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The Importance of Early Comprehensive Testing and Retesting in CLL (chronic lymphocytic leukemia)

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In a conversation at the December 2018 ASH meeting with Dr. Brian Koffman, Chief Medical Officer and EVP of the CLL Society, he and Dr. Kamala Maddali reviewed the latest research and her experience about what she calls the “cultural shift” in how chronic lymphocytic leukemia is diagnosed and treated. Dr. Maddali is a vice president for biopharma collaborations & companion diagnostics at Cancer Genetics Inc. of Rutherford, NJ. She has a pivotal role in biomarker and diagnostics strategy for novel drug development. Dr. Maddali formerly worked at a leading blood-testing company and at Merck Schering Plough.

Their discussion focused on how a new generation of blood tests identify the biomarkers that define specific CLL subtypes. Doctors equipped with the subtype information can then practice “precision medicine,” selecting a specific, tailored treatment that is known to be most effective with a particular CLL subtype. This approach shows a dramatic cultural shift away from the traditional approach to CLL treatment.

However, many community doctors have not adopted the use of these biomarker tests for their CLL patients. Drs. Koffman and Maddali note that the pace of innovation in CLL diagnosis and treatment during the past five years is unprecedented, but the pace of adoption of these innovations is very slow. Their discussion ends with ideas about how to accelerate the adoption rate.

Key Take Aways

  • “The moment you are diagnosed with CLL you need an oncologist to immediately evaluate certain genetic markers which will indicate the prognostic profile of the patient,” notes Dr. Maddali. “The minimum testing approach” includes the following prognostic and predictive markers:
    • ZAP 70 (level of zeta-associated protein 70 on the CLL cell), now used less often;
    • CD38 (protein on the CLL cell) also used less often;
    • 17p and 11q deletion and other chromosome changes;
    • TP53 (DNA gene mutation);
    • IGVH mutation status.
  • While many would agree with Dr. Maddali, other CLL experts argue that such testing is optional at time of diagnosis, but all agree that it is absolutely mandatory before any treatment is begun. Here is an article from the journal Blood that tackles this issue.
  • For more on prognostic and predictive testing, please see Dr. Koffman’s interview with Dr. Wierda.
  • Some prognostic and predictive markers are discovered using the following tests:
    1. Fluorescence In Situ Hybridization, known by its acronym FISH, helps identify abnormalities in blood chromosomes or other forms of genetic mutations inside the CLL cells such as deletion of the short arm of the 17th
    2. Flow cytometry analyzes cells from the blood, marrow or from a biopsy to provide information about surface markers on the cells and confirms the diagnosis of CLL. This is not trivial. Look at this interview from ERIC 2018 with Dr. Jennifer Brown on diagnosis.
    3. Next generation genetic sequencing (NGS) looks for missing genes such as TP53 that is found on short arm of the 17th chromosome (17p) and instructs the manufacturing for the protein P53, critical in repairing or killing off damaged cells. When P53 is missing or dysfunctional, drugs such as chemo that damage DNA are not effective. While nearly all patients with deletion 17p are missing TP53, a significant number of patients with a normal 17th chromosome also have dysfunctional P53. These patients would be missed if only FISH testing was done.
    4. IGVH Mutation tells us about how “mature” or mutated are our CLL cells. Mutated cells have received instructions to “mutate” which is a good thing. They are programmed to recognize only certain stimuli to reproduce and are thus less “promiscuous” and tend to grow more slowly and carry a better prognosis.
  • Here are two examples of how the biomarkers help clinicians determine specific CLL treatments:
    1. Young healthy IGVH mutated patients with no adverse other markers tend to get the longest remission with FCR chemo-immunotherapy (CIT).
    2. Patients with the 17p deletion or TP53 mutations will not respond well to any CIT but will often respond very well to novel agents such as ibrutinib, venetoclax, duvelisib and idelalisib.
  • Important caveats about these markers:
    1. While they are statistically indicative of a large group of CLL patients, they may not be predictive for specific individuals, explains Dr. Koffman. What’s more, some patients with very poor prognostic factors still do well. And other patients with excellent prognostic factors could still experience disease issues.
    2. These prognostic factors can change over time. It is very important to not just be tested once and be done. In fact, it is a good idea to be retested when a major clinical decision is looming. The exception is IGVH mutation that does not change over time.
  • Patients and the rest of the CLL community need to fill the community oncologist knowledge gap, contend Drs. Koffman and Maddali. Some community hematologists may not be aware of all the advances that have occurred in CLL testing and why it is so important for patients to know their CLL subtype. Increasing awareness of the importance of the biomarkers to strengthen the diagnosis, treatment and prognosis of CLL patients is critical to achieve the CLL culture change.
  • Only 20% of community hematologists are ordering IGVH.
    “Patient advocacy brings a very very pivotal role to changing the culture of every aspect of oncology diagnostics and treatment,” notes Dr. Maddali. “It is very important that you advocate about your own situation and also for others,” to make sure these tests are done and the biomarkers analyzed.

Author commentary:

When I was diagnosed with CLL in late 2005, initially I didn’t know much about subtypes. I had been told I had the 11q deletion and that I was considered a high-risk patient. Only later when I had 11 cycles of chemo (PCR and BR), and their relatively rapid failures, did I begin to understand the importance of knowing my subtypes and other markers. However, I frequently meet CLL patients who are unaware of their biomarkers, let alone the significance of them when it comes to treatment.  Dr. Maddali’ s minimum biomarker tests should be on every CLL patient’s list of questions for their oncologist.

Thanks for reading

Larry Marion

Link to the CLL Society’s glossary of terms that further defines each of these prognostic indicators:

Link to biomarker definition Link to