MYELOID AND LYMPHOID

MALIGNANCIES
M A R S H E L L T E N D E A N , D P C P
D E PA RT M E N T O F I N T E R N A L M E D I C I N E
FA C U LT Y O F M E D I C I N E U K R I D A , J A K A RTA

ACUTE MYELOSITIC LEUKEMIA

LMA are prevalent in 32% cases of leukemia.
The incidence :
0.8% among patients < 30 yo
2.7% among patients > 50 yo
13.7% among patients > 65 yo

RISK FACTORS :
Exposure :
Benzene exposure
Ionic radiation (1.5 years after exposure and peak at 6-7
years after exposure)

Inherited mutation :
Down syndrome (Trisomy chromosome 21) increase the risk
10-18 times for M7 leukemia
Bloom syndrome and falconi anemia

Cytotoxic agents :(alkylating agent and topoisomerase II

inhibitor)

CLASSIFICATION
The World Health Organization (WHO) which
includes different biologically distinct groups
based on clinical features and cytogenetic and
molecular abnormalities in addition to
morphology.
French-American-British (FAB) schema, the WHO
classification places limited reliance on
cytochemistry.

THE WHO CLASSIFICATIONS FOR AML :

AML with recurrent genetic abnormalities

AML with myelodysplasia-related changes
Therapy-related AML
AML not otherwise specified
AML with a translocation between chromosomes 8 and
21
AML with a translocation or inversion in chromosome
16
AML with changes in chromosome 11
Acute promyelocytic leukemia (APL, M3), which usually
has a translocation between chromosomes 15 and 17

CLINICAL PRESENTATION :
Patients with AML most often present with
nonspecific symptoms
Most complain of fatigue or weakness at the
time of diagnosis.
Fever is the initial symptom in 10% of
patients.
Signs of abnormal hemostasis are noted first
in 5% of patients.
Rarely patients may present with symptoms
from a myeloid sarcoma [e.g., monosomy 7,
trisomy 8, MLL rearrangement, inv(16),

PHYSICAL FINDINGS
Fever, splenomegaly, hepatomegaly, lymphadenopathy,
sternal tenderness, and evidence of infection and
hemorrhage are often found at diagnosis.
Significant gastrointestinal bleeding, intrapulmonary
hemorrhage, or intracranial hemorrhage occur most often
in APL.
Bleeding associated with coagulopathy may also occur in
monocytic AML and with extreme degrees of leukocytosis
or thrombocytopenia in other morphologic subtypes.
Infiltration of the gingivae, skin, soft tissues, or the
meninges with leukemic blasts at diagnosis is
characteristic of the monocytic subtypes and those with
11q23 chromosomal abnormalities.

HEMATOLOGIC PRESENTATION
The anemia is usually normocytic normochromic.
Leukocyte prentation :

The median presenting leukocyte count is about 15,000/L.

Between 25 and 40% of patients have counts <5000/L.
20% have counts >100,000/L.
Fewer than 5% have no detectable leukemic cells in the
blood.

Platelet counts <100,000/L are found at diagnosis

in 75% of patients, and about 25% have counts
<25,000/L

Figure 1. Presence of Auer Rod

Fig 2. Specific granules of PLA

DIAGNOSIS :
Leukemic blast cells in bone marrow samples
The percentage of blast cells.
Having at least 20 percent blasts is generally
required for a diagnosis of AML.
Specific chemical activity in blast cells
Characteristic markers (antigens) on the surface of blast
cells, such as CD13 or
CD33 (CD is an abbreviation for cluster designation).

DIAGNOSTICS
1. Bone marrow aspirate and trephine biopsy unless the
peripheral blast count is high.
2. Immunophenotyping [CD3, CD7, CD13, CD14, CD33, CD34,
CD64, CD117 and cytoplasmic myeloperoxidase (MPO)].
3. Cytochemistry (MPO or Sudan Black, combined est- erase).
Can be omitted if four-colour flow cytometry is available.
4. Cytogenetics [with reverse-transcription polymerase chain
reaction (RT-PCR) for AML 1-ETO and CBFB- MYH11 in nonacute promyelocytic leukaemia (APL) and promyelocytic
leukaemia (PML) and retinoic acid recep- tor-alpha (RARA)
in suspected APL; fluorescent in situ hybridisation (FISH) in
selected cases]

