prior authorization review panel mco policy submission a ......velcade (bortezomib), a specific,...

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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https://www.aetna.com/


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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http://aetnet.aetna.com/mpa/cpb/400_499/0404.html









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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http://therapy.62


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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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:





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]






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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Copyright © 2001-2020 Aetna Inc.

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

http://www.aetnabetterhealth.com/pennsylvania/providers/pharmacy

http://www.aetnabetterhealth.com/pennsylvania