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H&L Final > Acute Leukemias - DSA > Flashcards

Acute Leukemias - DSA Flashcards

1
Q

Essentials of dx for acute leukemia

A

o Short duration of sx – fatigue, fever, bleeding
o Cytopenias or pancytopenia
o >20% blasts in bone marrow
o Blasts in peripheral blood of 90%

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2
Q

Causes of acute leukemia

A
  • Radiation and toxins (benzene) leukemogenic
  • Chemotherapeutic agents – cyclophosphamide, melphalan, alkylating agents, etoposide
  • After treatment for myelodysplastic prodrome – Chr 5 and 7 abnormalities
  • Post etoposide – 11q23 – MLL
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3
Q

Acute Myeloid Leukemia (AML)

A
  • Adult – median age 60 yo, increasing incidence with advanced age
  • T(8;21) → chimeric RUNX1/RUNX1T1 protein
  • Inv(16)(p13;q22) – core-binding factor leukemias
  • Very poor prognosis – isolated monosomy 5 or 7
  • Presence of 2 or more monosomies or 3 or more separate cytogenic abnormalities
  • Internal tandem duplication in FLT3 – very poor prognosis
  • Poor prognosis: TET2, ASXL1, MLL-PTD, PHF6, DNMT3A
  • Favorable: lack FLT3-ITD mutations, has mutations of nucleophosmin1 (NPM1), IDH1 or IDH2
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4
Q

Acute promyelocytic leukemia (APL)

A
  • T(15;17) → PML-RARa interacts with retinoic acid receptor
  • blocks differentiation – overcome with retinoic acid
  • highly curable – over 90% with integration of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO)
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5
Q

Acute Lymphoblastic Leukemia (ALL)

A

• 80% of childhood acute leukemias; peak incidence 3-7 ys
• 20% of adult acute leukemias
• Immunologic phenotype
• Early B lineage and T cell
• Hyperdiploidy - >50 Chr esp. Chr 4, 10, 17 and t(12;21) – TEL-AML1 = better prognosis
• Unfavorable:
o hypodiploidy - <44 Chr
o Ph+ t(9;22), t(4;11) → fusion genes involving MLL gene at 11q23
o Complex karyotype of >5 Chr abnormalities

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6
Q

Mixed Phenotype Acute Leukemias

A
  • Blasts lack differentiation along lymphoid or myeloid lineage or blasts that express both lineage specific antigens
  • Very high risk – poor prognosis
  • Stem cell transplant advisable
  • Tyrosine kinase inhibitor in patients with t(9;22) translocations
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7
Q

S/S of Acute Leukemia

A
  • Ill days to weeks
  • Bleeding d/t thrombocytopenia
  • Skin and mucosal surfaces
  • Gingival bleeding, epitaxis, menorrhagia
  • Less common: widespread bleeding with DIC in APL and monocytic leukemia
  • Infection due to neutropenia
  • Risk rises when ANC less than 500/mcL
  • Cellulitis, pneumonia, perirectal infections
  • Death within few hours if abx delayed
  • Fungal infections commonly seen
  • Gum hypertrophy, bone and joint pain
  • Hyperleukocytosis – markedly elevated circulating blast count tWBC >100,000/mcL → impaired circulation
  • HA, confusion, dyspnea
  • Need emergent chemo with adjunctive leukopheresis
  • Mortality approaches 40% in first 48 hours
  • Exam:
  • Pale, have purpura and petechiae
  • Signs of infection may not be present
  • Stomatitis, gum hypertrophy, rectal fissures in monocytic leukemia
  • Variable enlargement of liver, spleen, LN
  • Bone tenderness – sternum, tibia, femur
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8
Q

Lab Findings of Acute Leukemia

A
  • Pancytopenia with circulating blasts
  • Blasts may be absent in peripheral smear – aleukemic leukemia
  • Bone marrow hypercellular, dominated by blasts
  • > 20% marrow blasts
  • Hyperuricemia
  • If DIC present:
  • reduced fibrinogen level
  • PT prolonged
  • fibrin degradation products or fibrin D-dimers present
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9
Q

