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Moderate-Dose Cyclophosphamide for Severe Aplastic Anemia:Potential Toxicity Outweighs Potential Benefit

December 30, 2021

While cyclophosphamide at high or more moderate doses can be active in severe aplastic anemia, a new study published in Blood reveals that a moderate dose of the drug failed to prevent relapse or clonal evolution and was associated with significant upfront toxicity. Even when optimal prophylactic strategies were used, this toxicity could not be circumvented.

Phillip Scheinberg, MD, study author and chief of clinical hematology at the Antônio Ermírio de Moraes Cancer Center Hospital, São José, Brazil, and colleagues devised the current study to investigate more "moderate" doses of cyclophosphamide given the better transfusional and antimicrobial (particularly antifungal) supportive care to prevent the complications associated with prolonged neutropenia. From September 2010 to February 2012, they assigned 22 patients with severe aplastic anemia to receive a "moderate" dose of cyclophosphamide (120 mg/kg) plus low-dose cyclosporine. All patients received antibacterial, antiviral, and antifungal prophylaxis.

In March 2012, the Data Safety Monitoring Board recommended terminating the study due to unacceptable rates of toxicity, clonal evolution, and deaths.

Patients in the study receiving a moderate dose of cyclophosphamide experienced an average of two months of severe neutropenia, during which they had serious and frequent infections.

"Despite the attractiveness of cyclophosphamide – low cost, readily available – its use cannot be justified given the insurmountable upfront toxicity when other, much better, and effective alternatives are available," study author Dr. Scheinberg told ASH Clinical News. "The prolonged hospitalizations and frequent admissions for complications associated with neutropenia negate the initial low cost associated with cyclophosphamide."

The current standard of treatment for severe aplastic anemia is immunosuppressive therapy with horse antithymocyte globulin (ATG); according to Dr. Scheinberg, investigations in severe aplastic anemia occurring over the last two decades have focused on finding alternative immunosuppressive regimens that could improve on the results of standard immunosuppressive therapy and work around their limitations. Despite earlier encouraging research with the drug, moderate-dose cyclophosphamide does not seem to hold much promise.

"In patients who tolerated the prolonged period of severe neutropenia, hematologic responses were observed, suggesting activity of this regimen," Dr. Scheinberg said. "Thus, cyclophosphamide continued to be attractive due to its low cost and worldwide availability — an aspect particularly important in developing countries where ATG is either not available or too costly."

Over a median follow-up of 2.2 years, the researchers found that neutropenia was profound and prolonged, and resulted in hospitalizations for serious infections, including fungal infections. Five patients required granulocyte transfusions for uncontrolled infections. The average number of hospitalizations within the first six months after cyclophosphamide was 2.1.

At six months, 41 percent of patients responded to the cyclophosphamide, with four complete responses and five partial responses. At one year, 22 percent of patients had clonal evolution.

At six months, 41 percent of patients responded to the cyclophosphamide, with four complete responses and five partial responses. At one year, 22 percent of patients had clonal evolution.

Based on these results, Dr. Scheinberg said that cyclophosphamide should not be used routinely in severe aplastic anemia outside clinical research protocols.

"Other regimens which include alternative, less toxic immunosuppressants and/or bone marrow–stimulating agents (such as eltrombopag) likely represent more appealing strategies to be investigated in severe aplastic anemia," he noted.


Scheinberg P, Townsley D, Dumitriu B, et al. "Moderate" dose cyclophosphamide for severe aplastic anemia has significant toxicity and does not prevent relapse and clonal evolution. Blood. 2014 September 3. [Epub ahead of print]


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