A limitation of current antihumoral therapies (plasmapheresis, intravenous immune globulin, and polyclonal antilymphocyte antibodies including rabbit antithymocyte globulin [rATG]) is their lack of direct effects on the major antibody-producing cell (the mature plasma cell) (1).
Bortezomib (Velcade, Millennium Pharmaceuticals, Cambridge, MA) is a first in class proteosomal inhibitor, that is Food and Drug Administration approved, for the treatment of multiple myeloma (a plasma cell neoplasm) (2). Bortezomib’s immune modulating effects are pleiotropic, and its antimyeloma properties are believed to result at least in part from its potent proapoptotic effects (3, 4). Bortezomib has also been shown to possess activity against nontransformed plasma cells in animal models (5–8).
A growing dissatisfaction with the results of standard antibody-mediated rejection (AMR) therapies led to a search for antihumoral agents with activity against plasma cells. This search led to the identificaton of bortezomib as an anti-plasma cell agent. In addition to anti-plasma cell properties, proteosomal inhibitors suppress T-cell function (9), and therefore they also have potential for treatment or prevention of cell-mediated allograft rejection. The initial experience described herein represents the first clinical use of bortezomib as an antihumoral agent.
METHODS
Definitions
Baseline serum creatinine is the mean of the five consecutive serum creatinine (sCr) measurements immediately preceding acute rejection; acute rejection is an increase in sCr level at least 20% above baseline sCr with histologic evidence of acute rejection defined by Banff ’97 criteria (update 2005) (10); AMR is defined by Banff criteria (11), biopsies consistent with AMR required two of three following characteristics: donor-specific antihuman leukocyte antigen (HLA) antibody (DSA), histologic changes consistent with AMR, and positive C4d staining in peritubular capillaries (PTC) ± other structures; acute cellular rejection (ACR) is defined by Banff ’97 criteria (update 2005) (10); mixed acute rejection is defined as ACR with DSA present or positive C4d staining in PTC or both.
Renal biopsies were graded using Banff ’97 criteria (update 2005) (10). C4d immunohistochemical staining was performed on each biopsy, and all evaluations performed by a single pathologist (L.A.).
Donor-Specific Antibody Testing
DSAs were identified using antigen bead panels by Luminex assay (Labscreen TM, One Lambda, Canoga Park, CA). Fluorescence intensity values were converted to molecules of equivalent soluble fluorescence (MESF) using a standard curve generated with Quantum TM 27 microbeads (Bangs Laboratories Inc., Fishers, IN).
CASE REPORTS
Histologic, sCr, and treatment data are listed in Table 1. Figure 1 (A and B) summarizes the immunodominant and nonimmunodominant DSA (iDSA) MESF levels during and after bortezomib treatment, respectively. Figure 2 shows the light micrographs of the allograft biopsies before and after bortezomib therapy. Follow-up ranged from 31 to 310 days, with a mean of 140 days.
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TABLE 1: Renal allograft function, biopsy, and treatment data
FIGURE 1.:
(A) Immunodominant donor-specific antihuman leukocyte antigen antibody (DSA) levels [expressed as molecules of equivalent soluble fluorescence (MESF)] levels after bortezomib treatment. (B) Non-immunodominant DSA MESF levels after bortezomib treatment.
FIGURE 2.:
Recipient 1: course 1, prebortezomib biopsy (PTD 223) demonstrates Banff IB ACR, early chronic rejection, and AMR. Postbortezomib biopsy (PTD 249) demonstrates borderline ACR with marked reduction in interstitial infiltrates
FIGURE 2.:
and tubulitis. Course 2, Prebortezomib biopsy (PTD 428) demonstrates no acute cellular rejection with evidence of transplant glomerulopathy. Postbortezomib biopsy (PTD 452) demonstrates no acute cellular rejection with an evidence of transplant glomerulopathy. Recipient 2: course 1, prebortezomib biopsy (PTD 95) demonstrates Banff IB ACR with mild tubular atrophy, mild interstitial fibrosis, and edema. Glomerular capillaries show thickening of the capillary walls. Glomerular C4d staining is positive (not shown). Postbortezomib biopsy (PTD 119) demonstrates borderline ACR, focal tubular atrophy, and interstitial fibrosis. Course 2, Prebortezomib biopsy (PTD 265) demonstrates borderline ACR with focal interstitial edema and inflammation. Postbortezomib biopsy (PTD 275) demonstrates borderline ACR with diffuse interstitial fibrosis and transplant glomerulopathy. Recipient 3: Prebortezomib biopsy (PTD 1766) demonstrates Banff IIA ACR. Glomerulitis is present with marked interstitial edema with some neutrophilic infiltrates. Postbortezomib biopsy (PTD 1790) resolving ACR, marked resolution of interstitial infiltrates, and persistence of interstitial edema. Recipient 4: Prebortezomib biopsy (PTD 180) demonstrates Banff IA ACR. Postbortezomib biopsy (PTD 192) borderline ACR with moderate tubular interstitial inflammation. Recipient 5: Prebortezomib biopsy (PTD 2825) demonstrates borderline ACR. Postbortezomib biopsy (PTD 1790) resolving ACR. Recipient 6: Prebortezomib biopsy (PTD 147) demonstrates Banff IA ACR. Postbortezomib biopsy (PTD 154) resolving ACR.
Patient 1
First Treatment Course
A 56-year-old diabetic man with a 0% CDC panel-reactive antibody (PRA), negative AHG-CDC crossmatch (CXM), and negative T and B flow cytometric crossmatches (FXM) received a living unrelated, four HLA antigen-mismatched kidney transplant in December 2006. Immunosuppression included basiliximab induction, mycophenolate mofetil (MMF), an investigational agent, and prednisone. On posttransplant-day (PTD) 223, sCr level increased to 3.0 mg/dL and renal allograft biopsy demonstrated a Banff IB ACR with C4d deposition in the PTC. DSA testing revealed high levels of two de novo DSA specificities (HLA DR53: 436,938 MESF; DQ7: 681,158 MESF). An investigational agent was converted to tacrolimus (levels targeted between 10 and 15 ng/mL), and plasmapheresis, rATG (1.5 mg/kg in 8 doses), methylprednisolone (250 mg in 3 doses), and rituximab (375 mg/m2) therapy were initiated. Sixteen days later (PTD 239), the patient failed to reverse his rejection (sCr 2.2 mg/dL, and biopsy Banff grade IA ACR with C4d positivity) and DSA levels remained increased. Bortezomib therapy (1.3 mg/m2 in 4 doses) was initiated on August 14, 2007 and 10 days later (PTD 249) the biopsy revealed ACR reversal and sCr level remained at 1.9 mg/dL. At the conclusion of bortezomib therapy, iDSA level decreased by 50%. At followup, out to 6 months after reversal, the patient remained rejection-free, sCr level decreased to 1.7 mg/dL, and DSA levels remained reduced.
Second Treatment Course
Six months postbortezomib, on PTD 424, the sCr level increased to 4.2 mg/dL, the two original de novo DSA specificities were markedly increased (anti-DR53: 680,000 MESF; anti-DQ7: 750,000 MESF), and the two new de novo DSA specificities (anti-A29: 120,000 MESF; anti-B51: 500,000 MESF) were present. Renal allograft biopsy demonstrated no rejection and transplant glomerulopathy (TG) with C4d deposition in PTC and glomerular capillaries. Rituximab (200 mg/m2) and a second course of bortezomib therapy (1.5 mg/m2) were initiated. On PTD 429, after one dose of bortezomib, he returned to the hospital with grade 3 diarrhea (assessed by NCI-CTC), which resolved promptly with antidiarrheal therapy. He also had a grade 2 thrombocytopenia (assessed by NCI-CTC). On PTD 452, sCr level decreased to 2.5 mg/dL and biopsy demonstrated no rejection and TG with focal C4d PTC immunostaining. All DSA levels (HLA -DR53, -DQ7, -A29, and -B51) were significantly reduced or undetectable. Currently, 4 months after the second bortezomib course, the patient has a stable DSA level and a sCr level of 1.8 mg/dL.
Patient 2
A 28-year old African American woman with type 1 diabetes mellitus (0% CDC-PRA) received a simultaneous kidney-pancreas transplant in April 2007. Immunosuppression included rATG induction (1.5 mg/kg in 4 doses), tacrolimus (initial target level 10 ng/mL), MMF (2 gm/day), and a prednisone taper to 5 mg/day by PTD 7.
Renal allograft biopsy on PTD 40 to evaluate a sustained increase of sCr (1.8 mg/dL) demonstrated acute glomerulitis, acute tubular injury, and borderline ACR, with de novo antidonor HLA-A1 (253,371 MESF) and HLA-B8 (106,348 MESF) antibodies (Fig. 2). Plasmapheresis, intravenous immunoglobulin (IVIg), and increased MMF dosing (3 gm/day) were instituted. By PTD 55, sCr level decreased to 1.4 mg/dL and repeated biopsy revealed mild chronic changes (tubular atrophy). Previously identified DSA levels (HLA A1: 235,992 MESF; HLA B8: 68,491 MESF) were unchanged; however, two new specificities (both class II major histocompatibility complex) were noted (HLA DR52: 35,000 MESF; DQ2: 47,000 MESF).
On PTD 64, sCr level remained increased at 1.6 mg/dL and biopsy revealed Banff ’97 grade IB ACR, and the two newly identified class II DSA levels increased markedly (HLA DR52: 271, 536 MESF; DQ2: 147,158 MESF). rATG therapy was initiated (1.5 mg/kg/dose) with improvement in sCr level to 1.3 mg/dL. Follow-up biopsy (PTD 78) demonstrated ACR resolution; however, early chronic TG was now present. On PTD 83, because of the relatively rapid progression to early TG and the continued DSA elevation, additional antihumoral therapy was initiated with rituximab and plasmapheresis. Despite rituximab and plasmapheresis, on PTD 95, the repeat biopsy now revealed grade IB ACR, positive C4d staining, and DSA levels remained elevated.
Bortezomib therapy (1.3 mg/m2×4 doses) was initiated on PTD 96. Biopsy on PTD 102 and 119 demonstrated ACR reversal, and by PTD 134 all DSA levels (HLA A1, B8, DR52, and DQ6) were significantly decreased or undetectable. It is important to note that the iDSA (anti-A1) was unaffected by all agents before bortezomib, and that anti-A1 levels decreased by more than 50% with bortezomib (Fig. 1A). Six months postbortezomib, acute rejection (ACR IA, sCr 2.4 mg/dL) and an increase in DSA levels occurred because of noncompliance. Corticosteroids were ineffective and sCr level increased to 6.5 mg/dL. A second course of bortezomib was initiated on PTD 269; however, the rejection was unrelenting and she returned to dialysis on PTD 286.
Patient 3
A 51-year-old woman with end-stage renal disease (ESRD) secondary to type I diabetes received a three antigen-mismatched simultaneous kidney-pancreas (0% CDC-PRA, negative AHG-CDC CXM, and negative T- and B-cell FXM) transplant in 2002. Immunosuppression included rATG induction (total dose 5 mg/kg), tacrolimus (initial target level=10 ng/mL), MMF 2 gm/day, and a methylprednisolone to prednisone taper to 5 mg/day by PTD 7. The patient remained rejection-free for 4.5 years (PTD 1766), when her sCr level increased from 1.4 to 3.5 mg/dL. Renal allograft biopsy revealed Banff grade IIA ACR with glomerular C4d staining and increased DSA levels (HLA DQ6: 428,000 MESF). The marked deterioration in renal function combined with vascular rejection and high DSA levels argued for combined ACR/AMR therapy. rATG and bortezomib therapies were initiated and repeated biopsy on PTD 1774 revealed improvement in ACR to Banff grade IB. Repeated biopsy, 7 days after the end of bortezomib therapy (PTD 1790), revealed that ACR resolution, sCr (l 3.1 mg/dL), and DSA levels had decreased by more than 50%. Currently, 10 months postbortezomib, the sCr is 2.8 mg/dL and both iDSA and non-iDSA levels remain substantially suppressed.
