Discussion and Conclusions
Several new medications have been added to the potential-cause of MRONJ
drug list. Among these, ipilimumab has been reported in three published
clinical cases as a possible cause of MRONJ, two as agent therapy and
one in association with denosumab.12,18 As far as
literature reports, MRONJ onset in all cases during ipilimumab therapy
or shortly after the conclusion. Our patient suspended the treatment
with ipilimumab 3 years before. Dabrafenib, trametinib, vemurafenib and
cobimetinib –the other chemotherapy drugs taken by the patient- have
never been reported as possible cause of MRONJ.
Therefore, diagnosis was the first issue we encountered in the
management of this case. For the symptoms and the clinical presentation,
the differential diagnosis was between alveolar osteitis (dry socket,
AO), MRONJ and osteoradionecrosis (ORN). ORN was the first possibility
to be discarded as the patients had no history of Head & Neck
radiotherapy. AO was carefully taken into account prior to start any
therapy. The clinical and radiographic appearance was indeed compatible
with such disease which is defined as “postoperative pain in and around
the extraction site, which increases in severity at any time between one
and three days after the extraction, associated with a partially or
totally disintegrated blood clot within the alveolar socket, with or
without halitosis”.19 Still, as a matter of fact,
most recent meta-analyses show that AO therapy should be more
symptomatic19,20 rather than therapeutic, as there is
no full comprehension of its pathogenesis and, above all, it is
considered as a “self-limiting” disease. The antibiotic therapy
prescribed by the dentist of the patient resulted useless, and no
improvement was observed after 4 months even with topic injection of
chlorhexidine and zinc oxide eugenol, which are reported between the
most successful treatment for AO.19,20 As reported in
literature, after the diagnosis, AO , regardless of the therapy, tends
to remit in a period of days or weeks, most
commonly20, whilst there is no report in scientific
literature of AO persisting for several months. AO was thus discarded in
the differential diagnosis process.
Furthermore, the presence of a bone sequestrum related to a non-healing
post-extraction socket, not visible at the first inspection but ejected
during antibiotic therapy, is an event more compatible with MRONJ (which
was possibly a stage 1 rather than a stage 0, as we evaluated during our
first visit) rather than AO.
As reported before, amongst the various anticancer therapies agents
administered to the patient, ipilimumab was the only drug which could be
related to MRONJ.
Ipilimumab was approved by the US Food and Drug Administration in March
2011 as an immunotherapy for the management of advanced (unresectable or
metastatic) melanoma patients.12 Ipilimumab is a
humanized monoclonal antibody against cytotoxic T-lymphocyte-associated
antigen-4 (CTLA-4). CTLA-4 is expressed both in activated T-cells and in
suppressor T-regulatory cells, binding to antigen presenting cells and
therefore diminishing T-cell responses. The block of the CTLA-4 is able
to improve the antitumor responses of activated T-cells. The result is a
significant incremented survival in patients with metastatic melanoma
undergoing ipilimumab.18,21 The immune response
induced by ipilimumab with only 4 cycles of treatment (about 2 months of
therapy) can persist for many years, inducing a kind of vaccination
against metastatic melanoma. In literature there are reported cases of
ipilimumab -related ONJ occurred during or shortly after the end of the
systemic therapy. The authors suggested that that Ipilimumab may have
been involved in the process of bone necrosis by empowering the number
of systemic activated T-cells presence. CTLA4 deficient activated
T-cells have been shown to be associated with osteonecrosis, as
activated T-cells may ignite osteoclastogenesis via osteoprotegerin
ligand, resulting in bone loss.22 Trauma from regular
oral activity or oral surgery (e.g. tooth extraction) could increase the
demand on this vulnerable bone to mend itself, resulting in localized
bone necrosis.12
Ipilimumab is known to have a 14.7 day blood
half-life23 while the patient described in our case
had completed Ipilimumab treatment 3 years before. As we have seen, the
real advantage of the drug is in the long-term efficacy with about 20%
of patients alive at 5, 7 and 10 years after treatment completion. This
long term efficacy is due to the immune-responses induced by checkpoint
inhibitors. Still, just like the anti-cancer effects, side effects can
last for many years.12 It is conceivable that,
similarly to pruritus, diarrhea, vitiligo, hepatitis, and
endocrinopathies, MRONJ may be also a late side effect under certain
circumstances. We suggest that the MRONJ onset may have been co-caused
by the ongoing target therapy (vemurafenib + cobimetinib) of the
patient. The effect of BRAF and MEK inhibitors in BRAF-mutant melanoma
can lead to an immune stimulatory microenvironment by enhancing
expression of immune stimulatory molecules and cytokines, reducing
immunosuppressive cell populations, and decreasing immunosuppressive
cytokines. The cell damage to the tumor by the target therapy may have
induced a tumor-antigen spreading, re-stimulating T-CELL activity whose
response had been increased and modulated by the effect of ipilimumab.
Moreover, it has been demonstrated that anti-BRAF therapy enhances the
reactivity and cytotoxicity of T cells24,25. The
re-activation of such empowered T-CELL clones may have lead the patient
into a window of time in which she was at risk for MRONJ, similarly to
when the patient was on treatment with ipilimumab.