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H39 Hematology Toronto Notes 2023
Hematologic Malignancies and Related
Disorders Leukemia:malignant cells arise in 8M
that may spread elsewhere (including
blood, lymph nodes,and lymphoid
tissue)
Lymphoma:malignant cells arise in
lymph nodes and lymphoid tissues that
may spread elsewhere (including blood
and 8M)
BUT the location where the malignant
cells are found does not solely define
the type of hematologic malignancy -
classified based on the characteristics
of the cell (histology,histochemistry,
immunophenotyping,cytogenetics,
molecular changes)
Chronic
Lymphocytic
Leukemia (CLL)
NaTve
MATURATION Acute
Lymphocytic Leukemia (ALL)
Multiple Myeloma
(MM)
Lymphomas OF
CELLS
Germination
») •
B-lymphocytes
Hematopoietic
stem cell
Lymphoid
progenitor
Plasma cell
T-lymphocytes
MATURATION Acute Myelogenous Leukemia (AML) Myeloproliferative Disorders Acute Leukemia
Definition (WHO):presence of 20%
blast cells or greater in the peripheral
blood or BM at presentation
Classification:divided into myeloid
(AML) and lymphoid (ALL) depending
on whether blasts are myeloblasts or
lymphoblasts,respectively
01
> Neutrophils
" Eosinophils
Basophils
CELLS
Granulocytes
Chronic Myelogenous
Leukemia (CML)
Monocytes
. >’
K
- , > Platelets
>
^^
Red Cells
if w Chronic Myelomonocytic
Leukemia (CMML)
Hematopoietic
stem cell
Myeloid
progenitor
Typical Age of Presentation of
Leukemias
ALL:Children and older adults
CML: 40-60 yr
AML, CLL:>60 yr
>
Essential Thrombocytosis --
Polycythemia Vera
Figure 15. Hematopoietic derivation of hematologic disorders
( Hematological Malignancies and Related Disorders)
Auer rods are pathognomonic for AML
( Lymphoid Disorders ) ( Myeloid Disorders )
Bask Initial Workup for all Hematologic
Malignancies:
1. ALL WOMEN OF CHILDBEARING AGE
must have a b-HCG before initiation of
treatment of any cancer diagnosis
2.ALL PATIENTS MUST HAVE Hepatitis
8 surface antibody (HBsAb),Hepatitis
B surface antigen (HBsAg),Hepatitis
B core antibody (HBcAb) collected
irrespective of cancer diagnosis and
must be treated to avoid reactivation
3. All aggressive lymphoma patients
must be screened for HIV
4.All patients must be screened for TB
risk factors
I I t
Lymphomas
• Hodgkin
• Non-Hodgkin
• B Cell
• T Cell
• Other cell origin
le g NK)
• Waldenstrom's
macroglobulinemia
Plasma Cell Dyscrasias
• Multiple myeloma
• MGUS
Leukemia
• ALL
• CLL
Leukemia
•AML
MPNs
•PV
•ET
•CML
•IMF
Figure 16. Overview of hematologic malignancies and related disorders
Myeloid Malignancies
Cure: survival that parallels agematched population
Complete Remission:tumour load
below threshold of detectable disease
(normal peripheral blood film,normal BM
with<5% blasts,normal clinical state)
Acute Myeloid Leukemia
Definition
• rapidly progressive malignancy characterized by failure of myeloid cells to differentiate beyond blast
stage
Epidemiology
• incidence increases with age; median age of onset is 65 yr; 80% of acute adult leukemias
• accountsfor 10-15% of childhood leukemias
Risk Factors +
• male, older age,smoking, obesity, MDS, benzene, radiation, Down Syndrome, alkylating agents, and
radiation therapy astreatment for previous malignancy
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lO Hematology Toronto Notes 2023
Pathophysiology
• etiology subdivided into:
primary:de novo
secondary:hematologic malignancies (e.g.myeloproliferative disorders and MDS) or previous
chemotherapeutic agents(e.g.alkylating agents)
• uncontrolled growth of blastsin marrow leads to:
suppression of normal hematopoietic cells
appearance of blasts in peripheral blood -risk of leukostasis
accumulation of blasts in other sites (e.g.skin, gums)
• metabolic consequences; T'
LS
Clinical Features
• signs and symptoms develop over a period of weeks
• manifestations of BM failure
• anemia, thrombocytopenia (associated with DIC in APL), neutropenia (and infection/fever)
• accumulation of blast cells in marrow
skeletal pain,bony tenderness (especially sternum)
• organ infiltration
gingival hypertrophy (particularly myelomonocytic leukemia) - may present to dentist first
CNS extramedullary involvement:confusion or altered mentalstatus
hepatosplenomegaly (also present in ALL)
lymphadenopathy
• skin:leukemia cutis
eyes: hemorrhages and/or whitish plaques, Roth spots, cotton wool spots, and vision changes
(uncommon)
• leukostasis/hyperleukocytosis syndrome (medical emergency)
large numbers of blasts interfere with circulation and lead to hypoxia and hemorrhage - can
cause diffuse pulmonary infiltrates, CNS bleeding, respiratory distress, altered mental status, and
priapism
more commonly associated with AML than ALL
• metabolic effects (aggravated by treatment)
-
T'
LS
increased uric acid -» nephropathy, gout
release of phosphate -> decreased Ca - decreased Mg -
’
release of procoagulants -> DIC (higher risk in APL)
hyperkalemia pre-treatment from blastic proliferation and spontaneous T'LS,further
hyperkalemia after treatment (from lysed cells). Note -some forms of AML can present with
hypokalemia due to secreted muramidase that causes K+ wasting from renal tubules
Investigations
• blood work
• CBC: anemia, thrombocytopenia, variable VVBC (most often cytopenias + blasts)
• INR, aPT T , I DP,fibrinogen (in case of DIC)
increased LDH, increased uric acid, increased POr
^
-(released by leukemic blasts), decreased Ca 2 t
,
increased/decreased K*
baseline renal and liver function tests
if considering treatment:screen for HBV, HCV, HIV,CMV serology
• peripheral blood film - circulating blasts with Auer rods (azurophilic granules) are pathognomonic
for AML
• BM aspirate for definitive diagnosis
• blast count:AML >20% (normal is <5%)
morphologic, cytogenetic, and/or immunophenotypic features are used to establish lineage and
maturation
• CXR to rule out pneumonia; ECCi, MUCiA scan prior to chemotherapy (cardiotoxic)
Treatment
• mainstay of treatment is chemotherapy (rapidly fatal without treatment)
• patients who are not eligible for intensive chemotherapy can be treated with low-dose cytarabine and
