Colony Stimulating Factors

Next up we have colony stimulating factors. Remember from somewhere about 1000 words ago that chemotherapy can absolutely torch the bone marrow.

The cytotoxic agents all target fast growing cells, and that means your white blood cells, your platelets, and your red blood cells can sustain heavy losses after each cycle.

This creates all sorts of problems.

Low WBCs open your patients up to infections. Low platelets introduce a bleeding risk. And low RBCs leave your patients feeling anemic and tired.

So, as loving health care professionals, we try to mitigate these risks. We try to prevent (or at least manage) them.

Most importantly, we aim to keep the WBCs (and specifically the neutrophils) in check. There's an entire section later in this post dedicated to neutropenic fever, so I won't spoil the surprise for you here. But suffice it to say (for now) that low neutrophils = low immune system.

Cancer patients are prone not only to the same infections that hamper all of us, but also to things that only cause infections in "immunocompromised" people. Things like TB, CMV, PCP and so on.

Further, many chemo regimens require a patient to keep a permanent central line in place. Mix this with frequently being in and out of health care facilities and you get a risk of super bugs like MRSA and Pseudomonas.

Granulocyte Colony Stimulating Factors (G-CSF)

Granulocyte is a fancy way of saying "neutrophils." The package insert lists off 5 or 6 indications, but at the end of the day it's simple...

We give these to either prevent or treat neutropenia (and all that's associated with neutropenia).

So if a patient's ANC (absolute neutrophil count) dips too low after a particular cycle of chemo, we'll give a G-CSF to help correct it (and start giving them prophylactically after the next cycle).

If the patient is receiving a chemo regimen that's expected to drop the ANC, we'll give a G-CSF prophylactically ahead of time.

How do you choose a G-CSF? Once again, it's convenience and formulary preference.

Here's a quick break down:

filgrastim [Neupogen] - 5 - 10 mcg/kg/day daily SubQ or IV

filgrastim-sndz [Zarxio] - biosimilar for Neupogen. The same dosing applies

tbo-filgrastim [Granix] - It's kind of like a biosimilar for Neupogen...but technically it obtained it's own FDA approval before the biosimilar program existed (so you cannot call it a biosimilar). It is not FDA approved for as many indications as Neupogen or Zarxio, but it is used in practice for all of the same things. For what it's worth, CMS has assigned the same J-code to Neupogen, Zarxio, and Granix. This basically means that CMS considers them interchangeable. The dosing is the same among all 3 agents.

pegfilgrastim [Neulasta], [Neulasta Onpro] - 6 mg SubQ once per cycle of myelosuppresive chemotherapy.

pegfilgrastim-jmdb [Fulphila] - biosimilar for Neulasta. The same dosing applies.

pegfilgrastim-cbqv [Udenyca] - biosimilar for Neulasta. The same dosing applies.

pegfilgrastim-bvez [Ziextenzo] - biosimilar for Neulasta. The same dosing applies.

pegfilgrastim-apgf [Nyvepria] - biosimilar for Neulasta. The same dosing applies.

sargramostim [Leukine] - 250 mcg/m2/day daily SubQ or IV. Leukine is actually a GM-CSF (it stimulates both granulocytes and macrophages). It's primarily used for stem cell/bone marrow transplants, although it also has an indication for AML.

Holy cow, that’s a lot of biosimilars. If the concept of biosimilars confuses you, you can get our quick and dirty summary here.

G-CSFs (and GM-CSFs) are pretty well tolerated, but here's a few quick clinical pearls...

For testing purposes, note the subtle differences in dosing.

Neupogen is mcg/kg and it's daily...

Leukine is mcg/m2 daily...

Neulasta is a flat dose in mg and it's only given once per cycle...

You can weed out multiple choice answers with this information.

We don't start any of these (except the Neulasta Onpro) until 24 - 72 hours after chemotherapy. Why? If we give them before or during chemotherapy, all of the neutrophils they stimulate are going to be killed by the chemo.

The Neulasta Onpro is a new, "on-body injector" that the nurse can stick on the patient in the infusion room the same day of chemotherapy. It auto-injects itself 27 hours later.

This saves the patient from returning to the infusion center a day or two later for Neulasta. Of note, the patient cannot shower while wearing Onpro.

One of the primary side effects of G-CSFs is bone pain (which makes sense given their mechanism). Somewhat strangely, we can use antihistamines (typically loratadine) to help manage this pain.

