Romiplostin may revert the thrombocytopenia in graft‐versus‐host disease

Abstract

The thrombocytopenia ensuing during acute graft‐versus‐host disease (GVHD) is multifactorial and may significantly compromise the prognosis of the patient; non‐immune persistent thrombocytopenia has been considered as an adverse prognostic factor in GVHD. We describe here the case of a 10‐year‐old girl who developed steroid‐refractory thrombocytopenia and who responded promptly to the subcutaneous delivery of romiplostin. To the best of our knowledge, this is the first description of the usefulness of the peptibody in the setting of GVHD.

Keywords:

• Romiplostin
• GVHD
• Graft‐versus‐host disease
• Thrombocytopenia

Introduction

Thrombopoietin (TPO) is the key cytokine involved in thrombopoiesis, and is the endogenous ligand for the TPO receptor that is expressed on the surface of platelets, megakaryocytes, and megakaryocytic precursors. First‐generation thrombopoietic agents were recombinant forms of human TPO, but their development was discontinued after prolonged thrombocytopenia due to neutralizing auto‐antibodies cross‐reacting with endogenous TPO was observed. Second‐generation thrombopoiesis‐stimulating molecules are now available, which have unique pharmacological properties and no sequence homology to endogenous TPO. Two of these new agents, romiplostim and eltrombopag, have already completed phase III trials in primary immune thrombocytopenia and have been granted marketing authorization for use in this disease. Phase II and III trials with these novel drugs are ongoing in other conditions characterized by thrombocytopenia, such as chemotherapy, chronic liver disease, the myelodysplastic syndromes, and other conditions.1,2

Allogeneic hematopoietic stem cell transplantation (HSCT) is an important therapeutic option for various malignant and nonmalignant conditions. As allogeneic HSCT continues to increase, greater attention is given to improvements in supportive care, infectious prophylaxis, immunosuppressive medications, and DNA‐based tissue typing. However, graft‐versus‐host disease (GVHD) remains the most frequent and serious complication following allogeneic HSCT and limits the broader application of this important therapy.3 GVHD is a consequence of interactions between the donor and host and their innate and adaptive immune responses. The fundamental interaction for induction of GVHD is the interaction of donor T cells with antigen‐presenting cells and that this interaction is regulated positively or negatively by a plethora of cytokines, chemokines, and several immune cell subsets. The hematological features of acute GVHD include pancytopenia and sometimes complete marrow failure occurs, which usually resolves if the GVHD is controlled.4 Non‐immune persistent thrombocytopenia has been considered as an adverse prognostic factor in GVHD.5 We present here the case of a 10‐year‐old girl who developed refractory thrombocytopenia during acute GVHD which finally resolved with the use of romiplostin. To the best of our knowledge, this is the first case of GVHD in which romiplostin has been successfully used.

Case history

This 10‐year‐old girl was diagnosed at age 3 as B‐cell acute lymphoblastic leukemia; she was treated with chemotherapy and went into a complete remission. After two relapses and refractory to chemotherapy, with 6% blast cells in the peripheral blood, she was allografted from her HLA compatible5,6 sibling on 6 June 2010, employing the ‘Mexican Method’ of reduced‐intensity conditioning.6 On day +15, she presented a cutaneous rash and a perianal vesicle which extended rapidly and whose histological study was consonant with acute GVHD; despite recovery of granulocytes above 0·5×10⁹/l, she had by then 3×10⁹/l platelets and was treated with prednisone, which limited the growth of the ulcer but did not resolve the thrombocytopenia (Fig. 1). The patient became a full chimera on day +22 and minimal residual disease assessed by flow cytometry7 since then has been consistently negative. On day 21 after the allograft, the patient remained with 3×10⁹/l platelets despite the use of prednisone (1 mg/kg/day). Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome were ruled out. At this point, subcutaneous romiplostin (5 μg/kg) was delivered the platelets rapidly increasing (Fig. 1). Romiplostin was delivered every 7 days for a total of three doses and the platelet count has remained in hemostatic levels until day +75 post‐allograft, the patient remaining a full chimera with 0% minimal residual disease.

Figure 1. Platelet count (×10⁹/l) after day 0 post‐allograft. Vertical arrows depict the subcutaneous delivery of romiplostin (5 μg/kg).

Discussion

Romiplostin is a 60 Da recombinant peptibody, produced by linking several copies of an active TPO‐binding peptide sequence to a carrier Fc fragment; it has been shown to be effective in ameliorating thrombocytopenia in patients with chronic idiopathic thrombocytopenic purpura and other thrombocytopenic conditions, is well tolerated and does not elicit cross‐reacting antibodies.8 Romiplostin is now being shown to be useful in other thrombocytopenic conditions such as dengue hemorrhagic fever (Rodríguez‐Mejorada, personal communication), myelodysplasia,9 and chemotherapy‐induced thrombocytopenia.10

The thrombocytopenia ensuing in patients with GVHD may stem from several mechanisms: impaired platelet production, increased platelet destruction, and combination of these mechanisms. The usefulness of romiplostin in this case may stem from the fact that the patient may have had a combined origin of the refractory thrombocytopenia: on the one hand, the impaired platelet production by a bone marrow which is recovering and damaged by the graft‐versus‐host reaction. and on the other hand, the mechanisms responsible for thrombocytopenia in GVHD. Additional studies are needed to confirm the usefulness of romiplostin in the setting of GVHD‐associated thrombocytopenia.