You are here

Treatment Strategies of Chronic Myeloid Leukaemia (CML) in the Senior Patient

Chapter 10 - Management of Chronic Myeloproliferative Neoplasia (MPN) in Elderly Patients

Nowadays, elderly patients generally get access to targeted therapeutics. Imatinib is most frequently used in this patient population. Only limited data on second or even third generation Tyrosine kinase inhibitors (TKI) in elderly patients are available. Recent data from large multicentre studies from the German CML study group, as well as the Italian GIMEMA CML Working Party, have addressed this particular issue in more detail.

Efficacy of Imatinib in Senior Patients

Both studies compared patients enrolled in phase III trials, below 65 years of age versus those patients ³65 years of age. The median daily dose was not different between both groups. In the German CML study IV, older patients achieved complete cytogenetic responses (CCR) and major molecular responses significantly later than younger patients (12.3 vs. 10.7 months and 24.1 vs. 15.9 months, respectively). Interestingly, when looking at the German data in more detail, the group recently reported that patients >65 years of age may have a particular benefit from higher imatinib doses (i.e. 800 mg qd). Elderly patients treated with high dose imatinib, respond similarly to younger high-dose imatinib-treated patients. In contrast, the Italian cooperative group (which also included patients receiving 800 mg daily, which is not the standard dose) was not able to detect any statistically significant differences in response rates between young and elderly CML patients (cumulative CCR rate 88 vs. 84% and 82 vs. 81%, respectively). The rate of treatment failures, progression and rate of CML-related deaths were also comparable, according to the European LeukemiaNet (ELN) guidelines.

The German CML IV trial also provided important insights regarding co-morbidities in CML patients, and how they may be drastically underestimated. As co-morbidities are more frequent in elderly patients, this topic is of particular importance for senior patients. Susanne Saussele and her co-workers demonstrated that rating the co-morbidity burden by means of the Charlson Co-Morbidity Index, allows survival predictions (during treatment with a TKI) to be made. Importantly, co-morbidity burden does not affect the response rate, but it does affects the likelihood of a patient dyeing from reasons not related to CML. It is therefore, of the utmost importance to focus (in addition to CML therapy) on the optimal management of co-morbidities. This data is supported by the Italian GIMEMA group. They demonstrated, in a large retrospective analysis that included 2784 adult CML patients, that CML-specific survival is comparable between different age groups (i.e. 18-29 vs. 30-59 vs >60 years). However, when focusing on overall-survival analyses, they also demonstrated a clearly lower survival rate in elderly patients, which nicely fits with the data from the German CML IV trial.

Efficacy of Second Generation TKI in Senior Patients

Similar to imatinib (at least for the higher dose), the other second generation TKIs (dasatinib, nilotinib and bosutinib) are all equally effective when comparing response data from elderly with younger CML patients. Data from the BELA, ENESTnd and DASISION studies all provide clear evidence that age is not a factor that predicts lower response rates. Thus all second generation TKIs can be considered for treatment of elderly CML patients. It should be noted that, in contrast to nilotinib and dasatinib, bosutinib is not approved for first line therapy. However, it is of particular importance (due to their specific side effect profile) that the optimal TKI selection is based on the co-morbidity burden, which an individual presents with, for example:

  • Physicians should use nilotinib carefully in patients with pre-existing arteriosclerosis, as the compound increases the risk of peripheral artery occlusive disease (PAOD). In addition, nilotinib also affects metabolic parameters, such as lipids and blood sugar. Therefore, patients with diabetes and hyperlipidaemia have to be carefully monitored during nilotinib therapy.
  • Dasatinib, may induce pulmonary hypertension and pleural effusion. Therefore, in patients with pre-existent pulmonary dysfunction it may not be the drug of choice.
  • Bosutinib, mainly affects the gastrointestinal tract by inducing diarrhoea, and the liver by inducing elevated liver parameters. Bosutinib should (if possible) be avoided in patients with pre-existing GI or hepatic diseases.

Generally, in elderly patients, personalised selection of the most appropriate TKI is of the utmost importance to guarantee long-term safety and also compliance. When Mutations are detected and only one second generation TKI is appropriate, surveillance and optimal side effect management are important to allow continued long-term therapy, and minimise time periods between stoppages.

Toxicity of Imatinib in Senior Patients

In the German trial, a higher proportion of older patients discontinued treatment (12.4% vs. 8.4%). Various differences were observed in the profile of grade III/IV adverse events (AEs). Haematologic AEs were more common in older patients compared to the younger patient cohort (leukopenia <2000 leukocytes/µl 4.2% vs. 2.8% and thrombocytopenia <50000/µl 4.2% vs. 2.8%, respectively). Most non-haematologic AEs were not different between the two age groups (gastrointestinal 29% vs. 28%, myalgia 17% vs. 16%). Oedaema and neurological symptoms were even higher in younger than older patients (17% vs. 23% and 6% vs. 15%, respectively), whereas dermatologic side effects were more frequent in the older patient population (17% vs. 13%).

Toxicity of Second Generation TKIs in Senior Patients

In the DASISION trial tolerability of dasatinib was evaluated in a post-hoc analysis grouping patients in the following age cohorts: <46, 46-65 and >65 years of age. Dasatinib exerts higher rates of fluid retention (13 vs 25 vs 35%), nausea/vomiting (10 vs 8 vs 35%) and rash (9 vs 12 vs 20%, respectively). Other haematological and non-haematological toxicities were not affected by age. However, age itself may not be the sole factor determining tolerability, as age is linked to co-morbidity. A report presented at ASH 2010 by Khoury and colleagues supports this idea, by demonstrating that toxicities are linked to a higher co-morbidity burden. Thus, dasatinib is effective and safe also in older patients.

In the nilotinib clinical trials, approximately 30% of patients were older than 65 years of age. No major differences in safety were observed in patients >65 years of age compared to patients <65 years. Bosutinib, another second generation TKI, was tested in Phase 1-3 clinical trials. In those trials up to 20% were more than 65 years of age with 4% older than 75 years of age. No overall differences in safety or effectiveness could be observed between the younger and elderly patients. Other reported clinical experiences, have not identified any differences in responses between elderly and younger patients.

« Previous Page Next Page »