TREATMENT :
Patients should be treated by a multidisciplinary
team that is experienced in the management of
acute myeloid leukaemia (AML) (recommendation
grade C; evidence level IV).
Patients opting for non-intensive chemotherapy
who are not entered into clinical trials should be
offered treat- ment with low-dose cytarabine.
Patients not able to tolerate chemotherapy should
be given best supportive care: transfusion support
and hydroxycarbamide to control the white cell
count (recommendation grade A; evidence level Ib)

TREATMENT OF AML

General measure and supportive care :

Hyperleucocytosis.
Prevention of tumour lysis syndrome
Red cell transfusion support
Platelet support
Granulocyte transfusions
Antibiotic and anti-infective therapy
Growth factors

 Treatment of younger adult patient

Induction Therapy
Consolidation Therapy

Goal of Completer Remission CR :

CR is defined as the recovery of normal bone marrow
cellularity with fewer than 5% blast cells and without a
detectable cytogenetic abnormality.
Elsewhere, the term morphologic remission is reserved
for patients who also have recovery of peripheral blood
counts with a neutrophil count >1x 109/ul and platelet
count exceeding 100 x 109/l (Cheson et al, 2003)

INDUCTION THERAPY :
Initial therapy :
Anthracycline/anthracycline-like drug given for 3 d
Cytarabine given over 710 d as a continuous infusion or
as a twice daily bolus.

The most commonly used regimen (Hann et al,

1997). :
Daunorubicin, given for 3 d at a dose of 4560 mg/m2
Cytarabine 200 mg/m2 either given as a bolus in divided
doses twice daily or as an infusion over 12 h for 10 d (3 +
10) regimen

 Consolidation Therapy :
Consolidation chemotherapy
Autologous, allogeneic-related or -unrelated donor
transplantation

PREMEYELOCYTIC LEUKEMIA
Tretinoin is an oral drug that induces the
differentiation of leukemic cells bearing the
t(15;17)
Tretinoin (45 mg/m2 per day orally until remission
is documented) plus concurrent anthracyclinebased chemotherapy (CR rates of 90-95%).
Following achievement of CR, patients should
receive at least two cycles of anthracycline-based
chemotherap

PROGNOSIS :
Patients with t(15;17) have a very good prognosis
(approximately 85% cured).
Those with t(8;21) and inv(16) a good prognosis
(approximately 55% cured).
While those with no cytogenetic abnormality have
a moderately favorable outcome (approximately
40% cured).
Patients with a complex karyotype, t(6;9), inv(3),
or -7 have a very poor prognosis.

CML

 The diagnosis of CML is established by identifying

a clonal expansion of a hematopoietic stem cell
possessing a reciprocal translocation between
chromosomes 9 and 22.
This translocation results in the head-to-tail fusion
of the breakpoint cluster region (BCR) gene on
chromosome 22q11 with the ABL1 (named after
the abelson murine leukemia virus) gene located
on chromosome 9q34.

GENE BCR-ABL MUTATION

3 CLINICAL PHASES
1) INITIAL CHRONIC PHASE
USUALLY <5% CIRCULATING BLASTS AND <10% BLASTS AND PROMYELOCYTES ARE NOTED, WITH THE MAJORITY OF CELLS BEING MYELOCYTES, METAMYELOCYTES, AND BAND FORMS

2) ACCELERATED PHASE
DISEASE ACCELERATION IS DEFINED BY THE DEVELOPMENT OF INCREASING DEGREES OF ANEMIA UNACCOUNTED FOR BY BLEEDING OR THERAPY; CYTOGENETIC CLONAL EVOLUTION; OR BLOOD OR MARROW BLASTS BETWEEN 10 AND 20%, BLOOD OR MARROW BASOPHILS 20%, OR PLATELET COUNT
<100,000/

3) BLAST CRISIS
BLAST CRISIS IS DEFINED AS ACUTE LEUKEMIA, WITH BLOOD OR MARROW BLASTS 20%. HYPOSEGMENTED NEUTROPHILS MAY APPEAR (PELGER-HUT ANOMALY) .

MOST PATIENTS ARE DIAGNOSED WHILE STILL IN THE CHRONIC PHASE.

