A Complex Karyotype in CLL Predicts Inferior Outcomes with Ibrutinib Therapy

A complex karyotype has been associated with poorer outcomes in both patients with treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL), but the prognostic significance for ibrutinib-treated patients was previously unknown.

Take Away Points:

• Complex karyotypes (CKT) are more predictive of a poor outcome on ibrutinib than even (del) 17p
• Our risks come when our cancer clonal is unstable and mutates so that it becomes unresponsive to therapy.

Preface:

Hematology in general and CLL specifically are full of jargon and acronyms that can be both overwhelming and daunting.  With time and experience, you’ll become familiar with the terminology and acronyms.  We will try to explain each medical term the first time it appears in an article, but we will use the true terminology so that you gain comfort and familiarity with the medical terms that you will see in your lab reports and in medical articles. We have provided a glossary as well as a list of abbreviations and acronyms for your reference.

Complex Karyotypes:

In this abstract from the researchers at MD Anderson Cancer Center, presented at ASH 2014, we learn that we are most likely to progress on ibrutinib therapy if we have a complex karyotype (CKT). For more about CKT, please see Prognostic Indicators Part 2. In fact, when controlling for CKT, del (17p) becomes a non-factor. I quote from the last lines of the abstract:

“This has important implications for treatment of pts. with del (17p); those without CKT appear to have equivalent outcomes with Ib(rutinib) compared to pts. without del(17p) and could potentially be managed with long-term ibrutinib) and close monitoring. In contrast, the inferior outcomes after initial response in pts. with CKT make them ideal candidates for treatment-intensification strategies after initial ibrutinib-based treatment, either with novel drug combinations or with allogeneic stem cell transplant, ideally in the context of well-designed clinical trials.”

Since 22 of the 26 patients with CKD also had del (17p) and 3 of the other 4 had (del) 11q, one might ask why is this important.

My hypothesis, shared by the authors and other researchers is that (del) 17p is basically a marker for genomic instability. The p53 gene that lives on the short arm of the 17th chromosome (17p) has been called the guardian of the gene. So too is ATM, found missing in action with (del) 11q, but to a lesser extent. The resulting genomic instability by definition is going lead to a poorer maintenance of the gene’s healthy integrity, resulting in a higher risk of clonal evolution, CKT and a possible mutation that confers resistance.

What Might It All Mean?

While it only my conjecture, to me is a strong argument in favor of studying how we might avoid drugs such as purine analogues (think fludarabine and pentostatin) and alkylating agents (think chlorambucil, bendamustine, and cyclophosphamide) frontline if we are not in that subgroup that is likely to get a deep and durable response. Please see Dr. Wiestner’s comment on this topic.

Those chemotherapy drugs work by damaging the DNA, the home of our genetic code.

Dr. Wiestner foretold the future in this short video clip from ASH 2011.

The genetic damage induced by chemotherapy may be worth the price if we get a meaningful remission, but we must carefully weigh the increased risk not only of the rare but dangerous secondary cancers, especially of the blood marrow, but also of the possible consequences of any increased genomic instability. This may explain the reason that all CLL patients, even those with the dreaded (del) 17p who are treatment-naïve (never had any therapy for their CLL), do much better with ibrutinib than those who have relapsed. That is not a surprise. In the era of chemotherapy, nearly all second-line remissions are less deep and deep durable than our first.

Here is the link to original abstract.

https://ash.confex.com/ash/2014/webprogram/Paper76261.html

Brian Koffman 3/7/15