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Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

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Page 1: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Lecture 6 and 7

Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders

Abdulkarim Aldosari

Page 2: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Objectives• Describe the etiology, pathogenesis, clinical features and treatment of MDS

• Describe laboratory diagnosis of MDS

• Differentiate the subtypes of MDS based on morphology and laboratory features

• Distinguish between MDS and AML on PB and BM smears

• Know the International Prognostic Scoring System (IPSS)

• List general features of chronic lymphocytic leukemia

• List diagnostic criteria of CLL

• Explain differential diagnostic criteria used to characterize lymphoproliferative disorders

• Name laboratory methods used to study lymphocytes in lymphoproliferative disorders

Page 3: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Myelodysplastic syndromes • The Myelodysplastic syndromes (MDS) are a collection of myeloid

malignancies characterized by one or more peripheral blood cytopenias.

• MDS are diagnosed in slightly more than 10,000 people in the United States

yearly, for an annual age-adjusted incidence rate of approximately 4.4 to 4.6

cases per 100,000 people.

• They are more common in men and whites.

• The syndromes may arise de novo or secondarily after treatment with

chemotherapy and/or radiation therapy for other cancers or, rarely, after

environmental exposures.

http://www.ncbi.nlm.nih.gov/books/NBK66015/

Page 4: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Myelodysplastic syndromes In Myelodysplastic diseases, the blood stem cells do not mature into healthy cells

Versus myeloproliferative diseases - the total number of blood cells increases, usually mature cells

• A heterogeneous group of clonal hematological malignancies

• Characterized by PB cytopenias, dysplastic blood cells, propensity to become acute leukemia

• Clinical outcome is variable

• Outcome is almost always fatal

• No cure except for allogeneic stem cell transplantation

Page 5: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

MDS etiology and pathogenesis

• Mostly affect the elderly – 70+ years

• Mostly male

• Risk factors – exposure to environmental and occupational products

Ammonia, petrochemicals, low dose irradiation, exposure to benzene, smoking, family

history

• Mechanism that causes MDS not well known Genetic mutations/defects

• Caused by a somatic mutation → a growth advantage of the neoplastic cell

Page 6: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

MDS etiology and pathogenesis

Which hematopoietic progenitor cell is responsible for the neoplastic

clone?

• Pluripotent stem cell or an omnipotent stem cell?

• Controversial subject > various studies done

• Blast cell population in leukemic patients = myeloid or myelomonocytic

• Only few cases the blasts are lymphoid

• Most studies show that blasts arise from repopulating stem cells committed to

myeloid differentiation

Page 7: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

MDS etiology and pathogenesisThe main biological feature of MDS is increased apoptosis –programmed cell death

Ineffective hematopoiesis seen in MDS – caused by abnormally high rate of intramedullary apoptosis

• Factors that are involved in stimulating apoptosis are increased and those which are

anti-apoptotic are decreased

TNF-α and TGF-β, Fas-ligand → initiate apoptosis

GM-CSF - anti-apoptotic

• TNF-α and TGF-β are both ↑ in MDS patients

• GM-CSF ↓ in MDS patients

• The balance between growth-stimulatory and growth-inhibitory cytokines may favor apoptosis

Page 8: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

MDS etiology and pathogenesisLoss of genetic material is the most common genetic anomaly found in MDS

MDS patients are missing key genes essential for maintaining normal hematopoiesis

No single gene found – focus of research

Characterized mainly by chromosomal deletions Either sections of a chromosome or the entire chromosome Versus chromosomal translocations in acute leukemias

Deletions follow a tumor suppressor gene model Tumor-suppressor genes generally encode proteins that inhibit cell proliferation – (in

MDS = apoptosis) Need mutated allele from both parents – recessive model Versus oncogene activity of acute leukemias

Missing genes → more genetic anomalies → disease progression

Page 9: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

MDS progressionCharacteristics of MDS changes as it progresses towards leukemia

• Blast cells ↑

• Leukocytosis replaces leukopenia

• Hepatoslenomegaly occurs

• Becomes a proliferative PB disorder

• Progression due to ↓ in medullary apoptosis, ↓ in apoptosis factors (Fas ligand)

• Multistep pathogenesis

• Normal → clonal and dysplastic → full blown malignancy → acute

Page 10: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Morphology of PB and BM in MDSReliable analysis of blast phenotype of MDS difficult

Blasts are not predominant in the BM and PB Determined using immunophenotyping Expression of CD34 > myeloid antigens > myeloid blasts

Blast in BM determine type of MDS at initial diagnosis

Different types of blasts and sideroblast according to FAB classification

• Type 1 myeloblast - variable size without granules or Auer rods

• Type 11 myeloblast– slightly larger with 1-20 granules

• Type 111 myeloblast –with ~20 granules, basophilic cytoplasm

• Type 1 sideroblast – 1-4 cytoplasmic iron-containing granules = 15-50% erythroblasts

• Type 11 sideroblast – 2-10 granules, scattered throughout cytoplasm

• Type 111 - ringed sideroblast

Page 11: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Morphology of PB and BM in MDSMDS characterized by multilineage morphological abnormalities

