Bortezomib (Velcade)
Number: 0675
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Note: Requires Precertification:
Precertification of bortezomib (Velcade), for multiple myeloma only, is required of all Aetna participating providers and members in applicable plan designs. For precertification of bortezomib (Velcade), for multiple myeloma only, call (866) 752-7021 (Commercial), or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.
For Medicare Part B plans, call (866) 503-0857, or fax (844) 268-7263.
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Criteria for Initial Approval
Aetna considers bortezomib (Velcade) for intravenous or subcutaneous administration medically necessary for treatment of the following indications:
- Acute lymphoblastic leukemia - relapsed or refractory disease;
- Adult T-cell leukemia/lymphoma - as a single agent for subsequent therapy;
- Kaposi sarcoma - as subsequent therapy;
- Antibody mediated rejection of solid organ;
- Follicular lymphoma - relapsed or refractory disease;
- Classic Hodgkin lymphoma - relapsed or refractory disease;
- Mantle cell lymphoma;
- Multicentric Castleman disease - as subsequent therapy;
- Multiple myeloma;
- POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome - in combination with dexamethasone;
- Systemic light chain amyloidosis;
- Waldenström macroglobulinemia/lymphoplasmacytic lymphoma.
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
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Continuation of Therapy
Aetna considers continued bortezomib (Velcade) therapy medically necessary for members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.
Related Policies
- CPB 0404 - Interferons
- CPB 0497 - Hematopoietic Cell Transplantation for Multiple Myeloma
- CPB 0524 - Zoledronic Acid
- CPB 0634 - Non-myeloablative Hematopoietic Cell Transplantation (Mini-Allograft / Reduced Intensity Conditioning Transplant)
- CPB 0672 - Pamidronate (Aredia)
Dosage and Administration
Approvals may be subject to dosing limits in accordance with FDA-approved labeling, accepted compendia, and/or evidence-based practice guidelines.
For all indications, dosing does not exceed 1.6 mg/m2 per dose and does not require more than 7 doses per 30-day period.
Below includes dosing recommendations as per the FDA-approved prescribing information.
Bortezomib is available as Velcade Intravenous Powder for Solution: 3.5 mg vials.
Velcade (bortezomib) may be administered intravenously at a concentration of 1 mg/mL or subcutaneously at a concentration of 2.5 mg/mL. Velcade (bortezomib) should not be administered by any other route.
Adults with Multiple Myeloma or Mantle Cell Lymphoma
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.
- Hepatic Impairment: Use a lower starting dose for persons with moderate or severe hepatic impairment.
- Dose must be individualized to prevent overdose.
- When administered intravenously, administer as a 3 to 5 second bolus intravenous injection.
Refer to Prescribing Information for guidance on dose adjustments.
Source: Fresenius Kabi, 2022; Takeda Pharmaceuticals, 2022
Experimental and Investigational
Aetna considers bortezomib experimental and investigational for all other indications, including the following because its effectiveness for these indications has not been established:
- Acute myeloid leukemia
- AIDS-related B-cell lymphoma
- Antibody-mediated autoimmune diseases (e.g., myasthenia gravis, rheumatoid arthritis and systemic lupus erythematosus)
- As monotherapy or in combination with other chemotherapeutics for the treatment of other hematological malignancies (e.g., 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
- Autoimmune encephalitis (including anti-NMDA receptor encephalitis)
- Chronic graft-versus host disease
- Cold agglutinin disease
- Cryoglobulinemic vasculitis
- Esophageal squamous cell carcinoma
- Evans syndrome
- 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 of renal significance
- Mucous membrane pemphigoid
- Plasmablastic lymphoma
- Post-transplant lymphoproliferative disorder
- Primary cutaneous anaplastic large cell lymphoma (ALCL)
- Ribosomopathies
- Smoldering (asymptomatic) myeloma
- Solitary plasmacytoma
- T-cell lymphomas (except adult T-Cell Leukemia/Lymphoma).
Aetna considers palbociclib plus bortezomib experimental and investigational for the treatment of mantle cell lymphoma because the effectiveness of this approach has not been established.
