Sorafenib Promotes Graft-Versus-Leukemia Activity in Mice and Humans through IL-15 Production in Leukemia Cells

Mathew, Nimitha R.; Baumgartner, Francis; Waterhouse, Miguel; Müller, Tony Andreas; Schmitt‐Gräff, Annette; Weber, Arnim; Osswald, Lena; Hanke, Kathrin; Solsona, Sònia Tugues; Spath, Sabine; Pfeifer, Dietmar; Follo, Marie; Claus, Rainer; Lübbert, Michael; Rummelt, Christoph; Bertz, Harmut; Marks, Reinhard; Wäsch, Ralph; Bettinger, Dominik; Schultheiß, Michael; Jilg, Cordula A.; Ullrich, Evelyn; Tanriver, Yakup; Klose, Christoph S. N.; Jung, Manfred; Vuong, Lam; Velden, W. van der; Thimme, Robert; Blazar, Bruce R.; Bubnoff, Nikolas von; Becher, Burkhardt; Duyster, Justus; Häcker, Georg; Finke, Jürgen; Arnold, Renate; Schiedel, Matthias; Zeiser, Robert

doi:10.1016/j.bbmt.2015.11.389

Cited by 12 publications

(13 citation statements)

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“…Ongoing post-HCT maintenance therapy studies use more FLT3-specific TKIs, such as quizartinib or gilteritinib. 47,48 They could help to better understand to which extent FLT3 selectivity versus immune-stimulatory off-target activities [27][28][29]49 govern the overall efficacy of sorafenib.…”

Section: Discussionmentioning

confidence: 99%

Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3–Internal Tandem Duplication Mutation (SORMAIN)

Burchert

Bug

Fritz

et al. 2020

JCO

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361

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PURPOSE Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the FMS-like tyrosine kinase 3 gene ( FLT3-ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT. PATIENTS AND METHODS In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with FLT3-ITD–positive AML in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40 placebo). Relapse-free survival (RFS) was the primary endpoint of this trial. Relapse was defined as relapse or death, whatever occurred first. RESULTS With a median follow-up of 41.8 months, the hazard ratio (HR) for relapse or death in the sorafenib group versus placebo group was 0.39 (95% CI, 0.18 to 0.85; log-rank P = .013). The 24-month RFS probability was 53.3% (95% CI, 0.36 to 0.68) with placebo versus 85.0% (95% CI, 0.70 to 0.93) with sorafenib (HR, 0.256; 95% CI, 0.10 to 0.65; log-rank P = .002). Exploratory data show that patients with undetectable minimal residual disease (MRD) before HCT and those with detectable MRD after HCT derive the strongest benefit from sorafenib. CONCLUSION Sorafenib maintenance therapy reduces the risk of relapse and death after HCT for FLT3-ITD–positive AML.

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Section: Discussionmentioning

confidence: 99%

Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3–Internal Tandem Duplication Mutation (SORMAIN)

Burchert

Bug

Fritz

et al. 2020

JCO

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361

293

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“…Treatment in this study started between days 45 and 120 post‐HCT (median: 70 days). It has been suggested that sorafenib has both cytotoxic and maturating effects on leukaemic cells (Liegel et al , ), and these effects may potentiate or synergize with the GVL effect (Mathew et al , ). Crenolanib is being studied as post‐HCT maintenance in FLT3 ‐mutated patients (NCT02400255).…”

Section: Small Moleculesmentioning

confidence: 99%

Treatment of relapsed/refractory acute myeloid leukaemia in adults

2018

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The prognosis of relapsed acute myeloid leukaemia (AML) is poor and treatment is challenging. While the most potent treatment modality for patients who achieve a complete remission after relapse is still allogeneic haematopoietic cell transplantation (allo-HCT), both transplant-related mortality and relapse rates are high and many patients are not candidates for this approach. After a few decades of relative stasis in this field, a large number of novel approaches have become available to tackle this highly fatal disease. This is mostly due to our improved understanding of disease pathogenesis (including targetable mutations) and the anti-leukaemia potential of the immune system. Several small-molecule inhibitors and immunotherapeutic options are being explored in clinical trials and many more are in pre-clinical phase. Future studies will focus on novel and mechanistically driven combinations, sequential treatments, and low-toxicity maintenance strategies. While cure of relapsed/refractory AML without allo-HCT is currently unlikely, treatments are becoming less toxic and remissions are lasting longer.

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“…45 This seems to be in part mediated by sorafenib promoting the secretion of IL-15 and promoting a significant graft versus leukemic effect. 46 Prospective evaluation of the use of midostaurin posttransplant maintenance is being investigated in the RADIUS trial (NCT01883362) and NCT01477606 with no published results at this time. Furthermore, whether or not IL-15 induction occurs with gilteritinib remains to be investigated.…”

Section: Maintenance Therapymentioning

confidence: 99%

Gilteritinib: An FMS-like tyrosine kinase 3/AXL tyrosine kinase inhibitor for the treatment of relapsed or refractory acute myeloid leukemia patients

Reed

Sen

Pierce

et al. 2020

J Oncol Pharm Pract

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Acute myeloid leukemia has recently undergone a significant transition into identifying and successfully inhibiting driver mutations leading to disease. One of the most common mutations in acute myeloid leukemia involves the protein FMS-like tyrosine kinase 3 (FLT3), which leads to ligand-independent activation of intracellular signaling cascades leading to the survival and proliferation of the acute leukemia blast cell. Preclinical studies have demonstrated the presence of two dominant types of mutations of this protein: internal tandem duplication and tyrosine kinase domain mutations. Successful inhibition of this protein has proven to be challenging. While FLT3 has been shown to be successfully inhibited and shown to improve overall survival in the frontline therapy of acute myeloid leukemia in combination with cytarabine and anthracycline, relapsed and refractory (R/R) patients have not been shown to be a successful population until recently. A phase III trial (ADMIRAL trial) demonstrated significant overall survival benefit in patients receiving gilteritinib compared to patients receiving salvage chemotherapy. This review will provide an overview of the preclinical, clinical, and practical use of gilteritinib in the treatment of patients with relapsed and refractory acute myeloid leukemia with FLT3 mutation.

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Sorafenib Promotes Graft-Versus-Leukemia Activity in Mice and Humans through IL-15 Production in Leukemia Cells

Cited by 12 publications

References 0 publications

Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3–Internal Tandem Duplication Mutation (SORMAIN)

Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3–Internal Tandem Duplication Mutation (SORMAIN)

Treatment of relapsed/refractory acute myeloid leukaemia in adults

Gilteritinib: An FMS-like tyrosine kinase 3/AXL tyrosine kinase inhibitor for the treatment of relapsed or refractory acute myeloid leukemia patients

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