Hematopoietic Cell Transplantation in Patients with Medication-Related Osteonecrosis of the Jaws

Accepted Manuscript Hematopoietic cell transplantation in patients with medication-related osteonecrosis of the jaws Hani Mawardi, B.D.S, DMSc, Brett Glotzbecker, M.D., Paul Richardson, M.D., SookBin Woo, D.M.D, M.M.Sc PII:

S1083-8791(15)00550-9

DOI:

10.1016/j.bbmt.2015.08.021

Reference:

YBBMT 53958

To appear in:

Biology of Blood and Marrow Transplantation

Received Date: 28 April 2015 Accepted Date: 12 August 2015

Please cite this article as: Mawardi H, Glotzbecker B, Richardson P, Woo SB, Hematopoietic cell transplantation in patients with medication-related osteonecrosis of the jaws, Biology of Blood and Marrow Transplantation (2015), doi: 10.1016/j.bbmt.2015.08.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Hematopoietic cell transplantation in patients with medication-related osteonecrosis of

Brett Glotzbecker M.D. ** Paul Richardson, M.D. *** Sook-Bin Woo, D.M.D, M.M.Sc ****

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Hani Mawardi, B.D.S, DMSc *

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the jaws: A case series

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* Clinical instructor, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine; Attending, Division of Oral Medicine and Dentistry, Brigham and Women’s Hospital

** Assistant Professor, Department of Medicine, Harvard Medical School; Physician,

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Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School

***LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center,

School

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Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical

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****Associate Professor, Department of Oral Medicine and Oral Pathology, Harvard School of Dental Medicine; Attending, Division of Oral Medicine and Dentistry, Brigham and Women’s Hospital

Corresponding author Hani Mawardi, BDS, DMSc

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Division of Oral Medicine and Dentistry Brigham and Women’s Hospital 75 Francis Street, Boston, MA 02115

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Tel: 617 732-6974 Fax: 617 264-6312

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[email protected]

There is no funding associated with this study.

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Running head for this study is: Hematopoietic cell transplantation in patients with

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MRONJ.

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This study has not been presented in part elsewhere.

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Abstract Objectives: Patients with medication-related osteonecrosis of the jaw (MRONJ) are at risk for developing infections, and often require long-term antimicrobial therapy for

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management. It is unclear whether patients with multiple myeloma (MM) who develop MRONJ experience increased morbidity when they undergo hematopoietic cell

transplantation (HCT). The aim of this study was to characterize the course of HCT in

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MM patients with MRONJ.

Methods: A retrospective chart review was conducted for patients with MM and MRONJ

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who underwent HCT between Decmber 2005 and Decmber 2014. Data collected included bisphosphonate use, MRONJ stage, positive blood cultures, number of febrile days, and length of hospital stay.

Results: Eleven patients (median age of 61; range 46-71) fulfilled the criteria. Patients

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received zoledronic acid (72.7%), pamidronate (18.1%) or a combination of both (9%). At the time of HCT, 10 patients were in stage 1 MRONJ with one in stage 0. All patients had only mandibular involvement. No patient developed pain/infection at the MRONJ

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site during hospitalization. Bacteremia with positive blood cultures for Staphylococcus aureus occurred in three patients (27.2%), and four patients (36.3%) developed fever

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lasting between 4 to 6 days (of whom one had positive blood cultures). The median length of hospital stay was 17 days (range 7-22 days). Conclusions: This data suggests that patients with MM and MRONJ who undergo HCT are not at increased risk of developing symptoms associated with the MRONJ site or HCT-related infectious complications, and their MRONJ is not worsened by HCT.