MYELOSUPPRESSIVE THERAPY, WAS FORMERLY THE MAINSTAY OF TREATMENT

TO CONVERT A PATIENT WITH CML FROM AN UNCONTROLLED INITIAL PRESENTATION
TO ONE WITH HEMATOLOGIC REMISSION AND NORMALIZATION OF THE PHYSICAL EXAMINATION AND LABORATORY FINDINGS

HYDROXYUREA (HYDREA), AN INHIBITOR OF DEOXYNUCLEOTIDE SYNTHESIS, IS THE MOST COMMON

MYELOSUPPRESSIVE AGENT USED TO ACHIEVE HEMATOLOGIC REMISSION.
THE INITIAL BLOOD CELL COUNT IS MONITORED EVERY 2-4 WEEKS, AND THE DOSE IS ADJUSTED DEPENDING ON THE
WBC AND PLATELET COUNTS.

Treatment
Prognostic factors

Sokal score =

= (11x age + 35x spleen + 89x blasts + 0,4x

platelet 550)/1000

Euro scale =

= (0,666x age /0 when age <50, 1 when >/ +

0,0420x spleen + 0,0584x blasts + 0,0413x
eosinophils + 0,2039x basophils /0 when basophils
<3%, 1 when basophils >3%/ + 1,0956x platelet /0
when platelet <15000G/l, 1 when >/) x 1000
Sokal
Euro
Low risk
<0,8
<780
Moderate risk
0,8-1,2
781-1479
High risk
>1,2
>1480

TREATMENT
IKT (imatinib, nilotinib,
dasatinib)
Allo- SCT

Treatment
Hydroxyurea

Often used initially for white cell count

reduction
Dose: 1-6g/d orally, depending on the
hight of the white cell count
The dose should be decreased to 1-2g/d
when the leukocyte count reaches
20000/l
Drug should be stopped if the white
count falls to 5000/l
Side effects: suppression of

Treatment
Interferon-alfa

In CML patients during preganancy

Patients with low risk (Sokal/Euro score) and
high TRM, patient not eligible for alloSCT
(treatment initiated before imatynib era)
Dose: 3million units/m subcutaneously 3 days
per week, and after 1 week 5 million u/m.
Maximal dose: 5 million u/m per day. After
maximal response (6-8 months) 3-5 million u/m
once or twice weekly
Dose should be reduced or teporarily
discontinued if the white cell count less than
5000/l or platelet count less than 50000/l

CGP57148; STI571; IMATINIB; GLIVEC

TK inhibitory activity
Stability to hydrolysis

N
N
Solubilisation

N
No PKC inhibition

Potent inhibition of Abl-K, c-kit and PDGF-R

Salts are soluble in water
Orally bioavailable
Not mutagenic

Cellular permeability

1992

Traetment
Imatinib mesylate (Gleevec)

Inhibits activity of mutant tyrosine kinase by

blocking ATP binding
Imatinib has less toxicity, is easier to administer,
and induces higher hematologic (90 percent vs.
75percent), cytogenetic (40 percent vs. 10
percent) and molecular (7% vs. 2 %) types of
remission
Dose: 400mg/d orally (maximal dose 600800mg/d in two divided doses)

TREATMENT OF BLAST CRISIS

Treatments for primary blast crisis, including imatinib,
are generally ineffective. Only 52% of patients
treated with imatinib achieved hematologicremission
(21% complete hematologic remission), and the
median overall survival was 6.6 months.
Patients who achieve complete hematologic
remission or whose disease returns to a second
chronic phase should be considered for allogeneic
HSCT.
Blast crisis following initial therapy with imatinib
carries a dismal prognosis even if treated with
dasatinib or nilotini

NOVEL AGENTS FOR CML TREATMENT

LYMPHOID
MALIGNANCIES

LEUKEMIA VS LYMPHOMA
Some malignancies of lymphoid cells almost
always present as :
leukemia (i.e., primary involvement of bone marrow and
blood)
Lymphomas (i.e., solid tumors of the immune system).