Background
U.S. Food and Drug Administration (FDA)-Approved Indications
- Treatment of adult patients with multiple myeloma
- Treatment of adult patients with mantle cell lymphoma
Compendial Uses
- Systemic light chain amyloidosis
- Waldenström macroglobulinemia/lymphoplasmacytic lymphoma
- Multicentric Castleman disease
- Adult T-cell leukemia/lymphoma
- Antibody mediated rejection of solid organ
- Acute lymphoblastic leukemia
- Follicular lymphoma
- Kaposi sarcoma
- Classic Hodgkin lymphoma
- POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome
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 progressed 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 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 overall 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 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.
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).
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 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 %), 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. 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).
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.
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 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 %) 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 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 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 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 %] 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), diarrhea (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 clinical 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 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".
In an editorial that accompanied the afore-mentioned study, Salles (2011) stated that "but 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 the field".
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 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 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, 2022) stated that there were no standard treatments for histiocytic sarcoma and that patients should be encouraged to enroll in clinical trials.
Marginal zone lymphoma is a type of B-cell lymphoma presenting primarily in the marginal zone. There are 3 types:- splenic marginal zone lymphoma;
- extra-nodal marginal zone B cell lymphoma (MALT lymphoma or "mucosa-associated lymphoid tissue"); and
- 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.
Also, an UpToDate review on "Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)" (Freedman, Friedberg, and Ng, 2022) did not mention the use of bortezomib as a therapeutic option.
An UpToDate review on "Treatment and prevention of post-transplant lymphoproliferative disorders" (Negrin and Brennan, 2022) did not mention the use of bortezomib as a therapeutic option.
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 "Treatment and prognosis of IgG4-related disease" (Moutsopoulos et al, 2022) 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 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.
Hepatocellular Carcinoma
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 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.
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.
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 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-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 was 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 AMR, these investigators 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, 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) stated 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) stated 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 demonstrated its effectiveness in treating ABMR, successfully reversing acute rejection, and/or reducing 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 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.
Dinoto and colleagues (2021) stated that N-methyl-d-aspartate receptor (NMDAR) encephalitis is a potentially treatable condition, although a small proportion of patients remains refractory to immunotherapy. Bortezomib is a proteasome inhibitor that has a promising role in autoimmune conditions. These researchers carried out an independent PubMed search employing "anti-N-methyl d-aspartate encephalitis AND bortezomib", including articles published between January 1, 2007 to April 15, 2021. A total of 14 articles were included totaling 29 patient; 16 patients (55.2 %) had a favorable outcome following bortezomib and 11 (37.9 %) patients developed side effects. The authors concluded that the overall quality of studies was poor. These researchers stated that future trials should aim to include more homogeneous and larger cohorts.
Autoimmune Encephalitis
Dinoto et al (2022) noted that autoimmune encephalitis represents a potentially treatable immune-mediated condition that is being more frequently recognized. Prompt immunotherapy is a key factor for the management of autoimmune encephalitis. First-line treatments include IV steroids, plasma exchange (PE), and IVIG, which can be combined in most severe cases. Rituximab and cyclophosphamide are administered as 2nd-line agents in unresponsive cases. A minority of patients may still remain refractory; thus, representing a major clinical challenge. In these cases, treatment strategies are controversial, and no guidelines exist. Treatments proposed for refractory autoimmune encephalitis include cytokine-based drugs (such as tocilizumab, IL-2/basiliximab, anakinra, and tofacitinib); plasma cell-depleting agents (such as bortezomib and daratumumab); as well as treatments targeting intra-thecal immune cells or their trafficking through the blood-brain barrier (such as intra-thecal methotrexate and natalizumab). The authors concluded that tocilizumab appeared to be the most effective option in refractory cases, whereas bortezomib could be useful, but more evidence is mandatory. The evidence for other treatments mostly relies on a small uncontrolled number of cases and no definite recommendations may be drawn. Moreover, these investigators noted that a randomized, multi-center trial including adult patients with antibody-mediated autoimmune encephalitides unresponsive to rituximab is currently enrolling patients to examine the effectiveness of bortezomib.
