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Prior Authorization Review Panel MCO Policy Submission
A separate copy of this form must accompany each policy submitted for review. Policies submitted without this form will not be considered for review.
Plan: Aetna Better Health Submission Date:02/01/2020
Policy Number: 0675 Effective Date: Revision Date:12/23/2019
Policy Name: Bortezomib (Velcade)
Type of Submission – Check all that apply:
□ New Policy Revised Policy* □ Annual Review – No Revisions □ Statewide PDL
*All revisions to the policy must be highlighted using track changes throughout the document.
Please provide any clarifying information for the policy below:
CPB 0675 Bortezomib (Velcade)
This CPB has been revised to: (i) restructure the medical necessity criteria for bortezomib (Velcade); and (ii) add medical necessity criteria for continued treatment with bortezomib.
Name of Authorized Individual (Please type or print):
Dr. Bernard Lewin, M.D.
Signature of Authorized Individual:
Proprietary Revised July 22, 2019
Proprietary
Bortezomib (Velcade) - Medical Clinical Policy Bulletins | Aetna
(https://www.aetna.com/)
Last Review
12/23/2019
Effective: 12/09/2003
Next Review: 07/10/2020
R eview History
Definitions
Additional Information
Clinical Policy Bulletin Notes
Bortezomib (Velcade)
Number: 0675 Policy *Please see amendment forPennsylvaniaMedicaid
at the end of this CPB.
Aetna considers bortezomib (Velcade) for intravenous or subcutaneous
administration medically necessary for treatment of the following
indications:
Adult T-cell leukemia/lymphoma - as a single agent for second-line
or subsequent therapy
Angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma
not otherwise specified, anaplastic large cell lymphoma,
enteropathy-associated T-cell lymphoma, monomorphic
epitheliotropic intestinal T-cell lymphoma, nodal peripheral T-cell
lymphoma with TFH phenotype, or follicular T-cell lymphoma
when all of the following criteria are met:
The disease is relapsed or refractory; or
The requested medication is used as a single agent for second-
line and subsequent therapy; or
The member is not a candidate for autologous stem cell
transplantation
Antibody mediated rejection of solid organ
Mantle cell lymphoma
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Multicentric Castleman’s disease - relapsed, refractory, or
progressive disease
Multiple myeloma
Pediatric acute lymphoblastic leukemia - relapsed or refractory
disease
Primary cutaneous anaplastic large cell lymphoma (ALCL) - as a
single agent for relapsed or refractory disease
Systemic light chain amyloidosis when the requested medication
will be used in any of the following regimens:
In combination with melphalan and dexamethasone; or
In combination with cyclophosphamide and
dexamethasone; or
In combination with dexamethasone; or
As a single agent
Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma
when the requested medication will be used in any of the
following regimens:
In combination with rituximab; or
In combination with dexamethasone; or
In combination with rituximab and dexamethasone; or
As a single agent.
Aetna considers continued treatment medically necessary in members
requesting reauthorization for a medically necessary indication who have
not experienced an unacceptable toxicity or disease progression while on
the current regimen.
Aetna considers bortezomib experimental and investigational for all other
indications, including the following because its effectiveness for these
indications has not been established:
Antibody-mediated autoimmune diseases (e.g., myasthenia gravis,
rheumatoid arthritis and systemic lupus erythematosus)
Anti-NMDA receptor encephalitis
As monotherapy or in combination with other chemotherapeutics
for the treatment of other hematological malignancies (e.g.,
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chronic lymphocytic leukemia, chronic myeloid leukemia, diffuse
large B-cell lymphoma, gastric MALT lymphoma, Hodgkin's
disease, mucosa-associated lymphoid tissue (MALT) lymphoma,
non-gastric MALT lymphoma, mycosis fungoides/Sezary
syndrome, myelodysplasia, primary cutaneous follicle center
lymphoma, primary cutaneous marginal zone lymphoma, small
lymphocytic lymphoma, splenic marginal zone lymphoma,
systemic ALCL), solid tumors (e.g., biliary tract cancer, breast
cancer, colon cancer, head and neck cancer, metastatic melanoma
(lung), non-small cell lung cancer, ovarian cancer, pancreatic
cancer, renal carcinoma, and androgen-dependent prostate
cancer), neuroendocrine tumors (e.g., carcinoid or islet cell tumors),
or sarcoma (including osteosarcoma),
Autoimmune disorders including autoimmune hemolytic anemia
and autoimmunity in children
Chronic graft-versus host disease
Cold agglutinin disease
Cryoglobulinemic vasculitis
Glioblastoma multiforme
Hepatic amyloidosis
Hepatocellular carcinoma
Histiocytic sarcoma
HIV infection and immunological/inflammatory conditions (e.g.,
arthritis, asthma, multiple sclerosis, and reperfusion injury)
Hyper IgG4 syndrome
Monoclonal gammopathy o f renal significance
Mucous membrane pemphigoid
Plasmablastic lymphoma
Post-transplant lymphoproliferative disorder
Smoldering (asymptomatic) myeloma
Solitary plasmacytoma.
Aetna considers palbociclib plus bortezomib experimental and
investigational for the treatment of mantle cell lymphoma because the
effectiveness of this approach has not beenestablished.
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See also CPB 0404 - Interferons (../400_499/0404.html),
C PB 0497 - Hematopoietic Cell Transplantation for Multiple Myeloma
(../400_499/0497.html)
, CPB 0524 - Zoledronic Acid (../500_599/0524.html),
C PB 0634 - Non-myeloablative Bone Marrow/Peripheral Stem Cell T
ransplantation (Mini-Allograft / Reduced Intensity Conditioning
T ransplant) (0634.html)
, and C PB 0672 - Pamidronate (Aredia) (0672.html).
Dosing Recommendations
Bortezomib is available as Velcade Intravenous Powder for Solution: 3.5
mg vials.
Velcade (bortezomib) may be administered intravenously at a
concentration of 1mg/mL or subcutaneously at a concentration of
2.5mg/mL. Velcade (bortezomib) should not be administered by any other
route.
For subcutaneous or intravenous use only. Each route of administration
has a different reconstituted concentration; Exercise caution when
calculating the volume to be administered.
The recommended starting dose of Velcade is 1.3 mg/m2 administered either as a 3 to 5 second bolus intravenous injection or subcutaneous injection Retreatment for multiple myeloma: May retreat starting at the last tolerated dose Dose must be individualized to prevent overdoseWhen administered intravenously, administer as a 3 to 5 second bolus
intravenous injection.
Refer to Prescribing Information for guidance on dose adjustments.
Source: Millennium Pharmaceuticals, Inc., 2019
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The proteasome, a multi-catalytic protease present in all eukaryotic cells,
plays an important role in the regulation of cell cycle, neoplastic growth,
and metastasis. Proteasome inhibitors specifically induce apoptosis in
cancer cells, but most proteasome inhibitors are not suitable for clinical
development. Velcade (bortezomib), a specific, selective inhibitor of the
26S proteasome, is a novel dipeptide boronic acid that is the first
proteasome inhibitor to have pr ogressed to clinical trials. The 26S
proteasome degrades ubiquitinated proteins responsible in regulating
intracellular concentrations of specific proteins, thereby maintaining
homeostasis within cells. Inhibition of the 26S proteasome prevents this
targeted proteolysis, thereby affecting multiple signaling cascades within
the cell. This disruption of normal homeostatic mechanisms can lead to
cell death. Experiments have shown that Velcade (bortezomib) is
cytotoxic to many types of cancer cells in vitro. In non‐clinical tumor
models Velcade (bortezomib) caused a delay in vivo tumor growth
including multiple myeloma.
A unique feature of bortezomib involves the inhibition of nuclear factor
(NF)-kappaB activation through stabilization of the inhibitor protein
IkappaB. Pre-clinical studies have demonstrated that through the
prevention of IkappaB degradation, bortezomib may block chemotherapy-
induced NF-kappaB activation and augment the apoptotic response to
chemotherapeutic agents. NF-kappaB is a transcription factor that
increases the production of growth factors (e.g., interleukin-6), cell-
adhesion molecules, and anti-apoptotic factors, all of which contribute to
the growth of the tumor cell and/or protection from apoptosis. In addition,
bortezomib appears to enhance the stabilization of p21 and p27, as well
as transcription factor p53.
In pre-clinical models of breast, lung, pancreatic, and ovarian tumor
types, bortezomib inhibited tumor growth and showed anti-angiogenic
properties. Bortezomib exhibited the greatest activity when combined
with standard chemotherapeutic agents, such as irinotecan, gemcitabine,
and docetaxel, suggesting its potential additive/synergistic role in
overcoming resistance to conventional chemotherapy. Evidence from
early clinical trials suggested that bortezomib can be given at
pharmacologically active doses in combination with standard doses of
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chemotherapy with manageable toxicities. Responses have been seen
and no evidence of additive toxicity has been exhibited in combination
agent trials.
Velcade (bortezomib) is approved by the U.S. FDA for mantle cell
lymphoma and multiple myeloma (MM). Bortezomib was initially approved
as a third-line treatment of relapsed and refractory multiple myeloma
(MM) by the U.S. Food and Drug Administration (FDA) under the
accelerated approval program. The FDA evaluated the safety and
effectiveness of bortezomib based on a study of 202 patients with
relapsed and refractory MM who had received at least 2 prior therapies
and showed disease progression on their most recent therapy (the
SUMMIT trial). Bortezomib was administered intravenously at 1.3
mg/m2/dose twice-weekly for 2 weeks, followed by a 10-day rest period
(21-day treatment cycle) for a maximum of 8 treatment cycles. In the
study population, the median number of previous therapies was 6, and 64
% of patients had received stem cell transplant or other high dose
therapy. Results (Blade criteria -- a rigorous assessment standard used
to describe changes in disease status, including a confirmation 6 weeks
later) in the 188 eligible and evaluable subjects included complete
response (CR) in 5 patients, for a CR rate of 2.7 % (95 confidence
interval [CI]: 1 % to 6 %); partial responses (PR) occurred in 47 patients
for a PR rate of 25 % (95 CI: 19 % to 32 %). Clinical remissions by
SWOG criteria were observed in 17.6 % of patients (95 % CI: 12 % to 24
%). The response lasted a median time of 1 year.
Another trial in 54 subjects with relapsed MM (the CREST trial) showed
similar responses. Patients were randomized to receive either 1.0 mg/m2
or 1.3 mg/m2 of bortezomib for Injection therapy for up to 24 weeks (days
1, 4, 8 and 11 of a 21-day cycle, for up to 8 cycles). For patients in the
1.3 mg/m2 treatment group, the overall response (defined as the
combined total of complete and partial remissions and minimal
responses) was 69 %. For patients in the 1.0 mg/m2 treatment group, the
overall response was 59 %. The ov erall median time to progression was
11 months.
The FDA approved a supplemental New Drug Application (sNDA) for
Velcade, which expands the label to include the treatment of patients with
MM who have received at least 1 prior therapy. The approval was based
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on data from the randomized phase III APEX study that compared single-
agent bortezomib to high-dose dexamethasone in 669 patients with
relapsed MM who had received 1 to 3 prior therapies (Richardson et al,
2005). The study demonstrated a significant survival advantage with
bortezomib in patients with MM who had received 1 to 3 prior therapies.
The combined complete and partial response rates were 38 % for
bortezomib and 18 % for dexamethasone (p < 0.001), and the complete
response rates were 6 % and less than 1 %, respectively (p < 0.001).
Median times to progression in the bortezomib and dexamethasone
groups were 6.22 months (189 days) and 3.49 months (106 days),
respectively (hazard ratio, 0.55; p < 0.001). The 1-year survival rate was
80 % among patients taking bortezomib and 66 % among patients taking
dexamethasone (p = 0.003), and the hazard ratio for overall survival with
bortezomib was 0.57 (p = 0.001). Grade 3 or 4 adverse events were
reported in 75 % of patients treated with bortezomib and in 60 % of those
treated with dexamethasone.
Velcade (bortezomib) should not be used in the following:
Velcade (bortezomib) should not be used in patients that are pregnant or lactating. Velcade (bortezomib) should not be used in patients that have hypersensitivity to Velcade (bortezomib), boron, or mannitol or any of the accompanying excipients. For first line Multiple Myeloma: Velcade (bortezomib) should not be used when Platelet Count is < 70,000 or Absolute Neutrophil Count (ANC) is < 1000. Velcade (bortezomib) is contraindicated for intrathecal
administration.
Mantle cell lymphoma (MCL) is a lymphoma that is refractory to most
current chemotherapy regimens. Several clinical studies have
demonstrated that bortezomib has clinical effects on MCL. Lenz et al
(2004) stated that new therapeutic strategies such as radioactively
labeled antibodies or molecular targeting agents (e.g. bortezomib or
flavopiridol) are urgently warranted to further improve the clinical outcome
of MCL. The NCCN guidelines (2004) also recommended bortezomib as
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a second-line treatment of MCL. According to the NCCN, first line
treatment of mantle cell lymphoma included rituximab plus combination
chemotherapy (e.g., hyperCVAD, CHOP, EPOCH).
Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of
generally aggressive neoplasms, which constitute less than 15 % of all
non-Hodgkin's lymphomas (NHLs) in adults. For the myriad forms of
aggressive peripheral T-cell lymphomas, treatment approaches similar to
those used for B-cell lymphomas have been used for patients with either
localized or advanced stage disease, with autologous hematopoietic cell
transplantation utilized in selected patients. Phase II studies of
bortezomib showed encouraging results in B-cell lymphomas (Goy, 2005;
O'Connor, 2005).
NCCN guidelines (2012) recommended use of bortezomib as second-line
therapy for relapsed or refractory angioimmunoblastic T-cell lymphoma,
peripheral T-cell lymphoma not otherwise specified, anaplastic large cell
lymphoma, or enteropathy-associated T-cell lymphoma in noncandidates
for transplant.
