SAN DIEGO, CA—Adult patients with acute lymphocytic leukemia (ALL) and lymphoblastic lymphoma (LL) treated with the Hyper-CVAD regimen are at very high risk for rapid bone loss from the high-dose corticosteroid early in their treatment, the first study to show such a loss concluded during at the 53rd American Society of Hematology Annual Meeting and Exposition. For this reason, investigators propose serial bone mineral density (BMD) measurements at six-month intervals. A trial of risedronate to prevent such bone loss showed mixed results.

Corticosteroids are a well-known cause of osteoporosis. Although virtually no information on osteoporosis in the adult ALL population exists, osteoporosis and fractures are not uncommon in patients receiving chemotherapy for non-Hodgkin lymphoma, and in survivors of childhood ALL, a high incidence of low bone density is observed. To determine whether use of the bisphosphonate risedronate can decrease amount of bone loss in adults with ALL/LL receiving chemotherapy with high-dose corticosteroids, Maria E. Cabanillas, MD, of the University of Texas M.D. Anderson Cancer Center, Houston, and colleagues conducted a randomized, double-blind, placebo-controlled study. A secondary study objective was survival in the treatment group vs. placebo.

Adult patients newly diagnosed with ALL or LL and receiving either Hyper CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) or the Berlin-Frankfurt-Muenster (BFM) regimen were eligible for the study. Exclusion criteria included a baseline T-score in the osteoporotic range (-2.5 SD or less), renal insufficiency, or currently taking a bisphosphonate, calcitonin, or anabolic steroid. Also excluded were patients with a 25-hydroxyvitamin D level <20 ng/mL with a low ionized calcium and high intact PTH, who were considered likely to have baseline bone demineralization and would have required high doses of vitamin D.

Patients were randomly assigned 1:1 to risedronate 35mg weekly or placebo weekly for 24 months; both arms also received vitamin D 800IU and calcium 1,000mg in divided doses. BMD was measured at baseline and at six, 12, and 24 months using a DXA scan. At six months, patients who had a BMD loss of >10% compared with baseline were taken off the study and unblinded. Patients were also withdrawn from the trial if they failed to achieve complete remission (CR) after 2 courses of induction therapy, or had disease recurrence after initial CR or stem-cell transplant.

A total of 72 patients were randomized, 36 to each treatment arm. Median age was 29 years in the risedronate arm and 42 years in the placebo arm (P=0.06). The majority of patients had a diagnosis of B lymphoblastic LL, 72% in the risedronate arm and 86% in the placebo arm, and had received the Hyper-CVAD based regimen, 89% vs 94%, respectively. At 6 months, 22 patients in the risedronate arm and 29 in the placebo arm had available DXA scans. When compared with baseline, patients in the placebo arm had a significantly greater decrease in BMD at the left hip (mean -0.12g/cm2) and right hip (mean -0.11g/cm2) compared with those in the risedronate arm (left and right hip mean -0.08 g/cm2) (P=0.03 and P=0.04, respectively). No significant differences were observed in lumbar spine measurements between the two groups at 6 months. Analysis of overall survival included all 72 randomized patients; no statistical difference was observed between the two groups.

In the risedronate arm, 11 of 22 patients (50%) were taken off the study due to significant decreases in percentage of BMD at any site, as were 18 of 29 patients (62%) in the placebo arm (P=0.28). One patient in the risedronate arm experienced a vertebral fracture during the first six months of chemotherapy.

Although risedronate prevented bone density loss in the hips in some patients with ALL, half of patients had significant bone loss and one fracture was reported,” Dr. Cabanillas concluded. Calling the results, “disappointing,” she added they suggest risedronate is not the bisphosphonate of choice to prevent patients with ALL from bone loss.

Future clinical trials will determine whether a more potent bisphosphonate or an agent such as a monoclonal antibody to RANK ligand can reduce fractures and improve quality of life.