Acute & Chronic Leukemias Therapeutics

hematologic malignancy

commonly known as blood cancers

3 main types
• leukemia - cancer starts in bone marrow
• lymphoma - cancer starts in lymphatic system → form masses
• multiple myeloma - derived from plasma cells, high WBC count

2 types of leukemia

acute
• acute myeloid leukemia (AML) - most common
➢ acute promyelocytic leukemia (APL) 5-20% of AML cases
• acute lymphoblastic leukemia (ALL) - most common childhood malignancy

chronic
• chronic myeloid leukemia
• chronic lymphocytic leukemia

acute leukemia: s/s

pancytopenia (anemia, neutropenia, thrombocytopenia)
• increased infections
• bruising/bleeding

weakness & fatigue

pallor

gingival hypertrophy → thrombocytopenia

SOB

acute myeloid leukemia (AML): epidemiology

most common type of acute leukemia
2nd most common leukemia
• 1% of adult cancer pts in US
• 4/100,000 adults

median age ~68yo

accounts for <10% of acute leukemias in children <10yo

nearly ALL cases associated w/ acquired gene mutations (environmental factors) - radiation, smoking

differential diagnosis

acute promyelocytic leukemia (APL)

acute myeloid leukemia (AML)

myelodysplastic syndromes (MDS)

B-cell or T-cell lymphoblastic leukemia/lymphoma (ALL)

acute myeloid leukemia (AML): differentiating labs

WBC variable
• low (<5%) - very high (100)

presence of myeloblasts >20%

anemia

thrombocytopenia

differentiating between myeloblasts & lymphoblasts - done using immunophenotyping

acute myeloid leukemia (AML): diagnosis

bone marrow biopsy or aspirate
• 20% blasts
• ANY % of blasts w/ cytogenetics t(8;21), inv(16), (t16;16) - mutation

acute myeloid leukemia (AML): treatment modalities

supportive care - 1st type of treatment received

remission induction therapy

consolidation chemotherapy or HSCT

maintenance - ONLY select pts

acute myeloid leukemia (AML): supportive care

1st type of treatment received

treat anemia, thrombocytopenia & hyperleukocytosis (WBC count >100 in pt w/ leukemia)
• blood transfusions
• platelet transfusions
• antibiotics - broad spectrum
• hydroxyurea - for hyperleukocytosis

infection prophylaxis (high risk)
• bacterial → fluoroquinolone (thru resolution of neutropenia)
• fungal → PJP prophylaxis w/ Bactrim; fluconazole or echinocandin (thru resolution of neutropenia)
• viral → HSV prophylaxis w/ acyclovir

tumor lysis syndrome (TLS) → allopurinol for prevention

graft vs host disease (GVHD)
• immune cells transplanted from non-identical donor (graft) recognize transplant recipient (host) as foreign → immune-related complications for recipient

acute myeloid leukemia (AML): supportive care - hydroxyurea

MOA - antimetabolite that selectively inhibits ribonucleotide diphosphate reductase (RDR) halting cells in G1 phase → cell death

dose 50-100 mg/kg/day until WBC <100,000
• weight based using actual or IBW
• 50% of dose IF CrCl <60 mL/min

administer tablets w/ water at same time each day
• hazardous drug handling precautions
• supplement w/ folic acid recommended (can cause macrocytosis)

d/c for toxicity - cutaneous vasculitis ulcerations, pancreatitis, interstitial lung disease (ILD)

drug interactions - live vaccines, meds that further myelosuppression (chemo, multiple sclerosis)

acute myeloid leukemia (AML): karyotype

strongest prognostic factor for response to induction therapy & survival
*treatment based on risk

risk - cytogenetics - gene mutations
• favorable - core binding factor: inv(16), t(16;16), t(8;21) - mutated NPM1 w/ or w/out FLT3-ITD → treat w/ chemo
• intermediate → treat w/ transplant
• unfavorable or adverse → treat w/ transplant

