Lec 1: Acute Leukemias

Question 1

Hematological oncology disease states: focusing on acute leukemias

Answer 1

Acute Leukemias consist of ALL (Adult acute lymphoblastic leukemia) and AML (Acute myeloid leukemia)

Question 2

What is acute leukemia?

Answer 2

• Classified based on cell of origin (myeloid vs lymphoid) - both arises from blood stem cells
• These leukemic blasts (immature cells)
  can “crowd out” normal cell in the bone marrow - This keeps the bone marrow from making healthy/ functioning blood cells.
• Fatal if untreated (within weeks – months) - symptoms can happen very quicky and progresses very quickly!
  .
  NOTE:
  Acute myeloid leukemia (AML) is a fast growing leukemia that starts in very immature forms of white blood cells (WBCs) called myeloblasts (or blasts for short). It’s also known as acute myelogenous leukemia.

As the blasts grow and multiply, they crowd out the normal cells in the bone marrow.

Question 3

Presentation of acute leukemias

Answer 3

• Leukocytosis or leukopenia
• Pancytopenia: fatigue, infections, gingival bleeding, ecchymoses, and epistaxis
  ———- Anemia
  ———- Neutropenia*
  ———- Thrombocytopenia
• Diagnosis: bone marrow (sent for pathology with morphologic examination, immunophenotyping, cytogenetic and molecular testing)
  ——- fluorescence in situ hybridization (FISH) a type of cytogenetic and molecular testing
  .
  NOTE: Neutropenia is due to disease and not a contraindication to start chemotherapy

Question 4

Tumor lysis syndrome (TLS) - what are the consequences/ what happens?

Answer 4

Question 5

Tumor lysis syndrome (TLS): Risk factors

Answer 5

• High risk malignancy (ALL, Burkitt’s lymphoma, diffuse large B-cell lymphoma)
• High tumor burden
• Patient factors: hyperuricemia, renal failure, etc.

Question 6

Prevention and management of TLS: What to use as prophylaxis before starting chemo? what is the management agent?

Answer 6

• Before starting chemotherapy: Allopurinol and Aggressive IV hydration
• Additional agents as needed: Rasburicase… Typically, reserved for highest risk patients or with high uric acid levels

Question 7

Treatment phases of AML

Answer 7

• Refractory/ relapsed can happen at any time
  -With intensive induction - you want to check for response and reevaluate after 1 cycle to make sure they are ok to continue

Question 8

AML: Patient assessment prior to starting treatment

Answer 8

• Patient age
• Comorbidities
• Type of AML (treatment related vs de novo)
• Cytogenetics and mutations – overall risk category
• Additional targets

Question 9

AML: Intensive Induction

Answer 9

Chemotherapy backbone: anthracycline (daunorubicin or idarubicin) with cytarabine
- “7 + 3”
- 3 days of anthracycline on days 1-3
- 7 days of cytarabine on days 1-7
.
Example regimen:
- Daunorubicin 60-90 mg/m2 D1-3
- Cytarabine 100-200 mg/m2 D1-7

Question 10

AML: Intensive Induction: therapy modifications and additions

Answer 10

Question 11

AML: Less intense options

Answer 11

Question 12

ALL background

Answer 12

Either B-cell ALL (B-ALL) Or T-cell ALL (T-ALL) - but we will be focusing on only B-ALL!

Question 13

B-ALL Treatment options

Answer 13

Question 14

B-ALL Treatment (targeted agent): BCR-ABL TKIs

Answer 14

• Can be added to protocol and regimens for Ph+ ALL
• PO chemotherapy
• Therapy selection: mutational panel, allergies, toxicities, inpatient (formulary limitation), outpatient (insurance approval)
  .
  1.) First generation: Imatinib
  2.) Second generation: dasatinib (Sprycel), nilotinib (Tasigna), bosutinib (Bosulif), ponatinib (Iclusig)

Question 15

B-ALL Treatment (targeted agent): BCR-ABL TKIs
.
Treatment options based on BCR-ABL1 mutation profile

Answer 15

No need to know this shid. Just know that Ponatinib has no mutation contraindications !!!!