Lineage dysplasia includes:

Dyserythropoiesis

a) In PB – macrocytic/normochromic anemia in 90% of cases, ↓ retic count,

macrocytosis, anisopoikilocytosis, basophilic stippling, dimorphic RBC

population (normochromic, hypochromic), Pappenheimer bodies, teardrop

(dacryocytes), schistocytes, elliptocytes, Howell-jolly bodies, acanthocytes

b) In BM – Erythroblasts with asynchronous cytoplasmic maturation,

internuclear bridging, nuclear budding, Howell-Jolly bodies, Basophilia,

ghosts cells, abnormal ringed sideroblasts (types 1 and 11)

Page 12: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Morphology of PB and BM in MDSMegaloblastoid change Megaloblastoid erythroid precursors with and multinucleation nuclear irregularities and a multinucleated erythroid precursor

Page 13: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Morphology of PB and BM in MDSCharacterized by multilineage morphological abnormalities

Lineage dysplasia includes:

Dysgranulocytopoiesis in peripheral blood neutropenia in 60% of cases nuclear and cytoplasmic dysplasia in 90% of cases neutrophilia possible pseudo-Pelger-Huët and variable degrees of hyposegmentation monolobulation (pseudo- Stodtmeister anomaly) variable degrees of hypogranulation pseudo-Dohle bodies rare hypergranulation abnormal chromatin

Page 14: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Stodtmeiser anomaly Stodtmeiser Pelger-Huet anomaly

Page 15: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Morphology of PB and BM in MDSDysgranulocytopoiesis in bone marrow

Pseudo-Pelger-Huët or Stodtmeiser anomaly, hypersegmentation ring formation chromatin sticks asynchronous nuclear-cytoplasmic maturation hybrid myelomonocytic cells vacuolated monocytes/myeloid precursors

Pelger-Huët anomaly is considered to be the most specific dysplastic marker for the diagnosis of MDS

Page 16: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Morphology of PB and BM in MDS

Ring formation Hypersegmentation with nuclear sticks

Page 17: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Morphology of PB and BM in MDSCharacterized by multilineage morphological abnormalities

Lineage dysplasia includes:

Dysmegakaryocytopoiesis

a) In PB – Thrombocytopenia in 60% of cases, platelet gigantism, ballooning,

hypogranulation, rare thrombocytosis associated with 5q-syndrome

b) In BM – micromegakaryocytes (dwarf or mononuclear megakaryocytes),

megakaryocytes with multiple small detached nuclei, or nuclei separated by

thin strand, “pawn ball” shape, cytoplasmic vacuoles

Page 18: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Morphology of PB and BM in MDSDiscrete nuclear lobes, or multinucleation Micromegakaryocytes

Pawn ball megakaryocyte.

Page 19: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

MDS Peripheral Blood Bone Marrow

Refractory anemia (RA)

Cytogenetic studies needed to diagnose- 50% of patients have clonal abnormalities

Most difficult to recognize and diagnose. Anemia 90% of cases (normochromic & macrocytic);

cytopenias; variable dyserythropoiesis; <1% blasts neutropenia,

dysmyelopoiesis & dysmegakaryopoiesis are rare

normal - hypercellular; erythroid hyperplasia with variable dyserythropoiesis;

normal myeloid & megakaryocytic lines; <5%

blasts; ringed sideroblasts < 15%

Refractory anemia with ringed sideroblasts (RAS)

Ringed sideroblast + lineage dysplasia enough to make diagnosis

Similar to RA; anemia (macrocytic or dimorphic); variable dyserythropoiesis;

<1% blasts neutropenia, dysmyelopoiesis &

dysmegakaryopoiesis are rare; cytopenias

ringed sideroblasts >15% nucleated cells

Refractory anemia with excess blasts (RAEB)

 

Anemia (macrocytic normochromic) ovalocytes and dacryocytes; 2 or more of dyserythropoiesis, dysmyelopoiesis

with hyposegmentation, hypogranulation; dysmegakaryopoiesis with thrombocytopenia, giant platelets;

<5% blasts

hypercellular; dyserythropoiesis,

dysmyelopoiesis, and dysmegakaryopoiesis;

5-20% blasts, no Auer rods; ringed sideroblasts variable

Refractory anemia with excess blasts in transformation (RAEB-t)

Can mimic M2 - AML

as in RAEB, but > 5% blasts, may contain Auer rods

 

as in RAEB, but 20-30% blasts or Auer rods

Chronic myelomonocytic leukemia (CMML)

monocytosis >1.0 x109/L; WBC ≤ 13 x109/L

<5% blasts; dysmyelopoiesis variable

as in RAEB, but ↑ monocytes & promonocytes ≥ 20%;

1-20% blasts; variable ringed sideroblast

FAB classification

Page 20: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

WHO classification

RA and RARS subdivided according to presence or absence of multilineage dysplasia

RAEB-t is eliminated; patients considered to have acute leukemia

CMML reclassified under a subgroup of myelodysplastic/myeloproliferative disorders

