Ann Hematol (2015) 94(Suppl 2):S149–S158 DOI 10.1007/s00277-015-2318-y
REVIEW ARTICLE
Management of adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukemia Delphine Rea
Received: 4 August 2014 / Accepted: 7 October 2014 # Springer-Verlag Berlin Heidelberg 2015
Abstract Tyrosine kinase inhibitors (TKIs) targeting the breakpoint cluster region-Abelson 1 (BCR-ABL1) oncoprotein represent an outstanding progress in chronic myeloid leukemia (CML), and long-term survival has become a reality. However, the majority of patients need to be treated during their entire life span; thus, outcome does not solely depend on treatment efficacy but also on how well therapy is tolerated. TKIs have an overall favorable safety profile in clinical practice. Although many patients may encounter adverse events, these usually occur early after treatment initiation, are mild to moderate in intensity and resolve spontaneously, or are easily controlled with adequate supportive care. Whenever treatment interruption is necessary, re-exposition to the same TKI or switch to an alternative TKI is successful in the majority of the cases. However, long-term safety issues have not been fully elucidated at present, especially for new-generation TKIs. Recent evidence has emerged that these new agents may sometimes impinge on vital organs such as the heart and lung in an irreversible fashion especially when comorbidities are present; thus, decision regarding of which TKI should be used must take into account disease-related, TKI-related, and patient-related variables. The purpose of this article is to provide an up-to-date review of common adverse events associated with TKIs and how these events may be optimally managed.
Keywords Chronic myeloid leukemia . Tyrosine kinase inhibitors
D. Rea (*) Service d’Hématologie Adulte, Hôpital Saint-Louis, AP-HP, 1, avenue Claude Vellefaux, 75475 Paris Cedex 10, France e-mail: [email protected]
Introduction ATP-competitive tyrosine kinase inhibitors (TKIs) targeting the breakpoint cluster region-Abelson 1 (BCR-ABL1) oncoprotein have revolutionized the prognosis of patients suffering from chronic myeloid leukemia (CML). Before the introduction of this class of drugs into the therapeutic arsenal against CML, the disease usually progressed within a few years to a rapidly fatal blast crisis. Nowadays, when TKI treatment is addressed appropriately, patients diagnosed with chronic phase (CP) CML can expect a near-to-normal life expectancy [1, 2]. Nonetheless, TKIs are considered as nondefinitively curative and current recommendation is to administer treatment daily in a continuous fashion and indefinitely [3]. As a consequence, high-quality treatment and care must not only integrate optimal disease control, but also management of adverse events and long-term treatment tolerability. Imatinib was licensed for CML after failure of prior interferon-alpha therapy in 2001 and became the gold standard for newly diagnosed CML in all phases in 2002 [4]. Since then, dasatinib, nilotinib, bosutinib, and ponatinib, four new-generation TKIs with greater potency for the BCR-ABL1 oncoprotein than imatinib, also active against a wide range of imatinib-resistant ABL1 kinase domain mutant clones, have expanded therapeutic options. Dasatinib was approved in 2006 for CML in all phases after resistance or intolerance to imatinib and in 2010 for newly diagnosed CP-CML [5–7]. Nilotinib was approved for CP- or accelerated phase CML after imatinib failure in 2007 and is licensed for newly diagnosed CP-CML since 2010 [8, 9]. Bosutinib is indicated since 2012 for CML in all phases in patients previously treated with at least one TKI and for whom imatinib, nilotinib, and dasatinib are not considered appropriate options [10]. Ponatinib has received marketing authorization for use in patients with all phases CML and resistance or intolerance to dasatinib or nilotinib and for whom subsequent treatment with
S150
imatinib is not clinically appropriate, or who have the gatekeeper BCR-ABL1 T315I mutation [11]. These five TKIs target the ATP-binding site of BCR-ABL1 and exert their antileukemic effect through the inhibition of the catalytic activation of the tyrosine kinase. They also bind to other protein kinases and non-kinases and may have additional mechanisms of action which are not completely understood. Imatinib and nilotinib inhibit platelet-derived growth factor receptor (PDGF-R) and c-KIT. Nilotinib also blocks the DDR1 kinase and the oxidoreductase NQO2 [12]. Dasatinib is a dual SRC/ABL inhibitor as well as an inhibitor of the PDGF-R, c-KIT, and ephrin receptor [13]. Bosutinib is a potent SRC and ABL inhibitor; it has many other targets such as CAMK2G and STE20 and does not inhibit PDGF-R and c-KIT [13]. Besides BCR-ABL1, ponatinib has been shown to inhibit FLT3, RET, c-KIT, and the members of the FGF-R, PDGF-R, and vascular endothelial growth factor receptor (VEGF-R) families of kinases [14]. Thus, these TKIs are not simply directed at leukemic cells and their use is associated with a wide variety of on- and off-target adverse events. In addition, they are all CYP3A4 substrates and have relevant drug interactions that can aggravate toxicities. Finally, TKI safety is also influenced by comorbidities as demonstrated in retrospective studies [15]. The purposes of this article are to provide an overview of adverse events related to the use of TKIs and to discuss shortand long-term clinical management, focusing on patients with CP-CML.