Question 16

B-ALL Treatment (targeted agent): Blinatumomab (Blincyto)

Answer 16

Question 17

B-ALL Treatment (targeted agent): Inotuzumab ozogamicin (Besponsa)

Answer 17

• Antibody-drug conjugate
• Targets CD22
• ADEs: hepatotoxicity including sinusoidal obstructive syndrome (SOS) and veno-occlusive disease (VOD)
• Cytoreduction maybe required before starting therapy
• Primarily used in the relapsed refractory setting
  .
  NOTE: targets cells very effectively! you need to make sure that patient WBC count is in safe limit before you can start this medication.

Question 18

B-ALL: High-dose methotrexate

Answer 18

• “High-dose” Methotrexate = doses ≥ 500 mg/m2 IV
• Requires urinary alkalinization (with IV hydration to maintain urine output)
  —- Typically, with IV sodium bicarbonate (with D5W, SWFI or 1/2NS) - adjusted as need to maintain alkalinization and avoid over alkalinization (CO2 > 30)
  —- Measure urine pH q void
  —- Urine pH must be ≥ 7 before starting methotrexate infusion and maintained until
  methotrexate cleared (urine must be basic at start and end of regimen until drug is cleared out)
  .
• Requires leucovorin rescue (used with high dose methotrexate!)
  —– Initial dosing based on protocol (either flat dose or BSA based dosing every 6 hours PO or IV).
  —– Dose increased if needed based on supratherapeutic time dependent methotrexate levels.
  .
  NOTE: we want urine pH at or above 7! Even if we have to give CO over the “normal limit” of 30! (30-33 is ok -the risk to this is minimal compared to accumulation of MTX) So if urine pH drops? give more Bicarb!

Question 19

B-ALL: High-dose methotrexate continued… monitoring, DDI, rescue medication

Answer 19

• Requires routine methotrexate level monitoring
  —– Typically starting at 24 hours post infusion
  —– At least daily until methotrexate cleared = MTX level of ≤ 0.05 μmol/L
  —– If accumulation suspected need to increase frequency of monitoring
• Avoid any drug-drug interaction which could interfere with methotrexate clearance
• Monitoring: Scr, Bicarb/CO2, urine pH, urine output, MTX levels
  .
  Rescue medication
  Glucarpidase:
• Emergency medication used if patient is at risk of life-threatening toxicity due renal
  toxicity/injury due to or while clearing methotrexate (impaired clearance,
  accumulating)
• Rarely used

Question 20

B-ALL: High-dose cytarabine

Answer 20

• High-dose considered generally ≥ 1,000 mg/m2
• ADE: Cerebellar and cerebral toxicity, conjunctivitis
  .
  Supportive care:
  -Eye drops start with cytarabine and continue for 48 hours after the completion
  —-Dexamethasone 2 drops each eye every 6 hours
  —-Artificial tears 2 drops each eye every 4 hours

Question 21

Intrathecal (IT) chemotherapy

Answer 21

• Indications: prophylaxis or treatment (this depends on the result - LD blast 0% OR they have not gotten diagnosis yet? = prop.)
• Any pediatric patient with acute leukemia (ALL or AML doesn’t matter) and adults with ALL: required to get diagnostic LP, with IT chemo given during procedure
  .
  Safety considerations:
• Sterile preparation
• No preservatives
• Prepare on demand (short turnaround time)
• Administration: Ommaya vs IT injection (different doses and volumes)

Question 22

Therapeutic agents and dosing for IT chemotherapy… Generally dosing schedule varies based on indication (treatment or
prophylaxis) and chemotherapy protocol…
WHAT ARE THE REGIMEN AND DOSING?

Answer 22