Blood cancer 19oct

BLOOD CANCERS
2016 update and relevant immunology basics
Zeena Nackerdien

BLOOD CANCERS
 From mature B cells
─ Uncommon
 Six types of HL,
including one
involving Reed-
Steenberg cells
 Subtypes include
─ Nodular
sclerosis
─ Mixed
cellularity
CHL
 From B cell/T cell
progenitors, mature
T/B cells, or NK cells
─ ~4% of all
cancers in
the USA
 >61 Types
 Non-Reedberg-
Steenberg-cell
disease = NHL
 DLBCL is most
common subtype
 Often occurs in
white blood cells,
but can also occur in
other types of cells
─ > common
in clildren
& teens
 4 Types
─ AML
─ CML
─ ALL
─ CLL
 Cancer of plasma cells in the
bone marrow
─ Uncommon, but risk
increases with age
 Molecular cytogenetic
classification of MM has been
proposed by a working group
─ Trisomies and IgH
translocations are the
most common
cytogenetic
abnormalities
Flat with shadow
HL HLNHL Lk
ALL, Acute lymphocytic leukemia; CHL, Classical Hodgkin’s lymphoma; AML, Acute myelogenous leukemia; CLL, Chronic lymphocytic leukemia; CML, Chronic myelogenous leukemia
DLBCL, Diffuse large B-cell lymphoma; HL, Hodgkin’s lymphoma; NHL,, Non-Hodgkin’s lymphoma; Lk, Leukemia; MM, multiple myeloma
1. http://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-non-hodgkin-lymphoma?source=search_result&search=non-hodgkin%27s+lymphoma&selectedTitle=1~150
2. http://www.cancer.org/cancer/non-hodgkinlymphoma/detailedguide/non-hodgkin-lymphoma-key-statistics; 3. Fonseca R, Bergsagel PL, Drach J, et al. Leukemia, 2009;23(12):2210-21
4. Rajan AM, Rajkumar SV. Blood Cancer J. 2015;5:e365.
MM

HODGKIN LYMPHOMA STATISTICS
% of all new US cancer
cases in 2016: 0.5
% of all US cancer
deaths in 2016: 0.2
Relative 5-year survival
rate (2006-2012): 86.2%
1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets 2016 . http://seer.cancer.gov/statfacts/html/hodg.html.

NON-HODGKIN LYMPHOMA STATISTICS
cases in 2016: 4.3
% of all US cancer
deaths in 2016: 3.4
rate (2006-2012): 70.7
1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheetshttp://seer.cancer.gov/statfacts/html/nhl.html.
.

LEUKEMIA STATISTICS
cases in 2016: 3.6
% of all US cancer
deaths in 2016: 4.1
rate (2006-2012): 59.7
1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program: http://seer.cancer.gov/statfacts/html/leuks.html.

MYELOMA STATISTICS
cases in 2016: 1.8
% of all US cancer
deaths in 2016: 2.1
rate (2006-2012): 48.5%
1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets. http://seer.cancer.gov/statfacts/html/mulmy.html.
.

What do we know about
Hodgkin Lymphoma management?
How to Approach
,
Workup, Stage &
individualize Treatment
of Hodgkin Lymphoma

HODGKIN LYMPHOMA: APPROACH The WHO defines 5 disease sub-
types ie, nodular sclerosing, mixed
cellularity (see the image below),
lymphocyte depleted, lymphocyte
rich, and nodular lymphocyte-
predominant. Up to 30% of cases of
classical Hodgkin lymphoma may be
positive for EBV proteins.
Differential diagnosis includes
excluding any other disease
presenting with lymphadenopathy
and constitutional symptoms, other
solid tumors and non-Hodgkin
lymphoma
How do doctors diagnose the disease?
What is the workup?
http://emedicine.medscape.com/article/201886-overview

HODGKIN LYMPHOMA: WORKUP Clinical and laboratory histories as
well as accurate staging are workup
fundamentals. Imaging (CT and
PET scanning), sampling (biopsy
and histologic findings), and an
assessment of prognostic factors
are required for staging.
Hematologic (complete blood cell
[CBC] count) and blood chemistry
studies may be non-specific, but
remain valuable in mapping the
extent of the disease.
What is the workup?
What are the disease stages??http://emedicine.medscape.com/article/201886-overview

