in particular are more poorly absorbed in a gastric pH that is higher, so consider proton pump inhibitors, H2 blockers, or antacids,” he said. “And patients who have had gastrectomies or gastric bypass may need an increased TKI dose”;
- Switch to an alternative TKI.
On this last point, Erba noted that the Australasian Leukemia Study Group TIDEL II trial, reported at the 2012 ASH Annual Meeting (Yeung et al, Abstract 3771) found that an early switch to nilotinib does not overcome the adverse outcome for CML patients failing to achieve molecular responses on imatinib.
HARRY ERBA, MD, PHD
Erba also questioned why the NCCN does not recommend increasing the dose of the current TKI, because there are data of higher doses of dasatinib and nilotinib in resisting patients: “I still question whether we have the right dose of nilotinib as first-line therapy for our CML patients,” he said.
Summarizing his presentation, Erba said:
- The risk of progression is greatest during initial therapy, in the first three years with a TKI;
- Identification of CML-CP patients at greatest risk of progression at initial presentation has not been possible;
- Changing to alternative therapy for early molecular-response failure has not yet been shown to change outcome for these patients; and
- Second-generation Abl TKIs are associated with higher rates of molecular response at three months and lower rates of progression compared with imatinib. “My question is not so much what to do with the patient on imatinib who is not hitting the milestone at three months, but rather, what is the best choice for a patient as initial therapy if our goal is to prevent progression to accelerated phase.”
To that, Erba added that he was “horribly conflicted” about his “intentionally provocative” lecture because he is a consultant for Novartis (maker of imatinib), but “this is how I feel.”