Friends
Obinutuzumab was approved for treatment naive patients, but in only in combination with chlorambucil.
That is a very limited indication and I don't like that
You might want to read my blog commentary on the issues swirling around this FDA decision.
Stay strong
Brian
Thanks for the link to your interesting commentary Brian on Gazyva/Obinutuzumab. It will indeed be interesting to see if this limited indication by the FDA influences future trial designs.
Most of the readers on this site will be wondering how many years will slip by before Gazyva is approved in their country, but this fast approval in the USA is a great start, even if it is for such limited usage.
Chris/CLLCanada has posted about the Gazyva approval, including links to the Gazyva Website and Gazyva Prescribing Drug Label here:
healthunlocked.com/cllsuppo...
Neil
Thanks Brian, always appreciate your input.
Thanks for posting your thoughts to your Blog Brian
The European Licensing Agency (EMA) licence application is awaiting approval ahead of this there has been a submission to NICE for Single Technology Appraisal of Obinutuzumab (Gazyva) for previously untreated chronic lymphocytic leukaemia which has been through NICE scoping and the full appraisal is awaiting confirmation to proceed from UK government health ministers.
The full appraisal should proceed following EMA licensing, FDA approval is encouraging news and should speed up progression. But until final trial data is released at ASH in December there will be little progress here in the UK.
As with the FDA application the EMA and NICE appraisals are focusing on use of Gazyva as front-line therapy in combination with Chlorambucil for treatment naive patients. these are those who may be unsuitable for treatment with FCR or BR and make up a significant population who may gain more effective treatment as a result of this in the UK.
At the moment this population only has Chlorambucil as a single agent approved by NICE in the UK for NHS use.. Perhaps this trial design may aid this changing? However following on from Brian's thoughts it should be noted that the Chloranbucil dose used in the trial is below the UK standard.
I believe for this drug to be considered in other applications specific data from relevent studies will be required.
It must be noted that there is also a second humanised monoclonal in with the EMA in combination with Chlorambucil that is Ofatummumab this is also in with NICE ahead of license approval and data being made available at ASH in December.
Ofatumumab failed when first submitted for NICE approval several years back. So it is important UK treating clinicians do have a next generation monoclonal available to them.
To my knowledge the novel small molecule BCR inhintors are not in the NICE system yet but following on close behind. It must be remembered that NICE approval rules are not flexable and drug will only be approved in relation to how it has been studied and the specific data that produces and the QALY nice.org.uk/newsroom/featur... It is therefor very likely that in the beginning novel therapies if approved in the UK will have very narrow applications to those populations in which it has been trialled in.This will also be some time in the future too
NICE approval is quite a lengthy process, CLLSA are represented in this process and will keep you informed on developments
Nick
You can read Dr. Sharman's views as well here ... He trailed Gazyva in early Phase 2. Very interesting on infusion reactions and MRD.
cll-nhl.com/2013/11/gazyva-...
Very interesting. Thanks. Jeff Sharman has had personal experience using the drug and the kindness to share his experience. He does good work for us CLLers at so many levels.
Sorry I cut the initial infusion reactions from my earlier reply this will need some work as it was with Rituximab. It is very encouraging that this therapy is providing MRD in some.
It was very interesting to read your blog, Brian. But I was surprised to see that the trial was comparing chlorambucil alone, against chlorambucil with obinutuzumab. As you say, that really does sound like a "fixed race". Maybe I am missing something, but it is disappointing to think single agent chlorambucil would have been chosen as a competitor just because it is easily beaten. It doesn't help our confidence in the researchers' integrity. Or are there other factors here, that I haven't understood?
Paula...chlorambucil has been the 'whipping boy' comparator for years...fludarabine and bendamustine were mainly approved using it ...
It is still one of the best therapies for older patients. Dr. Hamblin thought so... if it is properly dosed... there has been fudging of dosing of chlorambucil on occasion... The Bendamustine trial was a case in point... Hamblin thought...
'That seems to be alright, but then I read the paper more carefully. The two drugs were given according to quite different formulae. Bendamustine was given in a dose of 100mg/sq meter for two days every 4 weeks, while Chlorambucil was given in a dose of 0.8 mg/kg for two days every two weeks. It seems strange that two different calculations were used and even stranger when I see that rather than weighing the patients they used something called Broca's normal weight.