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Introduction: Patients with multiple myeloma (MM) or metastatic cancer to the bone often develop skeletal related events such as pain, pathologic fracture, spinal cord compression,

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and hypercalcemia.[1] Bisphosphonate therapy reduces such SREs, improves clinical

outcomes and improves survival.[2-5] However, patients with MM receiving intravenous bisphosphonate therapy may develop exposed and necrotic bone of the mandible and

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maxilla either spontaneously or after simple dento-alveolar surgery. This condition is

recognized as bisphosphonate-related osteonecrosis of the jaw, more recently relabeled

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“medication-related osteonecrosis of the jaw (MRONJ)” because other medications such as bevacizumab and sunitinib may have a similar effect.[6, 7] The American Association of Oral and Maxillofacial Surgeons defines MRONJ as the presence of exposed bone for at least eight weeks in patients with exposure to bisphosphonates and no history of

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radiotherapy to the jaw although a stage 0 lesion where there is no exposed bone, is also recognized (Table 1).[8-10] The prevalence of MRONJ has been reported to be between 2.0 to 3.8% in the oncology population. [4, 11]

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Infection is an overarching concern for patients with MRONJ. The necrotic bone may become a nidus for infection, especially with Actinomyces and Eikenella, further

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compromising the health and comfort of patients with cancer.[12, 13] Infection results in swelling, purulence, and/or pain in the jawbones. Such infections may lead to substantial morbidity such as chronic extra-oral draining sinuses requiring the use of long-term antibiotics.

Hematopoietic cell transplantation (HCT) is used for the treatment of hematologic malignancies such as leukemia, MM and bone marrow failure syndromes. Blood stream

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infection (BSI) is one of the frequent and serious complications.[14-16] Multiple risk factors are associated with BSI, including mucositis, presence of a central venous catheter and granulocytopenia.[17] The risk of BSI in the pre-engraftment phase has been

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reported in autologus HCT (auto-HCT ) to range from 21.3% and 50.0% with a comparable range of 20.3% to 55.0% in allogeneic HCT (allo-HCT).[18-24] The mortality from BSI in HCT patients ranged from 4.0% to 28.0%.[16, 21, 25]

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There is limited information on whether patients with MM and pre-existing MRONJ may experience an overall increase in infection (such as increased risk for BSI)

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or other morbidities during HCT. The aim of this study was to characterize the course of HCT and associated morbidities for patients with hematological malignancy and

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MRONJ.

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Material and Methods: A retrospective medical chart review was conducted for patients diagnosed with MM and concurrent MRONJ, who underwent HCT at Brigham and Women’s Hospital

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(BWH), Boston, MA from December 2005 to December 2014. Study subjects were identified from patients with MM who had undergone a comprehensive dental evaluation program (including full intraoral radiographs) performed by their community dentist who

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noticed the presence of MRONJ. MRONJ was subsequently confirmed by the attending dentist who evaluated the patient on admission.[26] Data was abstracted using a

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standardized template that collected patient demographics, medical history, medications, bisphosphonate history and duration of bisphosphonate therapy. Complete MRONJ history including initial symptoms, date of diagnosis and management was collected. MRONJ was diagnosed and staged 0 to 3 according to modified AAOMS criteria (Table

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1).[10] The diagnosis of MRONJ was made during the pre-HCT dental evaluation by the general dentist with input from the on-service attending dentist and confirmed by the dental service on admission. Transplantation data on prophylaxis regimen, febrile days

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during HCT, positive blood and urine cultures, use of antibiotics and length of hospital stay (LOS) were also collected. This study was approved by the BWH office for Human

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Research Subjects.

The characteristics of the study population were described with mean and

frequency (percent) for all patients unless indicated. The analysis was performed using SAS V9.2 (SAS Institute Inc., Cary, NC, USA). Patients were followed by the dental service on daily basis from admission until discharge only, but not beyond. Patients with post-discharge complications in the mouth

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are referred to the Division of Oral Medicine and Dentistry for management as outpatients. During admission, patients followed a protocol of tooth brushing twice a day using a soft tooth brush, and rinsing with chlorhexidine digluconate 0.12% mouth rinse

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and nystatin three times a day.

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Results: Patient demographics Eleven patients had complete records on MRONJ and HCT, and were included in

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this case series. There were 8 men and 3 women, and the median age was 61 (range 4671) who all had MM (Table 2). Patient 2 in this cohort (Table 2) had MM initially and underwent auto-HCT, but then developed AML for which he underwent allo-RIC-HCT.

