Adverse Events Associated With TKIs

Anemia, neutropenia, and thrombocytopenia, common hematologic toxicities associated with TKIs, should be managed “with transient interruptions of TKI therapy and dose modifications,” according to the NCCN Guidelines for Chronic Myeloid Leukemia.2


Continue Reading

Non-hematologic adverse events are summarized for each of the TKIs below. All of the agents may cause embryofetal toxicity.

Imatinib

The most frequently reported adverse reactions associated with imatinib are edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain.

Cardiac dysfunction, severe hepatotoxicity, tumor lysis syndrome, and gastrointestinal perforations (some fatal), have also been reported.

Benign reversible skin hypopigmentation may occur. Some studies have identified hypophosphatemia and decreased bone mineral density with imatinib treatment, necessitating monitoring for bone health.2

Dasatinib

Among patients treated with dasatinib, pleural effusion occurs at a higher rate in those with CML-AP (50%) than with CML-BP (33%) or CML-AP (29%). In addition, reversible pulmonary arterial hypertension is a rare but serious adverse event.2

In newly diagnosed CML-CP, the most common adverse reactions are fluid retention and diarrhea and, in those with resistance or intolerance to prior imatinib therapy, diarrhea, headache, fatigue, dyspnea, skin rash, nausea, and musculoskeletal pain. Cardiac dysfunction, including QT prolongation, and tumor lysis syndrome have also been reported.9

Nilotinib

The prescribing information for nilotinib includes a black box warning for risk of QT interval prolongation and sudden deaths.10 Ischemic heart disease, peripheral arterial occlusive disease, and ischemic cerebrovascular events have been reported in patients with newly diagnosed CML-CP who have received nilotinib, as has pancreatitis and elevated serum lipase, hepatotoxicity, electrolyte abnormalities, tumor lysis syndrome, and fluid retention, including pericardial and pleural effusion.

Recent results from the Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Extending Molecular Responses (ENESTxtnd) study in patients with newly diagnosed CML-CP confirmed major molecular response in 81.0% of patients at 24 months, even among those with dose reductions due to adverse events, many of whom were successfully re-escalated.11

The study allowed dose escalation from 300 to 400 mg twice daily and dose re-escalation for those who had their dose reduced because of adverse events.

Bosutinib

Gastrointestinal, hepatic, and renal toxicity and fluid retention may occur with bosutinib treatment. The most common adverse reactions are diarrhea, nausea, rash, vomiting, abdominal pain, respiratory tract infections, pyrexia, liver test abnormalities, fatigue, cough, and headache.6

Ponatinib

The prescribing information for ponatinib includes a black box warning for arterial occlusion, venous thromboembolism, heart failure, and hepatotoxicity.8

Ocular toxicity, fluid retention, hypertension, pancreatitis, cardiac arrhythmias, tumor lysis syndrome, reversible posterior leukoencephalopathy syndrome, and compromised wound healing and gastrointestinal perforation may occur.

The most common adverse reactions are abdominal pain, rash, constipation, headache, dry skin, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, increased lipase, vomiting, myalgia, and extremity pain.

Other and Future Treatment for CML

Omacetaxine mepesuccinate, a cephalotaxine ester, was approved in 2012 for the treatment of adult patients with CML-CP or AP with resistance and/or intolerance to 2 or more TKIs. Its mechanism of action includes inhibition of protein synthesis and is independent of direct BCR-ABL binding.12

Dr Kantarjian noted other agents being studied for CML, including the allosteric inhibitor, asciminib (ABL001), which enables dual targeting of BCR-ABL1, and the novel SUN-K706, which targets T315I resistance in CML.13,14

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7-30
  2. NCCN guidelines: chronic myeloid leukemia, version 1.2018. National Comprehensive Cancer Network website. https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Updated July 26, 2017. Accessed August 2017.
  3. Milojkovic D, Apperley JF, Gerrard G, et al. Reponses to second-line tyrosine kinase inhibitors are durable: an intention-to-treat analysis in chronic myeloid leukemia patients. Blood. 2012;119:1828-43.
  4. NCCN evidence blocks: frequently asked questions. National Comprehensive Cancer Network website. https://www.nccn.org/evidenceblocks/pdf/EvidenceBlocksFAQ.pdf. Accessed July 2017.
  5. NCCN guidelines: chronic myeloid leukemia, version 2.2017. NCCN evidence blocks. National Comprehensive Cancer Network website. https://www.nccn.org/professionals/physician_gls/pdf/cml_blocks.pdf. Updated January 19, 2017. Accessed July 2017.
  6. Bosulif (prescribing information). Pfizer, Inc website. http://labeling.pfizer.com/ShowLabeling.aspx?id=884. Updated April 2017. Accessed July 2017.
  7. Gleevec (prescribing information). Novartis website. https://www.pharma.us.novartis.com/sites/ www.pharma.us.novartis.com/files/gleevec_tabs.pdf. Updated April 2017. Accessed July 2017.
  8. Inclusig (prescribing information). Ariad, Inc website. http://www.iclusig.com/pi. Updated November 2016. Accessed July 2017.
  9. Sprycel (prescribing information). Bristol-Myers Squibb website. http://packageinserts.bms.com/pi/pi_sprycel.pdf. Updated April 2017. Accessed July 2017.
  10. Tasigna (prescribing information). Novartis website. https://www.pharma.us.novartis.com/sites/ www.pharma.us.novartis.com/files/tasigna.pdf. Updated February 2017. Accessed July 2017.
  11. Hughes TP, Munhoz E, Aurelio Salvino M, et al. Nilotinib dose-optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENEXTxtnd. Br J Haematol. 2017 Jul 12. doi: 10.1111/bjh. 14829 [Epub ahead of print]
  12. Synribo (prescribing information). Teva Pharmaceuticals, Inc website. http://www.synribo.com/pdf/synribo_pi.pdf. Updated December 2015. Accessed July 2017.
  13. Wylie AA, Schoepfer J, Jahnke W, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature. 2017;543:733-7.
  14. NCE projects/anti-cancer. Sun Pharma Advanced Research Company website. http://www.sunpharma.in/anti-cancer.htm. Accessed July 2017.