HODGKIN
LYMPHOMA: STAGING The Ann-Arbor classification system, mainly
citing lymph node involvement, is used to
stage the disease.
• Stage I - A single lymph node area or
single extranodal site
• Stage II - Two or more lymph node areas
on the same side of the diaphragm
• Stage III - Lymph node areas on both sides
of the diaphragm
• Stage IV - Disseminated or multiple
involvement of the extranodal organs
What are the disease stages?
How do doctors treat the disease?http://emedicine.medscape.com/article/201886-overview

HODGKIN LYMPHOMA: TREATMENT Therapies Examples
Radiation Therapy Involved-site RT
Induction ABVD regimen
Salvage
Chemotherapy
Stanford V regimen
Autologous/
Allogenic Stem Cell
Transplantation
Patient/someone
marrow stem cells
How do doctors treat the disease?
…Overview/Prognosis
Although the disease is considered curable.,
treatment is associated with long-term
toxicities and the potential for the
development of resistance.
The following relative 5-year survival rates
are associated with the respective localized,
regional and metastatic states of the disease
ie, 91.5%, 93.1%, and 77.3%.
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Protocols
ABVD regimen includes The ABVD regimen includes doxorubicin
[Adriamycin], bleomycin, vinblastine, and dacarbazine);
Stanford V regimen includes doxorubicin, vinblastine, mechlorethamine, etoposide,
vincristine, bleomycin, and prednisone given in a 28-day cycle
http://emedicine.medscape.com/article/201886-treatment; 2.
http://emedicinhttp://emedicine.medscape.com/article/201886-overview

Non-Hodgkin Lymphoma management?
How to Approach
,
Workup, Stage &
of Non-Hodgkin
Lymphoma

NON-HODGKIN LYMPHOMA (NHL):
APPROACH NHLs are clonal expansions of B cells
(85% of all NHLs) or T cells and/or NK
cells (15% derived from T/NK cells)
arising from an accumulation of lesions
affecting proto-oncogenes or tumor
suppressor genes, resulting in cell
immortalization. The t(14;18)(q32;q21)
translocation is the most common
chromosomal abnormality associated
with NHL.
Differential diagnosis includes
excluding any other disease presenting
with benign lymph node infiltration or
reactive follicular hyperplasia secondary
to infection
What is the workup?
Download
Key NHL subtypes

NON-HODGKIN LYMPHOMA
(NHL): WORKUP • Complete blood cell
(CBC) count
• Serum chemistry studies,
including lactate
dehydrogenase (LDH)
• Serum beta2-
microglobulin level
• HIV serology
• Chest radiography
• Computed tomography
(CT) scan of the neck,
chest, abdomen, and
pelvis
• Positron emission
tomography (PET) scan
• Excisional lymph node
biopsy
• Bone marrow aspirate
and biopsy
• Hepatitis B testing in
patients in whom
rituximab therapy is
planned because
reactivation has been
reported
• Other studies as needed
What is the workup?
What are the disease stages?http://emedicine.medscape.com/article/203399-overview

NON-HODGKIN
LYMPHOMA (NHL): STAGING
*A,B,X , and E sub-categories of stages:
A: No fever, no exaggerated sweating and no weight loss are present;
B: Fever, excessive sweating and weight loss are present;
X: Bulky disease (large masses of lymphocytes) is present;
E Category: The lymphoma has spread to areas or organs outside of the lymph nodes,
or to tissues beyond, but near, the major lymphatic areas.
https://www.lls.org/lymphoma/non-hodgkin-lymphoma/diagnosis/nhl-staging
More than half of all patients with intermediate
or aggressive disease and more than 80 percent of
all patients with indolent disease are diagnosed with
stage III or IV NHL.
Stage*/Description
I – 1 lymph node group
II –≥ lymph node groups on same side of
diaphragm
III – Lymph node groups on both sides of
diaphragm
IV – ≥ organs other than lymph nodes &
possible involvement of lymph nodes

NON-HODGKIN LYMPHOMA (NHL):
TREATMENT Therapies Examples
Growth factor Granulocyte-colony
stimulating factor
Infusional eg, CHOP
Radiation Therapy Involved-field RT
Autologous/
Allogenic Stem Cell
Transplantation
Patient/someone
marrow stem cells
NHL treatment varies depending on tumor stage,phenotype (B-
cell, T-cell or natural killer NK] cell/null-cell), histology (ie, low-,
intermediate-, or high-grade), symptoms,
performance status, patient age, and comorbidities
The following relative 5-year survival rates are associated with
the respective localized, regional and metastatic states of the
disease ie, 82.6%, 74.4%, and 63.1%.
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Protocols
In Special Populations
CHOP: Prednisone, methotrexate, leucovorin, doxorubicin, cyclophosphamide,
and etoposide—cyclophosphamide, etoposide, Adriamycin, cytarabine, bleomycin, Oncovin,
methotrexate, leucovorin, and prednisone (ProMACE-CytaBOM); Methotrexate,
bleomycin, doxorubicin (Adriamycin), cyclophosphamide, Oncovin, and dexamethasone
(m-BACOD); Methotrexate-leucovorin, Adriamycin, cyclophosphamide,
Oncovin, prednisone, and bleomycin (MACOP-B); RT, radiation therapy
http://seer.cancer.gov/statfacts/html/nhl.html