Bortezomib is administered intravenously (bolus) at a dose of 1.3 mg/m2
twice a week for 2 weeks, followed by a 10-day rest period. At least 3
days should elapse between consecutive doses of bortezomib. The most
common side effects associated with bortezomib include nausea, fatigue,
diarrhea, constipation, headache, decreased appetite, decreased
platelets and red blood cells, fever, vomiting, and peripheral neuropathy
(numbness and tingling, and occasionally pain in the extremities).
Bortezomib should be interrupted for any grade-3 non-hematological
(excluding neuropathy) or grade-4 hematological toxicity.
In a phase II clinical trial (n = 27), Markovic et al (2005) reported that
single-agent bortezomib, administered twice-weekly for 2 of every 3
weeks at a dose of 1.5 mg/m2, was not found to be effective in the
treatment of patients with metastatic melanoma.
In a multi-center phase II study (n = 21), Maki et al (2005) stated that
bortezomib has minimal activity in soft tissue sarcoma as a single agent.
These researchers concluded that if studied further in sarcomas,
bortezomib should be investigated in combination with agents with
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demonstrated pre-clinical synergy. In another phase II clinical (n = 16),
Shah et al (2005) found that despite achieving the surrogate biologic end
point, single-agent bortezomib did not induce any objective responses in
patients with metastatic carcinoid or islet cell tumors.
Dimopoulos et al (2005) noted that bortezomib is a selective proteasome
inhibitor which has shown significant activity in a variety of hematologic
malignancies including multiple myeloma, mantle cell lymphoma and
marginal zone lymphoma. Thus, this agent is worth studying in patients
with Waldenstrom's macroglobulinemia (WM). Patients with refractory or
relapsed WM were treated with bortezomib administered intravenously at
a dose of 1.3 mg/m2 on days 1, 4, 8 and 11 in a 21-day cycle for a total
of 4 cycles. A total of 10 previously treated patients with WM were
treated with bortezomib. Most patients had been exposed to all active
agents for WM and 8 patients had received 3 or more regimens. Six of
these patients achieved a partial response which occurred at a median of
1 month. The median time to progression in the responding patients is
expected to exceed 11 months. Bortezomib was relatively well-tolerated.
The more common toxicities were mild or moderate thrombocytopenia,
fever and fatigue while peripheral neuropathy occurred in 3 patients and 1
patient developed severe paralytic ileus. The authors concluded that
these preliminary data indicated that bortezomib is an active agent in
patients with heavily pretreated relapsed/refractory WM. Four cycles of
this agent may be adequate to assess sensitivity in this disease. They
noted that further studies are needed to confirm their results and to
evaluate combinations of bortezomib with other active agents.
In a phase II clinical study, Chen et al (2007) evaluated the effectiveness
and toxicity of single-agent bortezomib in WM. Symptomatic patients,
untreated or previously treated, received bortezomib 1.3 mg/m2
intravenously days 1, 4, 8, and 11 on a 21-day cycle until 2 cycles past
complete response (CR), stable disease (SD) attained, progression (PD),
or unacceptable toxicity. Responses were based on both para-protein
levels and bi-dimensional disease measurements. A total of 27 patients
were enrolled. A median of 6 cycles (range of 2 to 39) of bortezomib
were administered. Twenty-one patients had a decrease in
immunoglobulin M (IgM) of at least 25 %, with 12 patients (44 %)
reaching at least 50 % IgM reduction. Using both IgM and bi-dimensional
criteria, responses included 7 partial responses (PRs; 26 %), 19 SDs (70
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%), and 1 PD (4 %). Total response rate was 26 %. IgM reductions were
prompt, with nodal responses lagging. Hemoglobin levels increased by at
least 10 g/L in 18 patients (66 %). Most non-hematological toxicities were
grade 1 to 2, but 20 patients (74 %) developed new or worsening
peripheral neuropathy (5 patients with grade 3, no grade 4), a common
cause for dose reduction. Onset of neuropathy was within 2 to 4 cycles
and reversible in the majority. Hematological toxicities included grade 3
to 4 thrombocytopenia in 8 patients (29.6 %) and neutropenia in 5 (19
%). Toxicity led to treatment discontinuation in 12 patients (44 %), most
commonly because of neuropathy. The authors concluded that
bortezomib is effective in WM, but neurotoxicity can be dose limiting. The
slower response in nodal disease may require prolonged therapy,
perhaps with a less intensive dosing schedule to avoid early
discontinuation because of toxicity. They stated that future studies of
bortezomib in combination with other agents are warranted. Furthermore,
Vijay and Gertz (2007) noted that novel agents such as bortezomib,
perifosine, atacicept, oblimersen sodium, and tositumomab show promise
as rational targeted therapy for WM.
The published evidence for bortezomib in large B-cell lymphoma is limited
to small uncontrolled studies. Guidelines from the NCCN (2008) and the
National Cancer Institute (NCI, 2008) do did not state that bortezomib is
effective for diffuse large B-cell lymphoma (DLBCL). Evidence-based
guidelines from Cancer Care Ontario (Reece et al, 2006) reviewed the
evidence for bortezomib in DLBCL and other NHLs; the guidelines stated
that there is insufficient evidence to support the use of bortezomib outside
of clinical trials in patients with NHL.
There is limited published evidence for the use of bortezomib for systemic
light chain amyloidosis, consisting of 1 phase II clinical study (Kastritis et
al, 2007), small case series (Wechalekar et al, 2008), and case reports
(Borde et al, 2008). NCCN's Drug and Biologics Compendium (2008)
listed systemic light chain amyloidosis as an indication for bortezomib.
However, NCCN guidelines (2009) indicated that this and other
treatments for systemic light chain amyloidosis should be provided in the
context of a clinical trial.
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Kastritis et al (2007) assessed the activity and feasibility of the
combination of bortezomib and dexamethasone (BD) in patients with AL
amyloidosis. A total of 18 patients, including 7 who had relapsed or
progressed after previous therapies were treated with BD; 11 (61 %)
patients had 2 or more organs involved; kidneys and heart were affected
in 14 and 15 patients, respectively. The majority of patients had impaired
performance status and high brain natriuretic peptide values; serum
creatinine was elevated in 6 patients. Among evaluable patients, 94 %
had a hematological response and 44 % a hematological complete
response, including all 5 patients who had not responded to prior high
dose dexamethasone-based treatment and 1 patient under dialysis. Five
patients (28 %) had a response in at least 1 affected organ.
Hematological responses were rapid (median of 0.9 months) and median
time to organ response was 4 months. Neurotoxicity, fatigue, peripheral
edema, constipation and exacerbation of postural hypotension were
manageable although necessitated dose adjustment or treatment
discontinuation in 11 patients. The authors concluded that the
combination of BD is feasible in patients with AL amyloidosis. Patients
achieve a rapid hematological response and toxicity can be managed with
close follow-up and appropriate dose adjustment. This treatment may be
a valid option for patients with severe heart or kidney impairment.
Wechalekar et al (2008) reported preliminary observations on the
effectiveness of bortezomib in 20 patients with primary amyloidosis
(AL) whose clonal disease was active despite treatment with a median of
3 lines of prior chemotherapy, including a thalidomide combination in all
cases. Patients received a median of 3 (range of 1 to 6) cycles of
bortezomib and 9 (45 %) patients received concurrent dexamethasone.
Three (15 %) patients achieved complete hematological responses, and a
further 13 (65 %) achieved partial responses. Fifteen (75 %) patients
experienced some degree of toxicity, which in 8 (40 %) cases resulted in
discontinuation of bortezomib. The authors stated that bortezomib shows
promise in the treatment of systemic AL amyloidosis.
Guidelines from the NCCN indicated bortezomib as a single agent for
primary treatment of symptomatic hyperviscosity in WM. Treon et al
(2007) reported on an uncontrolled clinical study which found bortezomib
as an active agent in relapsed and refractory WM. In this study, 27
patients with WM received up to 8 cycles of bortezomib. All but 1 patient
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had relapsed/or refractory disease. Following therapy, median serum IgM
levels declined from 4,660 to 2,092 mg/dL (p < 0.0001). The overall
response rate was 85 %, with 10 and 13 patients achieving minor and
major responses, respectively. The investigators reported that responses
were prompt and occurred at median of 1.4 months. The median time to
progression for all responding patients was 7.9 months. The most
common grade III/IV toxicities were sensory neuropathies (22.2 %),
leukopenia (18.5 %), neutropenia (14.8 %), dizziness (11.1 %), and
thrombocytopenia (7.4 %). The investigators observed that sensory
neuropathies resolved or improved in nearly all patients following
cessation of therapy.
Chen and colleagues (2007) also found bortezomib an active agent in
WM. In an uncontrolled clinical trial, symptomatic patients with WM (n =
27), untreated or previously treated, received bortezomib on a 21-day
cycle until 2 cycles past complete response (CR), stable disease (SD)
attained, progression (PD), or unacceptable toxicity. A median of 6 cycles
(range of 2 to 39) of bortezomib were administered. The investigators
reported that 21 patients had a decrease in immunoglobulin M (IgM) of at
least 25 %, with 12 patients (44 %) reaching at least 50 % IgM reduction.
Using both IgM and bidimensional criteria, responses included 7 partial
responses (PRs; 26 %), 19 SDs (70 %), and 1 PD (4 %). Total response
rate was 26 %. The investigators reported that IgM reductions were
prompt, with nodal responses lagging. Hemoglobin levels increased by at
least 10 g/L in 18 patients (66%). The investigators observed that most
non-hematologic toxicities were grade 1 to 2, but 20 patients (74 %)
developed new or worsening peripheral neuropathy (5 patients with grade
3, no grade 4), a common cause for dose reduction. Onset of neuropathy
was within 2 to 4 cycles and reversible in the majority. Hematologic
toxicities included grade 3 to 4 thrombocytopenia in 8 patients (29.6 %)
and neutropenia in 5 (19 %). Toxicity led to treatment discontinuation in
12 patients (44 %), most commonly because of neuropathy.
Eom and associates (2009) performed a retrospective analysis of 69
patients with MM who received bortezomib-containing regimens (n = 30)
or vincristine, doxorubicin and dexamethasone (VAD; n = 39) before
collection of peripheral blood stem cells and autologous stem cell
transplantation (ASCT). Objective response rate (at least a partial
response) prior to ASCT was documented in 27 (90 %) of 30 and 31 (81.6
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%) of evaluable 38 patients with bortezomib-containing regimens and
VAD, respectively. The difference between the 2 groups was not
significant (p = 0.494). However, the high-quality response rate with very
good partial response (VGPR) or more in the bortezomib group was
significantly higher compared with the VAD group (66.7 % versus 34.2 %,
respectively, p = 0.006). The superiority of bortezomib-containing
regimens in the high-quality response rate remained significant for only
the newly diagnosed patients (n = 16, p = 0.008). The engraftment data
as well as stem cell harvesting were comparable between the 2 groups.
The major bortezomib-related toxicities were thrombocytopenias and
peripheral neuropathies; toxicities of VAD were hematologic and
infectious. After ASCT, the difference between the 2 groups did not reach
the level of statistical significance with respect to progression-free survival
(PFS) and overall survival (OS) (p = 0.498 and 0.835, respectively). The
authors concluded that the results of this retrospective comparison of
bortezomib-containing regimens with the VAD as induction treatment prior
to ASCT for MM provided a demonstration of the superiority of
bortezomib therapy in terms of achieving a high-quality response.
However, survivals following ASCT did not differ according to the
induction regimens.
In a single institution, phase II study, Uy and colleagues (2009)
examined the role of bortezomib as induction therapy before ASCT
and its role as maintenance therapy after ASCT for patients with MM. A
total of 40 patients were given bortezomib sequentially pre-ASCT and as
maintenance therapy post ASCT. Pre-transplant bortezomib was
administered for 2 cycles followed by high-dose melphalan 200 mg/m(2)
with ASCT of granulocyte colony stimulating factor-mobilized peripheral
blood mononuclear cells. Post-transplant bortezomib was administered
weekly for 5 out of 6 weeks for 6 cycles. No adverse effects were
observed on stem cell mobilization or engraftment. An overall response
rate of 83 % with a complete response + VGPR of 50 % was observed
with this approach. Three-year Kaplan-Meier estimates of disease-free
survival and OS were 38.2 % and 63.1%, respectively. Bortezomib
reduced CD8(+) cytotoxic T cell and CD56(+) natural killer cell peripheral
blood lymphocytes subsets and was clinically associated with high rates
of viral reactivation to varicella zoster. The authors stated that
interpretation of the role of bortezomib maintenance in myeloma based on
this single study is limited because of the relatively small sample size and
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relatively short duration of maintenance therapy. They noted that larger
prospective randomized studies of post transplant bortezomib are needed
and are currently ongoing.
Shapovalov et al (2010) hypothesized that proteasome inhibition will
induce Runx2 and Runx2-dependent Bax expression sensitizing
osteosarcoma cells to apoptosis. These researchers had shown that
bortezomib increased Runx2 and Bax in osteosarcoma cells. In vitro,
bortezomib suppressed growth and induced apoptosis in osteosarcoma
cells but not in non-malignant osteoblasts. Experiments involving intra-
tibial tumor xenografts in nude mice showed significant tumor regression
in bortezomib-treated animals. Immunohistochemical studies revealed
that bortezomib inhibited cell proliferation and induced apoptosis in
osteosarcoma xenografts. These effects correlated with increased
immunoreactivity for Runx2 and Bax. The authors concluded that these
findings indicate that bortezomib suppresses growth and induces
apoptosis in osteosarcoma in vitro and in vivo suggesting that
proteasome inhibition may be effective as an adjuvant to current
treatment regimens for these tumors.
Wiedmann and Mossner (2010) noted that carcinoma of the biliary tree
are rare tumors of the gastrointestinal tract with worldwide rising
incidence for intra-hepatic cholangiocarcinoma during the last years.
Although complete surgical resection is the only curative approach, this
can be accomplished in a minority of patients, since most of them present
with advanced disease. In addition, those patients who have undergone
complete surgical resection experience a high tumor recurrence rate.
