Khalid Ali MD

 NORMAL HEMATOPOIESIS
 Hematopoietic pluripotent stem cell has the
potential
◦ Self renewal
◦ Differentiation after commitment
 Lymphoid/myeloid
◦ Stable population of pluripotent stem cells which
generate lineage specific progenitors then mature
blood cell
◦ Effective hematopoiesis requires the interaction
 Hematopoietic growth factors
 Receptors
 BM microenvironment
 ALL
naïve

B-lymphocytes
Plasma
Lymphoid cells
progenitor T-lymphocytes

AML
Hematopoietic Myeloid Neutrophils
stem cell progenitor

Eosinophils

Basophils

Monocytes

Platelets

Red cells
 Myeloid maturation

myelobla promyelocyte myelocyte metamyelocyte band neutrophil

st

MATURATION
 Differentiation
Committed
Stem Cell cell
RBC
WBC
Platelets
Self Renewal …..
 Mutatio
n
Differentiation
Committed
Stem Cell cell
RBC
WBC
Platelets
Self Renewal …..

↑ Proliferation
 Operational classification separates the
malignancies into two
◦ Myeloid
◦ Lymphoid
 Proportion of morphologically &
immunophenotypically immature precursors
or blast percentage.
◦ Acute >20/30%
◦ Chronic <20/30%
 Hematological malignancies arise when the processes of
proliferation or apoptosis are corrupted in blood cells.
 If Mature differentiated cells are involved, the cells will
have a low growth fraction and produce indolent
neoplasm's such as the low-grade lymphomas or chronic
leukemia's, where patients have an expected survival of
many years.
 In contrast, if more primitive stem cells are involved, the
cells can have the highest growth fractions of all human
neoplasm's, producing rapidly progressive life-
threatening illnesses such as the acute leukemia's or
high-grade lymphomas.
13
 Blood Cancer (Neoplasm)

Myeloid Lymphoid
Neoplasm Neoplasm

1. Acute myeloid leukemia 1. Acute lymphoblastic leukemia

2. Chronic myeloid neoplasms 2. Chronic lymphoid neoplasms

a) Lymphomas
b) Myeloma and variants
c) Lymphoid leukemias
 HEMATOLOGIC
MALIGNANCIES

LYMPHOID MYELOID

OTHER
ACUTE ACUTE CHRONIC
LYMPHOPROLIFER
LYMPHOCYTIC MYELOID MYELOID
ATIVE
LEUKEMIA LEUKEMIA DISORDERS
DISORDERS
 CHRONIC MYELOID
DISORDERS

CHRONIC MYELO- MYELO-DYSPLASTIC

PROLIFERATIVE D/Os SYNDROMES(MDS)

CLASSIC ATYPICAL RA

ATYPICAL CML RARS

CML

CHRONIC

ET NEUTROPHILIC
LEUKEMIA
RAEB

CHRONIC

PV EOSINOPHILIC
LEUKEMIA
RAEBT

MF HES CMML

POST-PV AMM

POST-ET
Myeloproliferative Malignant
diseases Leukaemias lymphomas

chronic myeloid Acute myeloid Hodgkin’s

leukaemia leukaemia lymphoma
(CML) (AML)

Polycythemia Chronic myeloid Non-hodgkin’s

vera leukaemia lymphoma
(PV) (CML) (NHL)

Idiopathic Acute lymphatic

myelofibrosis leukaemia Burkitt's lymphoma
(MF) (ALL)

Essential Chronic cutaneous T-cell

thrombocythemia lymphatic lymphoma (CTCL)
(ET) leukaemia
(CLL)
hairy cell
leukaemia
(HCL)
CHRONIC MYELOPROLIFERATIVE
DISORDERS(CMPDs)
 Chronic myelogenous leukemia(CML)

 Polycythemia vera(PV)

 Agnogenic myeloid metaplasia ( AMM)

◦ Chronic idiopathic myelofibrosis(by WHO)

 Essential thrombocythemia( ET)

◦ Essential thrombocytosis
 Leukemia's are malignant disorders of the
hematopoietic stem cell compartment,
characteristically associated with increased numbers
of Primitive white cells in the bone marrow and/or
peripheral blood.
 The course of leukemia may vary from a few days or
weeks to many years, depending on the type.

19
 The incidence of all types of Leukemia in the
popn. Is ~ 10/10,000 per annum
 Males are more affected than females: Acute
leukemias-3:2,CLL(3:2),CML(1.3:1)
 Acute Leukemias occur in all age groups
-ALL peak age group 1-5 yr
-AML occur more > 50yrs
-Chronic leukemias more commonly middle
& older age groups
 Ionizing radiation- An increase in leukemia was
observed after the use of radiotherapy for ankylosing
spondylitis and diagnostic X-rays of the fetus in
pregnancy
 Cytotoxic drugs
 Retroviruses
 Genetic -There is a greatly increased incidence of
leukemia in the identical twins of patients with
leukemia .
 Immunological -Immune deficiency states.

21
 In acute leukemia there is proliferation of primitive
stem cells leading to an accumulation of blasts,
predominantly in the bone marrow, which causes
bone marrow failure.
 In chronic leukemia the malignant clone is able to
differentiate, resulting in an accumulation of more
mature cells.
 Leukemia's are traditionally classified into four main
groups:
◦ Acute lymphoblastic leukemia (ALL)
◦ Acute myeloid leukemia (AML)
◦ Chronic lymphocytic leukemia (CLL)
◦ Chronic myeloid leukemia (CML).
22
 The diagnosis of leukemia is usually suspected from
an abnormal blood count, often a raised white count.
 The diagnosis is made from examination of the bone
marrow.
 This includes:
 the morphology of the abnormal cells,
 analysis of cell surface markers
(immunophenotyping),
 clone-specific chromosome abnormalities and
 molecular changes.

