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.

Kinetics of T‐cell subset reconstitution following treatment with bendamustine and rituximab for low‐grade lymphoproliferative disease: a population‐based analysis

“…Smaller phase 2 trials also reported high rates (80–90%) of grade 3 lymphopenia (Ogawa et al , ) during treatment with BR. These observations have also been replicated in patients receiving bendamustine for diffuse large B‐cell lymphoma (Ohmachi et al , ) and for non‐haematological malignancies (Layman et al , ), consistent with a direct pharmacological effect. In October 2017, the EMA issued a notification of increased risk of Pneumocystis jirovecii (PJP) infections and other opportunistic infections in the context of bendamustine combination therapy, recommending appropriate prophylaxis to be considered.…”

“…It is evident from our data that higher cumulative dose intensity (≥1080 mg/m 2 ) confers a higher risk of CD4+ lymphopenia without evidence for superior efficacy (Friedberg et al , ). Given the independent correlation of cumulative bendamustine dose with delayed CD4+ recovery, together with the possibility of a preferential impact of the drug on the CD4+ cell subset (Layman et al , ; Ogawa et al , ), we caution against employing bendamustine at cumulative doses ≥1080 mg/m 2 . As a practical measure, EOT ALC, perhaps reflecting individual drug sensitivity, may serve as a simple and reproducible biomarker to predict delayed CD4+ recovery after treatment.…”

Triple-Negative Breast Cancer: A Review of Conventional and Advanced Therapeutic Strategies

“…Gefitinib (EGFR inhibitor) reduces cancer cell multiplication and enhances the cytotoxicities of carboplatin and docetaxel ( Figure 5) [70,71]. There are a number of different kinds of EGFR inhibitors trialed against TNBC such as the tyrosine kinase inhibitors (TKIs)-erlotinib and lapatinib along with the monoclonal antibodies (mAbs) such as cetuximab and panitumumab [72][73][74][75]. The reports of failures of EGFR-TKIs and mAbs, however, inspired combination therapy that includes mAbs and chemotherapeutics that proved to be a more efficacious.…”

Novel Approach to Chemotherapy and Administration Selection with Metronomic/Fractionated Dosing

“…Lymphocytopenia is a common side effect among various types of chemotherapies and can even be caused by the cancer itself. Several chemotherapies have been known to cause lymphocytopenia including temozolomide [71], everolimus [72], bendamustine [73], erlotinib [73], various purine analogs [74], and various cytotoxic chemotherapies [75]. Lymphocytopenia has the potential to reduce the body's own ability to eliminate cancer cells naturally, thus reducing the effectiveness of chemotherapy.…”