•
Approach to Heme
Malignancies
Lymphoma, Multiple Myeloma, Acute
Leukemia and Myeloid Disorders
Dr. Michelle Geddes
University of Calgary and
Tom Baker Cancer Centre
Nov 26, 2015
Objectives
• Organize the approach to working up
possible hematologic malignancies
• Review presenting symptoms and signs in
hematologic malignancies
• Outline the approach to therapy in different
hematologic malignancies
• Review disease and treatment
complications
Hematopoiesis
Lymphoid Malignancies
• Lymphoproliferative disorders
• B cells 80%, T cells 20% (terrible Ts)
• Chronic lymphocytic leukemia/small
lymphocytic lymphoma
• Acute leukemia (B cell ALL, T cell ALL)
Hodgkins Lymphoma
– Classical HL
– Nodular lymphocyte predominant HL
NonHodgkins Lymphomas
Indolent
Aggressive
Diffuse large B
Follicular
cell lymphoma
Gastric MALT
Small lymphocytic Peripheral T Cell
lymphoma
lymphoma
Double hit
Waldenstroms
lymphoma
Mantle cell
lymphoma
Very Aggressive
Burkitt
Lymphoblastic
lymphoma
Case 1 – possible lymphoma
• 23 year old woman with cervical lymph node
present for one month
• No infectious or B symptoms
• Pruritis
On exam – Temp 38 C
• 3 cm left anterior cervical LN, 4 cm left
supraclavicular lymph node
Labs - CBC – normal except WBC 15, neutrophils
13.2, eosinophils 1
• LDH elevated at 420
WHAT TESTS WOULD BE
HELPFUL TO DETERMINE IF
LYMPHOMA?
Making a Diagnosis…
• BIOPSY the Node!
– Excisional biopsy>needle core>FNA
• Other bloodwork can be helpful:
– CBC
– LDH
– ESR
– B2 microglobulin
– SPEP, quant immunoglobulins
• Bone marrow biopsy usually a staging
procedure, not preferred as diagnostic test
A BIOPSY IS DONE…
Hodgkins lymphoma – Reed Sternberg cell
Hodgkins Lymphoma
B cell lymphoma with surrounding reactive T cells
NOW WHAT?
STAGING LYMPHOMA
Lymph Node Regions
Staging (Ann Arbour System)
A – no B Symptoms
B – presence of B Symptoms
Staging Hodgkins Lymphoma
•
•
•
•
Physical Exam
History of B symptoms
CT neck, chest, abdomen and pelvis
? Bone marrow biopsy
– Not necessary if less than stage IIB HYL as
unlikely to be involved (unlike NHL)
• Hodgkins tends to have orderly spread
• PET scan
– If limited stage disease, confirm with PET
scan
PET scan
Treatment and Prognosis in
Hodgkins Lymphoma
Hodgkins Lymphoma
Limited Stage (I-II)
Favourable risk
Advanced Stage (III-IV)
Unfavourable risk
-large mediastinal adenopathy
-age >50
ESR >50 or >30 w/ B Sx
≥4 lymph node areas
Treatment and prognosis of
Limited Stage HL
• Favourable risk:
– ABVD (adriamycin, bleomycin, vinblastine and
dacarbazine) x2 and 30 Gy involved field RT
• Unfavourable risk:
– 4 cycles ABVD and 30 Gy IFRT
– If B symptoms or bulky 6 cycles ABVD and
IFRT
Treatment and prognosis of
advanced stage HL
• Good risk: ABVD x 6 +/- RT
• If adverse risk factors:
– Escalated dose BEACOPP
• Bleomycin, etoposide, adriamycin,
cyclophosphamide, vincristine, procarbazine,
prednisone
• More toxicities and infertility, MDS than ABVD;
ABVD used in those with few risk factors and
elderly
– PET CT scan after therapy for residual
disease
LOW GRADE
NON-HODGKINS LYMPHOMAS
Case 2
• 64 year old man comes to see his GP with
an enlarged lymph node in his groin
• Feels otherwise well, no B symptoms, no
symptoms related to enlarged node
• Physical exam shows 2 cm LN in both
axillae
• CBC, LDH, SPEP normal
• A diagnostic procedure is performed…
Follicular Lymphoma
Follicular lymphoma
• 70% of all low grade lymphomas
• Older population, usually relatively
asymptomatic at diagnosis with long
history of waxing and waning lymph nodes
– 75% with advanced stage
• Approximately 25% will transform at some
time to an aggressive DLCL
Treatment of Follicular
Lymphomas
• Generally watch and wait until symptomatic
– Most treatment not curative
– Exception – stage 1a or IIa nonbulky contiguous
disease given RT for cure
• Rituximab-Bendamustine is mainstay of first line
therapy treatment indicated
– fever, night sweats, weight loss, malaise, pain
– Bulky or symptomatic lymphadenopathy
– Impending organ compromise (compression,
pleural/pericardial effusions, ascites)
– Cytopenias secondary to bone marrow infiltration
Treatment of Follicular
Lymphomas
• Maintenance rituximab given q3 months
for two years to prevent relapse and
improve survival
Indolent Lymphomas
Follicular Lymphoma
