VOD1 Injury to the hepatic venous endotheliumEndothelial cell injury is seen in sinusoidal endothelial cells and

hepatocytes in zone 3 of the liver acinusDeposition of fibrinogen and factor VIII within the venular walls and liver sinusoidsVenular occlusionWidespread zonal liver disruption and centrilobular hemorrhagic necrosis, post-sinusoidal obstruction and portal hypertension

2 Weight gain, jaundice, peripheral edema, ascites, AMS/confusion, bleeding, renal failure, cardiopulmonary failure, hyperbilirubinemia, transaminitis, decreased synthetic function (albumin, INR, etc)

3 Heparin 4units/kg/hr D0D+30 or D/C, Ursodiol 12mg/kg/day/BID D-7 to D+304 Supportive care (minimize renal/hepatotoxic exposures, Na/fluid restriction, diuretics, HD for renal failure,

intubation/mechanical ventilation for respiratory failure), prostaglandin E, glutamine, vitamin E, alteplase, defibrotide,

GvHD1. Activation, proliferation and migration of donor T cells targeting non-self MHC antigens on recipient

tissues leading to immune tissue destruction2. Acute GvHD is defined as symptoms developing within +100 days post BMT which are mainly

localized to the skin, GI tract and liver. Chronic GvHD occurs after D+100 and can manifest as skin, liver, GI, respiratory, intraarticular or immune disease

3. Risk factors for GvHD include: older donor/recipient age, HLA mismatch, acute GvHD, unrelated or cord donor, viral reactivation, splenectomy, PBSC transplant

4. Clinical manifestations of GvHD include: maculopapular rash, alopecia, arthralgia, arteritis, transaminitis, increased bilirubin, cirrhosis, dysphagia, abdominal pain, diarrhea, bronchiolitis obliterans, cytopenias, pericarditis, pleural effusion

5. Tapering glucocorticoids is important to prevent adrenal crisis secondary to steroid HPA axis inhibition

6. Treatment for disease refractory to steroids after 3-5 days include: MMF, sirolimus, ATG, infliximab, thalidomide, photopheresis

mAbs1. An ideal mAb is specific against 1 target, interacts with the target leading to target cytotoxicity (ADCC, CDC,

apoptosis, immune destruction), should not be immunogenic and should only require single administration2. Mechanisms of action for mAbs include: ADCC, CDC, apoptosis-induction, and introduction of radioactive

cytotoxic entities3. Naming: murine =-mo-, chimeric=-xi-, humanized=-zu-, human=-mu-4. mAbs are advantageous over traditional chemotherapy because they target a specific antigen, have cytotoxic

effects at only the antigenic site, and are associated with fewer AEs5. Targets of current mAbs include: CD20, CD52, CD33, HER2, VEGFR, EGFR/HER1/ErbB

MTX/LCV1. DHFR inhibition leading to prevention of thymidine synthesis2. Mucositis, n/v/d, BMS, reash, alopecia, renal dysfunction, hepatoxicityfibrosis/cirrhosis3. HD-MTX improves drug distribution into larger solid tumors and sanctuary sites (CNS, testes), over and prevents

MTX resistant clones4. Given IT for CNS disease in leukemia, better CSF concentrations are achieved with a longer half-life; all while

decreasing systemic MTX exposure5. LCV works as MTX rescue by providing a reduced folic acid source to restore nucleotide synthesis in non-

malignant cells arrested by MTX administration. Additionally it competes with MTX for active membrane transport

6. LCV should start 24-48 hours after HD-MTX administration and continue until serum MTX level is <0.1 or per protocol

7. Methotrexate should be administered 10 days after peg-asparaginase to prevent pharmacological antagonism due to decreased rate of DNA replication following peg-asparaginase administration

Carboplatin Dosing1. The DLT of carboplatin BMS; primarily thrombocytopenia2. Children require a modified formula since they have greater weight variation, a larger variation in tissue

compartment and body size preventing assumption of constant non-renal clearance, the adult AUC formula under predict AUC in children by up to 41%