23
 Acute Leukemias(AL) is a clonal neoplastic d/o characterized by
the proliferation and accumulation of immature and
malignantly transformed cells in the bone marrow and
peripheral bloods.
 There is a failure of cell maturation in acute
leukemia
 These abnormal cells replace the normal marrow
tissues, including the hematopoietic precursor cells.
 The result is abnormal hematopoiesis or
insufficiency, manifested by leukopenia(decreased
normal white cells),thrombocytopenia, anemia with
or without leukocytosis in peripheral blood.
 Infiltration of various tissues or organs is also a
feature of acute leukemias
24
 Sudden onset

 If left untreated is fatal within a few weeks

or months

 AML is about 4X more common than ALL in

adults.
 In children the proportions are reversed,
the lymphoblastic variety being more
common.
 Develop as a result of a genetic alteration
within single cell in the bone marrow
a) Epidemiological evidence :
1. Hereditary Factors
 Fanconi’s anaemia
 Down’s syndrome
 Ataxia telangiectasia
2. Radiation,
Chemicals and
Drugs
3. Virus related
Leukemias
 Retrovirus :- HTLV
1 & EBV
b)Molecular Evidence
 Oncogenes :
 Gene that code for proteins involved in cell
proliferation or differentiation
 Tumour Suppressor Genes :
 Changes within oncogene or suppressor
genes are necessary to cause malignant
transformation.
Oncogene can be activated by :
 chromosomal translocation
 point mutations
 inactivation

 In general, several genes have to be altered to

effect neoplastic transformation
 Acute leukemia cause morbidity and mortality
through :-
◦ Deficiency in blood cell number and function
◦ Invasion of vital organs
◦ Systemic disturbances by metabolic imbalance
A. Deficiency in blood cell number or function
i. Infection
- Most common cause of death
- Due to impairment of phagocytic function
and neutropenia
ii. Hemorrhage
- Due to thrombocytopenia or 2o
DIVC or liver disease
iii. Anaemia
- normochromic-normocytic
- severity of anaemia reflects severity of
disease
- Due to ineffective erythropoiesis
B. Invasion of vital organs
- vary according to subtype
i. Hyperleukocytosis
- cause increase in blood viscosity
- Predispose to microthrombi or acute
bleeding
- Organs involed : brain, lung, eyes
- Injudicious use of packed cell
transfusion precipitate hyperviscosity
ii. Leucostatic tumour
- Rare
- blast cell lodge in vascular system forming
macroscopic pseudotumour – erode vessel
wall cause bleeding
iii. Hidden site relapse
- testes and meninges
C. Metabolic imbalance
- Due to disease or treatment
- Hyponatremia -vasopressin-like subst.
by myeloblast
- Hypokalemia due to lysozyme release by
myeloblast
- Hyperuricaemia- spont lysis of leukemic
blast release purines into plasma
 is a malignant (clonal) disease of the bone marrow in which early
lymphoid precursors proliferate and replace the normal
hematopoietic cells of the marrow.

 Arises from a single progenitor cell that has undergone genetic

damage leading to deregulated growth and arrest of differentiation.

 The lymph oblasts replace the normal marrow resulting in marked

decrease in the production of normal cells. they also proliferate in
organs other than marrow particularly in liver, spleen and lymph
nodes.
 Cancer of the blood affecting the white blood cell
known as LYMPHOCYTES.
 Commonest in the age 2-10 years
 Peak at 3-4 years.
 Incidence decreases with age, and is rare after 40
years.
 In children - most common malignant disease
 85% of childhood leukaemia
 EPIDEMIOLOGY
 In adults, ALL< AML
 In the United States, 1000 new cases of ALL
 Accounts for less than 20% of adult acute leukemia
 Sex: male to female: 1.5:1.
 Age: in children than in adults.

 Mortality/Morbidity:
 Only 20-40% of adults with ALL are cured with current regimens.
 The overall cure rate in children is 90%, while 50% of
adults are long-term disease-free survivors.
 This reflects the high proportion of adverse
cytogenetic abnormalities seen in adults with
precursor B cell ALL.

 Arise from the malignant transformation of a
myeloid precursor
 Continuous proliferation of myeloid precursors
with reduced capacity to differentiate into more
mature cellular elements
 Acute myeloid leukemia and related aggressive
myeloid neoplasms — AML is defined by greater
than 20 percent myeloid blasts in the bone marrow
or peripheral blood, or the presence of particular
cytogenetic abnormalities, regardless of the blast
count.
 AML causes bone marrow to produce too many immature white blood cells
(blast cells).
 Suppresses normal blood cell production.
◦ Anemia, leucopenia, thrombocytopenia
 AML is acquired from genetic damage to the DNA of
a single cell in the bone marrow; resulting in
malignancy.
 Diagnosed by clinical laboratory tests performed on
blood and bone marrow.
 Primarily affects adults and children younger than one year
old.
 Incidence is 3.5 out of 100,000 people.
 Rare in childhood (10%-15%)
 The incidence increases with age
 80% of acute leukemias in adults
 Most frequent leukemia in neonate
 Epidemiology
• Relative prevalence
•ALL = 11%
•AML = 46 %
•CML = 14 %
•CLL = 29 %

AML ALL
Incidence/100,000 3.5 (80% of AL) 1.4(20% of AL)

Age 60-65 yrs 3-4 yrs

Sex Ratio M:F 1.3:1 1.5:1

 Etiology

 Hereditary Disorders  Aquired

– Fanconi anemia factors/disorders
– Blooms syndrome
– Radiation exposure
– Downs syndrome
– Wiscott Aldrich .. – Chemicals
– Diamond Black fun… – Myeloploriferative
– Ataxia Telangiectasia Disorders
– Klienfelter’s Syndrome – Viruses
– Neurofibromatosis
– Siblings
 Age
◦ Older adults are more likely to develop AML
 Smoking
◦ 20% of AML cases are linked to smoking
◦ Doubles the risk of disease in people older than 60
 Genetic disorders
◦ Down syndrome, Fanconi’s anemia
 High doses of radiation
◦ Long-term survivors of atomic bombs
 Previous chemotherapy treatment
◦ Breast cancer, ovarian cancer, lymphoma
 Exposure to industrial chemicals
◦ Benzene
 Exposure to XRT
 Prior chemotherapy
◦ Alkylating agents (5-10 years after). Often a
myelodysplastic phase is present. Associated
cytogenetic abnormality is del 5 or del 7
◦ Topoisomerase II inhibitors (1-3 years), often
monocytic differentiation. Cytogenetic hallmark is
11q23
 Benzene exposure
 Down syndrome
◦ Often associated with M7 and mutations in GATA1 gene
 DNA repair defects
◦ Bloom syndrome, Fanconi anemias, neurofibromatosis,
and Li Fraumeni syndrome
Clinical features
 The clinical features are usually those of bone marrow
failure (anemia, bleeding or infection…).
 The majority of patients with acute leukemia,
regardless of subtype present with symptoms arising
from:
Anemia - shortness of breath on effort;
excessive tiredness, weakness
Neutropenia- recurrent infections
Thrombocytopenia - bleeding and bruising
Marrow infiltration - bone pain.