Ciano-Petersen et al (2022) stated that autoimmune encephalitides constitute an emerging group of diseases for which the diagnosis and management may be challenging; and are usually associated with antibodies against neuroglial antigens used as biomarkers. These investigators clarified the diagnostic approach to patients with encephalitis of suspected autoimmune origin in order to initiate early immunotherapy; and summarized the evidence of current immunotherapies and alternative options assessed for refractory cases. To-date, the general therapeutic approach consists of steroids, IVIG, and/or PE as 1st-line medications, which should be prescribed once a diagnosis of possible autoimmune encephalitis is established. For patients not responding to these treatments, rituximab and cyclophosphamide are used as 2nd-line immunotherapy. Furthermore, alternative therapies, chiefly tocilizumab and bortezomib, have been reported to be useful especially in refractory cases. Although the afore-mentioned approach with 1st and 2nd-line immunotherapy is widely accepted, the best therapeutic strategy is still unclear since most available evidence is gathered from retrospective non-controlled studies. Moreover, several predictors of good long-term prognosis have been proposed such as response to 1st-line therapies, mRS lesser than 4 at the worst neurologic status, no need for admission in ICU, and early escalation to 2nd-line immunotherapy. Therefore, the lack of solid evidence underlines the necessity of future well-conducted trials addressing both the best therapeutic regimen and the outcome predictors, but since autoimmune encephalitides have a relatively low incidence, international collaborations appeared imperative to reach a reasonable study population size.
Hara and Nakajima (2022) noted that anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is a well-defined autoimmune encephalitis that is responsive to early intensive immunotherapy. Recent international consensus regarding treatment of NMDARE provides a practical treatment algorithm for immunotherapy escalation, while considering a patient's age, disease severity, and other background information. First-line immunotherapy, which includes an IV corticosteroid pulse with the addition of either IVIG or PE, should be offered to all NMDARE-diagnosed patients as soon as possible. In cases where insufficient improvement follows a repeat of the 1st-line combination therapy (assessed on day 14 after the initial treatment), 2nd-line immunotherapy comprising rituximab or an IV cyclophosphamide pulse (IVCPA) is considered. Per the recent expert consensus, rituximab is preferred to IVCPA as the 2nd-line drug of choice, although the use of either drug in the treatment of NMDARE is off-label. Most patients show gradual improvement in the 1st few weeks following the introduction of 2nd-line therapy, although repeated and alternating use of both drugs is often required. Some patients, whose NMDARE was refractory to the afore-mentioned therapies, have also been successfully treated with tocilizumab or bortezomib. Moreover, several international clinical trials involving rituximab, inebilizumab, bortezomib, and rozanolixizumab in the treatment of autoimmune encephalitis (which includes NMDARE) are being carried out to establish high-grade evidence for the treatment of autoimmune encephalitis.
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 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.
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 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 initial 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 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 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 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.
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 TMZ 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 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 of patients.
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
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 with PBL.
Dittus et al (2018) stated that PBL is a rare and aggressive form of B-cell non-Hodgkin lymphoma (NHL). This subtype of lymphoma has a post-germinal center cell-of-origin called the plasmablast, and the immunophenotype is more consistent with that of a plasma cell than a lymphocyte. Because of these unique features, PBL is notoriously difficult to treat. Case reports and small reviews have evaluated the addition of agents directed against plasma cell disorders in combination with traditional lymphoma-directed regimens. These researchers described the largest case-series study (n = 8) to-date, with the longest follow-up, evaluating bortezomib in combination with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (V-EPOCH) for the treatment of PBL. The authors concluded that their findings showed that this was a safe and effective regimen with an ORR of 100 % and 2-year OS of 50 %. The authors stated that the main drawbacks of this study were its small sample size (n = 8) and its retrospective design. They stated that these findings will serve as an important platform for designing future prospective studies in PBL.
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 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.
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 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.
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.
Antibody-Mediated Autoimmune Diseases
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 colleagues (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 demonstrated hemolysis. Cold agglutinin and cryoglobulin tests were positive. There was no evidence for malignancies after blood, image, and pathologic tests. 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
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 active in previously 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.
