PROSPECTIVE ANALYSIS OF ADVERSE EVENT PROFILE OF PROTEASOME INHIBITOR-BASED ANTIHUMORAL THERAPY FOR RENAL TRANSPLANT CANDIDATES AND RECIPIENTS

CLINICAL IMMUNOSUPPRESSION - NEW AGENTS

R.C. Walsh¹, A.R. Shields², G. Mogilishetty³, A. Govil³, P. Roy-chaudhury⁴, S. Young⁵, G.E. Wall⁶, S. Safdar⁷, S. Huang⁷, M. Cardi⁷, R.R. Alloway³, E.S. Woodle^8
1Department Of Surgery, Division Of Transplantation, University of Cincinnati, Cincinnati/UNITED STATES OF AMERICA, ²Transplant Surgery, University of Cincinnati, Cincinnati/UNITED STATES OF AMERICA, ³Nephrology, University of Cincinnati, cincinnati/UNITED STATES OF AMERICA, ⁴Nephrology, University of Cincinnati, Cincinnati/UNITED STATES OF AMERICA, ⁵Department Of Internal Medicine, Division Of Nephrology, University of Cincinnati, Cincinnati/UNITED STATES OF AMERICA, ⁶Department Of Surgery, Division Of Transplantation, University of Cincinnati, Cincinnati/OH/UNITED STATES OF AMERICA, ⁷Nephrology, The Christ Hospital, cincinnati/UNITED STATES OF AMERICA, ⁸Transplant Surgery, University of Cincinnati, cincinnati/UNITED STATES OF AMERICA

Body: Introduction: Bortezomib-based therapy for the treatment of refractory antibody mediated rejection (AMR) has demonstrated utility. However, careful evaluation of the adverse event profile should be made as bortezomib gains broader application. This report summarizes a prospective evaluation of the adverse event profile in patients treated for AMR as well as renal transplant candidates undergoing desensitization with bortezomib. Methods: A total of 50 patients received 70 cycles of bortezomib (bortezomib 1.3 mg/m² x 4 doses) and were followed for a mean of 8.4 ± 7.6 months. These patients included 31 patients receiving treatment for AMR and 19 pre-transplant desensitization patients. Hematologic and gastrointestinal toxicity were graded with Common Terminology Criteria for Adverse Event (CTCAE). Peripheral neuropathy was evaluated by Functional Assessment of Cancer Therapy-cognitive function questionnaire. Bortezomib induced peripheral neuropathy (BIPN) was graded as: level 1 (parasthesia/numbness lasting ≤ 72 hours), level 2 (parasthesia/numbness lasting >72 hours), level 3 (parasthesia/numbness with pain), level 4 (parasthesia which limits walking), or level 5 (motor involvement). Highest level BIPN was recorded. Results: Patients were 42 ± 10 years of age and roughly half (54%) were male. Diabetic patients accounted for 22% of the population. At baseline, 24% of patients had peripheral neuropathy. These patients received a mean of 5.6 ± 5.0 bortezomib doses in 1.5 ± 0.5 treatment cycles. Demographics and adverse events are presented in table.

Age (Years)	42 ± 10
Male (%)	54%
African-American Ethnicity (%)	36%
Diabetic (%)	22%
PN at Baseline (%)	24%
Mean Number of Bortezomib Doses	5.6 ± 5.0
Mean Number of Bortezomib Cycles	1.5 ± 0.5
Baseline Hemoglobin (Hgb) (gm/dL)	11.4 ± 2.1
Hgb Nadir (gm/dL)	9.8 ± 2.5
Time to Hgb Nadir (Days)	12.9 ± 7.3
Incidence of CTCAE grade 3 Anemia [<8.0 – 6.5 gm/dL] (%)	27%
Incidence of Bortezomib Dose Reduction or Holding for Anemia (%)	4%
Baseline platelets (103 cells/mm3)	222 ± 82
Platelets at Nadir (103 cells/mm3)	112 ± 54
Time to Platelet Nadir (Days)	11.5 ± 4.3
Incidence of CTCAE grade 3 Thrombocytopenia [<50,000 – 25,000 cells/mm3 ] (%)	13%
Incidence of Bortezomib Dose Reduction or Holding for Thrombocytopenia (%)	11%
Baseline ANC (cells/mm3)	5,690±3,599
ANC at Nadir (cells/mm3)	3,621±1,869
Time to ANC Nadir (Days)	14.7 ± 11.3
Incidence of CTCAE grade 3 Neutropenia [<1,000 – 500 cells/mm3 ] (%)	3%
Incidence of Bortezomib Dose Reduction or Holding for Neutropenia (%)	1%
Incidence of CTCAE grade 1 Nausea / Vomiting (%)	37%
Incidence of CTCAE grade 2 Nausea / Vomiting (%)	6%
Incidence of CTCAE grade 1 Diarrhea (%)	3%
Incidence of CTCAE grade 2 Diarrhea (%)	11%
New-onset BIPN or Worsening of Baseline Neuropathy (%)	38%
Doses of Bortezomib Prior to BIPN	3.4 ± 1.8
BIPN Highest Level is 1 (%)	8%
BIPN Highest Level is 2 (%)	16%
BIPN Highest Level is 3 (%)	12%
BIPN Highest Level is 4 (%)	0%
BIPN Highest Level is 5 (%)	2%
Incidence of BK Viremia	2%
Incidence of Malignancy (%)	0%

Conclusions: Hematologic and gastrointestinal toxicities are the most commonly observed with bortezomib therapy in the renal transplant population. Dose reductions for these adverse events are rare and toxicities are generally mild and transient. New onset BIPN or worsening of baseline peripheral neuropathy is not uncommon; however, the incidence of severe BIPN is low. In patients with BIPN, all cases have resolved or improved following treatment. Prospective evaluation of bortezomib in renal transplant candidates and recipients demonstrates a reasonable adverse event profile.

Disclosure: All authors have declared no conflicts of interest.