Pancytopenia

Etiologies

• Hypocellular bone marrow: aplastic anemia, hypoplastic MDS

• Cellular bone marrow: MDS. aleukemic leukemia. PNH, severe megaloblastic anemia

• Marrow replacement (myelophthisis): myelofibrosis, metastatic solid tumors, granulomas

• Systemic diseases: hypersplenism. sepsis, alcohol

Clinical manifestations

• Neutropenia recurrent infections

• Thrombocytopenia mucosal bleeding & easy bruisability Aplastic anemia stem cell failure (lancet 2005365 1647)

• Epidemiology: 2-5 cases 10* y. biphasic (major peak in adolescents. 2nd peak in elderly)

• Etiologies idiopathic 2-2 3 of cases)

stem cell destruction: radiation, chemotherapy, chemicals (eg. benzene) idiosyncratic reaction to medications (eg. chloramphenicol. NSAIDs. sulfa drugs.

gold, antiepileptics, antithyroid) viruses (HHV-6. HIV, EBV. parvovirus B19); also post-hepatitis (non A, B. or C) immune disorders (SLE. GVHD post HSCT. thymoma)

PNH (see below); Fanconi s anemia (congenital disorder w pancytopenia, macrocytic anemia. T risk of MDS.AML & SCC of head & neck, and multiple physical anomalies) telomerase (hTERT) mutation (n£jm 2005:352:1413)

• Treatment and prognosis allogeneic HSCT: for young Pts -* -80% long-term survival and significantly i risk of malignant evolution, but has risk of transplant-related morbidity & mortality; if possible avoid transfusions (and alloimmunization) pre-transplant immunosuppression (CsA.ATG): 70-80% respond, with 80-90% 5-y survival in responders; 15-20% 10-y incidence of clonal disorders (mosdy MDS.AML PNH) supportive care: transfusions, antibiotics, possible utility of G-CSF and epo

Myelodysplastic syndromes (MDS)

• Acquired clonal stem cell disorder — ineffective hematopoiesis -» cytopenias.

dysmorphic blood cells and precursors, variable risk of leukemic transformation

• Epidemiology: 100 cases 10* y; median age 65 y

• Mechanisms etiologies: idiopathic or 2° to chemotherapy with alkylating agents.

topoisomerase II inhibitors;! risk with radiation.benzene

• Clinical manifestations: anemia (85%), neutropenia (50%), thrombocytopenia (25%)

• Diagnosis: dysplasia (usually multilineage) in peripheral smear (ovalomacrocytes, pseudo-Pelger-Huet anomaly. Auer rods) and bone marrow (blasts • RS)

Comparison of FAB and WHO Classification Systems for MDS

FAB Classification

Marrow WHO Classification

Refractory anemia (RA)

RA: isolated erythroid dysplasia 5% blasts ^ with 5q-syndrome: isolated del(5q)

15% RS Refractory cytopenias with multilineage dysplasia (RCMD): dysplasia in -2 lines

Refractory anemia with ringed sideroblasts (RARS) Refractory anemia with excess of blasts (RAEB) RAEB in transform. (RAEB-T) Chronic myelomonocytic leukemia (CMML) t(15;17).t(8;21).inv16. t(16;16) or Mil rearrang.

• 5% blasts RA^S: RA with -15% RS 15% RS RCMD with RS: RCMD with -15% RS RAEB-1:5-9% blasts in BM 5-20% blasts raeb.2: 10-19% blasts in BM 21-30% blasts Reclassified: AML w multilineage dyspl.

1000 pi MDS MPD: new category for CMML periph. monos Includes atypical CML and juvenile CMML Should be classified as AML regardless of bone marrow blast count

Treatment: intensity based on risk category (see below), age. performance status (PS) Poor PS. any risk — supportive care transfusions. G-CSF, epo. abx if needed Low intermediate risk lenalidomide (csp for 5q- syndrome: nejm 2005:352549); DNA

demythyiating agents (azacitidine or decitabine; Cancer 2000:1S: 1794 & ¡co 200120:2429) Intermediate high risk — DNA demethylating agents, combination chemotherapy (akin toAML therapy) or allogeneic HSCT if age - 60 Hypoplastic MDS — immunosuppressive regimen (CsA.ATG. prednisone)

• Prognosis: IPSS correlates with survival and progression to AML

International Prognostic Scoring System (IPSS)

Score

Risk group

Total score

Median survival

0

0.5

1 1.5 2

Low

0

5.7 y

Blasts (%)

<S

5-10

11-20 21-30

lnt-1

0.5-1

3.5 y

Karyotype

Good

Int.

Poor

lnt-2

1.5-2

1.2 y

Cytopenias

0 or 1

2 or 3

- - -

High

¿2.5

0.4 y

(BW 1997:89:2079)

(BW 1997:89:2079)

Paroxysmal nocturnal hemoglobinuria (PNH)

• Acquired clonal stem cell disorder inactivating somatic mutation of PIG-A gene —

inability to form GPI-anchor for CD55 & CD59 (inhib of complement) — complement-mediated RBC lysis, pit aggreg. & hypercoagulability

• Clinical manifestations: intravascular hemolytic anemia, venous thrombosis (esp.

intraabdominal, cerebral), deficient hematopoiesis (cytopenias): associated with aplastic anemia. MDS and evolution into AML

• Diagnosis: peripheral blood flow cytometry (1 CD55 & CD59)

• Treatment: supportive care (iron, folate, transfusions)

allogeneic HSCT for hypoplasia or severe thrombosis eculizumab (Ab inactivates terminal complement C5): i hemolysis (NE/M 2004:350352)

Myelophthisic anemia (see "Agnogenic Myeloid Metaplasia with Myelofibrosis")

• Infiltration of bone marrow

• Etiologies: agnogenic myeloid metaplasia with myelofibrosis, tumors, granulomas

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