Leukemias and Myelodysplastic Syndromes



Leukemias and Myelodysplastic Syndromes





MYELODYSPLASTIC SYNDROMES

Justin M. Watts

Virginia M. Klimek


Epidemiology



  • ˜10000 cases diagnosed annually in the United States


  • Incidence >20/100000 in adults >70 y → actual incidence probably higher, as some older adults w/MDS may go undiagnosed due to comorbid illnesses, etc.


  • Median age of onset ≥65 y; uncommon under age 50; male predominance (˜2:1)


  • RF: Cytotoxic chemotherapy (esp. alkylators & anthracyclines/etoposide), RT/exposure, benzene


Disease Biology/Pathogenesis (NEJM 2009;361:1872)



  • MDS consists of a group of acquired, clonal disorders of hematopoietic stem cells


  • Ineffective hematopoiesis → cytopenias & dysplastic changes in BM precursors & circulating blood cells


  • Several cytogenetic abnormalities are characteristic of MDS → +8, loss or deletions of chromosomes 5 or 7, del (20q)


  • Recurrent Mt in genes involved in RNA splicing machinery recently identified & implicated in subset of MDS cases (eg, SF3B1 Mt a/w RS)


  • Leukemic transformation: Evolution to AML varies greatly across subtypes → RAEB-2 (>50%), RARS (<5%)


Clinical Presentation



  • Non-specific sx such as fatigue, infxn, & bleeding d/t anemia (85%), neutropenia (50%), thrombocytopenia (25%)


  • Infxn common, resulting from neutropenia as well as impaired granulocyte function


  • Occasionally a/w autoimmune phenomenon (eg, vasculitis, ITP)


  • Progressive cytopenias (though time course can vary greatly depending on subtype)


  • Risk of transformation to AML



Diagnosis



  • DDx: AML, MPN (can be overlap), aplastic anemia, PNH, viral infxn (HIV, hepatitis, parvovirus), nutritional deficiencies (B12, copper), EtOH, meds, lead or arsenic poisoning


  • Most pts anemic, often w/macrocytosis (1/3 pts), & have ≥1 other cytopenia


  • Peripheral smear: Oval macrocytes, hyposegmented neutrophils (pseudo-Pelger-Huët cells), hypogranulated neutrophils & plt


  • BM: Typically hypercellular; ≥10% dysplasia in ≥1 myeloid lineage (neutrophils, RBC precursors, or megakaryocytes); impaired myeloid maturation; small &/or hypolobated megakaryocytes


  • BM exam also used to quantify the blast percentage & detect presence of RS (esp relevant if RA only)


  • Cytogenetic testing (karyotyping) mandatory; FISH optional → the value of routine FISH testing for common cytogenetic abnormalities is unclear in MDS


WHO Classification (2008)

FAB classification no longer used









































Classification


Pathologic Features


Refractory cytopenia w/unilineage dysplasia: RA (Hb < 10 g/dL), neutropenia (ANC < 1.8 k/µL), or thrombocytopenia (Plt < 100 k/µL)

<5%

≥10% dysplasia in affected cell lineage


<5% BM blasts; ≤1% PB blasts


<15% RS


No Auer rods; no monocytosis


Refractory anemia with ringed sideroblasts (RARS)

<5%

RA in the presence of ≥15% RS


<5% blasts


Refractory cytopenia with multilineage dysplasia (RCMD)

70%

≥10% dysplasia in 2 or more cell lines


<5% blasts; may or may not have RS


RA w/excess blasts-1 (RAEB-1)

25%

5-9% blasts, no Auer rods


RA w/excess blasts-2 (RAEB-2)

10-19% blasts, may have Auer rods


MDS w/isolated del(5q) (“5q-syndrome”)

5%

<5% blasts; del(5q)


MDS, unclassifiable (MDS-U)

<5%

+cytogenetic abnormality but <10% dysplasia & <5% blasts


Recurrent structural cytogenetic abnormalities, such as t(15;17), t(8;21), inv(16)/t(16;16), MLL gene rearrangements, are considered diagnostic of AML regardless of BM blast count.




