Severe Aplastic Anemia: Adding Eltrombopag Improves Hematologic Response, EFS

When added to standard immunosuppressive therapy, eltrombopag—an oral thrombopoietin-receptor agonist—improved hematologic responses in treatment-naïve patients with severe aplastic anemia. And it did so without any additional toxicity, according to results from the RACE study, which are published in The New England Journal of Medicine.

“In this prospective, randomized, multicenter trial, hematologic complete and overall responses at 3 months were significantly better with eltrombopag added to standard therapy than with standard therapy alone, and the quality and speed of hematologic recovery were better with the addition of eltrombopag as well, with no excess of toxic effects,” wrote Régis Peffault de Latour, MD, PhD, of the French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Saint-Louis Hospital and Université de Paris, and colleagues.

Since the 1980s, standard treatment for severe or very severe aplastic anemia consists of standard immunosuppressive treatment with horse antithymocyte globulin (ATG) plus cyclosporine, to which two-thirds of patients have a response. Efforts to improve on these results—including substitution with rabbit ATG, alemtuzumab, or cyclophosphamide; the addition of other immunosuppressive agents such as mycophenolate mofetil and sirolimus; and the addition of hematopoietic growth factors—have been unsuccessful.

Because eltrombopag had efficacy in patients with aplastic anemia who were refractory to treatment with immunosuppressive therapy, and was shown to be effective combined with standard horse ATG plus cyclosporine in a phase I/II study, Peffault de Latour and colleagues conducted this investigator-led, open-label, multicenter, phase III trial.

They randomized 197 patients age 15 years or older (median age: 53 years; 55% male) who were newly diagnosed with acquired severe (66%) or very severe (34%) aplastic anemia and ineligible for front-line hematopoietic stem-cell transplantation to one of two regimens:

• Group A: standard immunosuppressive therapy with horse ATG (40 mg/kg/d for 4 consecutive days) and oral cyclosporine (5 mg/kg/d from day 1 for a minimum of 12 months).
• Group B: standard immunosuppressive treatment plus oral eltrombopag (150 mg/d from day 14 through 6 months, or 3 months in those with complete response).

Bone marrow samples were obtained at baseline, 6 months, and 2 years, and a 31-gene targeted molecular bar-coded panel was used to analyze somatic myeloid-cancer associated mutations.

The primary end point of the study was complete hematologic response at 3 months, which researchers defined as a hemoglobin level >10 g/dL, an absolute neutrophil count of >1,000/mm³, and a platelet count >100,000/mm³ in patients not undergoing transfusion. Partial responses were defined as independence from red cell and/or platelet transfusions, and blood lineage not meeting severe aplastic anemia criteria, but not sufficient for a complete response.

After a median follow-up of 24 months, 10% of Group A patients and 22% of Group B patients demonstrated a complete response (pooled OR: 3.2; 95% CI: 1.3-7.8; P=0.01), with a lower overall response rate at 3 months in Group A patients (31% versus 59%, respectively).

At 3 months, 70 Group A patients and 39 Group B patients had no response; at 6 months, 14 and 11, respectively had an overall response (4 patients in both groups had a complete response; and 10 and 7, respectively, a partial response). Six-month overall response was 41% in Group A versus 68% in Group B, and researchers noted that “[b]etter responses were observed in Group B than in Group A at each time point and in all strata (i.e., the severity of aplastic anemia and age).”

Median time to a first response was longer in Group A patient compared with Group B (8.8 versus 3.0 months, respectively). By 12 months, complete response rates were 33% in Group A versus 52% in Group B. Times from partial to complete response were 5.1 versus 2.7 months, respectively. Median time to best response was longer in Group A patients (8.9 versus 3.9 months). Finally, Group B patients had a higher probability of a complete response at 3 months and of an overall response at 6 months.

Upon multivariate analysis, researchers found that randomization group, age, and disease severity were the only three factors associated with a response. More severe disease was a negative predictor for a complete response at 3 months and an overall response at 6 months. An age of 40 years or older was associated with a lower overall response rate at 6 months, but not with a lower complete response rate at 3 months.

