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Frontline Therapy in Chronic Lymphocytic Leukemia (CLL)

In science and medicine, information is constantly changing and may become out-of-date as new data emerge. All articles and interviews are informational only, should never be considered medical advice, and should never be acted on without review with your health care team.

Treatment decision should always be individualized. One size does not fit all with chronic lymphocytic leukemia (CLL). The best therapeutic option depends on several factors including:

  • Your age, your overall health, and any co-morbidities
  • Your prognostic factors (FISH and mutation status)
  • Your personal preference

Your choices are complicated, because despite what some say, there is no universal gold standard therapy in CLL. There may be significant disagreement between different well-meaning CLL experts, making it even harder to make a decision.

The approved frontline treatment choices broadly fall into three categories with significant overlap.

Chemo-immunotherapy (CIT):

Choices such as FCR (fludarabine-cyclophosphamide-rituximab) or BR (bendamustine-rituximab) that are worthy options for healthier young patients who enjoy all good prognostic factors (mutated and no bad findings on FISH)


Alkylating agents, including cyclophosphamide (C), bendamustine (B), and chlorambucil and purine analogues such as fludarabine (F), all work by interfering with the DNA needed for cell growth. There are dependent on an intact p53 pathway that is found on the short arm of the 17th chromosome. That is why they don’t work well in patients with deletion 17p.


Most of our cancerous B cells have markers on the surface that can be attacked by antibodies that are manufactured to attach to an identical site (monoclonal) on our cells. The most common target, used by rituximab, ofatumumab and obinutuzumab is called CD20 and is found on all B cells, cancerous or not. These three intravenous drugs are all known as anti-CD20 monoclonal antibodies or MaBs.

Several studies have shown that much better results come from combining chemotherapy with immunotherapy (CIT), explaining the popularity of FCR and BR.


Imbruvica (ibrutinib) is a novel oral agent that blocks the BTK (Bruton’s Tyrosine Kinase) receptor blocker and has shown strong results in both frontline and relapsed CLL, as well in patients with deletion 17p where CIT is usually ineffective. The BTK pathway is critical for our CLL cells. It is necessary to get the support and B cell signaling needed for staying in the protected niches of the lymph nodes and other safe havens, and for their long term survival. When it is blocked, the CLL cells leave the nodes and eventually die.

Clinical trials:

Many of the best treatment options are available within clinical trials, whether they consist of approved drugs used in new combinations and in new ways or unapproved novel agents either alone or in combination with approved drugs. The care in clinical trials tends to be excellent.

As my friend WWW likes to say, may your path be well chosen.

Brian Koffman, MD  9/26/16