Uwe Platzbecker1, Jan Moritz Middeke2, Katja Sockel2, Regina Herbst3, Dominik Wolf4, Claudia D Baldus5, Uta Oelschlägel2, Anke Mütherig2, Lars Fransecky5, Richard Noppeney6, Gesine Bug7, Katharina S Götze8, Alwin Krämer9, Tilmann Bochtler9, Matthias Stelljes10, Christoph Groth10, Antje Schubert2, Marika Mende2, Friedrich Stölzel2, Christine Borkmann2, Anne Sophie Kubasch2, Malte von Bonin2, Hubert Serve7, Mathias Hänel3, Ulrich Dührsen6, Johannes Schetelig2, Christoph Röllig2, Michael Kramer2, Gerhard Ehninger2, Martin Bornhäuser2, Christian Thiede2. 1. Medical Clinic and Policinic 1, Hematology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany; Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), and National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany. Electronic address: uwe.platzbecker@medizin.uni-leipzig.de. 2. Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), and National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany. 3. Klinikum Chemnitz, Klinik für Hämatologie und Onkologie, Chemnitz, Germany. 4. Medical Clinic 3, Universitätsklinikum Bonn, Bonn, Germany; UKIM5, Medical University Innsbruck, Innsbruck, Austria. 5. Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie, Campus Benjamin Franklin Charité, Berlin, Germany. 6. Universitätsklinikum Essen, Klinik für Hämatologie, Essen, Germany. 7. Universitätsklinikum Frankfurt, Medizinische Klinik 2, Universitätsklinikum Frankfurt, Frankfurt, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Frankfurt, Germany. 8. Technische Universität München, Munich, Germany. 9. Medizinische Klinik V, Universität Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany. 10. Universitätsklinikum Münster, Medizinischen Klinik A, Münster, Germany.
Abstract
BACKGROUND: Monitoring of measurable residual disease (MRD) in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) who achieve a morphological complete remission can predict haematological relapse. In this prospective study, we aimed to determine whether MRD-guided pre-emptive treatment with azacitidine could prevent relapse in these patients. METHODS: The relapse prevention with azacitidine (RELAZA2) study is an open-label, multicentre, phase 2 trial done at nine university health centres in Germany. Patients aged 18 years or older with advanced MDS or AML, who had achieved a complete remission after conventional chemotherapy or allogeneic haemopoietic stem-cell transplantation, were prospectively screened for MRD during 24 months from baseline by either quantitative PCR for mutant NPM1, leukaemia-specific fusion genes (DEK-NUP214, RUNX1-RUNX1T1, CBFb-MYH11), or analysis of donor-chimaerism in flow cytometry-sorted CD34-positive cells in patients who received allogeneic haemopoietic stem-cell transplantation. MRD-positive patients in confirmed complete remission received azacitidine 75 mg/m2 per day subcutaneously on days 1-7 of a 29-day cycle for 24 cycles. After six cycles, MRD status was reassessed and patients with major responses (MRD negativity) were eligible for a treatment de-escalation. The primary endpoint was the proportion of patients who were relapse-free and alive 6 months after the start of pre-emptive treatment. Analyses were done per protocol. This trial is registered with ClincialTrials.gov, number NCT01462578, and finished recruitment on Aug 21, 2018. FINDINGS: Between Oct 10, 2011, and Aug 20, 2015, we screened 198 patients with advanced MDS (n=26) or AML (n=172), of whom 60 (30%) developed MRD during the 24-month screening period and 53 (88%) were eligible to start study treatment. 6 months after initiation of azacitidine, 31 (58%, 95% CI 44-72) of 53 patients were relapse-free and alive (p<0·0001; one-sided binomial test for null hypothesis pexp≤0·3). With a median follow-up of 13 months (IQR 8·5-22·8) after the start of MRD-guided treatment, relapse-free survival at 12 months was 46% (95% CI 32-59) in the 53 patients who were MRD-positive and received azacitidine. In MRD-negative patients, 12-month relapse-free survival was 88% (95% CI 82-94; hazard ratio 6·6 [95% CI 3·7-11·8], p<0·0001). The most common (grade 3-4) adverse event was neutropenia, occurring in 45 (85%) of 53 patients. One patient with neutropenia died because of an infection considered possibly related to study treatment. INTERPRETATION: Pre-emptive therapy with azacitidine can prevent or substantially delay haematological relapse in MRD-positive patients with MDS or AML who are at high risk of relapse. Our study also suggests that continuous MRD negativity during regular MRD monitoring might be prognostic for patient outcomes. FUNDING: Celgene Pharma, José Carreras Leukaemia Foundation, National Center for Tumor Diseases (NCT), and German Cancer Consortium (DKTK) Foundation.