Myelosuppression Myelosuppression usually occurs soon after treatment initiation and recovery is rapid. Rather than a toxic effect on normal hematopoiesis, early myelosuppression may reflect a reduced reserve or a delayed recovery of normal hematopoietic stem cells present at diagnosis. In patients with newly diagnosed CP-CML treated with first-line imatinib at 400 mg QD in the IRIS trial, incidences of all-grade neutropenia, thrombocytopenia, and anemia by 12 months were 60.8, 56.6, and 44.6 %, respectively, and those of grades 3–4 were 14.3, 7.8, and 3.1 %, respectively [4]. At later time points, newly occurring or worsening cytopenias were rare [16]. In patients with newly diagnosed CP-CML in the ENESTnd trial, cytopenias were less frequent in the nilotinib 300 mg BID arm than with 400 mg QD of imatinib. The incidences of all-grade neutropenia, thrombocytopenia, and anemia by 12 months were 43, 48, and 38 %, respectively, and those of grades 3–4 were 12, 10, and 3 %, respectively [9]. First-line dasatinib in CP-CML at 100 mg QD in the DASISION study was more hematotoxic than imatinib at 400 mg QD. The incidences of all-grade and grade 3–4 neutropenia, thrombocytopenia, and anemia by 12 months were, 65, 70 and 90 %, and 21, 19 and 10 %,
Ann Hematol (2015) 94(Suppl 2):S149–S158
respectively [7]. Cytopenias may also occur in patients in whom TKI treatment is changed due to resistance or intolerance to prior TKIs and tend to be more severe than in the firstline setting [6, 8, 10, 11]. Although cytopenias with severe clinical consequences are rare in CP-CML, it is necessary to monitor blood cell counts weekly during the first month of treatment or until normalization, monthly during months 2 and 3, and then every 3 months unless otherwise indicated. In case of grade 1–2 cytopenias, interruption or dose reduction of TKIs are not necessary. In case of neutropenia or thrombocytopenia of grades 3–4, treatment may be interrupted until resolution and resumed at the same dose (Table 1). Long-lasting and recurrent cytopenias resulting in prolonged or repeated treatment interruptions and dose reductions may compromise TKI efficacy [17]. In these situations, supportive care with myeloid growth such as recombinant erythropoietin or granulocyte-stimulating factor may be helpful although these agents are not approved in this indication, and thrombopoietin receptor agonists have not been evaluated in CML [18, 19]. A change in TKI therapy may also be envisaged. However, hematologic crossintolerance between TKIs cannot be ruled out [20]. Late development of severe cytopenias is rather unusual and warrants investigations in search of progression to advanced phase CML, myelodysplasia, or other diseases.