Multiple Myeloma management?
How to Approach
,
Workup, Stage &
of Multiple Myeloma

MULTIPLE MYELOMA(MM):
APPROACH MM is usually defined byneoplastic
proliferation of plasma cells involving more
than 10% of the bone marrow are clonal
expansions of B cells. Patients with ≥ 60%
clonal plasma cell involvement of the marrow,
serum free light chain ratio of 100 or higher
(provided involved free light chain level ≥ 100
mg/L), and/or greater than one focal lesion
on MRI are defined as MM even in the absence
of end-organ damage.
Differential diagnosis includes excluding any
other condition eg, metastatic bone
disease/monoclonal gammopathies of
undetermined significance
What is the workup?
http://meetinglibrary.asco.org/content/159009-176
Download
MM diagnostic
criteria/related plasma
cell disorders

MULTIPLE MYELOMA
(MM): WORKUP • Serum and urine
assessment for
monoclonal protein
(densitometer tracing
and nephelometric
quantitation;
immunofixation for
confirmation)
• Serum-free light chain
assay (in all patients with
newly diagnosed plasma
cell dyscrasias)
• Bone marrow aspiration
and/or biopsy
• Serum β2-microglobulin,
albumin, and lactate
dehydrogenase
measurement
• Standard metaphase
cytogenetics
• Fluorescent in situ
hybridization
• Skeletal survey
• Magnetic resonance
imaging
What is the workup?

STAGING
The Revised ISS combines elements of tumor burden
& disease biology (± high-risk cytogenetic
abnormalitiesa/LDH) to create a unified prognostic
index.
Stage/Description
ISS Stage I – (Serum albumin > 3.5, serum
β2-macroglobulin < 3.5 & no high-risk
cytogenetics; Normal LDH
II – Neither Stage I/III
ISS Stage III– Serum β2-macroglobulin > 5.5
& high-risk* cytogenetics; Elevated LDH
*High-risk: [t(4:14), t(14;16), or del(17p)]
aAbnormalities such as t(4:14), t(14;16), t(14; 20), gain 1(q),
del(1p)or del(17p) influence disease course, response to therapy, and MM prognosis
ISS, International Staging System; LDH, lactate dehydrogenase
Rajkumar SV. ASCO Educational Handbook. Updated Diagnostic Criteria and Staging System for
Multiple Myeloma.2016. http://meetinglibrary.asco.org/content/159009-176.

TREATMENT Treatment Examples
Initial Chemotherapy eg, Bortezomib/
dexamethasone in non-
candidates
Adjunctive treatment Erythropoietin/
Corticosteroids/
Plasmapheresis/Surgery
Related bone disease
treatment
Bisphosphonates,
The deepest response in the first round is sought with
appropriate treatment; this should lead to better overall survival
in transplant & non-transplant patients.
The following relative 5-year survival rates are associated with
the respective Stage I, II and III disease stages ie, 82%, 62%, and
40%.
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Download Treatment
Protocols
http://emedicine.medscape.com/article/204369-overview;
http://meetinglibrary.asco.org/sites/meetinglibrary.asco.org/
files/edbook/176/images/EDBK_159009-table3.png

AML management?
How to Approach
,
Workup, Stage &
of Acute Myelogenous/
Myeloid Leukemia
(AML)

AML: APPROACH AML is a life-threatening condition, occurring
largely in older adults. Although a normal
karyotype can be a hallmark of de novo
myelodysplastic syndromes AML, tumors
characteristically have 11q23 abnormalities
involving the MLL gene. Secondary AML
associated with other diseases are prone to
relapse and exhibit resistance to
chemotherapy.
Differential diagnosis includes ruling out
other diseases eg, ALL, biphenotypic
leukemia, chronic myelogenous leukemia
blast crisis, and aplastic anemia.
What is the workup?
https://online.epocrates.com/diseases/27411/Acute-myelogenous-leukemia/Key-Highlights
ALL, acute lymphocytic leukemia; MLL gene, encodes histone-lysine N-methyltransferase 2A
Most common type of
acute leukemia
in adults

