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Prospective Evaluation of the Toxicity Profile of Proteasome Inhibitor–Based Therapy in Renal Transplant Candidates and Recipients

Schmidt, Nicole1; Alloway, Rita R.2; Walsh, R. Carlin1; Sadaka, Basma2; Shields, Adele R.1; Girnita, Alin L.3; Hanseman, Dennis J.4,5; Woodle, E. Steve1,6

doi: 10.1097/TP.0b013e318257acf6
Clinical and Translational Research
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Background A prospective intermediate-term evaluation of toxicities associated with bortezomib therapy for antibody-mediated rejection (AMR) and desensitization was conducted.

Methods Patients were graded for bortezomib-related toxicities: hematologic and gastrointestinal toxicities by Common Terminology Criteria for Adverse Events and peripheral neuropathy by modified Functional Assessment of Cancer Therapy questionnaire and Common Terminology Criteria for Adverse Events.

Results Fifty-one patients treated for AMR and 19 patients treated for desensitization received 96 bortezomib cycles (1.3 mg/m2 ×4 doses); mean (SD) follow-up was 16.3 (9.0) months. Patients treated for AMR and patients treated for desensitization were similar in age, gender, ethnicity, and baseline peripheral neuropathy. Patients treated for AMR received a mean (SD) of 4.9 (2.0) bortezomib doses in 1.3 (0.5) cycles; and patients treated for desensitization, a mean of 7.3 (1.6) doses in 1.8 (0.4) cycles. Prevalence of diabetes and anemia were higher at baseline in patients treated for AMR. In the AMR cohort, two cases of cytomegalovirus infection, two cases of BK virus infection, and one case of Epstein-Barr virus infection were observed. No cases of viral infection were observed in the desensitization cohort. Malignancies were not observed. Significant bortezomib toxicities included anemia and peripheral neuropathy, which were manageable. Anemia was more common in patients treated for AMR; and peripheral neuropathy, more common in patients treated for desensitization.

Conclusions Bortezomib-related toxicities in kidney transplant candidates and recipients are low in incidence and severity and vary based on treatment population.

1 Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH.

2 Division of Nephrology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.

3 Hoxworth Blood Center, Cincinnati, OH.

4 Division of Trauma and Critical Care, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH.

5 Center for the Sustainment of Trauma and Readiness Skills, United States Air Force, Cincinnati, OH.

6 Address correspondence to: E. Steve Woodle, M.D., Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 558, Cincinnati, OH 45267.

Partial funding for this work was provided by Millennium and Genzyme.

R.R.A. and E.S.W. received research support from Millennium.

All other authors declare no conflicts of interest.

E-mail: woodlees@uc.edu

R.R.A., A.R.S., and E.S.W. participated in making the study design. N.S., R.C.W., and B.S. participated in collecting data. N.S., R.C.W., A.L.G., and D.J.H. participated in analyzing data. N.S. and E.S.W. participated in preparing the initial manuscript draft. N.S., R.R.A., R.C.W., B.S., and E.S.W. participated in critically reviewing the article.

Received 25 August 2011. Revision requested 26 September 2011.

Accepted 27 March 2012.

Bortezomib is a first-in-class, small-molecule proteasome inhibitor that is approved by the U.S. Food and Drug Administration for the treatment of multiple myeloma, a plasma cell dyscrasia (1). Bortezomib exerts its effects primarily by binding and inhibition of the chymotryptic site in the β-subunit of the 26S proteasome, resulting in reversible proteasome inhibition (2–4). Bortezomib has three major effects that are believed to mediate its immune modulating properties: (1) initiation of endoplasmic reticulum stress and a terminal unfolded protein response in plasma cells (both transformed and nontransformed); (2) inhibition of cell cycle regulatory protein degradation, resulting in cell cycle arrest and apoptosis; and (3) inhibition of degradation of the inhibitor of κB, thereby preventing nuclear factor κB–mediated cell activation and inflammation (5–10).

Bortezomib toxicities have been well characterized in the multiple-myeloma population (11–13). Gastrointestinal toxicities, including nausea, vomiting, and diarrhea, range from 35% to 57% of patients receiving bortezomib. Peripheral neuropathy is reported in 36% to 41% of patients, with an incidence of grade 3 or 4 peripheral neuropathy in 8% to 9% of patients. Hematologic toxicities include anemia (20%–26%), thrombocytopenia (25%–35%), and neutropenia (19%–20%).

Our center has demonstrated that bortezomib therapy provides a potential means for rapid donor-specific antibody reduction or elimination in early acute antibody-mediated rejection (AMR) in renal transplant recipients (14–16). Reductions in human leukocyte antigen alloantibody levels were also demonstrated in desensitization studies with one and two cycles of bortezomib therapy (17). Because bortezomib-based therapy gains broader application in the transplant population, detailed prospective evaluations of its toxicity profile are needed. The purpose of this study was to prospectively analyze bortezomib toxicities in renal transplant candidates and recipients.

