Clofarabine for the treatment of adults with AML

Current therapy for older patients with acute myeloid leukemia is not optimal, as these patients have a poorer prognosis and cannot withstand intensive chemotherapy as well as younger patients can. Only about 45% of these patients obtain a complete response, and treatment-related mortality can range from 25% to 38%. In addition, older patients are more likely to have disease- or age-related changes in organ function.

Clofarabine (Clolar, Genzyme) has been studied in the treatment of various types of leukemia and is FDA approved for the treatment of childhood acute lymphoblastic leukemia. It is structurally related to fludarabine and cladribine, sharing some characteristics and avoiding others.

Clofarabine exerts its antineoplastic activity through several mechanisms. The active metabolite of clofarabine is its triphosphate form. This molecule competes with deoxyadenosine triphosphate for the ribonucleotide reductase and DNA polymerase, which leads to decreased DNA synthesis and repair, inhibits DNA strand elongation and cell replication. In addition, pretreatment with clofarabine before cytarabine administration leads to increases in intracellular concentrations of cytarabine triphosphate, the active form of cytarabine.

Lisa K. Lohr

Clofarabine has a large volume of distribution and has protein binding of about 50% in the blood. Hepatic metabolism is minimal, as most metabolism occurs intracellularly. About 50% to 60% of the dose is eliminated unchanged in the urine. Because of these characteristics, pharmacokinetic drug interactions as less likely with this agent compared with others.

The serum half-life is about five hours. The dose in childhood ALL is 52 mg/m² given IV daily for five days. The most common adverse effects include headache, nausea, vomiting, diarrhea, pruritis/dermatitis/palmar-plantar erythrodysesthesia (PPE), neutropenic fevers, increased liver function tests (LFTs), and infections. Capillary leak syndrome or systemic inflammatory response syndrome has been reported with clofarabine (although not seen in the trials described below) and some authors recommend pretreatment with corticosteroids. Clofarabine has moderate to severe emetogenicity.

Trial data

In one study (Faderl, 2006), 60 patients aged 50 years or older with AML or high-risk myelodysplastic syndrome (MDS) were treated with an induction regimen containing clofarabine and cytarabine. Patients could have had previous treatment only with hydroxyurea, single-agent chemotherapy, or biologic or targeted therapies. The chemotherapy regimen consisted of cytarabine 1 gm/m² per day, infused IV over two hours for five doses on days one to five. The clofarabine was administered at a dose of 40 mg/m² per dose, infused IV over one hour for five doses on days two to six. On days two to five, the clofarabine was administered four hours before the cytarabine. Patients could receive this induction regimen every four to six weeks, depending on leukemia response and patient recovery. Up to three cycles of chemotherapy could be given for determination of response (complete response or complete response with incomplete platelet recovery [CRp]).

The median age of the patients was 61 years with most patients older than 60 years. Most patients (90%) had AML and 10% of them had MDS. About one-half of the patients were diagnosed with secondary AML. One-half of the patients had abnormal karyotypes. The results from this trial are represented in table 1.

In the entire group, 52% of patients achieved a complete response and 8% had a complete response with incomplete platelet recovery. Patients with secondary AML or preceding MDS achieved a 33% response rate. The median duration of remission was 8.1 months (at 18.2 months of follow-up) for patients achieving a complete response and 1.8 months for patients receiving a CRp. The overall survival of patients with a complete response was 23.5 months.

The most common adverse effects seen were nausea/vomiting/diarrhea, myelosuppression, headaches, rashes, facial flushing and increased LFTs. In particular, 40% of patients suffered from PPE, mostly mild to moderate, but some severe. Most patients developed at least one episode of fever of unknown origin and many had documented infections such as pneumonia and septicemia as well. Eight patients (13%) died during the first or second induction courses, most with sepsis and multiorgan failure, and two patients with very serious skin abnormalities.

The authors concluded that this regimen is active in older patients with AML, achieving a good response rate (compared with other regimens in this population), with an acceptable toxicity profile (again compared with other regimens).

A more recent study (Faderl, 2008) by the same authors studied the use of clofarabine alone or in combination with low dose subcutaneous cytarabine. Patients were assigned to treatment groups using an adaptive randomization procedure. Seventy patients with AML or high-risk MDS and who were aged 60 years or older were included in the study. The median age was 71 years; 94% had AML and 6% had MDS. About 50% of the patients had secondary AML and 36% had unfavorable karyotypes. One group was treated with single-agent clofarabine at a dose of 30 mg/m²/dose daily IV infused over one hour. The other group received clofarabine as in the first group, plus cytarabine 20 mg/m²/dose subcutaneous daily for 14 days, starting on the first day of clofarabine. On days one to five the cytarabine was administered about four hours after the clofarabine dose. A second induction cycle was permitted for patients with stable disease or partial response, and consolidation cycles (of three and seven-days, respectively) were permitted for patients with complete response and CRp. The results of this trial are shown in table 2.

In both groups, the complete response rate was inferior in patients with secondary AML, abnormal karyotypes, FLT3 abnormalities or age greater than 64 years. In the total group as well as in all of these subgroups, the clofarabine/cytarabine combination offered a higher response rate than single-agent clofarabine. A total of 21% of patients died during the first course of chemotherapy, mostly due to infectious complications, multiorgan failure and bleeding complications.

The most common adverse effects were diarrhea, nausea, mucositis, increased LFTs and skin rashes. The increased LFTs were generally reversible within two weeks. PPE occurred in 13% of patients in both arms. The rate of adverse effects was not substantially different between the two groups. Myelosuppression occurred in nearly all patients, and infectious complications were frequent.

The authors concluded that the combination of clofarabine and low-dose subcutaneous cytarabine offered a higher response rate than single-agent clofarabine with comparable toxicity.

In addition to these trials, other researchers have investigated the use of clofarabine, alone and in combinations, in the first-line therapy of older patients with AML, as well as in refractory disease.

Lisa K. Lohr, PharmD, BCPS, BCOP, is a Clinical Pharmacist in Oncology and Bone Marrow Transplantation in the Department of Pharmacy Services at the University of Minnesota Medical Center and is a HemOnc Today Editorial Board member.

For more information:

• Faderl S. Blood. 2006;108:45-51.
• Faderl S. Blood. 2008;112:1638-1645.