47
 Examination may be unremarkable, but features
include:
Pallor

Fever (due to infection, not the disease itself)

Petechiae, purpura, bruises, fundal hemorrhage

Lymphadenopathy, hepatosplenomegaly (more in

lymphoblastic leukemias
Bone(sternal) tenderness

48
 Confirmation of diagnosis:

 Blood count- Hb low, WBC raised usually (sometimes low),

platelets low. neutropenia

peripheral blood examination. Blast cells almost

invariably seen, lineage identified morphologically,
confirmed with immunophenotyping.

 Bone marrow aspirate. Increased cellularity, reduced

erythropoiesis, reduced megakaryocytes, sometimes
trilineage dysplasia. Blast cells > 20% (often approaching
100%).

 Chest X-ray. Mediastinal widening often present in T

lymphoblastic leukemia.
49
 History & P/E
 CBC, ESR, BG,Peripheral Exam
 Bone marrow aspiration & Biopsy
 CXR,CT ..
 Biochemical studies (LDH, RFT,LFT,
Electrolyte,uric acid
 Coagualtion profile
 LP
 HLA Typing in patients eligible for Allogenic
SCT
Laboratory features
Laboratory Features Percentage
Anemia 90%

WBC
Elevated 60%
Normal 15%
Decreased 25%
25%pts > 50,000/mL
Platelets 90%
< 150,000 50%
< 50,000
 Definitive Dx: 20% (WHO) ,30%(FAB) blasts in the
BM/per.blood
 PROGNOSTIC FACTORS for ALL

Poor prognostic factors

 Leukocyte count >50,000
 very young ,<1 yrs & older patients,>10yrs
 mature B-cell or T-cell immunophenotypes
 FAB L3 subtype
 patients with hypoploidy and pseudodiploidy
 chromosomal translocations including the: t(8:14) , t(9:22) BCR-
ABL gene , t(1;19) E2A-PBX1 gene t(4;11)
 the response to initial treatment ( time to CR >4wks)
 ALL AML
Age <1 > 60 year
TWBC > 50 x 109/l High(>30x106/ml)
CNS present present (rare)
Sex male male/female
Cytogenetic t(9;22) monosomy 5, 7
 Untreated acute leukemia is invariably fatal, most
often within months.
 Treatment with curative intent may be successful,
or may fail because:
-leukemic cells cannot be eradicated or
-patient cannot sustain the therapy
-death occurring as early as if Rx not started
 Since curative treatment even for 'low-risk' acute
leukemia carries considerable morbidity and
potential mortality and that for 'high-risk' acute
leukemia even more, it is essential that the
'risk/benefit' ratio is clearly understood by
physician and patient alike.
55
1. Blood support :-
 platelet con. for bleeding episodes or if
the platelet count is <10x109/l with fever
 fresh frozen plasma if the coagulation screen
results are abnormal
 packed red cell for severe anaemia (caution :
if white cell count is extremely high)

57
2. Prevention and control infection
 barrier nursed
 Intravenous antimicrobial agents if there is a
fever or sign of infection
 Existing infections identified and treated (e.g. UTI,
oral candidiasis, dental, gingival and skin
infections)
3.Psychologic
al and social
support
 This is a key aspect of care.
 Patients should be kept informed, and their
questions answered and fears allayed as far
as possible.
 An optimistic attitude from the staff is vital.
 Delusions, hallucinations and paranoia are
not uncommon during periods of severe
bone marrow failure and septicemic
episodes, and should be met with patience
and understanding.

60
 Therapeutic regimen carefully explained to the
patient and informed consent obtained.
 The aim of treatment is to destroy the leukemic clone
of cells without destroying the residual normal stem
cell compartment from which repopulation of the
haematopoietic tissues will occur.
 There are three phases:

1.Remission induction - the bulk of the tumor is

destroyed by combination chemotherapy.
 The patient goes through a period of severe bone marrow
hypoplasia,
 requiring intensive support &
 inpatient care from specially trained medical and nursing
staff.

62
2.Remission consolidation:
◦ If remission has been achieved by induction
therapy, residual disease is attacked by therapy
during the consolidation phase.
◦ This consists of a number of courses of
chemotherapy, again resulting in periods of
marrow hypoplasia.
◦ In poor prognosis leukemia this may include a
stem cell transplant.

63
3.Remission maintenance- If the patient is still in
remission after the consolidation phase for acute
lymphoblastic leukemia, a period of maintenance
therapy is given, consisting of a repeating cycle of
drug administration.
◦ This may extend for up to 3 years if relapse does
not occur and is usually given on an outpatient
basis.
◦ Thereafter, specific therapy is discontinued and the
patient observed.

64
 Transplantation
◦ HST is indicated in young patients with high-risk features
whose disease is in the 1st CR (eg.ph+ ALL) … (LFS…50%)
◦ Duiring 1st remission remains controversiaL
◦ In standard risk patients it is reserved for relapse
66
Early side effects
 nausea and vomiting
 mucositis, hair loss, neuropathy, and renal
and hepatic dysfunction
 myelosuppression
Late effects
 Cardiac–Arrhythmias, cardiomyopathy
 Pulmonary–Fibrosis
 Endocrine–Growth delay, hypothyroidism,
gonadal dysfunction
 Renal–Reduced GFR
 Psychological–Intellectual dysfunction,
 Second malignancy
 Cataracts
CML
Chronic myelogenous leukemia
(CML)
INTRODUCTION
PATHOGENESIS
PHASES
CLINICAL PRESENTATION
DX
DDX
TREATMENT
 Definition:
 ● CML is a clonal Myeloproliferative neoplasm that
originates from an abnormal pluripotent (
primitive) hematopoietic stem cell.

 Dysregulated production of a particular lineage of

mature myeloids with fairly normal differentiation

 ● It is characterized by the presence of the

Philadelphia chromosome (Ph+) that results from
the translocation of genetic material between
chromosomes 9 and 22, t(9;22).

 ● The hallmark of its presentation is
leukocytosis, in which cells at all stages
of myeloid differentiation are present.
 ● CML generally runs a mild course initially
until it transforms to a frankly leukemic
(blast crisis) phase.