acute myeloid leukemia (AML): treatment

goal = cure

4 important predictors of outcome
• age - poorer prognosis in pts ≥ 60yo
• performance status - 0-2 for high-intensity remission induction; 0 = really good; 1-2 some limitations but good
• cytogenetics
➢ FLT-3 mutations = BAD; treat differently based on ITD or TKD mutations; midostaurin can be used for BOTH
➢ core binding factors = GOOD; inv(16), t(16;16), t(8;21)
• duration of 1st complete response (CR >12mo favorable)

acute myeloid leukemia (AML) treatment: remission induction

should begin immediately after diagnosis

intensive <60yo
• 7+3
• 7+3 + gemtuzumab ozogamicin (GO) (core binding factors, CD33+)
• 7+3 + midostaurin (FLT3 ITD or TKD mutation)
• 7+3 + quizartinib (FLT3-ITD only)

intensive >60yo - SAME as intensive <60 except unfavorable cytogenetics
• venetoclax + hypomethylating agents (HMA) azacitidine or decitabine - PO options
• venetoclax + low dose cytarabine

unfit for intensive therapy
• venetoclax + HMA
• venetoclax + low dose cytarabine
• glasdegib + low dose cytarabine
• gemtuzumab ozogamicin
• single agent HMA or low dose cytarabine
• IDH1 mutation - ivosidenib + azacitidine
• IDH2 mutation - enasidenib → TKI to prolong survival

bone marrow biopsy 14-21 days after chemotherapy given

goal - achieve complete remission (CR)
must meet below criteria
• absolute neutrophil count >1,000/mm³
• platelets >100,000/mm³
• pt independent of transfusions
• bone marrow blasts <5%
• absence of extramedullary disease
• disappearance of karyotype abnormalities - NOT required for CR

7+3

cytarabine 100 mg/m²/day as continuous infusions x7 days

anthracycline (daunorubicin 60-90 mg/m² OR idarubicin 12 mg/m²) daily for x3 days
• required renal & hepatic dose adjustments
• SE - 2ndary malignancies, cardiotoxicity (know echo before!), bone marrow suppression, moderate/high emetic potential, alopecia, red urine discoloration
• vesicants (highly reactive chemicals that combine with proteins, DNA, and other cellular components to result in cellular changes immediately after exposure) → avoid extravasation

anthracyclines: extravasation

symptoms - swelling, redness, tissue necrosis, ulceration (severe!)

treatment (central line → less risk)
• do NOT flush line
• cool compresses & elevate affected area - want to vasoconstrict & decrease blood flow
• antidote = dexrazoxane
• surgical debridement - can be avoided in most pts

cytarabine

MOA - pyrimidine analog converted into triphosphate form that incorporates into DNA

typically given as infusion over 1-3 hrs (continuous infusion)

hiDAC (high dose cytarabine) 3,000 mg/m²/dose IV q12h for 6 doses (days 1, 3, 5)
• dose reduce for age >60 & renal insufficiency

treatment specific SE - cerebellar & ocular toxicity

acute myeloid leukemia (AML) treatment: consolidation

consolidate once hematologic recovery & bone marrow demonstrating complete remission (CR)

goal - minimum residual disease (MRD)

allogeneic hematopoietic cell transplantation (HCT) w/ matched sibling or alternative donor - preferred for intermediate or high risk (unfavorable risk)

chemotherapy - preferred for favorable risk
• hiDAC (high dose cytarabine) - bridge therapy prior to transplant
➢ 3,000 mg/m²/dose IV q12h for 6 doses (days 1, 3, 5)

acute myeloid leukemia (AML) treatment: maintenance

goal - achieve long-term remission & survival by eliminating residual leukemic cells

