Review article summarises management strategies for those with CLL harbouring complex karyotype

[CLLerinOz]

On 6 January 2025, the journal BJ Haem published a review article titled Management strategies for patients with chronic lymphocytic leukaemia harbouring complex karyotype written by a team from Padua, Italy. The article summary explains its aims:

"Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease characterised by the uncontrolled proliferation of mature lymphocytes. A subset of CLL patients harbouring complex karyotype (CK) presents with poor prognosis and limited treatment options. This review aims to discuss the current understanding of such patient subset, including its molecular landscape, diagnostic approaches, treatment modalities and emerging therapies. Furthermore, it outlines strategies for personalised management to improve clinical outcomes in this challenging patient population."

A graphical abstract (see image above) is provided:

"Chronic Lymphocytic Leukaemia patients harbouring complex karyotype presents poor prognosis and limited treatment options due to its intrinsic genomic instability. This review aims to discuss the current understanding of such patient subset, including its molecular landscape, diagnostic approaches, treatment modalities and emerging therapies. Furthermore, it outlines strategies for personalised management to improve clinical outcomes in this challenging patient population."

The review highlights some things we've already known, eg the importance of getting appropriate testing done before each treatment decision. However, it highlights the increasing use of more expansive testing.

" . . . methodologies such as chromosome-banding analysis (CBA), chromosome microarray analysis (CMA) and genome-wide analysis offer a more expansive view of its genomic landscape, which led to the identification of chromosomal abnormalities in a relevant number of patients with CLL, being either quantitative, as for instance monosomies or trisomies, or qualitative, such as translocations, deletions, insertions and isochromosomes.² Of note, complex karyotype (CK), classically defined by the presence of at least three chromosomal alterations in the neoplastic clone, can be found in 15%–20% of patients at diagnosis, but such percentage goes up to 30%–40% among relapsed/refractory (R/R) cases.³, ⁴ In addition, up to 5% of patients with monoclonal B-cell lymphocytosis (MBL) can present with a CK in their clone.³"

It also highlights some things we might not have appreciated: that carrying five or more chromosomal abnormalities has a deeper impact on disease course than carrying fewer abnormalities (eg the previously defined three abnormalities).

"Although karyotype analysis through CBA has been widely used in haematology to refine diagnosis and prognostic stratification of several haematological malignancies, it has been widely accepted as prognostic and/or predictive factor for CLL only in the last few years. Currently, CBA is recommended to be performed before starting treatment by NCCN and the GCLLSG guidelines.⁷⁰, ⁷¹

While in both guidelines CK is defined by the presence of three or more chromosomal alterations, recently accumulating evidence points out the fact that CLL carrying five or more chromosomal abnormalities has a deeper impact on survival and response to novel therapies. Targeted therapies, such as second-generation BTK inhibitors or venetoclax-based combinations, can overcome the negative impact carried by a less-complex karyotype (i.e. <5 abnormalities)." (my emphasis)

There's a lot more information in the full paper which you can read here:

Serafin A, Ruocco V, Cellini A, Angotzi F, Bonaldi L, Trentin L, et al. Management strategies for patients with chronic lymphocytic leukaemia harbouring complex karyotype. Br J Haematol. 2025; 00: 1–10. doi.org/10.1111/bjh.19986

CLLerinOz

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[BigfootT]

That was a really good article. Thanks for posting. One tidbit I picked up which really caught my attention was this statement under the Prognostic Indicator section:

....it should be underlined that CK cases bearing trisomy 12 or 19 show an extremely indolent course, and therefore, not all chromosomal abnormalities should be considered equally unfavourable.36, 37

Any thoughts on that statement?

That's the first I've read or heard that. While my diagnosis is only within the past year (Tri12, U-CLL and Notch 1) I am definitely having node progression even though my blood work is normal so I'm not sensing an Indolent course in my future.

Thanks, Bigfoot

[SofiaDeo in reply to BigfootT]

Perhaps it referred to the "CLL presentation" of this disease, and not the "SLL presentation." You SLL'ers, being a smaller patient subset of CLL, don't have as much data to say if/to what extent, your disease course compares to the "mainly in the blood/marrow" version.

[CLLerinOz Administrator in reply to BigfootT]

An ASH 2024 abstract and interview with one of its authors, Jennifer R Brown MD, PhD, produced by VJHemOnc adds a little additional detail.

The abstract reports on a retrospective analysis of the Dana Faber Cancer Institute CLL Database "to evaluate overall survival (OS) and the impact of prognostic factors in CLL pts over the past 10 years".

The abstract, #583, titled Complex Karyotype, but Not Isolated TP53 mutation, Predicts Overall Survival in Chronic Lymphocytic Leukemia Patients in the Era of Targeted Therapy, notes that "Del(11q), del(13q), trisomy 12, NOTCH1 mutation, and white blood cell count did not affect OS".

Interestingly, they found that isolated TP53 mutation is not a significant factor affecting OS with targeted therapy.

ash.confex.com/ash/2024/web...

The video interview which is intended for medical professionals can be viewed on VJHemOnc's YouTube channel. "Dr Brown highlights the importance of complex karyotype, age, and beta-2 microglobulin in predicting OS and explains that isolated TP53 mutation was not significant."

youtu.be/hpzhcszUhjo?si=RN6...(Not working as expected?)

CLLerinOz

[BigfootT in reply to CLLerinOz]

That's interesting. I've watched Dr. Brown before in a number of webinars and VJhemonc's interviews. She's very good. Thanks for the response!

[Snakejaw]

Interesting stuff here, thank you for sharing it. I'm a bit of a collector of deletions myself, currently have 3 (11,13,17). This is the first I'm hearing about five being more indicative of poorer prognosis. I still consider myself a ranking member in the bad markers club.

[Analeese]

I am complex karyotype and unmutated, also with hypogammaglobulinemia. diagnosed with CLL in2020 I have also developed several Squamish cells one that was quite serious and required skin grafts . I am now dealing with thyroid nodules that are highly suspicious. That is a creepy test to have. You can watch it on the screen while they put a needle in your thyroid and wiggle it around in order to get multiple samples for your biopsy. It will be my second one in three months. I think I’d rather have a bone marrow biopsy.

My treatment for CLL was O&V. It will be three years since I completed treatment in March so I feel pretty lucky. Not that I ever stop worrying. I don’t, but I am grateful for this wonderful treatment that we are able to receive.

[CLLerinOz Administrator in reply to Analeese]

I’ve not had a thyroid biopsy but it doesn’t sound like much fun, that’s for sure. Hope you get reassuring results.

It’s great you’re enjoying the benefit of your V & O treatment nearly three years ago. That’ll be a milestone to celebrate in March

CLLerinOz

[Analeese in reply to CLLerinOz]

👍