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Eltrombopag increases rate of hematologic response in severe aplastic anemia
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ORLANDO, Fla. — The addition of eltrombopag to immunosuppressive treatment increased complete hematologic response rates in patients with treatment-naive severe aplastic anemia, according to results of a late-breaking abstract presented at the ASH Annual Meeting and Exposition.
These findings suggest eltrombopag (Promacta, Novartis) with immunosuppressive treatment — which includes horse antithymocyte globulin and cyclosporine — can accelerate the rate and quality of hematopoietic recovery in these patients.
Hematologic response rates to immunosuppressive treatment for severe aplastic anemia have ranged between 60% and 65% for 3 decades, despite attempts to improve outcomes.
Eltrombopag — an oral thrombopoietin receptor agonist — previously demonstrated activity in refractory severe aplastic anemia as a single agent, conferring hematologic responses in approximately 40% of patients.
Danielle Townsley, MD, MSc, a staff clinician in the hematology branch of the National Heart, Lung and Blood Institute of the NIH, and colleagues conducted this phase 2 single-center trial to evaluate the addition of eltrombopag to the standard immunosuppressive treatment in this setting.
“The thinking was eltrombopag might be able to expand the stem cell pool, increase response rates for severe aplastic anemia, accelerate count recovery and really prevent stem cell depletion, thereby possibly avoiding clonal progression,” Townsley said during her presentation.
The investigators enrolled 88 patients (median age, 31 years; range, 3-82) with treatment-naive severe aplastic anemia between July 2012 and October 2015. Twenty-six percent of patients had very severe disease (absolute neutrophil count [ANC] ˂ 200/µL), and 34% had more than 1% paroxysmal nocturnal hemoglobinuria clones.
All patients received the standard immunosuppressive treatment, as well as 150-mg daily eltrombopag in one of three schedules: starting day 14 until 6 months (n = 30); starting day 14 until 3 months due to an initial concern of hepatotoxicity (n = 30); concurrently with standard treatment from day 1 through 6 months (n = 27).
Complete response at 6 months served as the primary endpoint.
At 6 months, the overall response rate was 80% in the first cohort, 87% in the second cohort and 92% in the third. Six-month complete response rates were 33% in the first cohort, 26% in the second cohort and 54% in the third cohort.
In the total population, 3-month overall response rate was 80% and 6-month overall response rate was 85%. The complete response rate for all patients was 28% at 3 months and 34% at 6 months. Researchers noted these rates are significantly higher than historical rates (P < .001 for all).
Among partial responders, researchers observed improvements in median ANC (1,790/µL), hemoglobin (10 gm/dL) and platelets (60,500/µL) by 3 months.
Patients with very severe neutropenia in all three cohorts (n = 23) achieved an ANC greater than 500/µL in a median of 47 days. The seven patients with very severe anemia in the third cohort achieved these levels in a median of 35 days.
Among responders, the median time to transfusion independence was 32 days for platelets and 42 days for red blood cells.
Data from bone marrow biopsies showed improved cellularity in 80% of the patients without increased fibrosis. The median increases from baseline in CD34-positive bone marrow cells at 3 months was 17-fold for the first cohort and fourfold for the second (P < .001).
Researchers noted baseline factors such as telomere length, reticulocyte count, lymphocyte count, paroxysmal nocturnal hemoglobinuria did not predicted outcome, although they appeared prognostic in prior analyses.
Eltrombopag appeared well tolerated when combined with standard immunosuppressive treatment. Two patients discontinued use of the drug because of severe cutaneous reactions, and six additional patients withdrew prior to 6 months due to having refractory disease (n = 4) or evolution to myelodysplastic syndromes (MDS; n = 2). One patient died on study due to thymoma with paraneoplastic encephalopathy, and seven patients experienced clonal evolution.
Twelve patients underwent hematopoietic stem cell transplantation due to relapse (n = 3), refractoriness (n = 6) or evolution to MDS (n = 3).
After a median follow-up of 15 months (range, 1-42 months), cytogenetic abnormalities occurred in seven patients, including four with monosomy or a partial deletion of chromosome 7 and one each of complex (t(3;3)(q21;q26), -7;), deletion 13q that later normalized, and trisomy 6 and trisomy 15 in two metaphases.
Researchers sequenced 54 candidate genes that are recurrently mutated in MDS and acute myeloid leukemia and found that four of seven patients did not harbor somatic mutations prior to treatment or at the time of cytogenetic evolution.
“These results suggest that immediate institution of eltrombopag with immunosuppressive therapy may salvage and expand residual hematopoietic stem cells in aplastic anemia, accelerating the rate and quality of hematopoietic recovery,” Townsley and colleagues wrote. “Rapid blood count improvement and reduced transfusion burden support early use of eltrombopag for patients with newly diagnosed severe aplastic anemia.” – by Anthony SanFilippo
Reference:
Townsley DM, et al. Abstract LBA2. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: The study included off-label use of eltrombopag. Townsley and the other researchers report research funding from GlaxoSmithKline and Novartis.
Perspective
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Mrinal S. Patnaik, MBBS
Aplastic anemia is a significant problem, especially among younger patients. For patients with severe aplastic anemia (SAA), we traditionally have used equine antithymocyte globulin along with cyclosporine. This combination is usually associated with response rates of 60% to 70%. Over the last few years, we have seen encouraging responses with eltrombopag (Promacta, Novartis), an oral non-peptide agonist of the thrombopoietin receptor, currently approved for idiopathic thrombocytopenic purpura (ITP) and refractory aplastic anemia. Researchers at the NIH had used single-agent eltrombopag in patients with SAA who had not responded to antithymocyte globulin and cyclosporine and observed response rates of 30% to 40%.At this year’s ASH meeting, the researchers at the NIH presented a pivotal study in which they combined eltrombopag with antithymocyte globulin and cyclosporine upfront, to see if we could do better than what we have traditionally done. The trial included three cohorts that differed on when eltrombopag was administered and for how long. But, in common, eltrombopag was given at a higher dose than what is used for ITP. In the third cohort, eltrombopag was started along with antithymocyte globulin and cyclosporine and was continued for 6 months.
The overall response rate at 3 months was 80% and at 6 months was 85%, with complete response rates of 28% and 34% — much higher than what we have achieved with prior regimens. Importantly, the complete response rates went up from in the range of 10% to 30%-40%, which predicts fewer relapses and a lower rate of clonal evolution. The combination was well tolerated, and they did not see many interactions between cyclosporine and eltrombopag. If this study is validated, this could be a paradigm shift for how we manage severe aplastic anemia in the future.
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