What inspired you to study why some patients with chronic myeloid leukemia respond well to treatment while others develop drug resistance?
There are two unanswered questions in Chronic Myeloid Leukemia (CML):
- Why do some patients develop TKI (Tyrosine Kinase Inhibitor) resistance?
- Why do half of the patients with Deep Molecular Response relapse during Treatment-free periods?
These two burning questions have intrigued scientists and clinicians for the last few years. TKIs block the activated tyrosine kinase produced by the BCR::ABL1 translocation, or Philadelphia chromosome, that gives rise to CML. Some patients develop resistance even to the latest-generation agents. Half of them are found to have Tyrosine Kinase Domain (TKD) mutations, mostly at the sites where these drugs attach to ABL1.
However, we still do not know the reason for resistance or treatment failure in the majority of our patients. Major CML working groups worldwide are pursuing this. India has a lot of CML patients, and unlike the western population, where CML is mostly the disease of the elderly, ours are mostly young and middle-aged adults. We need to explore more to find the answers, especially in our population.
For readers who may not be familiar with the disease, what is chronic myeloid leukemia, and how has modern treatment improved patients’ lives?
Let us break down each term of Chronic Myeloid Leukemia to understand it better.
Chronic means long-standing or slow-growing.
Myeloid refers to the myeloid lineage of cells, which gives rise to Granulocytes (neutrophils, eosinophils, and Basophils), as well as Monocytes, erythrocytes, and Megakaryocytes.
Leukemia is derived from Greek terms Leukos, meaning “white,” and Haima, meaning “blood”. In the mid-1800s, German pathologist Rudolf Virchow coined the term “Leukemia” to denote an increase in immature white blood cell precursors in the peripheral blood.
Now, CML arises from reciprocal translocation of the long arms of chromosomes 9 and 22, fusing BCR with ABL. The resulting BCR::ABL fusion gene sits on a shortened chromosome 22, also called the Philadelphia Chromosome, and encodes a constitutively active tyrosine kinase — an enzyme that promotes continuous cell division and prevents apoptosis, or programmed cell death. As per the latest WHO guideline, CML has two phases: chronic, and blast crisis, where increased blasts give acute leukemia-like features.
CML has been the prototype for all malignancies. Not only was it the first malignancy to have a disease-defining mutation, but it also became the first malignancy to have a targeted therapy. That drug was featured on the cover of TIME magazine. From extended chemotherapy, CML patients began getting their disease controlled — though not cured — by a single oral tablet, which was revolutionary at the turn of the millennium. The quality of life improved drastically and with minimal expenses.
Why does treatment sometimes stop working even when patients initially respond well to therapy?
It has been observed 20%–30% of CML patients develop resistance or treatment failure. TKD (tyrosine kinase domain) mutations are mainly discovered as causes of secondary resistance. The search for mutations that could lead to primary resistance to TKIs is ongoing. CML working groups from the US and Australia have found promising results in the form of somatic mutations that could answer all the questions. We still do not have clear answers for all our patients as to why they develop resistance or go on to develop blast crisis even while on treatment.
Your study focuses on genetic testing. In simple terms, how can changes in a patient’s leukemia cells help doctors predict treatment response?
Today, we have three generations of TKIs and some new lineage drugs, like Asciminib, which is a “STAMP” inhibitor. STAMP means specifically targeting the ABL Myristoyl Pocket, which works by binding to a specific Myristoyl pocket, effectively overcoming resistance to traditional therapies. However, we need to know the type of TKD mutation present so that an appropriate drug can be provided to the patient.
For example, T315I is the most common TKD mutation encountered in our country and across Southeast Asia. These patients have historically responded only to the third-line TKI, i.e., Ponatinib, though Asciminib now offers another option. Similarly, we have mutations that guide which second-generation TKIs, such as Bosutinib, Dasatinib, or Nilotinib, would be effective in them.
How could next-generation sequencing (NGS) improve the way doctors choose treatments for patients with chronic myeloid leukemia?
As stated earlier, we are still searching for the reason for TKI resistance. Next-generation sequencing has opened up a vast avenue for us to investigate this gap. Somatic mutations, particularly in genes involved in epigenetic regulation, myeloid transcription, and signaling, have been found to influence disease behavior, such as blast crisis, and to occur in high-risk or TKI-resistant disease.
In the past, sequencing was a limiting factor in disease monitoring, but nowadays it is doable. We can run broad targeted myeloid panels ours covered 135 genes, detecting Single Nucleotide Variants (SNVs), Insertions and Deletions (Indels), and Copy Number Variants (CNVs). This will help us better understand the disease biology. It has been observed that Myeloid Neoplasms share a substantial repertoire of these somatic mutations, which have a long-term effect on disease progression, patients’ response to treatment, and overall survival.
What are the biggest challenges in using genetic testing routinely in clinical practice, especially in countries with limited healthcare resources?
The biggest challenge would be the cost and availability. These assays are available in metropolitan centers and larger tertiary hospitals, but the number of labs offering these services remains limited. Centers like ours struggle with the financial aspect, but in the near future, the panels will be available at a lower cost. Technology is advancing rapidly, and the main cost typically lies in library preparation and bioinformatics management.
Another challenge is the difficult decision of what to do with the result. A panel that reports a variant of uncertain significance, or a clonal hematopoiesis variant misread as a driver, can cause more harm than no test at all if it triggers an unnecessary change of therapy. So, caution is warranted in interpreting these results and modifying the further treatment of the patients.
Since the overall utility is restricted up front, a stratified approach is both good practice and cost-effective. We have described this in one of our articles, where we suggested when NGS should be done, when clinicians can consider it, and when we should avoid it altogether.
Looking ahead, how do you think genetic testing and personalized medicine will change the future of leukemia treatment?
Data on somatic mutations in CML are increasing worldwide, and the European LeukemiaNet (ELN) has addressed this in its latest update. We would make three predictions.
First, cost will stop being the main limit. Once panels are cheap and available beyond metro cities, the real constraint becomes interpretation, which needs reporting standards and trained clinicians. This is why we have argued for a minimum reporting checklist flagging variants that may reflect clonal hematopoiesis.
Second, we expect baseline profiling to be reserved for a defined high-risk subgroup, once prospective data show who benefits. We do not know that yet, and should not test first and rationalize afterward.
Third, and most importantly, genomics may help answer the treatment-free remission question — identifying in advance who can safely stop therapy. For young and middle-aged adults facing decades of daily medication, that would be a major change.
More extensive, multicentric studies are needed, and within the next decade we might find CML paving the way in cancer management and follow-up yet again.
