Serious Hematologic Complications Following Erlotinib Treatment

Case Reports

Case 1. A 67-year-old male patient was histologically diagnosed with inoperable, stage IIIB adenocarcinoma, with pleura infiltration and pleura infusion. This patient was treated with cisplatin 80 mg/m²-gemcitabine 1 gr/m² chemotherapy for six cycles. He achieved a partial response for a duration of six months. On disease progression 11 months after the beginning of chemotherapy, the patient was given erlotinib treatment (150 mg daily, for 4 months). This treatment was discontinued due to grade 4 thrombocytopenia. The bone marrow showed the megakaryocytes slightly reduced and no infiltration by abnormal cells was detected. The thrombocytopenia lasted for 4 months. A new bone marrow aspiration was performed and myelodysplastic syndrome was confirmed. In all of the mitoses, deletion of the lung arm of chromosome 20 from the band 20q11 till 20qter was found. The karyotype of the sample was 46,XY,del(20)(q11)[15]/47,idem,+ 21(7)/48,idem,21,+21[-3].

Case 2. A 70-year-old male patient was histologically diagnosed with inoperable, stage IIIB adenocarcinoma of the lungs. He was treated with cisplatin 80 mg/m² combined with paclitaxel 175 mg/m² for 6 cycles and achieved a partial response for 4 months. As second-line treatment, he was given erlotinib 150 mg daily, for 8 months; the patient had a partial response. The blood white cell count (WBC) increased to 92,000/μ/l. By discontinuing erlotinib the WBC dropped slightly to 82,000/μ/l. Analytically, the white cells were: 28% myelocytes, 4% promyelocytes, 8% metamyelocytes and 50% neutrophils. Believing that by discontinuing erlotinib, the abnormal WBC count might be reduced, we waited for 3 weeks but the count remained the same. The analysis of the DNA isolated by the bone marrow did not detect the V617F mutation in the JAK2 gene. However, the cells expressed the BCR-ABL fusion transcript. The level of expression was estimated by RT real-time PCR. The ratio of BCR-ABL mRNA level to GAPDH mRNA was 2×10⁻².

Case 3. A 60-year-old female was histologically diagnosed with inoperable, stage IIIB adenocarcinoma of the lung, in September 2004. As primary treatment, she received 3 cycles of chemotherapy with cisplatin 80 mg/m² + vinorelbine 25 mg/m²; radiotherapy (RT) of the primary lung lesions and of the mediastinum followed and the treatment was completed with 3 more cycles of cisplatin 80 mg/m² + vinorelbine 25 mg/m² chemotherapy. The primary treatment resulted in a partial response, with a duration of 10 months until disease progression. Another partial response was achieved with second-line therapy of 3 cycles of carboplatin 6 AUC + etoposide 120 mg/m² chemotherapy but this was discontinued because of severe hematologic toxicity (leukopenia). The second partial remission lasted 5 months. After tumor progression, the patient was given erlotinib, 150 mg daily, and the disease remained stable for 8.5 months, until the patient was admitted to hospital because of fever (38.6°C), anemia (Hct 28.8%), leukopenia (2,500 WBCs/μl) and thrombocytopenia (72,000 PLTs/μl). Hematological tests revealed 23% myeloblasts in the bone marrow aspiration and cytogenetic tests showed clonal abnormalities in 9/11 of the analyzed metaphases of bone marrow blast cells with karyotype: 46,XX,del(7)(q22), add(21)(q22), and the diagnosis of myelodysplastic syndrome (MDS), RAEB-T/t-AML, was confirmed. The patient was treated with best supportive care and died due to pneumonia 3.5 months later in a regional hospital.

Case 4. A 59-year-old female was histologically diagnosed with inoperable, stage IV squamous cell carcinoma of the lung in July 2007. As primary treatment, she received 6 cycles of carboplatin 6 AUC + etoposide 120 mg/m² chemotherapy. This primary treatment resulted in disease stability, which lasted for 8 months until disease progression. After tumor progression, the patient received second-line treatment with erlotinib, 150 mg daily, and the disease remained stable for 5.5 months, until the patient was admitted to hospital for further clinical and laboratory evaluation because of anemia (Hct 25.7%) and leucopenia (3.200 WBCs/μl). Hematological tests revealed 14% myeloblasts in the bone marrow aspiration and cytogenetic tests showed clonal abnormalities in 12/20 of the analyzed metaphases of bone marrow blast cells with karyotype: 47,XX,+8, t(5;9)(q13;q34) and the diagnosis of myelodysplastic syndrome (MDS), RAEB, was made. The patient continued to receive erlotinib treatment despite the tumor progression, as well as best supportive care. She died of respiratory failure due to lung cancer progression, 8.0 months later. The MDS appeared 14 months after chemotherapy (Table I shows the data for the aforementioned four patients).