Sequential Use of Romiplostim after Eltrombopag for Refractory Thrombocytopenia in Hydrocarbon-Induced Myelodysplasia

Abstract

We describe the clinical course of a 65-year-old male patient who suffered from hydrocarbon-induced myelodysplasia and was successfully treated with the thrombopoietin receptor agonist (TPO-RA), romiplostim. Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, cytopenias, and increased risk of leukemic transformation. Here, we present a clinical vignette of MDS-associated thrombocytopenia refractory to first-line drugs as well as the TPO-RA, eltrombopag. To date, romiplostim is an U.S. Food and Drug Administration (FDA)-approved drug for idiopathic thrombocytopenic purpura and thrombocytopenia secondary to liver disease. Of note, currently the FDA advises against its use in MDS based on previous long-term safety concerns. Since the therapeutic options for thrombocytopenia in MDS patients are sparse, repurposing and reassessing romiplostim in this setting have been the focus of recent studies. At the time of writing, no published double-blind randomized clinical trials have conducted a head-to-head comparison between romiplostim and eltrombopag in thrombocytopenic MDS patients. To the best of our knowledge, for a thrombocytopenic patient in the setting of MDS, this is the first documented report of refractory clinical response after a 2-year use of eltrombopag in which replacement of treatment with romiplostim resulted in sustained physiological counts of thrombocytes within four weeks.

Myelodysplastic syndromes (MDS) are a group of hematologic malignancies characterized by clonal hematopoiesis, one or more cytopenias, and abnormal cellular differentiation. MDS are caused by mutations in hematopoietic stem cells. ^{1 2} The precise cause of these mutations in most patients is not known, but in a subset, it is caused by exposure to cytotoxic chemotherapy, ionizing radiation, or environmental toxins, such as tobacco or benzene. Patients suffering from MDS may present with anemia, infections, bleeding, and are at increased risk of leukemic transformation. ³ Most deaths in MDS patients are due to the consequences of cytopenias rather than transformation to acute myeloid leukemia (AML); therefore, improving blood cell deficiencies is a priority in this setting. ⁴ Large studies have shown the increased risk of MDS among petroleum workers. ^{5 6} Benzene is a natural component of crude oil, which represents the most important source of benzene production. ⁷ The carcinogenicity of benzene has been exhaustively studied and demonstrated in a broad number of conditions, mainly hematologic, including MDS, acute myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, and lymphoma, among others. ⁸ Lead is a heavy metal associated with multisystemic insults, especially compromising the neurologic and hematologic systems. ⁹ Gasoline emissions are considered currently the most significant source of lead exposure. ¹⁰

The present communication describes a 65-year-old gentleman who worked as a professional gasoline truck driver for 25 years, who, after documented poisoning by benzene and lead, received sequential treatment with first eltrombopag and then romiplostim. The unsuccessful response to eltrombopag, prompted a trial with romiplostim, which resulted in normalization of platelet counts within 4 weeks of treatment. Successful sequential use of romiplostim after eltrombopag (and vice versa) has been previously described in the literature. However, the mechanisms of these differential effects are not fully understood. ^{11 12 13} Eltrombopag and romiplostim are U.S. Food and Drug Administration (FDA)-approved drugs indicated in immune thrombocytopenic purpura (ITP) and thrombocytopenia secondary to liver disease. ^{14 15 16 17 18 19} It is well documented that both drugs can bind to and activate the human thrombopoietin receptor MPL, present in pluripotent hematopoietic stem cells, megakaryocyte progenitors, and megakaryocytes. ^{20 21} Activation of the MPL receptor promotes megakaryocytes proliferation and differentiation, resulting in increased platelet production. ¹⁴ Nonetheless, eltrombopag and romiplostim are structurally different; eltrombopag is a nonpeptide agonist of the thrombopoietin receptor orally active, while romiplostim is a “peptibody” (a combination of a peptide and an antibody) injected subcutaneously. ¹³ Furthermore, eltrombopag and romiplostim activate the MPL receptors by dissimilar molecular mechanisms, which are described in our discussion. ¹²