Separate out patients with a 5q deletion syndrome

Diseases Blood findings Bone marrow findings CommentsRefractory anemia (RA) Anemia

No or rare blastsErythroid dysplasia only < 5% blasts < 15% ringed sideroblasts

5-10%

Refractory anemia with ringed sideroblasts

(RARS)

Anemia No blasts

Erythroid dysplasia only < 5% blasts ≥ 15% ringed sideroblasts

Makes up about 3% to 11% of MDS cases; also generally good prognosis

Refractory cytopenias with multilineage dysplasia (RCMD)

Cytopenias (bicytopenia or pancytopenia) No or rare blasts No Auer rods < 1 x 109/L monocytes

Dysplasia in ≥ 10% of cells in ≥ 2 myeloid cell lines < 5% blasts No Auer rods < 15% ringed sideroblasts

Makes up about 30% of MDS cases; about 10% of people with RCMD will develop

acute leukemia; less favorable prognosis.

Refractory cytopenias with multilineage

dysplasia and ringed sideroblasts

(RCMD-RS)

Cytopenias (bicytopenia or pancytopenia) No or rare blasts No Auer rods < 1 x 109/L monocytes

Dysplasia in ≥ 10% of cells in ≥ 2 myeloid cell lines < 5% blasts ≥ 15% ringed sideroblasts No Auer rods

Refractory cytopenias with excess blasts-1

(RAEB-1)

Cytopenias < 5% blasts No Auer rods < 1 x 109/L monocytes

Unilineage or multilineage 5-9% blasts No Auer rods

20% of MDS cases; About 25% develop acute myeloid leukemia (AML); poorer

prognosis

Refractory cytopenias with excess blasts-2

(RAEB-2)

Cytopenias 5-9% blasts ± Auer rods < 1 x 109/L monocytes

Unilineage or multilineage 10-19% blasts ± Auer rods

20%; Up to 40% may develop AML; the remainder of cases are fatal due to bone

marrow failure.

Myelodysplastic syndrome unclassified

(MDS-U)

Cytopenias ± Blasts ± Auer rods

Unilineage in granulocytes or megakaryocyte < 5% blasts No Auer rods

Variable; Lacks findings appropriate for classification into any other MDS category

MDS associated with isolated del(5q)

Anemia < 5% blasts Platelets normal or increased

Normal to increased megakaryocytes with hypolobulated nuclei 5% blasts No Auer rods Isolated del(5q)

< 5%; Affected cells are missing part of chromosome 5; generally good prognosis;

progression to acute leukemia occurs in less than 10% of patients.

Page 21: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Cytochemical abnormalities of MDS

• Cytochemical studies included iron stain, periodic acid-Schiff (PAS), peroxidase, butyrate esterase, chloroacetate esterase, and double esterase stains

• ↓activity and abnormal positive results of MPO, chloroesterase, alkaline phosphatase, SSB, dual esterase in myeloid and monocytic cells

• Especially more difficult to diagnose RARS, RAEB-t, CMML due to major qualitative and quantitative abnormalities, than RA

• The iron stain remained most helpful in identifying abnormal ringed sideroblasts, a feature of dyserythropoiesis - supports the diagnosis of MDS

• The PAS stain was helpful, if positive, in identifying patients with MDS; when negative did not help distinguish MDS from non-MDS hematologic disorders

• The combination of two stains, PAS and iron stain or PAS and double esterase -helpful in excluding MDS – negative results

Page 22: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Bone Marrow Histology of MDSAspirate and biopsy helpful to estimate:

• Cellularity – which cells are dysplastic

• Histological changes – displacement of hematopoiesis cells from their usual

sites

• Abnormal localization of immature precursors (ALIP) – may find clusters of

immature myeloid cells away from the BM trabeculae = early indicator of

leukemic transformation

• Myelofibrosis – Rare occurrence, associated with BM hypoplasia

Useful to determine dysmegakaryocytopoiesis, not so much for dyserythro- or

dysgranulopoeisis

Page 23: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Cytogenetics and molecular abnormalities of MDSClonal abnormalities present in 30-60% of patients with MDS

Most frequent abnormalities:

5q- = deletion of the long arm of chromosome 5

• The common deleted region always spans the chromosome band 5q31

• Several genes related to hematopoiesis are found on 5qGenes that encode cytokines and their receptors

• More frequent in RA

• Clinical features include macrocytic anemia, normal or ↑ platelet, mild leukopenia, monolobular or dwarf megakaryocytes, erythroid hypoplasia

• Affects mostly females

• Good prognosis – median survival ~8yrs

The prognosis of 5q deletions in MDS is generally favorable if they are not part of complex

abnormalities

Page 24: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Cytogenetics and molecular abnormalities of MDS

A. Deletion comprise any region located between band 5q13 and 5q33

B. Band 5q31 is consistently deleted in most patients

Page 25: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Cytogenetics and molecular abnormalities of MDSMonosomy 7 (-7)