 Variable tendency to progress to acute leukemia

 Abnormal chromosome 22(Philadelphia chr)

 10-20% of leukemia in adults
◦ Higher rate(about 50%) in our country
 Median age at presentation is 50years
◦ It is in the 30’s in our setup

 Predominantly neutrophils but also basophils

& eosinophils

73
 Etiology:
 ● No specific etiologic agent can be identified in CML.

  However, increased incidence has been noted after high

 dose ionizing radiation exposure.

 ● There has been no evidence for a causal association
 between CML and organic solvents, industrial chemicals
 or alkylating agents.

 ● There does not appear to be an inherited predisposition

 Philadelphia chromosome
◦ Balanced translocation between chromosome 9 &22

◦ The shorter( chr.22)

◦ c-ABL-BCR
 ABL-Abelson's murine leukemia virus
 BCR- Breakpoint Cluster Region

◦ Abl-Bcr
 Production of tyrosine kinase
 Invariably patients with CML have a
chromosome abnormality known as the
Philadelphia (Ph) chromosome.
 This is a shortened chromosome 22 and
is the result of a reciprocal translocation
of material with chromosome 9.

76
◦ All hematopoietic cells

◦ The first chromosome to be related to human

malignancy

◦ Karyotyping/FISH (Fluorescence In Situ Hybridization)

 The disease has three phases:
◦ Chronic phase: in which the disease is responsive to
treatment and is easily controlled, typically lasting
3-5 years
◦ Accelerated phase (not always seen): in which
disease control becomes more difficult
◦ Blast crisis: in which the disease transforms into an
acute leukaemia, either myeloid (70%) or
lymphoblastic (30%), which is relatively refractory to
treatment.
 Blast crisis occurs at a rate of 10% per year and is
the cause of death in the majority of patients.
Patient survival is therefore dictated by the timing
of blast crisis, which cannot be predicted.
80
Clinical presentation

 Exposure to ionizing radiation is the only

risk factor identified

 Asymptomatic in about 50%

◦ Detected during routine blood test

•In developed countries, 20% to 30% of patients
are diagnosed by the incidental finding of
leukocytosis.
 Presentation depends on the stage
 85% present in the chronic phase
 About 25% of patients are asymptomatic at
diagnosis.
 On examination the principal clinical finding is
splenomegaly, which is present in 90% of patients. In
about 10% the enlargement is massive, extending to
over 15 cm below the costal margin.
 A friction rub may be heard in cases of splenic
infarction.
 Hepatomegaly occurs in about 50% of patients.
 Lymphadenopathy is unusual.
82
 Symptoms
◦ Systemic sxs
◦ Abdominal fullness/pain/discomfort
 Early satiety
 Pain may radiate to the left shoulder
 Due to
 Splenomegaly
 Perisplenitis
 Splenic infarction
◦ Bleeding tendency
 Platelet dysfunction
 Signs
◦ Pallor
◦ Sternal tenderness
◦ Gouty arthrits
◦ Splenomegaly
◦ Hepatomegaly
 Presenting symptoms of 323 Ethiopian patients with
CML: TASH (2003-2010)
Symptom Number %
Abdominal mass and 257 80.0
discomfort
Weight loss 169 53.o
Fatigue 155 35.0
Sweating ± Fever 140 44.0
Anorexia 59 18.0
Abdominal pain 38 12.0
Bone pain 30 9.0
Bleeding tendency 19 6.0
Deafness* 7 2.0
Priapism* 4 1.0
No symptoms 16 5.0
Other 15 5.0
 Presenting manifestations of 323 Ethiopian patients
with CML: TASH (2003-2010)

Sign Number %
Splenomegaly 301 94.0
Sternal tenderness 224 70.0
Hepatomegaly 172 54.0
Pallor 163 51.0
Lymphadenopathy 32 10.0
Peripheral edema 22 7.0
Signs of CHF 10 3.0
Skin lesions 12 4.0
 Lab
◦ Anemia
◦ High WBC count
 Neutrophils at different stage of development
 Basophilia
 Eosinophilia
◦ Thrombocytosis in 50%
◦ Peripheral smears looks like the marrow
aspirate
◦ BM
 Non-specific granulocyte hyperplasia
◦ Philadelphia chromosome
 Peripheral blood: Leukocytosis with moderate
left shift (may even include 1-3% blasts)
 Eosinophilia and/or basophilia are common
 A few nucleated RBCs may be seen
90
 In the past
◦ Both clinical & lab
 Splenomegaly
 Neutrophilic leukocytosis
 Granulocyte series immature
 Low alkaline phosphatase level
 Current
◦ Philadelphia chromosome
 Karyotyping
 FISH (Fluorescence In Situ Hybridization)
 Molecular(PCR)
 Diagnosis:

 ● Current diagnostic criteria for CML require

the detection in the BM or peripheral blood of
the Ph1 or its products, the BCR-ABL fusion
mRNA or the BCR-ABL protein by FISH or QRT-
PCR.
DDX
 JUVENILE MYELOMONOCYTIC LEUKEMIA

 CHRONIC MYELOMONOCYTIC LEUKEMIA

 CHRONIC EOSINOPHILIC LEUKEMIA

 LEUKEMIOD REACTION

 OTHER PHILADELPHIA CHROMOSOME

MALIGNANCIES
 Clinical ddx
◦ Any condition that cause massive splenomegaly
( >8cm) BLCM
 HMS( HYPERREACTIVE MALARIAL SPLENOMEGALY)
 HAIRY CELL LEUKEMIA
 PV
 MF
 VISCERAL LEISHMANIASIS
 OTHER CONDITIONS ACCORDING TO THE SET UP
 Diseases Associated with Massive Splenomegaly*

Chronic myeloid leukemia
 Lymphomas Hairy cell leukemia
 Myelofibrosis with myeloid metaplasia
Polycythemia vera
 Gaucher's disease
 Chronic lymphocytic leukemia
 Sarcoidosis
 Autoimmune hemolytic anemia
 Diffuse splenic hemangiomatosis
* The spleen extends greater than 8 cm below left
costal margin and/or weighs more than 1000 g.
 CHEMOTHERAPY
◦ BUSULPHAN
◦ HYDROXYUREA
 NOVEL AGENT
◦ IMATINIB MESYLATE( GLIVEC)
◦ OTHERS ( Nilotinib, Dasatinib)
 STEM CELL TRANSPLANTATION
 INTERFERON
 OTHERS
◦ RADIOTHERAPY
 Imatinib, a tyrosine kinase inhibitor that
specifically blocks the enzymatic action of
the BCR-ABL fusion protein is first-line
treatment for the chronic phase.
 It has replaced alpha-interferon.
 Imatinib produces a complete
haematological response in over 95% of
patient, and 70-80% of these have no
detectable BCR-ABL transcripts in the
blood.
 Imatinib can be continued indefinitely.