LYMPHOMA

CONTRAST AND COMPARE

Hodgkins
Indolent
Cervical, mediastinal,
supraclavicular LAD
B sx common

Non-Hodgkins
Rapid (tumor lysis)
Abdominal, mediastinal
masses and LAD
Abdominal pain common
Intussusception and appy

HODGKINS VS. NON-HODGKINS

Indolent
Hodgkins

B symptoms
Hodgkins

Abdominal mass
presentation
NHL

60% of lymphomas
NHL

EBV association
BOTH

Reed Sternberg cells

Hodgkin

Starry Sky
NHL

Painless cervical
adenopathy presentation
Hodgkins

Associated with immune

dysfunction
BOTH

APPROACH TO DIANGOSIS :
Medical history :
The presence of B symptoms (fever, drenching night
sweats, unexplained weight loss >10% body weight over
6 months)
Fatigue, pruritus, alcohol-induced pain

Physical examination :
The presence of multiple lymphadenopathy

Cheson BDJ Clin Oncol 2014;

in press

 Bone marrow biopsy is no longer indicated in

patients undergoing PET/CT evaluation [III, B]
However, bone marrow biopsy must be carried
out if PET/CT is not available

LOCATION AT DIAGNOSIS HODGKINS

DISEASE

DIAGNOSTIC WORKUP
Tissue is needed for definitive histologic diagnosis
Sample the node that is most accessible

PE with careful attention and measurement of lymph

nodes
Labs

CBC with diff

ESR
LFT,Renal function
Alkaline phosphatase; ferritin,copper elevated
(Immune response decreased,
Cytokines Il 1,6,TNF- B symptoms,
Il 2 elevated)

DIAGNOSTIC & STAGING WORKUP

Cervical area US/CT/MR
Thoracic imaging
Chest Xray, CT scan of chest (ant/middle mediastinum)
best visualization of lung parenchyma, pleura

Abdominal imaging
US/CT/MRI
Lymphangiogram
Most reliable method of detecting retroperitoneal lymph nodes
Rarely done in children

DIAGNOSTIC & STAGING WORKUP

Gallium Scan/ PET scan
Search the body for other involvement

Staging laparotomy
Not used routinely any more
Previously done routinely as part of staging

Bone marrow biopsy

Recommended for stage IIB or higher
Bone marrow involvement at presentation is rare

Bone scan
Recommended for kids with bone pain, elevated alk phos,
or extranodal disease

CT OF CHEST

NUC MED & PET SCANS

CORSWOOT MODIFICATION OF THE ANN

ARBOR CLASSIFICATION :
Stage

Area of Involvement

Single lymph node group

II

Multiple lymph node groups on same side of

diaphraghm

III

Multiple lymph node groups on both sides

diaphraghm

IV

Multiple Extranodal sites or lymph nodes and

extranodal disease

Bulk >10 cm

Extranodal extension or single, isolated site of

extranodal disease

A/B

B : symptoms
- Fever of 38 for 3 consecutive days
- Drenching night sweats
- Unexplained loss of 10% or more of body weight in
the 6 months preceding diagnosis

DIAGNOSTIC WORKUP FOR HODGKIN

LYMPHOMA
Diagnosis
Lymph node biopsy (or a biopsy from another organ with
suspected affection)
Staging and risk stratification
Medical history and physical examination
X-ray of the chest
Contrast-enhanced CT scan of neck, chest and abdomen PET
Full blood cell count and blood chemistry
HBV, HCV and HIV screening
Pre-treatment examinations ECG
Echocardiography
Pulmonary function test
Reproductive counselling (in younger patients)
Serum pregnancy test (in younger female patients)
Cheson BDJ Clin Oncol 2014;
in press

REED-STERNBERG CELL

TREATMENT GUIDELINES HODGKIN

LYMPHOMA

Annals of Oncology : iii70iii75, 2014

PROGNOSIS INDEX FOR NHL

NHL THERAPY
Treatment Depend with The cell lineage
Chemo only
Surgery only for abdominal emergency
Radiation for SVC obstruction, or paraspinal compression

B cell
High dose intensive therapy

T cell
Similar to ALL therapy

COMPLICATIONS
Tumor related
SVC syndrome
Spinal cord compression
Pleural and pericardial
effusions
Pulmonary embolism
Obstructive uropathy
Pharyngeal/ airway obs

Metabolic
Tumor lysis
SIADH
Hypo/Hyperglycemia

GI
Bleeding, fistulae,
obstruction

Cytokine mediated
Cachexia, fever malaise

Hematologic
BM infiltration
Pancytopenia

TUMOR LYSIS!!!
Evaluate

Phosphorus
Uric acid
Calcium
Potassium

Life threatening emergency

Hydrate
Alkalinize