-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

3606 Half: A Prospective Multi-Centre Phase II Clinical Trial Evaluating the Efficacy and Safety of Tyrosine Kinase Inhibitors’ Discontinuation after Two-Step Dose Reduction in Patients with Chronic Myeloid Leukemia in Deep Molecular Remission

Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Clinical Trials, Clinical Research, Clinically Relevant, Diseases, Myeloid Malignancies
Monday, December 13, 2021, 6:00 PM-8:00 PM

Daniela Žácková, MD1*, Edgar Faber, MD, PhD2*, Lukáš Stejskal, MD3*, Michal Karas, MD, PhD4*, Petra Bělohlávková, MD, PhD5*, Hana Klamová, MD, PhD6*, Olga Černá, MD7*, Eduard Cmunt, MD, PhD8*, Petra Čičátková, MD1*, Lukáš Semerád, MD1*, Tomáš Horňák, MD1*, Anežka Kvetková, MD1*, Jiřina Procházková1*, Jitka Rychlíčková, PharmDr, PhD9*, Radka Štěpánová, MSc.9*, Adam Svobodník, PhD9*, Kateřina Machová Poláková, PhD6*, Ivana Ježíšková, PhD1*, Tomáš Jurček, PhD1*, Marek Borský, MSc.1*, Ondřej Wiewiorka, MSc.10*, Regina Demlová, MD, PhD9* and Jiří Mayer, Prof, MD1,11

1Department of Internal Medicine Hematology and Oncology, University Hospital Brno and Masaryk University, Brno, Czech Republic
2Dpt. of Hemato-oncology, University Hospital Olomouc and Palacký University, Olomouc, Czech Republic
3Dpt. of Hemato-oncology, University Hospital Ostrava and Ostrava University, Ostrava, Czech Republic
4Dpt. of Hemato-oncology, University Hospital Plzeň and Charles University, Plzeň, Czech Republic
54th Department of Internal Medicine and Hematology, University Hospital Hradec Králové and Charles University, Hradec Králové, Czech Republic
6Institute of Hematology and Blood Transfusion, Prague, Czech Republic
7Dpt. of Internal Medicine Hematology, University Hospital Královské Vinohrady and Charles University, Prague, Czech Republic
81st Dpt. of Internal Medicine – Hematology, General University Hospital and Charles University, Prague, Czech Republic
9Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
10Dpt. of Biochemistry, University Hospital Brno, Brno, Czech Republic
11Central European Institute of Technology (CEITEC) Masaryk University, Brno, Czech Republic

Background.

Treatment-free remission (TFR) has become a new treatment goal for chronic myeloid leukemia (CML) patients. However, usually abrupt tyrosine kinase inhibitors (TKIs) therapy discontinuation has been successful only in about half of eligible patients and it can cause burdening TKI withdrawal syndrome (TWS) in about 30% of them. Moreover, any robust clinical or biological factor predictive for successful TFR has not been identified yet. On top of that, sustainable deep molecular response (DMR) as the main prerequisite for TKI discontinuation attempt is achieved only in 20-40% of patients. The majority of CML patients, therefore, need to be treated with the effective and well-tolerated drug for a long time or even life-long.

Study design and methods.

With the recognition of all these aspects, we designed a nationwide prospective investigator-initiated phase II clinical trial HALF (ClinicalTrials.gov NCT04147533) in order to evaluate efficacy and safety of TKI discontinuation after previous two-step dose reduction in patients with CML in DMR (Fig. 1). Step-wise TKI dose reduction, i.e. half of the standard during the first 6 months after study entry, and the same dose given alternatively (every other day) during the next 6 months, was derived from pharmacokinetics and experimental data as well as from clinical trials’ results. We assume that the step-wise and eventually meaningful TKI dose reduction enables a higher rate of patients achieving successful TFR with less pronounce TWS, or even would represent a more reasonable and safer alternative to the complete and sudden TKI interruption. This unique nationwide academic project has been facilitated by hematological patients care centralization in the Czech Republic.

A primary study objective is to evaluate the proportion of patients in major molecular response (MMR) at 6 and 12 months and in TFR at 18, 24, and 36 months after the study enrollment, respectively, and molecular recurrence-free survival at all mentioned time points as well. Main secondary and exploratory objectives are: to evaluate the proportion of patients loosing MMR and in whom MMR and MR4.0 would be re-achieved after TKI re-introduction, time to MMR and MR4.0 re-achievement, FFS, PFS, OS, TWS, and QoL assessment, predictive factors for successful TFR identification, quantification of BCR-ABL1 using digital droplet PCR at both the DNA and mRNA levels, immunological profiling, BCR-ABL1 kinetics mathematical modeling, assessment of TKI pharmacokinetics, clonal hematopoiesis and pharmaco-economics.

Results.

The study was launched in December 2019; however, due to the COVID-19 outbreak, patients’ recruitment started on June 16, 2020. Here, characteristics of the first 74 patients included in the study until April 2021 are presented. There were 37 males and 37 females, with median age at the time of diagnosis of 53 years (range, 23-74) and at the time of the study entry of 67 years (range, 35-86). A median time of CML disease, TKI treatment, and DMR duration before the study initiation was as follows: 9.9 years (range, 4.4-22.5), 9.8 years (range, 4.2-20.2), and 7.3 years (range, 3.2-18.3), respectively. The ELTS score was low, intermediate, high and unknown in 62.2%, 21.6%, 13.5%, and 2.7% of patients, respectively. At the time of study entry, 58 patients (79.5%) were treated with imatinib, 10 (13.7%) with nilotinib, and 5 (6.8%) with dasatinib, respectively, whereas in 63 patients (86.3%) it was in the first line of therapy. With almost half of patients (48.6%), the TKI dose was already reduced at the time of study entry. With 10 (13.5%) patients, interferon-α treatment preceded TKI administration. At the time of this abstract preparation, on July 26, 2021, altogether 102 patients (from planned 150) have been enrolled in the study; 48 of them (47.1%) have already moved to the second de-escalation phase and 9 (8.8%) patients to the TFR phase. There were 2 cases of confirmed MMR loss (both in month 8 after the study entry) and no patient experienced symptoms resembling TWS.

Conclusions.

Despite the COVID-19 pandemic, the HALF study was successfully launched and initiated in the majority of centers, with 102 already included patients and continuing intensive enrolment. Based on our very preliminary results, the step-wise dose reduction seems to be an effective and safe approach. More included patients, longer follow-up and further analyses are needed in order to reach all set up objectives.

Disclosures: Žácková: Angelini: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Faber: Angelini: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Novartis: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Pfizer: Other: conference fees; TERUMO: Other: conference fees. Bělohlávková: Novartis: Consultancy; BMS/Celgene: Consultancy. Horňák: Angelini: Honoraria. Svobodník: Roche: Speakers Bureau; Janssen-Cilag: Speakers Bureau. Machová Poláková: Incyte: Consultancy; Angelini: Consultancy; Novartis: Research Funding. Mayer: Principia: Research Funding.

*signifies non-member of ASH