hvpomethylating agents in combination with venetodax (BCL-2 inhibitor)
• all AML subtypes are treated similarly, except APL with t(15:17) translocation
1. induction:chemotherapy to induce complete remission of AML
several possible regimens
patients with poor response to initial induction therapy - worse prognosis
supportive care - management ofTLS and DIC,febrile neutropenia/infections, transfusion
support (including platelet transfusions if <10 x I0’/L)
2. consolidation: to prevent recurrence
intensive consolidation chemotherapy
stem cell transplantation - allogeneic (younger patients with better performance status and/
or adverse cytogenetics)
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Hi1 Hematology Toronto Notes 2023
•supportive care
fever: pan-cultures,CXR,and start broad-spectrum antibiotics
• platelet and RBC transfusions
prevention and treatment of metabolic abnormalities
* allopurinol,rasburicase for prevention/management of hyperuricemia
• leukostasis
needs immediate cytoreductive therapy (i.e. hydroxyurea)
treatment strategy for APL
APL is an emergency as 13IC is often present at diagnosis
*
ATRA added to induce differentiation (should be started ASAP if APL is in the differential);
arsenic trioxide and ATRA combination therapy for APL issuperior to traditional
chemotherapy
%
MDS is a cause of macrocytic anemia
Efficacy of AiacitidineCompared with that ol
Conventional Caro Rojimeasin the Treatment
of Higher-risk Myelodysplastic Syndromes:a
Randomized, Open-label, Phase III Study
Uncet Oncol 2009;10:223-32
Purpose:la compare the efficacy of aiacitidine to
conventional core regimens (CMs) in patientswith
high- risk MDS.
Methods: 3'
J8 patients were randomly assigned
to receive aiacitidine (75 mg/npfd lor J days every
28days)or CCR (intensive chemo therapy, low-dose
cytarabine.orsipportive care atone).
Results:At median follow-up of 21.1 months,
aracitidinf treatment was associated with
significantly gieater median overall survival as
compared to OCRs (24.S months vs.1S.0 months,
respectirely: hazard ratio 0.58:85% Cl 0.43-0.77;
P’
0.0001).50.8% of patientsreceiving aiacitidine
were alive at 2 yearsas compared to 26.2% of
patients receiving CCRs(p<0.000l).Ihe most
frequent grade 3-4 adrerse event for all treatments
were peripheral cylopenias.
Conclusion: In patients mti high -risk M0S.
azacitidme treatmentsignificantly increases overall
survival as compared to conventional care.
Prognosis
•achievement of first remission
• 70-80% if S60 y/o, 50% if >60 y/o
median survival 12-24 mo
prognosis depends on cytogenetics, age, performance status, prior cytotoxic agents, or radiation
therapy
Myelodysplastic Syndromes
Definition
• heterogeneous group of malignant stem cell disorders characterized by dysplastic and ineffective
blood cell production resulting in peripheral cytopenias, and a variable risk of transformation to acute
leukemias
• syndromes defined according to WHO classifications
Pathophysiology
• disordered maturation:ineffective hematopoiesis despite presence of adequate numbers of progenitor
cells in BM (usually hypercellular); formed elements sometimes exhibit morphological and functional
defects
• intramedullary apoptosis: programmed cell death within BM
• both processeslead to reduced mature cells in periphery
• <30% develop AML
Risk Factors
• elderly, post-chemotherapv, exposures (benzene, tobacco, radiation), inherited genetic abnormalities
• incidence: 50 persons per million per year, rises to 200- 400 per million per year for age 70 or older
Clinical Features
• highly variable, commonly presents with symptoms of anemia (fatigue and dyspnea),
thrombocytopenia (bruising, bleeding, or petechiae), and neutropenia (recurrent infections) over
months-years
Investigations
• diagnosed by:
anemia ± thrombocytopenia ± neutropenia
• CBC and peripheral blood film
RBC: usually macrocytic with oval shaped red cells (macro-ovalocytes),decreased reticulocyte
count
• WBC:decreased granulocytes and abnormal morphology (e.g. bi-lobed or unsegmented nuclei
=
Pelger abnormality)
platelets: thrombocytopenia, abnormalities of size, and cytoplasm (e.g. giant hypogranular
platelets)
• BM aspirate and biopsy with cytogenetic analysis required for definitive diagn
BM: dysplastic and often normocellularfhypercellular
• cytogenetics: high-risk (partial or total loss of chromosome 7) and complex (>3 abnormalities)
Treatment
• low-risk of transformation to acute leukemia (Revised International Prognostic Scoring System
(IPSS-R) Very Low or Low)
EPO stimulating agents weekly is first line in reducing transfusion requirements (EPO level must
be <500 IU/L)
• if 5q deletion based on cytogenetics:lenalidomide PO
• supportive care:RBC and platelet transfusion (consider iron chelation if frequent RBC
transfusions)
• high-risk of transformation to acute leukemia (IPSS-R intermediate, high or very high)
supportive care (transfusion support)
• epigenetic therapy: DNA methyltransferase inhibitors (e.g. 5-azacltidine)
consider stem cell transplantation according to patient factors (age, frailty, overall health)
osis
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II 12 Hematology Toronto Notes 2023
Prognosis
• IPSS-R uses 5 factors to estimate mean survival:
cytology,% BM blasts, Hb, platelets, and ANC
based on the calculated score, a patient’s \1DS prognostic risk is “Very Low”, “Low",
“Intermediate”, “High", or “Very High" with a mean survival of 8.7, 5.3, 3.0, 1.6, and 0.8 yr,
respectively
Myeloproliferative Neoplasms
Definition
• clonal myeloid stem cell abnormalities leading to overproduction of one or more cell lines
(erythrocytes, platelets,and other cells of myeloid lineage)
Epidemiology
• mainly middle-aged and older patients (peak 60-80 yr)
Prognosis
• may develop marrow fibrosis with time
• all disorders may progress to AML
Table 31. Chronic Myeloproliferative Disorders
Use of Epoetin and Darbepoetin in Patients witii
Cancer
Bond 2008111:25-41
Clinical practice guideline update by American
Societies of Kematu'ogy and Clinical Oncology (2010).
