Severe and prolonged lymphopenia observed in patients treated with bendamustine and erlotinib for metastatic triple negative breast cancer

Abstract

Purpose: 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.

Patients and 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.

Conflict of interest statement

Conflict of interest The authors declare that they have no conflict of interest.

Figures

Fig. 1

Lymphocyte counts over time. Individual profiles (light gray lines) with average trend line (solid black) of lymphocyte counts. Reference lines (dotted black) are at 1.00 corresponding to presence of lymphopenia and 0.50 corresponding to the division between grade 2 and 3 lymphopenia. Created using Microsoft PowerPoint

Fig. 2

CD4 counts over time. Individual profiles (light gray lines) with average trend line (solid black) of CD4 counts. Reference lines (dotted black) are at 200 and 50, highlighting areas of grade 3 CD4 counts (<200–50) as well as areas of grade 4 CD4 counts (<50). Created using Microsoft PowerPoint