Patient 4
A 33-year-old patient with idiopathic ESRD (0% CDC-PRA, negative AHG-CDC CXM, and negative T- and B-cell FXM) received a living unrelated, four HLA antigen-mismatched kidney transplant in October 2007. Immunosuppression included basiliximab induction, MMF, an investigational agent, and a prednisone taper to 5 mg/day by 3 months posttransplant. On PTD 162, sCr level increased to 1.9 mg/dL (from a baseline of 1.2 mg/dL) and renal allograft biopsy demonstrated a mixed acute rejection (Banff IB) and high levels of two de novo DSA specificities (HLA DQ9 and HLA DR53). The investigational agent was converted to tacrolimus (levels targeted between 10 and 15 ng/mL) and rATG (1.5 mg/kg in 6 doses), with methylprednisolone pulse was initiated. MMF dose remained unchanged (2 gm/day). One week later (PTD 168), renal dysfunction persisted (sCr 2.0 mg/dL), renal allograft biopsy revealed persistent acute rejection (Banff IA), and DSA levels remained increased. Bortezomib therapy (1.3 mg/m2 in 4 doses) with rituximab (500 mg) was initiated on PTD 173 and on PTD 186, the biopsy revealed rejection reversal and all DSA levels decreased substantially. Currently, 1 month postbortezomib treatment, sCr level is 1.9 mg/dL and iDSA and non-iDSA levels remain suppressed.
Patient 5
A 29-year-old man with ESRD secondary to Alport’s syndrome received a living related, one haplotype-mismatched kidney transplant (0% CDC-PRA, negative AHG-CDC CXM, and negative T- and B-cell FXM). Immunosuppression included thymoglobulin induction, MMF, and cyclosporine, which was later converted to sirolimus as part of a clinical trial. He remained rejection-free for 7.5 years, when his renal function deteriorated to 1.8 mg/dL (from a baseline of 1.5 mg/dL) with proteinuria (1.4 gm/24 hr) on PTD 2774. Renal biopsy demonstrated chronic TG, severe arteriopathy, and a Banff IA ACR. DSA testing revealed high levels of two de novo DSA (HLA DR16: 450,000 MESF; HLA DQRw51: 200,000 MESF). Sirolimus was converted to tacrolimus and corticosteroids were given. On PTD 2825, sCr level was 2.8 mg/dL and biopsy-revealed chronic TG, severe arteriopathy, severe interstitial fibrosis, and borderline ACR. DSA levels remained increased (HLA DR16: 385,000 MESF; HLA DQRw51: 55,000 MESF) and bortezomib therapy (1.3 mg/m2 in 4 doses) was initiated. At the conclusion of therapy (PTD 2839), his sCr level decreased to 2.0 mg/dL, biopsy revealed no acute rejection. After postbortezomib plasmapheresis (PTD 2842), iDSA levels decreased by more than 70% (HLA DR16: 105,000 MESF) and non-iDSA levels decreased by 90% (HLA DQRw51 - 5,700 MESF). Currently, 3 months postbortezomib, the patient remains free of recurrent rejection with an sCr level of 2.3 mg/dL, and iDSA remain suppressed.
Patient 6
A 28-year-old woman with Wegner’s granulomatous received a deceased donor kidney transplant (0% CDC-PRA). Immunosuppression included basiliximab induction, mycophenolic acid, an investigational agent, and a prednisone taper to 5 mg/day by 3 months posttransplant. On PTD 120, her sCr level increased to 1.8 mg/dL (from a baseline of 0.8 mg/dL) and renal allograft biopsy demonstrated a Banff IIA ACR. Thymoglobulin rejection therapy was initiated and maintenance immunosuppression changed to tacrolimus or MMF, however, by PTD 140, her sCr level increased to 2.5 mg/dL and renal allograft biopsy demonstrated a Banff IB ACR and a de novo DSA (HLA DQ5: 70,000 MESF). Corticosteroids were given and 7 days later (PTD 147), biopsy demonstrated Banff IA ACR and DSA level was essentially unchanged. Bortezomib therapy (1.3 mg/m2) was initiated and 7 days later (PTD 154), biopsy revealed resolution of ACR. The fourth bortezomib dose was held dose secondary to a grade III febrile neutropenia (likely due to MMF and valganciclovir) without documented infection, which resolved with G-CSF. Renal allograft biopsy on PTD 171 demonstrated ACR resolution, and after three plasmapheresis sessions, DSA levels were dramatically decreased (HLA DQ5:120,000 MESF). On PTD 185, biopsy showed no evidence of acute rejection. Between PTD 185 and 206 the sCr level continued to increase, despite the absence of acute rejection and she returned to dialysis.