NOT needed for most pts
• recommended when pt is considered in remission but will NOT have hematopoietic stem cell transplantation HSCT (favorable risk group)
➢ azacitidine PO until progression
• FLT-3 mutation

acute myeloid leukemia (AML): relapsed/refractory disease

CBC, platelets every 1-3 months x2 years w/ bone marrow as clinically indicated

options
• clinical trial
• targeted therapy or chemotherapy → HCT
• repeat initial induction regimen IF 12 months or more since regimen

acute promyelocytic leukemia (APL): epidemiology

accounts for 5-20% of acute myeloid leukemia (AML) cases

600-800 new cases/yr in US

age distribution - different from acute myeloid leukemia (AML)
• incidence increases during 2nd decade of life & plateaus in early adulthood

some data suggests development after use of topoisomerase II inhibitor (etoposide, doxorubicin, mitoxantrone)

acute promyelocytic leukemia (APL)

subtype of acute myeloid leukemia (AML) characterized by accumulations of immature promyelocytes

arises from translocation of promyelocytic leukemia protein (PML) gene on chromosome 15 & retinoic acid (RAR-α) on chromosome 17 → t(15;17)

considered medical emergency (high early mortality)

goal = cure

acute promyelocytic leukemia (APL): coagulopathy

major cause of death in pts newly diagnosed

presentation
• hypofibrinogenemia
• disseminated intravascular coagulation

coagulation defect - can be worsened in 1st 7 days of induction therapy

treatment = supportive care
• consider replacement w/ fibrinogen, antithrombin w/ or w/out platelets

acute promyelocytic leukemia (APL): risk stratification

low risk
• WBC ≤10 × 10⁹/L
• platelets >40 × 10⁹/L
→ tretinoin + arsenic trioxide

intermediate risk
• WBC ≤10 × 10⁹/L
• platelets ≤40 × 10⁹/L
→ tretinoin + arsenic trioxide

high risk
• WBC >10 × 10⁹/L
• ANY platelets
→ differentiation agents + either idarubicin or gemtuzumab ozogamicin (GO)

acute promyelocytic leukemia (APL): differentiating agents

all-trans-retinoic acid (ATRA) - causes maturation & apoptosis of promyelocytic cells due to terminal differentiation
• start ATRA IF suspicion of APL

arsenic acid → apoptosis by degrading RAR-α oncoprotein

BOTH agents → synergy

continue for years until complete remission - used from induction thru remission

acute promyelocytic leukemia (APL) treatment: induction

low- & intermediate-risk
• all-trans-retinoic acid (ATRA or tretinoin) + arsenic trioxide (ATO) daily
• arsenic trioxide 0.15 mg/kg IV daily until CR or 60 days
• tretinoin 45 mg/m²/day PO daily until CR or 60 days
• prednisone 0.5 mg/kg daily used for differentiation syndrome prophylaxis
• can still consider regiments w/ chemotherapy - tretinoin + daunorubicin + cytarabine

high-risk
• all-trans-retinoic acid (ATRA or tretinoin) + idarubicin + arsenic trioxide (ATO)
➢ IF low EF → substitute idarubicin for gemtuzumab ozogamicin
• arsenic trioxide 0.15 mg/kg IV daily days 9-26
• tretinoin 45 mg/m²/day PO daily days 1-36
• idarubicin 6-12 mg/m² IV days 2, 4, 6, 8
• prednisone 1 mg/kg/day x10 or more days regardless of WBC

acute promyelocytic leukemia (APL): differentiation syndrome

cytokine storm caused by large number of promyelocytic cells undergoing differentiation & maturation w/ migration to organ systems

