CML Monitoring

Why do I need monitoring?

Monitoring is critical and it is a key part of how most cases of CML were transformed from life-threatening to manageable. The purpose of monitoring is determine how well the medication is doing its job. It’s reassuring to see the disease respond to the treatment, and a good response helps predict a good outcome over the years.

Patients that do not monitor their disease run the risk of failing to recognize that the leukemia might not be responding to treatment. Or the patient might fail to see that the disease had been responding to treatment and then quit responding—which could be a sign of relapse. Some patients have been shown to develop resistance to their medication and monitoring is one of the tools doctors use to identify those patients. The good news is that most monitoring today only requires a visit to the doctor and a blood sample.3

In addition, studies have shown that monitoring early and on the recommended schedule reduces overall healthcare costs.5,12

How is monitoring done?

Monitoring uses multiple lab tests.3  

Initially, general blood work could give a rough idea of progress. CML was likely suspected based on a high white blood cell count. Seeing this return to normal is a good start—but it’s not enough (see “CHR” in the graphic). Next, tests might be run to look for the Philadelphia chromosome itself. It should disappear over the course of treatment (see “CCyR”). Even though this is an even better sign, it’s still not sufficient to be sure that the leukemia is at low enough levels in the body.

This is where molecular testing methods come in. In order to measure the very small amounts of leukemia molecules that are in the body, these methods (e.g. PCR, qPCR, and RT-qPCR) are used by many laboratories. PCR can be a very sensitive and accurate laboratory method used to estimate the amount of leukemia molecules called “BCR-ABL1” in the body. These molecules are created by the Philadelphia chromosome. So, the lower the amount of BCR-ABL1, the less leukemia is present. The good news is that the PCR test is performed with a blood sample.

PCR was initially used for CML because of its potential to detect disease at these very low levels. Once the blood cell counts (CHR) and chromosome counts (CCyR) were back to normal, monitoring by PCR would begin. These days, it is important to be sure that PCR is ordered from the very start of diagnosis and throughout lifelong monitoring. For example, the doctor needs to be certain that the patient has the common form of BCR-ABL1 that can be monitored. Rare forms exist that cannot be monitored by typical PCR tests.3

Finally, be aware that not all PCR tests are created equal. Some give better answers than others.

What do the numerical results mean?

It’s important to understand the numbers reported on your test results. They help determine how well CML treatment is working. These results are measuring the amount of leukemia-causing molecules called “BCR-ABL1” in the body. The lower the amount of BCR-ABL1, the less leukemia is present. There are two numbering systems for these test results: %IS and MR.

What is the International Scale? (%IS)

This is a system to make monitoring values more consistent. In general, the lower the number, the better treatment is working. This is the goal of targeted therapy for CML.

In the early days of CML monitoring, there was no agreed upon standard way to measure the amount of BCR-ABL1 molecules in the body. This made comparing results from one test to another very difficult. It would be like trying to compare the height of a person in Texas with the height of a person in California—without anyone agreeing on how long a foot or a meter is.

In these early days of CML monitoring, PCR results for BCR-ABL1 were reported as a percentage (%). It’s not a percentage in the traditional sense; rather, it’s an arbitrary scale. As the value declines over time, it indicates that the treatment is working. If the value doesn’t go down, it is not working.

In order to generate these test results, most labs use different procedures, equipment, and materials. This previously led to a lot of differences between the numbers given to patients. A value of 20% in one lab might be called 0.2% in another.

Consistency was required. So the International Scale (IS) was developed to bring uniformity to BCR-ABL1 numbers.6 On this new scale, a value of 100 is the average value of an untreated patient with chronic phase CML. An individual’s results could be higher or lower. This is simply an agreed-upon starting place—called a “baseline”—to give everyone a common reference to monitor the disease.

On a lab report, these numbers might be listed as %IS or IS%—or in some cases, simply %.