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RESULTS

Results from 70 renal transplant candidates and recipients were analyzed: 51 patients treated for AMR and 19 patients treated for desensitization. Demographic data are presented in Table 1. Patients were similar in age, gender, and ethnicity. Patients treated for AMR showed a higher prevalence of diabetes at baseline and received less bortezomib per patient compared with patients treated for desensitization. For patients treated for AMR, quantitation of known prior immunosuppression within 1 month of AMR treatment and ongoing maintenance immunosuppression at the time of bortezomib initiation is summarized in Table 1. Treatment with antibody-depleting induction was not known for all patients. However, of those patients with data available, 75.0% received rabbit antithymocyte globulin and 17.5% received interleukin 2 inhibitors.

TABLE 1

TABLE 1

Hemoglobin, platelet, and absolute neutrophil count data are presented in Table 1 and Figure 1. Lower hemoglobin values were observed at baseline and nadir in patients treated for AMR compared with patients treated for desensitization. The AMR group also demonstrated a greater percent reduction in hemoglobin at nadir. Mean times to hemoglobin nadir did not differ between the two groups. In patients treated for AMR, grade 3 anemia and grade 4 anemia were reported more frequently, and there was a higher incidence of holding or reducing bortezomib dose because of anemia. Significant changes were identified by analysis of variance with repeated measures in hemoglobin values compared with baseline (Fig. 1A,B). A significant drop in hemoglobin level occurred at all time points in patients treated for AMR, but hemoglobin values recovered by day 30. No significant drops in hemoglobin values occurred in patients treated for desensitization, and the only significant change was an increase in hemoglobin values at day 7, which may be caused by a single outliner. Comparing the percent reductions in hemoglobin values at day 14, patients treated for AMR experienced a greater decrease in hemoglobin values compared with patients treated for desensitization (Fig. 2).

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

Neutropenia was a rare phenomenon in both patients treated for AMR and patients treated for desensitization. Although mean absolute neutrophil counts were lower at baseline in patients treated for desensitization versus patients treated for AMR, mean absolute neutrophil counts at nadir were similar and more than 3000 cells per mm3 in both groups. Grades 3 and 4 neutropenia incidences were low, necessitating a few dose reductions or holding. Although significant differences were observed in absolute neutrophil counts compared with baseline (Fig. 1C,D), they were not clinically significant. Absolute neutrophil counts actually increased at various time points and at day 14, the percent increase in absolute neutrophil counts was less in patients treated for AMR versus patients treated for desensitization (Fig. 2).

Thrombocytopenia was the most common reason for bortezomib dose reductions or holding in both transplant groups. Platelet counts in patients treated for AMR and patients treated for desensitization were similar at baseline. Platelets reached a nadir of approximately 44% to 50% of baseline, with an average time to nadir of 12 days. Although significant drops in platelet counts were observed (Fig. 1E,F), platelet counts in both groups returned to or above baseline by day 30. Patients treated for AMR and patients treated for desensitization experienced similar decreases in platelet counts, with no difference observed in the percent reduction of platelets at day 14 in both groups (Fig. 2).

Gastrointestinal adverse effects were experienced at similar rates in patients treated for AMR and patients treated for desensitization (Table 1). Gastrointestinal adverse effects were mild, and grade 3 or 4 gastrointestinal toxicities were not observed. Gastrointestinal adverse effects did not contribute to dose holding or reductions in patients treated for desensitization, and few dose modifications were required in patients treated for AMR.

Peripheral neuropathy rates were low (Table 1). The incidence of new-onset or worsening peripheral neuropathy was higher in patients treated for desensitization than in patients treated for AMR. The incidence of severe neuropathies (levels 4 and 5) was low. Time to onset and number of doses before onset of peripheral neuropathy symptoms were similar between groups, with onset occurring near the end of the first bortezomib cycle. Patients exhibited improvement in symptoms after treatment, with complete resolution of new-onset peripheral neuropathy observed in 91.7% of patients treated for AMR and 100% of patients treated for desensitization.

Several risk factors (baseline peripheral neuropathy, number of bortezomib doses, diabetes mellitus, and desensitization vs. AMR) were analyzed by univariate and multivariate analyses. The stepwise multivariate analysis revealed that bortezomib administration for desensitization as compared with AMR was the only factor associated with new-onset or worsening peripheral neuropathy (odds ratio, 3.830; P=0.02) (Table 2). Although the number of bortezomib doses and preexisting diabetes mellitus were significant in the univariate analysis, they were not significant in the stepwise multivariate analysis.

