FLA‐IDA salvage chemotherapy combined with a seven‐day course of venetoclax (FLAVIDA) in patients with relapsed/refractory acute leukaemia

Shahswar, Rabia; Beutel, Gernot; Klement, Piroska; Rehberg, Alina; Gabdoulline, Razif; Koenecke, Christian; Markel, Dominik; Eggers, H.; Eder, Matthias; Stadler, Michael; Hambach, Lothar; Ehrlich, Steve; Göhring, Gudrun; Schlegelberger, Brigitte; Dammann, Elke; Reuter, Marlene; Wichmann, Manfred; Neziri, Blerina; Ganser, Arnold; Thol, Felicitas; Heuser, Michael

doi:10.1111/bjh.16268

Cited by 27 publications

(26 citation statements)

References 10 publications

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“…Not surprisingly, venetoclax has been studied in combinations with intensive chemotherapy as well (summarized in Table 2). A retrospective report of 13 patients treated with FLAVIDA salvage therapy (fludarabine, cytarabine, and idarubicin in combination with venetoclax 100 mg daily for 7 days; dose reduced due to concurrent azole administration) compared to a control cohort received FLA-Ida (fludarabine, cytarabine, and idarubicin) reported a higher but not statistically significant CR/CRi rate of 69% compared to 47% in the control cohort [9]. A phase 1b/II trial of medically fit patients with R/R AML receiving FLAG-Ida induction and consolidation in combination with a 14 days course of venetoclax was conducted at MD Anderson.…”

Section: Venetoclax + Intensive Chemotherapymentioning

confidence: 99%

Emerging agents and regimens for AML

Liu

2021

J Hematol Oncol

116

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Until recently, acute myeloid leukemia (AML) patients used to have limited treatment options, depending solely on cytarabine + anthracycline (7 + 3) intensive chemotherapy and hypomethylating agents. Allogeneic stem cell transplantation (Allo-SCT) played an important role to improve the survival of eligible AML patients in the past several decades. The exploration of the genomic and molecular landscape of AML, identification of mutations associated with the pathogenesis of AML, and the understanding of the mechanisms of resistance to treatment from excellent translational research helped to expand the treatment options of AML quickly in the past few years, resulting in noteworthy breakthroughs and FDA approvals of new therapeutic treatments in AML patients. Targeted therapies and combinations of different classes of therapeutic agents to overcome treatment resistance further expanded the treatment options and improved survival. Immunotherapy, including antibody-based treatment, inhibition of immune negative regulators, and possible CAR T cells might further expand the therapeutic armamentarium for AML. This review is intended to summarize the recent developments in the treatment of AML.

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Section: Venetoclax + Intensive Chemotherapymentioning

confidence: 99%

Emerging agents and regimens for AML

Liu

2021

J Hematol Oncol

116

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“…The combination therapy of venetoclax with intensive therapy is currently under investigation. In our observational study, we treated 13 r/r AML patients with FLAG-IDA in combination with venetoclax (FLA-V-IDA; venetoclax given on days 1-7) and compared the results retrospectively with 81 r/r AML patients treated with FLAG-IDA alone [19]. Overall, the venetoclax combination therapy was well tolerated with no excess hematological toxicity.…”

Section: Novel Substances-non-targeted Venetoclaxmentioning

confidence: 99%

“…A key pathophysiological consequence of mutant IDH1 and IDH2 is the production of the oncometablite 2-hydroxgluterate (2-HG) [38]. While IDH1/2 mutations do not have major prognostic relevance [19,20], they have gained clinical significance due to the development of targeted therapies. Oral inhibitors have been introduced that inhibit the mutant form of the enzyme and block the production of 2-HG.…”

Section: Idh1 and Idh2 Inhibitionsmentioning

confidence: 99%

Treatment of Relapsed Acute Myeloid Leukemia

Thol

Ganser

2020

Curr. Treat. Options in Oncol.

