ASH 2014: Rough Notes from Dr. Clive Zent and Dr. Wiestner on Prognostic Factors and Resistance in CLL (chronic lymphocytic leukemia)

I found these notes that I had originally planned to use to develop blog posts based on a lecture that I attended at ASH 2014.

I still might do that, but first I am sharing this discovery in its raw form.

I took down all this information live on my laptop as it happened in December 2014 in a lecture hall at ASH, so expect it to be very rough and full of typos and mistakes. 

And don't take it for gospel! I have not done my usual fact checking.

Though it is still mostly unedited, I did try to clean it up a bit. Otherwise it would have been completely indecipherable for most. So I explained a few of the acronyms, improved the grammar, added the occasional punctuation, fixed some of the typos and provided some minimal text to help with context.

I wanted to share a sense of what I try to do at ASH and other cancer meetings. 

I wanted to share the velocity and volume of the information that sometimes comes from the podium. 

This is the raw material that I do my best to unpack, decode, make accessible, explain, contextualize, add relevant references, fact check, and publish here and elsewhere.

So this is hardly my usual blog post. I share it for two reasons:

1. First, it is full of incredibly valuable tidbits of information, albeit in bullet form with almost no explanatory notes.
2. Second, it shares a bit of a peek behind the curtains about what goes on at some of these huge medical conference.

Here goes.

Dr. Clive Zent

In the 1970s, the only testing for genetic testing and prognostic indicators was by karyotype analysis

Major limits- needs metaphase (not that common in CLL), needs BM (bone marrow). Only looks at whole chromosomes

1990s, we get FISH

Limits: can look at specific site only

Now we have a new era of genetic testing

Old school Sanger Sequencing needed 10% of mutation to find it, slow, expensive
PCR amplification needs only 1%
Next generation now look at whole gene- faster, cheaper
SNP arrays (clinical role unclear)
Copy # variations
Loss of heterozygosity

Usually only find 10-20 genes that are mutated
Usually found in " pathways"  controlling DNA repair such as TP53 + ATM
BRC
IGH

DNA damage responses ATM + TP53 related,  eons 4-9 (5-15%)
TP53 usually mono-alelle  5% at time of dx,
11q 10% (exon 68s)

Loss of function

Most common loss of one 17p with 80% of mutation on other gene
In contrast, 11q loss has only about 30% mutation on other gene
Can also have bi-allele losses

What does in mean?

Poor survival

BCR signaling pathways

no known mutations at start (abstract 297 disputes this) but somatic hypermutation, stereotypy

Notch1 10% at dx  in PEST domain
30% of those w RT
up to 20x inc risk of RT
BIRC3 11q22.2  near ATM  6 MB bases from 11q22.3  (asoc w loss of ATM0
significant on its own

RNA editing
SF3B1
splicing factor3 subunit 1
10% at dx
Poor Px dec resp to CIT

Clonal Evolution

No longer believe we develop new clones but start with small one that grow
Freq by FISH  (which is low) 4-5% year, but in next gen 20% after RX
Clinically important for resistance

Does clonal size matter?
Large # of mutations not findable yet, but sub clones of 17p matter even if low #

Comparison of MOLECULAR GENETICS AND PROGNOSIS

13q same as no CLL

TP53 BIRC3  worse

Moving forward

Very high risk-
 P53 and ATM (function testing)
High/intermediate

TP53 - No CIT ( chemo-immunotherapy)

Novel therapies then immune therapies including HSCT or CART1

NOTCH1 targeted theory
SF3B1

Summary Test TP53 and ATM (testing functioning coming soon)

Dr. Adrian Wiestner

Novel therapies in CLL
BCR Pathway
CLL a malignancy of anti-self" B cells
BCR  repertoire is skewed
Stereotyped BCR
often recognizes auto-antigen
Binds self motifs in itself

BCR activation in lymph nodes- CLL dependent on micro-envirnoments

IBRUTINIB NO MTD(maximum tolerated dose)!

RESPONSES WITHIN DAYS

Dramatic shrinkage of nodes but persistent lymphocytosis

With just 1 dose, lymph counts  jumps 50%

Larger patient to patient variability

Different patterns

Unmutated:  high ALC count quick up and downMutated: more SLL like, slower rise and fall- more durable results?

Most of the rise in ALC is from cell redistribution at first, but clear that IBRUT does much more
Measured tumor burden falls by CT and BMB

80-90% reduction: can start with trillion of cells

Cells in peril are not a concern: When you look they have inhibited BCR and NF kappa B and low Ki-67 suggesting no proliferation

Idelalisib PI3K delta  NO MTD!

Unaffected by adverse PX  factors inc 17p especially in first yr

IBR AEs
Diarrhea
AF 5% vs 0.5%  but much longer exposure
Bleeding mostly petechiae- not significant
Grade 3 or higher  no difference in either arm
IDEL AEs
Diarrhea 30%,7% colitis
20% Grade 3 Pneumonia

46% PFS  with 17p deletion

Complex karyotype  are the ones who progress- that is the group that progresses

PFS front line 17p del is >80%

Resistance:

Mutation Cysteine 481 is the problem,- IBRUT can no longer bind covalently (still weakly binds and  has some activity) Two cases of resistance, there was activated in PLC gamma 2 downstream (gain of function)

What about progression due to Richter's transformation?

Q: Is it more or less than without ibrutinib?

In 63 cases of 17p  RT was found in 23% at median of 12 months; risk factor was complex karyotype

Maybe it's actually less risk w Ibrut

Steve Treon

Ibrutinib in WM /LPL (Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma) by 

IGM falls by 75% and Hgb climbs

69% major response in WM