10-12 days after 1st dose of ATRA &/or arsenic acid

symptoms
• dyspnea w/ interstitial pulmonary infiltrates
• peripheral & pulmonary edema
• unexplained fever
• hypotension
• acute renal failure

risk factors
• WBC ≥10 × 10⁹/L
• BMI ≥30

acute promyelocytic leukemia (APL): differentiation syndrome treatment

prophylaxis - NOT universally done in clinical practice
• recommend for high-risk pts per NCCN
➢ weight based - prednisone 0.5 mg/kg/day
➢ fixed dose (easier!) - dexamethasone 10 mg q12h
• duration vary based on protocol

treatment
• dexamethasone 10 mg IV q12h x3-5 days, followed by 14-day taper
• consider holding differentiating agents (ATRA &/or arsenic acid) IF cardiorespiratory symptoms severe
• can still continue cytotoxic chemotherapy

acute promyelocytic leukemia (APL) treatment: consolidation & maintenance

consolidation therapy - based on regimen used in induction
• ATRA + ATO → ATRA + ATO
• ATRA + chemotherapy → continue chemotherapy agents (daunorubicin, cytarabine) ± ATRA
• IF high-risk pt, consider 4-6 cycles of intrathecal chemotherapy

after 1 cycle of consolidation therapy, pt should have minimal residual disease (MRD) measured using polymerase chain reaction (PCR)

NOT all protocols will have maintenance therapy
• agent will depend on induction & consolidation therapy
➢ ATRA
➢ 6-mercaptopurine &/or methotrexate (MTX)
• x1-2 years IF maintenance initiated

whichever protocol is initiated w/ induction, should be followed from induction thru maintenance

acute lymphoblastic leukemia (ALL): epidemiology

most common childhood malignancy
• 1/3 of ALL childhood malignancy
• 2,500-3,500 new cases in US each year
• incidence appears to be increasing → more accurate reporting?

B-cell lineage ~85% of ALL malignancies
T-cell lineage ~10-15% of ALL malignancies

NO known cause - considered to be 2ndary to environmental factors

certain genetic disorders - may increase risk

acute lymphoblastic leukemia (ALL): presentation

pancytopenia

pallor

fever

bruising

palpable liver & spleen (hepatomegaly & splenomegaly) - most common clinical findings of childhood leukemia

lymphadenopathy (swelling of lymph nodes) - present in nearly ½ of children; peripheral neuroblastic tumors (PNT) cells

acute lymphoblastic leukemia (ALL): differentiating labs

WBC - variable

lymphocytes >20%

decreased platelets - thrombocytopenia

decreased RBC - anemia

acute lymphoblastic leukemia (ALL): diagnosis

bone marrow biopsy or aspirate

cytogenetics - t(9;22) BCR-ABL mutation

acute lymphoblastic leukemia (ALL): treatment overview

remission induction phase

consolidation phase

maintenance phase

acute lymphoblastic leukemia (ALL): select prognostic features of adult

good risk
• WBC <30 ×10⁹/L
• induction response - complete remission
• negative CNS/extramedullary disease site
• age <35
• thymic T-cell immunophenotype

poor risk
• cytogenetics - BCR-ABL1 (Ph+)
• B cell - WBC >30 ×10⁹/L or T cell - WBC >100 ×10⁹/L
• immunophenotype - early T-cell precursor, pro-B cell
• age >35

acute lymphoblastic leukemia (ALL): treatment principles

goal = cure

varies based on
• age
➢ adolescents & young adults (AYA)
➢ adult
➢ older adult
• cytogenetics
➢ Philadelphia chromosome +

acute lymphoblastic leukemia (ALL) treatment: induction

goal - complete remission (hematologic) & eradication of 99% leukemic burden Philadelphia chromosome + or -

Ph+ ALL
• TKI + corticosteroid
• TKI + chemotherapy
➢ EsPhALL - cyclophosphamide, vincristine, daunorubicin, dexamethasone, cytarabine, MTX pegaspargase, prednisone
➢ hyper-CVAD - hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone

Ph-ALL
• NO TKI
• chemotherapy
➢ CALGB - daunorubicin, vincristine, prednisone, pegaspargase

backbone agents
• anthracyclines
• vincristine
• corticosteroids - dexamethasone or prednisone

further considerations
• CD-20+ ALL - regimen + rituximab
• Ph+ TKI - imatinib, dasatinib, ponatinib, nilotinib or bosutinib
➢ dasatinib & ponatinib - cross BBB
➢ optimal duration of BCR-ABL inhibitor - unknown; treatment continued even after allogeneic HCT

acute lymphoblastic leukemia (ALL) treatment: consolidation/intensification

goal - further eliminate residual disease & minimize relapse risk

depend on residual disease
• unclear benefit in adults
• blinatumomab ± TKI
• multiagent chemotherapy ± TKI - common protocol x6 cycles
➢ asparginase
➢ high-dose cytarabine
➢ high-dose MTX

HSCT - may be appropriate for ALL disease risk groups & preferred if Ph+

acute lymphoblastic leukemia (ALL) treatment: maintenance

routinely utilized - different from acute myeloid leukemia (AML)

goal - prolong remission

regimen
• weekly MTX + daily 6-MP + monthly vincristine/prednisone pulses
• blinatumomab
• Ph+ → TKI added
• continued x1-2 yrs

acute lymphoblastic leukemia (ALL) treatment: CNS prophylaxis

intrathecal chemotherapy - achieve adequate CNS concentrations
• decreases incidence of relapse given concurrently w/ chemotherapy cycle
• MTX &/or cytarabine

acute lymphoblastic leukemia (ALL): supportive care

tumor lysis syndrome - possible; like acute myeloid leukemia (AML)

infection prophylaxis - similar to AML
• bacterial, fungal & viral
• avoid Bactrim administration w/ high-dose MTX - may enhance adverse/toxic effects of MTX

growth factor support - want to cause myelosuppression
• regimens have high risk for febrile neutropenia
• utilize primary prophylaxis for induction therapy

chronic lymphocytic leukemia (CLL): differentiating labs

elevated WBC

due to elevated lymphocytes
• blasts - uncommon

chronic lymphocytic leukemia (CLL): s/s

B cell symptoms (chronic)
• severe fatigue
• drenching night sweats
• unintentional weight loss (10% or more actual BW) within 6 months
• unexplained fever

signs
• organomegaly (splenomegaly) - common
• presence of monoclonal B lymphocytes 5 × 10⁹/L or greater in peripheral blood
• bone marrow biopsy - NOT required

considered “disease of elderly” w/ average diagnosis at 70yo

Richter’s transformation (high grade lymphoma) - possible in 10% of pts

chronic lymphocytic leukemia (CLL): treatment using Rai score

Rai low & intermediate risk (0-II)
• observation
• indication for treatment
➢ B-cell symptoms
➢ progressive/bulky disease
➢ progressive cytopenias

Rai high risk (III-IV) → differential blood work
• initiate therapy

chronic lymphocytic leukemia (CLL): Rai system

stage 0 - lymphocytosis, lymphocytes in blood >5 ×10⁹/L clonal B cells &/or >40% lymphocytes in bone marrow → low risk

stage I - stage 0 w/ enlarged node(s) → intermediate risk

stage II - stage 0-I w/ splenomegaly, hepatomegaly OR both → intermediate risk

stage III^c - stage 0-II w/ Hgb <11.0 g/dL or hematocrit <33% → high risk

stage IV^c - stage 0-III w/ platelets <100,000/mm³ → high risk

chronic lymphocytic leukemia (CLL) treatment: with del17P/TP53 mutation

chemoimmunotherapy - NOT recommended w/ mutation due to low response rates

anti-CD20 - obinutuzumab, rituximab

Covalent Bruton's tyrosine kinase inhibitors (cBTKi) - PO, more tolerated
• acalabrutinib, zanubrutinib

chronic lymphocytic leukemia (CLL) treatment: without del17P/TP53 mutation

same regimen as w/ mutation

preferred regimens
• cBTKi
➢ acalabrutinib ± obinutuzumab
➢ zanubrutinib
• venetoclax + obinutuzumab

other recommended regimens
• cBTKi - ibrutinib (1st gen → HTN & cardiotoxicity)
• ibrutinib + venetoclax

chronic lymphocytic leukemia (CLL) treatment: BTK inhibitor

3 agents - acalabrutinib (newer), ibrutinib (older), zanubrutinib (newer)
• ALL - cause lymphocytosis on initiation
• SE - neutropenia, thrombocytopenia

consider Pneumocystis jirovecii pneumonia (PJP) & varicella-zoster virus (VZV) prophylaxis in pts at increased risk → Bactrim & acyclovir

