European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia

Abstract

Most reports on chronic myeloid leukaemia (CML) treatment with tyrosine kinase inhibitors (TKIs) focus on efficacy, particularly on molecular response and outcome. In contrast, adverse events (AEs) are often reported as infrequent, minor, tolerable and manageable, but they are increasingly important as therapy is potentially lifelong and multiple TKIs are available. For this reason, the European LeukemiaNet panel for CML management recommendations presents an exhaustive and critical summary of AEs emerging during CML treatment, to assist their understanding, management and prevention. There are five major conclusions. First, the main purpose of CML treatment is the antileukemic effect. Suboptimal management of AEs must not compromise this first objective. Second, most patients will have AEs, usually early, mostly mild to moderate, and which will resolve spontaneously or are easily controlled by simple means. Third, reduction or interruption of treatment must only be done if optimal management of the AE cannot be accomplished in other ways, and frequent monitoring is needed to detect resolution of the AE as early as possible. Fourth, attention must be given to comorbidities and drug interactions, and to new events unrelated to TKIs that are inevitable during such a prolonged treatment. Fifth, some TKI-related AEs have emerged which were not predicted or detected in earlier studies, maybe because of suboptimal attention to or absence from the preclinical data. Overall, imatinib has demonstrated a good long-term safety profile, though recent findings suggest underestimation of symptom severity by physicians. Second and third generation TKIs have shown higher response rates, but have been associated with unexpected problems, some of which could be irreversible. We hope these recommendations will help to minimise adverse events, and we believe that an optimal management of them will be rewarded by better TKI compliance and thus better CML outcomes, together with better quality of life.

De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial

“…1 However, TKI therapy is not without adverse effects 2 and is expensive 3 . This has led to CML specialists and patients asking whether after a few years of TKI therapy, the disease may be sufficiently suppressed to permit treatment discontinuation.…”

“…during pregnancy 11 , such patients have not hitherto been formally studied in a stopping trial. In addition, TKI dose reduction in patients with good responses to TKI therapy but also troublesome adverse events can ameliorate these yet maintain deep molecular response 2 . We therefore questioned whether some patients who might experience molecular recurrence on stopping TKI might nevertheless have been able to safely decrease TKI treatment without an increase in tumour burden.…”

Dasatinib Reversibly Disrupts Endothelial Vascular Integrity by Increasing Non-Muscle Myosin II Contractility in a ROCK-Dependent Manner

“…Moreover, dasatinib has a unique half-life of only 3 to 4 hours, and the peak plasma concentration (around 100 nmol/L) is achieved already 1 to 2 hours after oral intake of the drug (3,4). Although dasatinib is very effective in the treatment of Phþ leukemias, patients display frequent adverse effects such as diarrhea, pleural effusion, lymphocytosis, thrombocytopenia, and increased risk of bleeding, which primarily involves the gastrointestinal tract (5)(6)(7). Most of these events subside if the treatment with dasatinib is withdrawn.…”

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“…The off-target effects of TKI and severe adverse drug reactions have been largely reported. Notwithstanding the fact that these side effects impair quality of life, some of them potentially might modify also overall and healthy life expectancy through TKI-related events like pulmonary arterial hypertension, pleural effusion or cardiovascular events [3]. In addition, use of TKI is forbidden in pregnant women due to malformative effects and children growth is also altered by TKI in pediatric CML cases.…”