Σάββατο, 10 Δεκεμβρίου 2016

CUTTING DRUG DOSE IN CML?

SAN DIEGO — Some patients with chronic myeloid leukemia (CML) may be able to safely cut the dose of tyrosine kinase inhibitors (TKIs) in half and lower the rate of adverse effects without risking a relapse of disease, according to new findings.
"Of 174 patients in the trial, 93% of patients on half dose therapy showed no evidence of leukemia recurrence within 12 months," said study author Mhairi Copland, MD, PhD, from the Institute of Cancer Sciences, University of Glasgow, United Kingdom.
There were 12 molecular recurrences, she said, and all patients regained a remission level of MR3 or better within 4 months of resuming a full TKI dose.
These results, from the British De-Escalation and Stopping Treatment of Imatinib, Nilotinib or sprYcel (DESTINY) study, were presented here at the American Society of Hematology (ASH) 2016 Annual Meeting (abstract 938).
In this study, Dr Copland and colleagues sought to answer several questions. One was whether some patients with enduring good responses to modern TKI treatment can stop therapy.
She noted that although several studies report that 50% to 60% can do so, all the research is restricted to patients who have achieved a deep molecular response (less than molecular response 4 [MR4]).
The second question in the current study was: If patients with MR3 cannot stop therapy, can they lower the dose and reduce the incidence of adverse effects they may be experiencing?
Reduction Successful for Most
In the DESTINY study, patients in at least stable MR3 initially first decreased their TKI to half the standard dose for 12 months and then followed that by complete cessation.
The key requirements for inclusion into the trial were being in the first chronic phase of CML, receiving the same TKI since original diagnosis (one switch was permissible, if it was for intolerance to the initial drug), continuing to receive the TKI for at least 3 years, and having all polymerase chain reaction tests in the last 12 months showing at least MR3 (minimum of three tests, each with >10,000 ABL control transcripts).
At baseline, 148 patients were receiving imatinib (Gleevec, Novartis), 16 were receiving nilotinib (Tasigna, Novartis), and 10 were receiving dasatinib (Sprycel, Bristol-Myers Squibb). After 12 months of receiving half-dose therapy (imatinib 200 mg daily, nilotinib 200 mg twice daily, or dasatinib 50 mg daily), molecular recurrence was lower in patients with stable MR4 at baseline (three of 125 patients; 2.4%) compared with those with MR3 (nine of 49 patients; 18.4%; P < .001).
The authors found that median time to relapse was shorter among patients in the sustained MR3 group compared with those with sustained MR4 at entry (4.4 vs 8.7 months).
The probability of molecular recurrence on deescalation was not related to patient characteristics such as age, sex, performance status, prior TKI (imatinib vs second generation), or the duration of TKI therapy (median, 7.0 years overall).
All 12 patients who had a molecular recurrence were able to regain MR3 status within 4 months of resuming a full-dose TKI.
During the first 3 months of deescalation, the number of patient-reported common TKI adverse effects decreased, but it tapered off after that.
An interesting development, note the authors, was that 53 new musculoskeletal symptoms, which were typically mild and transient, were reported by 36 patients (21%).
There were also financial implications for halving the dose, Dr Copland explained.
"For all 174 patients, halving treatment saves £1,943,364 from an expected TKI budget of £4,156,969," she said. "This is a 46.7% saving."
In the MR4 group alone, the saving was £1,429,330 from an expected budget of £2,993,854 (47.7%), and in the major molecular response group alone, the saving was £514,034 from an expected budget of £1,163,115 (44.2%).
An Option for Some Patients
Commenting on the paper, Robert Hromas, MD, professor and chair, Department of Medicine, University of Florida/Shands Health Care System, Gainesville, noted that that dose reduction could be an option for some patients with CML.
"When the dose was reduced, there were 18% who relapsed, but they went back to a deep molecular remission when they were returned to full dose," he said in an interview.
There are some patients who have trouble tolerating TKIs, Dr Hromas noted. "And for these patients, you can reduce the adverse effects by cutting the dose, and this can work well for them," he said. "These are also expensive drugs, even for people who have insurance."
Dr Hromas also emphasized that none of the patients experienced any complications or showed any resistance to the drugs. "They went back to where they were once the higher dose was restarted, and back into a deep molecular remission."
The study was funded by Newcastle University, from general funding for UK CML trials. Dr Copland reported receiving honoraria from Novartis, Amgen, Pfizer, Shire, Bristol Myers Squibb, and ARIAD. Several coauthors also have disclosures, as noted in the abstract.
American Society of Hematology (ASH) 2016 Annual Meeting. Abstract 938. Presented December 5, 2016.

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