97
 Basic Clinical Questions:
 (1) Does patient with high Hb have a true
erythrocytosis or a normal RBC mass with a
low plasma volume?
 (2) If the RBC mass is elevated, is this primary
(i.e., neoplastic) or secondary to other
underlying causes?
 Polycythemia is defined as an increase in the
hemoglobin above normal
 The term erythrocytosis may be used
interchangeably with polycythemia, but some
draw a distinction between them:
 erythrocytosis implies documentation of
increased red cell mass,
 whereas polycythemia refers to any increase
in red cells.
 (Polycythemia is suspected when the) Concern
that the hemoglobin level may be abnormally
high is usually triggered at 170 g/L (17 g/dL)
for men and 150 g/L (15 g/dL) for women.
Hematocrit levels >50% in men or >45% in
women may be abnormal.
 Hematocrits >60% in men and >55% in
women are almost invariably associated with
an increased red cell mass.
 PV is a clonal disorder involving a multipotent
hematopoietic progenitor cell in which
phenotypically normal red cells, granulocytes,
and platelets accumulate in the absence of a
recognizable physiologic stimulus.
 The most common of the chronic
myeloproliferative disorders, PV occurs in 2
per 100,000 persons, sparing no adult age
group and increasing with age to rates as
high as 18/100,000.
 DEFINITION
◦ Clonal disease
◦ Increased RBC production independent of
normal regulatory mechanisms
◦ Panmyelosis
◦ Other causes of erythrocytosis should be ruled
out
 Absolute/relative
 Secondary/primary
 Relative Erythrocytosis
◦ Hemoconcentration secondary to dehydration,
diuretics, ethanol abuse, androgens or tobacco
abuse
 Absolute Erythrocytosis
◦ Hypoxia
 Carbon monoxide intoxication
 High oxygen-affinity hemoglobin
 High altitude
 Pulmonary disease
 Right to left cardiac or vascular shunts
 Sleep apnea syndrome
 Hepatopulmonary syndrome
 Renal Disease
◦ Renal artery stenosis
◦ Focal sclerosing or membranous glomerulonephritis
◦ Postrenal transplantation
◦ Renal cysts
◦ Bartter's syndrome
 Tumors
◦ Hypernephroma
◦ Hepatoma
◦ Cerebellar hemangioblastoma
◦ Uterine myoma
◦ Adrenal tumors
◦ Meningioma
◦ Pheochromocytoma
 Drugs
◦ Androgens
◦ Recombinant erythropoietin
 Familial (with normal hemoglobin function)
◦ Erythropoietin receptor mutation
 Polycythemia vera
 Relatively common among the MPDs

 Peak at 50 – 60y, but can occur at any age

 Males affected more than females

 No etiologic agent

 Underlying mechanism
◦ JAK-2 mutation
 JAK- Janus Associated Kinase
 Cells form BFU-e without EPO

 Low serum EPO

 Increased sensitivity to EPO

 JAK-2 mutation
◦ Expression of apoptosis inhibitors
◦ Other factors like IGF
 Thrombosis
◦ Macrovascular
 CNS & Abdomen
◦ Microvascular
 Vascular headaches
 Erythromelalgia & TIAs

 Hyperviscosity

 Platelet dysfunction
 Features of the clinical history that are useful
in the differential diagnosis include
◦ smoking history;
◦ current living at high altitude; or
◦ a history of congenital heart disease,
◦ sleep apnea, or
◦ Chronic lung disease.
 Patients with PV may be
 asymptomatic or
 Experience symptoms related to the
increased red cell mass or the underlying
disease process that leads to the increased
red cell mass.
 The dominant symptoms from an increased
red cell mass are related to hyperviscosity
and thrombosis (both venous and arterial),
because the blood viscosity increases
logarithmically at hematocrits >55%.
 Although splenomegaly may be the initial presenting sign
in PV, most often the disorder is first recognized by the
incidental discovery of a high hemoglobin or hematocrit.
 With the exception of aquagenic pruritus, no symptoms
distinguish PV from other causes of erythrocytosis.
 Uncontrolled erythrocytosis causes hyperviscosity, leading
to neurologic symptoms such as vertigo, tinnitus,
headache, visual disturbances, and TIAs
 Abdominal vessel thromboses are particularly common.
 Hypertension is often present.
 Symptoms related to hepatosplenomegaly.
 Peptic ulcer disease is common.
 Patients with hypoxemia may develop cyanosis on minimal
exertion or have headache, impaired mental acuity, and
fatigue.
 Digital ischemia, easy bruising, epistaxis, acid-
peptic disease, or gastrointestinal hemorrhage
may occur due to vascular stasis or
thrombocytosis.
 Erythema, burning, and pain in the extremities, a
symptom complex known as erythromelalgia, is
another complication of the thrombocytosis of PV
due to increased platelet stickiness.
 Given the large turnover of hematopoietic cells,
hyperuricemia with secondary gout, uric acid
stones, and symptoms due to hypermetabolism
can also complicate the disorder.
 Presenting signs and sx:
◦ None
◦ Secondary to hyperviscosity from high RBC mass:
headache, fullness in head, CHF, weakness, fatigue,
dizziness
◦ Secondary to platelet abnormalities: CVA, AMI, VTE,
bleeding, bruising
◦ Secondary to high blood histamine: pruritus, peptic
ulcer
◦ Splenomegaly in 75%
◦ Hepatomegaly in 40%
 Plethora