Unique Subtypes of MDS


5q-syndrome



  • Characterized by progressive anemia, preserved/elevated plt count, & del(5q) as sole cytogenetic abnormality


  • Female predominance; classically benign course w/low-risk of transformation to AML


  • In addition to dyserythropoiesis, micromegakaryocytes present in most cases (80%)


  • Excellent RR to lenalidomide, w/most pts achieving red cell transfusion-independence & some w/complete cytogenetic response (Blood 2011;118:3765)


Hypoplastic MDS



  • Rare, can be difficult to distinguish from aplastic anemia (cytogenetics helpful) although tx is similar


MDS/MPN overlap syndrome (also see MPN section)



  • Now classified separately from MDS


  • Pts have coexisting features of dysplasia & proliferation; blast count <20%; absence of specific genetic abnormalities such as BCR-ABL, JAK-2, PDGFRα/β


  • CMML: Characterized by peripheral monocytosis (>1000/µL), anemia & thrombocytopenia, dysplastic neutrophils, often massive splenomegaly


  • RARS-T (RARS & thrombocytosis) → RARS + Plt count >450 k/µL; frequently JAK-2 Mt positive


Prognosis



  • IPSS score most commonly used & best validated prognostic scoring system


  • Correlates w/OS & evolution to AML (Blood 1997;89:2079)








































    International Prognostic Scoring System (IPSS) Score

    0

    0.5

    1

    1.5

    2


    BM blasts (%)

    <5

    5-10

    —

    11-20

    21-30a


    Karyotypeb

    Good

    Int

    Poor

    —

    —


    Cytopenias

    0 or 1

    2 or 3

    —

    —

    —


    a Now considered AML per 2008 WHO classification.

    b Good = nl, -Y alone, del(5q) alone, del(20q) alone; Poor = complex karyotype (≥3 abnls) or chromosome 7 abnls; Intermediate = any other cytogenetic abnls.





























    Risk Group

    Total Score

    Median Survival


    Low

    0

    5.7 y


    Int-1

    0.5-1

    3.5 y


    Int-2

    1.5-2

    1.2 y


    High

    ≥2.5

    0.4 y



  • Revised IPSS (IPSS-R) score: Assigns greater prognostic significance to cytogenetics & utilizes 5 rather than 3 prognostic subgroups; uses modified cytopenia thresholds; subdivides original <5% blast count to ≤2% or 3-4% blasts (Blood 2012;120:2454)


  • Older age, poor PS, ↑ serum ferritin, & ↑ LDH also correlate w/↓survival but not transformation to AML



Treatment



  • Must consider age, PS, & IPSS score/risk status, & transplant candidacy


  • IPSS Low/Int-1 risk: Supportive care including ESAs (epoetin alfa or darbepoetin; esp if Epo level <500); consider ESA + G-CSF for RARS; lenalidomide (esp for 5q-syndrome); if progression → hypomethylating agents (azacitidine or decitabine)


  • IPSS Int-2/High risk: Hypomethylating agents → survival benefit compared to best supportive care (BSC) & some pts achieve CR (9-17%) (Lancet Oncol 2009;10:223; Cancer 2006;106:1794); consider induction chemo (AML regimen such as “7 + 3”)


  • Allogeneic transplant is only curative strategy, usu w/a matched related or unrelated donor


  • Hypoplastic MDS → can be treated like aplastic anemia w/antithymocyte globulin (ATG) & cyclosporine


  • Supportive care (regardless of risk & Rx strategy): ESAs, G-CSF, RBC & Plt transfusions, iron chelation Rx if needed (esp if transplant candidate), abx for neutropenic Ppx including antifungal agents (azoles)



ACUTE MYELOID LEUKEMIA (AML)

Justin M. Watts

Martin S. Tallman


Epidemiology



  • Incidence: Estimated 13800 new cases in the United States in 2012 (10200 death)


