Acute Leukemia

Prognostic Factors for ALL

- Cytogenetics - Age (older age = worse prognosis) - High WBC

MOA of Pegasparagase in treating ALL

- Lymphoblasts need asparagine for survival - L-asparaginase hydrolyzes asparagine - Inhibits protein synthesis and prevents tumor cell survival

Short term Emergency management APL --> WHY?

- Tretinoin (Vitamin A) ASAP to prevent intracranial hemorrhage caused by procoagulants on APL cells!

Gemtuzumab ozogamicin

- anti-CD33 antibody-drug conjugate attached to cytotoxic agent that disrupts DNA -->calicheamicin - used for CD33+ AML induction

Prognostic factors of AML

- cytogenetics - age - performance status - comorbidities - therapy related AML or antecedent MDS (precursor bone marrow disorder to AML)

Diagnosis of APL specifically can be done via detection of what genetic marker?

15:17 translocation

_____ is very similar to highly aggressive lymphoma

ALL

Most common type of leukemia

AML

AML Treatment Phases: APL Treatment Phases: ALL Treatment Phases:

AML Treatment Phases: 1. induction 2. consolidation 3, +/- maintenance APL Treatment Phases: 1. induction + 2. consolidation ALL Treatment Phases: 1. Induction 2. Consolidation 3. Maintenance Therapy 4. CNS prophylaxis (integrated into regimen)

Acute Promyelocytic Leukemia (APL) is subtype of

AML: acute myeloid leukemia

10% of AML cases are more specifically, _____ (sub-type)

APL

Rapidly progressive disease of early, Un-differentiated, immature blood cells.

Acute Leukemia

Risk stratification for ALL

Age < 40 (lower risk) or ≥40 (higher risk)

stage of acute leukemia treatment where you want to get rid of most of the disease, eradicate the bulk of the abnormal leukemic cells and restore "normal hematopoiesis"

Induction

APL TREATMENT HIGH RISK: Induction + Consolidation: Maintenance:

Induction: Tretinoin + Arsenic Trioxide + Anthracycline OR gemtuzumab Conduction: Mercaptopurine, MTX, tretinoin

APL TREATMENT Low RISK: Induction + Consolidation: Maintenance:

Induction: Tretinoin + Arsenic trioxide Conduction: N/A

Which Acute leukemia uses Tretinoin + arsenic trioxide for induction + consolidation

Low risk APL

AML Induction regimen for patients Age <60 or 60-70 with good performance status/no relevant comorbidities:

Low-Dose 7+3 regimen is gold standard LOW-DOSE Cytarabine 100mg/m2 continuous IV infusion x 7 days - With idarubicin 12mg/m2 OR Daunorubicin 60-90mg/m2 x 3 days

Maintenance ALL treatment

MTX, 6-MP, Vincristine, Steroids

What concerns arise near 3 weeks of 7+3 Therapy for AML

MYELOSUPPRESSION CONCERNS, mucositis: infection prevention and treatment --> Antibiotics/ G-CSF

Acute leukemia definition

Malignant transformation of immune cells that reside predominantly in bone marrow and blood. Cells do not differentiate past a certain stage and proliferate without control. Rapidly progressive disease of early, Un-differentiated, immature blood cells.

Therapeutic Objective of CNS prophylaxis (ALL)

Prevent CNS Disease!! --- required to prevent patient relapse and cerebellar syndrome

Adult ALL (> 40) FIT if ≥20% CD20+ treatment

Rituximab

Monitoring for Efficacy for APL

Similar to CML --> monitor for presence of 15:17 translocation --> cytogenetic and molecular remissions

Monitoring and Treatment of Toxicity Week 1 (d1-d8): Week 2-4:

Week 1 (d1-d8): · prevent and treat nausea/vomiting, tumor lysis, cytarabine syndrome -Nausea/Vomiting: antiemetics - Tumor lysis: hydration (2-3liters/m2/day) PLUS allopurinol 300mg PO daily +/- rasburicase 3-6mg (flat dose) Week 2-4: myelosuppression concerns (infection prevention and treatment), mucositis

Big role for pharmacists in ALL monitoring

highest rate of non-adherence in maintenance therapy and can lead to relapse or toxicity --> ENSURE ADHERENCE!