The main "really bad thing" to watch out for is splenic rupture. G-CSFs (and GM-CSFs) can clog up your spleen. A ruptured spleen can be fatal. There's also a small risk of anaphylaxis and other injection site reactions.

Erythropoietin Stimulating Agents

Erythropoietin Stimulating Agents (ESAs) are the same concept as G-CSFs, except they stimulate red blood cell (RBC) production.

The majority of ESA usage is in chronic kidney disease (CKD). Your kidneys supply your body with erythropoietin, and as their ability declines with time you get less erythropoietin.

Less erythropoietin = less RBCs (which means anemia, poor oxygenation, etc...). So it is very common to use an ESA in kidney failure.

Much less common is ESA use in cancer. As it turns out, ESAs are associated with an increased risk of death and tumor progression in cancer patients. They are only indicated for chemotherapy-induced anemia.

That means the patient must have very recently had (or currently be receiving) chemotherapy.

Additionally, ESAs are only for palliative chemo. If the treatment goal is "cure," ESAs cannot be used. ESAs are never used prophylactically. They are also not used for AML or CML. And you only treat to an Hgb of 10.

Alright, got all of that? Good.

ESAs come in a couple of flavors.

Epoetin alfa [Procrit], [Epogen] is dosed in units. It's usually given several times per week.

Epoetin alfa-epbx [Retacrit] - a biosimilar for epoetin alfa

Darbepoetin [Aranesp] is dosed in micrograms. It's usually given once every 1 - 2 weeks.

Therapeutically, all of the above are considered equally efficacious. Cost, convenience, and formulary will (again) drive your decision in terms of which to use.

As for a couple of clinical pearls...

You won't see an increase in Hgb/Hct for about 2 - 6 weeks. These are not drugs that work overnight. It takes time...and consistent use is key to achieving an increase. And even then, the benefits may be modest.

There are several risks associated with use. Most notably, hypertension, stroke and venous thromboembolism (VTE).

You'll find the general goal for ESAs is to decrease blood transfusions. We don't treat to a "normal" Hgb. We typically stop around 10 or 11.

This helps to mitigate some of the unpleasant side effects...as well as the unpleasant cost of ESAs.

And for your next round of "drug trivia," or for you HIV buffs, ESAs also carry an indication for zidovudine-induced anemia.

Their use here is pretty rare. We typically just switch patients from zidovudine to something else. But the indication is there, living as a remnant from an age where zidovudine was the only HIV drug.

Platelet Stimulating Agents

Last up, we have the platelets. It's a very rare day that you will see these used in chemotherapy. But for the sake of completeness, we're gonna include them here.

Platelet stimulating agents are used primarily in patients with idiopathic thrombocytopenia purpura (ITP). And even then, they're not first line agents.

We typically start with steroids or immune suppressants and graduate up to IVIG or even plasmapheresis (which is sort of like dialysis, but it filters the antibodies from your blood).

Platelet stimulating agents are added on only for refractory symptomatic treatment.

All of that is to say...

These are never going to be your first line treatment choices on a test. And relating to cancer, we tend to just use good ole fashioned platelet transfusions instead of exposing the patient to another drug that stimulates cell growth.

Anyway, as for the drugs...

Oprelvekin [Neumega] - The only platelet stimulating agent that has an FDA-approved indication for chemotherapy-induced thrombocytopenia. It's an IL-11 stimulator that stimulates megakaryocyte stem cells (which then go on to make platelets). It's usually dosed at 50 mcg/kg SubQ daily.

Eltrombopag [Promacta] - This is unique because it's given PO. It's a thrombopoetin receptor stimulator, which directly stimulates platelet production. It starts at 50 mg PO daily for adults and is dose-adjusted to keep the platelets above 50 (max dose of 75 mg daily).

Romiplostim [NPlate] - Similar to Promacta, except that it is a SubQ injection. But it is also a thrombopoetic receptor stimulator. It's starting dose is 1 mcg/kg once weekly and it's also dose-adjusted to keep platelets above 50 (max dose of 10 mcg/kg)

And for some clinical pearls...

These drugs all stimulate platelets...so there is an inherent clotting risk with all of them. Make sure to monitor your patient for signs of clotting.

Also, the formulation of Neumega is derived from E. coli, so there is a decent risk of anaphylactic infusion reactions. These will most likely occur on the first cycle.

And finally, these drugs just may not work for your patient. The general rule of thumb is that if there is no effect on platelet count after 4 weeks to discontinue use.