Deeper molecular response is a predictive factor for treatment-free remission after imatinib discontinuation in patients with chronic phase chronic myeloid leukemia: the JALSG-STIM213 study

Abstract

The objective of this prospective clinical trial (JALSG-STIM213, UMIN000011971) was to evaluate treatment-free remission (TFR) rates after discontinuation of imatinib in chronic myeloid leukemia (CML). CML patients who received imatinib treatment for at least 3 years and sustained deep molecular response for at least 2 years were eligible. Molecular recurrence was defined as loss of major molecular response (MMR). Of the 68 eligible patients, 38.2% were women, the median age was 55.0 years, and the median duration of imatinib treatment was 97.5 months. The 12-month TFR rate was 67.6%. Patients who lost MMR were immediately treated with imatinib again; all re-achieved MMR. Three-year treatment-free survival (TFS) was estimated as 64.6% using the Kaplan-Meier method. Undetectable molecular residual disease (UMRD) was defined as no BCR-ABL1 in > 100,000 ABL1 control genes using international scale polymerase chain reaction. UMRD at the study baseline was found to be predictive of continuation of TFR. Our findings suggest that CML patients who meet all the eligibility criteria that have commonly been used in the TFR trials are able to discontinue imatinib use safely. TFR may thus be valuable as a new goal for CML treatment in Japan.

Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: Recommendations for clinical practice from the French Chronic Myeloid Leukemia Study Group

“…In ENESTfreedom, a first‐line nilotinib cessation trial, the lowest TFR rates were observed in patients with a high Sokal score at diagnosis . In contrast, no obvious effect of the Sokal score was found in other trials such as KID, TWISTER, and JALSG‐STIM213 . Thus, we did not include prognostic scores at diagnosis among the selection criteria for TKI discontinuation in clinical practice.…”

“…The question of which level of DMR, namely MR4 or MR4.5, is best for TKI discontinuation is an important one. In JALSG‐STM213, patients in MR4.5 with undetectable BCR‐ABL1 transcripts just before imatinib discontinuation had significantly higher TFR probabilities than those in MR4.5 but with detectable residual disease . In ENESTfreedom, patients constantly in MR4.5 the year before nilotinib cessation had a greater chance to remain nilotinib‐free than patients in whom BCR‐ABL1 fluctuated between MR4 and MR4.5 .…”

“…In JALSG-STM213, patients in MR4.5 with undetectable BCR-ABL1 transcripts just before imatinib discontinuation had significantly higher TFR probabilities than those in MR4.5 but with detectable residual disease. 18 In ENESTfreedom, patients constantly in MR4.5 the year before nilotinib cessation had a greater chance to remain nilotinib-free than patients in whom BCR-ABL1 fluctuated between MR4 and MR4.5. 16 In EURO-SKI, whether BCR-ABL1 transcripts were detectable or not at the time of imatinib discontinuation did not seem to influence TFR rates.…”

“…16 In contrast, no obvious effect of the Sokal score was found in other trials such as KID, TWISTER, and JALSG-STIM213. 8,17,18 Thus, we did not include prognostic scores at diagnosis among the selection criteria for TKI discontinuation in clinical practice.…”

“…31 Other imatinib or secondgeneration TKI discontinuation studies, such as ISAV, KID, EURO-SKI, JALSG-STIM213, ENESTfreedom, STOP 2G-TKI, and DASFREE, adopted MMR loss to define molecular relapse. 17,18,23,27,[32][33][34] In these trials, major concerns after rapid TKI resumption due to MMR loss were exceptional, and the NCCN adopted MMR loss as a signal for promptly resuming TKI therapy in its guideline for TKI discontinuation in CML (version 2.2017). Notably, none of the TKI discontinuation trials performed to date have allowed patients to remain treatment-free above the threshold of a 0.1% IS ratio because upon MMR loss, a cytogenetic relapse followed by a hematologic relapse is expected to occur on account of the rapid growth kinetics of leukemic cells.…”