Risk factors for ALL

less well defined

Acute Promyelocytic Leukemia

t(15,17) balanced translocation, associated with DIC, responds to retinoic acid therapy

The signs and symptoms of leukemia result from

the lack of mature blood cells --> pancytopenia--> as the number of leukemia cells rises the number of normal cells in the bone marrow decreases --> low #s of RBCs, WBCs, platelets - RBCs- anemia - WBCs- infection - Platelets- bleeding, gingival bleeding

AML Consolidation for Favorable risk disease

High-dose Cytarabine (HIDAC) 3000mg/m2 over 3 hours every 12 hours on days 1,3,5 x 2-4 cycles

gold standard for diagnosis of AML and ALL

Bone marrow biopsy --> >20% leukemic blasts in bone marrow sample = positive leukemia

PRVs impacting Acute leukemia treatment common to AML and ALL

1. Cardiac, renal and hepatic function 2. Performance status (ECOG score) 3. Comorbidities 4. Fertility preservation (based on age) -alkylating agents, cyclophosphamide 5. Cytogenetics 6. Age (young = better in ALL, AML < 60) 7. Stem cell transplant (if applicable) 8. Cumulative Dose (anthracycline cardiotoxicity) 9. Line access (chemotherapy vesicants need central line for IV administration - vincristine, doxorubicin)

Signs and symptoms common in Acute leukemias: More common to ALL:

1. Complications of pancytopenia - low WBC/RBC and platelets (anemia, fatigue, weakness), thrombocytopenia (bleeding and bruising), neutropenia (infection) 2. Hemorrhagic findings [gingival bleeding, disseminated intravascular coagulation (DIC)] More common in ALL: lymphadenopathy and bone pain (more common in ALL)

what side effects arise with high-dose cytarabine but not low dose cytarabine

1. Conjunctivitis: at high-doses cytarabine crosses into conjunctival tissues and cause inflammation of the eyes 2. Cerebellar dysfunction

Goal(s) of treatment of APL malignancy (2)

1. Cure 2. Minimize early morbidity and mortality from disease (intracranial and pulmonary hemorrhage) and treatment

Risk factors for developing AML (4)

1. Environmental carcinogens (benzene) 2. Secondary AML due to prior myelodysplastic syndrome (MDS) -- (a precursor bone marrow disorder to AML) 3. Therapy related AML (due to topoisomerase II inhibitor (e.g. etoposide), alkylating agent (e.g. cyclophosphamide), or radiation exposure) 4. Down's syndrome

What does it mean that cancerous ALL blasts monoclonal?

"clones" of the parent cancerous cell

Risk stratification for AML

- Based on Cytogenetics! --> molecular mutations = genetic abnormality - Categories of Risk for AML • Favorable risk • Intermediate risk • poor risk

5 year overall survival for ALL - Children: - Adults: (40-69yo):

- Children: 88% - good - Adults: (40-69yo): 18-24% -bad

Trentinoin (APL urgent, induction for low/high and maintenance for High Risk) considerations

- Costly - Avoid fatty meals and vitamin A (duplicate therapy) - may cause pseudotumor cerebri, increased TG (monitor)

PRVs impacting treatment, especially for ALL

- Hepatitis Status: rituximab - Sanctuary Sites (CNS, testes, sinuses) where disease can hide from systemic chemotherapy

Monitoring for Efficacy ALL: - differences from AML? - When similar to CML? (cytogenetic/molecular response) - More use of ________ to assess disease burden

- differences from AML? -Similar to AML except no day 14 bone marrow biopsy - When similar to CML? (cytogenetic/molecular response) if Ph chrom + - More use of ________ to assess disease burden minimal residual disease (MRD)

Arsenic Triioxide (APL induction for low/high risk) side effects

- myelosuppression - differentiation syndrome -arthralgias/myalgia - QT prolongation

Before initiating treatment with the 7+3 (cytarabine + anthracyclien - either ida or dauno) , what must you do?