The doctor might want to confirm that any such value (%) from a lab is being provided on the International Scale. If it’s not, the reported numbers may be subject to the inconsistency discussed above. And since treatment guidelines require test results reported on the International Scale,3 the doctor might not be able to apply the standard of care.

What are MR values?

MR stands for “Molecular Response”. It is a system for showing how much improvement the patient has achieved since baseline. In other words, MR is a system for demonstrating how many BCR-ABL1 molecules have been eliminated from the blood. In general, the higher the number, the better the treatment is working.

MR is based on the International Scale (%IS values). Every time MR goes up by 1, it means that the leukemia level is 10 times lower. In other words, if an MR value increases by 1, the number of BCR-ABL1 molecules is 10 times lower than the previous measurement. For example, if MR values go from MR2 to MR3, the corresponding %IS values go from 1%IS to 0.1%IS—and indication that disease level has reduced 10x.

Previously, MR values were only reported for a few spots during monitoring, such as MR4 and MR4.5. Some labs still report only MR if the patient falls into one of these two “buckets”. For example, these labs will never report MR4.2 (0.0063%), only that MR4 was achieved. A doctor can help distinguish between these possibilities.

Is %IS or MR preferable?

Each numbering scale has pros and cons. It is important to remember that %IS values all have equivalent MR values. How the results are reported is often a matter of preference or historical precedent.

Some people prefer to look at %IS values because those values decrease as the level of leukemia in the body also decreases. However, %IS numbers can get very small and confusing. For example, 0.032%IS and 0.0032%IS look similar, even though they are 10 times different from each other.

Many people think of higher numbers as better. Since a higher MR indicates a better molecular response, some people prefer to review results as MR. It is easier for some people to look at the difference between MR3.5 and MR4.5 (equivalent to 0.032% and 0.0032%, respectively). This difference indicates a 10 times better molecular response than the previous result.

MR values can also make it easier to review meaningful changes. Suppose a result of 0.2483%IS is seen on one visit and then 0.2540%IS from a visit 3 months later. It might look like the numbers went up (worsened). It could be true. Or it could be the natural variability in lab measurements. Either way, it’s not a meaningful difference. It is easier to see how small the change is when reviewed in the other scale: MR2.61 and MR2.60, respectively. A doctor will need to help interpret any changes in numbers in the context of other clinical data.

What is the significance of MR4.5?

MR4.5 is a measure of very low remaining leukemia. It’s equivalent to 0.0032%IS, roughly 32,000-fold reduced from diagnosis. In other words, someone who has a result of MR4.5 has roughly 32,000 times fewer BCR-ABL1 molecules in their blood than they did when they were diagnosed. In clinical studies so far, none of the patients who achieved MR4.5 progressed to advanced phase of CML.7,8,9,10 It’s the deepest form of “safe harbor” that can be measured. In addition, CML treatment guidelines require that the patient have access to a PCR test with a sensitivity of at least MR4.5 if they want to discuss stopping treatment with their doctor.3

Are all PCR monitoring tests the same?

No, not all tests are created equal. Some tests can give inaccurate or highly variable results. This means they give results that are false, or that change randomly each time they are performed. Many tests are not cleared by the FDA, meaning they don’t have the benefit of stringent regulatory review for safety and efficacy. And most critically, many tests cannot measure the levels of Deep Molecular Response required for the standard of care. So it can be difficult for you and your doctor to understand if your results are low, lower, or extremely low.

Infographic  %IS and MR equivalents; info included with graphic in prior section, so either point to it or provide a cropped version herein with only the relevant info; consider including an arrow or other indication that many tests can’t get that deep, MR4.5

How often is monitoring performed?

