HSCT

Question 1

Definition: Conditioning

Answer 1

chemo +/- immunotherapy +/- total body irradiation to destroy person’s bone marrow prior to transplant. May include serotherapy (ATG or alemtuzumab) to prevent GVHD)

** Types **
Myeloablative
- requires stem cell rescue
- higher morbidity and mortality
Nonmyeloablative
- creates mixed chimerism
- relies on graft vs. tumor (GVT) effect to destroy remaining tumor cells

• *Notes**
• TBI avoided in children because of long term consequences

Question 2

Cyclophosphamide

Answer 2

** Indications **
Myeloablative HSCT Conditioning

• • AEs**
• cardiotoxicity (HF, myocarditis, arrhythmias)
• hemorrhagic cystitis
• VOD
• • Monitoring and Premeds**
• MESNA 1:1, hydration
• for heart palpitations and status (EKG and fluid management may be required)
• LFTs and ascites and jaundice
• • DDIs **
• prodrug requires CYP activation, so d/c CYP inhibitors 7 days prior to cyclophosphamide (ex: azoles, aprepitant, imatinib)

Question 3

Fludarabine

Answer 3

** Indications **
Non Myeloablative HSCT Conditioning

** AEs **
irreversible, progressive, fatal neurotoxicity (delayed 21 - 60 days after tx)

• • Monitoring and Prophylaxis**
• monitor for gait disturbances, speech difficulties, seizures, change in mental status, weakness

** Notes **
Renally eliminated, so requires renal adjust

Question 4

Busulfan

Answer 4

Indications
Myeloablative and Nonmyeloablative HSCT Conditioning

Requires therapeutic dose monitoring (TDM), with 1st and 3rd dose.

ADULT: AUC 900 - 1500; Css 615 - 1025
PEDS: AUC 900 - 1350; Css (615 - 922)

• *AEs**
• Seizures
• mucositis
• venooclusive disease (VOD)
• pneumonitis
• • Monitoring and Premeds**
• requires Keppra prior to prophylax seizures, continue until 24 hours after last dose
• LFTs and ascites and jaundice
• for lung tox (tx with high-dose steroids, usually within 4 months)
• • DDIs **
• acetaminophen shouldn’t be used, because glutathione required for busulfan metabolism
• CYP enzyme inducers (ex: phenytoin, dex, rifampin) will decrease efficacy by increasing metabolism. stop 7 days prior

Question 5

Veno-Occlusive Disease

Answer 5

** Consequences **
- weight gain
- hepatomegaly*
- jaundice*
- ascites
-hyperbilirubinemia
- CHF
- upper right quadrant pain *
need 2 - 3 * sx

• • Main Culprits **
• Busulfan
• cyclophosphamide
• *Treatment**
• defibrotide for at least 21 days, max 60

Question 6

GVHD

Answer 6

Acute (< 100 days post transplant)
- eyes, skin, GI and liver

Chronic (after 100 days)
- skin rash, N.V.D, abdominal cramping, jaundice, dry eyes

** Prophylaxis **
immunosuppressants post allogeneic transplant
- combination immunosuppressants to decrease toxicity

** Treatment **
Steroid pulses

** Notes **
stage IV GVHD has 0% survival

Question 7

Sirolimus

Answer 7

** Indication **
GVHD prophylaxis/Post HCST Immunosuppression

** Mechanism of Action**
Inhibition of T-lymphocyte activation

** AEs **

• • Monitoring **
• LFTs (dose reduce for hepatic impairment)
• • DDIs **
• CYP3A4 and p-gp substrate
• CNI DDIs, azoles increase [ ]
• • Notes**
• only available PO
• TDM (target 3 - 12)

Question 8

Cyclosporine

Answer 8

** Indication **
GVHD prophylaxis/immunosuppression post HCST

** Mechanism of Action**
Calcineurin inhibitor

** AEs **

• • Monitoring **
• SCr (must hold if > 2 mg/dL, and cut dose in half if SCr doubles)
• • DDIs **
• CYP3A4 and p-gp substrate
• increased [ ] with azoles, non-DHP calcium channel blockers and FQs
• decreased [] with CBZ, phenytoin, phenobarb, SJW, and nevirapine
• • Notes **
• Formulations are not interchangeable. (microemulsion usually used in HCST)
• TDM (target 200 - 400 ng/mL)

Question 9

Tacrolimus

Answer 9

** Indication **

** Mechanism of Action**
Calcineurin inhibitor

** AEs **

• • DDIs **
• CYP3A4 and p-gp substrate
• increased [ ] with azoles, non-DHP calcium channel blockers and FQs
• decreased [] with CBZ, phenytoin, phenobarb, SJW, and nevirapine
• • Monitoring **
• SCr (must hold if > 2 mg/dL, and cut dose in half if SCr doubles)
• • Notes **
• Requires TDM (target 5 - 10 ng/mL

Question 10

Mycophenolate

Answer 10

• • Indication **
• nonmyeloablative immunusuppression post HCST (with a calcineurin inhibitor)

** Mechanism of Action**
inhibition of DNA synthesis = lymphocyte apoptosis

• • AEs **
• nephrotox?
• • Monitoring **
• TDM: AUC0-12 60 - 60 mcg*hr/mL or Css >2.5 mcg/mL
• CrCL (dose reduce if <30)
• t. bili (dose reduce if >10
• • DDIs **
• acid- lowering drugs reduce absorption and bioavailability (ex: PPIs, H2RAs, cholestyramine)
• reduced [ ] with rifampin and corticosteroids (inducers)
• • Notes **
• mycophenolate mofetil (MMF) = prodrug
• CellCept = immediate release
• Myfortic = enteric coated
• IV to PO = 1:1