1. Assess LVEF via ECG or MUGA scan 2. Line access (requires central for anthracycline) 3. Liver function: may need to dose adjust 4. Sperm banking (anthracycline)

ALL (acute lymphoblastic leukemia) can be further divided based on 4 factors

1. B-cell ALL (precursor and mature subtypes) most common 2. T-cell ALL (precursor and mature subtypes) 3. Presence of philadelphia chromosome (BCR-ABL) 25%, most common in adults 4. CD2- cell marker expression (50% of all B cell ALL lineage)

AML Treatment: EMERGENCY short-term treatment due to leukocytosis (highly elevated WBC)

1. Hydroxyurea indicated: WBC > 100K or WBC >50K with symptoms of dyspnea, confusion 2. Leukapheresis generally, even if not exactly at the WBC count indication, if they have symptoms of Leukocytosis or airway obstruction GIVE HYDROXYUREA: sticky AML (myeloid cells) will clog arteries/airways --> dyspnea, airway compromise, seizures, death --> acts as a "bandaid" to keep everything under control Benefit >>>>>>> Risk regardless of symptoms!!!! -- risk of forgoing is too high Aside: -->if the patient truly has is CML, and not AML, those cells aren't as sticky and this wont be the solution but it is better to give than not bc better than having the patient have a seizure or airway compromise and die

PRVs related especially to AML (2)

1. Molecular Mutations (FLT-3, CD33+) 2. LEUKOCYTOSIS: need short-term EMERGENCY management --> (concern for tumor lysis and organ dysfunction due to leukostasis)/Tumor lysis/Coagulopathy/Infections --> Hydroxyurea needed to prevent/treat leukostasis when WBC > 100,000 or WBC > 50,000 with symptoms of dyspnea, confusion

Goals of treatment of AML and ALL malignancy (3)

1. Provide aggressive therapy to induce cure (if pt can tolerate) 2. Minimize short and long term toxicity 3. If patient cannot tolerate aggressive therapy, give palliative therapy to limit disease progression

Therapies that can lead to AML

1. TOPO II Inhibitors (etoposie) 2. Alkylating agents (cyclophosphamide) 3. Radiation exposure

2 main types of acute leukemia

1.. Acute lymphoblastic Leukemia (ALL) 2. Acute Myeloid Leukemia (AML) -->Acute Promyelocytic Leukemia (APL) is subtype of AML

Diagnosis of ALL/AML requires that at least ____% of cells in bone marrow to be blasts. A blood smear can be used to detect this (instead of a bone marrow biopsy but only if there are enough blasts in the blood).

20%

10 year overall survival of APL

80-90% VERY GOOD!!!! if you are going to have a leukemia, you would want APL

Pancytopenia

A condition that occurs when a person has low counts for all three types of blood cells: red blood cells, white blood cells, and platelets.

AML Induction regimen for patients Age <60 or 60-70 with good performance status/no relevant comorbidities: that have CD33-positive

low dose 7+3 and Gemtuzumab ozogamicin (anti-CD33 antibody-drug conjugate attached to cytotoxic agent that disrupts DNA)

AML Induction regimen for patients Age <60 or 60-70 with good performance status/no relevant comorbidities: that have FLT3-MUTATION

low dose 7+3 and MIDOSTAURIN

The most common type of ALL is

B-cell ALL --> 50% of B cell ALL lineage has CD20 marker expression

Purpose of CNS prophylaxis in ALL

CNS prophylaxis is starting during induction in the treatment of ALL to prevent it from spreading to the brain/CNS --> intrathecal MTX or intrathecal Cytarabine Decreases risk of CNS relapse to <5% vs. 30% without prophylaxis.

