Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML

Abstract

The second generation BCR/ABL kinase inhibitor nilotinib is increasingly used for the treatment of imatinib‐resistant chronic myeloid leukemia (CML). So far, nilotinib is considered a well‐tolerated drug with little if any side effects, although an increase in the fasting glucose level has been reported. We examined a series of 24 consecutive CML patients treated with nilotinib in our center for the development of non‐hematologic adverse events. Three of these 24 CML patients developed a rapidly progressive peripheral arterial occlusive disease (PAOD) during treatment with nilotinib. In all three cases, PAOD required repeated angioplasty and/or multiple surgeries within a few months. No PAOD was known before nilotinib‐therapy in these patients, although all three had received imatinib. In two patients, pre‐existing risk factors predisposing for PAOD were known, and one of them had developed diabetes mellitus during nilotinib. In the other 21 patients treated with nilotinib in our center, one less severe PAOD, one myocardial infarction, one spinal infarction, one subdural hematoma, and one sudden death of unknown etiology were recorded. In summary, treatment with nilotinib may be associated with an increased risk of vascular adverse events, including PAOD development. In a subgroup of patients, these events are severe or even life‐threatening. Although the exact mechanisms remain unknown, we recommend screening for pre‐existing PAOD and for vascular risk factors such as diabetes mellitus in all patients before starting nilotinib and in the follow up during nilotinib‐therapy. Am. J. Hematol. 2011. © 2011 Wiley‐Liss, Inc.

Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study

“…Imatinib is recognized as one of the best and safest first line treatments for chronic phase CML [5][6][7] and is associated with a normal or near-normal life expectancy among treated patients [8,9], even at diagnosis [10]. Imatinib induces complete cytogenetic response (CCyR) in up to 86% of CML patients, while major molecular responses (MMR) develop in 33-90% of the patients according to treatment duration [10,11].…”

Chronic myeloid leukemia: Second‐line drugs of choice

“…Cardiovascular events, including peripheral arterial vascular occlusive disease (PAOD, have been initially identified in second and third line treated patients [62][63][64], and subsequently reported in clinical trials in patients treated with first-line nilotinib therapy (median duration of therapy: 60 months), as well as in post-marketing reports. Cardiovascular events from clinical trials have included ischemic heart disease-related events, peripheral arterial occlusive disease (PAOD), and ischemic cerebrovascular events in a dose dependent [29,36] Monitoring Assessment of disease-related and vascular risks prior to commencement of therapy Risk factor modification for patients with pre-existing atherosclerosis Management Dose interruption or discontinuation Cardiac effects [29,36] Monitoring Monitor for signs consistent with heart failure Regularly monitor blood pressure during the course of therapy Specialist referral for patients at high risk for cardiovascular effects Management Dose modification or discontinuation for management of heart failure Medical control of blood pressure, as well as through dose modifications manner.…”

Next Generation Therapy in Chronic Myeloid Leukemia

“…Now, the second generation TKIs, such as Dasatinib and Nilotinib, have appeared. A unique spectrum of adverse events has occurred and been reported for both these TKIs [3,4]. For Dasatinib-treated patients, the occurrence of pleural effusion has been a clinical challenge, especially when pleural effusion becomes recurrent or is accompanied by pericardial effusion, pulmonary hypertension, or an infection.…”

“…Other non-hematologic adverse events of Nilotinib include diarrhea, folliculitis-like skin rash, and bleeding. There are a few reports of severe peripheral arterial occlusive disease (PAOD) and other vascular occlusive events (infarction) in patients receiving Nilotinib [3,4]. Several of these patients developed a rapidly progressive and highly resistant form of PAOD after switching from Imatinib to Nilotinib [3,4].…”

“…There are a few reports of severe peripheral arterial occlusive disease (PAOD) and other vascular occlusive events (infarction) in patients receiving Nilotinib [3,4]. Several of these patients developed a rapidly progressive and highly resistant form of PAOD after switching from Imatinib to Nilotinib [3,4]. The question is whether patients, who had a complete molecular response (CMR or MCyR) to Imatinib or Imatinib in combination with Interferon, could safely stop drug treatment?…”