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153

108

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This article is part of the Topical Collection on Leukemia Keywords Relapse AML I Salavage chemotherapy I Venetoclax I FLT3 inhibitors I IDH1/IDH2 inhibitors I CPX-351 Opinion statement Relapse is still a common scenario in acute myeloid leukemia (AML) treatment and occurs in 40-50% of younger and the great majority of elderly patients. The prognosis in relapsed AML patients is generally poor but depends largely on the timing of relapse (early versus late) and the possibility of allogeneic hematopoietic stem cell transplantation (HSCT). At the time of relapse, we again perform a mutational screening and cytogenetic analysis in all AML patients as clonal evolution of disease is frequent. Clinical trials should be first priority in all relapsed patients. In fit patients without prior transplant, we aim to perform HSCT after salvage therapy. In AML patients relapsing after HSCT and good performance status, intensive therapy can be considered with subsequent cellular therapy such as donor lymphocyte infusion (DLI) or a second HSCT. However, less than 20% of these patients are alive after 5 years. For those patients that are unfit, the therapeutic aim is to prolong life with acceptable quality of life. Here, hypomethylating agents (HMA), low-dose AraC (LDAC), and solely cytoreductive therapy with hydroxurea are options depending on first-line therapy. For those patients that have not been treated with venetoclax in first line, the combination therapy of venetoclax with demethylating agents achieves encouraging response rates. Venetoclax is currently also studied in combination with intensive salvage therapy. Importantly, for patients with isocitrate dehydrogenase (IDH) 1/2-mutated AML, ivosidenib, an IDH1 inhibitor, and enasidenib, an IDH2 inhibitor, present well-tolerated options in the setting of refractory or relapsed (r/r) disease even in elderly and heavily pretreated patients with response rates of 30-40%. Both substances have been approved by the U.S. Food and Drug Administration (FDA) for r/r AML patients with IDH1/2 mutations (but not yet by the European Medicines Agency (EMA)). For patients with FMS-like tyrosine kinase 3 (FLT3) mutations, treatment with the selective FLT3 inhibitor gilteritinib is well tolerated and leads to improved outcome compared with standard salvage therapy. The approval has been granted by the FDA and the EMA. Generally, we would recommend targeted therapy for IDH1/2-and FLT3-mutated AML if available. In order to improve outcome in relapsed AML, it

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“…In our observational study, 13 r/r AML patients received FLA-V-IDA (FLAG-IDA plus venetoclax given on days 1–7). 18 The outcomes of these 13 FLA-V-IDA patients were retrospectively compared to 81 r/r AML patients treated with conventional FLAG-IDA. Importantly, the addition of 7-day venetoclax did not result in excess hematological toxicity.…”

Section: Treatment Choice In Fit/transplant Eligible Patientsmentioning

confidence: 99%

Treatment for Relapsed/Refractory Acute Myeloid Leukemia

Thol

Heuser

2021

HemaSphere

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Patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) have a poor prognosis and treatment remains challenging. For the majority of r/r patients, allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment approach. Salvage therapy is given in order to reduce the leukemia load prior to transplantation. Patients achieving complete remission prior to allogeneic HSCT have a more favorable outcome. Intensive salvage regimens commonly consist of an anthracycline and high-dose cytarabine backbone. Donor lymphocyte infusions have shown efficacy in patients relapsing after allogeneic HSCT. For patients who cannot be intensively treated (eg, elderly AML patients), outcome is generally very poor and combinations with novel agents are currently under investigation. Mutational analysis should be repeated at the time of relapse to identify aberrations that can be targeted with new agents. For r/r AML patients with mutated fms-related tyrosine kinase 3 (FLT3), gilteritinib has shown superior results to intensive salvage regimens. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved gilteritinib for FLT3 mutated r/r AML patients. Ivosidenib and enasidenib, inhibitors for mutated isocitrate dehydrogenase (IDH) 1 and 2, respectively, have received approval for IDH1/IDH2 mutated r/r AML by the FDA (not EMA). APR-246 restores the function of mutated TP53 and early study results are promising. Other agents targeting CD47, menin, neural-precursor-cell-expressed developmentally down-regulated 8, as well as bispecific antibodies or chimeric antigen receptor T cells are under investigation. Further trials are needed to understand how to best combine novel agents with each other or with chemotherapy.

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FLA‐IDA salvage chemotherapy combined with a seven‐day course of venetoclax (FLAVIDA) in patients with relapsed/refractory acute leukaemia

Cited by 27 publications

References 10 publications

Emerging agents and regimens for AML

Emerging agents and regimens for AML

Treatment of Relapsed Acute Myeloid Leukemia

Treatment for Relapsed/Refractory Acute Myeloid Leukemia

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