Long term toxicities of Steroids and anthracyclines? Supportive Care:

Cardiotoxicity Steroid myopathies Osteonecrosis Supportive Care: ECGs and mineral supplementation for bones

Children/AYA specific induction/consolidation ALL: Fit adults:

Children/AYA specific induction/consolidation ALL: more dose-dense and higher use of pegasparagase Fit adults: more cyclophosphamide, if ≥CD20 positive --> rituximab

Therapeutic Objective (purpose) of Induction treatment

Clear bone marrow and peripheral blood of all leukemic blast cells in effort to restore normal blood cell growth and achieve complete remission (CR). Remission does not equal cure.

Stage of treatment of Acute leukemia that serves to remove minimal residual disease

Consolidation

Which Acute leukemia uses Tretinoin + arsenic trioxide + anthracycline OR gemtuzumab ozogamicin for induction + consolidation

High risk APL

When to use maintenance therapy for APL ? When to not?

High risk: 6-MP + MTX + Tretinoin Low Risk -- None

Side effects/Agent related variables of of low-dose Cytarabine + Idarubicin

Cytarabine (low dose) 1.Myelosuppression--> antibiotics 2. Alopecia 3. GI (N/V/D) --> antiemetics 4. Mucositis --> antibiotics 5. Cytarabine syndrome: (fever, rash myalgias) 6. Hepatic dysfunction Idarubicin/Daunorubicin 1. myelosuppression 2. alopecia 3. GI - antiemetic 4. Hepatic dysfunction-- potential dose adjust based on hepatic dysfunction 5. RED secretion -DAUNO-PT COUNSEL 6. Cardiotoxicity: monitor LVEF, monitor cumulative dose, consider ACEI or β-blockers 7. Vesicant: central line 8. potential Tumor lysis: allopurinol + hydration (or +/- raburicase)

Therapeutic Objective (purpose) of Consolidation/Post Remission Therapy

Eradicate minimal residual disease (MRD) and prevent relapse!! (high dose therapy to target sanctuary sites and potential resistance mechanisms)

APL Prognosis is based on:__________ High Risk/Low Risk?

High risk: ≥10 Low risk: < 10

Diagnosis of acute leukemias is done by? ALL Only:

GOLD STANDARD = BONE MARROW BIOPSY --> Definition = >20% cells in bone marrow sample to be leukemic blasts 1. Physical exam and history 2. CBC w/ differential 3. Blood chemistry studies 4. Blood smear (cell morphology, immunophenotyping -- (all?) 5. PET/CT (ALL only)

AML Consolidation for Favorable Intermediate risk disease

HIDAC or Stem Cell Transplant

Pegasparagase is used more in children/AYA (& < 40yrso) because it can be very toxic, why?

Has a very long half life --> VERY TOXIC

Which Acute leukemia uses Mercaptopurine + MTX + Tretinoin for maintenance

High risk APL

ALL induction and consolidation for children/AYA specifically

Higher use of pegaspargase More dose dense and dose intense than adult regimens - steroids, vincristine, anthracycline (especially during induction) - high dose cytarabine*, high dose methotrexate* (especially used during consolidation) -If Philadelphia chromosome (Ph) positive, add tyrosine kinase inhibitor (TKI)-imatinib, dasatinib, nilotinib and consider stem cell transplant

Pre-medication for pegasparagase

IFR-HS rxns: pre-medicate (antihistamine, CCS? ) - Anticoagulation therapy (bleeding/clotting risk) - Monitoring pancreas, liver and coagulation dysfunction

Poor risk AML Patients: Therapy related AML or Prior MDS--> Induction treatment? Consolidation Treatment? (Therapy related AML- topo II inhibitors - etoposide, alkylating agent -cyclophosphamide, radiation exposure, or Prior MDS- precursor bone marrow disorder)