Non-resectable biliary tract cancer is associated with a poor prognosis
due to wide resistance to chemotherapeutic agents and radiotherapy. It is
therefore essential to search for new therapeutic approaches. After
several years of pre-clinical research, the first clinical study data are now
available for this tumor entity. Inhibitors of the EGFR family, such as
erlotinib, cetuximab, and lapatinib were recently investigated. In addition,
bortezomib, an inhibitor of the proteasome, imatinib mesylate, an inhibitor
of c-kit-R, bevacizumab, an inhibitor of vascular endothelial growth factor
(VEGF), and sorafenib (BAY 43-9006), a multiple kinase inhibitor that
blocks not only receptor tyrosine kinases but also serine/threonine
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kinases along the RAS/RAF/MEK/ERK pathway, were studied, as well.
Although early evidence of anti-tumor activity was seen, the results are
still preliminary and require further investigations.
Follicular lymphoma (FL) is classified as a non-Hodgkin's lymphoma. It is
an indolent (slow-growing) cancer that affects B-cell lymphocytes. In a
phase II clinical trial, Di Bella et al (2010) evaluated the safety and
effectiveness of single-agent bortezomib in indolent B-cell lymphoma that
had relapsed from or was refractory to rituximab. A total of 60y patients
were enrolled: 59 were treated with bortezomib 1.3 mg/m(2) on days 1, 4,
8, and 11 for up to 8 21-day cycles; responders could receive 4 additional
cycles; maintenance was optional. Fifty-three evaluable patients
completed more than 2 cycles. The median age was 70 years, 53 %
female, Ann Arbor stage III-IIIE (28 %) and IV (65 %); 43 patients (72 %)
had more than 2 prior regimens; and 6 patients went on to maintenance.
Overall responses are as follows: 1 complete response (1.9 %), 3
unconfirmed complete response (5.7 %), 3 partial response (5.7 %), 34
stable disease (64.2 %), and 12 progressive disease (22.6 %). Median
time to response = 2.2 months (range of 1.2 to 5.3 months); duration of
response = 7.9 months (2.8 to 21.3 months); 1-year survival was 73 %
and 2-year survival was 58 %; median survival = 27.7 months (range
of 1.4 to 30.9 months); median progression-free survival = 5.1 months
(range of 0.2 to 27.7 months), median time to progression = 5.1 months
(range of 0.2 to 27.7 months), and median event-free survival = 1.8
months (range of 0.2 to 27.7 months). Treatment-related grade 3 or 4
adverse events included: thrombocytopenia (20 %), fatigue (10 %),
neutropenia (8.5 %), and neuropathy and diarrhea (6.8 % each). The
authors concluded that these findings showed that bortezomib has
modest activity against marginal zone and FL; it has the potential for
combination with other agents in low-grade lymphomas. Maintenance
therapy should be explored further.
Leonard and Martin (2010) stated that unlabeled and radiolabeled anti-
CD20 monoclonal antibodies have had a significant impact in the care of
patients with FL over the past decade. More recently, bendamustine has
demonstrated activity in refractory FL, and has been explored as initial
therapy and in novel combinations. Whereas outcomes for this patient
population have significantly improved, there remains substantial unmet
need for patients who require more effective and better-tolerated
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therapies. Novel anti-CD20 antibodies and other immunotherapies
against different B-cell antigens are under active investigation. The
proteosome inhibitor bortezomib and the immunomodulatory agent
lenalidomide have demonstrated single-agent activity and are currently in
randomized trials. Other novel compounds have demonstrated activity in
broad-based clinical studies in B-cell malignancies. However,
considerable challenges remain in efficiently demonstrating which patient
subsets can benefit from these novel compounds and which combinations
may have the greatest clinical benefit in further improving outcomes for
patients with FL.
In a phase III clinical trial, Coiffier et al (2011) compared the safety and
effectiveness of rituximab alone or combined with bortezomib in patients
with relapsed or refractory FL. Rituximab-naive or rituximab-sensitive
patients aged 18 years or older with relapsed grade 1 or 2 FL were
randomly assigned (1:1) to receive 5 35-day cycles consisting of
intravenous infusions of rituximab 375 mg/m(2) on days 1, 8, 15, and 22
of cycle 1, and on day 1 of cycles 2 to 5, either alone or with bortezomib
1·6 mg/m(2), administered by intravenous injection on days 1, 8, 15, and
22 of all cycles. Randomization was stratified by FLIPI score, previous
use of rituximab, time since last therapy, and region. Treatment
assignment was based on a computer-generated randomization schedule
prepared by the sponsor. Patients and treating physicians were not
masked to treatment allocation. The primary endpoint was progression-
free survival analyzed by intention-to-treat. A total of 676 patients were
randomized to receive rituximab (n = 340) or bortezomib plus rituximab (n
= 336). After a median follow-up of 33.9 months (IQR 26.4 to 39.7),
median progression-free survival was 11.0 months (95 % CI: 9.1 to 12.0)
in the rituximab group and 12.8 months (11.5 to 15.0) in the bortezomib
plus rituximab group (hazard ratio 0.82, 95 % CI: 0.68 to 0.99; p =
0.039). The magnitude of clinical benefit was not as large as the
anticipated prespecified improvement of 33 % in progression-free
survival. Patients in both groups received a median of 5 treatment cycles
(range of 1 to 5); 245 of 339 (72 %) and 237 of 334 (71 %) patients in the
rituximab and bortezomib plus rituximab groups,respectively,
completed 5 cycles. Of patients who did not complete 5 cycles, most
discontinued early because of disease progression (77 [23 %] patients in
the rituximab group, and 56 [17 %] patients in the bortezomib plus
rituximab group). Rates of adverse events of grade 3 or higher (70 [21 %]
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of 339 rituximab-treated patients versus 152 [46 %] of 334 bortezomib
plus rituximab treated patients), and serious adverse events (37 [11 %]
patients versus 59 [18 %] patients) were lower in the rituximab group than
in the combination group. The most common adverse events of grade 3
or higher were neutropenia (15 [4 %] patients in the rituximab group and
37 [11 %] patients in the bortezomib plus rituximab group), infection (15 [4
%] patients and 36 [11 %] patients, respectively), diarrhoea (no patients
and 25 [7 %] patients, respectively), herpes zoster (1 [less than 1 %]
patient and 12 [4 %] patients, respectively), nausea or vomiting (2 [less
than 1 %] patients and 10 [3 %] patients, respectively) and
thrombocytopenia (2 [less than 1 %] patients and 10 [3 %] patients,
respectively). No individual serious adverse event was reported by more
than 3 patients in the rituximab group; in the bortezomib plus rituximab
group, only pneumonia (7 patients [2 %]) and pyrexia (6 patients [2 %])
were reported in more than 5 patients. In the bortezomib plus rituximab
group 57 (17 %) of 334 patients had peripheral neuropathy (including
sensory, motor, and sensorimotor neuropathy), including 9 (3 %) with
grade 3 or higher, compared with 3 (1 %) of 339 patients in the rituximab
group (no events of grade greater than or equal to 3). No patients in the
rituximab group but 3 (1 %) patients in the bortezomib plus rituximab
group died of adverse events considered at least possibly related to
treatment. The authors concluded that although a regimen of bortezomib
plus rituximab is feasible, the improvement in progression-free survival
provided by this regimen versus rituximab alone was not as great as
expected.
In a phase II study, Conconi et al (2011) examined the linical activity of
bortezomib in relapsed/refractory mucosa-associated lymphoid tissue
(MALT) lymphoma. A total of 32 patients with relapsed/refractory MALT
lymphoma were enrolled; 31 patients received bortezomib 1.3 mg/m(2)
i.v., on days 1, 4, 8, and 11, for up to 6 21-day cycles. Median age was
63 years (range of 37 to 82 years). Median number of prior therapies was
2 (range of 1 to 4). Nine patients had Ann Arbor stage I, 7 patients had
stage II, and 16 patients had stage IV. Primary lymphoma localization
was the stomach in 14 patients; multiple extra-nodal sites were present in
10 patients. Among the 29 patients assessable for response, the overall
response rate was 48 % [95 % CI: 29 % to 67 %], with 9 complete and 5
partial responses. Nine patients experienced stable disease and 6 had
disease progression during therapy. The most relevant adverse events
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were fatigue, thrombocytopenia, neutropenia, and peripheral neuropathy.
After a median follow-up of 24 months, the median duration of response
was not reached yet. Five deaths were reported, in 2 patients due to
disease progression. The authors concluded that bortezomib is active in
relapsed MALT lymphomas. They stated that further investigations to
identify optimal bortezomib dose, schedule, and combination regimens
are needed since the frequent detection of dose-limiting peripheral
neuropathy.
Fowler and associates (2011) evaluated the response rate, progression-
free survival, and toxicity of the combination of bortezomib,
bendamustine, and rituximab (VBR) in patients with FL whose disease
was relapsed or refractory to prior treatment. Patients received 5 35-day
cycles of bortezomib, bendamustine, and rituximab: bortezomib
administered intravenously (IV) at a dose of 1.6 mg/m(2) on days 1, 8, 15,
and 22, cycles 1 to 5; bendamustine 50, 70, or 90 mg/m(2) IV over a 60-
min infusion on days 1 and 2, cycles 1 to 5; and rituximab 375 mg/m(2)
on days 1, 8, 15, and 22 of cycle 1 and day 1 of subsequent cycles.
Patients were assessed using the International Workshop Response
Criteria, with the primary end point of 60 % complete response rate. A
total of 73 patients were enrolled. During the dose-escalation phase, the
maximum-tolerated dose for bendamustine was not reached; the 90
mg/m(2) dose level was expanded for the efficacy assessment, and a
total of 63 patients received bendamustine 90 mg/m(2). In these 63
patients, the overall response rate was 88 % (including 53 % CR).
Median duration of response was 11.7 months (95 % CI: 9.2 to 13.3).
Median progression-free survival was 14.9 months (95 % CI: 11.1 to
23.7). Toxicities were manageable; myelosuppression was the main
toxicity (25 % and 14 % of patients experienced grade 3 to 4 neutropenia
and grade 3 to 4 thrombocytopenia, respectively). Transient grade 3 to 4
neuropathy occurred in 11 % of patients. The authors concluded that the
combination of bortezomib, bendamustine, and rituximab is highly active
in patients with FL who have received previous treatment. The authors
noted that "despite observed efficacy, our hypothesis that VBR would
predict a CR rate greater than 60 % was not met. Follow-up remains
short, and continued analysis of long-term responders and late effects of
treatment is ongoing..... It is possible that the efficacy observed in the
current study resulted entirely from bendamustine and rituximab".
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In an editorial that accompanied the afore-mentioned study, Salles (2011)
stated that "[b]ut given the toxicity and economic costs of these regimens,
in the absence of more convincing signals supporting their clinical activity
in patients with follicular lymphoma (as opposed to other lymphoma
subtypes), other therapeutic options (e.g., new antibodies,
immunomodulatory agents, kinase inhibitors, and so on) may be
considered higher priorities for clinical trials in thefield".
In a phase II clinical study, Sehn and colleagues (2011) evaluated the
safety and effectiveness of bortezomib added to rituximab,
cyclophosphamide, vincristine, and prednisone (R-CVP) in previously
untreated advanced-stage FL. Bortezomib (1.3 mg/m(2) days 1 and 8)
was added to standard-dose R-CVP (BR-CVP) for up to 8 cycles in
patients with newly diagnosed stage III/IV FL requiring therapy. Two co-
primary end points, complete response rate (CR/CR unconfirmed [CRu])
and incidence of grade 3 or 4 neurotoxicity, were assessed. Between
December 2006 and March 2009, a total of 94 patients were treated with
BR-CVP. Median patient age was 57 years (range of 29 to 84 years), and
the majority had a high (47 %) or intermediate (43 %) Follicular
Lymphoma International Prognostic Index score. BR-CVP was extremely
well-tolerated, with 90 % of patients completing the intended 8 cycles. No
patients developed grade 4 neurotoxicity, and only 5 of 94 patients (5 %;
95 % CI: 0.8 % to 9.9 %) developed grade 3 neurotoxicity, which was
largely reversible. On the basis of an intention-to-treat analysis, 46 of 94
patients (49 %; 95 % CI: 38.8 % to 59.0 %) achieved a CR/CRu, and 32
of 94 patients (34 %) achieved a partial response, for an overall response
rate of 83 % (95 % CI: 75.4 % to 90.6 %). The authors concluded that
addition of bortezomib to standard-dose R-CVP for advanced-stage FL is
feasible and well-tolerated with minimal additional toxicity. The complete
response rate in this high-risk population compares favorably to historical
results of patients receiving R-CVP. Given these results, a phase III trial
comparing BR-CVP with R-CVP is planned.
In a phase 2 clinical trial, Argiris et al (20110 examined the effects of
bortezomib followed by the addition of doxorubicin at progression in
patients with recurrent or metastatic adenoid cystic carcinoma (ACC) of
the head and neck. Eligibility criteria included incurable ACC, any
number of prior therapies but without an anthracycline, unidimensionally
measurable disease, Eastern Cooperative Oncology Group performance
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status 0 to 2, and ejection fraction within normal limits. Patients with
stable disease for greater than or equal to 9 months were excluded.
Patients received bortezomib 1.3 mg/m(2) by intravenous (IV) push on
days 1, 4, 8, and 11, every 21 days until progression. Doxorubicin 20
mg/m(2) IV on days 1 and 8 was added at the time of progression. A total
of 25 patients were enrolled, of whom 24 were eligible; the most common
distant metastatic sites were the lung (n = 22) and the liver (n = 7). There
was no objective response with single-agent bortezomib; best response
was stable disease in 15 (71 %) of 21 evaluable patients. The median
progression-free survival and OS were 6.4 months and 21 months,
respectively. Of 10 evaluable patients who received bortezomib plus
doxorubicin, 1 had a PR, and 6 had stable disease. The most frequent
toxicity with bortezomib was grade 3 sensory neuropathy (16 %). With
bortezomib plus doxorubicin, serious toxicities seen more than once were
grade 3 to 4 neutropenia (n = 3) and grade 3 anorexia (n = 2). The
authors concluded that bortezomib was well-tolerated and resulted in
disease stabilization in a high percentage of patients but no objective
responses. They stated that the combination of bortezomib and
doxorubicin was also well-tolerated and may warrant further investigation
in ACC.
