BiTE in ALL and AML

Ibrahim Aldoss, MD

Assistant Professor, City of Hope

Hematology and Hematopoietic Cell Transplantation

• NO CONFLICT OF INTEREST

Immune system as an anticancer therapy

• Immune surveillance plays a critical role in controlling

cancer development

• Cancer risk increased in congenital or acquired T cell defects

• Cytotoxic T cell has a remarkable capacity to target cancer

• Direct correlation between tumor T-cell infiltration and prognosis

• Xenograft models, T cells were able to eradicate tumors

• The activity of anti-CTLA-4 and PDL-1 inhibitors

• Reduced relapse after allogeneic HCT

• Successful T cell therapy is hampered by large number of

immune escape mechanisms

Stieglmaier J. 2015. Zhang. 2003. Whalin

2007. Galon 2006.

Bi-specific T cell engager (BiTE)

• BiTE is an antibody construct, linking scFvs of mAbs

for CD3 and surface molecules on targeted cells

• The construct is designed to approximate targeted tumor

cells in close range to T cells “immunological synapse”

• Leads to activation & polyclonal expansion of cytotoxic T

cells

• Activation of T-cells occurs independent of TCR specificity,

co-stimulation, or peptide antigen presentation

• Following synapse formation, T-cells release cytokines,

followed by activation of targeted cell caspase and apoptosis

Stieglmaier J et al. 2015.

Baeuerle PA et al. 2009.

Blinatumomab

Nagorsen et al. 2012.

Blinatumomab

• Blinatumomab is the first FDA approved BiTE

• The target is CD19

• Present on all mature B cells in blood and secondary

lymphoid tissue

• Presents on the vast majority of B-cell malignancies,

including ALL

• The FDA approval for R/R Ph- ALL

• CIVI x 28 days every 6 weeks

• Step-wise escalation in cycle 1

• 9 mcg/day on Days 1-7 and 28 mcg/day on Days 8-28

• For subsequent cycles, blinatumomab is administered

at 28 mcg/day on Days 1-28

• Hospitalization is recommended in the first 9 days

of cycle1

• Also in the first 2 days of cycle 2

• Not beyond cycle 2 for responders

• Pre-med with dexamethasone 20 mg IV 1 hour

before starting each cycle

• Recommended before escalating the dose,

• or when restarting after an interruption of ≥ 4 hours

• Pre-treatment with dexamethasone & step-wise

escalation reduced risk of significant CRS

• This is did not compromise blinatumomab activity

Lymphocyte kinetics during blinatumomab

• Very unique and predictable

• Both, B and T cells drop quickly

• T cells recovered & reached above baseline within

days

• Expansion of CD4 & CD8 effector memory cells

• No significant change in naïve T cells

Topp et al. 2011, Zhu. ASCO 2015, Klinger. 2012

Lymphocyte kinetics during blinatumomab

• Simultaneously, blinatumomab mediates normal B

cell depletion

• Significant hypogammaglobinemia

• IgM levels recover early upon completion, but IgG

and IgA recovery lag behind

• Naïve B cells recovered soon afterward but

memory/plasma cells do not

• Serum cytokines increase upon initiating

blinatumomab cycle 1

• IL-6, IL-10 and TNF

• No rise is observed in subsequent cycles among

responders Topp et al. 2011, Zhu. ASCO 2015, Klinger. 2012.

Zugmaier. 2014

Topp et al. 2011

Blinatumomab in MRD+ALL

MRD+ predicts poor outcomes in ALL

• N = 580

• MRD based on PCR of TCR and Ig gene rearrangement

• Done after induction/consolidation

• Worse outcomes were seen among non-transplanted pts

Probability of CCR Probability of survival

Gokbuget et al. Blood. . 2012;120:1868-76

Phase II MRD+ ALL Pilot Study

CMR = 80%

RFS = 61% on long f/u

4 remained in CR w/o further therapy Topp m et al. 2012. Topp et al. 2011.

• HCT did not improve OS

Topp m et al. 2012. Topp et al. 2011.

MRD+ ALL (BLAST Trial)

Goekbuget et al. ASH 2014. Goekbuget et

al. ASH 2015.

MRD+ ALL (BLAST Trial)

• CMR = 78%

• No significant difference in MRD response across

age, sex, line of treatment or burden of MRD

• 90% of patiens subsequently underwent

allogeneic HCT

• HCT did not improve OS or RFS

• Median OS = 36.5 months

Goekbuget et al. ASH 2014. Goekbuget et

al. ASH 2015.

MRD+ ALL (BLAST Trial)

Goekbuget et al. ASH 2014. Goekbuget et

al. ASH 2015.

Blinatumomab in

Relapsed/Refractory ALL

Phase II Pilot Study in R/R Ph- ALL

Topp MS et al. 2014.

• 52% of responders underwent allogeneic HCT

• Median OS = 9.8 months

• Median RFS = 7.6 months

• Plateau after 1.5 years Topp MS et al. 2014.

Zugmaier G et al. 2015.

Phase II Confirmatory study in R/R Ph- ALL

Topp MS et al. 2015.

Phase II Confirmatory study in R/R Ph- ALL

Topp MS et al. 2015.