  • Most common myeloid malignancy in adults


  • Median age of onset: ˜70 y


  • RF: Cytotoxic chemotherapy, IR, benzene exposure, trisomy 21, rare congenital syndrome (eg, Fanconi anemia, Klinefelter, dyskeratosis congenita)


Disease Biology/Natural History



  • Heterogeneous clonal disorder of hematopoietic stem cells (“blasts”)


  • Many genotypic variants (many w/prognostic relevance)


  • W/o Rx: ↑ blasts in BM & circulation & ↓ ANC/Hb/Plt; typically fatal in wks to mos d/t BM failure (infxn, bleeding) or organ infiltration


Clinical Presentation/Emergencies



  • Presenting s/s reflect ↓ hematopoiesis: Most commonly fatigue and/or infxn


  • Most pts are pancytopenic w/circulating blasts at dx → ˜50% have ↓ or nl WBC; ˜20% have WBC >100000/µL


  • Leukostasis can occur if WBC >50000/µL → vascular occlusion/hemorrhage (esp. of microcirculation) → visual disturbance/retinopathy, dyspnea/pulm infiltrates, myocardial ischemia, TIA/CVA → Rx w/hydration, hydroxyurea, leukapheresis


  • DIC: Very common in APL & frequent cause of early death (cerebral hemorrhage) → early admin. of ATRA critical at first suspicion of APL (ie, in the ER)


  • Tumor lysis syndrome (TLS) (more common w/ALL but can occur in AML): Ppx w/IVF & allopurinol, Rx includes forced diuresis, rasburicase, HD if sev.


  • CNS involvement in 2-3% of cases (RF: ↑ WBC, relapsed APL); w/u incl. eye exam, CT/MRI, usu defer LP until CR1 unless symptomatic (theoretical risk of CNS seeding)



Diagnosis



  • BM aspirate & bx w/flow cytometry, cytogenetics, & molecular studies (KIT, FLT3, NPM1, CEBPA are standard)


  • AML confirmed if ≥20% myeloblasts in BM or blood or recurrent cytogenetic abnormality


  • R/o ALL → morphology (Auer rods are pathognomonic for AML; N:C ratio often higher in ALL); immunophenotyping by IHC/flow; cytogenetics/molecular genetic studies


  • Common myeloid Ag: CD13, CD33, CD34, CD117, MPO


WHO Classification of AML (Blood 2009;114:937)

FAB classification no longer used

























W/recurrent genetic abnormalities

Core-binding factor (CBF) leukemias → t(8;21), inv(16)/t(16;16); t(15;17); MLL gene/11q23 abnls; t(6;9); inv(3)/t(3;3)a; t(1;22)b


W/multilineage dysplasia

Documented antecedent hematologic disorder (MDS/MPN) or dysplasia present in ≥50% of cells in ≥2 myeloid lineages (neutrophils, erythroid precursors, or megakaryocytes)


Rx-related (˜10-15% of AML)

RT/alkylating agents → monosomies or deletions of chromosome 5 or 7; onset ˜5-10 y after exposure; more common type


Topo II poisons (eg, etoposide, anthracyclines) → 11q23 abnls, t(15;17), t(8;21); typically 1-5 y after exposure


Not o/w specified

W/o maturation, w/min. differentiation, w/maturation, w/myelomonocytic, monoblastic, or monocytic differentiation less common → erythroid, megakaryoblastic, or basophilic leukemia; acute panmyelosis w/MF (rare)


Myeloid sarcoma (chloromas)

Extramedullary involvement may antedate BM disease (more common w/monocytic differentiation)


a 3q21q26 syndrome/EVI1 gene rearrangements → a/w thrombocytosis & very poor prognosis

b Very rare, megakaryoblastic phenotype, infant leukemia



Prognosis

Determined primarily by age & cytogenetic/molecular risk



  • Age >60 y is an independent poor-risk feature


  • Poor PS, high presenting WBC, antecedent hematologic disorder, Rx-related AML → poor-risk


  • Good-risk: APL (10-15% of all AML), +core binding factor (˜12%)