Escobar and colleagues (2011) noted that lung cancer therapy with
current available chemotherapeutic agents is mainly palliative. For these
and other reasons there is now a great interest to find targeted therapies
that can be effective not only palliating lung cancer or decreasing
treatment-related toxicity, but also giving hope to cure these patients. It is
already well-known that the ubiquitin-proteasome system like other
cellular pathways is critical for the proliferation and survival of cancer
cells; thus, proteosome inhibition has become a very attractive anti-
cancer therapy. There are several phase I and phase II clinical trials now
in non-small cell lung cancer as well as small cell lung cancer using this
potential target. Most of the trials use bortezomib in combination with
chemotherapeutic agents.
Dasanu (2011) stated that in the past 10 years, bortezomib moved in a
step-wise fashion from a benchside promise into a bedside reality and is
currently an important tool in the treatment of plasma cell disorders. This
investigator focused on the relationship between bortezomib and
hemolytic anemia. In animal models with lupus-like disease, this agent
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was shown to deplete the auto-reactive plasma cells and serum
autoantibody levels. In humans, 2 isolated reports advocate the efficacy
of bortezomib in autoimmune hemolytic anemia, but important concerns
remain with data interpretation and length bias. Conversely, bortezomib
may be causative of hemolytic anemia, as reported in a cohort of patients
with chronic lymphocytic leukemia. Concerted efforts of both basic and
clinical researchers are necessary to further explore the safety and
effectiveness of bortezomib in non-malignant disorders, including
autoimmune disorders and anemias.
An UpToDate review on “Histiocytic sarcoma” (Jacobsen, 2013) stated
that there were no standard treatments for histiocytic sarcoma and that
patients should be encouraged to enroll in clinicaltrials.
Marginal zone lymphoma is a type of B-cell lymphoma presenting
primarily in the marginal zone. There are 3 types: (i) splenic marginal
zone lymphoma; (ii) extra-nodal marginal zone B cell lymphoma
(MALT lymphoma or "mucosa-associated lymphoid tissue"); and (iii)
nodal marginal zone B cell lymphoma (NMZL). All 3 types of marginal
zone lymphoma are CD5- and CD10-negative.
Koprivnikar and Cheson (2012) noted that bortezomib is a novel
proteasome inhibitor initially approved for use in MM and currently under
continued investigation as a treatment for numerous subtypes of NHL.
One postulated mechanism of action in NHL is the ability of bortezomib to
ameliorate molecular dysregulation in NF-κB activation and regain cell
cycle control. Results of clinical trials have varied widely based on
lymphoma subtype. While response to bortezomib has been dismal in
patients with chronic lymphocytic leukemia and small lymphocytic
lymphoma, reasonable responses have been attained in patients with
mantle cell lymphoma; leading to its FDA approval as a second-line agent
for the treatment of mantle cell lymphoma in 2006. Bortezomib in
combination with R-CHOP has also been suggested to improve response
in certain molecular subgroups of diffuse large B-cell lymphoma. The role
of bortezomib in follicular and marginal zone lymphomas remains less
clear.
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Also, an UpToDate review on “Treatment of marginal zone (MALT)
lymphoma” (Freedman and Friedberg, 2013) did not mention the use of
bortezomib as a therapeutic option. Furthermore, the 2013 NCCN Drugs
and Biologics Compendium did not list marginal zone lymphoma as a
recommended indication of bortezomib.
An UpToDate review on “Treatment and prevention of post-transplant
lymphoproliferative disorders” (Negrin et al, 2013) did not mention the use
of bortezomib as a therapeutic option. Furthermore, the 2013 NCCN
Drugs and Biologics Compendium did not list PTLD as a recommended
indication of bortezomib.
The NCCN Drug and Biologics Compendium (2013) no longer
recommended bortezomib for the following indications: splenic marginal
zone lymphoma, gastric MALT lymphoma, non-gastric MALT lymphoma,
and follicular lymphoma.
Khan and colleagues (2010) noted that hyper IgG4 disease is a recently
described inflammatory disease characterized by lymphoplasmacytic
infiltration leading to fibrosis and tissue destruction. Whereas most cases
have been successfully treated with corticosteroids, recurrent or
refractory cases may benefit from alternative therapies. Bortezomib has
proven to be successful in the treatment of multiple myeloma, and its
mechanism indicates that it may have merit in autoimmune or other
plasmacytic disorders. The authors reported a patient with recurrent
pulmonary infiltration with IgG4 plasma cells, consistent with hyper IgG4
disease, who was successfully treated using a bortezomib-based
combination with minimal therapy-related toxicities.
An UpToDate review on "Overview of IgG4-related disease"
(Moutsopoulos et al, 2014) did not mention the use of bortezomib as a
therapeutic option.
Khandelwal et al (2014) stated that therapy of refractory autoimmunity
remains challenging. In this study, these investigators evaluated the
therapeutic effect of bortezomib in 7 patients (median age of 9.9 years)
with refractory autoimmunity. Four doses of bortezomib were
administered at a dose of 1 3.mg/m2 intravenously (n = 6) or
subcutaneously (n = 1) every 72 hours. Bortezomib was administered at
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a median of 120 days from laboratory confirmation of autoantibodies. All
patients had failed 2 or more standard therapies. Rituximab was
administered on the first day if B cells were present, and all patients
received plasmapheresis 2 hours prior to bortezomib administration. Six
patients experienced resolution of cytopenia; 2 of 6 patients experienced
recurrence of cytopenia after initial response. Adverse effects include
nausea (n = 1), thrombocytopenia (n = 2), Clostridium difficile colitis (n =
1)), febrile neutropenia (n = 1) and cellulitis at the subcutaneous injection
site (n = 1). The authors concluded that these findings suggested that
bortezomib may be beneficial in the treatment of refractory autoimmunity
in children. These preliminary findings need to be validated by well-
designed studies.
Gomez and colleagues (2014) noted that bortezomib is currently used to
eliminate malignant plasma cells in MM patients. It is also effective in
depleting both allo-reactive plasma cells in acute Ab-mediated transplant
rejection and their auto-reactive counterparts in animal models of lupus
and myasthenia gravis (MG). In this study, these researchers
demonstrated that bortezomib at 10 nM or higher concentrations killed
long-lived plasma cells in cultured thymus cells from 9 early-onset MG
patients and consistently halted their spontaneous production not only of
autoantibodies against the acetylcholine receptor but also of total IgG.
Surprisingly, lenalidomide and dexamethasone had little effect on plasma
cells. After bortezomib treatment, they showed ultra-structural changes
characteristic of endoplasmic reticulum stress after 8 hours and were no
longer detectable at 24 hours. The authors concluded that bortezomib
appears promising for treating MG and possibly other Ab-mediated
autoimmune or allergic disorders, especially when given in short courses
at modest doses before the standard immunosuppressive drugs have
taken effect. These in-vitro findings need to be studied in future clinical
trials.
In a phase II, open-label, multi-center clinical trial, Ciombor et al (2014)
evaluated the effectiveness and tolerability of bortezomib in combination
with doxorubicin in patients with advanced hepatocellular carcinoma, and
correlated pharmacodynamic markers of proteasome inhibition with
response and survival. These researchers examined the effectiveness of
bortezomib (1.3 mg/m2 IV on day 1, 4, 8, 11) and doxorubicin (15 mg/m2
IV on day 1, 8) in 21-day cycles. The primary end-point was objective
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response rate. Best responses in 38 treated patients were 1 partial
response (2.6 %), 10 (26.3 %) stable disease, and 17 (44.7 %)
progressive disease; 10 patients were unevaluable. Median PFS was 2.2
months. Median OS was 6.1 months. The most common grade 3 to 4
toxicities were hypertension, glucose intolerance, ascites, ALT elevation,
hyperglycemia and thrombosis/embolism. Worse PFS was seen in
patients with elevated IL-6, IL-8, MIP-1α and EMSA for NF-κB at the start
of treatment. Worse OS was seen in patients with elevated IL-8 and
VEGF at the start of treatment. Patients had improved OS if a change in
the natural log of serum MIP-1α/CCL3 was seen after treatment.
RANTES/CCL5 levels decreased significantly with treatment. The
authors concluded that the combination of doxorubicin and bortezomib
was well-tolerated in patients with hepatocellular carcinoma, but the
primary end-point was not met.
National Comprehensive Cancer Network guidelines (2015)
recommended the use of bortezomib as subsequent therapy with or
without rituximab for multicentric Castleman's disease (CD)that has
progressed following treatment of relapsed/refractory or progressive
disease.
Perry et al (2009) noted that antibody production by normal plasma cells
(PCs) against human leukocyte antigens (HLA) can be a major barrier to
successful transplantation. These investigators tested 4 reagents with
possible activity against PCs (rituximab, polyclonal rabbit anti-thymocyte
globulin (rATG), intravenous immunoglobulin (IVIG) and bortezomib) to
determine their ability to cause apoptosis of human bone marrow-derived
PCs and subsequently block IgG secretion in vitro. Rituximab, IVIG, and
rATG all failed to cause apoptosis of PCs and neither rituximab nor rATG
blocked antibody production. In contrast, bortezomib treatment led to PC
apoptosis and thereby blocked anti-HLA and anti-tetanus IgG secretion in
vitro. Two patients treated with bortezomib for humoral rejection after
allogeneic kidney transplantation demonstrated a transient decrease in
bone marrow PCs in vivo and persistent alterations in allo-antibody
specificities. Total IgG levels were unchanged. The authors concluded
that proteasome activity is important for PC longevity and its inhibition
may lead to new techniques of controlling antibody production in vivo.
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Everly et al (2009) described the biochemistry and physiology of
proteasome inhibition and discussed recent studies with proteasome
inhibitor therapy in organ transplantation. Traditional anti-humoral
therapies do not deplete PCs. Proteasome inhibition depletes both
transformed and non-transformed PCs in animal models and human
transplant recipients. Bortezomib is a first in a class proteasome inhibitor
that has been shown to effectively treat antibody-mediated rejection in
kidney transplant recipients. In this experience, bortezomib provided
reversal of histological changes and also induced a reduction in donor-
specific anti-HLA antibody levels. Recent experiences have also shown
that bortezomib reduces donor-specific anti-HLA antibody in the absence
of rejection. Finally, evidence has been presented that bortezomib
therapy depletes HLA-specific antibody producing PCs. The authors
concluded that proteasome inhibition induces a complex series of
biochemical events that results in pleiotropic effects on multiple cell
populations, and PCs in particular. Initial clinical results have provided
evidence that bortezomib effectively treats antibody-mediated rejection
and acute cellular rejection and reduces or eliminates donor-specific anti-
HLA antibody. They stated that carefully designed clinical trials are
needed to accurately define the role of proteasome inhibition in transplant
recipients.
Stegall and Gloor (2010) described recent studies regarding the
mechanisms of antibody-mediated rejection (AMR) and new clinical
protocols aimed at prevention and/or treatment of this difficult clinical
entity. These investigators noted that the natural history of acute AMR
after positive cross-match kidney transplantation involves an acute rise in
donor-specific alloantibody (DSA) in the first few weeks following
transplantation. Whereas the exact cellular mechanisms responsible for
AMR are not known, it seems likely that both pre-existing plasma cells
and the conversion of memory B cells to new plasma cells play a role in
the increased DSA production. One recent study suggested that
combination therapy with plasmapheresis, high-dose IVIG and rituximab
was more effective treatment for AMR than high-dose IVIG alone, but the
role of anti-CD20 antibody is still unclear. Two new promising
approaches to AMR focus on depletion of plasma cells with bortezomib
as well as the inhibition of terminal complement activation with
eculizumab. The authors concluded that the pathogenesis of AMR in
several different clinical settings is becoming clearer and more effective
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treatments are being developed. Whether the prevention or successful
treatment of AMR will decrease the prevalence of chronic injury and
improved long-term graft survival will require longer-term studies.
The American Association for the Study of Liver Diseases and the
American Society of Transplantation’s practice guideline on “Long‐term
management of the successful adult liver transplant” (Lucey et al, 2012)
made no reference to the use of bortezomib. Furthermore, an UpToDate
review on “Treatment of acute cellular rejection in liver transplantation’
(Cotler, 2013) does not mention the use of bortezomib as a management
tool.
Claes et al (2014) noted that standard treatments for antibody-mediated
rejection (AMR) -- rituximab, intravenous immunoglobulin, and/or
plasmapheresis -- aim to suppress the production and modulate the effect
of donor-specific antibodies (DSA) and remove them, respectively.
Proteasome inhibitors (PIs) such as bortezomib are potent therapeutic
agents that target plasma cells more effectively than rituximab to reduce
measurable DSA production. Little is known in adults, and no data exist
in children about effects of PIs to treat AMR on protective antibody titers.
These researchers presented a pediatric renal transplant recipient who
received bortezomib for relatively early AMR and whose antibody titers to
measles and tetanus were tracked. The AMR was treated successfully,
and these investigators noted no clinical decrease in the overall level of
protective immunity from pre-transplant baseline levels at almost 1 year
after AMR treatment cessation. The authors concluded that larger
studies will elucidate more clearly how proteasome inhibition to treat AMR
affects protective immunity in pediatric transplant recipients.
