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.