Original study
Subcutaneous Omacetaxine Mepesuccinate in Patients With Chronic-Phase Chronic Myeloid Leukemia Previously Treated With 2 or More Tyrosine Kinase Inhibitors Including Imatinib

https://doi.org/10.1016/j.clml.2013.03.020Get rights and content

Abstract

Introduction

Omacetaxine mepesuccinate (omacetaxine) is a first-in-class cephalotaxine that has demonstrated efficacy in CML. In this analysis we evaluated omacetaxine in CML patients with resistance or intolerance to 2 or more tyrosine kinase inhibitors (TKIs).

Patients and Methods

Data were pooled from 2 phase II trials of subcutaneous omacetaxine, administered at 1.25 mg/m2 twice daily for 14 consecutive days every 28 days until response, then for 7 days every 28 days as maintenance. Patients with resistance or intolerance to imatinib and at least 1 other approved TKI (dasatinib and/or nilotinib) were included; results for patients in chronic phase (CP) are reported here. Major cytogenetic response (MCyR) was the primary end point.

Results

Eighty-one patients with CML-CP (median age, 59 years; range, 26-83 years) were included in the analysis. All patients previously received imatinib, 69 (85%) previously received dasatinib, and 48 (59%) previously received nilotinib. Median omacetaxine exposure was 7.5 months (range, 0.03-38.6 months), with 13 patients ongoing. MCyR was reported in 16 patients (20%; one-sided 95% lower confidence limit, 12.8%), including 8 complete responses; median duration was 17.7 months (95% confidence interval, 4.1 months – not reached). Fifty-six patients (69%) achieved and/or maintained hematologic response for at least 8 weeks; median duration was 12.2 months (range, 8.4-26.2 months). Median failure-free and overall survival were 9.6 months and 34 months, respectively. Toxicity was mainly hematologic: the most common grade 3/4 adverse events were thrombocytopenia (67%), neutropenia (47%), and anemia (37%).

Conclusion

Omacetaxine produced clinically meaningful responses with acceptable tolerability in patients with CML-CP previously treated with 2 or more TKIs.

Introduction

Tyrosine kinase inhibitors (TKIs) that target the Bcr-Abl oncoprotein are the current standard of care for patients with chronic myeloid leukemia (CML). TKIs currently approved for first-line treatment include imatinib and the second-generation agents nilotinib and dasatinib. In newly diagnosed CML patients, the complete cytogenetic response (CCyR) rate achieved with these agents ranges from 65% to 82%,1, 2, 3, 4, 5 with a progression-free survival (PFS) rate ≥ 94% at 24 months.6, 7 Within 5 years, however, at least 25% of patients discontinue imatinib because of unsatisfactory response and/or toxicity.8, 9 Discontinuation rates for nilotinib or dasatinib as first-line therapy are 16% to 18% at 12 months4, 5 and 23% to 26% at 24 months.6, 10

Patients failing first-line TKI therapy with imatinib typically receive dasatinib or nilotinib. The CCyR rate is ≤ 50% in this setting, and the estimated PFS rate at 24 months is 75% to 80%.11, 12, 13, 14, 15, 16, 17 In patients who demonstrate resistance or intolerance to second-line TKI therapy, treatment options include allogeneic stem cell transplantation or a third TKI. Resistance to TKI-based therapy might arise as a result of a point mutation in the BCR-ABL gene or BCR-ABL gene amplification, and Bcr-Abl–independent mechanisms of resistance.18, 19, 20 Non-TKI therapeutic options that act independently of Bcr-Abl might have the potential to overcome these mechanisms of resistance and offer improved prognosis in patients resistant to multiple TKIs.

Omacetaxine mepesuccinate is a protein synthesis inhibitor that induces apoptosis in leukemic cells by reducing levels of multiple oncoproteins, including Bcr-Abl and MCL-1.21 In vitro studies show that omacetaxine can induce apoptosis of leukemic stem cells,21 which distinguishes it from TKIs and indicates clinical potential in persistent CML. Indeed, omacetaxine has shown promising activity in CML patients with resistance or intolerance to TKI therapy, including patients with TKI resistance driven by a T315I BCR-ABL mutation.8, 22, 23, 24

Here we evaluate the safety and efficacy of subcutaneous omacetaxine in chronic-phase CML patients with resistance or intolerance to 2 or more approved TKIs via a pooled analysis of data from 2 open-label phase II studies.25, 26

Section snippets

Study Group

Data from 2 multicenter, international, single-arm, open-label studies (CML-202 and CML-203) were included in this pooled analysis. All patients enrolled in the CML-202 study had resistance or intolerance to imatinib therapy and a history of the T315I BCR-ABL mutation. Patients enrolled in the CML-203 study had resistance or intolerance to imatinib and at least 1 other approved TKI (dasatinib and/or nilotinib). Patients in either study with resistance or intolerance to 2 or more approved TKIs

Patient Characteristics

One hundred and eight patients with chronic-phase CML were treated with omacetaxine in the CML-202 (n = 62) and CML-203 (n = 46) studies. Eighty-one patients had received at least 2 approved TKIs and had documented evidence of resistance or intolerance, and were included in this analysis (CML-202, n = 42; CML-203, n = 39; Figure 1). Median age was 59 years (range, 26-83 years); 98% had an ECOG performance status of 0 or 1 (Table 1). Thirty percent of patients had a hematologic response at study

Discussion

This analysis evaluated the activity of omacetaxine, a protein synthesis inhibitor, in chronic-phase CML patients with documented resistance or intolerance to 2 or more TKIs, using data pooled from 2 phase II trials. Omacetaxine demonstrated clinical activity in this heavily pretreated population, producing or maintaining hematologic response in 69% and MCyR in 20% of patients. Furthermore, responses were durable: median duration of hematologic response and MCyR were 12.2 months and 17.7

Conclusion

Durable hematologic and CyRs were observed after omacetaxine use in patients previously treated with 2 or more TKIs, with a relatively long median OS. Hematologic toxicity was common, but typically reversible with appropriate management. These results support omacetaxine as a treatment option for chronic-phase CML patients with resistance or intolerance to 2 or more TKIs.

Acknowledgments

The authors thank the investigators in the Omacetaxine-202 and -203 Study Groups: Sikander Ailawadhi, Maria Baer, Charles Chuah, Valérie Coiteux, Dan Douer, Robert Emmons, Gabriel Etienne, Thierry Facon, Agnès Guerci, François Guilhot, Andrzej Hellmann, Françoise Huguet-Rigal, Pierre Laneuville, Philipp Le Coutre, Laurence Legros, Armin Leitner, Frédéric Maloisel, David Marin, Tomas Masszi, Purvish Parikh, Delphine Réa, Candido Rivera, Philippe Rousselot, Lydia Roy, Richard Van Etten, Krzysztof

References (35)

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