Eskandary et al (2014) noted that the formation of DSA and ongoing AMR
processes may critically contribute to late graft loss. However,
appropriate treatment for late AMR has not yet been defined. There is
accumulating evidence that the bortezomib may substantially affect the
function and integrity of alloantibody-secreting plasma cells. The impact
of this agent on the course of late AMR has not so far been systematically
investigated. The BORTEJECT Study is a randomized controlled trial
designed to clarify the impact of intravenous bortezomib on the course of
late AMR. In this single-center study (nephrological outpatient service,
Medical University Vienna) these researchers plan an initial cross-
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sectional DSA screening of 1,000 kidney transplant recipients (functioning
graft at greater than or equal to 180 days; estimated glomerular filtration
rate (eGFR) greater than 20 ml/minute/1.73 m2). DSA-positive recipients
will be subjected to kidney allograft biopsy to detect morphological
features consistent with AMR. Forty-four patients with biopsy-proven
AMR will then be included in a double-blind placebo-controlled
intervention trial (1:1 randomization stratified for eGFR and the presence
of T-cell-mediated rejection). Patients in the active group will receive 2
cycles of bortezomib (4 x 1.3 mg/m2 over 2 weeks; 3-month interval
between cycles). The primary end-point will be the course of eGFR over
24 months (intention-to-treat analysis). The sample size w as calculated
according to the assumption of a 5 ml/minute/1.73 m2 difference in eGFR
slope (per year) between the 2 groups (alpha: 0.05; power: 0.8).
Secondary end-points will be DSA levels, protein excretion, measured
GFR, transplant and patient survival, and the development of acute and
chronic morphological lesions in 24-month protocol biopsies. The authors
stated that the impact of anti-humoral treatment on the course of late
AMR has not yet been systematically investigated. Based on the
hypothesis that proteasome inhibition improves the outcome of DSA-
positive late AM R, these i nvestigators suggest that their trial has the
potential to provide solid evidence towards the treatment of this type of
rejection.
Ejaz et al (2014) stated that development of DSA after kidney
transplantation is associated with reduced allograft survival. A few
strategies have been tested in controlled clinical trials for the treatment of
AMR, and no therapies are approved by regulatory authorities. Thus
development of anti-humoral therapies that provide prompt elimination of
DSA and improve allograft survival is an important goal. Proteasome
inhibitor-based regimens provide a promising new approach for treating
AMR. To-date, experiences have been limited to off-label bortezomib use
in AMR. Key findings with PI-based therapy are that they provide
effective primary and rescue therapy for AMR by prompt reduction in
immuno-dominant DSA and improvements in histologic and renal
function. Early and late AMR differ immunologically and in response to PI
therapy. Bortezomib-related toxicities in renal transplant recipients are
similar to those observed in the multiple myeloma population. Although
preliminary evidence with PI therapy for AMR is encouraging, the
evidence is limited. The authors stated that larger, prospective,
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randomized controlled trials with long-term follow up are needed.
Advancement in end-points of clinical trial designs and rigorous clinical
trials with more standardized adjunct therapies are also required to
explore the risks and benefits of AMR treatment modalities.
Kim et al (2014) noted that AMR, also known as B-cell-mediated or
humoral rejection, is a significant complication after kidney transplantation
that carries a poor prognosis. Although fewer than 10 % of kidney
transplant patients experience AMR, as many as 30 % of these patients
experience graft loss as a consequence. Although AMR is mediated by
antibodies against an allograft and results in histologic changes in
allograft vasculature that differ from cellular rejection, it has not been
recognized as a separate disease process until recently. With an
improved understanding about the importance of the development of
antibodies against allografts as well as complement activation, significant
advances have occurred in the treatment of AMR. The standard of care
for AMR includes plasmapheresis and intravenous immunoglobulin that
remove and neutralize antibodies, respectively. Agents targeting B cells
(rituximab and alemtuzumab), plasma cells (bortezomib), and the
complement system (eculizumab) have also been used successfully to
treat AMR in kidney transplant recipients. However, the high cost of
these medications, their use for unlabeled indications, and a lack of
prospective studies evaluating their efficacy and safety limit the routine
use of these agents in the treatment of AMR in kidney transplant
recipients.
An UpToDate review on "C4d staining in renal allografts and treatment of
antibody mediated rejection" (Klein and Brennan, 2014) statesd that “An
initial report also found that bortezomib, a proteosomal inhibitor, which is
approved for use in multiple myeloma, may be effective in the treatment
of AMR or mixed AMR and cellular rejection. Additional analysis of this
agent is required to better understand its potential role”.
An UpToDate review on "Acute renal allograft rejection: Treatment" (Chon
and Brennan, 2014) statesd that "Bortezomib -- US Food and Drug
Administration (FDA)-approved for treating multiple myeloma, bortezomib
is a proteosomal inhibitor that causes apoptosis of mature plasma cells.
Several case reports/series have dem onstrated its effectiveness in
treating ABMR, successfully reversing acute rejection, and/or reducing
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DSAs. A prospective, randomized, controlled study is needed to evaluate
the efficacy and safety of this drug. At present, the optimal treatment for
this entity in the setting of either acute or chronic allograft dysfunction is
unknown".
Garces, et al. (2017) reviewed the data on management of antibody
mediated rejection. The authors stated that removing plasma cells that
generate antibodies is the rationale behind using a proteasome inhibitor
(PI) as therapy for AMR. The authors stated that bortezomib, currently
approved for the treatment of multiple myeloma, has been used in
combination with PLEX, IVIG, or rituximab as a rescue therapy for AMR
with some encouraging results. The authors cited for support a study by
Woodle and colleagues who published their experience in a multicenter
collaborative study that by May 2010 had treated 60 AMR patients in 15
centers with bortezomib-based therapy.62 The PI-based protocol included
bortezomib (1.3 mg/m2/dose × 4 doses) preceded by a single rituximab
dose and PLEX prior to each bortezomib dose. Data are reported for 56
episodes of AMR ± acute cellular rejection occurring in 51 patients.
Transplanted organs with AMR included adult kidney (43), adult
kidney/pancreas (9), and pediatric heart (4). The majority of patients
undergoing repeat biopsy demonstrated histologic improvement. Garces,
et al. (2017) stated that the large experience reported by Woodle et
al. with PI-based AMR therapy demonstrated that it provides effective
AMR reversal, including substantial reductions in DSA levels.
Anti-NMDA Receptor Encephalitis
Scheibe and colleagues (2017) evaluated the therapeutic potential of
bortezomib in severe and therapy-refractory cases of anti-N-methyl-d-
aspartate receptor (anti-NMDAR) encephalitis. A total of 5 severely
affected patients with anti-NMDAR encephalitis with delayed treatment
response or resistance to standard immunosuppressive and B-cell-
depleting drugs (corticosteroids, cyclophosphamide, IVIGs, immuno-
adsorption, plasma exchange, rituximab) who required medical treatment
and artificial ventilation on intensive care units were treated with 1 o 6
cycles of 1.3 mg/m2 bortezomib. Occurrence of adverse events (AEs)
was closely monitored. Bortezomib treatment showed clinical
improvement or disease remission, which was accompanied by a partial
NMDAR antibody titer decline in 4 of 5 patients. With respect to disease
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severity, addition of bortezomib to the multi-modal immunosuppressive
treatment regimen was associated with an acceptable safety profile. The
authors concluded that this study identified bortezomib as a promising
escalation therapy for severe and therapy-refractory anti-NMDAR
encephalitis. Level of Evidence = IV.
Shin and associates (2018) examined the therapeutic potential of
bortezomib in patients with anti-NMDAR encephalitis who remain
bedridden even after aggressive immunotherapy. These researchers
consecutively enrolled patients with anti-NMDAR encephalitis who
remained bedridden after 1st-line immunotherapy (steroids and IVIG),
2nd-line immunotherapy (rituximab), and tocilizumab treatment, and
treated them with subcutaneous bortezomib. Clinical response, functional
recovery, and changes in antibody titer in the serum and cerebro-spinal
fluid (CSF) were measured. Before the bortezomib treatment, the 5
patients with severe refractory anti-NMDAR encephalitis were in a
vegetative state. During the 8 months of follow-up period, 3 patients
improved to minimally conscious states within 2 months of bortezomib
treatment, 1 failed to improve from a vegetative state. However, no
patient achieved functional recovery as measured by the modified Rankin
Scale score (mRS); 3 patients advanced to a cyclophosphamide with
bortezomib and dexamethasone regimen, which only resulted in
additional AEs, without mRS improvement. Among the 4 patients whose
antibody titer was followed, 2 demonstrated a 2-fold decrease in the
antibody titer in serum and/or CSF after 2 cycles of bortezomib. The
authors concluded that although there were some improvements in
severe refractory patients, clinical response to bortezomib was limited
and not clearly distinguishable from the natural course of the disease.
They stated that the clinical benefit of bortezomib in recent studies needs
further validation in different clinical settings.
Chronic Graft-Versus Host Disease
Blanco et al (2009) stated that in-vitro depletion of allo-reactive T cells
using bortezomib is a promising approach to prevent GVHD after
allogeneic stem cell transplantation. These researchers had previously
described the ability of bortezomib to selectively eliminate allo-reactive T
cells in a mixed leukocyte culture, preserving non-activated T cells. Due
to the role of regulatory T cells in the control of GVHD, in the current
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manuscript these investigators analyzed the effect of bortezomib in
regulatory T cells. Conventional or regulatory CD4(+) T cells were
isolated with immuno-magnetic microbeads based on the expression of
CD4 and CD25. The effect of bortezomib on T-cell viability was analyzed
by flow cytometry using 7-amino-actinomycin D staining. To investigate
the possibility of obtaining an enriched regulatory T-cell population in-vitro
with the use of bortezomib, CD4(+) T cells were cultured during 4 weeks
in the presence of anti-CD3 and anti-CD28 antibodies, IL-2 and
bortezomib. The phenotype of these long-term cultured cells was
studied, analyzing the expression of CD25, CD127 and FOXP3 by flow
cytometry, and mRNA levels were determined by RT-PCR. Their
suppressive capacity was assessed in co-culture experiments, analyzing
proliferation and IFN-gamma and CD40L expression of stimulated
responder T cells by flow cytometry. These researchers observed that
naturally occurring CD4(+)CD25(+) regulatory T cells were resistant to the
pro-apoptotic effect of bortezomib. Furthermore, they found that long-
term culture of CD4(+) T cells in the presence of bortezomib promoted
the emergence of a regulatory T-cell population that significantly inhibits
proliferation, gamma interferon (IFN-γ) production and CD40L expression
among stimulated effector T cells. The authors concluded that these
findings reinforced the proposal of using bortezomib in the prevention of
GVHD and, moreover, in the generation of regulatory T-cell populations,
that could be used in the treatment of multiple T-cell mediated diseases.
Blanco et al (2011) noted that current GVHD inhibition approaches lead to
abrogation of pathogen-specific T-cell responses. These researchers
proposed an approach to inhibit GVHD without hampering immunity
against pathogens: in-vitro depletion of allo-reactive T cells with
bortezomib. They showed that PBMCs stimulated with allogeneic cells
and treated with bortezomib greatly reduced their ability to produce IFN-γ
when re-stimulated with the same allogeneic cells, but mainly preserve
their ability to respond to cytomegalovirus stimulation. The authors
concluded that unlike in-vivo administration of immunosuppressive drugs
or other strategies of allo-depletion, in-vitro allo-depletion with bortezomib
maintained pathogen-specific T cells, representing a promising alternative
for GVHD prophylaxis.
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Koreth et al (2012) stated that HLA-mismatched unrelated donor (MMUD)
hematopoietic stem-cell transplantation (HSCT) is associated with
increased GVHD and impaired survival. In reduced-intensity conditioning
(RIC), neither ex-vivo nor in-vivo T-cell depletion (e.g., anti-thymocyte
globulin) convincingly improved outcomes. The proteasome inhibitor
bortezomib has immunomodulatory properties potentially beneficial for
control of GVHD in T-cell-replete HLA-mismatched transplantation.
These investigators conducted a prospective phase I/II clinical trial of a
GVHD prophylaxis regimen of short-course bortezomib, administered
once per day on days +1, +4, and +7 after peripheral blood stem-cell
infusion plus standard tacrolimus and methotrexate in patients with
hematologic malignancies undergoing MMUD RIC HSCT. They reported
outcomes for 45 study patients: 40 (89 %) 1-locus and 5 (11 %) 2-loci
mismatches (HLA-A, -B, -C, -DRB1, or -DQB1), with a median of 36.5
months (range of 17.4 to 59.6 months) follow-up. The 180-day
cumulative incidence of grade 2 to 4 acute GVHD was 22 % (95 % CI: 11
% to 35 %); 1-year cumulative incidence of chronic GVHD was 29 % (95
% CI: 16 % to 43 %); 2-year cumulative incidences of non-relapse
mortality (NRM) and relapse were 11 % (95 % CI: 4 % to 22 %) and 38 %
(95 % CI: 24 % to 52 %), respectively; 2-year progression-free survival
(PFS) and OS were 51 % (95 % CI: 36 % to 64 %) and 64 % (95 % CI: 49
% to 76 %), respectively. Bortezomib-treated HLA-mismatched patients
experienced rates of NRM, acute and chronic GVHD, and survival similar
to those of contemporaneous HLA-matched RIC HSCT at the authors’
institution. Immune recovery, including CD8(+) T-cell and natural killer
cell reconstitution, was enhanced with bortezomib. The authors stated
that a novel short-course, bortezomib-based GVHD regimen can
abrogate the survival impairment of MMUD RIC HSCT, can enhance early
immune reconstitution, and appeared to be suitable for prospective
randomized evaluation.
In a phase II clinical trial, Caballero-Velazquez et al (2013) evaluated the
safety and effectiveness of bortezomib in combination with fludarabine
and melphalan as reduced intensity conditioning before allogeneic stem
cell transplantation in patients with high risk multiple myeloma. A total of
16 patients were evaluable. The median number of previous line of
treatment was 3; all patients had relapsed following a prior autograft and
13 had previously received bortezomib; 15 of them either remained stable
or improved disease status at day +100 post-transplant, including 11
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patients with active disease. More specifically, 9 patients (56 %) and 5
patients (31 %) reached complete remission and partial response,
respectively; 25 % developed grade III acute GVHD. The cumulative
incidence of NRM, relapse and OS were 25 %, 54 % and 41 %,
respectively, at 3 years. Regarding the non-hematological toxicity (grade
greater than 2), 2 patients developed peripheral neuropathy, 2 patients
liver toxicity and 1 pulmonary toxicity early post-transplant. The
hematological toxicity was only observed during the first 3 cycles mostly
related to low hemoglobin and platelet levels. The authors concluded that
the current trial is the first one evaluating the safety and effectiveness of
bortezomib as part of a reduced intensity conditioning regimen among
patients with high risk multiple myeloma.