JCO 2009: 10;1607-14
Prognosis in Follicular
Lymphoma
Specific indolent lymphomas have
different treatment approach
• Mantle cell lymphoma – “indolent” lymphoma but
relatively aggressive course with med survival 3-5y
– R-CHOP then DHAP and autologous stem cell transplant
up front, maintenance Rituximab
• Gastric MALT, cutaneous indolent lymphomas
• Splenic marginal zone lymphoma ‘
– Splenectomy
• Hairy cell leukemia
– Splenomegaly and cytopenias
– Cladrabine single 5-7 day course: 91% CR, OS at 4y 96%
AGGRESSIVE LYMPHOMAS
Case 3
• 54 year old patient presents with rapid
development over 2-3 weeks of large left
supraclavicular lymph node
– Fevers, drenching sweats
– Appetite poor, weight loss10 lbs
• On exam: 5 cm left supraclavicular node
– Cachexia
• A diagnostic procedure is performed…
Diffuse large B cell lymphoma
Diffuse large B cell lymphoma
• Most common type of lymphoma, incidence
increases with age
– 25% of all NHL
•
•
•
•
Rapidly growing LNs, 30% have B symptoms
Advanced disease>localized disease
30% bone marrow involvement, most high LDH
Can be extranodal disease
– 5-10% risk of CNS relapse
Treatment of DLCL
• Limited stage (I-IIa non-bulky)
– If 0-1 IPI risk factors: R-CHOPx3 + IFRT
– If 3 risk factors: R-CHOP x 6
• Advanced stage (stage III-IV, bulky, B
symptoms)
– R-CHOP x6
– Add IFRT to sites of prior bulk
– PET scan after completion of therapy
Prognosis - International
Prognotistic Index
T cell aggressive lymphomas
• Overall, prognosis is worse than B cell
aggressive lymphomas
• Can present with T symptoms – terrible B
symptoms, systemic symptoms
T cell lymphoma
outcomes
Foss F M et al. Blood 2011;117:6756-6767
Treatment of Aggressive T cell
Lymphomas
• CHOP
– Overall, response in 50-70% with 5 year
disease-free survival around 30%
– Compared to 50-60% for high risk DLBCL
• CHEOP – adding etoposide may improve 3y
EFS (75% vs 51%) in patients 60y
• High risk fit patients often offered autologous
transplantation in 1st complete remission
HIGHLY AGGRESSIVE
LYMPHOMAS
Highly Aggressive Lymphomas
• B cell lymphomas∕leukemias
– Burkitts lymphoma
– Precursor B lymphoblastic leukemia ∕
lymphoma
• T cell lymphomas∕leukemias
– Precursor T lymphoblastic
leukemia ∕ lymphoma
Highly Aggressive Lymphomas
• Aggressive and prolonged inpatient protocols of
combined 4 or 5 drug chemotherapy drugs
– CNS prophylaxis and CNS-penetrating chemotherapy 
cranial irradiation
– 25% CNS relapse without treatment
• Overall survival 60% for T lymphoblastic
lymphoma and Burkitts
• Pediatric-based very aggressive 2y protocols for
ALL with 60% survival <age 60y
– High risk patients alloBMT
Chronic Lymphocytic Leukemia
• Indolent lymphoproliferative disorders with
median survival >15y overall
• Indications for treatment:
– cytopenias, B symptoms, symptomatic or
bulky lymphadenopathy, consitutional
symptoms
• Cytogenetics help determine prognosis
and treatment options
Current CLL treatment
Overall Survival FCR vs BR
Eichhorst B, et al. ASH 2014:19
Bruton’s tyrosing kinase inhibitor
Ibrutinib : duration of response
100%
PROGRESSIONFREE SURVIVAL
TN
R/R
96.3%
68.4%
(76.599.5)
Not
reached
(56.177.9)
Not
reached
TN
R/R
96.6%
79.9%
(77.999.5)
Not
reached
(69.087.3)
Not
reached
80%
30-mo PFS
60%
40%
TN
Median
PFS
R/R
+ Censored
20%
0
(95% CI)
0
6
12
18
24
30
36
42
100%
OVERALL
SURVIVAL
80%
60%
30-month
OS
40%
TN
(95% CI)
R/R
20%
+ Censored
Median OS
0
0
6
12
18
24
30
36
Months
O’Brien S, et al. ASCO 2014; Oral/Abstract #7014
Idelalisib + rituximab
Furman et al NEJM 2014
Idelalisib + R improves overall survival
Furman et al NEJM 2014
Lymphoma Summary
• Divided into indolent, aggressive and highly
aggressive malignancies
• Indolent lymphomas are not generally curable
with chemo and less symptomatic
– often diagnosed in advanced stage but with long
survival ie follicular
– watch and wait, less intensive chemotherapy
• Aggressive lymphomas often curable with
chemoradiation and are more symptomatic
– more often diagnosed in early stages
– chemotherapy  IFRT given at diagnosis for cure
Case 4
• 60yo man presents with pathologic
fracture of the humerus
• Fatigued, generally unwell for 6 months
• Labs:
– Hb 90, remainder of CBC normal
– Ca+ 2.7, creatinine 160, total protein 90
– What further investigations would you need to
do?