• Median RFS = 6.9 months for responders

• Median OS = 6.1 months for all patients

Topp MS et al. 2015.

Topp MS et al. 2015.

ALCANTRARA Study: R/R Ph+ ALL

• Median RFS = 6.7 months

• Median OS = 7.1 months

Martinelli et al. ASH 2015.

Predictors of Response for Blinatumomab

• Response was irrespective of prior chemo-

sensitivity or prior reception of allogeneic HCT

• Similar response in patients who did and did not

receive prior allogeneic HCT

• CR = 45% [N= 64] vs. 42% [n=125]

• Elderly had comparable outcomes when treated

with blinatumomab

Stein et al. ASH 2015. Kantarjian et al. ASCO 2015

Response to Blinatumomab Appears Higher

• Lower pre-treatment marrow blasts

• Lower pre-treatment marrow T regulatory cells

• Higher platelets count

• Higher peak of serum IL-10 after initiating therapy

Kantarjian et al. ASCO 2015. Duell J et al. ASH

2014. Zhu et. ASCO 2015

Outcomes of blinatumomab responders undergoing allogeneic HSCT

N = 34

Median RFS, months NE

95% CI 5.3–NE

RFS events, n

Relapse

Death

Patients censored, n

15

9

6

19

Stein AS. ASBMT 2016

N = 34

Median OS, months NE

95% CI 7.1–NE

OS events, n

Patients censored, n

12

22

Median follow-up: 13.9 (8.5−17.1) months

Median follow-up: 13.4 (9.4–14.6) months

100

80

60

40

20

0 0 1 2 3 4 5 6 7 8 9 10 11

Time Since alloHSCT, months Patients at Risk:

12 13 14 15 16 17 18 19 20 21 22 23

34 33 31 27 26 24 20 19 18 14 12 12 12 11 8 6 6 6 3 3 2 2 1 0

| Censored

100

80

60

40

20

0 0 1 2 3 4 5 6 7 8 9 10 11

Time Since alloHSCT, months Patients at Risk:

12 13 14 15 16 17 18 19 20 21 22 23

34 33 31 30 28 26 24 22 21 17 14 13 13 12 8 6 6 6 4 4 3 3 1 0

| Censored

Rela

pse-F

ree S

urv

ival, %

O

vera

ll S

urv

ival, %

12-month estimate: 54.0%

12-month estimate: 62.1%

Relapse ALL After Blinatumomab

• CD19- ALL relapse occurs

• Extra-medullary relapse/resistance is

observed

• This needs further evaluation to confirm

• Retreatment with blinatumomab is feasible

among relapsed CD19+ ALL

• 36% (4/11) of patients who achieved CR

• 1 patient retreated for the second time and

achieved a 3rd remission

Topp et a;. 2011. Topp et al. 2014. Topp et al. EHA 2015

Blinatumomab Toxicities

• Cytokine Release Syndrome

• Severe CRS usually occurs in R/R setting, especially

with higher disease burden

• Severe form is uncommon in patients treated for MRD

• 2% had grade III in R/R ALL

• With employing pre-dexa & step-wise escalation

• CNS toxicities

• Dose-limiting toxicity, and grade III/IV occurred in 22%

• Presented with symptoms of encephalopathy

• Usually reversible

Blinatumomab Toxicities

• Flu-like symptoms is common and usually

reversible

• Hypogammaglobinemia

• Elevated LFTs

• Infections

Toxicities management

Toxicity Grade Action

CRS

3 Withhold until resolved, then restart at 9mcg/day.

Escalate to 28 mcg/day after 7 days if toxicity doesn’t

recur

4 Discontinue permanently

Neurologic

al toxicity

3

Withhold until resolved to less than Grade 1 for 3 days,

then restart at 9mcg/day. Escalate to 28 mcg/day after 7

days if toxicity doesn’t recur If longer than 7 days to resolve, discontinue permanently

4 Discontinue permanently

Seizure If more than one seizure, discontinue permanently.

Others 3

Withhold until resolved to less than Grade 1 for 3 days,

then restart at 9mcg/day. Escalate to 28 mcg/day after 7

days if toxicity doesn’t recur If longer than 14 days to resolve, discontinue

permanently 4 Consider discontinuing permanently

Conclusion

• Blinatumomab is active in MRD+ and r/r ALL

• Both, Ph+ & Ph- ALL

• Activity is irrespective of chemo-sensitivity and prior

allogeneic HCT reception

• Potentially curative for MRD+ ALL

• Serves as a bridging therapy for allogeneic HCT in

advanced ALL

• Toxicity is manageable and usually reversible

Future Directions: Blinatumomab in ALL

• Optimizing drug delivery

• Incorporating blinatumomab in upfront therapy

• Blinatumomab is an ideal drug to combine with

other novel agents

• Better understand ALL genetics that predict better

response to therapy

BiTE in AML

• CD33 is universally expressed on AML cells

• AMG330 is CD3/CD33 bi-specific antibody

• Preclinical studies show high potency & efficacy in

destroying CD33+ human AML cells

Laszalo GS et al. 2014. Harrington et al. 2015

BiTE in AML