Initial Becommcndatiors
1. Initiate an ESA when Hb Is 100 gll
(10 gdl) in patients with palbalive chemotherapy
associated anemia lo decrease the need loi
transfusions
2. DscoctmuelSts when patient not respondmg to
treatment beyond 6-8 wk
3. Homtor iron stores and supplement lion intake for
ESA-treated patients when necessary
4. Use ESAs cautiously with chemotherapy orin
patients with an derated risk for thromboembolic
complications
5.1is Ml recommended that ESAbeused for therapy
in patients with cancel who are not recenmg
chemotherapy, asit increases thromboembolic
inks and lowerssurvival late. Patients with low
ink myelodysplasia are an cicepbon
CML PV IMF ET
Hct IN 1 1 a H
WBC t eta N
*
Pit t / a t /a n t
Marrow Fibrosis
Splenomegaly
Hepatomegaly
Genetic Association
2 i +++ t
+++
++
BCR ABlmut. JAK2 mut.|96%) JAK2 mut. (“50%)
CALR mut. ("30%)
JAK2 mut.("50%)
CALR mut.("30%)
MDS ineffective maturation
MPN overproduction of mature cells Chronic Myeloid Leukemia
Definition
• myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line
without the loss of their capacity to differentiate
Epidemiology
• occurs in any age group (mostly middle age to elderly) with a median age of 65 yr
Pathophysiology
• Rh chromosome
• translocation between chromosomes 9 and 22 is necessary and sufficient to result in CML
• the c-Abl proto-oncogene is translocated from chromosome 9 to “breakpoint cluster region”
(BCR) of chromosome 22 to produce BCR-ABL fusion gene, a constitutively active tyrosine kinase
Clinical Features
• 3 clinical phases
chronic phase: 85% diagnosed here
few blasts(<10%) in peripheral film
± slightly elevated eosinophils and basophils
no significant symptoms
• accelerated phase:impaired neutrophil differentiation
circulating blasts (10-20%) with increasing peripheral basophils (pruritus)
CBC: thrombocytopenia <100 x lO’/L or thrombocytosis
cytogenetic evidence of clonal evolution
worsening constitutional symptoms and splenomegaly (extramedullary hematopoiesis)
• blast crisis: more aggressive course, blasts fail to differentiate
blasts (>20%) in peripheral blood or BM; reflective of acute leukemia (1/3 ALL, 2/3 AML)
• clinical features
20-50% of patients are asymptomatic when diagnosed (incidental lab finding)
nonspecific symptoms
fatigue, weight loss, malaise, excessive sweating, fever
Basophilia is uncommon in other medical
conditions
Chronic Myeloproliferative Neoplasias:11-Year
Follow-Up ol Patients Receiving Imatinib lor the
first-line Treatment olCMl
NEJM 2012:376:917 927
Study long- term outcomes ol imatnnb treatment for
throait myeloid Itukemla.
Methods 1106 patients with Pn positive CML in
the cbionic phase were randomiied 1:1to unatinib
or interferon alpha plus cytaiabine.Crossover to
imatnnb was at lowed if no response by 6 mo or major
cytogenetic response by12 mo.
Resnlts:Assessing the unatinib arm after a median
of II yearsof follow- up.the complete cytogenetic
response rate was 83V Among patients who atta ned
a major molecular response alter 18 moot imatinib
tbeiapy.the overall survival at 10 yeais was 93% and
freedom lion CMl-related deaths was100%.
Conclusion : this 11-year update ol IRIS demonstrates
Ibe efficacy and safely of imatinib asliist-line therapy
for CMl patients.
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H43 Hematology Toronto Notes 2023
secondary tosplenic involvement
early satiety, LUQ pain/fullness,shoulder tip pain (referred)
splenomegaly (most common physical finding)
• anemia
bleeding:secondary to platelet dysfunction
• pruritus, PUD:secondary'to increased blood histamine
leukostasis, priapism,encephalopathy (rare):secondary to very elevated WBC (rare)
Investigations
•CBC with differential
elevated WBCs, decreased/normal RBCs, increased/decreased platelets, increased basophils
WBC differential shows a bimodal distribution, with predominance of myelocytes and
neutrophils
•peripheral blood film
leukoerythroblastic picture (immature red cells and granulocytes present, e.g. myelocytes and
normoblasts)
presence of different mid-stage progenitor cells differentiates it from AML
•BM biopsy
myeloid hyperplasia with left shift, increased megakaryocytes, mild fibrosis
•molecular and cytogenetic studies of BM or peripheral blood for Ph chromosome (or BCR-ABL
transcripts)
•abdominal imaging for spleen size
Treatment
•prophylactic:allopurinol
•chronic phase
imatinib mesylate inhibits proliferation and induces apoptosis by inhibiting tyrosine kinase
activity in cells positive for BCR-ABL. 2nd/3rd generation can be used as first line therapy
if loss of response or intolerance (~40%), trial of 2nd or 3rd generation TKls: dasatinib,
nilotinib,or bosutinib. Note:ponatinib only provided for theT3151 mutation
interferon-a: may improve response to TKls; typically now only used for pregnant patients
hydroxyurea in palliative setting to reduce WBCs
•accelerated phase or blast phase
for imatinib-naive patients, use imatinib
refer for clinical trial or 2nd/3rd generation TK1 and prepare for allogeneic stem cell transplant
patients, in blast phase typically get standard induction for acute leukemia
•stem cell transplantation may be curative: to be considered in young patients who do not meet
therapeutic milestones
•treatmentsuccessis monitored based on therapeutic milestones
hematologic: improved WBC and platelet counts, reduced basophils
cytogenetic: undetectable Rh chromosome in the BM
molecular:reduction/absence of BCR-ABL transcripts in periphery and marrow
Prognosis
•survival dependent on response
those achieving complete cytogenetic response (CCR) on imatinib by 18 mo of therapy:6 yr
overall survival >90%
those who do NOT'
achieve CCR on imatinib: 6 yr overall survival of 66%
•acute phase (blast crisis - usually within 3-5 yr of presentation if untreated CML)
2/3 acute phase CML have cellular featuressimilar to AML
unresponsive to remission induction
1/3 acute phase CML have cellular featuressimilar to ALL
remission induction (return to chronic phase) achievable
Erythromelalgia is a pathognomonic
miciovascular thrombotic complication
in PV and ET
Polycythemia Vera Cardiovascular Events and Intensity of Treatment
in Polycythemia Vera
NEJM 2013:368:22-33
Study:Prospective.PCI.mean follow-up of 283mo.