Further investigations
– SPEP shows IgG kappa monoclonal protein 32g,
– B2 microglobulin 4.2, albumin 30, CRP high, Ig
levels shows high IgG
– Serum free light chain index elevated at 326
– Skeletal survey – multiple lytic bony lesions
– Urine protein electropheresis and creatinine
clearance
• Dipstick may not be positive (picks up albumin)
– A bone scan is not helpful!
• Osteoclastic activity not osteoblastic in myeloma, does
not light up on bone scan
Diagnosis
CRAB (A)
• Calcium (>2.7)
• Renal failure (>176)
• Anemia (Hb<110)
• Bony lesions
• (Amyloidosis)
Cytogenetics and flow
cytometry are sent for
prognostic markers on bone
marrow aspiration
Staging multiple myeloma
• Always comes out of an MGUS
Stage B2
Microglobulin
Albumin
Median Survival
(months)
I
<3.5
and
35
62
II
≥3.5 and <5.5
and/or
<35
44
III
≥5.5
29
• FISH for: t(14;16), t(4;14), deletion 17 (17p-) and
del13q are prognostically important on bone
marrow aspiration
Treatment Approach in
Myeloma
• Transplant eligible
• Non-transplant eligible
Treatment algorithm
Transplant
eligible’
Standard risk
disease
CyBordD x 4-6
cycles
(Cyclophosphamide
Bortezomib
Dexamethasone)
Transplant
Eligible
High risk disease
17p del or t(4:14)
CyBordD (4-6) or
VRD (4-6)
Transplant
ineligible
CyBordD
9-12
cycles
(lenalidomide, bortezomib, dex)
Stem cell mobilization, autologous stem
cell transplant then VRD x 2 cycles
Maintenance with lenalidomide until
progression or bortezomib for 2 years
Bortezomib
q2 weeks
for 2 years
or
Len/Dex
until
progress
ion
All patients IV
bisphosphonate
monthly x2y
Prognosis post transplant in MM
Age >65y
In non-transplant eligible, OS 60-70% at 4y
Age <65y
Al-Mansour, et al. Adv Hematol. 2014; 2014: 652395.
Myeloid disorders
• Myelodysplastic syndromes
• Myeloproliferative disorders
– Essential thrombocytosis, polycythemia vera,
myelofibrosis
– CML – tyrosine kinase inhibitors
• Acute myeloid leukemia
– Intensive inpatient protocols with allogeneic
transplantation in high risk patients
– Hypomethylating agents or low dose
cytarabine in the elderly
What raises a red flag that there
is a myeloid disorder?
• Reasons to refer urgently:
– Blasts – always!
– Nucleated red blood cells
– >1 unexplained cytopenia or a severe cytopenia
– Unexplained elevated blood counts:
• Hb >185 in men or Hb>165 in women – check epo
levels, jak2V617F mutation if no obvious explanation
for high Hb
• Thrombocytosis >450 persistent – look for reactive
causes, iron deficiency
• Elevated white blood cells with left shift
Myelodysplastic Syndromes
• Clonal disorders of the bone marrow
characterized by:
– Low blood counts
– Ineffective production of blood cells
– Abnormal red cells, neutrophils and platelets
– Increased risk of developing AML
Mr. G. Olfer
•
•
•
•
72 yo man with anemia for 4 years
Mildly low neutrophil count, no infections
Platelets normal, no bleeding
Now hemoglobin down to 60s, transfusion
dependent with 4u red cells transfused
• Bone marrow biopsy shows MDS
• Refractory anemia with ringed sideroblasts
• What does this mean for him?