TABLE 2

TABLE 2

Comparisons of toxicities between multiple-myeloma and transplant populations demonstrated that the transplant population tended to have higher anemia rates but lower neutropenia rates and lower gastrointestinal toxicity rates (Table 3). Peripheral neuropathy toxicities were similar in multiple-myeloma and transplant populations.

TABLE 3

TABLE 3

Opportunistic infections and malignancies are presented in Table 1. Overall, there were two cases of cytomegalovirus (CMV) infections, one case of Epstein-Barr virus (EBV) infection, and two cases of BK virus infections, all in the AMR group. Opportunistic infections did not occur in the desensitization group. Malignancies were not reported in either group.

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DISCUSSION

Evaluation of medications in a new population requires efficacy and safety assessments in an adequate number of subjects. Reports on the use of bortezomib in renal transplantation to date have included relatively small populations; moreover, none have focused on the toxicities. The present study prospectively identified toxicity data in a relatively large patient population.

Particular attention was focused on peripheral neuropathy, which has been historically considered an important toxicity in the multiple-myeloma population (18). The incidence of peripheral neuropathy observed in the transplant population was similar to that reported for the multiple-myeloma population (11, 12). Of note, however, a higher incidence of preexisting peripheral neuropathy was noted in the transplant population primarily because of diabetes and uremia.

In our experience, peripheral neuropathy tended to occur more in patients treated for desensitization than in patients treated for AMR. A stepwise multivariate analysis was performed to assess the influence of risk factors on new-onset or worsening peripheral neuropathy. This analysis demonstrated that bortezomib administration for desensitization as compared with AMR was a risk factor for the development or worsening of neuropathy. Patients treated for desensitization are primarily predialysis and dialysis patients and therefore are subject to the influence of uremia, whereas the AMR population, who has better kidney function, is largely not affected by uremia. The higher incidence of uremia in the desensitization population may contribute to the higher incidence of peripheral neuropathy toxicity with bortezomib. Dialysis was not included as a variable in the univariate and multivariate analyses because 16 of the 19 patients treated for desensitization were on dialysis, which could be a confounding factor with the desensitization group itself. The desensitization group as a whole did receive more bortezomib doses compared with the AMR group. However, the number of bortezomib doses did not contribute to the development or worsening of peripheral neuropathy in the stepwise multivariate analysis. Although diabetes mellitus and baseline peripheral neuropathy are traditional risk factors for peripheral neuropathy, neither was associated with new-onset or worsening peripheral neuropathy in our analysis.

In the multiple-myeloma population, bortezomib-induced peripheral neuropathy usually presents as sensory effects (19–22). Similarly, in our transplant experience, peripheral neuropathy almost universally presented with numbness or tingling in the upper or lower extremities. Peripheral neuropathy has been shown to be reversible in most patients with multiple myeloma (21, 22). In our experience with transplant candidates and recipients, new-onset bortezomib-induced peripheral neuropathy was reversible in all but one patient (11/12 patients treated for AMR, 91.7%; 7/7 patients treated for desensitization, 100%).

Neutropenia and thrombocytopenia tended to occur at comparable rates in multiple-myeloma and transplant populations. Multiple myeloma is associated with myelosuppression, which may contribute to hematologic toxicity. In an analogous manner, dialysis and transplant patients experience myelosuppression caused by uremia, but transplant patients with AMR also receive myelosuppressive/antiproliferative agents as maintenance immunosuppressive therapy (primarily mycophenolate). Interestingly, antiproliferative immunosuppressive agents did not seem to increase neutropenia and thrombocytopenia rates because differences were not observed between transplant patients with AMR and dialysis patients or patients with uremia who underwent desensitization. Furthermore, grade 4 neutropenia and grade 4 thrombocytopenia were not complicated by hospitalizations in both AMR and desensitization patients.

Anemia tended to occur more often in patients treated for AMR than in patients treated for desensitization. A possible explanation for the increased incidence of anemia in patients treated for AMR is that patients treated for AMR were also receiving immunosuppressive medications (particularly mycophenolate). In contrast, patients treated for desensitization on dialysis were likely receiving erythropoietin therapy and ongoing hemoglobin monitoring during dialysis, thereby minimizing anemia.

Most bortezomib-related adverse events can be managed effectively by assiduous toxicity assessments, bortezomib dose reductions, and supportive measures (19, 20, 23). The most important method of managing peripheral neuropathy is early detection by frequent clinical assessments, with prompt dose modification or discontinuation. Dietary supplementation with L-carnitine or pyridoxine has been suggested as a means for minimizing bortezomib-related neurotoxicity (24); however, to date, we have not routinely used this approach. Pharmacologic management of bortezomib-related neuropathy is similar to other causes, with the use of anticonvulsants, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and analgesics (20, 25). With the recent FDA approval of subcutaneous bortezomib, this offers another approach to minimize peripheral neuropathy symptoms as well (2). From our experience, the overwhelming majority of peripheral neuropathies have been mild, and almost all cases have reversed over time. Gastrointestinal effects are usually mild and easily managed with antiemetics and antidiarrheal medications.