Monitoring should be performed every 3 months. This recommendation comes from the guidelines by the National Comprehensive Cancer Network. There is an opportunity to relax this a little bit (up to every 6 months) once the numbers have been below 1%IS (same as greater than MR2) for at least 2 years. Regardless, there is a strong preference to keep monitoring frequently to help catch problems earlier.3,12 As an added benefit, multiple studies have shown that molecular monitoring reduces overall healthcare costs when done early and per the recommended schedule.5,12

These guidelines can change over time. So consulting a doctor is critical.

What about stopping the medication?

It’s possible in certain situations. When TKIs were first released, these lifesaving drugs were believed to be lifelong therapies for all patients. But some people want to stop taking the medication, due to side effects or for financial reasons. Thankfully, some exciting developments in recent years have opened the door for some patients to stop taking their TKI.

First, this is not a discussion of a “drug holiday”. That’s when someone stops taking a medication temporarily for a particular reason, such as reducing side effects. Choosing to go on a drug holiday without consulting a doctor is not recommended in CML. In fact, not taking the medication as prescribed is a key indicator of poor clinical outcomes.12

This is a discussion about treatment discontinuation in an attempt to achieve treatment-free remission (TFR). In other words, this is the potential to have low disease activity even without treatment. Not everyone is eligible to attempt this. Not everyone even wants to try it. Only the doctor and patient can assess whether it’s desired and safe to try.

For about half of the people who discontinue their TKIs, the leukemia comes back within 6 months. They usually start taking the TKI therapy again. The other half of patients who discontinue TKI therapy go for years with very little evidence of the leukemia in their blood. Even if they show detectable levels of BCR-ABL1 (a positive PCR result), it might be safe so long as the number doesn’t go above 0.1%IS (below MR3).10,11 This is why many are calling this outcome a “functional cure”. Evidence of CML can still be observed, but the remission is stable even without the medication.

What factors influence whether someone can attempt to go treatment free?

Many factors come into play. It is critical to work with a doctor to consider this carefully. Currently, about half of CML patients are deemed eligible to attempt TFR.13

Key factors include access to an extremely sensitive lab test. The patient will also need to get PCR monitoring done far more frequently for a while. These items help ensure that the doctor can see early signs of the disease coming back.3

Here’s a quick checklist. It’s not exhaustive. Reviewing the opportunity with a doctor is required.

CML treatment guidelines from the National Comprehensive Cancer Network currently have many requirements to attempt TFR,3 including:

  • Consultation with a CML specialist
  • At least 18 years old
  • Chronic phase CML (no history of advanced or blast phase CML)
  • Taking TKI for >3 years
  • Prior positive result in a BCR-ABL1 PCR test
  • Deep Molecular Response: ≤0.01%IS (≥MR4) for ≥2 years (longer time may be better) based on the recommended monitoring schedule
  • Access to a PCR test that reports values on the International Scale (%IS and/or MR)
  • Access to a PCR test with a sensitivity of at least5 (0.0032%IS)
  • Access to a PCR test with <2 week turnaround time
  • Willingness for more frequent PCR monitoring:
    • Every 1 month (year 1)
    • Every 2 month (year 2)
    • Every 3 month (indefinitely) so long as >MR3 (<0.1%IS)

If <MR3 (>0.1%IS), resume TKI, then monitor every month until >MR3 (<0.1%IS), and then every 3 months (indefinitely)

What is the Asuragen QuantideX qPCR BCR-ABL IS Kit?

The QuantideX qPCR BCR-ABL IS Kit is the first FDA-cleared test for monitoring CML. It is the result of years of research and development. This test is used by clinical labs to provide physicians with PCR results that help determine how well CML therapy is working for a given patient. The QuantideX kit goes beyond the standard of care for sensitivity. And it provides accurate results on the International Scale.

  • PCR test
  • Works with blood samples
  • Reports values on the International Scale (%IS and MR)
  • Sensitivity of MR4.7 (0.0020%IS)
  • Fast turnaround time

Does the choice of test matter?

The best outcomes are supported by the best results.

Ask your doctor if your results are from the QuantideX qPCR BCR-ABL IS Kit.

