Discontinuation Of Dasatinib In Patients With CML Who Have Maintained Complete Molecular Response For At Least One Year: Results From a Prospective Discontinuation (DADI) Trial

It has been proposed that imatinib can be discontinued without molecular relapse at least in some CML patients. But little is known about whether the assumption could be exploitable for the second-generation ABL-tyrosine kinase inhibitors. Here we conducted a prospective, multicenter clinical trial to assess whether dasatinib can be discontinued without occurrence of molecular relapse in CML patients in complete molecular response (CMR).

In our Dasatinib Discontinuation (DADI) trial (Japan Primary Registries Network #UMIN000005130, http://rctportal.niph.go.jp/), main eligibility criteria for pre-registration were; CML patients in chronic phase, 15 years and older, undergoing dasatinib treatment used as a second-line therapy after confirmation of resistance or intolerance to imatinib treatment. Previous treatments with interferon-α (IFN-α) or nilotinib were allowed. In this trial, CMR was defined as “No detectable BCR-ABL transcript determined by international scale (IS)-based RQ-PCR at a single central laboratory (BML Inc., Tokyo, Japan, which obtains conversion factor (CF) 0.87).” Patients in CMR status confirmed by RQ-PCR at the central laboratory were pre-registered before the full enrollment for the discontinuation. The pre-registration period was between April 1, 2011, and March 31, 2012. The levels of BCR-ABL transcripts were monitored every 3 months throughout the pre-registration period during the dasatinib treatment. Patients with sustained CMR for one-year duration were then enrolled for the dasatinib-discontinuation stage. In order to detect molecular relapse after the dasatinib-discontinuation, RQ-PCR was performed monthly for the first 12 months, and then every 3 months for the subsequent follow-up. Molecular relapse was defined as positivity of BCR-ABL transcript by RQ-PCR even at one analysis point. Dasatinib was immediately reintroduced in patients who showed molecular relapse during the discontinuation period. After the relapse, RQ-PCR monitoring was performed 1 month, 3 months, 6 months, and 12 months after the reintroduction of dasatinib. Primary endpoint of this study was “Molecular relapse-free survival (MoRFS) rate at 6 months after discontinuation of dasatinib.” Total follow-up duration was set to be 36 months after the discontinuation. In addition to the molecular assessment of the BCR-ABL transcript level, increase of large granular lymphocytes (LGL) in the peripheral blood, in combination with flow cytometry analysis, was also investigated.

In total, 88 patients were pre-registered at 41 participating institutions in Japan. Among them, a total of 63 patients who maintained stable CMR for one year after pre-registration were enrolled for the dasatinib-discontinuation stage. All of these 63 patients (42 male, 21 female) had been treated with imatinib before the start of the dasatinib treatments. Among these 63, 14 were imatinib-resistant, and 35 were imatinib-intolerant. Other previous treatments were; IFN-α (n=12), nilotinib (n=4), IFN-α and nilotinib (n=1). Median age was 59.5 years (range 24-84). Sokal scores were; low 70%, intermediate 15%, and high 15%. In this interim analysis with a data cut-off date of 31 July 2013, 27 patients out of 88 pre-registered patients were over the observation period of 6 months after the dasatinib-discontinuation. Among 27, 12 patients achieved 6 months-sustained CMR after dasatinib-discontinuation. The estimated MoRFS at 6 months determined by Kaplan-Meier method was 44 % (95%CI 26-62). Reintroduction of dasatinib to the relapsed patients showed rapid molecular responses in all of them. Among the 15 patients who lost CMR after dasatinib-discontinuation, 13 patients were available for the evaluation of reintroduction to CMR. 12 out of 13 patients (92%) returned to CMR again within 3 months (7 patients at 1 month, and 5 patients at 3 months) after the reintroduction, and all these patients have sustained CMR up to now. The remaining one patient out of 13 also showed a marked reduction of the BCR-ABL transcript level at 3 months.

Dasatinib could be safely discontinued in a proportion of CML patients with stable CMR for at least one year, provided that frequent molecular monitoring is performed. Patients who lost CMR after dasatinib-discontinuation still maintained good sensitivity to the reintroduction of dasatinib.

Nakamae:Novartis: Honoraria, Speakers Bureau, Travel/accommodations/meeting expenses, Travel/accommodations/meeting expenses Other; BMS.: Consultancy, Honoraria, Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses Other. Hino:Chugai Pharma: Honoraria, Research Funding, Travel/accommodations/meeting expenses Other. Kimura:Bristol-Myers: Honoraria, Research Funding.