8hnding not described.
Population: 355 patients with MK2- posrtne
polycythemia sera being treated with phlebotomy,
hydrosyuiea.or both.
Intervention: Patients were randomned to a target
hematocrit <45% (low-hematocrit groopt or 45-50%
(high-hematocrit group).
Outcome:Composite of time unbl death from
cardiovascular causes of major thrombotic events.
Results:(he hazard ratio (Hi) for the primary
outcome was 3.91(95% Cl 1.45-10.53.P-0.00J).
while the HR for the primary outcome plussuperficial
venousthrombosis was 2.59 (95% Cl1.19-5.12.
P*
0.02|lor the high-hematocrit vs.low-hematocrit
group.
Conclusions:The hematocrit target of <45% was
associated with a lower incidence of CV death,mayor
thrombotic events,and supetheial venousthrombosis
in patientswith polycythemia vera.
Definition
• stem cell disorder characterized by elevated RBC mass (erythrocytosis) ± increased white cell and
platelet production
• diagnosis (WHO 2016) requires meeting either all 3 major criteria, or the first 2 major criteria and the
minor criterion
Major Criteria
1. Hb >165 g/L in men, >160 g/L in women, OR Hct >49% in men or >48% in women,OR
increased red cell mass (>25% above mean normal predicted value)
2. BM biopsy showing hypercellularity for age with trilineage growth ( panmyelosis) with
prominent ervthroid, granulocytic, and megakaryocytic proliferation
3. presence of )AK2 V617F or|AK2 exon 12 mutation
• Minor Criterion
1.serum EPO level below reference range for normal (must have the first two major criteria if
using EPO level) +
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H*H Hematology Toronto Xotes 2023
Clinical Features
• symptoms are secondary to high red cell mass and hyperviscosity (see Erythrocytosis, H7 )
• thrombotic complications:DVT, PE,Budd-Chiari (hepatic vein thrombosis), portal vein thrombosis,
thrombophlebitis, increased incidence ofstroke/TIA, and Ml
due to increased blood viscosity, increased platelet number,and/or activity
bleeding complications: epistaxis, gingival bleeding, ecchymoses, and Cil bleeding
if high platelet counts:associated with acquired VWD (although seen more with ET)
• erythromelalgia (burning pain in hands and feet and erythema of the skin)
associated with platelets >400 x 10*/L
pathognomonic microvascular thrombotic complication in PV and ET
• pruritus, especially after warm bath orshower (40%) due to cutaneous mast cell degranulation and
histamine release
• epigastric distress, PUD
due to increased histamine from tissue basophils, alterations in gastric mucosal blood (low due to
increased blood viscosity
• gout (hyperuricemia), due to increased cell turnover
• characteristic physical findings
plethora (ruddy complexion) of face (70%), palms
» splenomegaly (70%), hepatomegaly (40%)
Efficacy andSafety ollowiios« Aspirin:
in
Polyeythenaia Vera
NEJM 2004:350:114124
Study: Do.S e blind, placebo coitiolled. RC1.
Participants:518 patientswith polycythemia vera
(PV) with nodear indication for.ot contraindication
MSA therapy.
Intervention : Patients received either tow-dose ASA
100 mg daily|n*2S3|or placebo|a*265) and were
followed for uptoSyr.
Primary Outcome:Cumulative rate of (II nonfatal Ml,
nonfatalstroke,or death from cardiovascular causes
and the cumulative lateof|ll) the perilus 3 plus PE
and major venousIhiombosis.
•suits:Prunary outcomes(I) ard (II) were reduced
with treatment compared to placebo (RR 0,41; P-0.09
and PR 0.4;N1.03,respectively),there were no
differences in overall orcardiovascutar mortality and
major bleedmg episodes.
Conclusion low dose ASA can safely prevent
thrombotic complicationsin patients with PV.
Investigations (see Eryllirocylosis, H7)
• must rule outsecondary polycythemia if high EPO level
Treatment
• phlebotomy to keep hematocrit <45%
• hydroxyurea (prior thrombosis orsymptoms,severe coronary artery disease, refractory to
phlebotomy)
• ruxolitinib for those with insufficient response or intolerance to hydroxyurea
• low-dose ASA (for antithrombotic prophylaxis, will also treat erythromelalgia)
• allopurinol: as needed
• antihistamines:as needed
Ruxolitinib Versus Standard therapy for the
Treatment of Polycythemia Vera
HIM 2015:372:426-35
Purpose:To evaluate the efficacy andsafety of
ruxolitinib vs.standardtherapy in patents with PV
who had insufficient responses or eitoleiible side
elfects with hydroxyurea.