Induction treatment: dual-drug liposomal encapsulation of daunorubicin and cytarabine (Vyxeos®) Consolidation Treatment? Continue Vyxeos if unable to do stem cell transplant

AML Treatment for patients that require palliative therapy (not candidates for intensive therapy Age ≥ 70 Age 60-70 with poor performance status/comorbidities Induction: Consolidation

Induction: No standard --> tx continued indefinitely - Low-intensity therapy:Azacitidine OR Decitabine (DNA methylator) + Venetoclax (BCL-2 Inhibitor) - If CD33+: gemtuzumab ozogamicin Consolidation: - best supp. care: hydroxyurea, transfusions prn - If IDH1 mutation: ivosidenib - If IDH2 mutation: enasidenib - If FLT3 mutated: azacitabine/decitabine + sorafenib (multi-kinase inhibitor)

CNS prophylaxis for ALL

Intrathecal cytarabine, MTX Children: more use of cranial radiation frequent intrathecal chemo injections, even if no leukemia is seen in CNS at diagnosis

Therapeutic Objective (purpose) of Maintenance therapy

Keep patients in remission and relapse-free

Leukostasis

Medical emergency most commonly seen in patients with AML. It is characterized by an extremely elevated blast cell count and symptoms of decreased tissue perfusion: clotting, infections, tumor lysis

which ALL and APL related medication may require dose adjustments based on pharmacogenomic variability

Mercaptopurine (Thiopurine S-methyltransferase mutation) --> likely need lower dose --> do pharmacogenomic monitoring/tests before starting and/or if myelosuppression occurs

which diagnostic test is done ALL only?

PET/CT Scan

AML Consolidation for Favorable POOR risk disease

Stem Cell Transplant

ALL treatment for UNFIT Adult

Steroids PLUS If Ph+, add tyrosine kinase inhibitor (imatinib, dasatinib, nilotinib)

Why does myelosuppression, alopecia, N/V, mucositis, diarrhea occur with low-dose Cytarabine

When you are targeting normal cells in the S-phase or anthracycline (non-CC specific -) in the S-phase--> target bone marrow target hair follices (myelosuppression, alopecia), GI tract noraml skin cells are quickly replicating--> N.V diarrhea mucositis -- the sloughing of the GI tract

Side effects and Agent related variables of HIDAC treatment for AML

myelosuppression, alopecia, MORE N/V, diarrhea, mucositis, cytarabine syndrome (fever, rash, myalgia), hepatic dysfunction AND due to high-dose of cytarabine --> conjunctivitis (steroid eye drops), cerebellar toxicity --> ALWAYS ADJUST AND HOLD DOSE IF NECESSARY

Hydroxyurea use in AML

short-acting antimetabolite to leukapheresis to prevent/treat leukostasis

Why do we need the Consolidation treatment phase if 60-80% of newly diagnosed AML patients and 80-90% with ALL achieve CR (complete remission) with induction therapy?

Without consolidation therapy, relapse within 4-8 months. It is assumed that a substantial burden of leukemia cells persist (minimal residual disease=MRD) leading to relapse within weeks if no further therapy given.

myelodysplastic syndrome (MDS)

a precursor bone marrow disorder to AML

Median age of diagnosis of ALL (Hint: it stands out)

age 15! (YOUNG PATIENTS)

which AML inductionregimen is given to older, frail patientsW

azacitazine + venetoclax or decitabine + venetoclax (low-intensity)

key toxicity for Idarubicin (used in &+3)

hepatic dysfunction --> Hypersensitivity reactions to Ecoli formulation Related to protein synthesis MOA: - Hyperglycemia -- - Coagulopathy - monitor for coagulation dysfunction (bleeding/clotting), - Pancreatitis- monitor pancreas function - Hepatotoxicity - monitor LFTs - Hypersensitivity reaction -- H1/H2 blockers, CCS?

Categories of Risk for AML (3)

• Favorable risk(55-65% 5yrs) • Intermediate risk (24-40% 5yrs) • Poor risk (5-14% 5yrs)