Encouraging news in this abstract from CLL/SLL researchers at the Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, for those with aggressive/complex karyotype CLL/SLL*
Accelerated chronic lymphocytic leukemia/small lymphocytic lymphoma (A-CLL/SLL) is a histologically aggressive subtype of CLL/SLL that lies in between conventional CLL/SLL (C-CLL/SLL) and Richter transformation (RT) on the biological spectrum. Although the histologic criteria for A-CLL/SLL were defined 14 years ago, the clinical and genetic characteristics and survival outcomes of these patients have yet to be studied in the era of novel therapies. We retrospectively analyzed the clinicopathologic, genetic, and survival characteristics of 34 patients with confirmed tissue diagnosis of A-CLL/SLL and compared them with 120 patients with C-CLL/SLL. Patients with A-CLL/SLL had significantly higher frequencies of B-symptoms, anemia and thrombocytopenia, splenomegaly, higher LDH, and more advanced Rai stages. A-CLL/SLL showed a significantly higher frequency of TP53 mutations (55.0% vs. 11.5%;p < 0.0001) and deletions (38.2% vs. 8.3%;p < 0.0001), lower isolated del(13q) (5.8% vs. 27.5%;p < 0.0001), and increased incidence of RT (11.76% vs. 0.83%;p = 0.0025). The overall survival of patients with A-CLL/SLL was significantly lower than C-CLL/SLL (median survival: 6.17 years vs. not reached; 2 and 5-year survival rates: 75.5% vs. 94.7% and 53.3% vs. 93.7%, respectively; p < 0.0001); however, novel agents have improved the outcomes dramatically compared to the previously published data in the pre-BTKi era. Our results support the categorization of A-CLL/SLL as a distinct biologically aggressive subtype of CLL/SLL and highlight the need to revise the diagnostic criteria utilizing a multifaceted approach that integrates the overall pathobiological profile of the disease, in addition to the histology.
* @Jm954 has explained, with an example, what constitutes "Accelerated" CLL/SLL in her reply below.
Neil
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Good read, hopefully this will lead to more research and better treatments for accelerated CLL/SLL, so we do not have to undergo multiple CLL/SLL treatments.
Good abstract but nothing surprising there although interesting that they regard it as being in a grey zone between CLL and Richter's, they certainly share some of the same clinical features.
I don't think that your statement "Accelerated" CLL/SLL seems to fit with what is more generally known as complex karyotype CLL/SLL" is correct. Complex karyotype is well defined and a distinct group but accelerated CLL is less well defined and does not necessarily have complex karyotype.
In my own situation my accelerated CLL was diagnosed as a result of investigations for Richter's from a lymph node excision. On solid tissue samples (rather than blood or bone marrow) a histological stain called Ki67 can be done and this measures the mitotic index of the cells. Almost all CLL cells in the chronic phase are, at any one time, in a stage called G0 or non proliferating and the Ki67 is mostly around <5%. In accelerated CLL Ki67 is of the order of 30-40% (my own was 40%) so you can see that there is a dramatic difference.
The increased incidence of Richter's is probably due to a higher mitotic index which gives more opportunity for transformation. The large B cells that identify the DLBCL transformation are easily seen but accelerated CLL is still very large numbers of small B lymphs.
This is an interesting paper about two cases of accelerated CLL (defined by Ki67 index) from 2021, successfully treated with Ibrutinib. This wasn't possible in my case as I had failed Ibrutinib and Acalabrutinib because of two BTK mutations.
I've never been told that my Ki-67 around 40% indicated A-CLL, just it was "very aggressive". Also Atypical. Massive lymph nodes, 14AP x 21cm. MUM1 ~30%. Negative for CD5, CD200, Cyclin D1, BCL-6, CD49d and normal c-myc.
Positive Hans algorithm non-germinal centre DLBCL but PET/CT scan SUV ~4.
Unlike the 2 cases in that report I choose to be treated with V+O. Excellent complete response. Wasn't told the NHS couldn't do MRD testing as Atypical (flow cytometry gates on CD5) and not advised to get ClonoSEQ test privately.
I'm surprised that you're not 11qdel like me as you had massive LNs and are ATM deleted (usually associated with 11qdel). My own nodes did have high PET SUVs and PET was reported as probable Richter's.
I was treated with Acalabrutinib (no impact), a bispecific T cell engaging antibody (got worse) and finally V+R. It took a year but I had a good response of MRD negative to 10-6 and it was at that point that my Dr said it was AlloSCT time.
My Dr feels that treatment with Venetoclax should always be directed by MRD testing and it is possible to get that done in the UK on the NHS. Mine was done by both a local lab and by the HMDS Lab in Leeds ( hmds.info ). Arrangements will differ around the country. I'm not sure how your atypical cells make it difficult if they know what the atypical features are - they should be able to take that into account.
