Hematologic Malignancies: AML, ALL, CML, and CLL

Leukemia

A type of cancer of the blood and/or bone marrow that is characterized by an aberrant increase of immature white blood cells (WBCs) called blasts

•History and Physical

•CBC w/diff

•Folic acid and Vitamin B12

•Clotting panel-PT, INR, and fibrinogen

•Bone marrow biopsy-assessment of blasts: morphologic evaluation, cytogenetic analysis, and molecular analysis

•TLS panel- CMP, uric acid, magnesium, phosphorus, lactate dehydrogenase

What do we do for the initial evaluation for leukemia?

Uric acid is used to monitor metabolic abnormalities associated w/tumor lysis syndrome. When we lyse WBCs in chemotherapy, cell remains accumulate creating a build up of uric acid and electrolyte abnormalities

Why do we obtain uric acid labs in initial evaluation of leukemia?

•Cough

•Unexplained bruising

•Pain in bone, joints, or abdomen (due to overcrowding of WBCs)

•Frequent infection (functional neutropenia)

•Tiredness

•Unexplained fever

•Unexplained rash

•Unexplained weight loss

•SOB

•Paleness

•Drenching night sweats

•Lumps of swelling

Symptoms of leukemia?

AML

What is the most common form of leukemia?

•Increased age

•Gender, men more likely to develop AML

•Previous cancer treatment

•Exposure to high levels of radiation or dangerous chemicals

•Smoking

•Hx of blood disorders

•Genetic disorder

Risk factors of AML?

•Fever

•Fatigue

•Easy bruising/bleeding

•SOB

•Weight loss/loss of appetite

Symptoms of AML?

Diagnosis can be made if they meet one of the following criteria: (1). ≥ 20% myeloblasts in the marrow or blood (2). one of the following cytogenetic abnormalities even with < 20% blasts [t(8;21), t(16;16), and inv(16)]

Diagnosis of AML?

•Age > 60 y/o

•Baseline performance status

•Cytogenetic profile

•Mutational burden

•WBC at baseline

•Secondary AML

Prognostic factors of AML?

•Midostaurin

•Quizartinib

Which therapies are targeted for FLT3?

•Ivosidenib

•Enasidenib

Which therapies are targeted for IDH?

Gemtuzumab ozogamicin

Which AML therapies are targeted for CD33?

•Cytarabine 100-200 mg/m² continuous infusion for 7 days + Daunorubicin 60-90 mg/m² or idarubicin 12 mg/m² IV push for 3 days

•7+3+GO (only those with CD-33 positive disease): ADD on gemtuzumab ozogamicin 3 mg/m² IV (Max 4.5 mg/dose) on days 1, 4, and 7

What is 7+3/ 7+3+GO for AML?

•Consolidation therapy for patients with favorable risk

•Add GO if CD33+: Gemtuzumab ozeogamicin 3 mg/m² (max 4.5 g/dose) IV on day 1 of the first two cyles

•Cytarabine 1.5-3 mg/m² Q12H on days 1,3, and 5 for 3-4 cycles

What is HiDAC therapy for AML?

450-550 mg/m²

What is the max lifetime dose of doxorubicin?

Dexrazoxane (Zinecard)

What is a cardioprotective agent used for the prevention of doxorubicin cardiomyopathy?

Dexrazoxane (Totect)

What is used for the treatment of anthracycline extravasation?

LVEF<50%

At which LVEF would we not recommend an anthracycline?

Gemtuzumab ozogamicin

•Common uses: AML

•MOA: CD33 targeting antibody-drug conjugate with a calicheamicin derivative cytotoxic payload

•Boxed warning of hepatotoxicity (risk of veno-occlusive disease), myelosuppression, hemorrhage, and infusion rxns

•Supportive care includes corticosteroids, antipyretic (APAP), and an antihistamine

•Monitoring: CBC, LFTs, and vital signs during infusion

Midostaurin (Rydapt)

•Class: 1st generation, type 1 FLT3 inhibitor

•Indication (within AML): newly diagnosed FLT3- positive AML (both FLT3-ITD and FLT3-TKD) in combo w/standard chemotherapy induction and consolidation

•Toxicities: bone marrow suppression, GI (N/V), rash, and QT prolongation

Quizartinib (Vanflyta)

•Class: 2nd generation, type 2 FLT3 inhibitor

•Indications: newly diagnosed FLT3 internal tandem duplication (ITD) positive AML in combo w/standard chemo induction, consolidation, and maintenance

•DDI: CYP3A4

•BBW w/REMs program: QTc interval prolongation, electrolyte abnormalities (↓ K⁺, Mg²⁺, and Phos), and myelosuppression

•Monitoring: ECGs before and throughout therapy, hypokalemia or hypomagnesemia

Liposomal Daunorubicin-Cytarabine (CPX-351, Vyxeos)

•Dual-drug liposome of daunorubicin and cytarabine co-formulated in a 5:1 molar ratio

•Allows for longer drug exposure and longer half life

•Indication: therapy related AML or AML w/myelodysplasia-related changes

•Toxicities: cardiotoxicity, myelosuppression, hemorrhage, extravasation, N/V, hypersensitivity, and copper exposure (formulation utilizes copper)

•Monitoring: ECG/MUGA, CBC, infusion site for extravasation, and LFTs

•Pearls: longer time to recover their bone marrow, no alopecia, color of drug is deep purple

•Induction with 7+3±GO, and consolidation with HiDAC±GO

What is the treatment algorithm for AML that is fit for intensive chemotherapy, and has favorable risk?

Induction with 7+3+midostaurin/quizartinib and post-remission therapy with HiDAC+midostaurin/quizartinib and Allogeneic HSCT as soon as possible

What is the treatment algorithm for AML that is fit for intensive chemotherapy, with FLT-3 mutated disease?

Induction with dual-drug liposome encapsulation of daunorubicin and cytarabine induction and consolidation with dual-drug liposome encapsulation of daunorubicin and cytarabine and allogenic HSCT as soon as possible

What is the treatment algorithm for treatment related AML/antecedent MDS/CMML/AML-MRC that is fit for intensive chemotherapy?

Venetoclax (VEN) + hypomethylating agent (HMA)

Which low-intensity chemotherapy is preferred for AML patients?

Add on Ivosidenib± Azacitidine

How do we adjust low-intensity chemotherapy for AML if is there is an IDH1 mutation?

Add Enasidenib

How do we adjust low-intensity chemotherapy for AML if there is an IDH2 mutation?

No change

How do we adjust low-intensity chemotherapy for AML if there is a FLT-3 mutation?

Azacitidine (Vidaza: IV/SQ and Onureg PO)

•MOA: hypomethylating agent that is incorporated into the DNA and inhibits DNA methyltransferase, causing hypomethylation of DNA and subsequent cell death

•Common use: AML and myelodysplastic syndromes

•Route of administration:: IV, SQ, and PO

•Toxicities: myelosuppression, arthralgias, fever, and rash

•Monitoring: CBC, SrCr, and electrolytes

•Pearls: slow onset when used as monotherapy, may take up to 3-4 months to see a response

Decitabine (Dacogen)

•MOA: hypomethylating agent; incorporated into the DNA and inhibits DNA methyltransferase, causing hypomethylation of DNA and subsequent cell death

•Common uses: AML and myelodysplastic syndromes

•Route of administration: IV

•Toxicities: myelosuppression, arthralgias, fever, and rash

•Monitoring: CBC

•Pearls: slow onset when used as monotherapy, takes up to 3-4 months to see a response