Methods: 232 phlebotomy-dependent patients with
splenomegaly were randomly assigned to receive
ruxolitinib or standard therapy.
Primary Outcome:Hematocrit control through week
32 and spleen volume reduced >35% at week 32.
Results: 213, ol patients on ruxolitinib vs.1% of those
on standard -therapy achieved the primary outcome
(P<0.001|.C03i of patientson ruxolitinib and 20% on
standard therapy achieved henatocrit control. >35%
reduction in spleen volumewasseen in 30% and 1%
of patients in the two groups, respectively.Compared
to standard-therapy,ruxohtiinbwas associated with
a significantly greater rate of complete hematologic
remission (24% vs.9%;P-0.003).
Conclusion:Ruxolitinib wassuperior to standard
therapy m controlling hematocrit,reducing the spleen
volume, and improving symptomsassociated with
PV in patientswho had insufficient responsesor
intolerable side effects with hydroiyurea.
Prognosis
• 10-20 yr survival with treatment
• complicated by thrombosis, hemorrhage, leukemic transformation (AML)
Idiopathic Myelofibrosis
Definition
• excessive BM fibrosis leading to marrow failure
• characterized by anemia,extramedullary hematopoiesis,leukoerythroblastosis,teardrop red cells in
peripheral blood, and hepatosplenomegaly
Epidemiology
• rare, median age at presentation is 65 yr
Pathophysiology
• abnormal myeloid precursor postulated to produce dysplastic megakaryocytes that secrete fibroblast
growth factors
stimulates fibroblasts and stroma to deposit collagen in marrow
• increasing fibrosis causes early release of hematopoietic precursorsleading to:
leukoerythroblastic blood film (see below)
migration of precursorsto other sites: extramedullary hematopoiesis (leading to
hepatosplenomegaly)
Clinical Features
• anemia (severe fatigue is most common presenting complaint, pallor on exam in >60%)
• weight loss, fever, night sweats -> secondary to hypermetabolic state
• splenomegaly (90%) > secondary to extramedullary hematopoiesis; may cause early satiety and severe
left upper quadrant pain.
• hepatomegaly (70%) -> may develop portal hypertension
• bone and joint pain > secondary to osteosclerosis, gout
• signs of extramedullary hematopoiesis (depends on organ involved)
Investigations
• CBC: anemia, variable platelets, variable WBC
• biochemistry: increased ALP (liver involvement, bone disease), increased LDH (2°to ineffective
hematopoiesis), increased uric acid (increased cell turnover), increased Bit (2°to increased neutrophil
mass)
• blood film:leukoerythroblastosis with teardrop RBCs, nucleated RBCs, variable polychromasia, large
platelets, and megakaryocyte fragments
• molecular test: )AK2 (70%) and CALR(25%) mutations
• BM aspirate:
“dry tap"
in as many as 50% of patients(no marrow spicules aspirated)
• BM biopsy (essential for diagnosis):fibrosis, atypical megakaryocytic hyperplasia,thickening and
distortion of the bony trabeculae (osteosclerosis)
Myelofibrosis can be either primary
(idiopathic) or occur as a transformation
of an antecedent PV or ET
A "leukoerythroblastic" blood film (RBC
and granulocyte precursors) implies
BM infiltration with malignancy (eg.
leukemias,solid tumour metastases) or
fibrosis (e.g.IMF)
IMF typically has a dry BM aspirate
and teardrop RBCs (aspiration gives no
blood cells)
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H15 Hematology Toronto Notes 2023
Treatment
• allogeneic stem cell transplant is potentially curative
• )AK2 inhibitors(ruxolitinib, fcdratinib, or hydroxyurea)
• symptomatic treatment
• transfusion for anemia
• EPO: 30-50% of patients respond
androgensfor anemia (e.g.danazol has shown transient response with response rates of <30%)
hydroxyurea forsplenomegaly, thrombocytosis, leukocytosis,and systemic symptoms
interferon-a (assecond line therapy)
splenectomy (as third line therapy;associated with high mortality and morbidity)
• radiation therapy for symptomatic extramedullary hematopoiesis, and symptomatic
splenomegaly
« Double 8lind. Placebo Controlled Trial of
Ruxolilinib for Myelofibrosis
NE JM 2012:356:799-807
Study: Oouble-bliodedRCI of 309 patients wits
myelofibrosis raodomued to ruiolitinib or placebo.
Outcome:Primary outcomewas reduction in spleen
volume of »35% at 24*
rtSecondary outcomeswere
durability of response,symptom burden, and overall
survival.
Results: l greater proportion of patients an
ruiolitinib bad reduction in spleen volume >35%
(41.9% vs.0.7%|and Ibiswassustained in tJ%
at 41wk. tusobtimb also led to greatersymptom
improvement(45% vs.5.3%) and less mortality (13 vs.
24).There was no difference in rateof discontinuation
doe toadverse events(11.0% vs.10.6%) but anemia
and thrombocytopenia were more common with
ri.nr till b
Conclusions: luiolihiubreducedspleen sue,and
Improved symptoms and survival, compared with
placebo.