WHO 2008 Classification – A
collection of myelodysplastic
syndromes
Refractory Cytopenias with Unilineage Dysplasia (RCUD)
Refractory Anemia with Ring Sideroblasts (RARS)
Refractory Cytopenia with Multilineage Dysplasia
Refractory Anemia with Excess Blasts-1 (RAEB-1) (5-9% BM blasts)
Refractory Anemia with Excess Blasts-2 (RAEB-2) (10-19% BM blasts)
Myelodysplastic Syndrome - Unclassified
MDS Associated with Isolated del(5q)
< 20% blasts
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. 2008.
Goals of Therapy
•
•
•
•
Prolong survival
Quality of life
Improve symptoms
Reduce transformation to acute leukemia
How do we decide if patients have
lower risk or higher risk MDS?
•
•
•
•
•
Blood counts
Chromosome analysis
Blast counts in bone marrow
Age
Type of MDS
IPSS-R
Revised International Prognostic Scoring System
Parameter
Categories and Associated Scores
Very
good
Good
Intermediate
Poor
Very
Poor
0
1
2
3
4
≤2%
>2 - <5%
5 - 10%
>10%
0
1
2
3
≥100
80 - <100
<80
0
1
1.5
Absolute neutrophil count
(x 109/L)
≥0.8
<0.8
0
0.5
Platelet count
(x 109/L)
≥100
50 - 100
<50
0
0.5
1
Cytogenetics
Marrow Blasts
Hemoglobin (g/L)
Very good = del(11q)
Good = Normal, del(5q), del(12p), del(20q), double including del(5q)
Intermediate = del(7q), 8, 19, i(17q), any other single or double independent clones
Poor = inv(3)/t(3q)/del(3q), double including 7/del(7q), complex: 3 abnormalities
Very poor = Complex: 3 abnormalities
Greenberg P, Tuechler H, Schanz J, et al. Blood. 2012;120(12):2454
Lower risk MDS
• Growth factors i.e.
erythropoietin
– increase red cells and
reduce transfusions
• Transfusions, antibiotics,
supportive care
• Iron chelation for iron
overload from transfusions
– Usually if ferritin>1000
and/or 20 transfusions red
cells
Del 5q syndrome
• 10-15% of MDS
– Anemia
– Mild low white blood cells
– Atypical megakaryocytes, normal to elevated
platelets
– Transfusion dependence
– Normal blast count
Extended survival with low frequency of
AML transformation (10%)
Lenalidomide: RBC Transfusion
Independence in Del(5q) MDS
Erythroid Response Rate (N=148)
n (%)
95% CI
Transfusion independence*
99 (67)
59–74
≥50% decrease in no. transfusions
13 (9)
5–15
Total transfusion response
112 (76)
68–82
Transfusion Independence
Response Characteristics
Median
Range
Time to response (wk)
46
1–49
Hgb increase† (g/dL)
54
11–114
N Eng J Med, 2006; 355: 1456
Mr. G. Olfer
• After 2 years, his platelets drop to 14 and
he starts to have blasts in his peripheral
blood
• Bone marrow biopsy shows refractory
anemia with excess blasts-2
• Blasts 11%, complex cytogenetics
• Higher risk MDS
• What treatment options does he have?
Higher risk MDS
• Supportive care, transfusions
• Azacytidine Intermediate-2 and High risk
MDS, low blast count AML
– 7d subcutaneous injections every 4 weeks
– Associated with improved survival, lower rate
of developing acute leukemia
– Improved quality of life
Overall Survival: Azacitidine vs
Conventional Care Regimen
Proportion Surviving
1.0
0.9
p=0.0001
0.8
0.7
0.6
0.5
0.4
AZA
0.3
Conventional
Care
0.2
0.1
0.0
0
5
10
15
20
25
30
35
40
Time (months) from Randomization
Survival Difference 9.4 months
Oral azacytidine in development
Lancet Oncol 2009; 10:223-32.
Between a rock and a hard
place
Transplantation is
currently the only
curative therapy
for many hematologic
malignancies
Median age
at diagnosis is 65-70
Toxicity of
transplantation can
be prohibitive
Role of Clinical Trials
Other supports available
•
•
•
•
•
•
•
Home care
Wellspring
AAMAC
Leukemia and lymphoma society
Psychosocial services
Dieticians
Social work, home care, mobile lab
Questions?
Blood Moon