 Hyperviscosity signs & symptoms

 Bleeding or thrombotic episodes

 Hypertension

 Budd-Chiari syndrome

 Pruritis

 erythromelagia
 Labs (in addition to those previously
mentioned): blood volume studies, serum
erythropoietin, pulse oximetry,
carboxyhemoglobin, imaging studies as
indicated.
 Question: is bone marrow aspiration/biopsy
helpful in dx?
 High hemoglobin & HCT, NCNC pic
 Increased granulocytes with basophilia
 Increased plt count with atypical morphology
 High uric acid level
 High LAP score ( 70%)
 BM examination is non specific
 Tests that support this diagnosis include
elevated white blood cell count, increased
absolute basophil count, and thrombocytosis
 Asymptomatic
 Erythrocytic
 Inactive
 Postpolycythemic myeloid metaplasia
(secondary myelofibrosis)
 Acute myeloid leukemia
 Diagnostic criteria for PV were proposed in the
late 1960s by the Polycythemia Vera Study
Group (PVSG)
 Major criteria:
◦ A1: Hemoglobin >18.5 g/dL in men, >16.5 g/dL
women, or increased RBC mass (male: >35 mL/kg,
female: >32 mL/kg)
◦ A2: Presence of JAK2 mutation by polymerase chain
reaction (PCR)
◦ A3: Oxygen saturation >92% and no other cause for
secondary erythrocytosis
◦ A4: Splenomegaly
 Minor criteria:
◦ B1: Platelets >400,000/mm3
◦ B2: ANC >10,000 (WBC >12,000/mm3)
◦ B3: CT evidence of splenomegaly
◦ B4: Low serum erythropoietin level
 Diagnosis established by any of these
combinations:
◦ A1 + A2 (consider 1.5 g/dL lower Hgb cutoff if
A2 positive)
◦ A1, A3, A4
◦ A1 + A3 + any 2 category B criteria
 Other MPDs

 Causes of erythrocytosis
◦ Relative/ absolute
◦ Secondary
 Phlebotomy
 ASA
 Antihistamines, allopurinol
 Management of thrombotic risk factors
 Cytoreductive
◦ Intolerant to phlebotomy
◦ Symptomatic splenomegaly
◦ thrombocytosis
 Choice of therapy
◦ Age less than 40 – interferon
◦ Age above 40 - hydroxyurea
 Thrombosis due to erythrocytosis is the most
significant complication, and maintenance of
the hemoglobin level at 140 g/L (14 g/dL;
hematocrit <45%) in men and 120 g/L (12
g/dL; hematocrit <42%) in women is
mandatory to avoid thrombotic
complications.
 Secondary
◦ Viral infections (IM, CMV, HIV)
◦ Other infections (Pertussis, Toxoplasmosis, Cat-
scratch fever)
◦ Non-infectious (hypersensitivity, stress, post-
splenectomy)

 Primary
◦ CLL
◦ ALL
◦ Other LPDs
◦ Thymoma
 Chronic lymphocytic leukemia (CLL) is one of
the chronic lymphoproliferative disorders
(lymphoid neoplasms).
 It is characterized by a progressive
accumulation of functionally incompetent
lymphocytes, which are monoclonal in origin.
 CLL is identical disease with SLL at different
stages
 This is the commonest leukemia(in the west),
occurring predominantly in later life and increasing in
frequency with advancing years.
 It is almost invariably B lymphocytic in origin.
 In many patients it is a chance finding with no
symptoms,
 while others present with the features of marrow
failure or immunosuppression.
 The median survival may be 10 years, and may be
found to correlate with various presentation features.

12
8
Epidemiology of CLL

 The most common type of lymphoid leukemia

in the West-
◦ 30% of all leukemias
 Median age 60yrs
◦ 10% below the age of 50yrs
 Men are more affected- M:F= 2:1
 Etiology
◦ Unknown in the majority
◦ Familial clusters well described
◦ Radiation not related to increased incidence
 Pathogenesis
◦ Defective immune surviellance
◦ Clonal proliferation&
◦ Accumulation of incompetent, long-lived CD5+ B-
Cell
 Over expression of BCL-2 & BCL-XL ( antiapoptotic)
 25 %-asymptomatic (routine blood exam)
 Painless LN swelling
◦ Cervical usually
◦ Wax & wean
 Other features of immunodeficiency
◦ Infection, respiratory
 Sxs of autoimmune phenomenon
◦ Anemia & bleeding
◦ Increased reaction to insect bite
 Sxs due to organomegaly
 B-symptoms
 B-Symtoms
◦ Unintentional weight loss ≥ 10 percent of body
weight within the previous six months.
◦ Fevers of >100.5ºF (>38ºC) for ≥ 2 weeks without
evidence of infection.
◦ Drenching night sweats without evidence of
infection.
◦ Extreme fatigue
 Signs
◦ Pallor
◦ Generalized LAP
◦ Hepato-splenomegaly
◦ Skin
 Bleeding
 Vasculitis
 Leukemic Cutis
◦ Other organs
 Waldeyer’s Ring
 Membranoproliferative glomerulonephritis
Lab Features
 Anemia
◦ AIHA
◦ INFILTRATION
◦ BLEEDING
 Lymphocytosis
◦ SMUDGE / BASKET CELLS
 Granulocytes
 Thrombocytopenia
 Other tests
◦ Organ function test
◦ Uric acid & LDH
◦ Coomb’s test
◦ Serum protien Electrophoresis
◦ CXR &CT scan
 Blood count: Hb normal or low; WBC raised,
and may be very high; platelets normal or
low.
 Anemia- hemolysis, infiltration or bleeding
 Lymphocytes increased above 5 × 103/μL.
 Blood film: Smudge cells or "basket" cells
 Bone marrow: Reflects peripheral blood,
often very heavily infiltrated with
lymphocytes.

13
5
Dx of CLL
 Diagnostic Criteria
◦ The following 2 criteria must be met to dx CLL
 Absolute lymphocyte count in the PB ≥ 5000/µL and
(usually >10 x 109/L), with a preponderant population
of mature appearing small lymphocytes
 Demonstration of clonality of the circulating B-
lymphocytes by flowcytometry
 Finding bone marrow infiltration by the same
cells confirms the diagnosis.
13
8
DDX in CLL
 MBL
 Infectious causes of lymphocytosis/ reactive
◦ Viral
◦ Autoimmune d/s, drugs & allergy
◦ Splenectomy
◦ Thyrotoxicosis, adrenal insufficiency
 PLL
 HCL
 Mantle cell lymphoma
 Splenic marginal zone lymphoma
 Lymphoplasmacytic lymphoma
 Follicular Lymphoma
 Large granular lymphocytic Leukemia
 Cutaneous T-cell lymphoma
 Management of CLL depends on the 'stage'of
the disease:
 No specific treatment is required for most clinical
stage A patients unless progression occurs.
 Life expectancy is usually normal in older patients.
 The patient should be offered clear information about
CLL, and reassured about the 'benign' nature of the
disease, as the diagnosis of leukemia inevitably
causes anxiety.

