Making Treatment Free Remission “Feasible” in Low- and Middle- Income Countries - Outcomes, Patterns of Failure and Compliance of Treatment Free Remission (TFR) in Chronic Myeloid Leukemia (CML) from a Tertiary Care Cancer Centre in India
Authors: Punatar Sachin , Jindal Nishant , Gokarn Anant , Mirgh Sumeet , Chichra Akanksha , Nayak Lingaraj , Bagal Bhausaheb , Hande Vinod , Chavan Swapnil , Kumbhalwar Komal , Menon Hari , Khattry Navin 
Published: December 2024

Objectives:
Treatment free remission (TFR) is considered to be the new “goal of therapy” in newly diagnosed chronic phase CML in the current era. However, logistics and compliance vary greatly between different regions of the world, which could have an impact on the overall outcomes of TFR in CML-CP. In low- and middle- income countries (LMICs), where logistic challenges abound, applying the ELN or NCCN guidelines for patient selection and monitoring may not be feasible. Using more stringent criteria to select patients (pts) may facilitate TFR with less intense monitoring. The objectives of this study were to ascertain the outcomes, patterns of failure, and compliance issues in a cohort of pts with rigorous selection criteria but a more liberal monitoring schedule. We also evaluated the outcomes of pts who failed TFR.
Methods:
At our institute, we started a structured TFR program in March 2022. This retrospective analysis of a prospectively maintained database included pts who were initiated on TFR from March 2022 till 31st December 2023 with data updated till 30th June 2024. Pts needed to fulfil all of the following criteria to be initiated on TFR - a) 1st chronic phase CML b) always on imatinib 400 mg (or lesser) daily dose c) Minimum duration of therapy 8 years d) p210 transcript e) in continuous MMR for at least 5 years with annual monitoring and f) in MR4 for 3 consecutive years or MR4.5 for 2 consecutive years. The PCR monitoring plan after TFR initiation was as follows - a) 2-monthly during the 1st year b) 3-4 monthly in the 2nd year and c) 6 monthly in the 3rd year and beyond. The primary objective was to determine the molecular relapse free survival (MRFS). Molecular relapse was defined as loss of MMR (confirmed at least twice, 2 to 4 weeks apart). The date of loss of MMR was taken as the date of the 1st sample showing loss of MMR. Pts who died (without molecular relapse) because of unrelated causes were censored on the last date known to be in MMR. We also studied the patterns of relapse and compliance issues. Compliance was determined by the number of PCRs done in the 1st year (in the absence of loss of MMR) or till the time of loss of MMR (in pts who lost MMR), whichever was earlier. Pts with minimum 3 PCRs in the first 6 months and minimum 5 PCRs in the 1st year were considered compliant. For pts who lost MMR, imatinib was reinitiated at 400 mg daily dose. Standard statistical methods were used. The time to molecular relapse was taken from initiation of TFR to date of molecular relapse. Kaplan Meier method was used to calculate MRFS.
Results
Seventy pts were screened for TFR in the above time period, from which 1 patient did not fulfil the inclusion criteria. The remaining 69 pts were initiated on TFR and included in the analysis. The median age was 47 years (range 27 - 78 years) and 49 (71%) were males. The median time from diagnosis of CML to TFR was 13 years (range 8 - 21 years) and the median duration of continuous MMR before TFR was 8.1 years. Two pts who died of unrelated causes and 1 who restarted imatinib because of withdrawal symptoms (without loss of MMR) were censored on the last date of known MMR. With a median follow up time of 9 months, the median MRFS was not reached and 1-year MRFS was 80%. Overall, 13 of 69 pts (19%) failed TFR. Of these 13, 12 failures were in the initial 6 months of start of TFR. Of the 69 pts, 53 were in confirmed MMR at 6 months (12 had lost MMR, 2 died of unrelated causes, 1 restarted imatinib due to withdrawal symptoms and 1 patient had unavailable RQ-PCR). Of these 53, only 1 patient had TFR failure later (i.e beyond 6 months of TFR). Of the entire cohort of 69 pts, 57 (83%) were adequately compliant to PCR monitoring. Of the 12 non-compliant pts, 11 exhibited non-compliance in the initial 6 months of TFR. Of the 13 pts who lost TFR, 12 were restarted on imatinib (1 lost to follow up) with a median time from loss of MMR to restart of imatinib being 60 days. Of these 7 have undergone subsequent PCR testing after TFR failure - 6 of these 7 have attained MMR.
Conclusions:
Using strict criteria to initiate TFR in eligible pts, approximately 80% were able to have a successful TFR. Of the remaining 20% who had TFR failure, the majority (92%) failed in the initial 6 months with very few failures (&lt;2%) happening in those who continued to remain in MMR at 6 months. Most of the pts exhibited adequate compliance to the monitoring schedule. This study suggests that stringent criteria for initiating TFR with less stringent monitoring policy may be the way forward in LMIC countries like ours.