Follicular Lymphoma
In a randomized, multi-center, phase-II clinical trial, Blum and colleagues (2019) examined complete responses (CRs), safety and efficacy with ofatumumab and bendamustine and with ofatumumab, bendamustine, and bortezomib in patients with untreated, high-risk follicular lymphoma (FL). Patients with grade 1 to 3a FL and either a Follicular Lymphoma International Prognostic Index (FLIPI) score of 2 with 1 lymph node of greater than 6 cm or an FLIPI score of 3 to 5 were randomized to arm-A (ofatumumab, bendamustine, and maintenance ofatumumab) or to arm-B (ofatumumab, bendamustine, bortezomib, and maintenance ofatumumab and bortezomib). A total of 128 patients (66 in arm-A and 62 in arm-B) received treatment. The median age was 61 years, and 61 % had disease of greater than 6 cm; 29 % had an FLIPI score of 2, and 71 % had an FLIPI score of 3 to 5. In arm-A, 86 % completed induction, and 64 % completed maintenance. In arm-B, 66 % and 52 % completed induction and maintenance, respectively. Dose modifications were required in 65 % and 89 % in arms-A and arm-B, respectively. Clinically significant grade 3 to 4 toxicities included neutropenia (arm-A, 36 %; arm-B, 31 %), nausea/vomiting (arm-A, 0 %; arm-B, 8 %), diarrhea (arm-A, 5%; arm-B, 11 %), and sensory neuropathy (arm-A, 0 %; arm-B, 5 %). The estimated CR rates were 62 % (95 % CI: 50 % to 74 %) and 60 % (95 % CI: 47 % to 72 %) in arm-A and arm-B, respectively (p = 0.68). With a median follow-up of 3.3 years, the estimated 2-year PFS and OS rates were 80 % and 97 %, respectively, for arm-A and 76 % and 91 %, respectively, for arm-B. The authors concluded that the CR rates, PFS, and OS were not improved with the addition of bortezomib to ofatumumab and bendamustine in patients with high-risk FL. Although grade 3 to 4 toxicities were similar, more patients treated with bortezomib needed dose modifications and early discontinuation.
Plasma Cell Leukemia
Gonsalves et al (2018) noted that primary plasma cell leukemia (pPCL) is the most aggressive form of the plasma cell (PC) malignancy, multiple myeloma (MM). It has been commonly associated with the presence of a chromosome translocation involving the immunoglobulin heavy chain (IgH) locus on 14q32, that is t (11;14). Results from early phase clinical trials utilizing the selective Bcl-2 inhibitor, venetoclax, as a single-agent in patients with relapsed MM have had remarkable efficacy among patients with t (11;14) abnormality. The present case demonstrated the ability of a combination regimen incorporating Bcl-2 inhibition with daratumumab, bortezomib, venetoclax, and dexamethasone to induce a rapid and very deep hematologic response in a pPCL patient with t (11;14), even in a setting of very refractory disease. The authors concluded that this case highlighted the need to further study Bcl-2 inhibition-based therapy as an option for therapy in patients with pPCL with t (11;14).
Nakaya et al (2018) retrospectively analyzed 26 patients with pPCL registered from May 2005 until April 2015 by the Kansai Myeloma Forum; 20 patients received novel agents (bortezomib [n = 12] or lenalidomide), and their median survival of was 34 months. The median survival of patients who underwent ASCT was 40 months, those undergoing allogeneic SCT (allo-SCT) 55 months, and those undergoing both types of SCT (auto-allo) 61 months; whereas for those who did not undergo SCT it was 28 months (p = 0.845). The only statistically significant risk factor identified by multivariate analysis was hypercalcemia. The authors concluded that novel agents (bortezomib or lenalidomide) may improve the prognosis of pPCL, as may allo-SCT and/or ASCT, in these real-world patients; however, the prognosis of pPCL remains dismal. These researchers stated that further investigations are needed to assess clinical features and develop new treatment strategies.
The authors stated that this study had several drawbacks. First, there were relatively few patients analyzed (n = 12 I the bortezomib group) and it was a retrospective study. Second, although chromosomal abnormalities are thought to affect prognosis, they were only sought, and identified, in 9 patients. Limitations in the patients’ insurance policies prevented the authors from performing detailed chromosomal tests, including FISH, in the remaining patients; this problem needs to be addressed.