• Abnormalities in chromosome 7 occur in about 20 percent of MDS patients

• Common in patients who have prior chemotherapy exposure

• Associated with a poor prognosis

• Monosomy 7 + complex karyotype = short survival rate and ↑ progression to

AML

• Rarely seen in RA

• In children - > risk of bacterial infections independent of neutrophil count

Page 26: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Cytogenetics and molecular abnormalities of MDSTrisomy 8 (+8)

• Categorized as intermediate cytogenetic risk group

• The most frequent cytogenetic abnormality in de novo MDS in China

• Found in 15-20% of MDS

• 5-10% of MDS with +8 are treatment-related MDS

• Present in each FAB subgroup: up to 25-30% of RARS cases have +8; 15-20%

of other subgroups have +8

Page 27: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Cytogenetics and molecular abnormalities of MDSDeletion of part of chromosomes 11q, 20q

• 20q- alone is associated with a good prognosis regarding survival and potential for AML evolution

• pathogenic mechanism by which 20q- alters the hematopoietic stem cells is unknown

Anomalies of p17

• Where p53 gene reside

• Associated with hypolobulated granulocytes with cytoplasmic vacuoles

• Mainly refractory anemia with excess of blasts RAEB/ RAEB-t in MDS

Other rare chromosome abnormalities are present in a substantial portion of patients

Page 28: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Secondary MDS

After significant exposure to chemotherapy, radiotherapy or other toxic agents

Laboratory findings, clinical manifestations, evolution similar to new MDS

Higher frequency of chromosomal abnormalities

Greater tendency to early leukemic transformation

Page 29: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Clinical features of MDS• Symptoms associated with progressive bone marrow failure

• Depends on the degree of anemia, neutropenia, thrombocytopenia

• Patients without excess blast in BM may be asymptomatic for a long time

• Abnormal physical findings are not prominent, non specific

• Fatigue and malaise result from anemia.

• Signs and symptoms of chronic heart failure may develop in patients with underlying cardiac problems – in the elderly

• Petechiae, ecchymosis, and nose and gum bleeding- low platelet count. If underlying dysplastic changes were missed initially - may be mistaken for immune thrombocytopenia.

• Fever, cough, dysuria, or shock - serious bacterial or fungal infections associated with neutropenia.

Page 30: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

MDS in children• Rare- less than 5% of all blood cancers in children

• The median age at diagnosis in children is 7 years old

• RA is the most common subtype of childhood MDS.

• About half of all children with MDS are diagnosed with RA

RAEB and RAEB-t subtypes

• Symptomatic – fever, pallor, physical weakness/loss of strength

• Normocytic, normochromic anemia rather than macrocytic anemia

• ↑ risk of development of AML associated with Down’s syndrome, Fanconi’s

anemia

• Children with treatment-related and secondary MDS tend to have less favorable treatment outcomes than children with primary MDS

Page 31: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

PrognosisFactors that affect prognosis:

• The number of blast cells in the bone marrow.

• Whether one or more types of blood cells are affected.

• Whether the patient has symptoms of anemia, bleeding, or infection.

• Whether the patient has a low or high risk of leukemia.

• The nature and number of chromosome abnormality

• Whether the myelodysplastic syndrome occurred after chemotherapy or radiation therapy for cancer.

• The age and general health of the patient.

• The presence of abnormal localization of immature precursors (ALIP)

Page 32: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Prognostic scoring systems• The International Prognostic Scoring System (IPSS) - used to

help assess the severity of MDS

• Based on the IPSS score, the patient's history, and observations, a treatment plan is designed to address the MDS

• Based on

1. The presence of one or more low blood cell counts (cytopenias)

2. BM blast cell count

3. Cytogenetic results – chromosomal changes in the marrow cells

Page 33: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Prognostic scoring systems

Page 34: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Diagnostic problems with MDSDifficult to differentiate from aplastic anemia

• Clonal anomaly will confirm MDS

• BM smear for dysplastic changes

Differentiate from acute myelofibrosis (AML, M7)

• 15% of MDS show BM fibrosis – sMDS

• Dry tap in BM aspiration, trilineage dysplasia, cytopenias

• No organomegaly

• Cytogenic abnormalities

From essential thrombocytosis

JAK2 mutation in ET

Cytogenetic analysis – 5q- or other translocation in MDS

Page 35: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Diagnostic problems with MDSCMML to be differentiated from CML

• CMML, patients have an elevated number of monocytes in the blood

• CMML patients have abnormal looking (dysplastic) cells in their bone marrow

• CMML has features of both myelodysplastic syndrome and myeloproliferative disorder

• Cytogenetic studies to differentiate

Differentiate from Acute erythroid leukemia

• When the total population of BM erythroblasts > 50% of all nucleated cells

• Algorithm to help with diagnosis

Page 36: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari
Page 37: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Treatment of MDSAllogeneic stem cell transplantation – only therapy with potential to treat MDS

• Since most are elderly – not as practical

• Limited to younger patients <60yrs with a matched sibling

<55yrs unrelated but matched donor

High dose chemotherapy (without transplantation)

• Short lived response

• Response - < 20% of patients still in remission 2 years after therapy

Advances in pathogenesis – development of novel drugs

IPSS used to tailor therapy

Page 38: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

• For the elderly - IPSS low or intermediate-1 risk category – treat to improve hematopoiesis

• For younger patients – IPSS-2 or high risk – treat to improve survival

Page 39: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Review questionsThe most common dyserythropoietic finding in the bone marrow in MDS

a) Megaloblastoid development

b) Impaired hemoglobinization

c) Pseudo-Pelger- Huet cells

d) Agranular cytoplasm

Ans. a

Why should you test B12 and folate levels when entertaining a diagnosis of MDS?

