Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial

Platzbecker, Uwe; Middeke, Jan Moritz; Sockel, Katja; Herbst, Regina; Wolf, Dominik; Baldus, Claudia D.; Oelschlägel, Uta; Mütherig, Anke; Fransecky, Lars; Noppeney, Richard; Bug, Gesine; Götze, Katharina; Krämer, Alwin; Bochtler, Tilmann; Stelljes, Matthias; Groth, Christoph; Schubert, Antje; Mende, Marika; Stölzel, Friedrich; Borkmann, Christine; Kubasch, Anne Sophie; Bonin, Malte von; Serve, Hubert; Hänel, Mathias; Dührsen, Ulrich; Schetelig, Johannes; Röllig, Christoph; Kramer, Michael; Ehninger, Gerhard; Bornhäuser, Martin; Thiede, Christian

doi:10.1016/s1470-2045(18)30580-1

Cited by 275 publications

(213 citation statements)

References 29 publications

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“…Others found that pre‐emptive azacitidine could delay hematologic relapse until a median of 231 days after detecting initial evidence of residual disease, but hematologic relapse nonetheless occurred in 65% of post‐transplant patients . A follow‐up study that included non‐transplanted and HCT patients treated with pre‐emptive azacitidine reported a cumulative incidence of relapse of 49%, a median of 422 days after initial MRD detection . Similarly, after initial intensive chemotherapy for older patients with AML or MDS, maintenance azacitidine improved 12‐month disease‐free survival but not overall survival …”

Section: Discussionmentioning

confidence: 99%

Phase I/II multisite trial of optimally dosed clofarabine and low‐dose TBI for hematopoietic cell transplantation in acute myeloid leukemia

et al. 2019

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Clofarabine is an immunosuppressive purine nucleoside analog that may have better anti-leukemic activity than fludarabine. We performed a prospective phase I/II multisite trial of clofarabine with 2 Gy total body irradiation as non-myeloablative conditioning for allogeneic hematopoietic cell transplantation in adults with acute myeloid leukemia who were unfit for more intense regimens. Our main objective was to improve the 6-month relapse rate following non-myeloablative conditioning, while maintaining historic rates of non-relapse mortality (NRM) and engraftment.Forty-four patients, 53 to 74 (median: 69) years, were treated with clofarabine at 150 to 250 mg/m 2 , of whom 36 were treated at the maximum protocol-specified dose. One patient developed multifactorial acute kidney injury and another developed multiorgan failure, but no other grade 3 to 5 non-hematologic toxicities were observed. All patients fully engrafted. The 6-month relapse rate was 16% (95% CI, 5%-27%) among all patients and 14% (95% CI, 3%-26%) among high-risk patients treated at the maximum dose, meeting the pre-specified primary efficacy endpoint.Overall survival was 55% (95% CI, 40%-70%) and leukemia-free survival was 52% (95% CI, 37%-67%) at 2 years. Compared to a historical high-risk cohort treated with the combination of fludarabine at 90 mg/m 2 and 2 Gy TBI, protocol patients treated with the clofarabine-TBI regimen had lower rates of overall mortality (HR of 0.50, 95% CI, 0.28-0.91), disease progression or death (HR 0.48, 95% CI, 0.27-0.85), and morphologic relapse (HR 0.30, 95% CI, 0.13-0.69), and comparable NRM (HR 0.85, 95% CI 0.36-2.00). The combination of clofarabine with TBI warrants further investigation in patients with high-risk AML.

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Section: Discussionmentioning

confidence: 99%

Phase I/II multisite trial of optimally dosed clofarabine and low‐dose TBI for hematopoietic cell transplantation in acute myeloid leukemia

et al. 2019

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“…Several studies have suggested that treatment with hypomethylating agents (azacitidine or decitabine) may be beneficial for patients with AML and persistent or recurrent MRD. [82][83][84][85] The RELAZA2 trial was the largest prospective study to assess this issue. 84 One hundred and ninety patients with AML or myelodysplastic syndrome who achieved complete remission after chemotherapy or HSCT were monitored for MRD for 24 months with either PCR for mutant NPM1, leukemia-specific gene fusions (DEK-NUP214, RUNX1-RUNX1T1, or CBFB-MYH11) or donor chimerism in flow cytometry-sorted CD34 + cells (for patients who had undergone prior allogeneic HSCT).…”

Section: Hypomethylating Agents For Measurable Residual Disease-positmentioning

confidence: 99%

How close are we to incorporating measurable residual disease into clinical practice for acute myeloid leukemia?