14
0
 Indication for Rx:
-Evidence of bone marrow failure
-Massive or progressive lymphadenopathy or
splenomegaly
-Systemic symptoms such as weight loss or night
sweats
- Rapidly increasing lymphocyte count or
autoimmune cytopenias
 Initial therapy for those requiring RX (stages B &
C) usually consists of oral chemotherapy with the
alkylating agent chlorambucil.
 Supportive care is increasingly required in
progressive disease 14
1
 Disease-related progressive symptoms (e.g.,
weight loss without trying, fever without overt
infection, night sweats, weakness, or easy
fatigability)
 Progressively worsening anemia or
thrombocytopenia
 Autoimmune (Coombs-positive) hemolytic
anemia or autoimmune thrombocytopenia
 Bulky lymphadenopathy that is getting
progressively worse, and poses risk to the
patient from pressure on underlying tissues,
or causes significant cosmetic problems

 Massive splenomegaly that is worsening

progressively or results in hypersplenism
 Increased susceptibility to bacterial
infections. This may result from marked
◦ hypogammaglobulinemia, in which case intravenous
high-dose γ-globulin therapy has a proven
protective effect.
◦ Severe neutropenia or agranulocytosis may occur in
CLL, and may play a major role in the development
of bacterial sepsis
 Progressive hyperlymphocytosis.
• It is not possible to set a rigid upper threshold for
the blood lymphocyte count that must be met
before starting therapy, but we do not allow this
count to be more than 150 × 109 /L.
• Hyperviscosity syndrome associated with
hyperlymphocytosis in CLL can be catastrophic.
The rate of increase of blood lymphocyte count is of
importance;
• a short doubling time (≤12 months, actual or by
extrapolation) is an indication for therapeutic
intervention
 The overall median survival for patients with CLL is
about 6 years.
 The majority of clinical stage A patients have a
normal life expectancy but stage C patients have a
median survival of between 2 and 3 years.

 Approximately 50% of patients die of infection and

30% of causes unrelated to CLL.

14
6
Treatment of CLL
 Early stage & stable disease
◦ Observation without Rx
◦ Use of growth factors & IVIg
 Chemotherapy
◦ Alkylating agent ( Chlorambucil,
Cyclophosphamide)
◦ Nucleoside Analogues(purine analogues) –
Fludarabine, Cladribine
 Monoclonal Antibodies
◦ Rituximab (against CD20)
◦ Alemtuzimab ( against CD52)
 Combination Chemotherapy
◦ Fludarabine + Cyclophosphamide (FC)
◦ Fludarabine + Rituximab (FR)
◦ Fludarabine + Cyclophosphamide + Rituximab(FCR)
Lymphomas…
 The lymphomas are commoner than the
leukaemias and are increasing in incidence
 arise as the result of abnormal proliferation of
the lymphoid system, and
 hence occur at any site where lymphoid tissue
is found.
 Most commonly they are manifested by the
development of lymphadenopathy at single or
multiple sites

14
9
 The prognosis is determined
◦ by the specific subtype of lymphoma and
◦ the anatomical extent of disease and its bulk,
◦ the clinical course ranging from months to years.

 Classification
◦ Hodgkin's lymphoma…HL
◦ Non-Hodgkin's lymphoma…NHL

15
0
 15% of lymphomas, previously called Hodgkin’s disease
 First described by Thomas Hodgkin in 1832
 curable in over 70% of cases through the use of
radiotherapy and chemotherapy
 Hodgkin lymphoma is a group of cancers characterized by
Reed-Sternberg cells in an appropriate reactive cellular
background
 Predominantly B-cell disease
 An important clinical feature is its tendency
– arise within lymph node areas
– spread in an orderly fashion to contiguous areas of LN
15
1
 LN FNAC / biopsy :
◦ Malignant REED-STERNBERG ( RS) Cell: Bi-
nucleate cell with a prominent nucleolus.
Derived from B cell, at an early stage of
differentiation
◦ Reactive background of eosinophils,
lymphocytes, plasma cells.
◦ Fibrous tissue

15
2
REED-STERNBERG ( RS ) Cell
15
3
 Classic:
◦ Nodular Sclerosis (70%)
◦ Lymhocyte rich
◦ Mixed Cellularity (25%)
◦ Lymhocyte depleted
 Non-Classic
◦ Nodular Lymphocyte predominant(5%)

*REAL – Revised European,American,Lymphoma

15
4
 PATHOLOGICAL & CLINICAL FEATURES OF HL (Western Data)
HISTOLOGY (%) AGE PATHOLOGY CHARACTERISTICS &
SUBTYPE GROUP STAGES AT PRESENTATION
Lymphocyte- 5 20-40 L&H cells, difficult Males more affected,
Predominant pathologic Dx, stage I-IIA, late
Nodular form is a relapses &
NON-CLASSIC HL transformation to
NHL-HA
Nodular 65- 15-40 Lacunar cells, Females more affected,
sclerosis 80 birefrigent fibrotic mediastinal, hilar &
bands supraclavicular LAP,
stage I-IIIA/B
Mixed 20- 30-50 RS cells frequent, Retroperitoneal disease
Cellularity 35 necrosis, partial frequent, often
nodal involvement symptomatic stage II-
& heterogenous IVA/B
Lymphocyte - <5 40-80 RS cells numerous Febrile, wasting
Depleted & bizare/diffuse syndrome, liver & BM
fibrosis involvement common
stage II-IVB
 HL is uncommon disease
 2-3 cases/100,000 ( in US & Europe)
 Bimodal peak in the incidence
◦ 1st peak 20-30yrs
◦ 2nd peak 50yrs
 Histological subtype vary among different age
groups
 M:F= 1.4:1
 Different pattern in developing countries
◦ Earlier 1st peak
◦ Mixed cellularity subtype more common
 Strong association with HIV
◦ But still NON-AIDS DEFINING DISEASE
 In Ethiopia (132 adult cases studies)
◦ Median age 29yrs
◦ M:F 2:1
 Cause of HL is unknown
 Association/ predisposing factors
◦ EBV infection
◦ HIV
◦ ?Environmental & Occupation exposure
◦ Genetic predisposition
 Familial clusters
 Identical twins
 Lymphadenopathy:
◦ most often cervical region
◦ asymmetrical, discrete
◦ painless, non-tender
◦ elastic character on palpation ( rubbery)
◦ not adherent to skin ;fluctuate in size
◦ Contiguous spread via the lymphatic chain eg.
involvement of abdominal & thoracic LNs.
 Extra nodal disease - rare
 Hepatospleenomegaly