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It was prior to the second admission for allo-RIC-HCT for AML that the MRONJ was

Bisphosphonate and MRONJ history

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noticed.

All patients received zoledronic acid (72.7%), pamidronate (18.1%) or a combination of both (9.0%) with median duration of use of 24 months (range 3 to 96

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months). All patients had MRONJ in the mandible. Two patients presented with symptomatic stage 0 disease, 7 patients with stage 1, and 2 patients with stage 2 disease at the initial dental consultation; none had stage 3 disease (Figure 1). Patients were

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managed with observation only, and/or antibiotics, non-surgical sequestrectomy +/antibiotics. The median follow-up prior to HCT was 5 months (range 0-50). At the re-

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evaluation visit prior to HCT, both patients with stage 2 had improved to stage 1, and 1 patient with symptomatic stage 0 disease developed stage 1 disease. The rest remained in the same stage as presentation.

Hematopoietic stem cell transplant course

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Prior to HCT, all patients received comprehensive dental treatment. Eight patients underwent auto-HCT and 3 patients had allo-reduced intensity conditioning (RIC) HCT. At admission for HCT, 10 patients had stage 1 MRONJ and only 1 patient had

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symptomatic stage 0. The conditioning regimen for auto-HCT included melphalan and filgrastim, and that for allo-RIC-HCT was busulfan and fludarabine. Microbial prophylaxis for all patients included acyclovir, trimethoprim and sulfamethoxazole and

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levofloxacin except for 1 patient from the allo-RIC-HCT group who received acyclovir

sirolimus and methotrexate.

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and atovaquone. Graft-versus-host disease prophylaxis for allo-HCT included tacrolimus,

Table 3 shows their findings during their admission for HCT. All patients developed oral mucositis (severity ranging from Grade I to III) that was managed with morphine, oxycodone or/and fentanyl in addition to Caphosol (EUSA Pharma, UK). No

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patient developed pain/infection at the MRONJ site during hospitalization. Four patients (36.3%) developed fever lasting between 4 to 6 days (of whom one had positive blood cultures). The 3 positive blood cultures in 3 patients grew Staphyloccus aureus (S.

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aureus), one of which was from the Hickman catheter. Eight patients received antibiotics namely ceftazidime and vancomycin or both, and two patients received metronidazole

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(Table 3). The median LOS was 17 days (range 7-22 days). Following transplantation, MRONJ staging for all patients was maintained. None of the patients resumed bisphosphonate therapy following HCT. At the time of data abstraction, 3 patients were deceased within 6 months to 4 years after HCT.

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Discussion: Non-responding or relapsed MM patients on conventional therapy are often eligible for auto-HCT, and sometimes for allo-HCT.[27] BSI is considered one of the

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most frequent and serious complications in HCT.[14-16] Multiple risk factors have been linked to BSI including mucositis, presence of central venous catheter and granulocytopenia.[17] Organisms implicated in BSI in this population include bacteria and enterobacteriaceae ), fungi (aspergillus and

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(viridans streptococci, S. aureus

candida) and viruses (herpes simplex virus, adenovirus and cytomegalovirus).[22, 28, 29]

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There are many potential sources for these infections, and the oral cavity is an important putative site of origin for viridians streptococci. Typically, BSI is common during the period of hospitalization often resulting in fever, septicemia, positive blood cultures, increased LOS and increased morbidity. The reported crude mortality from BSI in HCT

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patients ranges from 4.0 to 28.0% in multiple studies,[16, 21, 25] and reducing morbidity and mortality is the basis for anti-microbial prophylaxis in this patient population.[28] Patients with MRONJ present with exposed necrotic bone in the jaw that is

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susceptible to secondary bacterial infection but is generally well-managed with a combination of topical antimicrobial rinses and systemic antibiotics. It is unclear whether

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patients with MRONJ who undergo HCT are more likely to develop either local or systemic infections compared to patients who are MRONJ-free. In theory, patients with MRONJ may be more susceptible to infection because of the presence of exposed bone and an open wound in the oral cavity. In addition, these patients have reduced capacity for epithelial regeneration and healing because of decreased levels of keratinocyte growth factor (KGF) within the gingival and mucosal tissues caused by bisphosphonates.[30]