Prognosis
• Dynamic International Prognostic Scoring System (D1PSS) Plusfor IMF uses 5 risk factors along with
karyotype, platelet count, and transfusion statusto predict survival
presence of constitutionalsymptoms; age >65; Hb <100 g/L;leukocyte count >25000/mm 3,
circulating blast cells 21%
• based on the calculated score, a patient'
s IMF is categorized as “low", “intermediate I
",
“intermediate 2",or "high"with a mean survival of 185, 78, 35, and 16 mo, respectively
eligible patients with intermediate 2 or high risk DIPSS are considered for allogeneic stem cell
transplant
risk of transformation to AML (8-10%)
Essential Thrombocythemia
Definition
• overproduction of platelets in the absence of recognizable stimulus
• must rule outsecondary thrombocythemia
Epidemiology
• increases with age; F:M=2:1, but F=M at older age
Diagnosis (2008 WHO Criteria Revised in 2016) requires meeting all four criteria
1.sustained platelet count >450 x 10’/L
2. BM biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased
number of enlarged, mature megakaryocytes; no significant increase or left shift of neutrophil
granulopoiesis or erythropoiesis
3. not meeting WHO criteria for PV, primary myelofibrosis, BCR-ABL CML, or MDS or other myeloid
neoplasms
4. most patients have a mutation in|AK 2 V617F, CALR, or MPL. A minority (~ I0%) have a mutation in
some other gene, which causes proliferation (hence “clonal marker")
Etiology of Secondary
Thrombocythemia
Infection
Inflammation (1BQ arthritis)
Malignancy
Hemorrhage
Iron deficiency
Hemolytic anemia
Post-splenectomy
Post-chemotherapy
Drugs (vinca alkaloids)
Clinical Features
• often asymptomatic
• vasomotorsymptoms (40%)
• headache (common), dizziness,syncope
• crythromelalgia (burning pain of hands and feet, dusky colour, usually worse with heat, caused
hy platelet activation -> microvascular thrombosis)
• thrombosis (arterial and venous)
• bleeding (often GI; associated with platelets >1000 x 107L)
• constitutionalsymptoms,splenomegaly
• pregnancy complications; increased risk of sp
• risk of transformation to AML (0.6-5%),myelofibrosis
ontaneous abortion
Investigations
• CBC:increased platelets:may have abnormal platelet aggregation studies or V WD studies
•|AK2 (and other) mutational assays
• BM hypercellularity, megakaryocytic hyperplasia, giant megakaryocytes
• increased K +,increased P043-(2°to release of platelet cytoplasmic contents)
diagnosis:exclude other myeloproliferative disorders and reactive thrombocytosis
Treatment
• low dose ASA
• cytoreductive therapy if thrombosis or thrombotic symptoms: hydroxyurea (HU) (lst-line therapy),
anagrelide, interferon-a, or 32P (age >80 or lifespan <10 yr)
There Is an asymptomatic “benign" form
of essential thrombocythemia with a
stable or slowly rising platelet count:
treatment includes observation, ASA.
sulfinpyrazone,or dipyridamole
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H46 Hematology Toronto Notes 2023
Lymphoid Malignancies
Acute Lymphoblastic Leukemia 75%of ALL occurs in children <6yn
second peak at age 40
Definition
• malignant disease of the BM in which early lymphoid precursors proliferate and replace normal
hematopoietic cells
• WHO subdivides ALL into two types depending on cell of origin
I. B-cell: precursor B lymphoblastic leukemia
2. T-cell: precursor T lymphoblastic leukemia
• the l-
'
rench-American-British (LAB) classification (LI, L2, L3) is no longer encouraged, as morphology
is not prognostic
Clinical Features
• see Acute Myeloid Leukemia, H39 for full list ofsymptoms
• distinguish ALL from AML based on Table 32
• clinical symptoms usually secondary to:
• BM failure: anemia, neutropenia (50% present with fever; also infections of oropharynx, lungs,
perianal region), and thrombocytopenia
organ infiltration: tender bones, lymphadenopathy. hepatosplenomegaly, meningeal signs
(headache, N/ V, visual symptoms; especially in ALL relapse)
Investigations
• >20% BM or peripheral blood lymphoblasts, with samples collected for flow cytometry,q'togenetics,
and molecularstudies
• Ph chromosome in ~25% of adult ALL cases
• CBC:increased leukocytes >100 x 109/L (occurs in 50% of patients); neutropenia, anemia, or
thrombocytopenia
• screen for TLS: increased uric acid, K '
, POTJ-, low Ca1
,
, high LDH
• screen for DIC: FT, aPTT,fibrinogen
• CXR: patients with ALL may have a mediastinal mass
• CT C/A/P and testicular ultrasound to screen for extranodal disease
• mandatory lumbar puncture to assessfor CNS involvement (ensure adequate platelet count and PT7
FITand delay until blasts have cleared from peripheral blood) at the time treatment is initiated
• HIV, HBV, HCV serologies,CMV Ab testing
Treatment
• eliminate abnormal clonal cells
1. induction chemotherapy:to induce complete remission, <5% blasts (restore normal hematopoiesis)
2. consolidation and/or intensification of chemotherapy
consolidation: continuing same chemotherapy to eliminate subdtnlcal leukemic cells
intensification: high doses of different (non-cross-reactive) chemotherapy drugs to eliminate
cells with resistance to primary treatment
3. maintenance chemotherapy:low dose intermittent chemotherapy over prolonged period (1 yr) to
prevent relapse
4.prophylaxis:CNS radiation therapy or methotrexate (intrathecal orsystemic)
• hematopoietic stem cell transplantation (for certain indications):potentially curative (due to pretransplant myeloablative chemoradiation and post-transplant graft-versus-leukemia effect) but relapse
rates and non-relapse mortality high
if BCK-ABL positive, tyrosine kinase inhibitors started up front and given continuously
• in relapse setting,CAR T-cell therapy, inotuzumab,or blinatumomab
Prognosis
• depends on response to initial induction, minimal residual disease testing or if remission is achieved
following relapse