CYP3A4 substrates → AVOID w/ CYP3A4 inducers & inhibitors

chronic lymphocytic leukemia (CLL): supportive care

infections - common cause of morbidity & mortality
• intravenous immunoglobulin (IVIG)
• antibiotic prophylaxis

autoimmune cytopenias
• autoimmune hemolytic anemia (AIHA)
• immune thrombocytopenia (ITP)
• pure red cell aplasia (PRCA)

tumor lysis syndrome
• esp. w/ venetoclax

chronic myeloid leukemia (CML): differentiating labs

elevated WBC & neutrophils
• could also see elevation in eosinophils & basophils (granulocytes)
• WBC median = 100

chronic myeloid leukemia (CML): s/s

asymptomatic - up to 50%
symptoms - fatigue, malaise, weight loss, bleeding, thrombosis (nonspecific)
signs - high WBC (up to 100), organomegaly, anemia

3 phases
• chronic (CP-CML) - increasing WBC & splenomegaly; cannot cure
• advanced (AP-CML) → transplant
➢ progressive myeloid maturation arrest (blasts 15-29% in bone marrow)
➢ drug therapy directed & minimizing increase in WBC stops working
• blast crisis (BP-CML) → transplant
➢ transformation to acute leukemia
➢ 30% or more blasts in bone marrow

chronic myeloid leukemia (CML): treatment

goal - remain in chronic phase & prevent progression to accelerated or blast phase
minimize toxicity

tyrosine kinase inhibitors (TKIs) - mainstay therapy
• 10-year overall survival = 80-90%

pts 1st categorized into low, intermediate or high risk
• low risk
➢ 1st gen TKI - imatinib
➢ start w/ 2nd gen TKI - bosutinib, dasatinib, nilotinib
• intermediate or high risk
➢ 2nd gen TKI - bosutinib, dasatinib, nilotinib

chronic myeloid leukemia (CML): early treatment milestones

BCR::ABL1 >10%
• 3 months = possible TKI resistance → switch to alternate TKI or continue same TKI
• 6 & 12 months = TKI-resistant disease → switch to alternate TKI (other than imatinib) & evaluate for allogeneic HCT; consider BCR::ABL1 kinase domain mutational analysis

BCR::ABL1 >1-10%
• 3 & 6 months = TKI-sensitive disease → continue same TKI; evaluate pt adherence & drug interactions; monitor response
• 12 months = possible TKI resistance → consider switch to alternate TKI or continue same TKI if complete cytogenetic response (CCyR) achieved

BCR:ABL >0.1-1%
• 3 & 6 months = TKI-sensitive disease → continue same TKI
• 12 months = TKI-sensitive disease → IF optimal - continue same TKI; IF not optimal - shared decision-making w/ pt

BCR:ABL ≤0.1%
• 3, 6 & 12 months = TKI-sensitive disease → continue same TKI

chronic myeloid leukemia (CML): mutations driving therapy

T315I mutation
• 1st & 2nd gen TKIs cannot be used
• preferred
➢ ponatinib - 3rd gen TKI
➢ asciminib
➢ omacetaxine - adherence concern

*assess adherence, drug interaction, test for mutation!

chronic myeloid leukemia (CML) treatment: accelerated or blast phase

accelerated
• preferred regimens - bosutinib, dasatinib, nilotinib, ponatinib
• allogeneic HCT

blast phase - treat as acute leukemia
• lymphoid (ALL)
• myeloid (AML)