AML: WORKUP A definitive diagnosis requires the presence of ≥ 20% blast
cells in the bone marrow. Immunochemistry and histological
methods are critical to establish the myeloid origin of the
leukemia. Tests may include:
• Physical exam/medical history
• CBC with differential
• Peripheral blood smear
• Coagulation panel
• Lumbar puncture
• HLA typing
• Imaging
• Molecular and immunophenotyping
What is the workup?
https://online.epocrates.com/diseases/27431/Acute-myelogenous-leukemia/Diagnostic-Approach
CBC, Complete Blood Cell count; HLA, human leukocyte antigen

AML:
STAGING
French, American, and British researchers (FAB)
as well as the WHO have devised separate staging
criteria.
FAB
WHO
• AML with certain genetic
abnormalities
• AML with myelodysplasia-related
changes
• AML related to previous
chemotherapy/radiation
• AML, not otherwise specified
• MO: Undifferentiated AML
• M1: AML + minimal maturation
• M2: AML + maturation
• M3: APML
• M4: AMML
• M4eos: AMML + eosinophilia
• M5: Acute monocytic leukemia
• M6: Acute erythroid leukemia
• M7: Acute megakaryoblastic leukemia
APML, acute promyelocytic leukemia; AMML, acute myelomonocytic leukemia;
WHO, World Health Organization;
http://www.cancer.org/cancer/leukemia-acutemyeloidaml/detailedguide/leukemia-acute-myeloid-myelogenous-classified
Summary
In the case of FAB staging, subtypes M0 through M5 all start in immature forms of white blood cells. M6 AML starts in very immature forms of
red blood cells, while M7 AML starts in immature forms of cells that make platelets. See complete WHO staging system description here.

AML: TREATMENT
Treatment* will depend on patient age, fitness, disease type
(presumptive or acute AML/acute promyelocytic leukemia
(APML). 1st/2nd/3rd-line/adj. therapies may include:
Menu
http://seer.cancer.gov/statfacts/html/amyl.html
AML, < 60 y or ≥ 60 y Relapsed /refractory AML/APMLAPML
• Induction CT
• Intrathecal cytarabine
• Postinduction
consolidation CT
• Stem cell transplant
• Low-dose subcutaneous
CT
• Induction CT:tretinoin +
an anthracycline
• Supportive care
• Consolidated
/maintenanceCT
• Cessation of drug +
corticosteroid
• Intrathecal cytarabine
• Clinical trial eval. or salvage CT +
stem cell transplant + supportive
care (AML, <60 y)
• Clinical trial eval. ± stem cell
transplant/reinduction reg.
(AML, ≥60 y)
• Salvage therapy+ Stem cell
transplant+Supportive care (APML)
Adj., adjuvant; CT, chemotherapy; eval., evaluation; reg., regimen
Overview/Prognosis (US statistics for 2006-2012)
Rates for new AML cases have been rising on average 3.4% over the last decade. Relative 5-year survival rate
for this cancer is 26.6%.

CLL management?
How to Approach
,
Workup, Stage &
of Chronic Lymphocytic
Leukemia (CLL)

CLL: APPROACH This chronic lymphoproliferative disorder
accounts for up to 30% of all leukemias in the
USA. Although it has different manifestations,
the disease is identical to the mature
(peripheral) B cell neoplasm small
lymphocytic lymphoma (SLL), one of the
indolent non-Hodgkin lymphomas. A CLL
precursor is called monoclonal B
lymphocytosis.
Differential diagnosis includes ruling out
other diseases eg, FL, Hairy Cell Leukemia,
Splenic Marginal Lymphoma.
What is the workup?http://emedicine.medscape.com/article/199313-differential
http://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-
chronic-lymphocytic-leukemia?source=search_result&search=chronic+lymphocytic+leukemia&selectedTitle=4~150
ALL, Acute Lymphocytic Leukemia;; CLL, chronic lymphocytic leukemia;
FL, Follicular Lymphoma.
Most common type of
chronic leukemia
in adults

AML: WORKUP • Microscopic
examination
• Clonality confirmed by
flow cytometry
• Serum immunoglobulin
level quantitation
• Serum-free light chain
assays
• Bone marrow aspiration
and biopsy
• Liver/spleen
ultrasonography
• Chromosomal Testing
What is the workup?
http://emedicine.medscape.com/article/199313-workup