Ans.

Megaloblastoid changes are often seen in the erythroid and megakaryocytic lines of MDS and are similar to abnormalities of megaloblastic anemia.

MDS should not be diagnosed if there is evidence of either a B12 or folate deficiency.

Page 40: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Chronic lymphocytic disorders• Clonal proliferations of morphologically and immunophenotypically

mature B or T lymphocytes

• Diagnosis based on morphology, immunology, cytogenetic, molecular and clinical features

• Leukemias = diseases affecting the BM and the PB

• Lymphomas = disease affecting extramedullary sites

• Chronic lymphoid leukemias have various stages

Early stage – small tumor cells, with low proliferation, prolonged

survival

Transformative stage – proliferation in extramedullary sites, increase

in large immature cells

Page 41: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Chronic lymphocytic disorders

• Advances in cytogenetics and molecular biology show that

hematopoietic neoplasms are associated with unique genotypic profile

• Genotype affects the development and the clinical features of the

disease

• Advances in the development of monoclonal antibodies → identification

of unique immunophenotypic profile for most leukemias and

lymphomas

• Advances have enhanced accuracy and reproducibility of diagnosis

Page 42: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Chronic lymphocytic leukemia

• A monoclonal disorder characterized by a progressive accumulation of

functionally incompetent lymphocytes.

• Most common form of leukemia found in adults in Western countries

• In some people with CLL, the disease grows and progresses slowly

• May take years for symptoms to appear or for treatment to be needed

• Some patients may never need treatment for their CLL

Page 43: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Chronic lymphocytic leukemia• In other patients the disease grows more quickly and needs treatment

sooner.

• Some patients die rapidly, within 2-3 years of diagnosis, because of complications from CLL, but most patients live 5-10 years

• 90% people diagnosed with CLL are over the age of 50

• Mostly affects men – incidence is twice that of women

• When present - symptoms are related to anemia, thrombocytopenia and

neutropenia

• Signs and symptoms may develop gradually

Page 44: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Chronic lymphocytic leukemia• B lymphocyte neoplasm (B-CLL) – T lymphocyte very rare

• CLL is a stage of small lymphocytic lymphoma (SLL) -a type of B-cell

lymphoma primarily in the lymph nodes

• CLL and SLL are considered the same underlying disease but with different

clinical presentation

• Included in the lymphoproliferative disorders

Page 45: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Chronic lymphocytic leukemiaCharacterized by lymphocytosis in PB and BM

• Accumulating lymphocytes in CLL → crowding out of other cells

• → neutropenia, anemia, thrombocytopenia

• → Organ infiltration → adenopathy, splenomegaly, hypersplenism

Neoplastic cells of CLL are more fragile than normal lymphocytes > burst open during smear preparation > smudge cells (bare nuclei)

Smudge cells can also be found in reactive lymphocytosis and other neoplasms

Therefore not diagnostic

Reduce smudge cells by mixing a drop of albumin with a drop of blood prior to

making smear

Page 46: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

CLL morphology

CLL in PB with smudge cells CLL in BM, with numerous mature- appearing lymphocytes

Page 47: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Chronic lymphocytic leukemia

Characterized by altered humoral immunity (antibody mediated immunity)

• Due to suppression of all classes of immunoglobulin (Ig) →

hypogammaglobulinemia → increased susceptibility to infections

• Production of autoantibodies → autoimmune disease - idiopathic

thrombocytopenia or autoimmune hemolytic anemia

15-35% of patients develop autoimmune hemolytic anemia at some time during

course of the disease

• Immune-mediated destruction of red blood cells and platelets =

unique feature that is not present in other kinds of leukemia

Page 48: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Chronic lymphocytic leukemia

51% of B-CLL patients positive for Bence-Jones paraproteinemia

• Bence Jones proteins are considered the first tumor marker; made by plasma

cells;

• The presence of these proteins in a person's urine is associated with a

malignancy of plasma cells

Page 49: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Cause and physiological process of CLLNo specific cause known

Possibly due to viral infections

• B-CLL cells from some patients appear to be a malignant transformation of an antigen-committed B cell responding to the human T-lymphotropic virus type 1 (HTLV-1) infection

• HTLV-1 infection seems to precede development of CLL in some patients

May be due to failed apoptosis

• B-CLL cells have been shown to have high levels of anti-apoptotic agents (protein BCL2)

• The proto-oncogene BCL2 is a known suppressor of apoptosis, resulting in a long life for the involved cells