Short

Ravandi

2019

Haematologica

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Assessment of measurable residual disease, also called “minimal residual disease,” in patients with acute myeloid leukemia in morphological remission provides powerful prognostic information and complements pretreatment factors such as cytogenetics and genomic alterations. Based on data that low levels of persistent or recurrent residual leukemia are consistently associated with an increased risk of relapse and worse long-term outcomes, its routine assessment has been recommended by some experts and consensus guidelines. In addition to providing important prognostic information, the detection of measurable residual disease may also theoretically help to determine the optimal post-remission strategy for an individual patient. However, the full therapeutic implications of measurable residual disease are uncertain and thus controversy exists as to whether it should be routinely incorporated into clinical practice. While some evidence supports the use of allogeneic stem cell transplantation or hypomethylating agents for some subgroups of patients in morphological remission but with detectable residual leukemia, the appropriate use of this information in making clinical decisions remains largely speculative at present. To resolve this pressing clinical issue, several ongoing studies are evaluating measurable residual disease-directed treatments in acute myeloid leukemia and may lead to new, effective strategies for patients in these circumstances. This review examines the common technologies used in clinical practice and in the research setting to detect residual leukemia, the major clinical studies establishing the prognostic impact of measurable residual disease in acute myeloid leukemia, and the potential ways, both now and in the future, that such testing may rationally guide therapeutic decision-making.

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“…A retrospective study in 10 patients with NPM1-mutated disease with MRD noted a decrease in MRD levels of at least 1 log in 7 of the patients. 39 A novel HMA, SGI-110 (or guadecitabine), currently is being examined for posttransplantation disease recurrence in combination with DLI for patients with MRD (ClinicalTrials.gov identifier NCT02684162). Twenty of 59 prospectively screened patients developed a decrease in donor chimerism and received preemptive azacitidine treatment; 16 patients (80%) responded with improvement or stabilization of donor chimerism.…”

Section: Hypomethylating Agentsmentioning

confidence: 99%

“…Cancer September 15, 2019 The recurrence-free survival rate was 46% (95% CI, 32%-59%) at 12 months in the 53 MRD-positive patients who received azacitidine. 39 A novel HMA, SGI-110 (or guadecitabine), currently is being examined for posttransplantation disease recurrence in combination with DLI for patients with MRD (ClinicalTrials.gov identifier NCT02684162). To the best of our knowledge, studies with HMA to date have focused primarily on the posttransplantation setting, and therefore generalizability may be limited when applied to other clinical scenarios with MRD.…”

Section: Continuedmentioning

confidence: 99%

Current treatment strategies for measurable residual disease in patients with acute myeloid leukemia

Percival

Estey

2019

Cancer

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Patients with acute myeloid leukemia (AML) who achieve a morphologic complete remission still can have measurable residual disease (MRD) detected by multiparametric flow cytometry, molecular methods, or cytogenetics. Such patients with MRD have a high risk of disease recurrence over a short timeframe, but optimal treatment strategies are unknown. Outcomes with conventional treatment, including allogeneic hematopoietic cell transplantation, are worse than those for patients without MRD. Herein, the authors review current strategies, including novel clinical trials, targeted toward patients with MRD. Cancer 2019;125:3121-3130.

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Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial

Cited by 275 publications

References 29 publications

Phase I/II multisite trial of optimally dosed clofarabine and low‐dose TBI for hematopoietic cell transplantation in acute myeloid leukemia

Phase I/II multisite trial of optimally dosed clofarabine and low‐dose TBI for hematopoietic cell transplantation in acute myeloid leukemia

How close are we to incorporating measurable residual disease into clinical practice for acute myeloid leukemia?

Current treatment strategies for measurable residual disease in patients with acute myeloid leukemia

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