Page 1

Inotuzumab Ozogamycin (I0), a CD22 Monoclonal Antibody Conjugated to Calecheamicin, Given Weekly, Is Active in Refractory-Relapse Acute Lymphocytic Leukemia Jabbour E1, O’Brien S1, Thomas D1, Jorgensen J2, Kebriaei P3, Rytting M1, York S1, Ravandi F1, Kwari M1, Faderl S1, Rios MB1, Cortes J1, Fayad L4, Tarnai R6, Wang S1, Champlin R3, Advani A5, Kantarjian H1 From the Departments of Leukemia1, Hematopathology2, Cellular Therapy and Stem Cell Transplant3 and Lymphoma and Myeloma4 at MD Anderson Cancer Center, Houston, Texas; the Department of Hematology Oncology and Blood Disorders at the Cleveland Clinic5, Cleveland, Ohio; and PPD Immunochemistry6.


Disclosures Elias Jabbour, M.D. Research Support/P.I.

Pfizer

Employee

-

Consultant

-

Major Stockholder

-

Speakers’ Bureau

-

Scientific Advisory Board

-


3

•  The antibody-antigen

complex is rapidly internalized upon binding to CD22

Tumor Cell

•  Calicheamicin is released inside the tumor cell -  Calicheamicin is more

potent than other cytotoxic chemotherapeutic agents •  Calicheamicin binds to DNA, inducing doublestranded DNA breaks

•  Development of DNA

breaks is followed by apoptosis of the tumor cell

3

Nucleus

Internalization

Calicheamicin binds to DNA

CD22

Inotuzumab ozogamicin


Inotuzumab in ALL. Background

•  CD22 expression in more than 90% of ALL •  Response rate 15 to 68% in NHL •  Phase II dose 1.8 g/m2 IV Q 3-4 weeks -  DLT – thrombocytopenia

•  Response rate 57% in 49 pts with R/R ALL •  Preclinical studies: lower more frequent exposure schedules may offer better activity

Advani. JCO 2010;28:2085-93; Kantarjian. Lancet Oncol 2012;13:403-11


Inotuzumab in ALL. Aims

• Evaluate the efficacy of weekly

inotuzumab in refractory-relapsed ALL

• Evaluate the regimen toxicity


Inotuzumab in ALL. Eligibility

• Refractory or relapsed CD22 – positive ALL

• Adults and children were allowed • Bili ≤ 1.5 mg/dL, SGOT/SGPT < 3X ULN, Cr ≤ 2 mg/dL


Inotuzumab in ALL. Design

• Inotuzumab 0.8 mg/m2 on D1, 0.5 mg/m2 on D8 and D15; repeat Q 3-4 wks

•  Responding patients continue for up to 8 cycles

•  Early stopping rule: OR < 40% •  Total 20 patients; later increased to 40


Inotuzumab in ALL. Study Group (N=27) Characteristic

Category

Age (yrs)

≥ 60

9 (33)

PS (ECOG)

≥2

2 (7)

Salvage status

S1, CRD1 < 12 mos

10 (37)

S1, CRD1 ≥ 12 mos

1 (4)

S2

6 (22)

≥ S3

10 (37)

Prior allo SCT

Yes

2 (7)

Karyotype

Ph-positive

8 (30)

T (4;11)

3 (11)

Diploid

4 (15)

Other

12 (44)

> 90

20 (74)

70-89

5 (19)

50-69

2 (7)

% CD22 – positive

No. (%)


Inotuzumab in ALL. Study Group (N=27) Characteristic

Category

Age (yrs)

≥ 60

9 (33)

PS (ECOG)

≥2

2 (7)

Salvage status

S1, CRD1 < 12 mos

10 (37)

S1, CRD1 ≥ 12 mos

1 (4)

S2

6 (22)

≥ S3

10 (37)

Prior allo SCT

Yes

2 (7)

Karyotype

Ph-positive

8 (30)

T (4;11)

3 (11)

Diploid

4 (15)

Other

12 (44)

> 90

20 (74)

70-89

5 (19)

50-69

2 (7)

% CD22 – positive

No. (%)


Inotuzumab in ALL. Definition of Response

•  Complete remission:

•  Disappearance of all clinical and/or radiologic evidence disease •  Neutrophil count > 1.0 x109/L •  Platelet count >100x109/L •  Normal marrow differential (< 5% blasts)

