Cumulative Incidence of Treatment-Free Remission (TFR) for Patients with Chronic Myeloid Leukemia (CML): The Adelaide Experience

Background:

For patients (pts) meeting specific clinical criteria, a trial of tyrosine kinase inhibitor (TKI) cessation is a safe option if regular quantitative RT-PCR (qRT-PCR) monitoring is performed and TKI is promptly recommenced in the event of molecular relapse [Mahon, Lancet Oncology 2010; Ross, Blood 2013]. With expert opinions incorporating TKI cessation into global guidelines such as the National Comprehensive Cancer Network and an increasing number of clinical trials demonstrating its success with both first and second-generation agents, treatment-free remission (TFR) is steadily being adopted into mainstream practice.

Aim:

To determine the proportion of pts becoming eligible and achieving a TFR attempt in a single academic centre.

Patients and Methods:

Adult pts receiving their primary CML management at the Royal Adelaide Hospital were included. We excluded pts referred specifically for clinical trials, transplantation, second opinions, and those with incomplete data. Clinical and molecular data from the period January 2008 to July 2017 were analysed. Specific TKI therapy was not mandated. Minimum criteria for qualifying for a TFR attempt were ≥3 years of TKI therapy and ≥2 years of sustained deep molecular response (DMR, BCR-ABL1 <0.0032% IS; MR4.5), similar to the TWISTER study. History of blast crisis, atypical BCR-ABL1 transcripts and development of T315I mutation precluded TFR qualification. Pts were censored at the time of allogeneic stem cell transplantation. TKI cessation due to toxicity or pregnancy was not classified as a TFR attempt. Monthly BCR-ABL1 qRT-PCR was instituted for all pts embarking on a trial of cessation for a minimum of 12 months. Molecular relapse was defined as loss of major molecular response (MMR) as per current recommendations (single BCR-ABL1 value ≥0.1% IS), except in 20 pts enrolled in the TWISTER trial, where restart criteria was presence of detectable rising BCR-ABL1 levels in 2 consecutive tests. In the event of molecular relapse, TKI recommencement occurred. Durable TFR was defined as no molecular relapse ≥12 months after TKI cessation.

Results:

A total of 245 pts were included in our analysis with a median follow-up of 6 yrs (0.2-19.2 yrs). Forty-seven pts will never qualify for TFR by our institution criteria due to death, allogeneic stem cell transplantation, loss to follow up, development of a T315I mutation and presence of atypical BCR-ABL1 transcripts. In total, 103 pts became eligible for a TFR attempt with an increasing proportion of pts becoming eligible for TFR with longer duration of TKI exposure (Table 1, Figure 1), from 16% at 4 yrs compared to 61% at 14 yrs. Eighty-two pts (80% of eligible pts) attempted TFR. The median age at TFR attempt was 61 yrs (range 34-89 yrs) and 55% (n=45) were male. The proportion of pts attempting TFR rose with longer duration of TKI exposure from 3% at 4 yrs compared with 53% at 14 yrs. The median duration of TKI treatment prior to TFR was 7.45 yrs (range 3-15.7 yrs) and the median duration of MR4.5 prior to TKI cessation was 2.8 yrs (range 2-9.9 yrs). The TKI at the time of the first TFR attempt in decreasing order of frequency was imatinib (n=53, 65%); nilotinib (n=18, 22%), dasatinib (n=10, 12%) and bosutinib (n=1, 1%). Durable TFR was achieved in 33 pts (40%) on the first attempt with a minimum follow-up of 12 months; 10 pts have <12 months follow-up. Cumulative incidence of TFR attempts and durable TFR were 53% and 31% respectively by 14 years. Achievement of durable TFR had a higher likelihood of success with longer duration of TKI exposure (see Table 1). Molecular relapse occurred in 39 pts, 9 of whom underwent a second TFR attempt after a median interval of 5.6 yrs (0.3-9.7 yrs). One patient had a third TFR attempt.

Conclusion:

TFR in published literature is achieved in 40-50% of cessation attempts for pts who meet the qualification criteria and these figures are in line with our real-world experience. Many pts (40%) ceased TKI outside of a clinical trial with close medical supervision and monthly PCR monitoring to ensure timely TKI recommencement if TFR failure occurred. Duration of TKI exposure correlated with TFR success which is comparative to recent data presented by the EUROSKI study. With longer follow-up, the availability of second generation TKIs for pts not achieving DMR on imatinib and the potential role of second and third attempts at TFR, we have observed a steady increase in eligibility for TFR, TFR attempts and durable TFR.

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