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Fever is one of the most common complications during the course of HCT. One study reported 98.0% of patients (102/104) who underwent HCT (53 had auto-HCT and 51 had allo-HCT) developed at least one episode of fever.[24] Two additional studies

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reported fever incidence to be 81.0-92.0%.[31, 32] Having a diagnosis of MRONJ while undergoing HCT does not seem to increase the risk of fever. In this study, four patients (36.3%) developed fever lasting between 4 to 6 days compared to 0-4 days in MRONJ

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patients and 0-5 days in MRONJ-free patients as reported in the literature.[33] Bacteremia and fungemia are associated with up to 25.0% and 5.0% of febrile episodes

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respectively in neutropenic patients.[34, 35] Three patients out of 11 (27.2%) in our study developed positive blood cultures compared with 21.3% to 50.0% in auto-HCT and 20.3% to 55.0% in allo-HCT.[18-20, 22-24] All three patients with BSI in this cohort had positive blood cultures for S. aureus (100%), which accounts for up to 39.0% of BSI

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infection.[23, 31, 36] No patient in our cohort died from complications of a S. aureus infection, where the mortality of such infections ranges from 3.3-15.0%.[21, 32] Eight patients received antibiotics namely ceftazidime and vancomycin or both, and two

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patients received metronidazole. One out of the eight patients received antibiotics for mucositis coverage only. The median use of antibiotics was 4.5 days (range 1-15). The

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median LOS for our cohort was 17 days (range 7-22) compared to a median LOS for auto-HCT and allo-HCT of 19 days (range 10-40) and 26 days (range 11-104) respectively in our institution between 2007-2013 (unpublished data). Others reported somewhat longer median LOS of 22 days (range 17-77) in auto-HCT and 32 days (range 12-56) in allo-HCT where the conditioning regimen may be different.[24] For patients who did not develop BSI, LOS has been reported to be 19 days (range 15-25) versus 26

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days (range 18-38) for those who did.[23] In this study, LOS for 3 patients who developed BSI was 15, 18 days and 22 days. As such, the impact of having MRONJ when undergoing HCT is not different from not having MRONJ from the point of view

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of incidence of bacteremia, fever or LOS. Undergoing HCT did not worsen MRONJ in that no patients developed a higher stage of MRONJ.

There has been only one other study by on the outcome of patients with MM and

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MRONJ who underwent HCT.[33] In that study, 10 patients with MM and MRONJ who underwent auto-HCT were matched to 40 MRONJ-free patients who also underwent

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auto-HCT. Six of 10 patients had stage 2 MRONJ prior to HCT, and 4 were in stage 1 disease; none were in stage 0 disease but those are difficult to recognize. In contrast, 10 of our patients had stage 1 disease and 1 had symptomatic stage 0 disease. In that study, the incidence of bacteremia, number of febrile days, and length of hospital stay in

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MRONJ and MRONJ-free patients were the same, and also similar to our findings. While their study and ours both showed an incidence of bacteremia of 30.0%, all blood cultures in our group grew S. aureus while theirs grew Pseudomonas aeruginosa, species,

Sphingomonas

paucimobilis,

and

coagulase-negative

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Corynebacterium

Staphylococcus.[33] The median LOS was 14.5 days (range 14-20) for MRONJ patients

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and 17 days (range 14-21) for MRONJ-free patients compared to a median LOS in our study of 17 days (range 7-22). This study is limited by its retrospective nature and the small number of cases, the

latter because the incidence of MRONJ in MM is low (approximately 2.0% to 3.0% in oncology patients) and lower yet in the HCT population. Another limitation of this study is the lack of a matched control population that was MRONJ-free. Patients were not

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followed after they were discharged and there is no follow-up on whether or when the lesions healed. However, if they had developed pain in the area of MRONJ, we believe that the patients would have been referred to us for management.

