Toxicity and Outcome Assessment of Concurrent Gabapentin or Pregabalin Administration with High-Dose Melphalan in Autologous Hematopoietic Cell Transplant Patients

Abstract

Introduction L-type amino acid transporter 1 (LAT1) and 2 (LAT2) are responsible for the transport of large neutral amino acids across the intracellular membrane. These transporters appear to have drug-carrying functionality with certain medications such as gabapentin (GP), pregabalin (PG), melphalan, levodopa, methyldopa, and baclofen. It is likely that concurrent administration of either GP or PG occurs in patients receiving HD-Mel conditioning which could theoretically result in changes in cellular uptake, mucosal injury, and survival. Methods A retrospective review of patients with multiple myeloma who received outpatient HD-Mel from January 2012 to July 2016 was conducted. Patients? 18 years who received melphalan ? 140 mg/m2 were included. Exclusion criteria included concomitant use of levodopa, methyldopa, or baclofen; or deviation from an anti-emetic regimen of steroids, ondansetron, and fosaprepitant. The primary endpoint was rate of mucositis. Secondary endpoints included hospital admission rate, parenteral nutrition (TPN) utilization, patient-controlled analgesia (PCA) initiation, intravenous (IV) opioid requirements, use of topical mucosal agents, use of antidiarrheals, use of rescue anti-emetics, number of days of nausea or vomiting, median daily pain scores, time to neutrophil engraftment, time to platelet-20 engraftment, time to platelet-50 engraftment, 30-day treatment-related mortality (TRM), 100-day TRM, progression-free survival (PFS), and overall survival (OS). Results Eighty patients were enrolled including 30 patients who received concomitant GP/PG and 50 control patients. Rates of mucositis were 59% vs. 52% for grade 1, 24% vs. 19% for grade 2, 7% vs. 10% for grade 3, 10% vs. 19% patients with no mucositis (p = 0.833) in the GP/PG group vs. the control group, respectively. Admission rate was found to be to be 10% in the GP/PG treated group compared with 18% in the control group (p = 0.439). No significant differences in TPN or PCA usage, IV opioid use, topical mucosal agent use, antidiarrheal use, rescue anti-emetic use, days of nausea/vomiting, or pain scores were observed. Time to neutrophil engraftment, platelet-20 engraftment, and platelet-50 engraftment were not significantly different between treatment groups. No patients in the GP/PG treated group and 6% (n = 3) of patients in the untreated group experienced TRM within 100 days (p = 0.288), with similar median PFS and OS. When patients were stratified by GP/PG dose, a correlation with higher doses and lower incidence of mucositis, nausea, vomiting, and pain was observed, although statistical significance was not reached. Conclusion It appears safe to continue GP/PG therapy throughout HD-Mel therapy with no negative outcomes described currently. Larger studies are needed to better characterize the clinical implications of concomitant therapy.