15
9
Sites of Disease Involvement in Untreated Patients with Hodgkin's Disease

Anatomic Site Involvement (%)

Waldeyer's ring 1–2

Cervical nodes 60–70

Axillary nodes 30–35
Mediastinum 50–60
Hilar nodes 15–35

Para-aortic nodes 30–40

Iliac nodes 15–20
Mesenteric nodes 1–4
Inguinal nodes 8–15

Spleen 30–35
Liver 2–6
Bone marrow 1–4
Total extranodal 10–15
• Asymptomatic LAP
• Mediastinal Lap
• Splenomegaly & Hepatomegaly
• Systemic symptoms
• Other nonspecific & paraneoplastic syndromes
– Intra-abdominal disease
– Alcohol Induced pain
– Cholestasis
– Skin
– Neurological
– Nephrotic syndrome
– Others – anemia, eosinophilia, thrombocytosis,
leukopenia/ lymphocytosis, hypercalcemia
 Stage I : Involvement of a single lymph node region or
lymphoid structure (e.g., spleen, thymus, Waldeyer's ring)

 Stage II : Involvement of two or more lymph node regions

on the same side of the diaphragm (the mediastinum is a
single site; hilar lymph nodes should be considered
"lateralized" and, when involved on both sides, constitute
stage II disease)

 Stage III : Involvement of lymph node regions or lymphoid

structures on both sides of the diaphragm
◦ Stage III (1) Subdiaphragmatic involvement limited to spleen,
splenic hilar nodes, celiac nodes, or portal nodes

◦ Stage III(2) Subdiaphragmatic involvement includes paraaortic, iliac,

or mesenteric nodes plus structures in III1

16
2
 Stage IV : Involvement of extranodal site(s)
beyond that designated as "E“
◦ More than one extranodal deposit at any location
◦ Any involvement of liver or bone marrow

 E=Localized, solitary involvement of

extralymphatic tissue, excluding liver and
bone marrow

A : Absence of ‘B’ symptoms

B : B symptoms present
16
4
 CBC: Anemia ( normochromic / normocytic),
eosinophilia, neutrophilia, lymphopenia
 ESR -raised
 ↑LFT- (liver infil / obs at porta hepatis)
 RFT- prior to treatment
 Urate , Ca,
 ↑LDH - adverse prognosis
 CXR- mediastinal mass
 CT thorax / abdomen / pelvis-for staging.

16
5
 Radiotherapy
 Combination chemotherapy
 Combined modality treatment
 High dose chemotherapy followed by
autologous-SCT
 Allo-SCT
 MOPP :
Nitrogen Mustard,
Vincristine (Oncovir)
Procarbazine,
Prednisolone
 ABVD:
Adriamycin,
Bleomycin,
Vinblastine,
Dacarbazine
 Higher dose for relapse or younger pts with poor
prognostic features.

16
7
 8 times more common
 Strongly associated with HIV
◦ AIDS DEFINING ILLNESS
 Non-Hodgkin lymphoma (NHL) represents a
monoclonal proliferation of lymphoid cells
and may be of B-cell (70%) or T-cell (30%)
origin.
 The incidence of these tumours increases
with age,
 to 62.8/million population per year at age
75, and
 the overall rate is increasing at about 3% per
year.
16
9
 Cannot be attributed a single cause
 Chromosomal translocations:
◦ t (14, 18)
 Infection:
◦ Virus:EBV, HTLV,HHV-8, HIV
◦ Bacteria: H.Pylori - Gastric lymphoma
 Immunology:
◦ Congenital immunodeficiency,
◦ Immunocompromised patients - HIV, organ
transplantation.
 Staging/Investigations—similar to HD.

17
0
 Widely disseminated at presentation
 Nodal involvement:
Painless lymphadenopathy, often cervical
region is the most common presentation
 Hepatospleenomegaly
 Extranodal :
Intestinal lymphoma ( abdominal pain, anemia,
dysphagia);
CNS ( headache, cranial nerve palsies, spinal
cord compression) ;
Skin, Testis; Thyroid; Lung;
Bone marrow (low grade)- Pancytopenia
17
1
 Systemic symptoms
◦ Sweating, weight loss, itching
◦ Metabolic complications:
 Hyperuricemia,
 Hypercalcemia,
 Renal failure
 Compression syndrome:
◦ Gut obstruction
◦ Ascites
◦ Local mass effect-SVC obstruction

17
2
17
3
 REAL
 Clinical / Working Formulation
◦ Low grade
◦ Intermediate grade
◦ High grade

17
4
 Low Grade - Indolent
◦ Slow growing over months - years
◦ Older population
◦ Often no other symptoms
◦ No curative therapy
 Intermediate Grade - Aggressive
◦ Growth over weeks to months
◦ Variable age range
◦ Variable other symptoms / organ compromise
◦ Potentially curable with aggressive chemotherapy
 High Grade - Very Aggressive
◦ Growth over weeks
◦ Variable age range
◦ Usually systemically unwell, similar to acute leukemia
◦ Potentially curable with aggressive chemotherapy
• INDOLENT
– Survival of untreated disease measured in years
– Even CR does not lead to a cure
– Not curable with conventional treatment
• AGGRESSIVE
– Survival of untreated disease measured in months
– CR required for cure
– Curable with conventional treatment
• HIGHLY AGGRESSIVE
– Survival of untreated disease measured in weeks
– CR required for cure
– Curable with conventional treatment
 Low grade:
 Asymptomatic : No treatment ;
 Radiotherapy for localised disease (Stage 1)
 Chemotherapy: mainstay is
Chlorambucil; Initial response good , but repeated
relapses, median survival 6-10 yrs;
◦ Newer: Fludarabine, 2-CdA
(Chlorodeoxyadenosine)
 Monoclonal antibody.

17
7
Aggressive ( high / intermediate grade):
 Chemotherapy: mainstay
CHOP
 -every 3 weeks, at least 6 cycles
Cyclophosphamide
Doxorubicin Hydrochloride
Vincristine
Prednisolone

17
8
 Low grade : Median survival –10 yrs
 High Grade:
◦ Increasing age, advanced stage,
concomitant disease, raised LDH,T- cell
phenotype :- Poor prognosis.

17
9
Thank u