3. AUC is preferred over BSA due to more consistent exposure with PK-based dosing which ultimately increases response, AUC dose escalation has shown better responses in relapsed pediatric solid tumor patients, and decreased risk toxicity

4. Schwartz formula should be used to calculate CrCl in pediatric patients but is inaccurate in children <6 mo old5. Corrected GFR is adjusted to reflect the GFR as based on the size of the average adult BSA (1.73m2) while

uncorrected GFR is the GFR based on the patient’s actual BSA6. The three pediatric derived formulas are the Newell, Mann/Pein and Marina formula

TLS1. TLS is caused by the rapid lysis of cells following chemotherapy administration which leads to the spillage of

intracellular uric acid, potassium and phosphorus into the plasma causing uric acid nephropathy, secondary hypocalcemia and subsequent nephrolithiasis and arrhythmias.

2. Hyperkalemia, hyperphosphatemic, hyperuricemia and hypocalcemia3. Risk indicators for higher-risk disease include: Bulky disease or large tumor burden sensitive to chemotherapy or

rapidly proliferating disease (eg Burkitts), LDH >2x UNL, WBC >100K4. Management for low-risk patients is monitoring or based on clinical judgement. Intermediate-risk patients

require hydration at 1.5-2x MIVF with or without urine Alkalinization with sodium bicarbonate and allopurinol. High-risk patients should receive hydration plus rasburicase.

5. Uric acid samples following rasburicase administration must be immediately placed on ice

Aplastic Anemia1. Aplastic anemia is pancytopenia secondary to hypoplasticity or aplasticity of the bone marrow2. Medications implicating in causing aplastic anemia include: alkylating agents, antimetabolites, Anthracyclines,

carbamazepine, phenytoin, chloramphenicol, quinacrine, sulfonamides and acetazolamide3. Most commonly presents as anemia with fatigue and pallor, neutropenia and thrombocytopenia with visual

disturbances secondary to retinal hemorrhage4. New diagnosis patients may benefit from ATG, CSA, and steroids while severe aplastic anemia requires BMT5. Unrelated donor BMT patients also receive fludarabine, TBI, and a second dose of thymoglobulin (6mg/kg total

vs. 4mg/kg)6. Fludarabine can cause neurotoxicity, tachypnea and visual disturbances

Intrathecal Chemotherapy1. Factors influencing drug BBB permeability include: lipophilicity, unionized state, lower MW, limited PPB, and

high affinity for CNS protein carriers2. Advantages to IT chemotherapy administration include higher CSF concentration, minimization of systemic

toxicity, and longer elimination half-lives3. Disadvantages include: the need for and risk of LP, volume must match !0% of the patient’s CSF volume, and risk

of chemical arachnoidosis, leukoencephalopathy, subacute myelopathy and cognitive/learning disabilities.

4. Dosing is based on age rather than weight or BSA due to the necessity that the volume of IT administred must correlate with the CSF volumeof the patient

5. Toxicities associated with IT methotrexate include chemical arachnoidosis, leukoencephalopathy, subacute myelopathy and cognitive/learning disabilities

6. Methotrexate, cytarabine and hydrocortisone are drugs that are currently administered IT

Long-Term Complications of Chemo1. Treatment strategies for pediatric malignancies include chemotherapy, radition and combinations of the two.2. Endocrine reproductive effects include delayed/arrested puberty, hypogonadism, premature menopause3. Agents with higher incidences of cognitive dysfunction include IT therapy, cytarabine, methotrexate, cranial

irraditation4. Anthracyclines and high-dose cyclophosphamide are associated with cardiac toxicity5. Strategies for prevention of cardiotoxicity include limiting total exposure to <300mg/m2, dexrazoxane

administration, screening/ECHO or MUGA/EKG prior to each cycle and on an ongoing basis, avoidance of QT prolonging drugs, heart healthy lifestyle modifications