More than a quarter of patients with severe aplastic anemia remain pancytopenic despite immunosuppressive therapy, and others have suboptimal responses in at least one lineage. We have developed a program to ask whether use of a drug stimulating the c-mpl receptor, which binds the endogenous hormone thrombopoietin, could stimulate human hematopoietic stem cells in vivo. Murine, our own rhesus, and human data all suggest that thrombopoietin can stimulate primitive hematopoietic stem and progenitor cells to proliferate without terminal differentiation. The small molecule oral thrombopoietin mimetic eltrombopag was initially developed to overstimulate platelet production from marrow megakaryocytes to compensate for platelet destruction in immune thrombocytopenia purpura ITP). We originally developed a protocol utilizing eltrombopag in a phase 1/2 clinical trial for patients with refractory severe aplastic anemia. We reported that eltrombopag had efficacy in this setting with 44% (11/25) of patients having clinically significant hematologic responses (Olnes et al, NEJM 2012). We then reported additional safety and efficacy data on an expanded cohort of 43 patients, confirming an overall response rate or 40% with 3 to 4 months of treatment, including tri- and bilinear responses (Desmond et al, Blood, 2014). The majority of patients who remained on eltrombopag in an extension study (14/17) continued to show improvement, and 7 eventually had significant increases in neutrophil, red cell, and platelet lineages. Five patients with robust near-normalization of blood counts had drug discontinued at a median of 28.5 months after entry (range, 9-37 months), and all maintained stable counts a median of 13 months (range, 1-15 months) off eltrombopag. Eight patients, including 6 nonresponders and 2 responders, developed new cytogenetic abnormalities on eltrombopag, including 5 with chromosome 7 loss or partial deletion. This program resulted in FDA approval of a new labeled indication for eltrombopag in August 2014, and European commission approval in late 2015 for eltrombopag treatment of refractory aplastic anemia. This is the first new drug approved for aplastic anemia in decades and the first drug approved specifically for the refractory aplastic anemia patient population. In addition, a collaborative trial carried out with Dr Neal S Young and his Branch documented that EPAG added to standard immunosuppression for untreated severe AA resulted in improved outcomes (Townsley et al, NEJM, 2017), leading to a 2nd FDA/EHA approval for EPAG in AA based on our studies. During the current reporting period, we completed analysis and published the results of an additional clinical protocol (13-H-0133), asking whether more prolonged administration of eltrombopag to patients with refractory SAA, for 6 months instead of 3 months, and starting at a dose of 150mg/day instead of employing dose escalation, would improve response rate and rescue a larger fraction of refractory patients, based on the observation that patients in the initial trial improved markedly after the primary 3 month end point if they remained on drug. The response rate in 40 patients enrolled in this trial at the primary 6 month end point was 50%, not significantly improved over the initial trial. However, 25% of patients (5/20) did not reach response criteria at 3 months but were responders at 6 months, and thus were salvaged by the more prolonged treatment. Responses were faster than on the initial trial, due to starting at full dose, in contrast to dose escalation in the original trial, with no additional toxicity. We have combined both cohorts for molecular analyses asking whether EPAG impacts on clonal progression, and whether HPSC carrying mutations in specific genes linked to myeloid malignancies or other clones defined by new somatic mutations are specifically stimulated by EPAG treatment. Whole exome sequencing was performed in baseline samples and 6 month samples in all responding patients, and in any patient that developed cytogenetic abnormalities while on study. We found no evidence for specific clonal expansions related to EPAG treatment. The cytogenetic progression rate in both trials combined is now 19%. Of note, all patients that developed monosomy 7 or other deleterious chromosome 7 