Ulysses Road to Ithaca! MR4.5 at 24 Months Predicts Treatment Free Remission and Survival
Authors: Singh Aakanksha , Agrawal Narendra , Ahmed Rayaz , Bhurani Dinesh , Singh Reema , Raychaudhuri Jyotishankar 
Published: December 2024

Cure or TFR for CML remains cherished milestone and ideal patient selection still remains elusive. In the present study, we aimed to evaluate if response milestones and kinetics impacted TFR & TFS (survival). Method: Single center retrospective study at RGCIRC, New Delhi and accessed medical records from January 2005 till June 2024. Included CML CP/AP patients (&gt;18 years) receiving first or second-line treatment (due to toxicity) for minimum 3 years that achieved sustained DMR (MR4.5 for 2 years), confirmed by qPCR within 4 months interval. TKi dose was reduced by 25% every 6 months (de-escalation phase). MMR loss (relapse) triggered treatment reintroduction at same dose. Cut-off date for analysis- June 29, 2024. Results: Our study included 87 patients followed up for median duration- 119 months (range 62 to 238). Sokal score was evenly distributed, low risk- 57.4% vs advanced risk - 42.6%; whereas ELTS had skewed distribution low risk- 72.4%, advanced risk- 27.6%. Of 87 patients, 85 were in chronic phase and 2 in accelerated phase. 77% were treated- Imatinib, 5.7% Dasatinib and 17.2% Nilotinib. 14.9% were shifted to second line TKi due to tolerance issues. 6 of 87 patients experienced TKi interruption were treated with IFN-alpha, 5/6 had sTFR (successful TFR). 50/87 (57.4%) patients experienced sTFR. Cumulative median TKi exposure in sTFR was 119 months and failed TFR (fTFR)- 127 months, p value- 0.85. Median MMR duration for sTFR- 90 months, fTFR- 100 months, p value- 0.93. However, median MR4.5 duration for sTFR- 89 months, fTFR- 55 months, p value- 0.05. EMR at 3 months was similar across (sTFR- 90 %, fTFR- 100%, p value- 0.93). Median time to MMR was 16 months- sTFR, 20 months- fTFR, p value- 0.82. Median time to MR4.5 was 20 months in sTFR versus 50.5 months in fTFR, p value- 0.02. Shorter time to achieve MR4.5 (less than 24 months) and longer the duration of MR4.5 favorably prognosticated sTFR on logistical regression. Median TFS in patients who achieved MR4.5 at &lt; 24 months was 68 months (range- 27 to NR) versus &gt;24 months was 32 months (range- 4 to 56), p value- 0.003. Incidence of withdrawal syndrome was 21% (majorly in initial 12 months). Of 37 patients (42.6%) who relapsed post discontinuation, 18 relapsed in 6 months, 12 in 24 months and 7- late, i.e. till 36 months. Discussion: Discontinuation trials like EURO-SKI, TWISTER and STIM1 reported successful TFR in 50-60% patients. A recent trial by Luo J et al, randomized 125 CML patients with MR4.5 over five years in two cohorts: group1- abrupt discontinuation and group2- de-escalation. The relapse free survival was inferior in discontinued group compared to de-escalation group. 57.4% patients in our study did not relapse after discontinuation of TKis, an improvement over 46% reported in the STIM2 trial, which had similar long follow up on Imatinib, could be attributed to slow de-escalation (2 years). Our patients also experienced less withdrawal syndrome (21%) in contrast to the DES CML trial, again due to slow de-escalation. 5/6 patients exposed to IFN- alpha remained in TFR post TKi discontinuation, likely secondary to lymphocyte subset modification, mononuclear cells differentiation into dendritic cells and activation of cytotoxic T cells specifically against CML progenitors. We did not report higher relapse rates in advanced Sokal and ELTS scores, similar to DES-CML study and contrasting to STIM1 trial. Additionally STIM, EURO- SKI & DES CML trial suggested longer TKi exposure and duration of MMR favorably prognosticated TFR. In contrast, we found that neither duration of MMR nor TKi exposure could prognosticate TFR. Both duration of MMR and TKi exposure appeared crude indicators as both lumped patients with sustained deeper responses (&gt;MMR). Prolonged treatment in absence of deep response, in fact reflected disease with low level persistence of TKi resistant CML progenitors/ LSCs and exhausted immune profile, un-modifiable on current TKi therapy. Median time to achievement of MR4.5, i.e. &lt; 24 months and duration of MR4.5 prior to discontinuation prognosticated sTFR and improved TFS, thus indicators of inherently favorable biology. Exquisite TKi sensitivity, modelled on early disease response kinetics ably revealed patients faring well on TFR. Conclusion: Our analysis underpins significance of early response kinetics and deep durable responses in predicating treatment discontinuation. MR4.5 at 24 months- another milestone or writing on the wall?