1130 - Vertebral fractures in patients with B-cell chronic lymphocytic leukemia before and after ibrutinib treatment

In population-based analysis before the era of targeted agents B-cell chronic lymphocytic leukemia (B-CLL) has been associated with increased risk of vertebral and axial fractures. This fracture risk may be due to intrinsic factors of the disease but also to the treatment with steroids or chemotherapy. The direct impact of novel targeted agents on bone fragility in these patients has not been recognized yet. Previous experimental studies suggested that ibrutinib may inhibit osteoclast differentiation and function so it was supposed that it might be used in the treatment of osteoclast-related diseases, such as osteoporosis and rheumatoid arthritis. However, recent retrospective studies found a higher incidence of vertebral fractures in patients treated with ibrutinib.
In order to evaluate incidence of fractures in relation to ibrutinib treatment we designed a retrospective study. All B-CLL patients treated with ibrutinib in our center were evaluated. We included patients with CT scan immediately before the introduction of ibrutinib in the pretreatment work-up and with follow-up CT scan that was done for the evaluation of response. Total of 57 patients out of 97 met the criteria for inclusion in this study.
In our group there were 35 males and 22 females. Median age at diagnosis was 64.5 years (range 46-84 years), median age at ibrutinib start was 71 years (range 53-86 years), while median duration of B-CLL before ibrutinib was 5.5 years (0-16 years). Ibrutinib was first line treatment in 16 patients (28.1%) while 41 (71.9%) were previously treated. Total of 35 patients received glucocorticoids (18 as a part of therapeutic protocols, 17 as premedication with anti-CD20 antibody). There were 24 patients with Rai III/IV or Binet C clinical stage, while 23 patients had lymphoma like tumor distribution (TD), median total tumor mass (TTM) was 11.28.
Patients were followed for 344.9 patient-years from diagnosis. On pre-treatment CT scan 7 patients had at least one vertebral fracture (range 1-3) while 50 patients had no vertebral fractures. None of patients with fractures had them detected by the time of diagnosis thus making incidence rate up to 0.02 per patient-year (95% CI 0.01-0.043). All patients in this cohort had CT for evaluation of response and these patients were followed for 132.6 patient years while on ibrutinib. Total of 9 patients had new vertebral fractures (6 with no previous fractures and 3 with new additional fractures) making incidence rate at least 0.068 per patient year (95% CI 0.035-0.13). This is significantly higher than before ibrutinib treatment (p < 0.05). Since all new fractures were detected in the initial 1.5 years of ibrutinib treatment, incidence rate was calculated at first 6, 12 and 18 months and compared to pretreatment incidence rate. The highest incidence rate was observed in the first 6 months with incidence rate ratio compared to pre-ibrutinib of 8.95 (95% CI 2.24-32.75).
Patients on ibrutinib were also evaluated for the presence of standard fracture risk factors including previous steroid use and other fractures, sex, secondary causes of osteoporosis, smoking and alcohol use. Bone mineral density measurement was mostly not available as it was usually not performed before ibrutinib therapy. Only female sex was significantly associated with early vertebral fractures (p < 0.05). We also evaluated factors associated with B-CLL. We compared previous treatments, stages, lymphocytosis, lymph nodes and spleen size, bone marrow infiltration, TTM and TD, as well as response to therapy with special emphasis on marrow changes and redistribution of tumor mass. None of these factors were found to be related except a trend for lower pretreatment hemoglobin in patients who developed new fractures after ibrutinib initiation.
In conclusion, until recently ibrutinib has not been regarded as a drug that could significantly impair bone health, but latest observations recorded signals of a possible increase of fractures associated with ibrutinib therapy. Although we cannot establish a causal relationship, the occurrence of multiple osteoporotic vertebral fractures shortly after the initiation of the ibrutinib suggests that this drug might play a role in bone fragility and requires further analysis with prospective studies.