Photo by Steven Fruitsmaak
Bone density scanner
ORLANDO, FL—A single, 4 mg-dose of the bisphosphonate zoledronic acid (ZA) prior to allogeneic hematopoietic stem cell transplant (HSCT) prevents femoral neck (FN) bone loss at day 100 in patients with lymphoid or myeloid malignancies, according to new research.
The study also suggests that patients who receive risk-adapted ZA therapy after transplant can experience significant reductions in bone loss between days 100 and 365.
However, patients with acute and chronic graft-versus-host disease (GVHD) continue to be at risk of bone loss.
Eric Wong, of the Royal Melbourne Hospital in Parkville, Australia, presented these findings at the 2017 BMT Tandem Meetings (abstract 53) on behalf of the Australasian Leukaemia and Lymphoma Group.
“Previous studies have demonstrated that efforts to prevent bone loss through calcium and vitamin D supplementation as well as hormone-replacement therapy alone have been ineffective in preventing bone loss,” Wong explained.
And monthly pamidronate begun prior to HSCT reduces, but does not prevent, FN bone density loss.
So Wong and his colleagues began a trial of ZA, which is approximately 100-fold more potent than pamidronate.
Study design
The researchers enrolled 82 patients into the phase 2 ALLG BM07 trial. All patients received a single shot of ZA prior to HSCT conditioning.
All patients also received vitamin D and calcium supplements, and pre-menopausal women received hormone replacement therapy.
Depending on their risk of bone loss, patients received individualized ZA therapy after transplant. Researchers assessed the patients’ bone density at days 100, 180, 270, and 365 post-HSCT. Patients at high risk of bone loss received additional doses of ZA.
Risks for bone loss included bone mineral density (BMD) reduction of 5% or greater compared to baseline, prednisolone exposure of 1 mg/kg/d or greater for 2 weeks, or prednisolone exposure of 10 mg/d or more for 6 weeks
The primary endpoint of the study was the change in FN BMD at days 100 and 365 after HSCT compared to baseline.
The researchers also compared patients’ FN BMD with 35 untreated historical controls assessed at the same time points.
Patient characteristics
Seventy patients were alive and had not relapsed at day 100. Most (87%) were 60 years or younger, 60% were male, 53% had myeloid disease, 43% lymphoid, and 4% other disease.
“The most common indications for transplant were acute myeloid leukemia and acute lymphoblastic leukemia,” Wong said, “which, together, formed over 50% of the entire cohort.”
Seventy percent of patients were ECOG status 0 or 1, and 30% were 2 or greater.
Most (59%) had received myeloablative conditioning, the predominant regimens being busulfan/cyclophosphamide or cyclophosphamide/total-body irradiation. And the most common reduced-intensity conditioning regimen was fludarabine/melphalan.
Fifty-six percent of patients had a sibling donor, and 43% had a matched unrelated donor.
Thirty-eight percent of patients developed acute GVHD—19% grade 1, and 19% grade 2 to 3.
“Of note,” Wong said, “no patient developed grade 4 acute GVHD.”
Patients received a median of 2 ZA doses (range, 1–4), including the pre-transplant dose.
Sixty patients received at least 1 dose of ZA between day 100 and day 365, including 33% who received multiple doses.
At day 100, 33 patients received additional ZA. At day 180, 27 patients received additional ZA, including 8 patients who did not have it at day 100. And at day 270, 18 patients had additional ZA, including 1 patient who had no additional ZA at earlier time points.
Results
At day 100, there was no statistically significant change in FN bone density compared with baseline. The mean change was -2.6% (range, -6.6% to 1.4%).
For patients with acute GVHD, however, the change in bone density was significant (P=0.03). Patients with grade 1-2 GVHD had a mean change of -1.6% ± 3.7%, and patients with grade 3-4 GVHD had a mean change of -8.5% ± 11.2%.
Sixty-five patients were available for the day 365 efficacy analysis.
Bone density did not change significantly between day 100 and 365 for the entire group.
“By day 365,” Wong noted, “there was a net loss of bone density of -2.9%.”
But by day 365, patients with extensive chronic GVHD had significantly more bone loss compared with patients who had no chronic GVHD (P=0.03).
Age, sex, duration of cyclosporine, and mean steroid dose were not associated with a change in bone density at day 100 or 365, although there was a trend for an association between high steroid exposure and increased bone loss (P=0.07).
When the researchers compared the patients to untreated historical controls, patients who received ZA had significantly less bone loss at day 100 (P=0.001) and day 365 (P<0.0001).
The researchers observed no serious adverse events with ZA.
Wong concluded that patients with extensive GVHD are a “high-risk cohort that needs augmented therapies.”
