For patients with newly diagnosed chronic myeloid leukemia (CML), aggressive dose escalation of imatinib failed to improve response and survival rates compared with a standard dose escalation following European LeukemiaNet (ELN) guidelines, according to results from a phase III study published in Blood Advances. However, the researchers identified a subset of younger patients who may benefit from aggressive dose escalation if they have tolerated imatinib well.
Because up to 20 percent of patients with CML have disease that is resistant to imatinib at the standard 400-mg dose, dose-escalation guidelines for patients with suboptimal responses have been published. With this prospective randomized study, Koichi Miyamura, MD, of the Japanese Red Cross Nagoya First Hospital and colleagues evaluated whether using more sensitive assessments of clinical response than those outlined in the ELN criteria could improve outcomes for patients taking imatinib. (For expert commentary on the findings of this paper, see Perspectives at the end of this article.)
The trial included 245 patients with previously untreated Philadelphia chromosome (Ph)–positive chronic-phase CML. All participants had adequate liver and kidney function, normal heart and lung function, and an Eastern Cooperative Oncology Group performance status of 0 to 3.
Patients began treatment with imatinib 400 mg/day and were randomized to one of two dose-escalation strategies based on measurements of response at three and six months:
- In group A, dose escalation was performed according to ELN criteria: Imatinib dose was increased from 400 mg to 600 mg if a patient did not achieve complete hematologic response within 3 months or a partial cytogenetic response (PCyR) within 6 months of treatment initiation (n=122)
- In group B, imatinib dose was increased from 400 mg to 600 mg if a patient did not achieve a complete cytogenetic response (CCyR) within 3 months or a major molecular response (MMR) within 6 months of treatment initiation (n=123).
Cytogenetic responses were evaluated by G banding of ≥20 marrow cells in metaphase; CCyR was defined as no Ph-positive cells, and PCyR was defined as 1 to 35 percent Ph-positive cells. Molecular responses were measured by reverse-transcription real-time quantitative polymerase chain reaction. MMR was achieved when <100 BCR-ABL mRNA copies were detected per 1 mg of RNA, corresponding to a 3-log reduction from the standardized baseline.
In the first year of treatment, several patients in each group required dose reductions or discontinuations of imatinib 400 mg (31 in group A and 19 in group B), leading to median dose intensities of 375.1 mg/day in group A and 424.2 mg/day in group B (ranges not reported).
At six months post-treatment initiation, there was trend in cytogenetic response that favored aggressive dose escalation (78.7% vs. 69.4%; p=0.09), the authors reported. However, at 12 months, the CCyR rate was comparable between both groups (81.8% for group A vs. 84.3% for group B; p value not reported).
Rates of MMR at 12 months and 24 months (the study’s primary and secondary endpoints) also were similar between groups A and B:
- 12-month MMR: 52.1% vs. 58.7% (p=0.3)
- 24-month MMR: 70% vs. 68.3% (p value not reported)
Per study protocol, 56 patients in group B were intended to increase their dose to 600 mg at three months because they did not achieve CCyR; however, only 28 of these patients (50%) increased their dose. The 65 patients who achieved CCyR maintained their dose through assessment at six months, when 34 patients were intended to increase their dose because they did not achieve MMR. Again, only half of patients (n=17) underwent a dose increase. (Two patients did not receive a molecular response test.)
“In contrast, in group A, only four and six patients failed to increase the dose at three and six months, respectively,” the researchers reported.
Dose-escalation strategy did not appear to affect survival outcomes: The three-year overall survival rate was high and similar between groups A and B (99.3% vs. 97.4%; p value not reported), with no difference observed between groups for three-year progression-free survival (PFS; 89.1% vs. 94.2%; p=0.17; median follow-up not provided).
The primary reason for maintaining a 400-mg dose was adverse events (AEs), with a higher incidence of grade 3/4 lymphocytopenia and anemia in group B than group A (11 vs. 6 and 9 vs. 3, respectively). “However, in this study, the incidence of non-hematologic AEs was equivalent in both groups, and the aggressive dose-escalation group did not show a higher frequency of withdrawal due to drug toxicity, compared with the standard dose-escalation group (21% and 20%, respectively),” Dr. Miyamura commented.
They also observed that the dose-escalation protocol in group B was associated with higher rates of molecular response: “Among the 42 patients who received increased dose according to the protocol, 25 (60%) achieved MMR at 12 months, whereas only 14 of 40 patients (35%) who did not receive an increased dose achieved MMR (p<0.05).”
Based on these findings, the authors proposed that, although “the early aggressive dose escalation failed to produce a better molecular response at 12 months, … for patients who tolerate imatinib well but show inadequate response at an early time point, aggressive dose escalation may contribute to achieving a better outcome.”
Dr. Miyamura also noted that certain patients would benefit from switching to another medication, rather than increasing imatinib dose, and that the findings from this study could aid clinicians in identifying those patients. “Before making changes to other medicines, dose escalation at an early stage could confirm whether the drug currently being used has reached the optimal individual concentration,” he said. “The strategy of starting imatinib at 400 mg, carefully observing disease response and AEs, and increasing imatinib to 600 mg in patients who do not have a major response (CCyR at 3 months and MMR at 6 months) is an effective means of finding this concentration.”
During the study, only half of the patients completed dose-escalation per study protocol, which the authors noted may limit the implications of these findings.
The authors report relationships with Novartis, the manufacturer of imatinib.
“While this study suggests that an aggressive escalation in imatinib dose may offer a modest benefit for improving rates of MMR at 12 months in patients with CML, this subtle trend evaporated by 24 months and did not translate into a difference in PFS – which was excellent for both groups. According to the analysis, a starting dose of imatinib 400 mg may be appropriate in most patients and following standard ELN escalation recommendations is sufficient for achieving long-term PFS. For a subset of younger patients who are tolerating imatinib well, the as-treated analysis within this study suggests that aggressive dose escalation may shorten the time to achieving an MMR. This finding may have implications for successfully stopping tyrosine kinase inhibitor therapy in the future.”
Alexandra Stevens MD, PhD
Baylor College of Medicine
Texas Children’s Hospital