Replies to post #167861 on Biotech Values

[biomaven0]

And here is the extract of the paper by Tefferi I posted a bit back on SI:

Two papers in Leukemia recently reported the prevalence of PAOD in tyrosine kinase inhibitor (TKI)-treated patients with chronic myeloid leukemia (CML)1, 2 Conflict of interest statements declared ‘editorial assistance’ from Novartis pharmaceuticals (manufacturer of nilotinib and imatinib) for one of the reports2 My comments will focus on the other report by Kim et al.,1 who prospectively screened 129 CML patients for pathological PAOD, using ankle-brachial index (ABI). Pathological PAOD (defined by <0.9 ABI) was documented in 6.3% of patients receiving imatinib as first-line therapy, 26% receiving nilotinib as first-line therapy and 35.7% receiving nilotinib as second-line therapy (P<0.05). Clinically overt PAOD was seen in five patients, all of whom were exposed to nilotinib therapy. The detrimental effect of nilotinib was evident despite a shorter duration of treatment (median 30 vs 102 months for imatinib). Cardiovascular risk factors were similar between the two groups.

In the second part of their study, Kim et al.1 reviewed 27 cases of TKI treatment-associated overt PAOD accrued from several collaborating centers and discovered that all but one of these patients were exposed to nilotinib therapy, including 20 patients who were receiving nilotinib as first- or second-line treatment of CP-CML. These events were severe enough to require percutaneous transluminal angioplasty in 33.3% of the cases, stent implantation in 22.2%, amputation in 22.2% and surgery in 18.5%.

The observations from Kim et al.1 are consistent with those of earlier3, 4 and more recent5, 6 reports associating nilotinib with accelerated atherosclerosis. Aichberger et al.3 reported a 33% incidence of PAOD, myocardial infarction, spinal infarction or subdural hematoma, among 24 CML patients treated with nilotinib. Tefferi et al.4 described two patients who experienced sudden death or severe PAOD/CAD; continued nilotinib treatment in the latter patient was associated with rapid progression of intra- and extracranial atherosclerosis leading to stroke.6 Most recently, Levato et al.5 reported their single-institution experience with 82 CML patients treated with imatinib (n=55) or nilotinib (n=27); four (14.8%) nilotinib-treated patients developed severe PAOD or other vascular disease. In contrast, none of the 55 imatinib-treated patients developed PAOD and only one experienced myocardial infarction, despite a longer median duration of treatment with imatinib (79.5 months) vs nilotinib (21.5 months).

Taken together, the above observations strongly implicate nilotinib therapy as being proatherogenic.