BACKGROUND: Monitoring of measurable residual disease (MRD) in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) who achieve a morphological complete remission can predict haematological relapse. In this prospective study, we aimed to determine whether MRD-guided pre-emptive treatment with azacitidine could prevent relapse in these patients. METHODS: The relapse prevention with azacitidine (RELAZA2) study is an open-label, multicentre, phase 2 trial done at nine university health centres in Germany. Patients aged 18 years or older with advanced MDS or AML, who had achieved a complete remission after conventional chemotherapy or allogeneic haemopoietic stem-cell transplantation, were prospectively screened for MRD during 24 months from baseline by either quantitative PCR for mutant NPM1, leukaemia-specific fusion genes (DEK-NUP214, RUNX1-RUNX1T1, CBFb-MYH11), or analysis of donor-chimaerism in flow cytometry-sorted CD34-positive cells in patients who received allogeneic haemopoietic stem-cell transplantation. MRD-positive patients in confirmed complete remission received azacitidine 75 mg/m2 per day subcutaneously on days 1-7 of a 29-day cycle for 24 cycles. After six cycles, MRD status was reassessed and patients with major responses (MRD negativity) were eligible for a treatment de-escalation. The primary endpoint was the proportion of patients who were relapse-free and alive 6 months after the start of pre-emptive treatment. Analyses were done per protocol. This trial is registered with ClincialTrials.gov, number NCT01462578, and finished recruitment on Aug 21, 2018. FINDINGS: Between Oct 10, 2011, and Aug 20, 2015, we screened 198 patients with advanced MDS (n=26) or AML (n=172), of whom 60 (30%) developed MRD during the 24-month screening period and 53 (88%) were eligible to start study treatment. 6 months after initiation of azacitidine, 31 (58%, 95% CI 44-72) of 53 patients were relapse-free and alive (p<0·0001; one-sided binomial test for null hypothesis pexp≤0·3). With a median follow-up of 13 months (IQR 8·5-22·8) after the start of MRD-guided treatment, relapse-free survival at 12 months was 46% (95% CI 32-59) in the 53 patients who were MRD-positive and received azacitidine. In MRD-negative patients, 12-month relapse-free survival was 88% (95% CI 82-94; hazard ratio 6·6 [95% CI 3·7-11·8], p<0·0001). The most common (grade 3-4) adverse event was neutropenia, occurring in 45 (85%) of 53 patients. One patient with neutropenia died because of an infection considered possibly related to study treatment. INTERPRETATION: Pre-emptive therapy with azacitidine can prevent or substantially delay haematological relapse in MRD-positive patients with MDS or AML who are at high risk of relapse. Our study also suggests that continuous MRD negativity during regular MRD monitoring might be prognostic for patient outcomes. FUNDING: Celgene Pharma, José Carreras Leukaemia Foundation, National Center for Tumor Diseases (NCT), and German Cancer Consortium (DKTK) Foundation.
Authors: Firas El Chaer; Uma Borate; Rémy Duléry; Shernan G Holtan; Arjun Datt Law; Lori Muffly; Samah Nassereddine; Rory M Shallis; Kate Stringaris; Justin Taylor; Steven M Devine; Mohamad Mohty; Christopher S Hourigan Journal: Blood Adv Date: 2021-03-23
Authors: Michael Heuser; Bennet Heida; Konstantin Büttner; Clara Philine Wienecke; Katrin Teich; Carolin Funke; Maximilian Brandes; Piroska Klement; Alessandro Liebich; Martin Wichmann; Blerina Neziri; Anuhar Chaturvedi; Arnold Kloos; Konstantinos Mintzas; Verena I Gaidzik; Peter Paschka; Lars Bullinger; Walter Fiedler; Albert Heim; Wolfram Puppe; Jürgen Krauter; Konstanze Döhner; Hartmut Döhner; Arnold Ganser; Michael Stadler; Lothar Hambach; Razif Gabdoulline; Felicitas Thol Journal: Blood Adv Date: 2021-05-11
Authors: Elizabeth F Krakow; Boglarka Gyurkocza; Barry E Storer; Thomas R Chauncey; Jeannine S McCune; Jerald P Radich; Michelle E Bouvier; Elihu H Estey; Rainer Storb; David G Maloney; Brenda M Sandmaier Journal: Am J Hematol Date: 2019-11-08 Impact factor: 10.047