•  CRp:

•  CR except platelets < 100x109/L

•  Marrow CR:

•  CR without recovery of neutrophils or platelet counts

•  Partial remission:

•  Peripheral blood count recovery as for CR, but with •  Decrease in marrow blasts of > 50% and not more than 25% abnormal cells in the marrow


Inotuzumab in ALL. Response (N=27) Response CR CRp CRi (marrow CR) Resistant Death < 4 wks OR: 3 CR + 8 CRp + 3 CRi

No. (%) 3 (11) 8 (30) 3 (11) 11 (41) 2 (7) 14 (52)


Inotuzumab in ALL. CG response (N=10) Parameter

CG Response

CR CRp CRi (marrow CR) CGCR: 2 CR + 5 CRp + 2 CRi

CR 2/2 CR 5/6 CR 2/2 9/10 (90%)

Overall CGCR

9/23 (39%)


Inotuzumab in ALL. MRD (N=14)

Parameter CR CRp CRi (marrow CR) MRD negative: 3 CR + 7 CRp + 1 CRi Overall MRD negative

MRD Negative N (%) 3/3 (100) 7/8 (88) 1/3 (33) 11/14 (79) 11/27 (41)


Inotuzumab in ALL. Progression-free Survival + Response Duration


Inotuzumab in ALL. Overall Survival +/- Censoring at Allo-SCT


Inotuzumab in ALL. Overall Survival by Salvage Number


Inotuzumab in ALL. OS by Treatment Response


Inotuzumab in ALL. Side Effects Side effect

Grade 1-2 (%)

Grade 3-4 (%)

Drug fever (D1-2)

3 (11)

4 (15)

Hypotension (D1-2)

4 (15)

0

1 (4)

0

SGPT/SGOT

6 (22)

2 (7)

Lipase/Amylase

1 (4)

0

LFT Bilirubin Liver enzymes


Inotuzumab in ALL. Prognostic Factors Characteristic

Category

No.

No. Response (%)

Age (yrs)

<60 ≥ 60

9 18

6 8

PS (ECOG)

0-1 ≥2

25 2

13 (52) 1 (50)

Salvage status

S1 S1, CRD1 < 12 mos S1, CRD1 ≥ 12 mos S2 ≥ S3

11 10 1 6 10

8 (73) 8  (70) 1 (100) 3 (50) 3 (30)

Karyotype

Diploid Ph-positive t (4;11) Other

4 8 3 12

2 3 2 7

% CD22 – positive

>90 70-89 50-69

20 5 2

11 (55) 2 (40) 1 (50)

Prior ASCT

Yes

2

(67) (44)

(50) (38) (67) (58)

0


Inotuzumab in ALL. Subsequent Allo SCT

• 8/27 pts underwent ASCT after inotuzumab: - 2/8 pts had a prior transplant

• 0/8 cases of VOD observed


Inotuzumab in ALL. Comparison of Weekly vs Monthly regimen

Parameter OR (%) CGCR (%) MRD negative (%) Median OS (mos) Kantarjian. Lancet Oncol 2012;13:403-11

Inotuzumab QW Q4W N=27 N=49 52 57 90 89 79 63 7 5


Inotuzumab in ALL. Response by Inotuzumab Clearance and AUC Observed Clearance vs Response

Observed Total AUC vs Response


Inotuzumab in ALL. Response by Inotuzumab Maximal Plasma Concentration


Inotuzumab in ALL. Efficacy Comparison to MD Anderson Data Base % ORR Inotuzumab Overall Parameter N=76

Monthly Weekly N=49 N=27

Chemotherapy N=459

Pvalue

Overall

55

57

52

32

<0.001

S1

71

69

73

38

0.004

S2

47

46

50

23

0.032

â&#x2030;Ľ S3

50

67

30

13

<0.001


Inotuzumab in ALL. Conclusions

• ORR 52%: very high for single agent

therapy • Correlation of response with Clearance and AUC • Better safety profile, no VOD, no severe LFTs increase • Plans:

- Pivotal trial of weekly inotuzumab vs standard of care in R/R ALL - Combination with low-intensity chemotherapy in older patients (>60 yrs) with ALL ongoing

Inotuzumab Ozogamycin (I0),  

cancer, tratamiento contra el cancer

Read more
Read more
Similar to
Popular now
Just for you