Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial Francois-Xavier Mahon, Delphine Rea, Joelle Guilhot, Francois Guilhot, Francoise Huguet, Franck Nicolini, Laurence Legros, Aude Charbonnier, Agnes Guerci, Bruno Varet, Gabriel Etienne, Josy Reiff ers, Philippe Rousselot, on behalf of the Intergroupe Francais des Leucemies Myeloides Chroniques (FILMC) Lancet Oncol 2010; 11: 1029–35 R1 이치훈 / Prof. 어완규

Introduction Imatinib  standard of care for CML  Induces durable responses and prolongs event-free survival and progression-free Survival current practice  to continue treatment indefinitely  ability of imatinib to eradicate the CML clone is uncertain Aim  to assess persistence of CMR after discontinuation of imatinib  to establish the factors that could be associated with CMR persistence

Methods-Patients Inclusion criteria (19 participating institutions in France)  18 years and older  Confirmed diagnosis of CML in chronic or accelerated phase  Treated with ongoing imatinib at any dose for at least 3 years  sustained CMR for at least 2 years  Philadelphia chromosome : 100% of bone-marrow cells  autologous transplantation or interferon α, imatinib in combination with interferon α, pegylated interferon α, or cytarabine was allowed. Exclusion criteria  immunomodulatory treatments (exception of interferon α)  other malignancies  previous allogeneic haemopoietic stem-cell transplantation

Procedures Sustained CMR  remission lasting more than 2 consecutive years and confirmed with five datapoints of BCR–ABL analyses by quantitative RT-PCR during these 2 years molecular biology follow-up  quantification of BCR–ABL transcripts with quantitative RT-PCR  from peripheral blood every month in the first year / every 2 months after 1 year every 3 months after 2 years Molecular relapse  positivity of BCR–ABL transcripts with a ratio of BCR–ABL to ABL of 10– ⁵ or more  increase in relation at two successive assessments In cases of molecular relapse  recommended to reintroduce imatinib treatment

Statistical analysis Time to molecular relapse relapse-free survival with the Kaplan-Meier method as potential prognostic factors  age, sex, Sokal risk group, previous interf eron α therapy, time from CML diagnosis to initiation of imatinib treatment, duration of imatinib therapy, time to CMR, and CMR duration until discontinuation of imatinib

Results 54 46

molecular relapse : 42 patients, mostly within 6 months molecular relapse-free survival : 41% (95% CI 29–52) at 1 year 38% (27–50) at 2 years 42 pts-rise in BCR–ABL transcripts of 1 log per month Two patients- decreasing levels of BCR–ABL transcripts at the time of second analysis ( fluctuating level)  CMR

the probability of a sustained CMR at 12 months did not diff er between patients with previous interferon α treatment (56%) and patients with imatinib(66%) as initial treatment.

Highest Sokal score group and female sex : predictive of worsened prognosis, Long duration of imatinib : predictive of improved prognosis

Results All in molecular relapse  imatinib 400 mg daily for 1–2 months after confirmation of molecular relapse. All patients remained sensitive:  16 of 42 patients who relapsed showed decreases in their BCR–ABL levels  26 achieved CMR A median time of 3 months (range 1–5) was necessary for CMR to recur. No event such as loss of haematological response or progression to advanced phase was noted. The absence of development of mutant BCR–ABL phenotypes was probably because of the very low level of BCR–ABL at the time of molecular relapse and the rapidity to treatment rechallenge.

Discussion 39% of patients remained in CMR after discontinuation of imatinib at 12 months, the probability of persistent CMR at 12 months was 41% (95% CI 29–52) Imatinib is capable of long- term disease control in patients with CML, but up to now treatment has needed to be continued for an indefinite time.

Discussion In this trial, patients who had a molecular relapse after discontinuation retained sensitivity to the drug, suggesting that discontinuation does not lead to acquired resistance to imatinib and does not raise any further safety issues. However, sustained deep molecular remission : infrequent  candidates are rare. However, CMR and the depth of molecular response to imatinib increase with time.

Discussion Duration of responses, especially CMR, is of major importance in planning imatinib discontinuation strategies Most molecular relapses were rapid.  35 of 42 relapses in the 69 (>1 year f/u) occurred within 3 months.  relapses arise from residual leukaemic cells with a fast kinetic of proliferation (1 log per month) which is very similar to a mathematical model reported previously  important information about optimal molecular monitoring schedules in tyrosine kinase-inhibitor discontinuation strategies

Discussion However, strikingly heterogeneous kinetics for the molecular relapses  A third of relapses did not follow logarithmic kinetics, and in less than 5% of patients the BCR–ABL transcript detection did not lead to a progression of the leukaemic burden. (fluctuating molecular relapse) Sokal score, sex, and length of imatinib treatment : key predictive factors  need to be confirmed, Sokal score suggest a signature of aggressiveness Imatinib has a substantial duration of treatment effect.  Postulation : in the long term, imatinib might induce a type of leukaemic stem cell exhaustion

Discussion How to make sure that eradication has been achieved  Improvement of the sensitivity of leukaemic cell detection  examination of bone-marrow cells or bone-marrow CD34+ cells with more sensitive PCR technology some patients with CML could be cured with tyrosine kinase-inhibitor treatment alone Study in progress  second-generation tyrosine kinase inhibitors  cohort of patients, only treated with imatinib  plan to treat molecular relapse after imatinib discontinuation by second-generation tyrosine kinase inhibitors

Conclusion imatinib can be safely stopped, a stable CMR has been obtained low Sokal score, male sex, and imatinib treatment duration  Factors predictive of CMR maintenance after imatinib withdrawal Sustained CMR will become the next molecular endpoint in future trials. In the meantime, tyrosine kinase-inhibitor therapy should be discontinued only in the context of an ongoing clinical trial.