ORLANDO, Fla.—Erlotinib has an acceptable toxicity profile in patients with myelodysplastic syndrome (MDS) and anti-leukemic activity in higher-risk MDS patients after failure of hypomethylating agents, results of an interim analysis of a phase 2 trial have found.

Preclinical data have suggested erlotinib has in vitro and in vivo efficacy in MDS and acute myeloid leukemia (AML) by inducing apoptosis in MDS and AML cell lines and primary myeloblasts, promoting myeloid differentiation (Boehrer et al. Blood. 2008;111:2170-180). An antitumor effect of erlotinib has also been demonstrated in an AML xenograft mouse model, and isolated case reports have documented hematologic activity in patients with lung cancer and concomitant MDS or AML.

Rami S. Komrokji, MD, of Moffitt Cancer Center, Tampa, Fla., and colleagues conducted a 2-stage phase 2 study to determine activity of erlotinib in the treatment of MDS. Patients eligible for the study included confirmed intermediate (int)-2 or high-risk MDS, low or int-1 risk patients with symptomatic anemia/transfusion dependent-anemia, or patients with platelet counts <50 x 109/L or a significant clinical hemorrhage requiring platelet transfusions, ANC <1 x 109/L, and refractory anemia with excess blasts (RAEB)-t by FAB classification. Excluded were patients who had prior intensive induction chemotherapy, malignancy in the past 2 years, known history of HIV infection, and ECOG PS 3/4.

Primary end point was overall response rate (ORR: complete response, partial response, marrow complete response, or hematologic improvement) as defined by the International Working Group 2006 consensus criteria, the investigators reported in a poster presentation during the 52nd American Society of Hematology Meeting and Exposition.

Oral erlotinib 150 mg/day was administered for 16 weeks. Dose adjustments occurred for diarrhea, rash, and pulmonary toxicity. Assessments included baseline and weekly complete blood counts and repeat bone marrow aspirate and biopsy at 8 and 16 weeks. Patients who did not respond were removed from the study after 16 weeks. Those who responded (ie, who had at least a hematologic response) continued on erlotinib until disease progression or relapse. In stage 1 of the study, an ORR in at least 2 of the first 20 patients was necessary to expand accrual to 15 additional patients.

Of 25 patients enrolled, 2 were subsequently found to be ineligible: the first had myeloblasts >30%, and the second, who did receive erlotinib, had low-grade MDS that had progressed to chronic myeloid leukemia. Of these 24 patients, median age was 71 years (range, 64-80 years); 18 (75%) were male, and the majority (96%) were Caucasian. World Health Organization classification was as follows: refractory cytopenia with multilineage dysplasia, 1 (4.2%); RAEB-I, 8 (33.3%); RAEB-II, 8 (33.3%); chronic myelomonocytic leukemia, 2 (8.3%); AML, 4 (16.7%); and MDS-unclassified, 1 (4.2%). International Prognostic Scoring System risk was low in 2 (8.3%) patients, int-1 in 7 (29.2%), int-2 in 8 (33.3%), and high in 7 (29.2%). Median number of prior treatments was 2 (range, 1-4), and all patients had received a hypomethylating agent (azacitidine or decitabine).

For the 23 eligible patients, best responses were 3 marrow complete responses (13.0%) and 1 hematologic improvement (4.4%), for an ORR of 17.4% (95% CI, 5-39); 6 patients (26.1%) had stable disease. Four deaths occurred on study; 1 case each of sepsis, intracranial hemorrhage, sudden death, and AML. Most common grade 3/4 toxicities were diarrhea in 5 patients (20.8%), thrombocytopenia in 4 (16.7%), and acne/acneiform rash in 4 (16.7%).

Precise non-EGFR kinase targets responsible for activity of erlotinib in myeloid malignancies have not yet been determined but may involve aberrant Lyn-, Syk-, and mTOR-mediated signaling.

Off Label Use: Erlotinib use for MDS is investigational.