title: Severe and prolonged lymphopenia observed in patients treated with bendamustine and erlotinib for metastatic triple negative breast cancer.
abstract: OBJECTIVE
  Triple negative breast cancers (TNBC) frequently have high epidermal growth factor receptor (EGFR) expression and are sensitive to DNA-damaging agents. Improved therapies are needed for this aggressive malignancy.
  
  
  METHODS
  We performed a phase I trial of bendamustine and erlotinib, an EGFR tyrosine kinase inhibitor, in patients with metastatic TNBC, ECOG performance status ≤2, and ≤1 prior chemotherapy for metastatic disease. Each 28-day cycle included intravenous bendamustine on days 1, 2 and oral erlotinib on days 5-21 with dose escalation according to a 3 + 3 phase I study design. Dose-limiting toxicity (DLT) was determined by toxicities related to study therapy observed during cycle 1.
  
  
  RESULTS
  Eleven patients were treated, 5 on dose level 1 and 6 on dose level 2. One patient had DLT on dose level 2. However, cumulative toxicities were observed, including grade 3/4 lymphopenia in 91 % (95 % CI 0.59-0.998) with progressively decreased CD4 counts and grade ≥3 infections in 36 % (95 % CI 0.11-0.69) of patients.
  
  
  CONCLUSIONS
  Combination therapy with bendamustine and erlotinib causes excessive toxicity with severe, prolonged lymphopenia, depressed CD4 counts, and opportunistic infections and should not be pursued further. Future trials of bendamustine combinations in TNBC patients should account for potential cumulative lymphocyte toxicity necessitating patient monitoring during and after treatment.
authors: Division of Medical Oncology, Stefanie Spielman Comprehensive Breast Center, The Ohio State University Comprehensive Cancer Center, B411 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43210, USA. rachel.layman@osumc.edu
authors: Rachel M
authors: RM
authors: Layman
authors: Amy S
authors: AS
authors: Ruppert
authors: Melinda
authors: M
authors: Lynn
authors: Ewa
authors: E
authors: Mrozek
authors: Bhuvaneswari
authors: B
authors: Ramaswamy
authors: Maryam B
authors: MB
authors: Lustberg
authors: Robert
authors: R
authors: Wesolowski
authors: Susan
authors: S
authors: Ottman
authors: Sarah
authors: S
authors: Carothers
authors: Anissa
authors: A
authors: Bingman
authors: Raquel
authors: R
authors: Reinbolt
authors: Eric H
authors: EH
authors: Kraut
authors: Charles L
authors: CL
authors: Shapiro
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069461:Bendamustine Hydrochloride; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018791:CD4 Lymphocyte Count; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008231:Lymphopenia / Q000139:chemically induced* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D012720:Severity of Illness Index
chemical_list: D009588:Nitrogen Mustard Compounds; D011799:Quinazolines; D000069461:Bendamustine Hydrochloride; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors