Title A multicenter clinical study evaluating the confirmed complete molecular response rate in imatinib treated patients with chronic phase chronic myeloid leukemia by using the international scale of real time quantitative polymerase chain reaction
(c)2013 Ferrata Storti Foundation. This is an open access paper. doi:10.3324/haematol.2013.085167 The online version of this article has a Supplementary Appendix. Manuscript received on January 27, 2013. Manuscript accepted on May 7, 2013. Correspondence: naotot@doc.med.akita u.ac.jp Introduction The introduction of imatinib mesylate, a specific breakpoint cluster region Abelson1 (BCR ABL1) tyrosine kinase inhibitor, has improved the outcome of patients with chronic myeloid leukemia (CML) A multinational, randomized phase III study (IRIS) demonstrated that imatinib is significantly superior to interferon a plus low dose cytarabine as first line therapy in terms of hematologic and cytogenetic responses, tolerability, and progression free survival in patients with newly diagnosed chronic phase CML (CML CP) Continuous treatment with imatinib as initial therapy induced durable responses in a high proportion of CML CP patients at a 5 year follow up. Cumulative complete hematologic response and complete cytogenetic response rates at 60 months were 98% and 87% respectively. Based on the results of these and other studies, imatinib has become the standard therapy for CML CP. Molecular response assessment is valuable in evaluating the therapeutic efficacy of tyrosine kinase inhibitors in CML. A major molecular response (MMR) is an important surrogate biomarker for the prediction of long term outcome of imatinib treatment in CML. CML CP patients who achieved MMR at 18 months had a significantly lower risk of disease progression than patients who did not achieve MMR. Recently, complete molecular response (CMR) has been evaluated in clinical studies as a surrogate biomarker for the prediction of long term outcome of imatinib therapy in CML CP. CMR is defined as at least a 4.5 log reduction of BCR ABL1 transcripts or undetectable transcripts by real time quantitative polymerase chain reaction (qRTPCR) In a landmark analysis by Press et al. CML patients who achieved CMR by 18 months had a significantly longer relapse free survival than patients who achieved MMR. In an intention to treat analysis, the cumulative incidence of CMR on imatinib therapy was 0.5% at 1 year and 8.3% at 5 years in newly diagnosed CML CP patients. CMR may also represent a new surrogate biomarker in the era of second generation tyrosine kinase inhibitors, which have produced significantly superior molecular responses compared with imatinib. In the Evaluating Nilotinib Efficacy and Safety in Clinical Trialsnewly diagnosed patients (ENESTnd) phase III study, significantly more patients achieved CMR at 12, 24, and 36 months in the nilotinib groups than in the imatinib group (11% 25% and 32% with 300 mg nilotinib twice daily, respectively; 7% 19% and 28% with 400 mg nilotinib twice daily, respectively; and 1% 9% and 15% with imatinib, respectively) The Dasatinib versus Imatinib Study In Treatment Naive CML patients (DASISION) a phase III trial, also showed that significantly more patients achieved CMR at 24 months in the dasatinib group than in the imatinib group (17% versus 8% Moreover, CMR may be a first milestone toward the development of a successful strategy for discontinuation therapy. In the Stop Imatinib (STIM) study, 41% of CML patients with a stable CMR for at least 2 years were able to sustain the CMR 12 months after cessation of imatinib. In an update of the STIM trial at 48 months of follow up, the overall probability of maintenance of CMR at 24 and 36 months was 39% (95% CI 29 48) qRT PCR based molecular monitoring of BCR ABL transcripts is used to assess treatment response in CML. qRTPCR is only clinically useful if it is conducted under a rigorous quality control regimen so that fluctuations in the BCR ABL1 level can be confidently attributed to a biological cause rather than assay variation. An international scale has been proposed to further improve the value of qRT PCR results in the setting of clinical practice. The European Leukemia Net (ELN) defined MMR as BCRABL1 transcripts =0.1% compared with ABL (or other house keeping gene) transcripts in peripheral blood by the standardized international scale of qRT PCR (IS PCR) CMR is defined as undetectable transcripts at different times in peripheral blood by nested PCR (sensitivity >10) Because the potential for patients' eligibility for tyrosine kinase inhibitor cessation studies is becoming a more widely discussed topic and area for research, Cross et al. recently reviewed the standardized definitions of molecular response in CML based on BCR ABL1 transcript levels. According to the latest definitions of molecular response, MR3 is defined as BCR ABL1 transcripts =0.1% MR4 as BCR ABL1 transcripts =0.01% and MR4.5 as BCR ABL1 transcripts =0.0032% The purpose of this multicenter clinical study was to evaluate CMR rates in imatinib treated CML CP patients with MMR using the IS PCR. The correlation of CMR with clinical, immunological, and pharmacokinetic parameters in CML CP patients was also evaluated.