Significance of deeper molecular responses in patients with chronic myeloid leukemia in early chronic phase treated with tyrosine kinase inhibitors

Abstract

Most patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with tyrosine kinase inhibitors (TKI) achieve complete cytogenetic response (CCyR). An increasing number of patients also achieve deep molecular responses (MR). We determined the frequency and significance of deep MR after TKI therapy for CML in CP. MR included: major molecular response (MMR), MR4, MR4.5, and undetectable transcripts (UND), ie BCR-ABL/ABL of ≤0.1%, ≤0.01%, ≤0.0032%, and undetectable transcripts, respectively. 483 patients received imatinib 400mg/day (IM400, 71, July 2000-April 2001), imatinib 800mg/day (IM800, 204, June 2001-July 2005), nilotinib (NILO, 106, July 2005 to date), or dasatinib (DASA, 102, November 2005 to date). UND rates at 36 months were 18.1%, 30.6%, 29.2%, and 28.6%, respectively. Patients achieving UND have superior transformation-free survival (TFS) and overall survival (OS) versus those obtaining ≤MMR, but not other MR levels. At the 18- and 24-month landmark analysis patients achieving UND have no advantage in TFS and OS compared to those achieving a lesser degree of MR. Among patients achieving MR4.5, those who maintain it for ≥2 years (susMR4·5) have no additional benefit in TFS or OS. Most patients with early CP CML receiving TKI achieve MMR. BCR-ABL transcripts become undetectable in a significant fraction of them. Deeper MR at 18 or 24 months are not associated with a benefit in TFS or OS. Furthermore, achieving susMR4·5 does not appear to further reduce the risk of transformation or death.

Chronic myeloid leukemia: reminiscences and dreams

“…Thus far, there is little evidence of a statistically significant improvement in overall survival (OS), though long-term follow up confirmed a superior rate of freedom from progression compared with patients with less deep molecular responses at the same time points. 8 The advent of TKIs in the treatment of CML has opened a new era of precision medicine for diverse malignancies in which relatively non-specific and often toxic drugs are gradually being replaced by safer and better tolerated agents whose mechanism of action is precisely defined, and for which the treatment algorithm is guided by individual patient genomic information. 9 Indeed, many TKIs have activity against other tyrosine kinases and could, therefore, be useful in treating patients whose malignancies harbor these gene mutations.…”

Molecular monitoring to improve outcomes in patients with chronic myeloid leukemia in chronic phase: Importance of achieving treatment‐free remission

“…With 5 years of follow-up in ENESTnd, 54% of patients in the nilotinib 300-mg twice-daily arm achieved MR 4.5 and 96% of patients had freedom from progression to AP/BC (vs. the imatinib arm: 31% [P < 0.0001] and 92% [P 5 0.0403], respectively) [16]. Retrospective landmark analyses of other independent clinical trials have demonstrated similar associations between deeper molecular responses and improved OS, event-free survival, and failure-free survival [20,29,35]. For example, patients who achieved a confirmed MR 4.5 at 4 years on frontline imatinib in the German CML IV trial had significantly higher OS at 8 years than patients who did not achieve this level of stable molecular response [20].…”

“…Thus, ELN recommends use of the term molecularly undetectable leukemia, together with the number of control gene transcripts, over the term CMR [11]. A response of MR 4.5 is easier to standardize than undetectable leukemia and represents a deep, measurable level of molecular response with similar clinical relevance [29]; for these and other reasons, MR 4.5 is a common criterion for TFR studies.…”

Measurement ofBCR-ABL1transcripts on the International Scale in the United States: current status and best practices

“…[11] A separate study found a correlation between achievement of undetectable disease (assay sensitivity: 1 BCR-ABL1 transcript in 100,000 ABL1 copies; equivalent to MR 5 on the IS) and transformation-free survival and OS (versus patients with BCR-ABL1 IS 0.1%) on imatinib, nilotinib, or dasatinib therapy. [38] In the German CML-IV study, there was a correlation between achievement of MR 4.5 and OS in patients treated with imatinib, and no patient who achieved MR 4.5 had progressed after a median followup of 3 years. [10] In addition, several treatment-free remission studies have been initiated in patients following treatment with imatinib and second-generation TKIs, with stringent molecular response criteria for eligibility.…”