Herrera et al (2014) stated that GVHD induces significant morbidity and
mortality after allogeneic hematopoietic stem cell transplantation.
Corticosteroids are standard i nitial therapy, despite limited efficacy and
long-term toxicity. Based on their experience using bortezomib as
effective acute GVHD prophylaxis, these investigators hypothesized that
proteasome-inhibition would complement the immunomodulatory effects
of corticosteroids to improve outcomes in chronic GVHD (cGVHD). They
undertook a single-arm phase II clinical trial of bortezomib plus
prednisone for initial therapy of cGVHD. Bortezomib was administered at
1.3 mg/m(2) i.v. on days 1, 8, 15, and 22 of each 35-day cycle for 3 cycles
(15 weeks). Prednisone was dosed at .5 to 1 mg/kg/day, with a
suggested taper after cycle 1. All 22 enrolled participants were evaluable
for toxicity; 20 were evaluable for response. Bortezomib plus prednisone
therapy was well-tolerated, with 1 occurrence of grade 3 sensory
peripheral neuropathy possibly related to bortezomib. The overall
response rate (ORR) at week 15 in evaluable participants was 80 %,
including 2 (10 %) complete and 14 (70 %) partial responses. The organ-
specific complete response rate was 73 % for skin, 53 % for liver, 75 %
for gastro-intestinal (GI) tract, and 33 % for joint, muscle, or fascia
involvement. The median prednisone dose decreased from 50 mg/day to
20 mg/day at week 15 (p < 0.001). The combination of bortezomib and
prednisone for initial treatment of cGVHD was feasible and well-
tolerated. The authors concluded that they observed a high response
rate to combined bortezomib and prednisone therapy; however, in this
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single-arm study, they could not directly measure the impact of
bortezomib. These researchers noted that proteasome inhibition may
offer benefit in the treatment of cGVHD and should be further evaluated.
Al-Homsi et al (2015) noted that an effective GVHD preventative
approach that preserves the graft-versus-tumor effect after allogeneic
hematopoietic stem cell transplantation (HSCT) remains elusive.
Standard GVHD prophylactic regimens suppress T cells indiscriminately
and are suboptimal. Conversely, post-transplantation high-dose
cyclophosphamide selectively destroys proliferating allo-reactive T cells,
allows the expansion of regulatory T cells, and induces long-lasting clonal
deletion of intra-thymic anti-host T cells. It has been successfully used to
prevent GVHD after allogeneic HSCT. Bortezomib has anti-tumor activity
on a variety of hematological malignancies and exhibits a number of
favorable immunomodulatory effects that include inhibition of dendritic
cells. Thus, an approach that combines post-transplantation
cyclophosphamide and bortezomib seems attractive. These investigators
reported the results of a phase I study examining the feasibility and safety
of high-dose post-transplantation cyclophosphamide in combination with
bortezomib in patients undergoing allogeneic peripheral blood HSCT from
matched siblings or unrelated donors after reduced-intensity
conditioning. Cyclophosphamide was given at a fixed dose (50 mg/kg on
days +3 and +4). Bortezomib dose was started at 0.7 mg/m2, escalated
up to 1 .3 mg/m2, and was administered on days 0 and +3. Patients
receiving grafts from unrelated donors also received rabbit anti-thymocyte
globulin. The combination was well-tolerated and allowed prompt
engraftment in all patients. The incidences of acute GVHD grades II to IV
and grades III and IV were 20 % and 6.7 %, respectively. With a median
follow-up of 9.1 months (range of 4.3 to 26.7), treatment-related mortality
was 13.5 % with predicted 2-year disease-free survival (DFS) and OS of
55.7 % and 68 %, respectively. The authors concluded thatth4e findings
of this study suggested that the combination of post-transplantation
cyclophosphamide and bortezomib is feasible and may offer an effective
and practical GVHD prophylactic regimen; the combination, therefore,
merits further examination.
Al-Homsi et al (2017) stated that GVHD hampers the utility of allogeneic
hematopoietic stem cell transplantation (AHSCT). In a phase I/II clinical
trial, these researchers determined the feasibility, safety, and efficacy of a
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novel combination of post-transplantation cyclophosphamide (PTC) and
bortezomib for the prevention of GVHD. Patients undergoing peripheral
blood AHSCT for hematological malignancies after reduced-intensity
conditioning with grafts from HLA-matched related or unrelated donors
were enrolled in this trial. Patients received a fixed dose of PTC and an
increasing dose of bortezomib in 3 cohorts, from 0.7 to 1 and then to 1.3
mg/m2, administered 6 hours after graft infusion and 72 hours thereafter,
during phase I. The study was then extended at the higher dose in phase
II for a total of 28 patients. No graft failure and no unexpected grade
greater than or equal to3 non-hematologic toxicities were encountered.
The median times to neutrophil and platelet engraftment were 16 and 27
days, respectively. Day +100 treatment-related mortality was 3.6 % (95
% CI: 0.2 % to 15.7 %). The cumulative incidences of grades II to IV and
grades III and IV acute GVHD were 35.9 % (95 % CI: 18.6 % to 53.6 %)
and 11.7 % (95 % CI: 2.8 % to 27.5 %), respectively. The incidence of
chronic GVHD was 27 % (95 % CI: 11.4 % to 45.3 %; PFS, OS, and
GVHD and relapse-free survival rates were 50 % (95 % CI: 30.6 % to
66.6 %), 50.8 % (95 % CI: 30.1 % to 68.2 %), and 37.7 % (95 % CI: 20.1
% to 55.3 %), respectively. Immune reconstitution, measured by CD3,
CD4, and CD8 recovery, was prompt. The authors concluded that the
combination of PTC and bortezomib for the prevention of GVHD is
feasible, safe, and yields promising results. They stated that the
combination warrants further examination in a multi-institutional trial.
Jain and colleagues (2018) stated that pulmonary cGVHD (p-cGVHD)
following allogeneic HSCT is devastating with limited proven treatments.
Although sporadically associated with pulmonary toxicity, bortezomib
may be effective in p-CGVHD. In a pilot, open-label study, these
researchers sought to establish safety and tolerability of bortezomib in
patients with p-cGVHD. The primary end-point was AEs. Efficacy was
assessed by comparing forced expiratory volume in one second (FEV1)
decline prior to p-cGVHD diagnosis to during the bortezomib treatment
period. The impact on pulmonary function testing of prior long-term
bortezomib treatment in MM patients was also assessed as a safety
analysis. A total of 17 patients enrolled in the pilot study with a mean time
to p-cGVHD diagnosis of 3.36 years (± 1.88 years). Bortezomib was well-
tolerated without early drop-outs. The median FEV1 decline prior to the
diagnosis of p-cGVHD was -1.06 %/month (-5.36, -0.33) and during
treatment was -0.25 %/month (-9.42, 3.52). In the safety study, there was
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no significant difference in any PFT parameter between 73 patients who
received bortezomib and 68 patients who did not for MM. The authors
concluded that bortezomib had acceptable safety and tolerability in
patients with compromised pulmonary function. The efficacy of
proteosomal inhibition should be assessed in a large trial of patients with
p-cGVHD.
Furthermore, an UpToDate review on “Treatment of chronic graft-versus-
host disease” (Chao, 2018) does not mention bortezomib as a therapeutic
option.
Glioblastoma Multiforme
In a phase-II clinical trial, Kong and associates (2018) evaluated the
safety and efficacy of up-front treatment using bortezomib combined with
standard radiation therapy (RT) and temozolomide (TMZ), followed by
adjuvant bortezomib and T MZ for less than or equal to 24 cycles, in
patients with newly diagnosed glioblastoma multiforme (GBM). A total of
24 patients with newly diagnosed GBM were enrolled. The patients
received standard external beam regional RT with concurrent TMZ
beginning 3 to 6 weeks after surgery, followed by adjuvant TMZ and
bortezomib for less than or equal to 24 cycles or until tumor progression.
During RT, bortezomib was given at 1.3 mg/m2 on days 1, 4, 8, 11, 29,
32, 36, and 39. After RT, bortezomib was given at 1.3 mg/m2 on days 1,
4, 8, and 11 every 4 weeks. No unexpected AEs occurred from the
addition of bortezomib. The efficacy analysis showed a median PFS of
6.2 months (95 % CI: 3.7 to 8.8), with promising PFS rates at greater than
or equal to 18 months compared with historical norms (25.0 % at 18 and
24 months; 16.7 % at 30 months). In terms of OS, the median OS was
19.1 months (95 % CI: 6.7 to 31.4), with improved OS rates at greater
than or equal to 12 months (87.5 % at 12, 50.0 % at 24, 34.1 % at 36 to
60 months) compared with the historical norms. The median PFS was
24.7 months (95 % CI: 8.5 to 41.0) in 10 MGMT methylated and 5.1
months (95 % CI: 3.9 to 6.2) in 13 un-methylated patients. The estimated
median OS was 61 months (95 % CI: upper bound not reached) in the
methylated and 16.4 months (95 % CI: 11.8 to 21.0) in the un-methylated
patients. The authors concluded that the addition of bortezomib to
current standard radio-chemotherapy in newly diagnosed GBM patients
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was tolerable. The PFS and OS rates appeared promising, with more
benefit to MGMT methylated patients. They stated that further clinical
investigation is needed in a larger cohort ofpatients.
Hepatic Amyloidosis
Hasan and colleagues (2018) noted that amyloidosis is a rare disorder
with a wide spectrum of presentations and anomalies. It is subdivided
into 2 broad categories based on protein deposition; primary and
secondary amyloidosis. It can present as a single-organ involvement or
as a diffuse infiltrative multi-organ process. Isolated hepatic amyloidosis
presentation is a rare phenomenon that develops due to insoluble
amyloid deposition in liver . Its clinical presentation is usually vague and
ranges from mild hepatomegaly with elevated liver enzymes to acute liver
failure and hepatic rupture. Currently, there are scarce data available
regarding therapeutic options for biopsy-proven hepatic amyloidosis.
These investigators presented a case of hepatic amyloidosis and its poor
outcome to new molecular targeted chemotherapy. The case described
emphasized the need for additional studies to establish specific treatment
protocols and further characterize adverse effects to reduce the mortality
and morbidity associated with this terminal illness.
Mucous Membrane Pemphigoid
Saeed and colleagues (2017) noted that mucous membrane pemphigoid
(MMP) is a rare, autoantibody-mediated disease characterized by
mucocutaneous blistering including oral, ocular, laryngeal, and skin
involvement. Treating MMP is challenging, with few effective therapies
available. These investigators reported successful treatment of a patient
with treatment-refractory MMP with bortezomib. These researchers
hypothesized that using bortezomib to target plasma cells would help this
patient. The authors concluded that bortezomib may be a potential
therapeutic option for cases of refractory MMP and other autoantibody-
mediated diseases that do not respond to rituximab. Moreover, they
stated that larger studies and randomized controlled trials (RCTs) are
needed to better understand the safety and efficacy of bortezomib for
autoantibody-mediated diseases like MMP.
Plasmablastic Lymphoma
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Guerrero-Garcia and colleagues (2017) stated that plasmablastic
lymphoma (PBL) is a rare and hard to treat disease. With current
standard chemotherapeutic regimens, PBL is associated with a median
OS of 12 to 15 months. These researchers performed a systematic
review of the literature through March 31, 2017 looking for patients with a
diagnosis of PBL who were treated with bortezomib, alone or in
combination. They identified 21 patients, of which 11 received
bortezomib in the front-line setting and 10 received bortezomib in the
relapsed setting; 11 patients were HIV-positive and 10 were HIV-
negative. The overall response rate (ORR) to bortezomib-containing
regimens was 100 % in the front-line setting and 90 % in the relapsed
setting. Furthermore, the 2-year OS of patients treated up-front was 55
%, and the median OS in relapsed patients was 14 months. The authors
concluded that although the sample size was small (n = 21), they
believed their findings were encouraging and should serve as rationale to
examine bortezomib-based regimens in patients withPBL.
Acute Lymphoblastic Leukemia
Zhao et al (2015) reported the findings of 9 pre-treated patients aged
greater than 19 years with relapsed/refractory acute lymphoblastic
leukemia (ALL) who were treated with a combination of bortezomib plus
chemotherapy before allogeneic hematopoietic stem cell transplantation
(allo-HSCT); 8 (88.9 %) patients, including 2 Philadelphia chromosome-
positive ALL patients, achieved a complete remission (CR). Furthermore,
the evaluable patients have benefited from allo-HSCT after response to
this re-induction treatment. The authors concluded that bortezomib-
based chemotherapy was highly effective for adults with
refractory/relapsed ALL before allo-HSCT. They stated that this regimen
deserved a larger series within prospective trials to confirm these results.
Buontempo et al (2016) noted that bortezomib is a new targeted
therapeutic option for refractory or relapsed ALL patients. However, a
limited efficacy of bortezomib alone has been reported. A terminal pro-
apoptotic endoplasmic reticulum (ER) stress/unfolded protein response
(UPR) is one of the several mechanisms of bortezomib-induced
apoptosis. Recently, it has been documented that UPR disruption could
be considered a selective anti-leukemia therapy. CX-4945, a potent
casein kinase (CK) 2 inhibitor, has been found to induce apoptotic cell
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death in T-ALL pre-clinical models, via perturbation of ER/UPR pathway.
