Analysing and Resequencing Gene Panels from the UK CLL4 trial (1999-2004) is helping patients today.

[Jm954]

The CLL4 study compared conventional chlorambucil therapy versus fludarabine - alone or in combination with cyclophosphamide - note there was no Rituximab in those days. End points were: survival, response to therapy, duration of response, toxicity and quality of life. For patients who required further treatment after relapse or second line therapy for non-responders, a second randomisation compared treatment guided by the protocol versus treatment guided by the in-vitro drug sensitivity DiSC assay.

Between 1999 and 2004, a total of 777 patients were enrolled in the trial. With follow-up of patients still continuing up to 20 years later, CLL4 has also provided an opportunity to investigate the prognostic value of a number of factors, including four genetic markers by FISH analysis, IGHV gene mutation status, beta2 microglobulin level, CD38 and ZAP-70 expression, mutation of the Notch1, SF3B1 and EGR2 genes and expression of CLLU1. Long-term data from the study have been used in an overview of international studies resulting in a robust prognostic system for CLL (CLL-IPI).

In 499 CLL4 cases they employed targeted re-sequencing of 22 genes, identifying 623 mutations. After background mutation rate correction, 11/22 genes were recurrently mutated.

Gene mutations in TP53 (with/without del(17p), termed ‘TP53ab’) and EGR2 were associated with reduced PFS. TP53aband recurrent mutations in SF3B1, NOTCH1 (+3′UTR), EGR2, RPS15, NFKBIE, BRAF, KRAS and NRAS were associated with reduced OS. Mutations in MYD88 were confined to IGHV-mutated (IGHV-M) cases, having no significant impact on OS in this subgroup of patients. TP53 mutations were associated with poor response, NOTCH1 + 3′UTR mutations were associated with death from Richter’s syndrome, whilst TP53, SF3B1, NOTCH1 + 3′UTR, KRAS and EGR2 were significantly associated with  a less than 10 year survival.

HOWEVER, remember that this data regarding survival is before most of the new targeted treatments and needs to be interpreted with caution nowadays. The main contribution of this study is in looking back at old samples and identifying common mutation information and perhaps their significance in today's therapeutic landscape.

More here; nature.com/articles/s41375-...

hematologyadvisor.com/home/...

Jackie

[Sushibruno]

I know this is old but i need to be careful what i read. I dont know why I'm like this and can't be a stronger person like allot of you here.

[sllincolorado in reply to Sushibruno]

Hi Sushibruno. You are very brave - you are willing to let us know how you feel. That is not an easy thing to do. This helps all of us. This data may be helpful in understanding how old studies are helping us now - but I selfishly only look at things with very current dates. The drug I am taking (acalabrutinib) was only approved for use for general CLL use several months after I started taking it. I take comfort in the great research that continues to be done with "old" studies and understand that the changes in treatment for CLL are moving forward astoundingly quickly.

Beautiful day in Boulder Colorado. Looking forward to getting in a walk during my work day.

Sending you lots of healing thoughts.

[Sushibruno in reply to sllincolorado]

Thank you my intention is not to offend anyone in any way. I put out what's on my mind somehow this helps me. Thank you for your wonderful response. Enjoy your walk😊. And i thank God that there are better treatments or there.👍

[johnl]

What exactly is +3UTR. ? john

[Jm954 Administrator in reply to johnl]

John,

Briefly, it's a ‘non-coding' mutation clustered to the 3′-UTR (3 prime end of an UnTranslated Region)of NOTCH1 found in 2% (11/506) previously the untreated patients.

The presence of these 3′-UTR mutations causes a novel splicing event, preferentially between a cryptic donor site located in the last exon and a newly created acceptor site in the 3′-UTR of exon 34, resulting in the removal of the PEST sequence and constitutive activation of downstream signaling.

The discriminatory power of the mutation status of 3′-UTR region of the NOTCH1 gene to predict outcomes is improved with the inclusion of non-coding mutations. Patients with non-coding NOTCH1 mutations have similar outcomes to those with coding mutations, with shorter time to first treatment and shorter overall survival than wild-type cases.

Hope this helps

Jackie