DISCUSSION
Our initial experience in developing AMR therapies began with high-dose tacrolimus therapy in the early 1990s (23–27). Over the past several years, like many centers, we have gained experience with plasmapheresis or IVIg, rATG, and rituximab in treating AMR and in desensitization. In our experience, currently available AMR therapies (IVIg, plasmapheresis, rATG, and rituximab) have provided occasionally effective, yet unreliable and suboptimal results. Limitations of current AMR therapies include (1) AMR reversal tends to be gradual than prompt, (2) expense, (3) rejection reversal rates below 80%, (4) common appearance of chronic rejection after AMR treatment, and (5) long-term persistence of DSA after therapy. Since these limitations may be due to the lack of effects on mature plasma cells, bortezomib’s effects on mature plasma cells may represent a quantum advance in antihumoral therapy.
Patients in this series had substantial rejection episodes refractory to plasmapheresis, IVIg±rATG±rituximab. Six patients had both ACR and AMR (mixed rejection). Despite these vigorous and refractory rejection episodes, each allograft was salvaged and opportunistic infection did not occur.
Bortezomib therapy provided resolution of refractory ACR in treated patients. This observation is likely due to the effects of bortezomib on T-cell function including apoptosis induction in activated T cells, T-cell depletion, NF-kB inhibition, reduced major histocompatibility complex class I expression, and decreased Th1 responses (5, 7, 12–15). Also, proteosomal inhibition effects on dendritic cell function (reduced costimulatory molecule expression, reduced cytokine production, and apoptosis) may have contributed (13, 16, 17). Effects on B lymphocyte linage cells include inhibition of IL-6 production by bone marrow stromal cells leading to apoptosis in various stages in B-cell maturation (18).
Bortezomib also provided a marked and sustained reduction in both iDSA and non-iDSA in all patients within 2 to 4 weeks following regardless of the magnitude of DSA levels. The in vitro and in vivo evidence of bortezomib’s activity against mature, antibody secreting plasma cells may underlie bortezomib’s antihumoral efficacy in humans. Thus, by targeting plasma cells, bortezomib may directly eliminate the source of deleterious DSA.
Pre-bortezomib therapies may have provided a “milieu” that allowed effective bortezomib therapy. However, as evidenced by the treatment of patient 5, who received bortezomib without prior antihumoral therapy, DSA reduction can be achieved with bortezomib alone. The effectiveness of bortezomib in reducing DSA levels may be of significance in AMR as recent studies have shown correlation between AMR and DSA levels during and after therapy (19, 20). Others have suggested that antibody levels and histologic changes, but not C4d, influenced eventual outcome in AMR (21, 22).
The early appearance of chronic rejection within 1 to 2 weeks of AMR therapy was noted in two patient and is not an uncommon occurrence after aggressive rejection episodes. This observation of rapid progression to chronic rejection in AMR argues for more aggressive therapeutic approaches. One such approach was used with bortezomib therapy in the third patient in this report, where bortezomib therapy was used concomitantly with additional agents (rATG, rituximab) at an earlier point in the acute rejection process.
Rebound in DSA levels was noted in some of the patients at different intervals after bortezomib treatment. This observation will be important to follow long-term in these patients to determine the full extent of rebound. Moreover, it is important to note that the bortezomib regimen used in the present study included only a single cycle of therapy. As noted above, safety data from the present study and from myeloma studies indicate that multiple cycles may be a reasonable approach for enhancing bortezomib therapy.
Several approaches exist for enhancing the efficacy of bortezomib in AMR and ACR therapies. First, alterations in dosing intensity and density may enhance efficacy. Experience with has shown that several cycles of bortezomib therapy (each consisting of four doses over 11 days with a 10-day inter-cycle rest period) are usually required to induce remission in refractory multiple myeloma (28, 29). Therefore, examination of two or more cycles of bortezomib therapy may be a useful approach for enhancing bortezomib efficacy. In addition, combination therapy with rituximab and bortezomib may enhance therapy because of the combined deletion of mature, antibody-secreting plasma cells and their precursors.
In conclusion, bortezomib therapy provides effective treatment of mixed (AMR and ACR) rejection with minimal toxicity and provides sustained iDSA and non-iDSA reduction. Bortezomib represents the first approach for targeting plasma-cells in humoral responses, whose clinical potential should be promptly investigated in transplantation and autoimmune diseases.
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