Dermatologic adverse events Dermatologic adverse events are most of the time mild to moderate, arise during the first months of therapy, and are self-limited. Occurrence and severity are usually dose-related, and TKI treatment may be pursued in most cases, arguing in favor of direct toxic pharmacological effects rather than immunogenic or allergic mechanisms. Skin rashes induced by imatinib usually consist in maculopapular eruptions. Other patterns have been reported such as pigmentary changes, photosensitization, lichenoid reactions, psoriasiform eruptions, pseudoporphyria, exanthematous pustulosis, neutrophilic dermatosis, panniculitis, and Stevens-Johnson syndrome [21, 22]. In patients with newly diagnosed CP-CML treated with imatinib at 400 mg QD in the IRIS study, all-grade and grade 3–4 cutaneous rashes by 12 months were reported in 33.9 and 2 % of patients, respectively [4]. With nilotinib, perifollicular hyperkeratotic and erythematous maculopapular eruptions occur frequently. Incidences by 12 months of all-grade and grade 3–4 cutaneous rashes were 31 and
REVIEW ARTICLE
Management of adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukemia Delphine Rea
Received: 4 August 2014 / Accepted: 7 October 2014 # Springer-Verlag Berlin Heidelberg 2015
Abstract Tyrosine kinase inhibitors (TKIs) targeting the breakpoint cluster region-Abelson 1 (BCR-ABL1) oncoprotein represent an outstanding progress in chronic myeloid leukemia (CML), and long-term survival has become a reality. However, the majority of patients need to be treated during their entire life span; thus, outcome does not solely depend on treatment efficacy but also on how well therapy is tolerated. TKIs have an overall favorable safety profile in clinical practice. Although many patients may encounter adverse events, these usually occur early after treatment initiation, are mild to moderate in intensity and resolve spontaneously, or are easily controlled with adequate supportive care. Whenever treatment interruption is necessary, re-exposition to the same TKI or switch to an alternative TKI is successful in the majority of the cases. However, long-term safety issues have not been fully elucidated at present, especially for new-generation TKIs. Recent evidence has emerged that these new agents may sometimes impinge on vital organs such as the heart and lung in an irreversible fashion especially when comorbidities are present; thus, decision regarding of which TKI should be used must take into account disease-related, TKI-related, and patient-related variables. The purpose of this article is to provide an up-to-date review of common adverse events associated with TKIs and how these events may be optimally managed.
Keywords Chronic myeloid leukemia . Tyrosine kinase inhibitors
D. Rea (*) Service d’Hématologie Adulte, Hôpital Saint-Louis, AP-HP, 1, avenue Claude Vellefaux, 75475 Paris Cedex 10, France e-mail: [email protected]
Introduction ATP-competitive tyrosine kinase inhibitors (TKIs) targeting the breakpoint cluster region-Abelson 1 (BCR-ABL1) oncoprotein have revolutionized the prognosis of patients suffering from chronic myeloid leukemia (CML). Before the introduction of this class of drugs into the therapeutic arsenal against CML, the disease usually progressed within a few years to a rapidly fatal blast crisis. Nowadays, when TKI treatment is addressed appropriately, patients diagnosed with chronic phase (CP) CML can expect a near-to-normal life expectancy [1, 2]. Nonetheless, TKIs are considered as nondefinitively curative and current recommendation is to administer treatment daily in a continuous fashion and indefinitely [3]. As a consequence, high-quality treatment and care must not only integrate optimal disease control, but also management of adverse events and long-term treatment tolerability. Imatinib was licensed for CML after failure of prior interferon-alpha therapy in 2001 and became the gold standard for newly diagnosed CML in all phases in 2002 [4]. Since then, dasatinib, nilotinib, bosutinib, and ponatinib, four new-generation TKIs with greater potency for the BCR-ABL1 oncoprotein than imatinib, also active against a wide range of imatinib-resistant ABL1 kinase domain mutant clones, have expanded therapeutic options. Dasatinib was approved in 2006 for CML in all phases after resistance or intolerance to imatinib and in 2010 for newly diagnosed CP-CML [5–7]. Nilotinib was approved for CP- or accelerated phase CML after imatinib failure in 2007 and is licensed for newly diagnosed CP-CML since 2010 [8, 9]. Bosutinib is indicated since 2012 for CML in all phases in patients previously treated with at least one TKI and for whom imatinib, nilotinib, and dasatinib are not considered appropriate options [10]. Ponatinib has received marketing authorization for use in patients with all phases CML and resistance or intolerance to dasatinib or nilotinib and for whom subsequent treatment with
S150
imatinib is not clinically appropriate, or who have the gatekeeper BCR-ABL1 T315I mutation [11]. These five TKIs target the ATP-binding site of BCR-ABL1 and exert their antileukemic effect through the inhibition of the catalytic activation of the tyrosine kinase. They also bind to other protein kinases and non-kinases and may have additional mechanisms of action which are not completely understood. Imatinib and nilotinib inhibit platelet-derived growth factor receptor (PDGF-R) and c-KIT. Nilotinib also blocks the DDR1 kinase and the oxidoreductase NQO2 [12]. Dasatinib is a dual SRC/ABL inhibitor as well as an inhibitor of the PDGF-R, c-KIT, and ephrin receptor [13]. Bosutinib is a potent SRC and ABL inhibitor; it has many other targets such as CAMK2G and STE20 and does not inhibit PDGF-R and c-KIT [13]. Besides BCR-ABL1, ponatinib has been shown to inhibit FLT3, RET, c-KIT, and the members of the FGF-R, PDGF-R, and vascular endothelial growth factor receptor (VEGF-R) families of kinases [14]. Thus, these TKIs are not simply directed at leukemic cells and their use is associated with a wide variety of on- and off-target adverse events. In addition, they are all CYP3A4 substrates and have relevant drug interactions that can aggravate toxicities. Finally, TKI safety is also influenced by comorbidities as demonstrated in retrospective studies [15]. The purposes of this article are to provide an overview of adverse events related to the use of TKIs and to discuss shortand long-term clinical management, focusing on patients with CP-CML.
