Elsevier

Leukemia Research

Volume 38, Issue 12, December 2014, Pages 1430-1434
Leukemia Research

A phase I/II trial of Erlotinib in higher risk myelodysplastic syndromes and acute myeloid leukemia after azacitidine failure

https://doi.org/10.1016/j.leukres.2014.09.014Get rights and content

Highlights

  • We report a phase I/II trial of Erlotinib in higher risk MDS.

  • 30 patients received Erlotinib orally after resistance to azacitidine treatment.

  • This outpatient treatment was well tolerated. Maximum tolerated dose was 150 mg/d.

  • Response was observed in 6 patients (20%).

  • These results warrant further investigation of this drug in combination.

Abstract

Survival after azacitidine (AZA) failure in higher-risk myelodysplastic syndromes (MDS) is poor and new treatment options are needed. Erlotinib, an oral inhibitor of the epidermal-growth-factor-receptor (EGFR), has shown in preclinical models some efficacy in higher risk MDS and acute myeloid leukemia (AML). In this phase I/II trial, 30 patients received 100 mg/day (n = 5) or 150 mg/day (n = 25) of Erlotinib orally after primary or secondary resistance to AZA treatment. Eighteen MDS and 12 AML patients were treated. This outpatient treatment was well tolerated with limited grade III–IV extra hematological toxicities (skin (n = 1), and diarrhea (n = 3). Response was observed in 6 patients (20%) including 1 complete remission (CR), 1 marrow CR and 4 hematological improvement (2 erythroid and 2 on platelets). Median duration of response was 5 months.

Erlotinib appears to induce a significant number of responses in higher risk MDS/AML having failed AZA treatment. Given the good safety profile of Erlotinib, its combination with other drugs could be tested in the future in MDS and AML.

Introduction

Myelodysplastic syndromes (MDS) are clonal stem cell disorders characterized by ineffective hematopoiesis leading to blood cytopenias and by a variable risk of progression to acute myeloid leukemia (AML). Higher risk MDS, that include patients classified as high or intermediate 2 risk by the International Prognostic Scoring System (IPSS), have a high incidence of progression to AML and short survival. Current reference treatments for higher risk MDS are hypomethylating agents, mainly azacitidine (AZA), that has demonstrated a survival improvement over conventional treatments [1]. However, only about 60% of the patients respond to AZA, and the median duration of response remains short (about 12 months). In addition, patients with primary or secondary AZA failure have a very short survival (median about 6 months) [2], without any efficacious therapeutic option available so far except allogeneic stem cell transplantation, restricted to a limited number of patients.

The epidermal-growth-factor-receptor (EGFR), a member of the HER/Erb-B family of tyrosine kinases receptor, is expressed and deregulated in a broad spectrum of solid tumors, including lung, breast and colon cancer. The EGFR inhibitor Erlotinib has demonstrated its efficacy in those tumors, and has been approved in various countries including the US and Europe for the treatment of several solid tumors (non small cell lung cancer, pancreatic cancer) [3], [4].

Despite the absence of EGFR on the surface of the hematopoietic cells, we and others have shown that, at least in vitro, Erlotinib was able to induce apoptosis, cell cycle arrest and differentiation in MDS and AML cell lines, and in marrow cells from patients with AML and MDS [5]. Moreover, in a xenograft model, we showed that clinically achievable doses of Erlotinib reduced the risk of AML evolution compared to controls. In addition, 3 published case reports have suggested that Erlotinib could have some anti leukemic effect in AML patients [5], [6], [7].

Based on those findings, we assessed in a phase I–II trials the safety and efficacy of Erlotinib in higher risk MDS and AML having failed azacitidine. We compared in particular our results with those of a similar study very recently published by another group [9].

Section snippets

Patients and methods

This multicenter, single-arm, open-label, phase I–II study of Erlotinib (clinicaltrials.gov (NCT 01085838) conducted by the Groupe Francophone des myelodysplasies (GFM) was approved by a French Ethical committee (Comité de Protection des personnes, ile de France X) and the French health authority (ANSM). Signed informed consent was obtained from each participant.

Inclusion criteria were (1) WHO RAEB-2 or acute myeloid leukemia with 20–30% blasts (refractory anemia with excess blasts in

Baseline patient characteristics

Between July 2010 and July 2012, 30 patients (20 males, 10 females) were included in 9 centers, 10 in the escalating dose phase I study and 20 in the phase 2 study (Table 1). Median age was 77.5 years (range 53–86). At the onset of azacitidine, 3 of the 30 patients had acute myeloid leukemia with 20–30% blasts (refractory anemia with excess blasts in transformation, according to FAB), and the other 27 had higher risk MDS. The median number of cycles of azacitine received before inclusion was 18

Discussion

In this phase I/II trial of Erlotinib in higher risk MDS, an oral daily dose of 150 mg was achievable with tolerable toxicity, and 20% of the patients responded. This was similar to the 14% overall best response rate reported by the Lee Moffitt's series in a similar group of patients [9]. The rationale for using Erlotinib was based on our work and that of other groups, showing an effect of this drug of MDS and AML cell lines and fresh cells. In those cells, Erlotinib induces cell cycle arrest,

Acknowledgements

We would like to acknowledge Pr. Pierre Fenaux for editorial and content suggestions and Simone Boehrer for having initiated this project.

Author's contributions: ST, SB, PF, LA: Designed the study, accrued patients, analyzed results and assembled the manuscript. TP, OBR, EW, JD, ER, MH and EJ: Contributed patients and assisted with manuscript preparation. ST, SB, MS and GK: Coordinated biological assays and provided preclinical datas. VS: Provided biostatistical support and assisted with

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