Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib

Cortes, Jorge; Hochhaus, Andreas; Coutre, Philipp D. le; Rosti, Gianantonio; Pinilla‐Ibarz, Javier; Jabbour, Elias; Gillis, K.; Woodman, Richard C.; Blakesley, Rick E.; Giles, Francis J.; Kantarjian, Hagop M.; Baccarani, Michele

doi:10.1182/blood-2010-11-318949

Cited by 61 publications

(44 citation statements)

References 17 publications

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“…Importantly, the probability of crossintolerance across different TKIs is generally low. [20][21][22] This is particularly true for nonhematologic adverse events which occur infrequently, particularly at a grade 3 or 4 level, and rarely lead to treatment discontinuation for the same adverse event. In contrast, hematologic adverse events, particularly thrombocytopenia, are more likely to lead to cross-intolerance.…”

Section: Sequencing and Safetymentioning

confidence: 99%

Chronic myeloid leukemia: sequencing of TKI therapies

Cortes

Kantarjian

2016

Hematology

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Multiple tyrosine kinase inhibitors (TKIs) are available for managing patients with chronic myeloid leukemia. Although most patients have a favorable outcome with their initial therapy, whether imatinib or a second-generation TKI was used, some will require subsequent use of one or more different TKIs. Such sequencing might be indicated in a reactive way (ie, for patients who have experienced resistance or intolerance to their initial therapy) or in a proactive way (ie, for patients with a somewhat favorable outcome who have not reached an "optimal" outcome). Sequencing of TKIs has become standard practice, and the proper use of sequenced TKIs is likely to optimize outcomes and resource utilization. Learning Objectives• Assess the different scenarios in which TKI sequencing can be used in patients with chronic myeloid leukemia • Critically review the outcomes associated with sequencing of TKI in patients with chronic myeloid leukemia Tyrosine kinase inhibitors (TKIs) became standard therapy for patients with chronic myeloid leukemia (CML) not long after the first patient received STI571 (later known as imatinib mesylate) on a phase I clinical trial. 1 The initial approved indication was for patients with resistance to or intolerance of interferon alpha-based therapy, the standard at the time. By 2003, imatinib was approved as frontline therapy for CML, 2 and since then, nearly all patients with access to TKIs have received them as initial therapy. Shortly thereafter, secondgeneration agents, including dasatinib, nilotinib, and bosutinib, with increased potency, different structures that allowed them to overcome most mutations leading to resistance to TKIs, and different toxicity profiles, were introduced and eventually received regulatory approval. Later, ponatinib, a drug with activity against T315I and all mutations tested, proved effective in overcoming resistance in most patients, even those who had received 3 or more prior TKIs. All TKIs were eventually compared with imatinib in the first-line setting, and they generally demonstrated higher response rates, with deeper and faster responses which, in the case of dasatinib and nilotinib, were sufficient to lead to their approval as initial therapy for patients with chronic phase CML (CML-CP). This rapid development has resulted in the availability of multiple TKIs, and along with this, the sequential use of various TKIs in patients with CML-CP (Figure 1).The use of sequential TKI therapy, regardless of the choice of initial therapy, is perhaps more common than is usually appreciated. Despite the professed efficacy of initial therapy with TKIs, at least onethird of all patients initially treated in clinical trials with any TKI for newly diagnosed CML, whether imatinib or a second-generation TKI, have received at least one additional TKI. After 5 years of follow-up in the DASISION trial (in the final report), 39% of patients initially treated with dasatinib and 37% of those treated with imatinib are no longer receiving their initial therapy.3 Similarly, the 5-ye...

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Section: Sequencing and Safetymentioning

confidence: 99%

Chronic myeloid leukemia: sequencing of TKI therapies

Cortes

Kantarjian

2016

Hematology

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“…Only 7 of 40 (18%) patients with hematologic imatinib intolerance discontinued nilotinib, all due to grade 3/4 thrombocytopenia. 18 In a dasatinib trial in patients with CP-CML, 6 of 46 (13%) patients had hematological cross-intolerance on dasatinib 100 mg once daily and subsequently discontinued dasatinib. 19 However, nonhematological crossintolerance to imatinib was uncommon with both nilotinib (2 of 109; 2%) and dasatinib 100 mg once daily (9 of 225; 4%).…”

Section: Management Of Treatment-related Adverse Effectsmentioning

confidence: 99%

“…One hundred patients were enrolled between 2007 and 2009; 69 patients had at least 12 months of follow-up (median, 24 months; range, [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30], and 42 (61%) of these 69 patients relapsed (40 before 6 months, 1 patient at month 7, and 1 at month 19). At 12 months, the probability of persistent molecular remission for these 69 patients was 41%.…”

Section: Discontinuation Of Therapymentioning

confidence: 99%

Educational Session: Managing Chronic Myeloid Leukemia as a Chronic Disease

Hochhaus

2011

Hematology

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Elucidation of the pathogenesis of chronic myeloid leukemia (CML) and the introduction of tyrosine kinase inhibitors (TKIs) has transformed this disease from being invariably fatal to being the type of leukemia with the best prognosis. Median survival associated with CML is estimated at Ͼ 20 years. Nevertheless, blast crisis occurs at an incidence of 1%-2% per year, and once this has occurred, treatment options are limited and survival is short. Due to the overall therapeutic success, the prevalence of CML is gradually increasing. The optimal management of this disease includes access to modern therapies and standardized surveillance methods for all patients, which will certainly create challenges. Furthermore, all available TKIs show mild but frequent side effects that may require symptomatic therapy. Adherence to therapy is the key prerequisite for efficacy of the drugs and for long-term success. Comprehensive information on the nature of the disease and the need for the continuous treatment using the appropriate dosages and timely information on efficacy data are key factors for optimal compliance. Standardized laboratory methods are required to provide optimal surveillance according to current recommendations. CML occurs in all age groups. Despite a median age of 55-60 years, particular challenges are the management of the disease in children, young women with the wish to get pregnant, and older patients. The main challenges in the long-term management of CML patients are discussed in this review.

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“…Cortes et al previously reported that cross-intolerance to nilotinib in imatinib-intolerant patients with CML is infrequent, particularly for patients with nonhematologic adverse events, which is the most common reason for imatinib intolerance (22). This minimal crossintolerance resulted in more patients achieving the planned nilotinib doses and translated into significant clinical responses.…”

Section: Discussionmentioning

confidence: 99%

Molecular Response to Nilotinib in a Patient with Imatinib-intolerant e19a2-positive Chronic Myeloid Leukemia

Kajiguchi

Okuno

et al. 2014

Intern. Med.

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The BCR-ABL1 fusion gene is the molecular marker of chronic myeloid leukemia (CML). The e19a2 transcript is a rare variant associated with various clinical presentations and courses of CML. We herein present a case of e19a2-positive CML who was intolerant to initial treatment with imatinib and successfully responded to subsequent nilotinib therapy. She achieved a major molecular response and has since be able to sustain it. According to the literature, achieved molecular response by imatinib monotherapy has not yet been reported in e19a2-positive CML patients. Second generation tyrosine kinase inhibitors may therefore be a more effective treatment for e19a2-positive CML patients.

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Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib

Cited by 61 publications

References 17 publications

Chronic myeloid leukemia: sequencing of TKI therapies

Chronic myeloid leukemia: sequencing of TKI therapies

Educational Session: Managing Chronic Myeloid Leukemia as a Chronic Disease

Molecular Response to Nilotinib in a Patient with Imatinib-intolerant e19a2-positive Chronic Myeloid Leukemia

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