Lab findings of ALL

A

• especially T cell – mediastinal mass visible on CXR
o Don’t express mature T cell makers (CD3, 4, 8)
o Express combination of CD2, CD5, CD7
o Do not express surface Ig
• B cell: CD19, CD10
• All ALL express TdT – terminal deoxynucleotidyl transferase
• Lymphoma type: CD19, CD20, surface Ig, but TdT –
o Treat with aggressive lymphoma regimens

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10
Q

Meningeal leukemia lab findings

A

blasts in CSF

• Most common in monocytic types of AML, ALL

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11
Q

AML lab findings

A
  • Auer Rod – eosinophilic needle-like inclusion in cytoplasm
  • CD13 or CD33
  • Myeloperoxidase +
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12
Q

Differential dx for acute leukemia

A

o AML must be distinguished from CML and myelodysplastic syndromes
o Acute Leukemia resembles left-shifted marrow recovery from toxic insult
• Repeat marrow study in several days to check for maturation
o ALL separated from CLL, lymphomas, hairy cell leukemia
• Maybe confused with atypical lymphocytosis of mononucleosis and pertussis

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13
Q

Treatment goals for acute leukemia

A

• Up to 60 yo – acute leukemia treated to cure

  • Obtain remission:
  • normal peripheral blood with resolution of cytopenias
  • normal bone marrow with no excess blasts
  • normal clinical status
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14
Q

Treatment for AML

A
  • Anthracycline (daunorubicin or idarubicin) PLUS cytarabine alone or with other agents
  • → complete remission in 80-90% under 60 yo
  • 50-60% remission of older patients
  • Older patients not candidates for traditional chemo: 5-azacitidine, decitabine, or clofarabine
  • Over 60 poor prognosis, standard chemo 10-20% become long term survivors
  • Reduced-intensity allogenic transplant improves outcomes – up to 40% may be cured
  • Favorable genetic profile: tx with chemo alone or with autologous transplant - cure 60-80%
  • Don’t enter remission or high-risk genetics – cure rates of less than 10% if chemo alone; refer for allogenic stem cell transplant
  • Intermediate-risk – cure rates 35-40% with chemo, 40-60% with allogenic transplant
  • FLT3 +: midostaurin added to induction, consolidation, and maintenance prolongs event free and overall survival
  • Prognosis poor if recurs after initial chemo
  • Second remission: 20-30% chance of cure with transplantation
  • Targeted tx at recurrent genetic mutations: FLT3, IDH1/IDH2
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15
Q

Treatment of ALL

A
  • Adults – combination chemo – daunorubicin, vincristine, prednisone, asparaginase
  • Complete remission in 90%
  • Ph+ need tyrosine kinase inhibitor – dasatinib added to initial chemo
  • > 60 yo – may be treated with tyrosine kinase inhibitor based regimen – 90% remission
  • Less myelosuppressive than AML – does not necessarily produce marrow aplasia
  • Receive CNS prophylaxis so meningeal sequestration of leukemic cells does not develop

• Tx decisions made on age and disease risk factors
• Younger than 39 yo – better outcomes under pediatric protocols
• Low risk – chemo alone with 70% chance of cure
• Intermediate risk – 30-50% cure with chemo
• High risk – rarely cured with chemo alone
o Best treated with allogeneic transplantation

• Minimal residual disease testing guides tx following induction
• Relapsed disease: bispecific Ab blinatumomab
o Bridge to transplant
o Autologous T cell engineered to express anti-CD19 antigen receptor (CART-19) for pediatric and adult relapsed B-ALL

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16
Q

Prognosis of acute leukemia

A

o 70-80% adults with AML under 60 yo complete remission, ~50% cured using risk-adapted post-remission therapy
• Older adults – 50% complete remission, cure rates very low – 10-20% even if they achieve remission and receive post remission chemo

o ALL
• Less than 39 yo – excellent outcomes after chemo followed by risk-adapted intensification and transplant – cure rates 60-80%
• Adverse cytogenetics, poor response to chemo, or older age much lower chance of cure – 20-40%