CLL:
STAGING
The Rai-Sawitsky (USA) and Binet (Europe)
systems have been used to classify disease stages.
http://emedicine.medscape.com/article/199313-workup#c9
Rai-Sawitsky
Low risk (formerly stage 0) – Lymphocytosis in the blood and
marrow only (25% of presenting population)
Intermediate risk (formerly stages I and II) – Lymphocytosis with
enlarged nodes in any site or splenomegaly or hepatomegaly (50%
of presentation)
High risk (formerly stages III and IV) – Lymphocytosis with
disease-related anemia (hemoglobin <11 g/dL) or
thrombocytopenia (platelets <100 x 10 9/L) (25% of all patients)
Binet
Stage A – Hemoglobin greater than or equal to 10 g/dL, platelets
greater than or equal to 100 × 10 9/L, and fewer than 3 lymph node
areas involved
Stage B – Hemoglobin and platelet levels as in stage A and 3 or
more lymph node areas involved
Stage C – Hemoglobin less than 10 g/dL or platelets less than 100 ×
10 9/L, or both

CLL:
TREATMENT
The estimated number of new cases for 2016 is 18,960. Relative US 5-year survival
rates (2006-2012) were 82.6%.
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Chemotherapy
Regimens
Patients with low-risk, stable diease (Binet A) require only periodic
follow-up. Rapid disease progression warrant chemotherapies ranging from
nucleoside analogs to biologics. Symptoms include:
• Weight loss of more than 10% over 6 months
• Extreme fatigue
• Fever related to leukemia for longer than 2 weeks
In addition, allogeneic stem cell transplantation is the
only known curative therapy. Pneumococcal and influenza vaccines
are needed (patients are prone to common and unusual
Infections).
http://emedicine.medscape.com/article/199313-treatment#d1
http://seer.cancer.gov/statfacts/html/clyl.html

EMERGING THERAPIES
Targeted agents and Immunotherapies

IMMUNE CHECKPOINT AXIS: NEW TREATMENTS
CD-27
PD-1/
PD-L1
TIM-3
CTLA-4
4-1BB
(CD137) LAG-3
OX40
CD40L
• Ipilimumab
• Tremelimumab
Anti-PD1
• Nivolumab
• Pembrolizumab
• Pidilizumab
• AMP-224
Anti-PD-L1
• Avelumab
(MSB0010718C)
• MEDI4736
• MEDL3280A
• BMS-936559
• Urelumab (BMS-663513)
• PF05082566
• Varlilumab (CDX-1127)
Immune-checkpoint inhibitors target
the inhibitory signals transduced through
the PD-1– PD-L1 axis and CTLA-4 interactions
Agonist
• Dacetuzumab
• Chi Lob 7/4
• CP-870893
Inhibitory
receptors/Blocking
antibodies
Activating
receptors/Agonistic/
Antagonistic
antibodies
MED16469
Antagonist
• Lucatumumab
CTLA-4, cytotoxic T-lymphocyte-associated protein 4;
PD-1, programmed cell death protein 1;
PD-L1, programmed cell death 1 ligand 1
Batlevi CL, Matsuki E, Brentjens RJ, Younes A.
Nat Rev Clin Oncol. 2016;13(1):25-40.
T cells recognize antigens
presented on the MHC by the
TCR. The fate of T cells upon antigen
recognition is determined by the
additional ligand–receptor interactions
between the T cells and APCs
(or tumor cells). The co-stimulatory
signals activated via CD28,
4-1BB (CD137), OX40, and CD27
promote activation of T cells, whereas
those sent via CTLA-4 and PD-1 decrease
T-cell activation. Various treatment
modalities are being developed
to modulate these signals.

CLINICAL EFFICACY OF IMMUNE
CHECKPOINT INHIBITORS
ORR (%)
B-NHL
DLBCL
FL
T-NHL
HL
PR (%)CR (%)
Response
Duration*SD (%)
26
36
40
17
87
10
18
10
0
26
16
18
30
17
61
52
27
60
43
13
NA
22 weeks
Not
reached
NA
NA
Nivolumab
*Median Duration of Response ; B, B-cell; CR, Complete Response; DLBCL, Diffuse Large B-cell Lymphoma; FL,
Follicular Lymphoma; HL, Hodgkin Lymphoma; NHL, Non-Hodgkin Lymphoma; PR, Partial Response; ORR, Overall
Response Rate; OS, overall survival; PFS, Progression-free Survival; SD, Stable Disease; T, T-cell
PFS: 86% at
24 weeks
OS: median
not reached

