Elsevier

Leukemia Research

Volume 67, April 2018, Pages 27-31
Leukemia Research

Research paper
Identification of chronic myeloid leukemia patients treated with imatinib who are potentially eligible for treatment discontinuation by assessing real-life molecular responses on the international scale in a EUTOS-certified lab

https://doi.org/10.1016/j.leukres.2018.01.018Get rights and content

Highlights

  • Real-life molecular responses on international scale in EUTOS-certified laboratory.

  • 53.4% of patients were in deep molecular responses ≥MR4.5 at last visit.

  • 36.2% of patients had ≥MR4.5 and were treated for >5.8 years; 26.7% for >8 years.

  • Potential patients for treatment-free remission attempt outside clinical trials were identified.

Abstract

A retrospective study was performed to describe molecular responses (MR) on the international scale (IS) in patients with chronic myeloid leukemia (CML) treated with imatinib in routine clinical practice in Belgium and to identify patients potentially eligible for treatment discontinuation. The analysis included 116 patients with CML in chronic phase at treatment centers sending blood samples for molecular follow-up to a single EUTOS-certified laboratory. IS MR from the last patient visit between October 2014 and April 2015 were retrospectively collected. Most patients (93.1%) had an IS MR corresponding to an optimal response per European LeukemiaNet 2013 guidelines; 53.4% (62/116) of patients were in deep molecular responses ≥MR4.5 at their last visit (mean treatment duration: 91.0 months) among whom 36.2% (42/116) had been receiving imatinib for >5.8 years and 26.7% (31/116) for >8 years (margins of error: 8.74% and 8.05%, respectively). These patients would likely have the highest chance of staying in treatment-free remission (TFR) upon discontinuation, based on published TFR trial data. Although our study only provides a snapshot in time of a patient’s last MR reported, without precise information regarding MR duration, the study settings could nevertheless support the feasibility of attempting TFR outside clinical trials in the future.

Introduction

Targeted therapy with BCR-ABL1 tyrosine kinase inhibitors (TKIs) has prompted a revolution in the management of chronic myeloid leukemia (CML). Thanks to TKI treatment, CML has now become a chronic condition for most patients. In 2001, the European Medicines Agency approved the first TKI, imatinib, for the treatment of CML. Although second- and third-generation TKIs have been approved since then, imatinib is often still considered as the gold standard for CML treatment [1].

Monitoring the response to TKI therapy at regular intervals is critical for optimal long-term outcomes of the patient. Molecular monitoring involves the measurement of BCR-ABL1 transcript levels in peripheral blood relative to those of a control gene transcript by real-time quantitative reverse-transcription polymerase chain reaction (RQ-PCR). The results are expressed on the international scale (IS) as a percentage, with 100% BCR-ABL1 corresponding to the standardized baseline and ≤0.1% BCR-ABL1 (i.e. a 3-log reduction from standardized baseline) corresponding to a major molecular response (MMR or MR3) [2].

The European LeukemiaNet (ELN) has updated its guidelines for the management of CML in 2013 to optimize treatment for CML patients [3]. Responses to TKI first-line treatment are defined as either “optimal” (BCR-ABL1 transcript levels ≤10% at 3 months, <1% at 6 months, and ≤0.1% from 12 months onward) or as “failure” (BCR-ABL1 transcript levels >10% at 6 months and >1% from 12 months onward), requiring a change in treatment, with an intermediate “warning zone” in between, necessitating more frequent monitoring and closer follow-up. The achievement of an MMR is considered as the primary goal of TKI treatment as it is associated with very high rates of progression-free survival [4].

Due to longer follow-up and the broadening spectrum of TKIs, an increasing number of patients now achieve and maintain a deep molecular response (DMR), such as MR4.5 which is defined as a 4.5-log reduction of BCR-ABL1 transcripts from the standardized baseline, corresponding to either detectable disease with ≤0.0032% BCR-ABL1 transcripts or undetectable BCR-ABL1 transcripts with 32 000-99 999 ABL1 transcripts or 77 000-239 999 GUSB transcripts [5]. Based on published research, no single patient in MR4.5 has ever progressed on TKI therapy [6]. Furthermore, achievement of a deep and stable MR4.5 (or deeper MR) is often a prerequisite to be included in a treatment-free remission (TFR) clinical trial, where the goal is sustained TKI discontinuation without relapse [7].

