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17p, TP53, and Me (#3)

Posted by Frederick Wasti
Apr 23 2012

[Please note that, if you haven't already made your way through my previous two posts on "17p, TP53, and Me", below, I would ask you to try doing so before proceeding with this continuation - Thanks a lot.]

Well, whether or not you were able to follow along with my attempts to connect p53 deletion to TP53 malfunctioning, to uncontrolled growth, and to difficulty with therapy, you may be able to appreciate this third "17p, TP53, and Me" installment.

During the latter half of the Twentieth Century, medical methods of treating CLL often met with some success. Many CLL patients seemed to show a naturally slow leukemic growth rate anyway (in other words, their leukemia was indeed more chronic than acute). Many other patients did receive benefit from some of the earlier forms of chemotherapy that were used with them. However, there were always a few CLL patients who displayed rapid progression and who also failed to show much response to the standard treatments that were often successful for many other patients. We now know that these differences in outcomes are due primarily to the molecular basis of individual differences between CLL patients. (Please note that 17p deletion is not the only genetic defect that impacts CLL, but, as will be pointed out below, it is the most damaging genetic effect to own.)

As was stated just this year, "Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, with some patients displaying an indolent clinical course with a similar survival to that of normal individuals, whereas others display a poor outcome with a median survival between 1 and 5 years". So, I would like to devote this blog entry to a smattering of quotations from recent scientific literature relating the effect of genetics on disease progression and treatment success. (Yes, there are a few new technical words included here and there, but I don't think it's worth trying to explain each and every one of them - the overall gestalt of the quotes below will convey the general situation adequately, I do believe.)

[2007] "Independent prognostic factors associated with rapid disease progression and short survival times include 17p- (approximately 67% to 75% 2-year survival). [...] 17p- predicts for treatment failure with alkylating agents, as well as fludarabine, and short survival times. [...] Genes potentially involved in the pathogenesis of CLL have been identified in a subset of cases with 17p13- (p53). For example, p53-pathway based therapies, such as fludarabine, appear ineffective in patients with p53 genetic abnormalities associated with resistance to treatment. In addition, 17p- correlates with mutated p53 along with poor response rates and short duration of response to the standard therapeutic options, including alkylating agents, rituximab, and fludarabine, and with short survival duration in patients with CLL."

[2008] "Patients with advanced CLL and 17p deletion have a very poor prognosis even after intensive chemotherapy."

[2008] "The 17p13.1 deletion that causes loss of the p53-encoding TP53 gene is the most powerful predictor of a poor response to conventional therapy and shortened survival in patients with chronic lymphocytic leukemia (CLL)."

[2009] "About 10 percent of people with CLL have deletions in the short arm of chromosome 17 (del 17p). The critical gene in this region that is typically deleted is TP53. People who have CLL with del 17p tend to have higher-risk disease and usually do not respond as well to standard initial therapy."

[2009] "Deletion of 17p in chronic lymphocytic leukemia (CLL) is associated with resistance to conventional therapy and a poor clinical outcome."

[2010] "Although the deletion of 17p is associated with poor outcome in different malignancies (e.g., acute myeloid leukemia, myeloma, and CLL), its impact on outcome is particularly striking in CLL."

[2011] "Deletion 17p is found in ~7% of CLL patients [...] and confers the highest risk. While the deletion frequently encompasses most of short arm of chromosome 17, the minimally deleted region always involves 17p13, the locus of the TP53 gene encoding the tumor suppressor p53. In addition, the majority of CLL patients with monoallelic deletions of 17p have point mutations in the remaining TP53 allele, thus completely inactivating a critical component of the DNA damage response pathway. It is well-established that CLL patients with p53 inactivation respond poorly to conventional fludarabine or alkylating agent-based regimens, possibly because both agents require p53-dependent pathways to induce cell death. Patients who do not respond to fludarabine have a median overall survival of ~10 months."

[2011] "Mutations of TP53 were found in 7.6% of patients. There was no significant correlation between TP53 mutations and age, stage, IGHV gene mutations, CD38 and ZAP-70 expression, or any other chromosomal abnormality other than 17p deletion, in which concordance was high (96%). TP53 mutations were significantly associated with poorer overall response rates (27% v 83%) and shorter progression-free survival (PFS) and overall survival (OS); 5-year PFS: 5% v 17%; 5-year OS: 20% v 59%)."

[2012] And my favorite description of all: "The 17p deletion is the mother of all poor prognostic factors for CLL."

Well, all of the above does indeed sound a bit bleak, but there is hope, too. Now that CLL scientists are aware of the significance of a number of distinctive molecular genetic situations affecting CLL, efforts have been made to work on different modes of therapy to work around them, and that brings me to my current situation: Instead of undergoing the so-called "gold standard" treatment known as "FCR" (named for a cocktail of Fludarabine, Cyclophosphamide, and Rituximab, which does work quite well for some non-17p patients), I am participating in a clinical trail at the Dana-Farber Cancer Institute in Boston that is specifically aimed at trying to aid 17p-deleted patients such as myself, using therapies that do not depend on affecting the TP53 gene in order to slow down the growth of leukemic cells.

And this is all very exciting stuff !!! (<g>)

Categories: Leukemia