In conclusion, significant bortezomib-related toxicities include anemia and peripheral neuropathy, which vary based on the treatment population. Anemia tends to occur more in patients treated for AMR. Peripheral neuropathy tends to occur more in patients treated for desensitization. All other toxicities occur at similar or lower frequencies than the multiple-myeloma population. The incidence of dose reduction/modification because of adverse events is rare. Toxicities of bortezomib are relatively low in incidence and severity, are largely transient, and can be managed by frequent clinical assessments, dose modifications, and pharmacologic interventions.

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MATERIALS AND METHODS

Approval from the institutional review board was obtained from the University Hospital and Christ Hospital (Cincinnati, OH), allowing for the use of patient data for publication.

Kidney transplant recipients who received bortezomib-based therapy for AMR between July 2007 and October 2010 and kidney transplant candidates who received bortezomib-based therapy for desensitization between June 2009 and September 2009 at the University Hospital and Christ Hospital in Cincinnati, Ohio, were analyzed. All patients received treatment with at least one cycle of bortezomib (1.3 mg/m2 ×4 doses given 72 hr apart). Methylprednisolone was administered before each bortezomib dose, as 100 mg intravenously before the first and second doses and 50 mg intravenously before the third and fourth doses. All patients who received bortezomib for desensitization were part of a research protocol. Bortezomib for AMR was either used as part of a research protocol or used off-label in a clinical setting.

Antiviral, antifungal, and Pneumocystis jirovecii pneumonia (PCP) prophylaxis were administered to patients treated for AMR according to institution standard of care. Antiviral prophylaxis with either valganciclovir or valacyclovir and the duration of treatment depended on the recipient and donor EBV and CMV serostatus. Valganciclovir was administered for 1 year in CMV-negative recipients of CMV-positive donors and for 90 days in CMV-positive recipients regardless of the donor’s CMV serostatus. Valacyclovir was administered for 30 days to CMV-negative recipients of CMV-negative donors. Antiviral prophylaxis with valacyclovir was continued for 1 year in EBV-negative recipients of EBV-positive donors. Antifungal prophylaxis with nystatin was administered for 90 days. PCP prophylaxis with sulfamethoxazole/trimethoprim, pentamidine, or dapsone was administered for 1 year. Antiviral, antifungal, and PCP prophylaxis was administered to patients treated for desensitization per physician discretion.

The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used to grade hematologic and gastrointestinal toxicities for each bortezomib cycle (Table 4) (26). Hematologic toxicities evaluated included anemia, neutropenia, and thrombocytopenia. Gastrointestinal toxicities evaluated included diarrhea, nausea, and vomiting. Before each bortezomib dose and during follow-up, the Functional Assessment of Cancer Therapy scale/Gynecologic Oncology Group–Neurotoxicity questionnaire was administered to each patient, and peripheral neuropathy symptoms were then graded according to severity and duration (Table 5) (27, 28). A modified version of the CTCAE criteria was used to grade each patient for peripheral neuropathy symptoms, with two patients graded twice because repeated cycles were greater than 10 months apart (Table 6).

TABLE 4

TABLE 4

TABLE 5

TABLE 5

TABLE 6

TABLE 6

Dose modifications were made based on toxicity severity. Therapy was held until toxicity was resolved and then reinitiated at a 25% dose reduction for CTCAE grade 3 hematologic and nonhematologic toxicities, excluding peripheral neuropathy. Dose modifications for peripheral neuropathy were based on CTCAE criteria following the package insert recommendations listed in Table 7 (2).

TABLE 7

TABLE 7

Opportunistic infections were evaluated for each patient. CMV infections and EBV infections were defined as either viremia or tissue invasive disease. BK virus infections were defined as either viremia or nephropathy.

All analyses were performed according to the intention-to-treat principle. Variables were compared using chi-square test for categorical variables and the Student’s t test, analysis of variance with repeated measures, Mann-Whitney U test, and unpaired t test for continuous variables. P values less than 0.05 were considered statistically significant. Multivariate logistic regression was used to assess risk factors for new-onset or worsening of peripheral neuropathy. All variables with univariate P values of 0.15 or less were included in the full and stepwise multivariate analyses.

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Keywords:

Toxicity; Proteasome inhibitors; Desensitization; Antibody-mediated rejection

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