17
Q

Essentials of diagnosis of CML

A

o Elevated WBC
o Markedly left-shifted myeloid series, low % of promyelocytes and blasts
o BCR/ABL gene – Philadelphia Chromosome (Ph+), T(9q;22q)
• 9q – Ableson murine leukemia virus homolog

18
Q

Myeloproliferative general considerations

A

o Myeloproliferative – overproduction of myeloid cells

• Differentiate and circulate in increased numbers in peripheral blood

19
Q

Early CML - chronic phase

A
  • Normal bone marrow function
  • WBC differentiate
  • Neutrophils combat infection normally

o Untreated CML – unstable → accelerated → acute blast phase (acute leukemia)

20
Q

S/S of CML

A
  • Middle age – median age 55 yo
  • Fatigue, night sweats, low grade fevers
  • Hypermetabolic state d/t overproduction of WBCs
  • Splenomegaly – abdominal fullness
  • Rare: leukostasis – blurred vision, respiratory distress, priapism
  • WBC >100,000/mcL but less than 500,000/mcL
  • Sternal tenderness – marrow overexpansion
  • Acceleration: fever in absence of infection, bone pain, splenomegaly
21
Q

Lab Findings for CML

A
  • Median WBC count 150,000/mcL, can be only modestly elevated
  • Peripheral blood
  • Left shifted with mature forms dominating
  • Blasts less than 5%
  • Basophilia, eosinophilia
  • RBC morphology normal – rare nucleated RBC
  • Platelet count normal or elevated
  • Marrow:
  • Hypercellular
  • Left-shifted myelopoiesis
  • Myeloblasts less than 5%
  • PCR: BCR/ABL gene in peripheral blood test
22
Q

Lab findings for accelerated and blast phases of CML

A
  • Progressive anemia, thrombocytopenia
  • Increasing % of blasts in blood and marrow
  • Blast phase CML when blasts >20% bone marrow cells
23
Q

Ddx for CML

A

o Early CML differentiated from reactive leukocytosis assoc. w/ infection
• WBC less than 50,000/mcL
• Splenomegaly absent
• BCR/ABL not present

o From other myeloproliferative dz:
• Hct should not be elevated
• RBC morphology normal – nucleated RBC rare or absent
• Definitive dx – BCR/ABL gene

24
Q

Tx for CML

A

o Extreme hyperleukocytosis – emergent leukopheresis w/ myelosuppressive tx

o Chronic phase:
• Tyrosine inhibitor: imatinib, nilotinib, dasatinib targeting abl kinase
• Imatinib – 98% hematologic control of chronic phase – 400 mg/day; 30% major molecular at 1 yr
• Nilotinib 71% major molecular at 300-400mg BID for 2 yr; Dasatinib 64% major molecular at 100 mg/day for 2 yrs
o Can salvage 90% of those failing imatinib tx
• Bosutinib – dual bcr/abl tyrosine inhibitor – resistant or intolerate to other TK inhibitors
o 20% complete cytologic response, not active against T315I mutation
• Hematologic complete remission within 3 mo of tx initiation
• Major cytologic response 3-6 mo – when less than 35% of metaphases Ph+
• Major molecular response within 12 mo – 3 log reduction of BCR/ABL transcript in quantitative PCR
• Excellent prognosis, 100% progression free at 8 years
• Monitor and PCR for T315I mutation if BCR/ABL transcript increasing or suboptimal response
• Mutation sensitive to 3rd generation – ponatinib
o High rate of vascular thrombotic complications
• Allogenic stem cell transplantation if cannot achieve good molecular response or progress following tx

o Advanced stage – TK inhibitor alone or with myelosuppressive chemo
• Consider for allogenic stem cell transplantation

25
Q

Course and prognosis of CML

A

o Imatinib tx – 80% survive without progression at 9 yrs

o With good molecular responses – excellent prognosis – 100% survival at 9 years

26
Q

Essentials of diagnosis of chronic lymphocytic leukemia

A

o B-cell lymphocytosis >5000/mcL

o Coexpression of C19, CD5 on lymphocytes

27
Q

General considerations of CLL

A

o Clonal malignancy of B lymphocytes
o Indolent – slowly progressive accumulation of long-lived small lymphocytes
o Immunosuppression, bone marrow failure, organ infiltration with lymphocytes
o Immunodeficiency – inadequate Ab production
o Advanced dz – damage by direct tissue infiltration