Myelosuppression Myelosuppression usually occurs soon after treatment initiation and recovery is rapid. Rather than a toxic effect on normal hematopoiesis, early myelosuppression may reflect a reduced reserve or a delayed recovery of normal hematopoietic stem cells present at diagnosis. In patients with newly diagnosed CP-CML treated with first-line imatinib at 400 mg QD in the IRIS trial, incidences of all-grade neutropenia, thrombocytopenia, and anemia by 12 months were 60.8, 56.6, and 44.6 %, respectively, and those of grades 3–4 were 14.3, 7.8, and 3.1 %, respectively [4]. At later time points, newly occurring or worsening cytopenias were rare [16]. In patients with newly diagnosed CP-CML in the ENESTnd trial, cytopenias were less frequent in the nilotinib 300 mg BID arm than with 400 mg QD of imatinib. The incidences of all-grade neutropenia, thrombocytopenia, and anemia by 12 months were 43, 48, and 38 %, respectively, and those of grades 3–4 were 12, 10, and 3 %, respectively [9]. First-line dasatinib in CP-CML at 100 mg QD in the DASISION study was more hematotoxic than imatinib at 400 mg QD. The incidences of all-grade and grade 3–4 neutropenia, thrombocytopenia, and anemia by 12 months were, 65, 70 and 90 %, and 21, 19 and 10 %,
Ann Hematol (2015) 94(Suppl 2):S149–S158
respectively [7]. Cytopenias may also occur in patients in whom TKI treatment is changed due to resistance or intolerance to prior TKIs and tend to be more severe than in the firstline setting [6, 8, 10, 11]. Although cytopenias with severe clinical consequences are rare in CP-CML, it is necessary to monitor blood cell counts weekly during the first month of treatment or until normalization, monthly during months 2 and 3, and then every 3 months unless otherwise indicated. In case of grade 1–2 cytopenias, interruption or dose reduction of TKIs are not necessary. In case of neutropenia or thrombocytopenia of grades 3–4, treatment may be interrupted until resolution and resumed at the same dose (Table 1). Long-lasting and recurrent cytopenias resulting in prolonged or repeated treatment interruptions and dose reductions may compromise TKI efficacy [17]. In these situations, supportive care with myeloid growth such as recombinant erythropoietin or granulocyte-stimulating factor may be helpful although these agents are not approved in this indication, and thrombopoietin receptor agonists have not been evaluated in CML [18, 19]. A change in TKI therapy may also be envisaged. However, hematologic crossintolerance between TKIs cannot be ruled out [20]. Late development of severe cytopenias is rather unusual and warrants investigations in search of progression to advanced phase CML, myelodysplasia, or other diseases.
Dermatologic adverse events Dermatologic adverse events are most of the time mild to moderate, arise during the first months of therapy, and are self-limited. Occurrence and severity are usually dose-related, and TKI treatment may be pursued in most cases, arguing in favor of direct toxic pharmacological effects rather than immunogenic or allergic mechanisms. Skin rashes induced by imatinib usually consist in maculopapular eruptions. Other patterns have been reported such as pigmentary changes, photosensitization, lichenoid reactions, psoriasiform eruptions, pseudoporphyria, exanthematous pustulosis, neutrophilic dermatosis, panniculitis, and Stevens-Johnson syndrome [21, 22]. In patients with newly diagnosed CP-CML treated with imatinib at 400 mg QD in the IRIS study, all-grade and grade 3–4 cutaneous rashes by 12 months were reported in 33.9 and 2 % of patients, respectively [4]. With nilotinib, perifollicular hyperkeratotic and erythematous maculopapular eruptions occur frequently. Incidences by 12 months of all-grade and grade 3–4 cutaneous rashes were 31 and