• BCL-2 seen in 80% of B-CLL cells

• Presence of p53- tumor suppressor gene in CLL –del of 17p

Page 50: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari
Page 51: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Cause and physiological process of CLLDeregulation of cell cycle regulatory genes

• Abnormality of the regulation of cell proliferation

• CLL is characterized by the gradual accumulation of small mature B cells which are in the G0/G1 phase of the cell

• Cell Cycle progression governed by interactions between cyclins, cyclin-dependent kinases (CDKs), cyclin-dependent kinase inhibitors

• cyclin D1 and D3 mRNA levels correlated positively with lymphocyte doubling time (LDT)

• cyclin D1 and D3 mRNA levels were 4 to 6-fold higher in CLL cells than in normal peripheral blood B cells

• http://www.ncbi.nlm.nih.gov/pubmed/16109604

Page 52: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari
Page 53: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Immunologic features for studying lymphocytes

• 20% of circulating lymphocytes have surface Igs and are B cells

• 61-89% are T cells

• 22% are NK cells

• It is not possible to differentiate by morphological features only

• Need to differentiate in lymphoproliferative disorders

• As lymphocyte matures from pluripotent stem cell → lymphoid tissue –

acquire developmental markers – identify subpopulations

Page 54: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Immunologic features for studying lymphocytes

• Malignant B-cells do not progress normally; do not become plasma cell –

arrested development – at earlier stage

• Genetic recombination – generate an immature B cell that expresses

functional sIg

• Characteristic immunophenotype for B-CLL – expression of sIg

Page 55: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Chromosomal abnormalities

• Most common in B-CLL is an extra chromosome 12 = trisomy 12 Occurs in 15-20% of cases

• May occur alone or with other deletions or translocations of chromosome 13q14 Most common chromosomal abnormality – 13q14-23.1 In 25% of cases Early clonal abnormality Suggestive of a loss or inactivation of a tumor suppressor gene Undetectable at cytogenetic level Detectable in 50% of CLL cases using molecular probes for the 13q14 region

• Presence of multiple chromosomal abnormalities = poor prognosis indicator Trisomy 12 Del 11q Del 17p13 (p53) 13q, 14q abnormalities

Page 56: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Chromosomal abnormalities

Page 57: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Chromosomal abnormalities

Page 58: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Clinical course of CLL

• Median survival for CLL = 4-5yrs

• 50% of patients live beyond 5yrs

• 30% have a 10yr survival

• Can be indolent, asymptomatic, may not require any treatment

• Until lymphocytosis of the PB, BM, lymphadenopathy, splenomegaly, anemia, neutropenia, thrombocytopenia, autoimmune symptoms, and infection develops

• This can take up to 10-15yrs to develop after initial diagnosis

Page 59: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Clinical course of CLL

• On the other hand – 20% of cases have aggressive clinical course

• Rapid progression > Death within 1-2yrs

• Not clear why the variation in response to the disease

• Various prognostic markers used to help predict outcome CD38, ZAP-70, and mutational status of Ig heavy chain variable region (VH)

ZAP-70 = protein normally expressed near the surface membrane of T cells and natural killer cells. It is part of the T cell receptor, and plays a critical role in T-cell signaling

Aggressive CLL = higher expression of CD38, ZAP-70, “unmutated” Ig VH gene

• Clinical and pathologic data have been used to try to predict prognosis, to identify stages and risk groups

Page 60: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Staging of CLLTwo staging systems are in common use for CLL:

• Modified Rai staging in the United States

Has historical precedent and widely used

• Binet staging in Europe

• Neither is completely satisfactory - both have often been modified.

• These CLL staging systems have been unable to provide information regarding

disease progression due to its heterogeneity

Page 61: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Rai-Sawitsky staging of CLLOriginal 5-stage staging system was revised in 1987 to a simpler 3-stage system

The revised system divides patients into low-, intermediate-, and high-risk groups

Low risk (formerly stage 0)

• Lymphocytosis in the blood and marrow (≥ 5 x 109/L in PB, ≥ 30% lymphs in BM)

• 25% of presenting population

• Median survival > 12.5yrs

Page 62: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Rai-Sawitsky staging of CLLIntermediate risk (formerly stages I and II)

• Lymphocytosis + enlarged lymph nodes - Median survival (Ms) 8.5yrs

• Lymphocytosis + enlarged spleen or liver, ± lymphadenopathy – Ms 6yrs

• 50% of presentation

High risk (formerly stages III and IV)

• Lymphocytosis + anemia (Hgb < 11 g/dL), ± enlarged nodes, spleen, liver – Ms 1.5yrs

• Lymphocytosis + thrombocytopenia (plts <100 x 109/L), ± anemia, organomegaly –

Ms 1.5yrs

• 25% of all patients

Page 63: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Binet staging of CLLStage A

