NEW YORK (Reuters Health) – Treatment-free remission (TFR) seems to be feasible for patients with chronic myeloid leukemia (CML) who achieve a sustained deep molecular response (DMR) after discontinuing second-line nilotinib, researchers suggest.
“The first-in-class tyrosine kinase inhibitor (TKI) imatinib opened the era of targeted therapy and dramatically improved overall survival in CML patients,” Dr. Vasily Shuvaev of the Russian Research Institute of Hematology and Transfusiology in Saint Petersburg, Russia, told Reuters Health.
After U.S. Food and Drug Administration approval of imatinib in 2001, Dr. Shuvaev said by email, “the 10-year overall survival for CML increased from 17%-47% to 83%.”
“However,” he added, “the euphoria from those results subsequently were slightly diminished by the fact that only about half of patients could tolerate the treatment and achieve stable cytogenetic and molecular responses.”
This led to the development of second- and third- generation TKIs, he said, “and now the current standard of CML management is continuous TKI treatment.”
Monthly TKI therapy costs in the U.S. vary from $2,700 for imatinib to $5,300 for ponatinib, $11,000 for bosutinib and $130,00 for nilotinib and dasatinib, according to Dr. Shuvaev. “All of these led to an avalanche-like increment of financial budget burden.”
This prompted efforts to explore TKI cessation in CML patients with long-lasting DMRs.
Most previous studies of TFR looked at imatinib, he noted. “The current study is the first large, prospective trial evaluating TFR in patients who achieved sustained DMR only after switching from imatinib to nilotinib; the primary objective was to determine the TFR rate at 48 weeks after stopping treatment in this patient population.”
Dr. Shuvaev and colleagues enrolled 163 CML patients in the chronic phase. All had received TKI therapy for at least three years (more than 4 weeks with imatinib, then at least two years with nilotinib) and had achieved MR4.5 on the International BCR-ABL1IS scale – indicating a major cytogenic response to treatment – while receiving nilotinib. Those patients entered a one-year consolidation phase, during which they received nilotinib.
Patients with sustained MR4.5 during consolidation were eligible to stop treatment. Those who did not sustain a major molecular response during TFR reinitiated nilotinib treatment.
As reported online February 19 in Annals of Internal Medicine, 126 of the 163 patients in the consolidation phase were eligible for the TFR phase. Of those, 73 (58%) maintained TFR at 48 weeks and 67 (53%), at 96 weeks.
Of the 56 patients who reinitiated nilotinib therapy, 52 regained MR4.5.
No participants progressed to the accelerated phase or to a blast crisis. Musculoskeletal pain was more frequent during the first 48 weeks after nilotinib discontinuation (42%) than during consolidation (14%).
Dr. Shuvaev noted, “The genesis of this adverse event is still unknown,” but may be due to rebound syndrome that results in a cytokine imbalance.
“The rate of musculoskeletal pain decreased to 15% in the second year of TFR,” he added.
Principal author Dr. Timothy Hughes of the South Australian Health and Medical Research Institute in Adelaide, told Reuters Health, “The practical implication for clinicians is that CML patients who have achieved a DMR only after switching to the more potent TKI nilotinib can now be considered potentially eligible for a TFR attempt, as long as they fulfill the prerequisites that are outlined in the nilotinib label.”
“We didn’t see a difference in the TFR success rate in the group who had switched because of a poor response to imatinib,” he said by email. “This is a group where more caution should be applied, since several other studies have found a lower rate of success in this setting,” he added.
Dr. Jerald Radich, of the Fred Hutchinson Cancer Research Center in Seattle and chair of the National Comprehensive Cancer Network CML Guidelines Committee, has been involved in several CML trials of nilotinib.
Reuters Health asked if the therapy is better than other currently available treatments.
“Depends on how you look at it,” he said by email. “It is clearly better than the first-generation drug, imatinib, but there are no clear long-term survival differences.”
“It is better at getting deeper responses,” he said, “and thus probably is a better choice if you want to explore possible discontinuation of the drug.”
However, he added, “nilotinib has more cardiovascular complications than imatinib” and, as noted by Dr. Shuvaev, “it is more expensive than generic imatinib.”
The study was primarily funded by Novartis, which employed two coauthors during the conduct of the study. Dr. Hughes and seven coauthors report receiving fees from the company.
SOURCE: http://bit.ly/2CzEPfq
Ann Intern Med 2018.
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