Turns out that NHS labs and consultants don't use the same terms that are used in clinical reports.
I've had another look at the CC letter to my GP it said "Interphase FISH shows deletion of ATM". More recent CC letters say "FISH studies showed SF3B1 variant and ATM deletion".
So I looked at the Molecular Analysis - Marrow report, it says :-
Interphase FISH shows monoallelic deletion of ATM in 95% of cells but no TP53 deletion.
I think FISH only tests 11q, 13q, 17p and Tri12.
Targeted next generation sequencing (NGS) analysis of a panel of key genes associated will CLL has identified a clinically significant (tier 1) variant c.1873C>t p.(Arg625Cys) in SF3B1, with a variant allele frequency (VAF) of 20%.
NGS test included ATM transcript version NM_000051.3 and NM_012433.4 for SF3B1, so I'm actually del(11q) without ATM mutation.
CLL14 genetics for 421 CLL patients, 26 ATMmut out of 77 del(11q) and 26 del(11q) out of 53 ATMmut.
In this early report for V+O from CLL14 trial, ATMmut and SF3B1mut had non-significant hazard ratios lower than unity.
del(11q) was associated with mutated ATM (OR, 6.12; P < .01) and BIRC3 (OR, 7.31; P < .01), both located on 11q, but also with NFKBIE (OR, 4.24; P < .01;). Patients with normal karyotype had a higher incidence of SF3B1 mutations (OR, 2.56; P < .01) and fewer TP53 mutations (OR, 0.35; P = .05).
(OR odds ratio)
I don't have the FISH report and now I'm wondering if I am/not del(13q). There is a possibility that the Molecular Analysis report only refers to poor markers from FISH.
Out of 15 subjects on CLL14 that were del(11q)+SF3B1mut 9 were also del(13q). In the whole cohort 221 out of 421 were del(13q). Then from the 15 I can remove the 7 that are ATM mut, 2 with Notch1, 2 XPO1 and 1 del(17p)/TP53mut, that leaves 3, 2 of which are del(13q) and all 3 are IgHV unmut.
Thank you for this, Neil. Do you happen to know whether O&V leads to anaemia? My stored iron was in the normal range before treatment but when they tested again at end of treatment it was 8. Should be a minimum of 30, I gather. I suppose the other question is whether anaemia is a predictor for aggressive CLL?
Thank you also for your constant and knowledgeable sharing of information with us all.
Incidentally, as far as I can see your post isn’t locked on this occasion. Is that because you’re happy to share this info with the general public? Just curious.
When I find something of general interest to anyone with CLL, I might post it unlocked, as that's how most new members find our community, through online searches. (That's why I deliberately spelled out "chronic lymphocytic leukemia/small lymphocytic lymphoma: unraveling CLL/SLL" in my title.)
CLL typically causes anaemia as it progresses, through reducing red blood cell production capacity as bone marrow infiltration increases, spleen enlargement filtering more red blood cells out of the blood before they reach the end of their life expectancy (should be about 100 days) and sometimes auto-immune destruction (AIHA). All CLL treatments can cause (nearly always) temporary anaemia, due to bone marrow suppression by the treatment protocol. It's usually only temporary, until the bone marrow recovers. That's why the anaemia trigger for starting treatment is when haemoglobin drops under 100; it allows for a buffer from the impact of treatment on your bone marrow before transfusions are required (typically under 80).
Sometimes there's incomplete recovery of the bone marrow after treatment, particularly for the older 'chemo' style treatments. Chronic inflammation (which can be caused by CLL) can increase hepcidin production, blocking iron transporters and reducing absorption, causing iron entrapment within storage pools, ultimately causing functional iron deficiency. I noticed that while my red blood cell count increased into the normal range during treatment, my haemoglobin recovery stalled. When I raised this with my CLL specialist, he conjectured that chronic inflammation from CLL could be the cause. Like you, I noticed my iron stores took a hit during treatment (ferritin dropped to 11). My specialist arranged an iron infusion and my haemoglobin recovered to the best it's been dating back to several years before my CLL/SLL diagnosis.
During my hospital stay earlier this year when they were investigating the possibility of RT (they were quite certain that's what I had based on my symptoms, but I had just had a PET scan a couple of weeks before and nothing lit up enough to suggest this), they never formally diagnosed me verbally with A-CLL but that was my conclusion based on my own online reading and review of my (many) labs. One thing that was mentioned in my bloodwork reports was the presence of "medium" sized cells. V+P is propping me up quite nicely for now. Hope this helps someone.
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