ORR (%)
HL
DLBCL
FL
T-NHL
HL
PR (%)CR (%)
Response
Duration*SD (%)
66 21 45 21 Not
reached
Pembrolizumab
*Median Duration of Response ; B, B-cell; CR, Complete Response; HL, Hodgkin Lymphoma; PR, Partial Response;
ORR, Overall Response Rate; SD, Stable Disease; T, T-cell

ORR (%)
B-NHL
HL
(post allo
SCT)
PR (%)CR (%)
Response
Duration*SD (%)
11.1
14.3
5.6
0
5.6
14.3
NA
NA
NA
NA
Ipilimumab
*Median Duration of Response ; B, B-cell; CR, Complete Response; HL, Hodgkin Lymphoma; NHL, Non-Hodgkin
Lymphoma; PR, Partial Response; ORR, Overall Response Rate; SD, Stable Disease; T, T-cell

CHIMERIC ANTIGEN RECEPTORS (CAR) FEATURES
CARs consist of an extracellular antigen-recognition domain and a signaling
domain that provides ‘signal 1’ to activate T cells (1st-generation CARs). Co-
signaling domain providing ‘signal 2’ is present in 2nd-generation CARs. Two co-
stimulatory signaling domains are present in 3rd-generation CARs.
First-generation
Second-generation
Third-generation
Antigen-
recognition
domains
Signaling
DomainsSignal 1
Signal 1
Signal 1
Signal 2 Signal 2
Jackson HJ, Rafiq S, Brentjens RJ. Nat Rev Clin Oncol. 2016;13(6):370-83.

CAR-T CELL TARGETS FOR THE TREATMENT OF
HEMATOLOGIC MALIGNANCIES
Your Logo
Target
• CD22
• CD20
• ROR1
• Ig
• CD30
• CD123
• CD33
• LeY
• BCMA
• CD138
Structure
• CD3 and CD28
• CD3  or CD3  & 4-1BB
• CD3  and 4-1BB
• CD3  and CD28
Malignancy
• FL, NHL, DLBCL, B-ALL
• CD20+-malignancies
• CLL, SLL
• CLL, low-grade B-cell malignancies
• HL, NHL
• AML
• AML
• AML
• MM
• MM
Does not include CD19 targets. AML, acute myeloid leukemia; B-ALL, B-cell acute lymphoblastic leukaemia; BCMA, B-cell maturation antigen; CLL, chronic
lymphocytic leukaemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; HL, Hodgkin lymphoma; LeY, Lewis Y antigen; MM, multiple myeloma;
NHL, non- Hodgkin lymphoma; ROR1, inactive tyrosine-protein kinase transmembrane receptor ROR1; SLL, small lymphocytic lymphoma

APPROACHES TO IMPROVING CAR-T TREATMENT
CAR, chimeric antigen receptor; IL-12, inerleukin-12; NK, natural killer; NKG2, natural-killer-cell-recognition domain;
e.g. infusion of tumour-targeted
CAR- T cells together with
B-cell-specific CAR-T cells
CAR-T
cell
Armored
CARs
Dual-
receptor
chemokines/
CARs
NK cell-
receptor
CARs
Combination
Therapies
B-cell
eradication
Targeting
tumor
vasculature
e.g. VEGFR-2-
specific CAR-T
cells
e.g. IL-12-
secreting CAR-T
cells
e.g. CAR T cells co-
expressing tumour-
specific CAR and
chimeric cytokine
receptor 4β
e.g. NKG2-based CAR
e.g. CAR-T cells and
checkpoint blockade

SIDE EFFECTS: CYTOKINE RELEASE SYNDROME ETC.
SYMPTOMS
1. Hypotension, vascular leak, coagulopathy, cytopenia
2. Respiratory/renal insufficiency
3. Myalgia, fevers
4.Neurological complications, including dyphasia,
confusion, delirium, visual hallucinations, seizure-like
activity
DIAGNOSTICS
1. C-reactive protein
2. Ferritin
TREATMENT/MANAGEMENT
1. Vasopressors
2. Ventilatory support
3. Corticosteroids
4. Anti-IL-6 receptor antibody (tocilizumab) therapy
5. Supportive care
Jackson HJ, Rafiq S, Brentjens RJ. Driving CAR T-cells forward. Nat Rev Clin Oncol. 2016;13(6):370-83.
Different “off-switches” eg,
genes & drugs are being tested
to mediate serious
cytotoxicities