Long-term outcomes were similar in both groups, with a 2-year overall survival of 85% in Group A, compared with 90% in Group B, with a hazard ratio for death of 0.57 (95% CI: 0.24-1.37) in Group B compared with Group A, and of 1.32 (95% CI: 0.55-3.21) for relapse risk. Older age was the only characteristic associated with both worse overall survival and relapse risk. In all, 22 patients died during the study, 14 Group A patients and eight Group B patients. Hematopoietic stem-cell transplantation was necessary in 23 patients (12 vs 11, respectively).

Researchers also found no significant differences in the incidence of relapse 18 months after response, with 11% of Group A patients experiencing relapse, compared with 19% of Group B patients.

Event-free survival (EFS) was lower in Group A compared with Group B (34% vs 46%, respectively), with no response being the most common treatment failure in both groups. Upon multivariate analysis, patients in Group B experience reduced risk in the first 6 months (HR for treatment failure events: 0.42; 95% CI: 0.25-0.72).

“The addition of eltrombopag to standard immunosuppressive therapy did not result in significantly improved overall survival, which was expected considering the additional effect of rescue treatment. The 85% to 90% 2-year overall survival rate is higher than most rates observed in multicenter studies involving patients with severe aplastic anemia,” wrote Peffault de Latour and colleagues. “Nevertheless, eltrombopag added to standard immunosuppressive therapy significantly increased event-free survival from 34% to 46% at 2 years through the reduction in initial refractoriness to immunosuppression. However, the reintroduction of eltrombopag was the most common event in the experimental group; this finding provides justification for further studies with longer follow-up to improve long-term treatment in patients with aplastic anemia.”

The incidence of adverse events was similar in the two groups. Eltrombopag was discontinued before 6 months in 10 patients due to elevated liver enzyme levels, slight increases in reticulin deposition in bone marrow, or other reasons.

Global health status and physical, social, and emotional measures improved over time in both groups, with minimal between-group differences.

In an accompanying editorial, Phillip Scheinberg, MD, PhD, of Hospital A Beneficência Portuguesa, São Paulo, Brazil, reviewed the context of treatment for severe aplastic anemia.

“The backbone of therapy in patients with severe aplastic anemia is antithymocyte globulin (ATG), which is composed of serum containing polyclonal xenogeneic antibodies obtained from animals that have been sensitized to human T cells. ATG is lymphocytotoxic and causes lymphodepletion in humans. ATG plus cyclosporine became standard immunosuppressive therapy in 1991 after a randomized trial showed that this combination was superior to ATG alone. The next 20 years were disappointing, given that several alternative regimens did not perform better than horse ATG plus cyclosporine, and the enthusiasm to investigate new immunosuppressive therapies was dampened,” he wrote.

The importance of this study lies, according to Scheinberg, in the hematologic responses of patients treated with eltrombopag added to standard treatment with horse ATG and cyclosporine.

“At all landmark time points, the combination of horse ATG–cyclosporine plus eltrombopag was superior to standard therapy and produced a higher and more rapid complete and overall hematologic response, which translated into earlier transfusion independence, fewer complications from pancytopenia, and better quality of life. Among patients who had a response, these benefits were even more pronounced,” noted Scheinberg.

He added that results may have been better had eltrombopag been started on day 1 instead of day 14, citing outcomes of a previous trial. Nevertheless, concluded Scheinberg, these results from Peffault de Latour et al are highly significant.

“The European investigators conducted an important trial that supports horse ATG-cyclosporine plus eltrombopag as the new standard in severe aplastic anemia. Longer-term follow-up is under way to further elucidate, with direct internal control, events of relapse, high-risk clonal evolution, and death, which thus far have not differed between the groups in this trial. It is hoped that it will not take another 30 years before the next important advancement occurs in the medical management of severe aplastic anemia,” he wrote.

1. The addition of eltrombopag to standard immunosuppressive therapy improved the rate, speed, and strength of hematologic response in treatment-naïve patients with severe aplastic anemia, without additional toxic effects.

2. Hematologic complete and overall responses at 3 months were significantly better with eltrombopag added to standard immunosuppression with horse ATG plus cyclosporine than with standard therapy alone.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

Cat ID: 118

Topic ID: 78,118,730,118,717,192,925