Targeting CD19 in B-cell ALL
Anjali S. Advani, MD
Director, Inpatient Leukemia Unit
Associate Professor, Cleveland Clinic Lerner College of Medicine
Staff, Department of Hematologic Oncology and Blood Disorders
Taussig Cancer Institute, Cleveland Clinic
Cleveland, Ohio
Disclosures for Anjali S. Advani, MD Royalty N/A
Receipt of intellectual property/ Patent holder
N/A
Consulting fee EUSA, Sigma Tau, Pfizer
Speakers bureau N/A
Fees for non-CME services N/A
Contracted research N/A
Ownership interest (stocks, stock options)
N/A
Other N/A
N/A = Not Applicable (no conflicts listed) Presentation includes discussion of off-label or unapproved use of a drug or medical device: N/A
Adult ALL: Novel Approaches Needed
57% 38% 12% 41%0
20
40
60
80
100
< 30 y (n = 280)
30-59 y (n = 350)
> 60 y (n = 129)
Overall (n = 759)
Overall survival at 3 years for 759 adults enrolled on 5 CALGB trials:
1988-2001
Courtesy of Wendy Stock
Lymphoblast
Blinatumomab
Epratuzumab
Inotuzumab
Alemtuzumab
Rituximab
Monoclonal Antibodies in Pre-B ALL
CD19 and ALL
• CD19 is the most commonly expressed
Ag in pre-B ALL and has the highest
density of expression
• Type I transmembrane protein of the Ig
superfamily and regulates B-cell fate
through modulation of the B-cell receptor
SGN19a
• Antibody drug conjugate
• Humanized anti-CD19 mAb and potent cytotoxic
drug monomethyl auristatin F (microtubule
disrupting agent)
• CD19: favorable characteristics for targeted drug
delivery
-- limited normal tissue penetration
-- internalizes rapidly
In vitro data; clinical trials ongoing.
Albertson TM et al. AACR 2013; Abstract 2412.
Combotox
• 1:1 mixture of 2 immunotoxins
• Coupling deglycosylated ricin A chain to
monoclonal Abs against CD22 + CD19
• DLT: vascular leak
• Responses: decreased blast counts, PRs
• Phase 1 trial in combination with cytarabine:
NCT01408160 based on synergy in a murine
model.
Apoptosis
Cytotoxic T Cell B Lymphoblast
Proliferation
Redirected cell lysis
Activation
Anti-CD19 Ab
Anti-CD3 Ab
BiTE
MT103
MT103
Blinatumomab (MT103)® A T Cell-Engaging BiTE Antibody
Adapted from: Nagorsen D et al. Blood 2009; 114: abstr 2723
Grade 3-4 Adverse Events
(Topp MS et al. Blood 2011; 29: 2493-2498)
MeDRA Organ System
Class Term
Number of Patients (%)
Blood and Lymphatic
Leukopenia
Lymphopenia
Granulocytopenia
Thrombocytopenia
2 (9.5%)
7 (33.3%)
1 (4.2%)
1 (4.2%)
Nervous System Disorders
Syncope/ convulsion
Seizure
Headache
Somnolence
1 (4.8%)
1 (4.8%)
1 (4.8%)
1 (4.8%)
Infections
Catheter-related
Bacterial sepsis
Bronchopneumonia
2 (9.5%)
1 (4.8%)
1 (4.8%)
Investigations
ALT increased
Albumin decreased
Amylase decreased
Blood Ig decreased
1 (4.8%)
1 (4.8%)
1 (4.8%)
5 (23.8%)
.
Hematologic RFS. (A) For all patients, (B) For the 9 HSCT patients, (C)
For the 11 patients not receiving HSCT
Topp M S et al. Blood 2012;120:5185-5187
Copyrighted material
Effect of anti-CD19 BiTE Blinatumomab in
Adult Patients with Relapsed/ Refractory B-
precursor ALL
• 25 out of 36 patients evaluable
• 17 out of 25 (68%) achieved a CR or CR with
partial hematologic recovery (CRh)
• Median response duration: 7.1 months; median
overall survival: 9.7 months.
• Of the 6 relapses, 3 patients developed a CD19
negative clone.
• This latter mechanism of resistance is a concern
with the development of antibody-targeted
therapies.
Topp MS et al. J Clin Oncol. ASCO Annual Meeting. 2012; Abstract 6500.
Blinatumomab 00103311 (TOWER study)
• A Phase 3 Randomized Open Label Study
Investigating the Efficacy of the BiTE Antibody,
Blinatumomab vs. Standard of Care
Chemotherapy in Adult Subjects with Relapsed/
Refractory Pre-B ALL
Newly diagnosed Ph neg B-ALL, age 40-70
Remission Induction chemotherapy; start donor search
Randomize (stratify by: intent for Chemotherapy vs BMT post Blin; MRD status)
Blinatumomab
28 mcg/d
CI for 4 wks x 2
cycles
Delayed Intensification and Maintenance Chemotherapy +/- Blinatumomab; [May go to HSCT (any suitable donor & regimen) at investigator’s discretion]
Intensification
MRD Assessment
E1910 A Phase III
Randomized
Trial of
Blinatumomab
for Newly
Diagnosed bcr-
abl negative B
ALL in Adults
CR Chemotherapy
backbone hybrid of
E2993 with
modifications
adapted
from C10403
S1318
• A Phase 2 Study Of Blinatumomab and POMP
(Prednisone, Vincristine, Methotrexate, 6-
Mercaptopurine) for Patients ≥ 65 Years of Age with
Newly Diagnosed Ph- Acute Lymphoblastic
Leukemia (ALL) and of Dasatinib, Prednisone and
Blinatumomab for Patients ≥ 65 Years of Age with
Newly Diagnosed Ph+ ALL
S1318: Ph- Cohort
Induction with Blinatumomab for 1 cycle
CR or CRi
Yes No
Re-induction with
Blinatumomab x 1 cycle Post-remission
therapy with
Blinatumomab x 3
cycles
POMP chemotherapy x 18 months
CR or CRi
Summary-1
• Several novel antibody based therapies, such as
Blinatumomab, are demonstrating encouraging
results in ALL and some of these drugs will likely
be approved soon for the treatment of relapsed
ALL.
• However, the emergence of resistance in clones
lacking the respective target indicates a need to
target other molecules in patients with ALL and to
consider evaluation of these antibody-based
therapies in the upfront setting.
Summary-2
• Ultimately, it is likely that sequencing of these
agents will be important in future trials; and the
addition of such therapies will likely change the
paradigm of alloHSCT.