Antibody-drug conjugate
targeting CD30 eg, Brentuximab
vedotin
Brentuximab vedotin and
augmented ICE (ifosfamide,
carboplatin, etoposide) prior to
autotransplant
PET-adapted sequential salvage therapy with
brentuximab vedotin followed by augmented ICE
Panobinostat
OTHER EMERGING HL TREATMENTS
(RELAPSED/REFRACTORY/SALVAGE THERAPIES)
HL, Hodgkin Lymphoma
http://www.managinghodgkinlymphoma.com/melanoma/faq-library/117-what-new-emerging-treatments-for-relapsed-refractory-hl-are-most-likely-to-improve-patient-outcomes
http://www.ascopost.com/issues/april-15-2014/better-options-emerging-for-salvage-therapy-in-hodgkin-lymphoma.aspx

PI3K inhibitor eg,
Idelalisib
Btk inhibitors eg, Ibrutinib
Syk inhibitors eg, fostamatinib
BCL-2 inhibitors eg,
Venetoclax
Anti-CD20 monoclonal
antibodies eg,
obinutuzumab
Antibody-drug conjugates
EZH2 inhibitors
OTHER EMERGING B-CELL NHL TREATMENTS
NHL, Non-Hodgkin Lymphoma; EZH2, the catalytic subunit of the polycomb repressor 2 complex; PI3K, phosphatidyl-inositol-3-kinase; Syk, spleen tyrosine kinase
Cheah CY, Fowler NH, Wang ML. Annals of Oncology. 2016 (e-pub).

Quizartinib: FLT3
inhibitor
ASP-2215: FLT3 inhibitor with activity
against TKD resistance mutation
AG-221: IDH2 inhibitor
AG-120: IDH1 inhibitor
ABT-199: BCL-2 inhibitor
OTHER EMERGING AML TREATMENTS
ASCO Educational Handbook. Emerging Therapies for Acue Myeloid Leukemia. Progress at Last?: http://meetinglibrary.asco.org/content/161258-176
The most targeted protein is FLT3 because of its role as the most common recurrent genetic alteration in patients with de novo AML. FLT3
internal tandem duplications occur in 30% of AML cases, and portend a poor prognosis, especially in patients with a high allelic ratio.

Cyclin-dependent
kinase inhibitors
BCL-2 inhibitors
Heat shock protein 90 inhibitors
Histone deacetylase
inhibitors
Small modular
immunopharmaceuticals
EMERGING REFRACTORY CLL TREATMENTS
http://www.medscape.com/viewarticle/756581_9
http://www.onclive.com/insights/cll-2015/emerging-treatments-for-chronic-lymphocytic-leukemia
The selective BCL2 inhibitor venetoclax (ABT-199) has demonstrated significant results as both a single agent and in combination with rituximab (Rituxan).
The primary side effect for venetoclax is tumor lysis syndrome, which must be carefully managed in the first 4 to 6 weeks of administration. Duvelisib is a
phosphoinositide-3 (PI3)-kinase delta inhibitor that differs from the current FDA-approved PI3-kinase inhibitor idelalisib (Zydelig) in that duvelisib also
inhibits the gamma isoform of PI3 kinase. This could potentially affect T-cells and myeloid cells. Ublituximab (TG-1101) is a novel monoclonal antibody that
targets CD20 and may potentially have superior ADCC vs. other anti-CD20 antibodies.

Elotuzumab
Carfilzumab
Pomalidomide
Panobinostat
Ixazomib
Anti-CD38
antibodies
EMERGING MM TREATMENTS
http://www.onclive.com/publications/oncology-live/2015/june-2015/new-paradigm-emerging-in-multiple-myeloma-therapy?p=1
Zagouri F, Terpos E, Kastritis E, Dimopoulos MA. Expert Opinion on Emerging Drugs. 2016;21(2):225-37.
Amongst emerging antibodies,
elotuzumab which targets
SLAMF-7 and daratumumab
which targets CD38, have been
recently approved by FDA for
patients with
relapsed/refractory MM. Both
agents are well tolerated.
Multiple clinical trials
incorporating these
monoclonal antibodies in MM
treatment are currently
ongoing

IMMUNITY BASICS
• Two cooperative defense
responses against pathogens
– Non-specific/innate immunity
– Specific/acquired/adaptive immunity
• Hematopoietic stem cells give rise
to myeloid & lymphoid lineages
• Myeloid lineage includes:
– Thrombocytes
– Erythroid cells
– Granulocytes (most abundant cells in
normal peripheral blood)
– Monocytes
• Lymphoid lineage includes:
– Lymphocytes
. Lebman D. Lippincott Illustrated Reviews Flash Cards: Immunology (First Edition). Wolters Kluwer; 2016.
Granulocytes are the most abundant cells
in normal peripheral blood