Tabchi et al (2019) stated that MM usually follows a clinical course leading to refractoriness and limited therapeutic options in advanced stages, which might need bridge therapies to either ASCT or novel therapies. These researchers reported their experience with the high-dose chemotherapy mCBAD (modified cyclophosphamide, bortezomib, doxorubicin, and dexamethasone) regimen in newly diagnosed MM (NDMM), relapsed/refractory MM (RRMM), and PCL patients. They searched their electronic records database for MM patients who received mCBAD from 2010 to 2016 for 28-day cycles of cyclophosphamide 350 mg/m2 intravenously (I.V.) twice-daily with mesna 400 mg/m2 I.V. daily (days 1 to 4), bortezomib 1.3 mg/m2 subcutaneously/I.V. (days 1, 4, 8, 11), doxorubicin 9 mg/m2 daily continuous infusion (days 1 to 4), dexamethasone 40 mg orally daily (on days 1 to 4, 9 to 12, 17 to 20). International Myeloma Working Group (IMWG) criteria were used for response assessment and diagnosis. Descriptive statistics, Fisher exact test, χ2, Wilcoxon rank sum, and Kaplan-Meier were used for statistical purposes. A total of 140 patients met the inclusion criteria. A median of 2 cycles of therapy was administered. The overall response rate (ORR) was 85 % in patients with RRMM (n = 116) and 100 % in NDMM (n = 13) and PCL (n = 11) patients. Respective median PFS (mPFS) for NDMM, PCL, and RRMM were 19.61 months (95 % confidence interval [CI]: 5.26 to not applicable [NA]), 7.56 months (95 % CI: 4.7 to NA), and 4.64 months (95 % CI: 3.75 to 6.73). Patients with RRMM who used mCBAD as a bridge to ASCT (36.2 %) had mPFS (11.48 months; 95 % CI: 7.52 to 15.9 months) compared with those who did not (mPFS: 3.19 months; 95 % CI: 2.4 to 3.75 months). Cytopenias occurred in more than 90 % of patients, and febrile neutropenia was noted in 26 %. All cases of treatment-related mortality (8 %) occurred in patients with RRMM, except for 1 patient with PCL. The authors concluded that mCBAD resulted in high response rates in myeloma and PCL, however, with high treatment-related mortality. Its use in RRMM should be limited to patients who have immediate need for therapy without other therapeutic options and who have good performance status (score of 0-1) or NDMM if novel agents are not available depending on practice setting. These investigators stated that mCBAD can be a therapeutic option for patients with PCL. This was a small (n = 11 for PCL), retrospective study.
Acute Myeloid Leukemia
In a phase-II clinical trial, Tomlinson and associates (2019) reported that the combination of bortezomib and pegylated liposomal doxorubicin (PLD) at FDA-approved doses demonstrated minimal and non-durable anti-leukemic activity, in a cohort of acute myeloid leukemia (AML) patients selected for non-intensive therapy. That all patients with improving marrow blasts after cycle 1 progressed during cycle 2 of therapy was disappointing, given prior observations of bortezomib in AML. The authors concluded that the findings of this study suggested that proteasome inhibition alone was insufficient to augment sensitivity to anthracyclines, and further investigation is needed to optimize dosing or identify further evidence of synergy.
Aplenc and colleagues (2020) stated that new therapeutic strategies are needed for pediatric AML to reduce disease recurrence and treatment-related morbidity. The Children's Oncology Group Phase-III AAML1031 trial examined if the addition of bortezomib to standard chemotherapy improves survival in pediatric patients with newly diagnosed AML. This trial randomized patients younger than 30 years of age with de-novo AML to standard treatment with or without bortezomib. All subjects received the identical chemotherapy backbone with either 4 intensive chemotherapy courses or 3 courses followed by AHSCT for high-risk patients. For those randomized to the intervention arm, bortezomib 1.3 mg/m2 was given on days 1, 4 and 8 of each chemotherapy course. For those randomized to the control arm, bortezomib was not administered. A total of 1,097 patients were randomized to standard chemotherapy (n = 542) or standard chemotherapy with bortezomib (n = 555). There was no difference in remission induction rate between the bortezomib and control treatment arms (89 % versus 91 %, p = 0.531). Bortezomib failed to improve 3-year EFS (44.8 ± 4.5 % versus 47.0 ± 4.5 %, p = 0.236) or OS (63.6 ± 4.5 versus 67.2 ± 4.3, p = 0.356) compared with the control arm. However, bortezomib was associated with significantly more peripheral neuropathy (p = 0.006) and intensive care unit (ICU) admissions (p = 0.025) during the 1st course. The authors concluded that the addition of bortezomib to standard chemotherapy increased toxicity but did not improve survival; these data did not support the addition of bortezomib to standard chemotherapy in children with de-novo AML.