Case Presentation

A 65-year-old male with a past medical history of insulin-dependent diabetes mellitus, hyperlipidemia, right lower extremity amputation, and a 25-year history of driving a fuel truck presented with complaints of petechiae, ecchymoses, easy bleeding, and bruising, as well as dry skin. A preliminary diagnosis of ITP was made. Initial treatment with corticosteroids was unsuccessful. Azathioprine treatment was initiated, but later discontinued due to poor tolerance by the patient and side effects, including nausea, vomiting, and rash. A subsequent bone marrow biopsy led to a diagnosis of myelodysplasia with medullary hypoplasia and marked thrombocytopenia. Blood testing showed a lead level of 55 μg/dL, delta aminolevulinic acid dehydratase of 85 mol/L/24 hours, hemoglobin 7.1 g/dL, hematocrit 21%, platelets 22 K/μL, poikilocytosis, anisocytosis, and giant platelets. The concentration of benzene was determined to be 98 μg/L by atomic absorption spectroscopy of the patient's urine sample. Azacitidine was subsequently prescribed, with no clinical improvement. For the next 2 years, the patient was treated daily with 75 mg of the bone marrow stimulant eltrombopag and 20 mg of methylprednisolone (both orally administered). Platelet counts remained at 22 K/μL, with a hemoglobin of 9 g/dL and a hematocrit of 25%. At the time of our initial encounter, eltrombopag was discontinued, methylprednisolone reduced to 10 mg, and subcutaneous romiplostim was started at a dose of 1.0 μg/kg. After the first week of treatment, the platelet count increased to 33 K/μL and giant platelets were detected. The romiplostim dose was doubled (2.0 μg/kg weekly), and the platelet count increased to 68 K/μL by the end of the second week. The romiplostim dose was further increased to 3.0 μg/kg, resulting in a platelet count of 135 K/μL by the end of the third week. Romiplostim was maintained at a constant weekly dose over the next 4 weeks, with platelets reaching 156 K/μL. Romiplostim was subsequently discontinued, and after 8 weeks of no treatment, the platelet count remained stable at 135 K/μL. Seven months following romiplostim treatment, the patient continues to have a normal complete blood count and is asymptomatic ( Fig. 1 ).

Fig. 1.

Total platelet count per microliter after initiation and discontinuation of the thrombopoietin receptor agonist romiplostim, including a 2-week follow-up.

Discussion

Thrombocytopenia is present in more than 50% of MDS patients and is linked with higher mortality and increased bleeding risk. ^{22 23} Bleeding is a major concern in MDS, since it can range from nonlife-threatening bleeding events like petechiae, bruising, epistaxis, retinal hemorrhages, and gingival bleeding to potentially deleterious events such as intracranial or pulmonary hemorrhage. ²⁴

In 2012, Aoki et al reported the first case of a patient with refractory ITP previously treated with eltrombopag, which was responsive to romiplostim. ¹¹ On the other hand, in 2013 D'Arena et al described two ITP patients resistant to romiplostim but cured with eltrombopag. ²⁵ Romiplostim and eltrombopag are considered equally effective in adults with ITP; however, a comparative analysis on the effectiveness has not been conducted in MDS patients. ¹⁵ Preclinical studies on megakaryocytic cell lines proved that romiplostim and eltrombopag have different proliferative capabilities. ²⁶ It is unclear why romiplostim and eltrombopag can be effective in refractory MDS patients who received one of these two drugs; however, the absence of cross-resistance between these two thrombopoietin receptor agonist (TPO-RA) suggests that substantial differences may exist in their mechanisms of action. ¹¹ It is well established that romiplostim and eltrombopag activate the MPL receptor by different mechanisms; romiplostim binds to the extracellular domain of the MPL receptor, mimicking the effects of endogenous thrombopoietin. Conversely, eltrombopag exerts its effect by interacting with the transmembrane domain of the MPL receptor. ¹² Therefore, activation of the MPL receptor by endogenous thrombopoietin or romiplostim results in upregulation of STAT, AKT/PI3K, and MAPK effectors. In contrast, eltrombopag promotes the activation of the STAT pathway, but not of AKT. ^{27 28} Currently, TPO-RA is not approved by the FDA for MDS patients. Although controversial, early studies suggested that TPO-RA may increase the risk of progression to. ⁴ In 2014, a double-blind randomized controlled trial of romiplostim for MDS was suspended due to increased blast cell counts. Additionally, two participants treated with romiplostim developed bone marrow fibrosis. ²⁹

In summary, although the jury is still out, it is possible that MDS patients with low risk of leukemic transformation may represent good candidates for sequential treatment of eltrombopag-romiplostim (or vice versa) when persistent bleeding represents a significant complication in refractory thrombocytopenia. Further clinical and preclinical research is required to clarify who are the best candidates for sequential treatment with TPO-RA in MDS patients.