Thread by @ahmaruroojzaidi

Alright, should we do this? I'm going to attempt my first mini-#tweetatorial on this little capsule right here...

#hydroxyurea is currently the mainstay of disease modifying therapy in #sicklecell disease and with the new landscape of therapeutics, I think we should dive in /1

It was a century before its first clinical use in cancer that hydroxyurea was created by Drs. Dresler and Stein in Germany. The first approval for clinical use came in 1967 from the @US_FDA for oncological indications. /2

And then in 1984, two key papers in @NEJM and @jclinicalinvest by Letvin et al and Platt et al - FETAL HEMOGLOBIN production! And this of course was the 🔑 that unlocked the potential of HU in SCD. This was the game changer. /3

And in short order, the Phase I/II study out of @JohnsHopkins and Charache et al, first showed us what happens to patients with SCD on HU.

Because we don't just start people on medications for fun, without due diligence. Its science, bro. /4

You know how this story goes...

Increase in fetal hemoglobin.

No serious toxicity.

Patient's red cells developed striking macrocytosis (became bigger).

Hemoglobin concentrations increased. /5

But what does it do to pain? In 1995, the Phase III trial for HU showed what we needed it to - yes, you have LESS pain with hydroxyurea. Charache et al @JohnsHopkins bringing the 🔥. Approval of the use of hydroxyurea in adults with SCD came from @US_FDA in 1998. /6

But what the heck is hydroxyurea doing to my body? Why are nurses wearing gloves when they give it to me? Is it chemo? These questions come up frequently, and perhaps a look at how HU affects our bodies is warranted /7

Ribonucleotide reductase is an enzyme in our body that helps generate the LEGOs that build our DNA, and hydroxyurea shuts down this enzyme, reducing the amount of available LEGOs, causing all production of DNA to stop.

But in the RBC.../8

A stop of hematopoiesis causes red blood cell kinetics to be wacky when they recover; such ‘stress erythropoiesis’ features higher HbF through recruitment of early erythroid progenitors that keep their HbF-producing capacity

These red cells are bigger and more deformable. /9

This beautiful image illustrates (@BloodJournal ) exactly where hydroxyurea could be altering the balance in favor or survival and pain-free existence...Fetal hemoglobin, lower neutrophils and reticulocytes, improved rheology, reduced hemolysis, nitric oxide (NO) release /10

And the data to support HU kept pouring in...2010 prospective nonrandomized study involving 131 adults with SCD (all genotypes) followed for five to eight years found that death was lower in hydroxyurea-treated individuals compared with controls (10 versus 25 percent).../11

In pediatrics too! #SickleCell /12

And while we are on the subject of pediatrics, we should talk about BABY HUG a double-blinded, placebo-controlled randomized trial of infants 9–17 months of age with #SickleCell (also how Pediatric is that acronym😅😅) /13

The use of a lower dose of HU, didn't stop the trial from showing a tremendous reduction in acute clinical complications like fewer episodes of dactylitis and other painful vaso-occlusive events, fewer transfusions, and reduced numbers of hospitalizations. No bad events! /14

So all the kids are on it then right? Data published are dreary. 7963 children, six states, 2005 to 2012, 22,424 person-years, 78 percent had 0 days of hydroxyurea, 3 percent had 1 to 30 days, and 20 percent had >30 days. average number of days' supply in a year was 189. /15

Maybe this is related to safety concerns about this hydroxyurea? Maybe. But more likely is that we haven't presented this data accurately or correctly to families.

Does hydroxyurea cause cancer? Your doctor says no. But what do the data say? /16

NO EVIDENCE FROM PUBLISHED LITERATURE THAT HYDROXYUREA CAUSES CANCER IN #SICKLECELL

AND THIS IS CERTAINLY TRUE FOR OUR CLINICAL PRACTICE AS WELL.../17

Also from the experience of over 200 adults on the MSH trial - nine years after the trial started, three patients had developed a malignancy, including one each of breast, cervix, and uterus cancer. No additional cancers described after an additional 17.5 years of follow-up. /18

A 2004 report described outcomes in 122 children treated with hydroxyurea for up to eight years. No effects on growth or increased numbers of acquired DNA mutations. Clear that HU has sustained hematologic efficacy with
apparent long-term safety! /19

But enough about that - can I give you some #RealTalk?

There are concerns about taking hydroxyurea when wanting to start a family. It's a no-no for women who are planning to start a family. But it's also documented to reduce sperm count in men. An important consideration. /20

That being said, I want to quote Dr. Pat McGann from @CincyChildrens on why HU is a MUST.

"Hydroxyurea is the only available oral medication with proven disease-modifying benefits for the treatment of SCA... /21

"There is a large and overwhelming body of evidence consistently documenting the safety and efficacy of hydroxyurea...Hydroxyurea provides many benefits for SCA including reduction of both acute and chronic complications of this serious and life-threatening disease..." /22

The REACH trial was a real-world example bringing those words to life...A total of 635 children were enrolled; retention rate was 94.2% (!!!!!!) at 3 years of treatment.... Hydroxyurea therapy led increase in both the hemoglobin and fetal hemoglobin levels. /21

As compared with the pretreatment period, the rates of vaso-occlusive pain, nonmalaria infection, malaria, transfusion, and death decreased in this cohort of patients from sub-Saharan Africa with #SickleCell /22

We have just scratched the surface here folks...but I hope this is a good start to some light reading about hydroxyurea in #SickleCell.

This is the crown jewel in the therapeutic crown for now...and seems like it will be for a long time to come. /fin