Efficacy and safety of romiplostim in refractory aplastic anaemia: a Phase II/III, multicentre, open‐label study

Jang, Jun Ho; Tomiyama, Yoshiaki; Miyazaki, Kôji; Nagafuji, Koji; Usuki, Kensuke; Uoshima, Nobuhiko; Fujisaki, Tomoaki; Kosugi, Hiroshi; Matsumura, Itaru; Sasaki, Ko; Kizaki, Masahiro; Sawa, Masashi; Hidaka, Masaaki; Kobayashi, Naoki; Ichikawa, Satoshi; Yonemura, Yuji; Enokitani, Kouki; Matsuda, Akihisa; Ozawa, Keiya; Mitani, Kinuko; Lee, Jong Wook; Nakao, Shinji

doi:10.1111/bjh.17190

Cited by 29 publications

(34 citation statements)

References 17 publications

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“…Consistent with these observations, we found that Epag significantly increase CFU in the 2 nd /3 rd plating but not the 1 st plating. Several TPO-R agonists demonstrate similar hematopoietic activities in aplastic anemia, including TPO peptide mimetic romiplostim (37,38), which does not inhibit TET2. In the multilineage recovery of AA patients, the TET-inhibitory effect of Epag may be secondary to TPO-R activation.…”

Section: Discussionmentioning

confidence: 99%

Eltrombopag inhibits TET dioxygenase to contribute to hematopoietic stem cell expansion in aplastic anemia

Guan¹,

Hasipek²,

Jiang³

et al. 2022

Journal of Clinical Investigation

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Eltrombopag, an FDA-approved non-peptidyl thrombopoietin receptor agonist is clinically used for the treatment of aplastic anemia, a disease characterized by hematopoietic stem cell failure and pancytopenia, to improve platelet counts and stem cell function. Eltrombopag treatment results in a durable tri-lineage hematopoietic expansion in patients. Some of the eltrombopag hematopoietic activity has been attributed to its off-target effects including iron chelation properties. However, the mechanism of action for its full spectrum of clinical effects is still poorly understood. Here, we report that eltrombopag bound to the TET2 catalytic domain and inhibited its dioxygenase activity, which was independent of its role as an iron chelator. The DNA demethylating enzyme TET2, essential for hematopoietic stem cell differentiation and lineage commitment, is frequently mutated in myeloid malignancies. Eltrombopag treatment expanded TET2 proficient normal hematopoietic stem and progenitor cells, in part, due to its ability to mimic loss of TET2 with simultaneous thrombopoietin receptor activation. On the contrary, TET inhibition in TET2 mutant malignant myeloid cells prevented neoplastic clonal evolution, in vitro and in vivo. This mechanism of action may offer a restorative therapeutic index and provide a scientific rationale to treat selected patients with TET2-mutant or TET-deficiency-associated myeloid malignancies.

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Section: Discussionmentioning

confidence: 99%

Eltrombopag inhibits TET dioxygenase to contribute to hematopoietic stem cell expansion in aplastic anemia

Guan¹,

Hasipek²,

Jiang³

et al. 2022

Journal of Clinical Investigation

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“…In this dose‐finding study, the more optimal dose appeared at 10 μg/kg or higher which is being applied in further development. In a 31‐patient cohort, romiplostim in the second line was associated with an 84% overall response rate in which 39% were trilineage 209 . Other retrospective studies have also shown activity of romiplostim in refractory SAA but at a lower rate 215 .…”

Section: Therapymentioning

confidence: 89%

“…In a 31-patient cohort, romiplostim in the second line was associated with an 84% overall response rate in which 39% were trilineage. 209 Other retrospective studies have also shown activity of romiplostim in refractory SAA but at a lower rate. 215 Further data will better define the role of romiplostim in this setting.…”

Section: Eltrombopag In Refractory Severe Aplastic Anaemiamentioning

confidence: 99%

Acquired severe aplastic anaemia: how medical therapy evolved in the 20th and 21st centuries

Scheinberg

2021

Br J Haematol

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The progress in aplastic anaemia (AA) management is one of success. Once an obscure entity resulting in death in most affected can now be successfully treated with either haematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST). The mechanisms that underly the diminution of haematopoietic stem cells (HSCs) are now better elucidated, and include genetics and immunological alterations. Advances in supportive care with better antimicrobials, safer blood products and iron chelation have greatly impacted AA outcomes. Working somewhat 'mysteriously', anti-thymocyte globulin (ATG) forms the base for both HSCT and IST protocols. Efforts to augment immunosuppression potency have not, unfortunately, led to better outcomes. Stimulating HSCs, an often-sought approach, has not been effective historically. The thrombopoietin receptor agonists (Tpo-RA) have been effective in stimulating early HSCs in AA despite the high endogenous Tpo levels. Dosing, timing and best combinations with Tpo-RAs are being defined to improve HSCs expansion in AA with minimal added toxicity. The more comprehensive access and advances in HSCT and IST protocols are likely to benefit AA patients worldwide. The focus of this review will be on the medical treatment advances in AA.

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“…These patients eventually died as a result of AML and MDS, respectively. In previous studies on TPO-RA treatment for AA, clonal evolution and AML have been observed at an incidence of 3-19% and 0-4%, respectively [2,4,17,19,27]. However, it is also reported that secondary MDS or AML occurs in 15-20% of patients with AA regardless of the use of TPO-RAs [28].…”

Section: Discussionmentioning

confidence: 99%

Real-World Experience of Treatment With Thrombopoietin Receptor Agonists in Anti-thymocyte Globulin-Naïve Patients With Aplastic Anemia: An Observational Retrospective Analysis in a Single Institution

Iino

Sato

Jinguji

et al. 2021

Preprint

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Thrombopoietin receptor agonists (TPO-RAs) are used to treat bone marrow failure in aplastic anemia (AA). Treatment with TPO-RAs, cyclosporine A (CsA) and anti-thymocyte globulin (ATG) induces remission and a sustained response. However, the efficacy of TPO-RAs without ATG remains unclear. We retrospectively assessed 45 patients with AA refractory to CsA and naïve for ATG treatment who received eltrombopag without ATG at our hospital during 2017-2021. Of these, 28 (62%) achieved a hematologic response in at least one lineage after six months of treatment, and 38 (84%) achieved best response at any point during the follow-up period. Four patients (25%) achieved trilineage responses during the follow-up period. Five patients switched from eltrombopag to romiplostim because of adverse events or lack of efficacy. Two developed hematologic malignancies. Eltrombopag was effective even in elderly ATG-ineligible patients with severe AA. The two-year overall survival rate was 84.3%, with a median follow-up of 26.3 months. Time from diagnosis to eltrombopag treatment initiation tended to affect the response (p = 0.0727), but no factors that significantly predicted hematologic response were identified. In conclusion, patients who are ineligible for ATG treatment because of age, complications, or even severe AA should nevertheless be considered for TPO-RA treatment.

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Efficacy and safety of romiplostim in refractory aplastic anaemia: a Phase II/III, multicentre, open‐label study

Cited by 29 publications

References 17 publications

Eltrombopag inhibits TET dioxygenase to contribute to hematopoietic stem cell expansion in aplastic anemia

Eltrombopag inhibits TET dioxygenase to contribute to hematopoietic stem cell expansion in aplastic anemia

Acquired severe aplastic anaemia: how medical therapy evolved in the 20th and 21st centuries

Real-World Experience of Treatment With Thrombopoietin Receptor Agonists in Anti-thymocyte Globulin-Naïve Patients With Aplastic Anemia: An Observational Retrospective Analysis in a Single Institution

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