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P13Kδ Blockade Increases Genomic Instability in B cells

In science and medicine, information is constantly changing and may become out-of-date as new data emerge.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.

In the journal Nature, a highly technical article was published last month that deserves our attention.

Researchers have shown that directly blocking the P13Kδ (phosphatidylinositol 3-kinase δ) pathway by drugs such as idelalisib and duvelisib and to a lesser extent, indirectly blocking the same pathway by drugs such as ibrutinib, may have some worrisome unintended effects.

How clinically significant are these effects is far from certain. There is a big jump from mouse models and isolated Bcells to human cancer, but here is what we learned.

Take Away Points:

  • We know that blocking the P13Kδ pathway results in a profound therapeutic benefit in CLL.
  • P13Kδ blockade also increases the expression of an enzyme called AID (activation-induced cytidine deaminase) that has a broad effect on genomic instability.
  • Increased expression of AID can initiate potentially pre-cancerous chromosomal changes that can be involved in the development and progression of lymphoma.
  • Mouse models show increased tumor growth with increased AID.
  • A similar increased AID expression has lead to increased drug resistance in CML (chronic myelogenous leukemia).

So while they are not directly damaging to DNA, research such as this teaches us that drugs that block the P13Kδ may still have genotoxic effects and can lead to increased mutations through indirect mechanisms.

This is a complex article but it reminds us that CLL is a complicated disease and any drug may have unexpected effects.

Here is a link to the abstract:

In summary:

The researchers showed that PI3Kδ blockade, so helpful in CLL when produced by drugs such as idelalisib or to a lesser extent indirectly by ibrutinib, also increases genomic instability in both normal and cancerous B cells.

This effect should be carefully considered because we patients are often on these drugs for years.

There are no free lunches, but I am very grateful for these game-changing medicines and also grateful for those doing the research on what we need to watch out for down the line.

Brian Koffman, MD 3/7/17