Transcript Common Side Effects

The Increasing
Use of Targeted
Therapies for
Leukemia and
Lymphoma
Shira Dinner, MD
Northwestern University
Educational Objectives
• Define terminology used regarding leukemia
• Describe the latest developments in the
treatment of acute lymphoblastic leukemia (ALL)
 Blinatumomab
 Inotuzumab ozogamicin
 Chimeric antigen receptor T cells
• Engage patients and caregivers in clinical trial discussions
on emerging therapies in ALL
• Identify strategies fro optimal patient care
 What is the best treatment for me?
Common Terminology in Leukemia
• Acute:
 Develops from immature cells in the bone marrow that replicate quickly
and aggressively
 The cells do not grow up and perform their normal function (i.e. fight
infection)
• Chronic:
 Develops from mature cells that do not function normally
 Typically progresses more slowly
• Acute lymphoblastic leukemia:
 An aggressive cancer that develops from a type of white blood cells in
the bone marrow called lymphocytes
Common Terminology in Leukemia
• Complete remission (CR)
 The absence of any signs or symptoms of the disease
 < 5% blast cells in the bone marrow (when looking at the cells under a
microscope) and no evidence of leukemia anywhere outside of the bone
marrow
• Minimal residual disease (MRD)
 A very low level of leukemia cells that remain in the bone marrow that
cannot be seen by the microscope
 Detected by looking for certain gene or chromosome mutations that
may be present in the leukemia or by looking at antigens (proteins) on
the surface of the leukemia cells
• Refractory disease
 The leukemia does not respond to treatment or does not achieve a CR
• Relapsed disease
 The leukemia was in CR, but has now come back
Common Terminology in Leukemia
• Overall survival (OS)
 The length of time from either the date of diagnosis or the start of
treatment for a disease that patients diagnosed are still alive.
 In a clinical trial, measuring the overall survival is one way to see how
well a new treatment works.
• Progression free survival
 The length of time during and after the treatment of a disease that the
disease remains in remission or does not get worse.
Immunotherapies
Using the immune system to attack the leukemia
• Antibody: A Y shaped protein
made by the immune system
to identify, bind, and
neutralize harmful things
(antigens) such as infections
in the body
• Immunotherapies: Use
antibodies created in the lab
to recognize and attack the
leukemia cells
Antigens in ALL
• There are many different
proteins or antigens on the
surface of ALL cells that we
can design antibodies to
target as part of
immunotherapies
Blinatumomab: bispecific T cell engaging
antibody
Phase 2 Blinatumomab in
Relapsed/Refractory ALL
Pts (%)
CR/CRi during first 2 cycles, n (%)
CR
CRi
Allogeneic SCT after CR/CRi
Median Overall Survival
81/189 (43%)
63/189 (33%)
18/189 (10%)
32 of 81 (40%)
6.1 months
80% of patients had received at least 1 prior chemotherapy
to treat relapsed or refractory ALL
Topp et al. Lancet Oncology 2015;16(1):57-66.
Blinatumomab: Side effects
•
•
Most Common side effects
− Fever
−
Headache
− Neutropenic fever
113 (60%)
65 (34%)
53 (28%)
Neurologic side effects occurred in 98 (52%) patients, all reversible
• This could include confusion or delirium to rarely stroke or seizure
symptoms
− Most were mild and resolved spontaneously
74 (76%)
− Most occurred during Cycle 1
85 (87%)
•
29 pts discontinued for neuro side effects
Topp et al. Lancet Oncology 2015;16(1):57-66.
Topp et al. Lancet Oncology Jan;16(1):57-66.
