CRISPR for SCD

[nimbus]

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Seems like a new world but not without its challenges. Would love some insights/opinions from those directly involved.

F.D.A. Approves Sickle Cell Treatments, Including One That Uses CRISPR (Published 2023)

People with the genetic disease have new opportunities to eliminate their symptoms, but the treatments come with obstacles that limit their reach.

www.nytimes.com

FDA Approves World’s First Crispr Gene-Editing Drug for Sickle-Cell Disease
FDA Approves World’s First Crispr Gene-Editing Drug for Sickle-Cell Disease

 

[gutonc]

Definitely cool but it's going to take some time before it's a paradigm shifting treatment.

If you read the article, you'll note that only 9 centers are being considered for being able to administer the treatment and even the most ambitious of them say they can only treat 5-10 people a year. Even at maximum rate and assuming no obstructions by insurance companies or CMS (ROFLMAO), it would take 1100 years to treat the 100K people currently living with SCD in the US.

 

[CatFactorial]

Agree with above

Also, even if done at select centers, haplo HCT in SCD is curative

 

[HemeOncHopeful19]

Agree with above

Also, even if done at select centers, haplo HCT in SCD is curative

I mean surely we can shoot for loftier goals than a haplo HCT though.

 

[CatFactorial]

I mean surely we can shoot for loftier goals than a haplo HCT though.

Meaning what? Compelling data for haplo in SCD, and it is less costly if less lofty.

 

[gutonc]

Meaning what? Compelling data for haplo in SCD, and it is less costly if less lofty.

I think I'm in both camps here.

Something "better" than haplo SCT would be great. But we also need something both easier and cheaper, and this therapy clearly isn't that...yet.

 

[CatFactorial]

Allo HCT is not what it was in terms of transplant related morbidity and mortality. PTCy, ruxolitinib, ECP, plenty of highly effective GVHD meds.

Also, sickle cell does not require any graft versus leukemia effect, so one can crank up the immunosuppression and quash any GVHD without worrying about relapse

 

[gutonc]

Allo HCT is not what it was in terms of transplant related morbidity and mortality. PTCy, ruxolitinib, ECP, plenty of highly effective GVHD meds.

Also, sickle cell does not require any graft versus leukemia effect, so one can crank up the immunosuppression and quash any GVHD without worrying about relapse

So then, to play devil's advocate here, why aren't we doing 10-20K of them a year? or even 5K?

I will also freely admit that I stopped keeping up with SCT the minute I passed my boards a decade ago. I will again learn all about it next year in order to forget it again before Labor Day.

 

[HemeOncHopeful19]

So then, to play devil's advocate here, why aren't we doing 10-20K of them a year? or even 5K?

I will also freely admit that I stopped keeping up with SCT the minute I passed my boards a decade ago. I will again learn all about it next year in order to forget it again before Labor Day.

Why in the world would you review SCT for Onc boards, don’t waste that time!

UpToDate cites 15% GVHD for Sickle Cell Transplant. All I meant was surely we can shoot for a better treatment in the future, whether it’s this new fangled genie-therapy or something we’ve yet to discover! Did not mean to offend our resident transplanter 🙂

 

[Duke1K]

So then, to play devil's advocate here, why aren't we doing 10-20K of them a year? or even 5K?

I will also freely admit that I stopped keeping up with SCT the minute I passed my boards a decade ago. I will again learn all about it next year in order to forget it again before Labor Day.

Donor availability has been a major issue (now obviated by haplo), as well as comfort of transplanters with this population (particularly being less successful in adults with higher TRM/GvH for a non-lethal condition), and probably health equity issues re: access and referrals.

Gene therapy will inevitably be less expensive over time and if curative, worth the money for a young sickle cell patient (unlike other very expensive onc meds that have no chance for cure). The haplo data is extremely encouraging but without good biomarkers to predict GvH, the preferred option with all things being equal is gene therapy. Right now I'd rather transplant SCD but 10 years from now, most likely gene therapy.

 

[CatFactorial]

So then, to play devil's advocate here, why aren't we doing 10-20K of them a year? or even 5K?

I will also freely admit that I stopped keeping up with SCT the minute I passed my boards a decade ago. I will again learn all about it next year in order to forget it again before Labor Day.

Only done at few programs which have considerable experience and logistical support and have the right patient population (Hopkins, Vanderbilt, etc)

In SCD, donor grafts require marrow, not peripheral blood stem cells, so only places where folks are credentialed to do OR marrow harvests would work for a sickle program

While I have treated HbSS patients with bad GVHD, they are the exception to the rule. ATG, PTCy and marrow grafts really reduce the risk of GVHD

 

[gutonc]

Only done at few programs which have considerable experience and logistical support and have the right patient population (Hopkins, Vanderbilt, etc)

In SCD, donor grafts require marrow, not peripheral blood stem cells, so only places where folks are credentialed to do OR marrow harvests would work for a sickle program

While I have treated HbSS patients with bad GVHD, they are the exception to the rule. ATG, PTCy and marrow grafts really reduce the risk of GVHD

Which (to play devil's advocate again) puts it about the same level of accessibility as CRISPR based treatment.

 

[CatFactorial]

Which (to play devil's advocate again) puts it about the same level of accessibility as CRISPR based treatment.

Fair enough

 

[randomhemoncpd]

Only done at few programs which have considerable experience and logistical support and have the right patient population (Hopkins, Vanderbilt, etc)

In SCD, donor grafts require marrow, not peripheral blood stem cells, so only places where folks are credentialed to do OR marrow harvests would work for a sickle program

While I have treated HbSS patients with bad GVHD, they are the exception to the rule. ATG, PTCy and marrow grafts really reduce the risk of GVHD

Are there a lot of transplant centers that don’t have the capacity to do marrow grafts? I’d figure most transplant centers that do more than a few token allos a year should have the capacity to do them.

Decision making with allo for non malignant conditions is always hard — at the end of the day the best techniques we have still leave some risk of NRM, GVHD, etc so it’s still only reserved for the worst of the worst cases (recurrent acute chest, strokes despite maximal medical management, etc). Yes you don’t worry about recurrent disease so you can go lower on conditioning and optimize GVHD prophylaxis but too little conditioning and your graft will fail (especially with a marrow graft despite only needing partial chimerism) and too much immunosuppression raises the risk of infections especially in patients who are already iron overloaded, functionally asplenic, etc.

In good hands it goes pretty well most of the time, but even still occasionally things will hit the fan and you wonder what the natural history for that patient would have been with intensive medical management.

No doubt that gene therapy will become the standard at some point in the future for these monogenic marrow disorders but in the interim we’ll still wrestle with the role of allo for these patients.

 

[SurfingDoctor]

Seems like a new world but not without its challenges. Would love some insights/opinions from those directly involved.

F.D.A. Approves Sickle Cell Treatments, Including One That Uses CRISPR (Published 2023)

People with the genetic disease have new opportunities to eliminate their symptoms, but the treatments come with obstacles that limit their reach.

www.nytimes.com

FDA Approves World’s First Crispr Gene-Editing Drug for Sickle-Cell Disease
FDA Approves World’s First Crispr Gene-Editing Drug for Sickle-Cell Disease

I knew the dude who published the first clinical trial in NEJM back in 2021. Complete douchebag…

That being said, CRISPR will change the world far beyond blood dysplasias.