In this study, these researchers analyzed in T- and B-ALL pre-clinical
settings, the molecular mechanisms of synergistic apoptotic effects
observed after bortezomib/CX-4945 combined treatment. They
demonstrated that, adding CX-4945 after bortezomib treatment,
prevented leukemic cells from engaging a functional UPR in order to
buffer the bortezomib-mediated proteotoxic stress in ER lumen. These
investigators documented that the combined treatment decreased pro-
survival ER chaperon BIP/Grp78 expression, via reduction of chaperoning
activity of Hsp90. Bortezomib/CX-4945 treatment inhibited NF-κB
signaling in T-ALL cell lines and primary cells from T-ALL patients, but,
intriguingly, in B-ALL cells the drug combination activated NF-κB p65 pro-
apoptotic functions. In fact in B-cells, the combined treatment induced
p65-HDAC1 association with consequent repression of the anti-apoptotic
target genes, Bcl-xL and XIAP. Exposure to NEMO (IKKγ)-binding
domain inhibitor peptide reduced the cytotoxic effects of bortezomib/CX-
4945 treatment. The authors concluded that these findings demonstrated
that CK2 inhibition could be useful in combination with bortezomib as a
novel therapeutic strategy in both T- and B-ALL.
Yeo et al (2016) reported their experience with a promising re-induction
regimen for children with relapsed ALL who are unable to receive
asparaginase. This was a single-institution, retrospective review of the
safety and activity of bortezomib, dexamethasone, mitoxantrone, and
vinorelbine (BDMV) in patients with relapsed ALL. Complete remission
and adverse events (AEs) after re-induction were study end-points.
Patients treated with BDMV between 2012 and 2015 were identified.
Response and AEs were assessed by review of medical records.
Standard response criteria were used and AEs were graded based on
NCI CTCAEv4.0; 7 of 10 patients achieved CR after 1 cycle of BDMV,
with 4 achieving minimal residual disease negativity. The most common
greater than or equal to grade-3 non-hematological toxicities were
infection (91 %), gastro-intestinal (45 %), metabolic (45 %), and
cardiovascular (9 %). The authors concluded that BDMV is an active re-
induction regimen for children with relapsed ALL who cannot receive
asparaginase. The toxicity profile was as expected for this patient
population. They stated that further prospective clinical trials are needed
to evaluate the safety and efficacy of BDMV.
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Iwasa et al (2017) stated that the poor prognosis of adults with B cell
precursor ALL (BCP-ALL) is attributed to leukemia cells that are protected
by the bone marrow (BM) microenvironment. These researchers
examined the pharmacological targeting of mesenchymal stromal/stem
cells in BM (BM-MSCs) to eliminate chemo-resistant BCP-ALL cells.
Human BCP-ALL cells (NALM-6 cells) that adhered to human BM-MSCs
(NALM-6/Ad) were highly resistant to multiple anti-cancer drugs, and
exhibited pro-survival characteristics, such as an enhanced Akt/Bcl-2
pathway and increased populations in the G0 and G2/S/M cell cycle
stages. Bortezomib interfered with adhesion between BM-MSCs and
NALM-6 cells and up-regulated the matri-cellular protein SPARC
(secreted protein acidic and rich in cysteine) in BM-MSCs, thereby
reducing the NALM-6/Ad population. Inhibition of SPARC expression in
BM-MSCs using a small interfering RNA enhanced adhesion of NALM-6
cells. Conversely, recombinant SPARC protein interfered with adhesion
of NALM-6 cells. The authors concluded that these findings suggested
that SPARC disrupts adhesion between BM-MSCs and NALM-6 cells.
Combined treatment with bortezomib and doxorubicin prolonged the
survival of BCP-ALL xenograft mice, with a significant reduction of
leukemia cells in BM. They stated that these findings demonstrated that
bortezomib contributes to the elimination of BCP-ALL cells through
disruption of their adhesion to BM-MSCs, and offer a novel therapeutic
strategy for BCP-ALL through targeting of BM-MSCs.
Iguchi et al (2017) reported the results of a clinical trial designed to
evaluate the safety of bortezomib combined with induction chemotherapy
in Japanese children with refractory ALL. A total of 6 patients with B-
precursor ALL were enrolled in this study; 4-dose bortezomib (1.3
mg/m2/dose) combined with 2 standard induction chemotherapies was
used. Prolonged pancytopenia (grade-4) was observed in all patients; 4
of the 6 patients developed severe infectious complications. Peripheral
neuropathy (grade-2) occurred in 5 patients. The individual plasma
bortezomib concentration-time profiles were not related to toxicity and
efficacy; 5 patients were evaluable for response, and 4 patients achieved
CR or CR without platelet recovery (80 %). The authors concluded that
4-dose bortezomib (1.3 mg/m2/dose) combined with standard re-
induction chemotherapy was associated with a high risk of infectious
complications induced by prolonged neutropenia, although high efficacy
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has been achieved for Japanese pediatric patients with refractory ALL.
Attention must be given to severe infectious complications when
performing re-induction chemotherapy including bortezomib.
Du et al (2017) stated that despite advances in the treatment of T-cell ALL
(T-ALL), the outcome of T ALL treatment remains unsatisfactory,
therefore, more effective treatment is urgently required. The present
study examined the cytotoxicities of bortezomib in combination with
daunorubicin against human Jurkat and Molt 4 T ALL cells and primary T
ALL cells. Compared with treatment alone, co-exposure of cells to
bortezomib and daunorubicin resulted in a significant increase in cell
death in the Jurkat cells, as evidenced by the increased percentage of
Annexin V-positive cells, the formation of apoptotic bodies. In addition,
the administration sequence of bortezomib and daunorubicin had an
effect on cell viability. Treatment with bortezomib followed by
daunorubicin treatment was more effective, compared with treatment with
daunorubicin followed by bortezomib. Co-treatment with bortezomib and
daunorubicin markedly enhanced the activation of caspase 3, 8 and 9,
which was reversed by the pan-caspase inhibitor, Z VAD FMK. In
addition, co-treatment with bortezomib and daunorubicin enhanced the
collapse of mitochondrial transmembrane potential and up-regulated the
pro-apoptotic protein, B cell lymphoma 2 (Bcl 2)-interacting mediator of
cell death (Bim), but not Bcl 2 or Bcl-extra-large. Consistent with this, it
was demonstrated that co-treatment of bortezomib and daunorubicin
efficiently induced apoptosis in primary T-ALL cells, and cell death was
associated with the collapse of mitochondrial transmembrane potential
and the up-regulation of Bim. The authors concluded that these findings
indicated that the combination of bortezomib and daunorubicin
significantly enhanced their apoptosis-inducing effect in T-ALL cells,
which may warrant further investigation in pre-clinical and clinical
investigations.
In a review on “Bortezomib for the treatment of hematologic malignancies:
15 years later’ (Robak and Robak, 2019) stated that continued clinical
studies are needed to confirm the value of bortezomib for patients with
indolent and aggressive B-cell non-Hodgkin lymphomas and acute
leukemias.
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Horton and colleagues (2019) noted that while survival in pediatric ALL is
excellent, survival following relapse is poor. Previous studies suggested
proteasome inhibition with chemotherapy improves relapse ALL response
rates. In a phase-II Children's Oncology Group clinical trial, these
researchers tested the hypothesis that adding bortezomib to
chemotherapy increases CR rates (CR2). Evaluable patients (n = 135,
103 B-ALL, 22 T-ALL, 10 T-lymphoblastic lymphoma) were treated with
re-induction chemotherapy plus bortezomib. Overall CR2 rates were 68 ±
5 % for precursor B-ALL patients (less than 21 years of age), 63 ± 7 % for
very early relapse (less than 18 months from diagnosis) and 72 ± 6 % for
early relapse (18 to 36 months from diagnosis). Relapsed T-ALL patients
had an encouraging CR2 rate of 68 ± 10 %. End of induction minimal
residual disease (MRD) significantly predicted survival. MRD negative
(MRDneg; MRD less than 0.01 %) rates increased from 29 % (post-cycle
1) to 64 % following cycle 3. Very early relapse, end-of-induction
MRDneg precursor B-ALL patients had 70 ± 14 % 3-year event-free
survival (EFS) and OS rates, versus 3-year EFS/OS of 0 to 3 % (p =
0·0001) for MRDpos (MRD greater than or equal to 0.01) patients. Early
relapse patients had similar outcomes (MRDneg 3-year EFS/OS 58 to 65
% versus MRDpos 10 to 19 %, EFS p = 0.0014). The authors concluded
that these findings suggested that adding bortezomib to chemotherapy in
certain ALL subgroups, such as T-cell ALL, is worthy of further
investigation.
National Comprehensive Cancer Network’s Drugs & Biologics
Compendium (2019) lists pediatric acute lymphoblastic leukemia as a
recommended indication of bortezomib.
Therapy for relapsed/refractory Ph-negative B-ALL, or in combination w ith das atinib or imatinib for relapsed/refractory Ph- positive B-ALL as a component of COG AALL07P1 regimen Therapy for relapsed/refractory T-ALL as a component of a bortezomib-containing regimen (e.g., bortezomib, vincristine, doxorubicin, pegaspargase, and prednisone or dexamethasone)
Antibody-Mediated Autoimmune Diseases
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Kohler and colleagues (2019) stated that the clinical characteristics of
autoantibody-mediated autoimmune diseases are diverse. Yet, medical
treatment and the associated complications are similar (i.e., the
occurrence of long-term adverse effects and that many patients are non-
responders). Thus, new therapeutic options are needed. Bortezomib is
effective in the treatment of MM and data from experimental models and
case reports suggested an effect in the treatment of autoantibody-
mediated autoimmunity. In a phase-IIa clinical trial, these investigators
will examine the effect of bortezomib on a shared surrogate parameter for
clinical efficacy, namely change in autoantibody levels, which these
researchers chose as primary parameter. They designed this study with
altogether n = 18 treatment-refractory patients suffering from myasthenia
gravis, rheumatoid arthritis (RA), and systemic lupus erythematosus
(SLE) that will be treated with bortezomib add-on to pre-existing therapy.
Primary end-point is the change in autoantibody levels 6 months
following therapy; secondary end-points include concomitant medication,
disease-specific clinical scores and measures of quality of life (QOL) and
activities of daily living (ADL). Safety parameters include
neurophysiological and clinical signs of peripheral neuropathy as well as
potential central nervous system side (CNS) effects determined by
olfactory and neuropsychological testing. The study has been approved
by the local ethical committee and first participants have already been
enrolled. This proof-of-concept study will contribute to improve the
understanding of plasma cell-specific treatment approaches by assessing
its safety and efficacy in reducing serum levels of antibodies known to
mediate autoimmune disorders.
Cold Agglutinin Disease / Cryoglobulinemic Vasculitis
Liu and c olleagues (2019) noted that concomitant cryoglobulinemic
vasculitis and cold agglutinin disease (CAD) is an extremely uncommon
clinical scenario. The role of bortezomib in the treatment of
cryoglobulinemic vasculitis needs further investigation. These
investigators presented the case of a 72-year old woman presented with
a 25-year history of cyanosis of the extremities after cold exposure, which
worsened and was accompanied with purpuric skin lesions and
proteinuria in recent years. Laboratory data dem onstrated hemolysis.
Cold agglutinin and cryoglobulin tests were positive. There was no
evidence for malignancies after blood, image, and pathologic tests.
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Subject was diagnosed with concomitant cryoglobulinemic vasculitis and
CAD; she was treated with bortezomib-based regimen, including
bortezomib, cyclophosphamide, and dexamethasone. The patient
responded well to the treatment. Both symptoms and laboratory tests
significantly improved. The patient's condition was in a state of sustained
remission in the 6-month follow-up. The authors concluded that this rare
case promoted further understanding of these 2 diseases and suggested
that bortezomib is a promising treatment in type I cryoglobulinemic
vasculitis. Moreover, these researchers stated that larger controlled
studies are needed for a detailed treatment strategy, although great
challenges exist because of the low incidence.
Monoclonal Gammopathy of Renal Significance
Lee and colleagues (2019) stated that monoclonal gammopathy of renal
significance (MGRS) refers to renal diseases resulting from the
nephrotoxic effects of monoclonal proteins secreted from non-malignant
clonal B cells or plasma cells, that do not meet criteria for MM, WM,
chronic lymphocytic leukemia (CLL), or lymphomas. Renal disease in
MGRS can result from monoclonal immunoglobulin deposition to different
parts of the kidney and includes a wide spectrum of glomerular, tubule-
interstitial and vascular renal diseases. Recognizing MGRS is important
because renal outcomes are poor and treatments targeting the underlying
clonal disease have been associated with improved renal survival. In a
case report, these investigators presented the case of a patient with
proliferative glomerulonephritis with monoclonal immunoglobulin deposits
(PGNMID) subtype of MGRS who underwent a phased clone directed
treatment of induction and extended bortezomib maintenance therapy to
achieve renal response. The authors noted that through a single case
report, it is certainly not possible to establish a role for extended
bortezomib therapy. They stated that long-term follow-up with larger
study population is needed to validate this extended approach. These
investigators stated that it would be interesting to examine how the time
to relapse post-clone directed therapy impacts renal outcomes. They
noted that this patient had renal relapse within 6 months following
completion of therapy.
Palbociclib plus Bortezomib for the Treatment of Mantle Cell Lymphoma
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Martin and associates (2019) stated that in MCL, cyclin D1 combines with
CDK4/6 to phosphorylate Rb, releasing a break on the G1 to S phase cell
cycle. Palbociclib is a specific, potent, oral inhibitor of CDK4/6 capable of
inducing a complete, prolonged G1 cell cycle arrest (pG1) in Rb+ MCL
cells. The proteasome inhibitor bortezomib is FDA-approved for
treatment of MCL. Palbociclib-induced pG1 appears to sensitize MCL
cells to killing by low-dose bortezomib, potentially improving its activity
and tolerability. In a phase-I clinical trial, these researchers examined the
effects of palbociclib plus bortezomib in patients with previously treated
MCL. Participants received palbociclib at 75-mg (dose level 1), 100-mg
(dose level 2), or 125-mg (dose levels 3 and 4) on days 1 to 12 of each
21-day cycle in addition to intravenous bortezomib 1.0 mg/m2 (dose
levels 1, 2, 3) or 1.3 mg/m2 (dose level 4) on days 8, 11, 15 and 18. A
total of 19 patients with a median age of 64 years and an average of 2
prior therapies were enrolled; 2 subjects experienced dose limiting toxicity
(DLT): thrombocytopenia (dose level 1) and neutropenia (dose level 3).