Glossary

  • %IS: an estimate of the level of leukemia in the blood, lower numbers mean less evidence of leukemia
  • Advanced Phase: a rapidly progressing disease that is Accelerated (rapid uncontrolled growth) and then Blast crisis (difficult to control and dangerous)
  • BCR-ABL1: abnormal genetic molecules created by the Philadelphia chromosome that cause CML, sometimes called a “fusion gene”
  • Bone Marrow: spongy tissue inside some bones (e.g. hip and thigh) that produces many types of blood cells
  • Breakpoints: the exact spot where there is a break in the genes involved in CML
  • Chronic Phase: a long, slow-growing period of CML, often without symptoms, but can progress to Advanced Phase if not treated
  • Chromosome: a long strand of DNA
  • Complete Hematologic Response: CHR, results from blood work have returned to normal, including white blood cells and platelets
  • Complete Molecular Response: CMR, PCR results for BCR-ABL1 are undetectable in a particular test, sensitive tests are better
  • Complete Cytogenetic Response: CCyR, cytogenetic results where the Philadelphia chromosome is undetectable, roughly equivalent to ≤1%IS (≥MR2), 100-fold lower than at diagnosis
  • Cytogenetic Test: a method of examining the structure of the chromosomes, assess the presence or amount of the Philadelphia chromosome
  • Deep Molecular Response: DMR, a sustained period of monitoring where PCR results for BCR-ABL1 are extremely low (<0.01%IS, >MR4), 10,000-fold lower than at diagnosis
  • Early Molecular Response: EMR, PCR results for BCR-ABL1 have reduced to ≤10%IS (≥MR1), 10-fold lower than at diagnosis, at both 3 and 6 months after starting TKI
  • International Scale: IS, a standardized scale for estimating the level of leukemic cells in the blood by measuring BCR-ABL1 (reported as %IS)
  • Leukemia: a group of cancers that affect blood cells
  • Leukemic cells: white blood cells that multiply abnormally; they are immature, meaning that they’re not ready for their normal functions like destroying infectious agents
  • Log reduction: a 10-fold drop in BCR-ABL1 results, such as MR1 to MR2
  • Major Molecular Response: MMR, PCR results for BCR-ABL1 have reduced to ≤0.1%IS (≥MR3) after starting TKI treatment, 1,000-fold lower than at diagnosis
  • Minimal Residual Disease: MRD, general term for the low number of leukemic cells that might persist after treatment
  • Monitoring: a program of testing over time to assess how well CML therapy is working
  • MR value: molecular response, an estimate of the level of leukemia in the blood, higher numbers mean less evidence of leukemia
  • Myeloid: relating to bone marrow and to red blood cells, platelets, and certain types of white blood cells
  • PCR: Polymerase Chain Reaction, a specialized method to estimate the amount of BCR-ABL1 in the blood (also called RT-qPCR or qPCR)
  • Philadelphia Chromosome: a random mistake in the DNA that causes CML, sometimes abbreviated Ph+
  • t(9;22): the translocation also known as the Philadelphia chromosome, resulting from chromosomes 9 and 22 switching sections with each other
  • Treatment-Free Remission: TFR, a lifelong period of monitoring where PCR results for BCR-ABL1 are extremely low or undetectable after discontinuing TKI therapy
  • Tyrosine Kinase Inhibitor: TKI, a class of medications that target the molecules that cause CML
  • Translocation: a type of mistake in DNA where two sections break and then switch with each other
  • White Blood Cell: WBC, also called a leukocyte, cells that circulate the body and help fight infection and disease

CML Monitoring

Footnotes

  1. *

    American Cancer Society. (2020, Jan 8). Key Statistics for Chronic Myeloid Leukemia. https://www.cancer.org/cancer/chronic-myeloid-leukemia/about/statistics.html

  2. **

    Huang, X., Cortes, J., & Kantarjian, H. (2012). Estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. Cancer, 118(12), 3123–3127.

