Tomorrow We Need a Cure

September 22nd marks World CML Day and this year the motto has seen an important addition, from “today, together we are treated” to “Today, together we are treated, tomorrow we need a cure”.

This is representative of how the global community of CML patients are currently, on the whole, treated very well, but there is a new target in sight for CML patients – a cure.

Each cell within the human body contains 23 pairs of chromosomes. The chromosomes contain all the genetic information that control the functioning and appearance of the body.

It was discovered in the late 1960’s that over 90% of CML patients have an aberrant chromosome (named the Philadelphia chromosome) formed by the joining of sections from chromosome 22 and chromosome 9. The chromosomes have joined at very specific points, bringing together the BCR gene on chromosome 22 and ABL gene on chromosome 9 to form one new gene, BCR-ABL. CML patients who have the chromosome rearrangement are Philadelphia positive (Ph+).

The protein formed from this gene is called a tyrosine-kinase. The protein is produced ordinarily in healthy cells but this new version, formed by the joining of two genes, is oncogenic (cancer causing). It is for this reason, that tyrosine kinase inhibitor (TKI) drugs were developed for the treatment of CML. The first of these, Imatinib, was released in 1999 and within a few years became the first-line therapy due to the dramatic increase in long-term survival of patients.

The use of Imatinib sees complete haematological response in the majority of patients, meaning that no Ph+ cells are found within the blood. Furthermore, 60 to 80% of patients will have complete cytogenetic remission where the level of Ph+ cells in the bone marrow is below 1.5%.

Despite the success, around 1 in 3 patients will become resistant or are intolerant to the side effects. Therefore, a number of second-generation TKIs were developed that have slightly different targets to Imatinib. There are now 5 different TKI drugs available for patients and consequently, with daily oral tablets, the majority of CML patients will have normal life-span and be relatively symptom/side-effect free. Hence, “today, together we are treated”.

According to studies around half of patients will achieve major molecular response (MMR) after 12 months of treatment, which means that levels of Ph+ are below 0.1%. This is highly indicative of both long-term progression-free and event-free survival of patients. However, clinical guidance at the moment requires patients to remain on treatment, as they are unsure whether the cancer will return with removal of treatment or whether treatment-free remission (TFR) will be observed and maintained.

This is what researchers are now focussed on finding out. There are a range of different clinical trials currently ongoing that are observing the response to removal of TKI drugs. For example, ‘DESTINY’ is a trial studying the effect of halving the dose of Imatinib, Nilotinib or Sprycel for 12 months after MMR is achieved and then removing treatment altogether. Other studies include ‘ENESTfreedom’ where patients are recruited if they have been on Nilotinib for more than 2 years and have Ph+ levels of below 0.0032%. The patients are then observed on Nilotinib for one year and their treatment is removed if Ph+ levels are never higher than 0.01%. Patient’s treatment is restarted if loss of MMR (Ph+ >0.1%) is observed.

Nilotinib is, however, the only CML treatment that currently offers patient’s the opportunity to stop treatment outside of clinical trials. This means that for now the majority of the CML community will have to wait and see if results from clinical trials demonstrate long-term treatment-free remission (TFR). Indeed if this is the case, we must then begin to consider whether long-term remission equates to the cure for CML. So, there is a chance that “tomorrow” we may see a cure.

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