• good prognostic factors: young, WBC <30 x 109/L,T-cell phenotype, absence of Ph chromosome, early
attainment of complete remission
• achievement of first remission:60-90%
• childhood ALL:75% long-term remission (>5 yr)
higher cure rates in children because of better chemotherapy tolerance, lower prevalence of BCRABL fusion gene (associated with chemotherapeutic resistance)
• adult ALL: 30-40% 5 yr survival
Treatment
m
ot ALL vs. AML
No proven benefit of maintenance
chemotherapy in AML
No routine CNS prophylaxis In AML
Table 32. Differentiating AML From ALL
<
*
>
AML ALL
Big people (adults)
Big blasts
Big mortality rate
Lots of cytoplasm
Lots of nucleoli(3-5)
Lots of granules and Auer rods
Myeloperoxidase. Sudan black stain
Maturation delect beyond myeloblast or promyelocyte
Small people (kids)
Small blasts
Small mortality rate (kids)
Less cytoplasm
Few nucleoli (1-3)
No granules andno Auer rods
PAS (periodic acid-Schlff)
Maturation defect beyond lymphoblast
To Differentiate AML from ALL
Remember Big andSmALL
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Hi7 Hematology Toronto Notes 2023
Lymphomas
Definition
• collection of lymphoid malignancies in which malignant lymphocytes accumulate in lymph nodes
and lymphoid tissues
• leading to Ivmphadenopathy, extranodal disease, and constitutional symptoms
Table 33. Ann Arbor System for Staging Lymphomas
American Society of Hematology
Choosing Wisely Recommendation
Limit surveillance CT scans in
asymptomatic patients after curativeintent treatment for aggressive
lymphoma
Stage Description
I Involvement of a single lymph node region or extralymphatic oigan/site (Stage IE)
Involvement ol:2 lymph node regions or an extralymphatic site and lymph node regions on same side of diaphragm
Involvement of lymph node regions on both sides of the diaphragm;may or may not be accompanied by single extra lymphatic site
or splenic involvement
Diffuse involvement of one or more extralymphatic organs includingBM
II
III
IV
• subtypes
A = absence of B-symptoms(tec Approach to Lymphaclcnopathy, H 12 )
B = presence of B-symptoms
Table 34. Chromosome Translocations
• Ann Arbor staging can be used for
both Hodgkin and non-Hodgkin
lymphoma,but gradefhistology is
more important for non-Hodgkin
lymphoma because the outcome
differs significantly depending on
type of lymphoma
• Prognostic scores are different for
indolent vs.aggressive lymphomas
• Highly aggressive lymphomas act like
acute leukemias
Translocation Gene Activation Associated Neoplasm
«(2:5) ALK1 mutation Anaplastic large celllymphoma
Burkitt's lymphoma
Follicular lymphoma
Mantle cell lymphoma
Mucosa-associated lymphoid tissue (MAlt)
t(8;14)
t(14;18)
c-Myc activation
Bcl-2 activation
Overexpression of cyclin D1 protein
MAlfl activation
1(11:14)
« (11:18)
Hodgkin Lymphoma
Definition
• malignant proliferation of lymphoid cells with Reed-Sternberg cells
Epidemiology
• bimodal distribution with peaks at 20 yr and >50 yr
• association with Lpstein-Barr virus in up to 50% of cases and causal role not determined
Clinical Features
• asymptomatic Ivmphadenopathy (70%)
non-tender,rubbery consistency
cervical/supraclavicular (60-80%), axillary (10-20%), inguinal (6-12%)
• splenomegaly (50%) ± hepatomegaly
• mediastinal mass
• found on routine CX R, may be symptomatic (cough)
rarely may present with superior vena cava syndrome and pleural effusion
• systemic symptoms
B-symptoms (>1 of: unintentional weight loss >10% of body weight within previous 6 mo,
temperature >38°C,or night sweats for 2 wk without evidence of infection), extreme fatigue
especially in widespread disease, and pruritus
• non-specific/paraneoplastic
• starts at a single site in lymphatic system ( node) and spreadsfirst to adjacent nodes
disease progresses in contiguity with lymphatic system
Hodgkin Is distinguished from nonHodgkin lymphoma by the presence of
Reed-Sternberg cells
Hodgkin lymphoma classically presents
as a painless,non-tender,firm,rubbery
enlargement of superficial lymph nodes,
most often in the cervical region
Investigations
• CBC
anemia (chronic disease,rarely hemolytic), eosinophilia, lymphopenia, platelets normal or
increased early disease, and decreased in advanced disease
•
biochemistry
• HIV, HBV. HCV serologies
liver enzymes and/or LI is(liver involvement)
renal function tests (prior to initiating chemotherapy)
• ALP,Ca 2*(bone involvement)
ESR (prognosis), LLtH (staging, monitor disease progression)
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HI8 Hematology Toronto Notes 2023
•imaging
CT chest (lymph nodes, mediastinal mass),CT abdomen/pelvis (liver orspleen involvement), and
PET scan
• cardiac function assessment (MUGA scan or echocardiography): for patients at high-risk of pretreatment cardiac disease (age >60, history of HTN, CHE, PUD,CAD, Ml, CVA), treatment can be
cardiotoxic
PETs:if history of lung disease (COPD,smoking, and previous radiation to lung)
•excisional lymph node or core biopsy confirms diagnosis
•BM biopsy to assess marrow infiltration (only necessary if B-symptoms, PET'
positive marrow on
imaging, nr cytopenia)
Treatment
•stage 1-11: chemotherapy (ABVD (adriamycin, bleomycin, vinblastine, dacarbazine)) followed by
involved field or involved site radiotherapy (XRT)
•stage 111-1V:chemotherapy (ABVD or BEACOPP (bleomycin, etoposide, adriamycin,
cyclophosphamide, vincristine, procarbazine, and prednisone)) ± XRT for bulky disease
•relapse, resistant to therapy: high dose chemotherapy and autologous stem cell transplant, anti
-CD30
Ab therapy
• PE T scan results essential in assessing disease response
Complications of Treatment
•cardiac disease:secondary to XRT, adriamycin cardiomyopathy (1% of patients)
•pulmonary disease:secondary to bleomycin (interstitial pneumonitis)
•infertility: <3% with ABVD (important to discusssperm banking/egg retrieval prior to initiation of