• Hemoglobin ≥ 10 g/dL, no anemia

• Platelets ≥ 100 × 109/L, no thrombocytopenia

• Fewer than 3 lymph node areas involved

Stage B

• Hemoglobin and platelet levels as in stage A

• 3 or more lymph node areas involved

• Ms 5yrs

Stage C

• Hemoglobin < 10 g/dL

• Platelets < 100 × 109/L, or both

• Ms 2yrs

After successful treatment of immune cytopenias, CLL may be down-staged

Page 64: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Staging of CLLStaging systems do not predict whether patient’s clinical course is more likely to be slow moving or progressive

Most reliable predictive factor for slow growing CLL blood lymphocyte doubling time (LDT) greater than12 months Non-diffuse pattern of BM lymphocyte infiltration + a Rai stage of 0,1 or 11 (low or

intermediate)

Progressive clinical course and shorter survival Short LDT – less than 12 months diffuse lymphocyte infiltration of the BM + Rai of 111 or 1V (high risk) ↑ β2-microglobulin, CD23 in serum

Presence of chromosomal abnormalities

Page 65: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Transformation of CLLProlymphocytic transformation

Low grade, slow progression

Richter’s syndrome Diffuse large-cell lymphoma Rapid progression Accounts for 5% of all deaths in CLL p53 present in 40% of patients -associated with resistance to chemotherapy

Acute leukemiaUnusual in CLL

Terminal transformationWhen there is a proliferation of a new population of immature cells

Appearance of chromosomal changes not previously present

More malignant clone → resistance to therapy

Poor prognosis

Page 66: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Clinical features of CLLPatients > 50yrs presenting with lymphadenopathy, lymphocytosis

CBC with differential shows absolute lymphocytosis > 5000 B-lymphocytes/µL Lymphocytosis must persist for longer than 3 months 30% lymphocytosis of the BM consisting of morphologically mature appearing

lymphocytes Lymphocytes with hyper-clumped nuclear chromatin pattern, smudge cells

Positive sIg, CD19, CD20, CD5, CD23, CD43

• Cytopenia caused by clonal bone marrow involvement establishes the diagnosis of CLL regardless of the peripheral B-lymphocyte count

• Clonality must be confirmed by flow cytometry.

Page 67: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Other features of CLL• Varies from no treatment to the use of chemotherapeutic agents with or

without radiation therapy

• Prognosis – 50% 5yr survival; 30% ≤ 10yr survival

• Differential diagnosis – ALL, PLL, SLL, HCL, Sezary syndrome, LGL, ATCL, SCCL,

Waldenstrom’s macroglobulinemia, viral infection

Page 68: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Clinical features and differential diagnosis of CLL

• Microscopic examination of PB smear is indicated to confirm lymphocytosis

Morphologically identical to SLL

• Presence of smudge cells = artifacts from lymphocytes damaged during the

slide preparation.

• Large atypical cells, cleaved cells, and prolymphocytes

may account for up to 55% of peripheral lymphocytes.

If >55%, prolymphocytic leukemia (B-cell PLL) is a more likely diagnosis

Page 69: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Clinical features and differential diagnosis of CLL

Page 70: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Diagnosis of CLLCLL can be diagnosed morphologically via immunophenotyping – immunoperoxidase and flow cytometry

• Using monoclonal abs to detect specific surface antigens (cluster differentiation CD antigens)

• The typical CLL phenotype is CD5+, CD23+, FMC7-, weak expression of surface Ig (sIg) and weak or absent expression of membrane CD22 and CD79b

• CD 19, CD 20, CD79a, CD5, CD23, CD45, faint CD11 = B-CLL

• Characteristic for B-CLL = detection of a predominance of sIg with κ or λ light-chain restriction = monoclonality

Page 71: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Diagnosis of CLLPeripheral blood flow cytometry - most valuable test to confirm a diagnosis of CLL

• Confirms the presence of circulating clonal B-lymphocytes expressing CD5, CD19, CD20(dim), CD 23, and an absence of FMC-7 staining

Bone marrow aspiration and biopsy with flow cytometry is not required in all cases of CLL.

may be necessary in selected cases to establish the diagnosis and to assess other complicating features such as anemia and thrombocytopenia

Lymph node biopsy - if lymph node(s) begin to enlarge rapidly in a patient with known CLL

to assess the possibility of transformation to a high-grade lymphoma When such transformation is accompanied by fever, weight loss, and pain, it is termed

Richter syndrome

Page 72: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Diagnosis of CLL

• Molecular testing now exists that may help predict prognosis or clinical course -

not necessary for the diagnosis or staging of CLL

• At present, these tests are not recommended for routine use, although this

may change with further research.

• Chromosomal evaluation using FISH can identify certain chromosomal

abnormalities of CLL with prognostic significance.

Patients with del(17p) tend to have a worse prognosis, as well as resistance to therapy

with alkylating agents and purine analogues.

Patients with del(11q) also have a worse prognosis and bulky lymphadenopathy at

presentation.

