Does Bisphosphonate-Induced Osteonecrosis of the Jaw (BONJ) Preclude Intensive Chemotherapy? Oral and Infectious Toxicities Associated with Autotransplantation In Patients with BONJ.
Authors: Varadarajan Prakash , Toro Juan , Craig Robert M. , Schneider Deanna , Chao Ju-Hsien , Haile David , Freytes Cesar O. 
Published: October 2019

Abstract
Abstract 1314

Background:
Bisphosphonate-induced osteonecrosis of the jaw (BONJ) is a recently recognized adverse reaction associated with intravenous bisphosphonate use. The incidence of BONJ is estimated to be between 5–15% of patients with multiple myeloma (MM) treated with biphosphonates. Relevant to this complication, areas of osteonecrosis can harbor bacteria with the potential to cause infection and bacteremia during prolonged periods of myelosuppression. Furthermore, it is unclear if BONJ can worsen mucositis associated with cytotoxic therapy or if intensive chemotherapy can impair the healing of osteonecrosis. Since autologous peripheral blood stem cell transplantation (APBSCT) is an integral part of the treatment of MM, it is important to determine toxicities associated with APBSCT in patients with BONJ.

Study Purpose:
To determine the oral and infectious toxicities associated with APBSCT in patients with multiple myeloma and BONJ.

Method:
This is a retrospective analysis of patients with MM and BONJ who underwent APBSCT between January 2005 and June 2010. All the patients were evaluated for dental clearance by local dentists prior to referral to our institution. Before transplantation, all the patients underwent another oral evaluation by our institution's dentist who specializes in oral and maxillofacial pathology and is experienced in the evaluation and care of transplant patients.

Results:
During the study period, 176 patients underwent APBSCT for MM at our institution. Ten male patients, or 6% of all patients, were diagnosed with BONJ prior to transplantation. The median age of patients with BONJ was 60 years (range, 39–70). BONJ developed a median of 444 days (range, 187–2194) after the initiation of treatment with bisphosphonates. Patients with BONJ received a median of 15 infusions of biphosphonates (range, 6–60) before the diagnosis of BONJ was established. Six patients received zoledronate, 3 received pamidronate and one received both. Eight of the 10 patients with BONJ were diagnosed by our dentist. Five patients received dental care by local dentists a median of 5 months (range 1–7) before they were seen at our facility where they were examined by our dentist. Two of the five patients had received extractions placing them at risk of developing BONJ. None of the patients received radiation to the jaw or had lytic lesions in the jaw area.
The transplant conditioning regimen was similar for all patients: melphalan 100 mg/m2 daily for 2 days. Six patients developed neutropenic fever for a median of 4 days (range, 1–9). Bacteremia was diagnosed in 3 patients and 1 met criteria for catheter-related bacteremia (CRB) as defined by the Centers for Disease Control of the United States. The incidence of CRB in patients with BONJ appears similar to the 13% CRB observed at our institution during the study period. The organisms isolated from the blood were Pseudomonas aeruginosa, Corynebacterium species, Sphingomonas paucimobilis and Coagulase-negative staphylococcus, the last 2 were cultured from one patient. None of these organisms are predominantly found in the oral cavity but have been well described as pathogens in immunosuppressed hosts. Seven patients with BONJ developed mucositis posttransplantation but only one patient experienced grade 3 mucositis as defined by the Common Toxicity Criteria version 3. Of the remaining patients, 3 developed grade 1 and 3 developed grade 2 mucositis posttransplantation. Patients without BONJ had a similar frequency of mucositis: 31% of patients did not experience any mucositis, another 31% developed grade 1, 30% developed grade 2 and only 7% developed grade 3 mucositis. There was no treatment-related mortality within one year posttransplantation. So far, only 1 patient has died of progressive disease 13 months after APBSCT. Of interest, BONJ healed in nine patients posttransplantation with conservative management and 3 patients had bisphosphonates reintroduced with no recurrence of BONJ.

Conclusion:
Autologous stem cell transplantation can be performed safely in patients with BONJ. The incidence of oral and infectious toxicities observed in patients with BONJ appears similar to the incidence observed in patients without BONJ transplanted during the same period of time. BONJ was not recognized by most practitioners who referred patients for transplantation. Finally, BONJ healed in most patients after the transplant with conservative management.

Disclosures:
No relevant conflicts of interest to declare.