I didn't have a clue what Broca's normal weight was and I am pretty sure that most people reading the paper won't have either. So I Googled it. It turns out to be the height in centimetres minus 100. Does this give the same answer as weighing? By no means. I am 176cm high so my Broca weight is 76kg. Alas my scales make me 90 kg.
If I calculate the dose of chlorambucil I would have got under the LRF4 formula it would have been 148 mg, but under the Bendamustine paper formula it would have been 123 mg. I'm afraid my ideal weight is a little less than my actual weight. For my mother the discrepancy would have been even more. She is only 5ft 3, but weighs about the same as me. The Bendamustine paper would have given her 96 mg of Chlorambucil while the LRF4 calculation would have given her 139 mg. Since most people today weigh considerably more than their ideal weight, it looks to me that the chlorambucil dose given in this trial was too low for a fair comparison.'
mutated-unmuated.blogspot.c...
Have just read your link to Dr Hamblin's article, Chris. (Well I read some of it - most was way beyond my limited brainpower). His criticism of the Bendamustine/Chlorambucil trial is very powerful - quite frightening really. Certainly doesn't allay anyone's fears re researcher's integrity. I also followed Neil's link to Chaya's endorsement of Dr H's opinion, and she is even more forceful about it.
It's hard to think they can get away with calculating doses in such different, biased ways, like that. Has anyone from that research project been directly challenged about this, and if so, I wonder what their response was?
Trouble is, these things throw doubt onto all trials, especially with Bendamustine, which is probably unfair.
Here is the early CALGB discussion by Dr. Hamblin dealing with fludarabine and chlorambucil.
'Far be it for me to suggest that there was any irregularity in the choice of dose of chlorambucil in the CALGB trial, but the effect of this choice has been to maximize sales of fludarabine.' 
mutated-unmuated.blogspot.c...
And what do you think of Dr. Hamblin's comment further down:
"More important 8.8% developed Richter’s syndrome, which as we now know is frequently cause by failure of control of existing EBV infection."
Some RT is EBV related, some is not. Any drug that suppresses immunity increased the risk of EBV reactivation. Add to that drug that damages DNA, and it is easy to understand Dr. H's concern.
EBV as Brian says is only involved in some RT, and now the feeling is it more in Hodgkin's RT than DLBCL. A recent paper in Blood suggest that along with NOTCH1 and MYC pathway
'Cell cycle deregulation via inactivation of TP53 and of CDKN2A was a main mechanism in the histologic transformation from CLL-phase, being present in approximately half of the cases, and affected the outcome of the RS patients.'
Further, RT lesions are genetically different than either the two types of DLBCL and there is a CLL Richter's phase, that predates the actual transformation...
This is one of a number of papers coming out of Italy, which seems to be doing a fair amount of RT research...
How weird that they would use a table to assess dosage when one is weighed at every consultation and that information is therefore readily available.
Unless of course not all cinics weigh at every visit.
Bub
Read Chaya Venkat's Update on this, where Chaya praises Dr Hamblin's independent, honest appraisal of the Bendamusine/Chlorambucil trial:
updates.clltopics.org/1498-...
Broca's normal weight probably would have given much closer dosages to the dose per square metre when it was first proposed in 1871 given the slimmer population back then - but given it doesn't take into account weight, I'd be very interested in the drug company's scientific reasoning for using it in place of the method used for Bendamustine patients. This different dose calculation methodology would have also complicated keeping this trial a double blind trial...
I can't believe patients on the trial weren't weighed regularly either. I've had about 20 haematology appointments and never been treated for CLL, yet the only time that I wasn't weighed was when the scales were out of order and even then I'm pretty sure I was asked whether my weight had changed.
Neil
Thanks Neil
I had read and forgotten this update ages ago, before I joined the site. We owe so much to Chaya, the amount of work she put in. I always feel she made a bridge through the minefield of information for people like me who come to CLL knowing nothing, but with a need to learn. Once I've caught up with information kindly provided by Hairbear, I think its time for me to revisit Chaya's website. I understand a little more each time.
I hope life is being kind to her now she has put her devotion to helping we CLLers behind her and moving forward with her life.
Thank you
Bub
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