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All stages of MRONJ with the exception of stage 0 disease present with exposed bone in the oral cavity with loss of epithelial integrity. It would be reasonable to infer that as a result of this, that area would be more susceptible to bacterial ingress, in the same

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manner that ulcerative mucositis leads to a higher incidence of bacteremia.[37, 38] However, comparing the HCT outcome parameters of these 11 patients to national and

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published average reveals a similar outcome. In addition, this study confirms the findings of that of Vadrajan et al[33] in that there is no difference in morbidity in patients with

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MRONJ who undergo allo-HCT, compared to patients who did not have MRONJ.

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Conclusion: The incidence of HCT-related complications in patients with MM and MRONJ including positive blood cultures, febrile days during HCT, and LOS are comparable to

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MRONJ-free patients. These data confirm findings from a previous report, and indicate that MRONJ patients, especially those in Stage 1 disease are not at higher risk of inpatient HCT-related infection and toxicities. In brief, MRONJ does not adversely

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impact HCT outcome and HCT does not worsen the course of MRONJ.

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Table 1. MRONJ staging criteria.[8, 39] Stage

Criteria

At risk category

No apparent necrotic bone in asymptomatic patients who have been

Stage 0

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treated with either oral or IV bisphosphonates.

AS: asymptomatic, non-exposed bone; SS: symptomatic non-exposed

findings. Stage 1

Asymptomatic exposed necrotic bone, or fistulae that probes to bone

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without evidence of infection Stage 2

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bone. Stage 0 is usually associated with other clinical or radiographic

Symptomatic and infected exposed necrotic bone, or fistulae that probes to bone. This is evidenced by pain, erythema with or without purulent discharge

Exposed and necrotic bone or fistulae that probes to bone associated

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Stage 3

with pain, infection and one or more of the following: Pathologic fracture

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Oral antral/oral nasal communication

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Osteolysis extending to the inferior border of the mandible or

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sinus floor

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Table 2: Patient demographic and clinical data. Bisphosphonate used

Site of MRONJ

Stage of MRONJ at initial consultation/stage at HCT

Time of initial consultation to HCT (months)

Patient 1

46/M

Zoledronic acid

Left mylohyoid ridge

1/1

0

Patient 2

65/M

Pamidronate and Zoledronic acid

Lingual of right mandible in area of second molar

0ss/1

Patient 3

58/F

Pamidronate

Lingual of right mandible in area of second molar

1/1

Patient 4

69/M

Zoledronic acid

Right lingual mandibular torus; facial of right mandible in area of first premolar

1/1

5

Patient 5

60/F

Zoledronic acid

Sinus tract in right mandible in between first and second molar

0ss/Oss

9

Patient 6

53/F

Posterior right mandibular alveolar ridge

1/1

10

0.5

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Pamidronate

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Age/gender

50

Patient 7

62/M

Zoledronic acid

Bilateral lingual myloyoid ridge

1/1

30

Patient 8

68/M

Zoledronic acid

Lingual of right mandible in area of first molar

1/1

0

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71/M

Zoledronic acid

Left mylohyoid ridge

2/1

12

Patient 10

58/M

Zoledronic acid

Left lingual mandible in the area of extracted mandibular second molar

1/1

0

Patient 11

52/M

Zoledronic acid

Left lingual mandible in area of first and second molar

2/1

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Patient 9

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1.5

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Table 3: Patient transplantation course and outcome. Type of HCT/Conditioning regimen

Prophylaxis regimen

No. of febrile days

Positive blood cultures/organis m

Antibiotic and days used

LOS

Alive/deceased

Patient 1

MM

Auto/ melphalan

4

No/NA

Ceftazidime/4

17

Alive

Patient 2

AML*

Allo-RIC -HCT/ busulfan, fludarabine

Acyclovir, sulfamethoxazole and trimethoprim, levofloxacin Acyclovir and atovaquone