abnormalities did so within the first 3-6 months, suggesting potential preferential stimulation of a pre-existing clone. Other cytogenetic abnormalities appeared later, were often transient whether on or off drug, and were not accompanied by dysplastic changes or leukemic progression. This study was published this reporting year (Winkler et al, Blood, 2019). During the reporting period, we completed preliminary analyses of 34 patients enrolled in a clinical trial (11-H-0134) examining safety and efficacy of eltrombopag in patients with moderate aplastic anemia or unilineage cytopenias. The response rate was 50% at the primary endpoint of 4 months, including in a patient with the inherited Diamond-Blackfan Anemia (DBA). Patients tolerated doses up to 300mg/day without significant toxicity. We noted a lower rate of cytogenetic progression (6%) than in the prior trials in severe refractory aplastic anemia, and no patients with chromosome 7 cytogenetic progression. 65% of patients were able to have EPAG discontinued for a robust multi lineage response, however the majority needed to have the drug restarted to maintain counts, in contrast to our prior experience in refractory severe aplastic anemia. This work was presented orally at the American Society of Hematology meeting December 2018 and will be submitted for publication in FY2020. Based on data generated in all three trials, we made the observation that eltrombopag acts as a clinically-relevant iron chelator, raising blood levels of iron and resulting net iron loss in patients on the drug long term. Several patients have required oral iron supplementation. We hypothesize that the activity of EPAG in reversing anemia in the inherited ribosomopathy DBA may be due to the potent intracellular chelating activity of EPAG, because recent laboratory studies suggest that erythroid development is inhibited in DBA due to slowed protein synthesis in erythroid progenitors, with a resulting imbalance in global chain production versus heme biosynthesis, leading to free heme/increased intracellular iron and toxic accumulation of reactive oxygen species. We have designed a clinical trial to test the activity of EPAG in DBA and this protocol has gone through NHLBI review, drug company application for provision of EPAG for the trial, and is currently undergoing IRB submission, with hopes to begin the trial in FY2020. In collaboration with Dr Andre Larochelle, we have elucidated the likely mechanism of EPAG activity in patients with high endogenous levels of TPO. This work was described in his annual report and was published this year (Alvarado et al, Blood, 2019).
| Zhao, Zhen; Sun, Qian; Sokoll, Lori J et al. (2018) Eltrombopag mobilizes iron in patients with aplastic anemia. Blood 131:2399-2402 |
| Panch, Sandhya R; Bozik, Michael E; Brown, Thomas et al. (2018) Dexpramipexole as an oral steroid-sparing agent in hypereosinophilic syndromes. Blood 132:501-509 |
| Dulau-Florea, Alina E; Young, Neal S; Maric, Irina et al. (2018) Bone Marrow as a Source of Cells for Paroxysmal Nocturnal Hemoglobinuria Detection. Am J Clin Pathol : |
| Zhao, Xin; Feng, Xingmin; Wu, Zhijie et al. (2018) Persistent elevation of plasma thrombopoietin levels after treatment in severe aplastic anemia. Exp Hematol 58:39-43 |
| Townsley, Danielle M; Scheinberg, Phillip; Winkler, Thomas et al. (2017) Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med 376:1540-1550 |
| Corat, Marcus A F; Schlums, Heinrich; Wu, Chuanfeng et al. (2017) Acquired somatic mutations in PNH reveal long-term maintenance of adaptive NK cells independent of HSPCs. Blood 129:1940-1946 |
| Bat, Taha; Bat, Betul E; El-Moghraby, Ahmed et al. (2016) Thrombopoietic status of patients on haemodialysis. Br J Haematol 172:954-7 |
| Balakumaran, Arun; Mishra, Prasun J; Pawelczyk, Edyta et al. (2015) Bone marrow skeletal stem/progenitor cell defects in dyskeratosis congenita and telomere biology disorders. Blood 125:793-802 |
| Desmond, Ronan; Townsley, Danielle M; Dunbar, Cynthia et al. (2015) Eltrombopag in aplastic anemia. Semin Hematol 52:31-7 |
| Jung, Moonjung; Dunbar, Cynthia E; Winkler, Thomas (2015) Modeling Human Bone Marrow Failure Syndromes Using Pluripotent Stem Cells and Genome Engineering. Mol Ther 23:1832-42 |
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