About 1 in every 526 people in the U.S. will be diagnosed with chronic myeloid leukemia (CML) this year, but most of these people will achieve their normal life expectancy thanks to tyrosine kinase inhibitors (TKIs).
When it was approved in 2001, the first TKI drug transformed CML from a death sentence with a life expectancy of approximately six years to a livable chronic illness. But lifelong TKI treatment comes with costs: It places a significant financial burden on patients and payers, and the side effects can create challenges for hospitals as well as harm patients’ quality of life.
Recently, researchers found that the highly sensitive DNA quantification technique Droplet Digital PCR (ddPCR) could reliably determine when a patient can safely discontinue treatment.
TKIs: A savior and a burden
TKIs reverse a physiological imbalance that promotes the growth of cancer cells in the blood. An aberrant fusion gene called BCR-ABL1 produces a hyperactive tyrosine kinase protein that causes overgrowth of several blood cell types, including red and white blood cells. When these cancerous cells crowd out healthy cells, they can cause a range of systemic symptoms including anemia, infection, and blood clotting abnormalities.
TKIs counteract this effect by inhibiting the kinase, thereby inhibiting tumor growth. While TKIs have high therapeutic value, they are not always 100% effective, putting patients at risk of recurrence. To be safe, oncologists tend to keep patients on TKI therapy for longer than may be needed, sometimes for the rest of their life.
Treating cancer and preventing recurrence are the top priorities for an oncologist. But patients also need protection from the burdens of treatment, including side effects that can impact quality of life in several ways. For example, patients have reported severe side effects, especially after years of ongoing treatment.
Patients may become fatigued more easily, making it difficult to exercise or play sports. The treatment can cause diarrhea, forcing patients to think twice about participating in activities with limited bathroom access. Women on TKIs are advised not to get pregnant due to the increased risk of miscarriage.
The ongoing side effects can cause emotional strain and depression. Furthermore, ongoing TKI treatment is expensive, costing nearly $150,000 per year per patient. This high price tag puts financial pressure on uninsured patients as well as payers.
Overall, TKIs have shown incredible success in extending the lives of those living with CML. Still, patients, providers and payers can all benefit from discontinuing TKI treatment when it is safe to do so.
Measuring CML on a molecular level
Quantifying BCR-ABL1 mRNA levels in CML patients’ blood enables oncologists to calculate molecular response (MR), an index of treatment effectiveness. After three months of treatment, oncologists use MR to determine if their patients need to change their course of therapy. After finding an effective treatment, doctors serially monitor MR to assess disease burden over time and confirm therapeutic goals.
MR can be measured using one of several techniques, including PCR, quantitative PCR (qPCR), Droplet Digital PCR (ddPCR) and next-generation sequencing (NGS). An oncologist aims to detect—or in the case of qPCR and ddPCR, quantify—circulating BCR-ABL1 transcripts. Currently, there are four FDA-cleared or approved BCR-ABL1 diagnostics, all based on either qPCR or ddPCR technology.
High BCR-ABL1 levels indicate active disease, while undetectable levels indicate that a patient may be in remission. Because BCR-ABL1 levels decline slowly, many patients must remain on TKIs for years to achieve a deep molecular response—a greater than four-log reduction in BCR-ABL1 levels (MR4 according to the international scale).
If a patient maintains this state for two years, they have reached a sustained deep molecular response (sDMR). Current data suggests that patients who have been on TKI therapy for at least three years and are in sDMR can attempt stopping TKI treatment, a phase known as treatment-free remission (TFR).
Finding the best molecular diagnostic
Many of the questions oncologists and patients have surrounding TKI discontinuation originate from uncertainty in the techniques used to measure MR. It is possible that BCR-ABL1 levels could decrease enough to evade detection by the gold-standard diagnostic technique—qPCR—while remaining at high enough concentrations to lead to recurrence. These remaining cancer cells are referred to as minimal residual disease (MRD).
Current data suggest that 50% to 60% of patients who appear to be in sDMR as indicated by qPCR still harbor MRD and are likely to relapse. One study examining treatment discontinuation in 142 CML patients found ddPCR could detect more cases of MRD than qPCR. This indicates that ddPCR is more accurate and sensitive when detecting and monitoring BCR-ABL1 levels compared to qPCR. The authors suggested that ddPCR technology could make sDMR easier to confirm and therefore make it easier to identify patients eligible for treatment discontinuation.
Another study examined several factors that predict relapse, including BCR-ABL1 levels measured using ddPCR technology. Next to treatment duration, BCR-ABL1 levels following treatment discontinuation were the strongest predictor of relapse. In fact, ddPCR technology detected BCR-ABL1 transcripts in 75 patients that were negative by qPCR.
Overall, these data indicate that there is hope for people in sDMR who wish to discontinue treatment. The more sensitive the BCR-ABL 1 testing platform, the more confident a physician can be that a patient will achieve a successful TFR. With this deeper level of certainty that a negative result is accurate, an oncologist can discontinue their patient’s treatment, sparing them from years or even decades of debilitating side effects.
Giving patients and oncologists more information and options
The decision to stop cancer treatment is a complex and emotional decision made between a patient, their family and their physician. Some CML patients may feel relieved to stop treatment, while others will be hesitant to discontinue a regimen that is working.
Oncologists may choose to keep their patients on TKIs out of an abundance of caution, even at the cost of the patient’s overall health and potential financial burden. Yet mounting data shows that there is a reasonably safe route for TKI treatment discontinuation in patients experiencing sDMR.
Hopefully, these data will help start more conversations about how oncologists can help patients enjoy the additional years TKIs have given them by ceasing treatment when the time is right.
Photo: aldomurillo, Getty Images