Esophageal Squamous Cell Carcinoma
Zhang and colleagues (2020) noted that esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancer types in China. In recent years, progress has been made in various types of cancer genomics including ESCC. However, the clinical significance of genomic variation of ESCC remains poorly defined. In the present study, genomic sequencing data from 469 ESCC cases were analyzed and potential therapeutic targets in the Druggable Genome Interaction Database (DGIdb) were screened. A series of potential therapeutic target genes and pathways were identified, of which treatment of ESCC with bortezomib potently inhibited the proliferation of 5 ESCC cell lines and administration of bortezomib resulted in significant tumor xenograft regression in SCID mice. It was also identified that kinase insert domain receptor (KDR), which had drug recommendations from all 6 sources integrated by the DGldb and harbored significant amplification in ESCC, might be a down-stream target of zinc finger protein 750 (ZNF750). ZNF750 acts as a transcription factor and has been demonstrated to harbor frequently inactivating mutations in ESCC by previous independent studies. In the present study, KDR was up-regulated upon ZNF750 knockdown and the rescue of ZNF750 also resulted in marked restoration of KDR. KDR knockdown in stable ZNF750-knockdown KYSE150 and KYSE140 ESCC cells significantly attenuated the promotion of cell growth, colony formation, invasion and migration induced by ZNF750 knockdown. Further experiments found that apatinib treatment resulted in profound inhibition of cell proliferation and invasion. The authors concluded that the findings of this study provided insight for genomic alterations as potential therapeutic targets in ESCC and supported the possibility of a therapeutic strategy targeting the proteasome in ESCC. These findings also suggested that targeting KDR may be an effective way to treat ESCC, not only in KDR variant cases, but also in individuals with ZNF750 mutations and deletions.
Evans Syndrome
Beydoun and colleagues (2020) stated that treatment of refractory Evans syndrome (ES) remains a challenge in hematology practice. Due to rarity of this condition, evidence-based approaches are limited and often treatment choices stem from small case series or anecdotal experiences. There is mounting evidence that some patients have genetic defects that could be targeted with promising preliminary results. These researchers described 3 very refractory pediatric ES cases treated with bortezomib without adverse effects; 2 of the 3 patients had dramatic and long-lasting recovery that started following the initial doses of the drug. The authors concluded that clinical trials to examine the role of bortezomib in the treatment of ES are needed.
Ribosomopathies
Orgebin and colleagues (2020) stated that ribosomopathies are a group of rare diseases in which genetic mutations cause defects in either ribosome biogenesis or function, given specific phenotypes. Ribosomal proteins, and multiple other factors that are needed for ribosome biogenesis (rRNA processing, assembly of subunits, export to cytoplasm), could be affected in ribosomopathies. Despite the need for ribosomes in all cell types, these diseases result mainly in tissue-specific impairments. Depending on the type of ribosomopathy and its pathogenicity, there are many potential therapeutic targets. These investigators reviewed the available literature of ribosomopathies, discussed current treatments, and introduced the new therapeutic perspectives based on recent research. Diamond-Blackfan anemia, currently treated with blood transfusion prior to steroids, could be managed with a range of new compounds, acting mainly on anemia, such as L-leucine. Treacher Collins syndrome could be managed by various treatments, but it has recently been shown that proteasomal inhibition by MG132 or bortezomib may improve cranial skeleton malformations. Developmental defects resulting from ribosomopathies could also be treated pharmacologically after birth; thus, it might be possible to treat certain ribosomopathies without using multiple treatments such as surgery and transplants. The authors concluded that ribosomopathies remain an open field in the search for new therapeutic options based on recent understanding of the role of ribosomes and progress in gene therapy for curing genetic disorders.
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