Most patients (pts) with chronic phase CML treated with tyrosine kinase inhibitors (TKIs) can expect a near-normal life-expectancy, but TKI-related toxicity may cause ongoing morbidity. TKI discontinuation has emerged as a goal for many such pts. The ALLG CML8 study (TWISTER; ACTRN12606000118505) and the French STIM study both began in 2006 and showed that >40% of CML pts with undetectable minimal residual disease (UMRD) for at least 2 years on imatinib (IM) treatment were able to stop IM and remain in stable UMRD. Since then >2000 pts in clinical trials have attempted TFR, but few have reported follow-up of ≥5 years to inform the true durability of TFR. Here we update the outcomes of pts on TWISTER, including ongoing MRD analysis in stable TFR using highly sensitive patient-specific BCR-ABL1 DNA PCR.
Eligible pts had UMRD for ≥2 years and IM treatment for ≥3 years before cessation. Per protocol IM was recommenced if there was detectable BCR-ABL1 mRNA in two consecutive samples at any level. The primary endpoint was molecular relapse-free survival (MRFS) at 2 years. RQ-PCR was performed centrally for at least 2 years from study entry, and in local laboratories thereafter. The current status of pts was updated via a questionnaire sent to all investigators concerning survival and disease response. The rate of MRFS was estimated using the Kaplan-Meier method. Nested DNA PCR was performed in selected Adelaide pts, as previously described (Ross, Leukemia 2010), using primers specific for each patient's genomic BCR-ABL1 fusion sequence. Twenty replicates were performed, each containing 500 ng amplifiable DNA, quantified using GUSB DNA Q-PCR. At low levels of MRD the number of positive replicates and Poisson statistics were used to calculate the BCR-ABL1 copy number.
Forty chronic phase CML pts were enrolled from August 2006 to August 2011. The pt characteristics were previously reported (Ross, Blood 2013). The median follow-up was 96 months (range 35-130 mo). Three pts died after molecular relapse from causes unrelated to CML (myeloma, heart failure, unknown). No pt progressed to advanced phase CML. Invasive cancers were diagnosed in two pts (myeloma, endometrial carcinoma). The latest relapse was at 27 mo, as previously reported. The estimated MRFS rate at 8 years was 45.0% (95% confidence interval 31.9% - 63.4%; Figure 1A).
Nine pts in long term TFR were additionally monitored by BCR-ABL1 DNA PCR for a median follow-up of 8.6 years (range 5.8 - 10.8 years) after study entry (Figure 1B) comprising 158 time points. Six patients had BCR-ABL1 DNA detected in >4 samples from the first year of TFR, enabling more precise quantification. In this subgroup the median level of BCR-ABL1 DNA decreased from 10-5.3 in the first year to 10-6.2 in the latest 3 years of TFR (P<0.0001; Figure 1C).
IM re-treatment was given to 22 pts, all of whom regained UMRD after a median interval of 3 mo (range 0-17 mo). Ten of these pts attempted TFR a second time (TFR2). The median duration of TKI re-treatment prior to TFR2 was 67 mo (range 20-79 mo). Results of the TFR2 attempt are available for 7 pts: 2 pts lost MMR (at 1, 8 mo); 5 pts remained in MMR off treatment (follow-up 13-27 mo) of whom 3 maintained UMRD.
Our results confirm the safety of IM discontinuation and long-term stability of TFR in appropriately selected CML pts with close molecular monitoring. No late relapses or cases of TKI-resistant CML were reported. Around half of pts who experienced molecular relapse have attempted TFR a second time and 5/7 maintained MMR at 12 months after TKI cessation. BCR-ABL1 DNA was detectable in all pts in TFR, in at least one time point. Quantitative results have low precision near the limit of detection, but where we could more accurately measure MRD there was a significant decline from the first 12 months to the last 3 years in all cases analyzed.
Figure 1 (A) Rate of TFR in all 40 patients. Estimate of the rate of MRFS (95% confidence interval indicated by dashed lines) (B) BCR-ABL1 DNA PCR monitoring of MRD in TFR patients. Positive samples are represented in black, and negative samples in white; DNA is represented by triangles and mRNA by circles. (C) Quantitative analysis of BCR-ABL1 DNA during TFR. The first 12 months are compared with the last 3 years in 6 patients in long term TFR.
Shanmuganathan: Novartis: Honoraria, Other: Travel Support; Bristol-Myers Squibb: Honoraria, Other: Travel Support. Mills: Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Specialised Therapeutics: Honoraria. Yeung: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding. White: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Grigg: Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses. Schwarer: Specialised Therapeutics: Honoraria; Amgen: Honoraria; Roche: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Branford: Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Ariad: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Hughes: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Asterisk with author names denotes non-ASH members.