0

No/NA

NA/NA

7

Alive

Patient 3

MM

Auto/ melphalan

6

Yes/ S.aureus

Ceftazidime; vancomycin/1; 5

18

Deceased

Patient 4

MM

Auto/ melphalan

0

Yes (from Hickman line drainage)/ S.aureus

Vancomycin/15

15

Alive

Patient 5

MM

Auto/ melphalan

None

Yes/ S.aureus

Ceftazidime; vancomycin/5; 13

22

Alive

Patient 6

MM

Allo-RIC-HCT/ busulfan, fludarabine

None

No/NA

NA/ NA

8

Deceased

Patient 7

MM

Auto/ melphalan

5

No/NA

Ceftazidime; vancomycin/ 8;6

20

Deceased

Patient 8

MM

Auto/ melphalan

Acyclovir, sulfamethoxazole and trimethoprim, levofloxacin Acyclovir, sulfamethoxazole and trimethoprim, levofloxacin Acyclovir, sulfamethoxazole and trimethoprim, levofloxacin Acyclovir, sulfamethoxazole and trimethoprim, levofloxacin Acyclovir, sulfamethoxazole and trimethoprim, levofloxacin Acyclovir, atovaquone, levofloxacin

4

No/NA

Ceftazidime; vancomycin; metronidazole/8; 3; 2

17

Alive

Patient 9

MM

Auto/ melphalan

None

No/NA

18

Alive

Patient 10

MM

Allo-RIC-HCT/ busulfan, fludarabine

None

No/NA

Ceftazidime; vancomycin; metronidazole (for mucositis coverage)/1; 3; 2 NA/NA

8

Alive

Patient 11

MM

Auto/ melphalan

None

No/NA

NA/NA

15

Alive

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Acyclovir, sulfamethoxazole and trimethoprim, levofloxacin Acyclovir, sulfamethoxazole and trimethoprim, levofloxacin Acyclovir, levofloxacin

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Diagnosis

HCT, hematopoietic cell transplantation; LOS, length of hospital stay; MM, multiple myeloma; AML, acute myeloid leukemia; RIC, reduced intensity conditioning; Auto, autologous; allo, Allogeneic. * Pat

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Figure 1: Case #11 A) Initial visit : stage 2 MRONJ on the left lingual mandible prior to HCT. Patient presented with pain, gingival erythema, bleeding and periodontal pocket of 8 mm. Necrotic bone was filed down with a bone file, and amoxicillin and clavulanic

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acid 875-125/twice a day for 2 weeks and chlorhexidine 0.12% mouth rinse prescribed;

B) and C) patient at follow up visit was asymptomatic (MRONJ stage 1), with persistent

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A

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8 mm periodontal pocket.

B

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[2] Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. The New England journal of medicine.

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Osteonecrosis of the jaw and renal safety in patients with newly diagnosed multiple myeloma: Medical Research Council Myeloma IX Study results. Br J Haematol. 2014. [4] Morgan GJ, Davies FE, Gregory WM, Szubert AJ, Bell SE, Drayson MT, et al. Effects of induction and maintenance plus long-term bisphosphonates on bone disease in

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[15] Marena C, Zecca M, Carenini ML, Bruschi A, Bassi ML, Olivieri P, et al. Incidence of, and risk factors for, nosocomial infections among hematopoietic stem cell transplantation recipients, with impact on procedure-related mortality. Infect Control

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Hosp Epidemiol. 2001;22:510-7.

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[17] Castagnola E, Faraci M. Management of bacteremia in patients undergoing hematopoietic stem cell transplantation. Expert review of anti-infective therapy. 2009;7:607-21.

[18] Reich G, Mapara MY, Reichardt P, Dorken B, Maschmeyer G. Infectious

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complications after high-dose chemotherapy and autologous stem cell transplantation: comparison between patients with lymphoma or multiple myeloma and patients with solid tumors. Bone marrow transplantation. 2001;27:525-9.

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Study highlights •

Patients with medication-related osteonecrosis of the jaw (MRONJ) are not at higher risk of inpatient hematopoietic cell transplant (HCT)-related infection and

•

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toxicities.

The incidence of HCT-related complications in patients with multiple myeloma and MRONJ including positive blood cultures, febrile days during

HCT has no impact on MRONJ, in terms of causing pain or infection, or

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upstaging of disease.

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•

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HCT and length of stay are comparable to MRONJ-free patients.