Inotuzumab Ozogamicin (IO):
antibody-drug conjugate
Phase 3 IO vs Standard of Care (SOC)
chemotherapy in relapsed/refractory ALL
Baseline characteristic
INO (n=109)
SOC (n=109)
CR1 duration ≥ 12 mo
43%
35%
Age < 55 yo
61%
63%
Salvage 1
67%
63%
Safety
The most common serious side effects were low blood counts
Serious liver or gallbladder side effects occurred in 9% INO vs 3% SOC
Veno-occlusive liver disease (VOD) 14% INO vs 1% SOC
VOD: blockage in small veins in the liver that can cause fluid
Retention and increased liver function tests (esp bilirubin)
INO: 5 VOD events during treatment, 10 post SCT (2 fatal)
DeAngelo et al. EHA 2015. Abstract 2073
IO Efficacy
INO (n=109)
SOC (n=109)
Median duration of
treatment
8.3 weeks (0.1-26.4)
0.9 weeks (0.4-15.1)
CR/CRi
80.7
33.3
S1
87.7
31.3
S2
66.7
37.9
Median DOR, mo
4.6 (3.9-5.4)
3.1 (1.4-4.9)
MRD negativity
78.4
28.1
Treatment discontinuation:
83% INO mainly due to CR
89% SOC mainly due to resistant disease
AlloHSCT
44% INO vs 18% SOC
DeAngelo et al. EHA 2015. Abstract 2073
Chimeric Antigen Receptor T Cells
Generation of CAR T Cells
ψ
α-tumor scFv
ScFv
5’ LTR
VH
SD
CD28
ζ chain
3’ LTR
SA
2. Subclone CAR gene into a vector
CD28
CD3ζ
VL
1. Construct a CAR
3. Transduce and expand
patient T cells ex vivo
Retroviral vector encoding CD19 CAR cDNA
CAR
T cell
CD19
Genetically modified
CD19-targeted T cell
Tumor cell
Common Side Effects
• Cytokine release syndrome (CRS)
 Fever
 Hypotension
 Respiratory insufficiency
• Neurological changes or symptoms




Delirium/disorientation
Global encephalopathy (tremors, seizure-like jerks)
Aphasia
Seizure
• Can occur within 1-14 days of T cell infusion
 Patients must be monitored in the hospital
• More severe symptoms in patients with higher leukemia disease
burden
Results of CAR T cell trials
Trial
Patients +ALL
CR
prior to N(%)
CAR T
infusion
MRD
HSCT
negative
N (%)
DFS
OS
UPenn
pediatri
c and
adult
MSKCC
adult
30 (25
pediatri
c, 5
adult)
43
80%
27 (90)
23 (77)
3 (10%)
63% at 6 78% at 6 90%
months months
43%
51%
36 (84)
29 (83)
12
(28%)
28%
after 12
months
77%
52%
NCI
adult
20
NR
14 (70)
12 (60)
10
(50%)
79% at 51.6% at 75%
4.9
10
months months
for MRD
negative
patients
30%
Median
8.5
months
CRS
%
Neuro
Side
effects
N(%)
Remaining questions with CAR T cells
• How long do CAR T cells last in the body?
• Do you need an allogeneic stem cell transplant after
achieving remission with CAR T cells?
• Could patients be retreated with CAR T cells?
Possible side effects of CAR T cells
• Cytokine release syndrome
• Fever
• Neurotoxicity
• T-cell infusion reaction
• Tumor lysis syndrome
• Low B-cell levels (increased infection risk)
• GVHD
• The virus used to engineer the T cells could
replicate in the patient’s body
• Uncontrolled T-cell proliferation
• The genetically modified product may insert
itself into the patient’s DNA and cause other
cancers
Key toxicities observed in the
Phase 1 studies
Potential toxicities of CAR T
cell therapy, but not
observed in the Phase 1
studies
19
Summary
• New therapies for leukemia and lymphoma are taking
advantage of copying or utilizing the immune system to
attack the cancer
• Several new immunotherapies are available for ALL
 No clinical trials have compared blinatumomab vs IO vs CAR T cells
 We do not yet know which is the “best” treatment or what order
we should give the treatments in
 It is important to consider side effects when selecting a treatment
with your doctor
• Blinatumomab: neurologic side effects, cytokine release syndrome
• IO: liver side effects
• CAR T cells: CRS, neurologic side effects
• Talk to your doctor about a clinical trial