Page 73: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Mantle cell -derived from a subset of center cells in the mantle region of lymphoid follicles. MCL represents 2-10% of all non-Hodgkin lymphomas

Page 74: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Clinical features and differential diagnosis of CLL

• Patients with < 5000 B-lymphocytes/µL + lymphadenopathy and (-)

cytopenias more likely = small lymphocytic lymphoma (SLL)

diagnosis should be confirmed by lymph node biopsy

• Patients with a clonal B-cell population < 5000/µL (-) lymphadenopathy or

organomegaly, cytopenia, or other disease-related symptoms = monoclonal B-

lymphocytosis (MBL)

MBL progress to CLL at a rate of 1-2% per year

Page 75: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Differential diagnosis of CLLALL – morphological differences of the proliferating population

Smooth, nuclear chromatin of lymphoblasts in ALL versus, dense nuclear chromatin of CLL TdT (+) for ALL, TdT (-) for CLL

B-prolymphocytic leukemia (B-PLL) – > 55-75% prolymphocytes <10% in CLL If 11-55% = Prolymphoid transformation = mixed cell type of CLL/PLL CD24/CD22, ± CD10 Strong expression of sIg and CD20 (+) FMC-7

antigen expressed on mature human B cells used in immunophenotypic analysis and differential diagnosis of lymphomas and leukemias

Sezary syndrome – a type of cutaneous T-cell lymphoma CTCL) which belongs to a larger group of disorders

known as non-Hodgkin’s lymphomas Sezary cells = malignant T lymphocytes, mature memory T cells Mycosis fungoides in the skin pleomorphic abnormal T cells with convoluted nucleus CD2, CD3, CD4, CD5 CD7 (-), CD8 (-)

Page 76: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Differential diagnosis of CLL

Hairy cell leukemia - abnormal growth of B cells

The cells look "hairy" under the microscope because they have fine

projections coming from their surface

CD19/20/24; CD22 CD25; CD103

CD5(-)

Pancytopenia

Tartrate resistant acid phosphatase TRAP (+)

T-granular lymphocytosis

Lymphocytosis

Anemia; neutropenia; thrombocytopenia

Large cell size, moderate cytoplasm with prominent vacuoles

CD2, CD3, CD8, CD57 (HNK-1)

Page 77: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

ALOT, acute leukemia orientation tube; AML, acute myeloid leukemia; BC, blast crisis; BCP, B-cell precursor; BM, bone marrow; CLL, chronic lymphocytic leukemia; CLPD, chronic lymphoproliferative disorders; CML, chronic myeloid leukemia; CSF, cerebrospinal fluid; FL, follicular lymphoma; HCL, hairy cell leukemia; LN, lymph node; LST, lymphoid screening tube; MCL, mantle cell lymphoma; MDS, myelodysplastic syndrome; MPD, myeloproliferative disorders; PCD, plasma cell disorders; PCST, plasma cell screening tube; PNH, paroxysmal nocturnal hemoglobinuria; SST, small sample tube.

Page 78: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Other methods for diagnosing CLLMolecular probes – rearrangements of B-cell Ig and T-cell receptor genes

Cytogenetics – chromosomal abnormalities

Cytochemistry –

Electron microscopy

Page 79: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

TreatmentChemotherapy

The most common treatment for CLL is the chemotherapy drug fludarabine.

Radiation therapy an alternative or used in conjunction with other therapy

Stem cell transplantation Only used to treat the occasional young patient with aggressive CLL, since most

patients with CLL live so long that the risk of transplant can seldom be justified.

Investigational therapy – clinical trials Clinical trials currently available to UCSF patients include Flavopiridol for CLL cases

that don't respond to standard treatment. Flavopiridol kills CLL so quickly that blood salt and acid-base abnormalities arise, potentially causing kidney failure

http://www.ucsfhealth.org/conditions/chronic_lymphocytic_leukemia/treatment.html

Page 80: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Review questionsWhat are the consequences of the accumulation of the lymphocytes in the peripheral blood and bone marrow in a patient with CLL?

• A) Neutropenia

• B) Anemia

• C) Thrombocytopenia

• D) All of the above

• E) None of the above

Ans.: D

Page 81: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Review questionsA cell that could suggest that lymphocytes in CLL are not normal is a:

• A) Smudge cell

• B) Lymphoblast

• C) Monoblast

• D) All of the above

• E) None of the above

Ans. A

Page 82: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Review questionsWhich type of MDS demonstrates a mild decreased white blood cell (WBC) count (3.9 ´ 10/L), increased erythropoiesis and normal numbers of blast cells in the marrow, and <15% sideroblasts?

• A) Refractory anemia with ringed sideroblasts (RARS)

• B) Refractory anemia (RA)

• C) Refractory anemia with excess blasts (RAEB)

• D) Chronic myelomonocytic leukemia (CMML)

• E) None of the above

Ans. B

Page 83: Lecture 6 and 7 Myelodysplastic syndromes; Chronic lymphocytic leukemia and related lymphoproliferative disorders Abdulkarim Aldosari

Review questions• What is the purpose of transfusing granulocytes to a patient with RA?

• A) Prevent hemorrhages

• B) Prophylaxis to infection

• C) Increase blood volume

• D) Decrease plasma viscosity

• E) None of the above

Ans.: B