chemotherapy)
•secondary malignancy in irradiated field
• <2% risk of MDS, AML (secondary to treatment, usually within 8 yr)
solid tumours of lung or breast (>8yr after treatment)
• non-Hodgkin lymphoma
•hypothyroidism: post XRT
Prognosis
•Hasendever adverse prognostic factors:
1.serum albumin <40 g/L
2. Hb <105 g/L
3.male
4.stage IV disease
5. age S45 yr
6. leukocytosis (VVBC >15 x I0’/L)
7. lymphocytopenia (lymphocytes <0.06 x I0*/L or <8% of WBC count or both)
•each additional adverse prognostic factor decreasesfreedom from progression at 5 yr (EEP)
Treatment of HL depends on stage:
treatment of NHL depends on histologic
subtype
International Prognostic Factors
Project 1998
Prognostic Factors FFP
84%
1 77%
2 67%
3 60%
4 51%
5-7 42%
FFP -freedom from progression at 5yr
Non-Hodgkin Lymphoma
Definition
• malignant proliferation of lymphoid cells of progenitor or mature B- or T-cells
Classification
• can originate from both B- (85%) and T- or NK- (15%) cells
• B-cell NHL: e.g. diffuse large B-cell lymphoma,follicularlymphoma, Burkitt’
slymphoma, and
mantle cell lymphoma
WHO/REAL classification system:3 categories of NHLs based on natural history
1. indolent (35-40% of NHL):e.g. follicular lymphoma,small lymphocytic lymphoma/CLL, and
mantle cell lymphoma
2. aggressive (
-50% of NHL): e.g. diffuse large B-cell lymphoma
3. highly aggressive (
-5% of NHL):e.g.Burkittslymphoma
'
1-cell NHL:e.g. mycosisfungoides(indolent TCL of the skin), peripheral T-cell lymphoma-not
otherwise specified (PTCL-NOS), and anaplastic large cell lymphoma
Clinical Features
• painless superficial lymphadenopathy, usually >1 lymph node region, rapid growth in aggressive
lymphomas
• can have localized or widespread adenopathy (more common in indolent NHL)
• constitutionalsymptoms are less common in Hodgkin lymphoma
• cytopenia: anemia ± neutropenia ± thrombocytopenia can occur when BM is involved
• abdominal signs ± hepatosplenomegaly, retroperitoneal, and mesenteric involvement
• oropharyngeal involvement in 5-10% with sore throat and obstructive apnea
• extranodal involvement: most commonly Gl tract, testes, bone, and kidney
• CNS involvement in 1% (often with HIV, testicular DLBCL or >2 extranodal sites)
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H49 Hematology Toronto Notes 2023
Investigations
. C;BC;
normocytic normochromic anemia
autoimmune hemolytic anemia rare (more common in CLL)
advanced disease: thrombocytopenia, neutropenia, and leukoerythroblastic blood him
• peripheral blood film may show lymphoma cells
• flow cytometry of peripheral blood only if lymphocytosis is present
. biochemistries, HIV, HBV, HCV serologies
• increase in uric acid
abnormal Ll'Tsin liver metastascs
increased LDH (rapidly progressing disease and poor prognostic factor)
• SPEP and immunoglobulin quantitation (screen for high IgM monoclonal protein and hyperviscosity
in indolent lymphomas,specifically lymphoplasmacytic lymphoma)
• staging:CT neck, chest, abdomen, pelvis, and BM biopsy
• PET imaging pre- and post-therapy to ensure post treatment remission
• diagnosed by:
lymph node biopsy:excisional biopsy is preferred,core biopsy (ENA is unreliable)
BM biopsy:sub-optimal mode of diagnosis as BM is involved in only 30% of high-grade
lymphomas
Treatment
indolent NHL,localized disease (e.g.stage 1or II)
radiotherapy to primary site and adjacent nodal areas
splenectomy:splenic marginal zone lymphoma
• goal of treatment in stage 111 or IV indolent NHL is symptom management
watchful waiting
• radiation therapy for localized symptomatic disease
• bendamustine plus rituximab, an anti-CD20 Ab, is superior to CHOP and rituximab (CHOP-R)
for advanced stage disease
• obinutuzumab ( novel anti-CD20 Ab) issuperior to rituximab for advanced stage follicular
lymphoma (GALLIUM Trial)
• aggressive lymphoma:goal of treatment is curative
combination chemotherapy:CHOP is mainstay, plus rituximab if B-cell lymphoma
• radiation for localized / bulky disease
CNS prophylaxis with high-dose methotrexate if certain sites involved (e.g. testes)
relapse,resistant to therapy: high dose chemotherapy, autologous SCT,CAR T-cell therapy in
second relapse
• highly aggressive lymphoma
• Burkin lymphoma:short bursts of intensive chemotherapy:"CODOX-M” chemotherapy regimen
also often used ± IVAC with rituximab
CNS prophylaxis and (TLS) prophylaxis
Complications
• hypersplenism
• infection
• autoimmune hemolytic anemia and thrombocytopenia
• vascular obstruction (from enlarged nodes)
• bowel perforation
• (TLS particularly in very aggressive lymphoma):sec Tumour Lysis Syndrome, H 54
Prognosis
• follicular lymphoma: Follicular Lymphoma International Prognostic Index is used: age >60; >4 nodal
areas; >6 cm nodal areas;elevated LDH; Lugano stage 11I-1V; Hb <120 g/L; high p-2 microglobulin;
BM involvement
based on calculated risk, mean 5 yr survival ranges from 53-91%
rarely curative, typically relapsing and remitting course with risk of transformation to aggressive
lymphoma such as diffuse large B-cell lymphoma
• diffuse large B-cell lymphoma:
'
Ihe International Prognostic Factor Index is used (5 adverse prognostic
factors):age >60; Ann Arborstage (Ill
-IV ); performance status (ECOG/Zubrod 2-4); elevated LDH; >1
extranodal site
based on calculated risk, mean 5 yr survival ranges from 26-73%
-40% rate of cure
NHL:Associated Conditions
Immunodeficiency (e.g.HIV)
Autoimmune diseases(e.g.SLE)
Infections(e.g.EBV)
Common Chemotherapeutic Regimens
R-CHOP:cyclophosphamide,
hydroxydoxotubicin (Adriamycin!
),
vincristine (Oncovin1), prednisone
ABVO:adriamycin, bleomycin,
vinblastine, dacarbazine
BEACOPP:bleomycin,etoposide,
adriamycin. cyclophosphamide,
vincristine, procarbazine, and
prednisone
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