  3. ***

    National Comprehensive Cancer Network. (2020, Jan 30). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), Chronic Myeloid Leukemia (version 3.2020). https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf

  4. ****

    Lemonick, M. D. and Park, A. (2001, May 28). New Hope For Cancer. Time, 157(21), cover.

  5. *****

    Jabbour, E. J., Siegartel, L. R., Lin, J., Lingohr-Smith, M., Menges, B., & Makenbaeva, D. (2019). Impact of earlier versus later monitoring on disease progression and healthcare costs among patients with chronic myeloid leukemia in the United States. Leukemia & lymphoma, 60(3), 668–674.

  6. ******

    Hughes, T., Deininger, M., Hochhaus, A., Branford, S., Radich, J., Kaeda, J., Baccarani, M., Cortes, J., Cross, N. C., Druker, B. J., Gabert, J., Grimwade, D., Hehlmann, R., Kamel-Reid, S., Lipton, J. H., Longtine, J., Martinelli, G., Saglio, G., Soverini, S., Stock, W., … Goldman, J. M. (2006). Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood, 108(1), 28–37.

  7. *******

    Hehlmann, R., Müller, M. C., Lauseker, M., Hanfstein, B., Fabarius, A., Schreiber, A., Proetel, U., Pletsch, N., Pfirrmann, M., Haferlach, C., Schnittger, S., Einsele, H., Dengler, J., Falge, C., Kanz, L., Neubauer, A., Kneba, M., Stegelmann, F., Pfreundschuh, M., Waller, C. F., … Hochhaus, A. (2014). Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 32(5), 415–423.

  8. ********

    Kantarjian, H. M., Hochhaus, A., Saglio, G., De Souza, C., Flinn, I. W., Stenke, L., Goh, Y. T., Rosti, G., Nakamae, H., Gallagher, N. J., Hoenekopp, A., Blakesley, R. E., Larson, R. A., & Hughes, T. P. (2011). Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. The Lancet. Oncology, 12(9), 841–851.

  9. *********

    Kantarjian, H. M., Shah, N. P., Cortes, J. E., Baccarani, M., Agarwal, M. B., Undurraga, M. S., Wang, J., Ipiña, J. J., Kim, D. W., Ogura, M., Pavlovsky, C., Junghanss, C., Milone, J. H., Nicolini, F. E., Robak, T., Van Droogenbroeck, J., Vellenga, E., Bradley-Garelik, M. B., Zhu, C., & Hochhaus, A. (2012). Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood, 119(5), 1123–1129.

  10. **********

    Rousselot, P., Charbonnier, A., Cony-Makhoul, P., Agape, P., Nicolini, F. E., Varet, B., Gardembas, M., Etienne, G., Réa, D., Roy, L., Escoffre-Barbe, M., Guerci-Bresler, A., Tulliez, M., Prost, S., Spentchian, M., Cayuela, J. M., Reiffers, J., Chomel, J. C., Turhan, A., Guilhot, J., … Mahon, F. X. (2014). Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 32(5), 424–430.

  11. ***********

    Laneuville P. (2018). When to Stop Tyrosine Kinase Inhibitors for the Treatment of Chronic Myeloid Leukemia. Current treatment options in oncology, 19(3), 15.

  12. ************

    Guérin, A., Chen, L., Dea, K., Wu, E. Q., & Goldberg, S. L. (2014). Association between regular molecular monitoring and tyrosine kinase inhibitor therapy adherence in chronic myelogenous leukemia in the chronic phase. Current medical research and opinion, 30(7), 1345–1352.

  13. *************

    Mauro, M. (2019, Feb). Understanding Treatment-Free Remission and How It Impacts You: Frequently Asked Questions for Patients and Advocates. The Max Foundation. http://mypcr.org/wp-content/uploads/2019/02/My_PCR_TFR_FAQ.pdf

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