Original studySubcutaneous Omacetaxine Mepesuccinate in Patients With Chronic-Phase Chronic Myeloid Leukemia Previously Treated With 2 or More Tyrosine Kinase Inhibitors Including Imatinib
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)
- et al.
Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION)
Blood
(2012) - et al.
Interferon-alpha or homoharringtonine as salvage treatment for chronic myeloid leukemia patients who acquire the T315I BCR-ABL mutation
Blood
(2007) - et al.
Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial
Lancet Oncol
(2011) Part II: management of resistance to imatinib in chronic myeloid leukaemia
Lancet Oncol
(2007)- et al.
Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy
Blood
(2007) - et al.
Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance
Blood
(2007) - et al.
High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance
Blood
(2002) - et al.
Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia
Cancer Cell
(2002) - et al.
Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase
Blood
(1995) - et al.
Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation
Blood
(2012)
The clinical significance of achieving different levels of cytogenetic response in patients with chronic phase chronic myeloid leukemia after failure to front-line therapy: is complete cytogenetic response the only desirable endpoint?
Clin Lymphoma Myeloma Leuk
The durable clearance of the T315I BCR-ABL mutated clone in chronic phase chronic myelogenous leukemia patients on omacetaxine allows tyrosine kinase inhibitor rechallenge
Clin Lymphoma Myeloma Leuk
The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up
Blood
Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure
Blood
Subset analysis of response to treatment of chronic phase CML in a phase 1 study of ponatinib in refractory hematologic malignancies [Abstract]
Blood (ASH Annual Meeting Abstracts)
Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure
Blood
Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study
J Clin Oncol
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2019, Abeloff’s Clinical OncologyHeme oxygenase-1: A new druggable target in the management of chronic and acute myeloid leukemia
2017, European Journal of Medicinal ChemistryCitation Excerpt :It is endowed with high anti-leukemic activity, even in patients with the T315I mutation in BCR-Abl protein. Unfortunately, its activity is coupled to a number of relevant side-effects (high incidence of myelosuppression, infections) which limit its therapeutic usage [39]. Nevertheless, under attentive hematologic control, Omacetaxine mepesuccinate can be considered a further available weapon to fight CML in patients resistant to or intolerant of TKIs.
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2017, Critical Reviews in Oncology/HematologyCitation Excerpt :Other treatment options for this patient are limited and not without risk. They include omacetaxine mepesuccinate (Cortes et al., 2015b; Cortes et al., 2013b; Synribo, 2017) or interferon-α combined with a TKI (Itonaga et al., 2012; Cornelison et al., 2011) or used alone prior to resumption of a second-generation TKI after disappearance of the T315I-mutated clones. A 3-cohort clinical trial (AP24534-14-203; NCT02467270) is currently ongoing with the goal of comparing the efficacy and safety of 3 different starting doses of ponatinib (15 mg, 30 mg, and 45 mg, with reductions to 15 mg upon achievement of MCyR) in patients resistant to at least 2 TKIs.
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2017, Leukemia ResearchCitation Excerpt :Myleosuppression was the most common adverse event and was reported in all 5 patients. Two multicenter, international, single-arm, open-label studies further evaluated the role of omacetaxine in CML: CML-202, a trial that included individuals who had resistance or intolerance to imatinib and a history of the T315I mutation, and CML-203, a trial that included patients with resistance or intolerance to imatinib and at least one other approved TKI [60]. Data from these trials were pooled in analysis together; a total of 81 patients were included.