28
Q

S/S of CLL

A
  • 90% after age 50 yo, median age 70 yo
  • Incidental finding of lymphocytosis
  • Fatigue or lymphadenopathy
  • 80% lymphadenopathy, 50% hepato- or splenomegaly
  • Variant – prolymphocytic leukemia – more aggressive
  • Larger, more immature cells
  • Complicated by autoimmune hemolytic anemia or autoimmune thrombocytopenia – 5-10%
  • Richter syndrome – isolated LN transforms into aggressive large cell lymphoma
29
Q

Lab findings for CLL

A
  • Isolated lymphocytosis
  • WBC >20,000/mcL, may be markedly elevated to several hundred thousand
  • 75-98% circulating cells lymphocytes
  • small, mature
  • condensed chromatin
  • Hct and platelet count normal at presentation
  • Hypogammaglobinemia – 50%
  • Small amount of IgM paraprotein in serum
  • Immunophenotype: CD19, CD5 – also seen in mantel cell
  • Distinguished by: CD23, low expression of surface Ig, CD20, absence of translocation or overexpression of cyclin D1
  • IgVH somatic mutation: more indolent form – express low levels of CD38, no ZAP70
  • Unmutated IgVH with high ZAP70 expression – not as well, sooner treatment required
  • Del 17p (TP53)– worse prognosis
  • Del 11q (ATM) inferior prognosis
  • Del 13 q more favorable outcome
30
Q

Ddx of CLL

A

o Exclude viral infections, pertussis
o Waldenstrom macroglobulinemia, hairy cell leukemia, mantle cell lymphoma – distinguished by morphology, immunophenotype, bone marrow
o Monoclonal B-cell lymphocytosis – less than 5000/mcL B-cells – precursor to B-CLL

31
Q

Treatment of CLL

A

o Indications for tx: progressive fatigue, symptomatic lymphadenopathy, anemia, or thrombocytopenia
• Rai stage II or III/IV

o Initial tx under age 70 without significant comorbidities: fludarabine with cyclophosphamide and rituximab OR bendamustine with rituximab (better tolerated, fewer adverse effects, results shorter time to progression)

o Older patients or young patients with comorbidities: chlorambucil orally q3weeks for 6 mo
• Combine with obinutuzumab – significant responses 75% - at molecular level in 17%
• Oral ibrutinib – inhibitos Bruton tyrosine kinase – 420 mg/day – 71% response, 75% progression free at 26 mo
• Nonhematologic adverse effects – diarrhea, fatigue, nausea
• Caution with CYP3A inhibitors or inducers
• Serious bleeding if used with warfarin

o Relapsed or refractory – ibrutinib and idelalisib
• Marked lymphocytosis d/t tumor cell release from LN into blood – decreases lymphadenopathy
• Del 17q: ibrutinib – sustained duration of response – 85% at 2 yrs
• Relapsed all genetic groups– idelalisib – 150 mg BID with rituximab

o Associated autoimmune hemolytic anemia or immune thrombocytopenia – rituximab, prednisone, or splenectomy
• Avoid fludarabine – exacerbates

o Rituximab – caution in past HBV – reactivates

o Recurrent bacterial infections and hypogammaglobuinemia – prophylactic infusions of gamma globulin

o Nucleoside analogue tx need anti-infective prophylaxis for P. jirovecii pneumonia, herpes viruses, invasive fungal infections until T cell recovery

o Allogeneic transplant – curative – used only if cannot be controlled by standard therapies
• Non-myeloablastive – encouraging results
• Early transplant with Chr 17q del

32
Q

Prognosis of CLL

A

o Stage 0-I: 10-15 yr
o Stage III or IV: 2 years
o High risk and resistant forms – allogeneic transplant overcome risk factors, long term dz control

H&L Final (12 decks)

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