Although no DLTs were observed at dose level 4, all participants needed
dose delays during cycle 2 due to cytopenias, and the study team
decided to stop the trial; 4 of 19 patients achieved a clinical response,
including 1 patient with a CR; 3 patients received treatment for more than
1 year, including 1 patient receiving single-agent palbociclib for more than
6 years. The combination of palbociclib 125-mg on days 1 to 12 plus
bortezomib 1.0 mg/m2 on days 8, 11, 15, and 18 of a 21-day cycle was
feasible and ac tive in pr eviously treated MCL, with the primary toxicity
being myelosuppression. The authors concluded that this regimen may
be worthy of further evaluation in patients with non-blastoid MCL following
failure of other newer agents.
National Comprehensive Cancer Network (NCCN) Recommendations
The NCCN Drugs and Biologics Compendium (NCCN, 2019)
recommends bortezomib for the following:
B-Cell Lymphomas
Mantle Cell Lymphoma
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Preferred less aggressive induction therapy for stage I-II
disease (localized presentation, extremely rare) as initial
therapy, or for partial response, progression, or relapse after
initial treatment with involved site radiation therapy alone, or
for aggressive stage II bulky, III, or IV disease or symptomatic
indolent stage II bulky, III, or IV TP53 mutation positive disease
in patients who are not candidates for high-dose
therapy/autologous stem cell rescue as a component of VR-CAP
(bortezomib, rituximab, cyclophosphamide, doxorubicin, and
prednisone) regimen [2A]
Second-line therapy for stage I-II disease, aggressive stage II
bulky, III, or IV disease, or symptomatic indolent stage II bulky,
III, or IV disease to achieve complete response after partial
response to induction therapy, or for relapsed or progressive
disease following an extended response duration to prior
chemoimmunotherapy (> expected median progression free
survival) [2A for single-agent therapy or in combination with
rituximab; 2B in combination with bendamustine and rituximab
and as a component of VR-CAP]
as a single agent or in combination with rituximab
(preferred regimens)
in combination with bendamustine and rituximab
as a component of VR-CAP (bortezomib, rituximab,
cyclophosphamide,doxorubicin,andprednisone)regimen
(if not previously given)
Castleman's Disease
Subsequent therapy with or without rituximab for multicentric CD
that has progressed following treatment of relapsed/refractory or
progressive disease [2A]
Multiple Myeloma
Primary therapy for symptomatic multiple myeloma or for disease
relapse after 6 months following primary induction therapy with
the same regimen [1 for combination with dexamethasone and
lenalidomide; 2A for all others]
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in combination with dexamethasone and lenalidomide
(preferred regimen)
in combination with dexamethasone and cyclophosphamide
(preferred primarily as initial treatment in patients with acute
renal insufficiency o r those who have no access to
bortezomib/lenalidomide/dexamethasone)
in combination with dexamethasone for non-transplant
candidates (useful in certain circumstances)
in VTD-PACE (bortezomib, thalidomide, dexamethasone,
cisplatin, doxorubicin, cyclophosphamide and etoposide)
regimen for transplant candidates (useful in certain
circumstances, generally reserved for the treatment of
aggressive multiple myeloma)
Therapy for previously treated multiple myeloma for relapse or
progressive disease in [1 in combination with dexamethasone with
or without daratumumab, panobinostat, pomalidomide or
liposomal doxorubicin; 2A for all others]
combination with dexamethasone and lenalidomide (preferred
regimen)
combination with dexamethasone and daratumumab
(preferred regimen)
combination with dexamethasone and bendamustine
combination with dexamethasone and liposomal doxorubicin
combination with dexamethasone and cyclophosphamide
combination with dexamethasone
combination with elotuzumab and dexamethasone
combination with panobinostat and dexamethasone for
patients who have received at least two prior regimens,
including bortezomib and an immunomodulatory agent
combination with pomalidomide and dexamethasone for
patients who have received at least two prior therapies,
including an immunomodulatory agent and a proteasome
inhibitor and who have demonstrated disease progression on
or within 60 days of completion of the last therapy
VTD-PACE (bortezomib, thalidomide, dexamethasone, cisplatin,
doxorubicin, cyclophosphamide, and etoposide) regimen
(useful in certain circumstances, generally reserved for the
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treatment of aggressive multiple myeloma)
Maintenance therapy [1 for maintenance therapy for response or
stable disease following autologous stem cell transplant; 2A for all
others]
as a single agent for symptomatic multiple myeloma after
response to primary myeloma therapy
in combination with lenalidomide (useful in certain
circumstances) for symptomatic multiple myeloma after
response to primary myeloma therapy or for response or
stable disease following autologous stem cell transplant
Primary therapy for symptomatic multiple myeloma [1 for all
others; 2A for combination with dexamethasone and doxorubicin,
or for combination with daratumumab, thalidomide, and
dexamethasone]
in combination with dexamethasone and doxorubicin for
transplant candidates (useful in certain circumstances)
in combination with dexamethasone and thalidomide for
transplant candidates (useful in certain circumstances)
in combination with daratumumab, thalidomide, and
dexamethasone for transplant candidates (useful in certain
circumstances)
in combination with daratumumab, melphalan, and prednisone
for non-transplant candidates
Pediatric Acute Lymphoblastic Leukemia
Therapy for relapsed/refractory T-ALL as a component of a
bortezomib-containing regimen (e.g. bortezomib, vincristine,
doxorubicin, pegaspargase, and prednisone or dexamethasone)
[2A]
Therapy for relapsed/refractory Ph-negative B-ALL, or in
combination with dasatinib or imatinib for relapsed/refractory Ph-
positive B-ALL as a component of COG AALL07P1 regimen [2A]
Primary Cutaneous Lymphomas
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Mycosis Fungoides/Sezary Syndrome
Systemic therapy as treatment for [2B]
relapsed or persistent stage IA mycosis fungoides (MF) with B1
blood involvement, with or without skin-directed therapy
relapsed or persistent stage IB-IIA MF with B1 blood
involvement, with or without skin-directed therapy
stage IIB MF with limited tumor lesions refractory to multiple
previous therapies, with or without skin-directed therapy
relapsed or refractory stage IIB MF with generalized tumor
lesions, with or without skin-directedtherapies
stage IIB MF with generalized tumor lesions that is refractory to
multiple previous therapies or progression
relapsed or persistent stage III MF, with or without skin-
directed therapies
stage III MF that is refractory to multiple previous therapies
relapsed or persistent stage IV Sezary syndrome
relapsed or persistent stage IV non Sezary or visceral disease
(solid organ), with or without radiation therapy for local control
large cell transformation (LCT) with limited cutaneous lesions
that is refractory to multiple previous therapies
relapsed or persistent LCT with generalized cutaneous or
extracutaneous lesions, with or without skin-directed therapy
Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders
Therapy for primary cutaneous anaplastic large cell lymphoma
(ALCL) with multifocal lesions, or cutaneous ALCL with regional
nodes (excludes systemic ALCL), as a single agent for
relapsed/refractory disease [2B]
Systemic Light Chain Amyloidosis
Treatment for newly diagnosed disease or consider for
relapsed/refractory disease as a repeat of initial therapy if relapse-
free for several years [2A]
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in combination with cyclophosphamide and dexamethasone
(preferred)
as a single agent or in combination with dexamethasone with
or without melphalan
Treatment for relapsed/refractory disease as a single agent or in
combination with dexamethasone with or without melphalan [2A]
T-Cell Lymphomas
Adult T-Cell Leukemia/Lymphoma
Second-line or subsequent therapy as a single agent for
nonresponders to first-line therapy for acute or lymphoma
subtypes [2A]
Peripheral T-Cell Lymphomas
Second-line and subsequent therapy for relapsed/refractory
anaplastic large cell lymphoma, peripheral T-cell lymphoma not
otherwise specified, angioimmunoblastic T-cell lymphoma,
enteropathy-associated T-cell lymphoma, monomorphic
epitheliotropic intestinal T-cell lymphoma, nodal peripheral T-cell
lymphoma with TFH phenotype, or follicular T-cell lymphoma, in
patients with no intention to transplant as a single agent [2B]
Hepatosplenic Gamma-Delta T-Cell Lymphoma [2B]
Second-line and subsequent therapy as a single agent for
refractory disease after 2 primary treatment regimens in patients
with no intention to transplant.
CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":
Code Code Description
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Code Code Description
Other CPT codes related to the CPB:
96372,
96374,
96375,
96376,
96379
Therapeutic drug administration
96401 Chemotherapy administration, subcutaneous or
intramuscular; non-hormonal anti-neoplastic
96409,
96411,
96413,
96415,
96416,
96417
Intravenous chemotherapy administration
HCPCS codes covered if selection criteria are met:
J9041 Injection, bortezomib (Velcade), 0.1 mg
J9044 Injection, bortezomib, not otherwise specified, 0.1 mg
Other HCPCS codes related to the CPB:
J1094 Injection, dexamethasone acetate, 1 mg
J1100 Injection, dexamethasone sodium phosphate, 1 mg
J8530 Cyclophosphamide; oral, 25 mg
J8540 Dexamethasone, oral, 0.25
J8600 Melphalan; oral, 2 mg
J9070 Cyclophosphamide, 100 mg
J9245 Injection, melphalan hydrochloride, 50 mg
J9312 Injection, rituximab, 10 mg
ICD-10 codes covered if selection criteria are met:
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Code Code Description
C82.00
C82.59,
C82.80
C82.99
Follicular lymphoma of lymph nodes [second line
therapy follicle center lymphoma]
C83.10 -
C83.19
Mantle cell lymphoma
C84.40 -
C84.79
Mature T/NK-cell lymphomas
C86.2 Enteropathy-type (intestinal) T-cell lymphoma
C86.5 Angioimmunoblastic T-cell lymphoma
C86.6 Primary cutaneous CD30-positive T-cell proliferations
[primary cutaneous anaplastic large cell lymphoma
(ALCL) with multifocal lesions and cutaneous ALCL with
regional nodes (excludes systemic ALCL)]
C88.0 Waldenstrom macroglobulinemia [lymphoplasmacytic
lymphoma] [as a single agent, in combination with
dexamethasone, or in combination with rituximab
(Rituxan) for primary therapy, progressive or relapsed
disease or salvage therapy for disease that does not
respond to primary therapy]
C90.00 -
C90.02
Multiple myeloma [not covered for smoldering
(asymptomatic) myeloma]
C91.00 –
C91.02
Acute lymphoblastic leukemia [Pediatric]
C91.50 -
C91.52
Adult T-cell lymphoma/leukemia (HTLV-1-associated)
D47.Z2 Castleman's disease
E85.0 -
E85.9
Amyloidosis [systemic light chain]
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Code Code Description
T86.11,
T86.21,
T86.31,
T86.41,
T86.810,
T86.850,
T86.890
Transplant rejection of kidney, heart, heart-lung, liver,
lung, intestine, or other transplanted tissue [antibody
mediated rejection of solid organs]
ICD-10 codes not covered for indications listed in the CPB ( not all-inclusive):
B20 Human immunodeficiency virus (HIV) disease
B97.35 Human immunodeficiency virus, type 2 [HIV-2] as the
cause of diseases classified elsewhere
C00.0
C81.99,
C82.60
C82.69,
C83.00
C83.09,
C83.30
C83.99,
C84.00
C84.19,
C84.A0
C86.6,
C88.2
C88.3,
C88.8
C88.9,
C90.10
C90.32,
C91.10
C91.42,
C91.6
Neoplasms
D47.2 Monoclonal gammopathy [renal significance]
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D59.0 -
D59.9
Acquired hemolytic anemia
D89.1 Cryoglobulinemia
D89.811 Chronic graft-versus-host disease
E85.0 -
E85.9
Amyloidosis [hepatic amyloidosis]
G04.81 Other encephalitis and encephalomyelitis [anti-NMDA
receptor encephalitis]
G35 Multiple sclerosis
G70.00 -
G70.01
Myasthenia gravis
J45.20 -
J45.998
Asthma
L12.1 Cicatricial pemphigoid
M00.00 -
M19.93
Arthropathies
M05.00
M06.9,
M08.00
M08.99
Rheumatoid Arthritis
M32.0 –
M32.9
Systemic lupus erythematosus (SLE)
T86.00 -
T86.99
Complications of transplanted organs and tissue
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Code Code Description
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2. Adams J. Proteasome inhibition in cancer: Development of PS
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3. Berenson JR, Ma HM, Vescio R. The role of nuclear factor-kappaB
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4. Schenkein D. Proteasome inhibitors in the treatment of B-cell
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administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy
Bulletin contains only a partial, general description of plan or program benefits and does not constitute a
contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes.
Participating providers are independent contractors in private practice and are neither employees nor agents of
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Clinical Policy Bulletin may be updated and therefore is subject to change.
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AETNA BETTER HEALTH® OF PENNSYLVANIA
Amendment to Aetna Clinical Policy Bulletin Number: 0675
Bortezomib (Velcade)
The Pennsylvania Medical Assistance Program considers bortezomib (Velcade) to be Medically Necessary as a second line treatment for Mycosis Fungoides/Sezary Syndrome.
Pennsylvania Medicaid uses Aetna Better Health Pharmacy Guidelines for most medications. Please see https://www.aetnabetterhealth.com/pennsylvania/providers/pharmacy
For the Pennsylvania Medical Assistance plan Bortezomib may also be medically necessary for:
• AIDS-Related Kaposi Sarcoma - AIDS-Related Kaposi Sarcoma • B-Cell Lymphomas - AIDS-Related B-Cell Lymphomas • Primary Cutaneous Lymphomas - Mycosis Fungoides/Sezary Syndrome • T-Cell Lymphomas - Hepatosplenic Gamma-Delta T-Cell Lymphoma
www.aetnabetterhealth.com/pennsylvania revised 12/23/2019