Acquired pure red cell aplasia (aPRCA) is a rare anemia. For primary or secondary aPRCA, immunosuppression is typically initiated with corticosteroids, sometimes in combination with cyclosporine A. Additional immunosuppressants shown to be effective include cyclophosphamide and, recently, sirolimus, a mammalian target of rapamycin inhibitor (mTOR). However, researchers say “substantial uncertainty remains regarding the best treatment strategy in the absence of high-quality evidence.”
Hervé Lobbes, MD, of Clermont-Ferrand University Hospital in France, and colleagues conducted a systematic review and meta-analysis of 24 studies encompassing 753 patients (49% male) with aPRCA from January 1, 1967, to September 30, 2022. Researchers aimed to evaluate the efficacy of the most common treatment strategies in aPRCA, as well as the most efficacious strategy by subgroup as expressed through overall response rate (ORR). The risk of bias was moderate to high using the ROBINS-I tool, and substantial heterogeneity (I2>50) was retrieved.
Regardless of the disease or treatment, the combined ORR for all strategies was 59.2% (95% CI 52.4-66; I2 = 86%).
Corticosteroids as monotherapy were given to 25% (186) of all study patients, resulting in an ORR of 46.9% (95% CI 33.6-60.2; I2 = 78%), and in all subgroups of aPRCA, corticosteroids consistently provided the lowest ORR.
Cyclosporine A was the most frequently prescribed immunosuppressive drug (384 patients, or 51%), yielding an ORR of 74.1% (95% CI 66.1-82.1; I2 = 59%) in the overall population. When cyclosporine A was used as monotherapy (137 patients, or 18.2%), it showed an ORR of 83.2% (95% CI 72.3-94.1; I2 = 58%). The line of treatment did not yield significantly different ORRs (73.3% in first line vs. 75.6% in second line). Researchers found no improvement in combining corticosteroids and cyclosporine A in patients (ORR of 77.3%). Researchers said “high uncertainty remains” regarding this recommendation.
Use of sirolimus in refractory or cyclosporine A-intolerant patients showed an ORR that was 13% higher than cyclosporine A alone (86.6% [95% CI 67.9-100; I2 = 67%]) and even higher in cases where sirolimus was used as monotherapy (88.7%, 61/64 cases). Moreover, when analyzed by subtype, sirolimus use resulted in the highest ORR in both primary aPRCA (88% [CI 95% 68.7-100; I2 = 75%]) and autoimmune disease-associated aPRCA (90.3% [95% CI 60.7-100; I2 = 9%]). Nevertheless, sirolimus was only reported in 8.5% of the study population (64 patients, three studies) and was only used after cyclosporine A failure or side effects. Although its efficacy appears high, “uncertainty remains on the possible cumulative effect of previous lines of therapy,” researchers said.
Additionally, though controlled studies on mTOR inhibitors in aPRCA are limited, other studies report a number of adverse effects. “Long-term follow-up safety data are still required to consolidate the positioning of [sirolimus] in the therapeutic strategy of autoimmune cytopenia,” researchers said.
Cyclosporine A was the most effective agent in thymoma-associated aPRCA, providing an ORR of 89.7% (95% CI 80.1-99.3; I2 = 29%).
Cyclosporine A and cyclophosphamide showed similar ORRs (63% and 61%, respectively) in aPRCA associated with large granular lymphocyte leukemia.
Researchers cited significant limitations affecting choice of treatment decisions, including the lack of data on time to therapeutic response and length of response, which prevented researchers from assessing how follow-up duration affected the efficacy of individual drugs. Additionally, the lack of individual data limited the identification of the population who were able to discontinue immunosuppressive therapy without relapse. Such absence of standardization in data collection resulted in “a high degree of uncertainty regarding the generalizability of these results,” researchers said.
Further controlled studies are required “to precisely determine the efficacy of these drugs in the management of this severe condition,” researchers said. Although this study does not pose firm conclusions on the effectiveness of these therapies, it does provide precise estimates for designing a study that would. Still, researchers caution the management of transfusion-related iron overload and recommend “a rigorous assessment of treatment safety.”
Any conflict of interest declared by the authors can be found in the original article.
Lobbes H, Lega JC, Le Guenno G, et al. Treatment strategy for acquired pure red cell aplasia: a systematic review and meta-analysis [published online ahead of print, 2023 Aug 25]. Blood Adv. doi: 10.1182/bloodadvances.2023010587.