WHITE BLOOD CELLS
Neutrophil
Eosinophil
Basophil Neutrophil
Monocyte
Lymphocyte

WHITE BLOOD CELLS: NEUTROPHILS
Approximately 50 to 80% of all white blood cells are neutrophils.
These cells stain pink or purple-blue when using neutral dyes.
The bone marrow has large reservoir that can be mobilized in response to an
infection/inflammation.
1. Lebman D. Lippincott Illustrated Reviews Flash Cards: Immunology (First Edition). Wolters Kluwer; 2016
2 https://www.britannica.com/science/neutrophil.

WHITE BLOOD CELLS: EOSINOPHILS
Eosinophils make up less than 1% of white blood cells.
These cells contain large granules and a nucleus, as seen by acid stains (eosin).
Eosinophils play roles in mediating certain allergic reactions. IL-5 is linked to a
specific allergic response and stimulates eosinophil growth.
Abbreviations: IL-5, interleukin 5
2. https://www.britannica.com/science/eosinophil

WHITE BLOOD CELLS: BASOPHILS
Basophils make up ~0.4% of white blood cells.
Histological characteristics can be determined with a basic stain.
Mediates hypersensitive reactions of the immune system.
2 https://en.wikipedia.org/wiki/White_blood_cell
3. https://www.britannica.com/science/basophil

WHITE BLOOD CELLS: MONOCYTES
Monocytes are the largest blood cells (15-18 µm) and make up ~7% of white
blood cells.
Cells are types of phagocytes ie, surround and kill microbes, ingest foreign
materials, remove dead cells, and boost immune responses.
2. https://www.britannica.com/science/blood-biochemistry/Red-blood-cells-erythrocytes#toc257811

WHITE BLOOD CELLS: LYMPHOCYTES
Lymphocytes make up ~20 to 40% of white blood cells.
Two primary cell types, T and B cells, originate in the thymus and bone
marrow, respectively. These cells comprise “immunologic memory,” ie, a rapid
response to a 2nd encounter with the same antigen.
2. https://www.britannica.com/science/lymphocyte

WHITE BLOOD CELLS: LYMPHOCYTES
Human natural killer (NK) cells, the 3rd member of the lymphoid lineage, are
large granular lymphocytes. These cells outnumber B cells by 3 to 1.
The three cell types contribute to antiviral responses. Different types of T cells
are referred to as helpers/killers. Uncontrollable growth of lymphocytes can
result in blood cancers. The most common blood cancer is lymphoma.
2. https://www.britannica.com/science/lymphocyte
3. Caligiuri MA. Human natural killer cells. Blood. 2008;112(3):461-9.
T cell
B cell
NK cell

ANTIBODY STRUCTURE
Interchain
Disulfide
bonds
Antigen
binding
Biological
Activity
mediation
Interchain
Disulfide
bonds
Fab
Fc
𝑉𝐻
𝑉𝐿
𝐶 𝐻
𝐶𝐿
Light-chain Hypervariable regions
Heavy-chain Hypervariable regions
𝐶 𝐻2
𝐶 𝐻3
VL and VH: variable regions
CL and CH: constant regions
Complement-binding region
Carbohydrate

MHC
protein
Processed
viral
antigen
Interleukin - 1
HelperT
cell
T cell receptor
that fits the
particular antigen
Virus
Macrophage
Antigen –
presenting cell
CytotoxicT cell
Proliferati
on
MHC
protein
Viral
antigen
Infected cell
destroyed by
cytotoxicT
cell
Interleukin
- 2
T CELL

B Cell
Antibodie
s
Secretion
Plasma cell
B – cell receptor
(BCR)
B cell
Mitosis
and
Differentia
tion
Lymphokines
Helper T cell

Tumo
ur
cell
NK Cell
Apoptosis
Necrosi
s
Fas
(CD95
)
Fasl
(CD95L
)
NK
cell
Perforin
ADCC FcR
A
g
A
b
Granzy
me B

Granzyme
Perforin
Granzyme
release
Perforin
pore
Target
cell
Endocytosis
Granule
exccytosis
Receptor
CTL
Target Cell For CTL

CREDITS
• Slides 47-59: slideteam.net

Blood cancer 19oct

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