Currently, the ELN guidelines of 2013 state that discontinuation of TKI therapy may only be attempted in clinical trials [3]. More recently, based on the growing evidence from clinical trials, Hughes and Ross have published recommendations for treatment discontinuation outside the clinical trial context [7]. When TFR in CML will become routine clinical practice, standardized IS reporting of MR4.5 will be key.

Since December 2010, the laboratory of molecular biology in Haemato-oncology at Hôpital Erasme – Université Libre de Bruxelles (ULB) in Belgium is certified by the European Treatment and Outcome Study (EUTOS) for routine testing of MRs in CML patients and, since September 2014, for reporting DMRs on IS until MR4.5 (and in most cases the laboratory is able to measure MR5).

We aimed to describe and visualize the real-life IS MRs at one given timepoint according to the ELN 2013 guidelines of a cohort of Belgian patients with CML in chronic phase (CML-CP) treated with imatinib, and for whom the molecular follow-up was performed by an institutional laboratory offering accurate standardized RQ-PCR results as specified in the specialized literature [7]. This study enabled us to describe the patients potentially eligible for a TFR attempt should this become part of routine clinical practice in the future.

Section snippets

Study design and participants

This was a retrospective, non-randomized phase IV study (IMSTAGRAM or “Imatinib Status Diagram” study) conducted in the laboratory of molecular biology in Haemato-oncology at Hôpital Erasme – ULB in Brussels, Belgium. Data were collected from CML-CP patients treated with imatinib and who had IS MR tests routinely performed at this laboratory between October 2014 and April 2015. As CML patients see their haematologists at least once every 6 months, we chose a study period of 7 months to include

Patients and treatments

Data from 116 CML-CP patients were recorded in the study database. Overall patient characteristics are shown in Table 1. The Sokal risk score was not available for 45 patients (38.8%).

Overall IS MR

In total, 108 (93.1%) patients had an IS MR corresponding to an optimal response per ELN 2013 guidelines at last MR measurement. Of the 8 (6.9%) patients with a non-optimal response, 7 (6.0%) had a response corresponding to a “warning” and 1 (0.9%) had a response corresponding to a “failure” of treatment (Fig. 1).

Discussion

Treatment of CML with imatinib or other TKIs has been a great therapeutic success, with CML now becoming a chronic disease for the vast majority of patients [[7], [10]]. A DMR of MR4.5 or deeper is obtained in a substantial proportion of patients with CML-CP under TKI therapy. Data in the literature shows that patients achieving DMR have a low risk of progression and a high rate of long-term survival [[6], [7], [11], [12]]. These encouraging results have prompted clinicians to initiate

Conclusions

This study enabled us to describe the patients who may become suitable for a TFR attempt, if TFR attempts would be part of routine clinical practice. We described and visualized the IS MR at one time point of a cohort of Belgian CML-CP patients treated with imatinib per ELN 2013 guidelines. Most patients had an optimal response to the treatment, and more than half were in MR4.5 or deeper at last MR measure. Of these, 36.2% (margin of error: 8.74%) were in MR4.5 or deeper and treated with

Author disclosures

PH, BD and HEH have received consultancy fees, honoraria and research funding from Novartis Pharma SA/NV. WP and KP are employed by Novartis Pharma SA/NV. AH and FSB report no potential conflicts of interest.

Funding source

This work was supported by Novartis Pharma SA/NV, Belgium.

Acknowledgments

The authors would like to thank all the departments of Haemato-oncology that regularly send blood samples of CML patients and that have provided all clinical data needed for this study. Those departments of Haemato-oncology are listed in alphabetical order: CHU Ambroise Pare (Mons), Institut Jules Bordet (Bruxelles), CHU Brugmann (Bruxelles), CHIREC (Clinique Edith Cavell – Bruxelles), Hôpital Erasme-ULB, Grand Hôpital de Charleroi (Charleroi), Groupe Jolimont (Jolimont-Lobbes,

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1

Current address: Laboratoire d'Hématologie, Grand Hôpital de Charleroi, Site St Joseph, Rue de la Duchère 6, 6060 Gilly, Belgium.

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