  • Most pts have an intermediate or unfavorable risk at presentation


AML Genetics and Risk (Blood Rev 2004;18:115; Blood 2010;116:354)

˜45% pts have nl cytogenetics

Karyotype

Molecular Mutations


Favorable prognosis

t(15;17); t(8;21); inv(16)/t(16;16)

NPM1 (FLT3-); CEBPA (biallelic)


Intermediate prognosis

Nl; −Y; +8

CEBPA


Unfavorable prognosis

inv(3)/t(3;3); −5/del(5q); −7/del(7q); t(6;9); 11q23; complex cytogenetics (≥3 unrelated abnls)

FLT3-ITD




  • Favorable karyotypic abnls are considered favorable regardless of other cytogenetic abnls


  • c-KIT Mt portends less favorable prognosis in pts w/t(8;21) [but probably not in pts w/inv(16)/t(16;16)]


  • Some data that NPM1 & IDH co-Mt may be very favorable, & that FLT3-ITD confers an esp poor prognosis in presence of other, newly discovered “poor-risk” Mt (eg, TET2, ASXL1, & DNMT3A) (NEJM 2012;366:1079)


  • A monosomal karyotype (≥2 monosomies or 1 w/other structural abnl) carries an extremely poor prognosis



Treatment



  • Induction chemo (“7 + 3”): 7 d of infusional cytarabine & 3 d of dauno or idarubicin; RCTs confirmed high-dose dauno (90 mg/m2) superior (OS benefit) to standard dose (45 mg/m2) (NEJM 2009;361:1235); can use dauno 60 mg/m2 in older pts w/good PS


  • Confirm CR (<5% blasts) w/BM bx upon peripheral count recovery; persistent cytopenias >28 d after chemo → likely residual leukemia


  • Can repeat 1 course of induction w/“5 + 2” or alternative regimen if no CR


  • Postremission (consolidation) Rx: High-dose cytarabine (HiDAC) → optimal dose under debate → in younger pts current standard is 3 g/m2 × 6 doses for 3-4 cycles (cerebellar tox rare but potential SE; modify dose in older pts)


  • No proven benefit to multiple courses of HiDAC, esp. in older pts & non-CBF leukemias


  • Allogeneic HCT in appropriate pts (unfavorable prognosis, strongly consider if intermediate-risk) w/suitable donor (RIC for pts >50-60 y)


  • Autologous HCT rarely used, though may benefit pts w/favorable or intermediate risk who received high-dose dauno (Blood 2011;117:5306)


  • No proven role for maintenance chemotherapy in AML (despite numerous studies)


  • If relapse → salvage chemo (eg, MEC → mitoxantrone, etoposide, cytarabine) vs. clinical trial → goal to achieve CR2 & consolidate w/alloHCT


  • MUD & matched sibling donor (MRD) HCT now have similar outcomes; UCB has expanded donor pool (Blood 2010;116:4693)


  • Hypomethylating agents (5-aza, decitabine) have benefit in older pts not candidates for intensive chemo (J Clin Oncol 2010;28:562)


  • Supportive care: IVF, abx for FN, antimold antifungal ppx if prolonged neutropenia, TLS ppx w/allopurinol (rasburicase if ↑ UA & risk for tumor lysis), RBC & plt transfusions, hydroxyurea if ↑ WBCs (leukapheresis rarely needed)


Outcomes (Blood 2005;106:1154; J Clin Oncol 2009;27:61)



  • ˜70-80% of younger pts (<60 y) & ˜40-50% of older pts (>60 y) will achieve CR w/induction chemo (+CR correlates w/survival)


  • OS ˜35-40% in younger adults; better prognosis in APL & CBF leukemias


  • Older pts have dismal prognosis (OS ˜10%), d/t medical comorbidities & underlying disease biology/genetics (eg, ↑ risk of antecedent MDS, monosomal karyotype)


Acute Promyelocytic Leukemia (APL)

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Aug 17, 2016 | Posted by in ONCOLOGY | Comments Off on Leukemias and Myelodysplastic Syndromes

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