Inotuzumab Oxagamicin in ALL

Chiara Sartor, MD

Institute of Onco-hematology

L. e A. Seràgnoli Dipartimento d Medicina Specialistica,

Diagnostica e Sperimentale

10° Seminario annuale dei RICERCATORI

Azienda Ospedaliera, Università egiovani scienziati insieme per la ricerca applicata e la diagnostica avanzata

13 Gennaio 2014ore 8.00 - 18.30

Aula MurriComplesso Didattico “A. Murri” - Area S.OrsolaPoliclinico S.Orsola-Malpighi - Bologna

Partecipazione

Per partecipare al seminario è necessaria lapre-iscrizione sul sito web: www.crba.it,

oppure inviando richiesta all’indirizzo e-mail: crba@aosp.bo.it

Data la limitata capienza dell’aula, saranno accettate le iscrizioni fino ad esaurimento dei posti disponibili.

La partecipazione è gratuita.

Accreditamento ECM

E’ stata inoltrata richiesta alla Regione E. Romagna per la concessione dei crediti E.C.M. per i dipendenti

dell’Azienda Ospedaliera S. Orsola-Malpighi appartenenti alla seguenti categorie: medici, biologi,

biotecnologi, chimici,tecnici sanitari di laboratorio biomedico.

Alla consegna del questionario E.C.M. verrà rilasciato il materiale didattico inerente gli argomenti trattati

nel corso del seminario.

Al termine dei lavori verrà rilasciatoun attestato di partecipazione.

Segreteria Scientifica e Organizzativa:

Vilma Mantovani, CRBA

e-mail: crba@aosp.bo.it

Relatori e Moderatori

Adelia Aquilano U.O. Nefrologia S. Stefoni, Policlinico S.Orsola-Malpighi

Maurizio Baldassarre U.O. Semeiotica Medica M. Bernardi, Policlinico S.Orsola-Malpighi

Massimiliano Bonafè Dip. Medicina Specialistica, Diagnostica, Sperimentale e CRBA, Università di Bologna

Elisa Boschetti U.O. Medicina Interna R. Corinaldesi, Policlinico S.Orsola-Malpighi

Elisa Brighenti Dip. Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna

Paolo Caraceni U.O. Semeiotica Medica M. Bernardi e CRBA, Policlinico S.Orsola-Malpighi

Giovanna Cenacchi Dip. Scienze Biomediche e Neuromotorie, Università di Bologna

Pasquale Chieco CRBA, Policlinico S.Orsola-Malpighi

Leonarda D’Angelo U.O. Gastroenterologia G. Bazzoli, Policlinico S.Orsola-Malpighi

Sabrina De Carolis Dip. Medicina Specialistica, Diagnostica, Sperimentale Università di Bologna

Roberto De Giorgio U.O. Medicina Interna R. Corinaldesi e CRBA, Policlinico S.Orsola-Malpighi

Chiara Donadei U.O. Nefrologia S. Stefoni, Policlinico S.Orsola-Malpighi

Flaminia Fanelli U.O. Endocrinologia R. Pasquali, Policlinico S.Orsola-Malpighi

Chiara Fazio U.O. Gastroenterologia G. Bazzoli, Policlinico S.Orsola-Malpighi

Francesca Fornari U.O. Medicina Interna L. Bolondi e CRBA, Policlinico S.Orsola-Malpighi

Paolo Garagnani Dip. Medicina Specialistica, Diagnostica, Sperimentale Università di Bologna

Fiorella Giancola U.O. Medicina Interna R. Corinaldesi, Policlinico S.Orsola-Malpighi

Felice Giangaspero Dip. Scienze Radiologiche, Oncologiche e Ana-tomopatologiche, Ospedale Umberto I, Univer-sità La Sapienza di Roma e IRCCS Neuromed

Catia Giovannini U.O. Medicina Interna L. Bolondi e CRBA, Policlinico S.Orsola-Malpighi

Laura Gramantieri U.O. Medicina Interna L. Bolondi e CRBA, Policlinico S.Orsola-Malpighi

Gaetano La Manna U.O. Nefrologia S. Stefoni e CRBA, Policlinico S.Orsola-Malpighi

Vilma Mantovani U.O. Genetica Medica M. Seri e CRBA, Policlinico S.Orsola-Malpighi

Elena Marasco CRBA, Policlinico S.Orsola-Malpighi

Sara Marinelli U.O. Medicina Interna L. Bolondi, Policlinico S.Orsola-Malpighi

Marina Martello U.O. Ematologia M. Cavo Policlinico S.Orsola-Malpighi

Giovanni Martinelli U.O. Ematologia M. Cavo e CRBA, Policlinico S.Orsola-Malpighi

Roberta Mazza U.O. Endocrinologia R. Pasquali, Policlinico S.Orsola-Malpighi

Marco Mezzullo U.O. Endocrinologia R. Pasquali, Policlinico S.Orsola-Malpighi

Lorenzo Montanaro Dip. Medicina Specialistica, Diagnostica, Sperimentale e CRBA, Università di Bologna

Marina Naldi Centro Interdipartimentale Ricerche Biologiche, Università di Bologna

Uberto Pagotto U.O. Endocrinologia R. Pasquali e CRBA, Policlinico S.Orsola-Malpighi

Valentina Papa U.O. Anatomia e Istologia Patologica Grigioni ff, Policlinico S.Orsola-Malpighi

Cristina Papayannidis U.O. Ematologia M. Cavo, Policlinico S.Orsola-Malpighi

Anna Prossomariti U.O. Gastroenterologia G. Bazzoli, Policlinico S.Orsola-Malpighi

Luigi Ricciardiello U.O. Gastroenterologia G. Bazzoli e CRBA, Policlinico S.Orsola-Malpighi

Veronica Salvatore U.O. Medicina Interna L. Bolondi, Policlinico S.Orsola-Malpighi

Simona Tavolari SSD Oncologia Medica, Policlinico S.Orsola-Malpighi

Federica Tomassoni U.O. Nefrologia S. Stefoni, Policlinico S.Orsola-Malpighi

Relatori e Moderatori

ü  In contrast with pediatric patients, the outcome in adults remains dismal, despite high initial complete remission (CR) – long term remission @5y 30%, survival @5y after relapse 7%

ü  Further intensification of chemo-regimens means increasing already significant toxicity

ü  Antibody therapies represent a promising approach

ALL status of the art

Cheson et al. NEJM 2008; 359:613-626

Lymphoblasts express various targetable surface antigens: CD19, CD20, CD22, CD52 Ideal target: Ø High percentage of blasts expressing the antigen Ø High density of antigen expression Ø Lack of expression on normal cells

ADC- Antibody Drug Conjugate

1. Target

2. Antibody

3. Linker

4. Payload

Mechanisms of antibodies in ALL treatment: •  Naked antibodies •  Immunotoxins •  BiTE

4. Payload = calicheamicin – DNA damaging agent – attacks cancer cell irrespectively of cell cycle resulting in DNA double stranded breaks and cell death

1. Target: CD22+ lymphoblasts

2. Antibody: antiCD22 – humanized IgG4 – designed to have no activity on its own

3. Linker: 4-(4-acetylephenoxy)butanoic acid linker – pH dependend à cleaved in acid environment

CD22 expression at specific time-points of B-cell development

CD22 is expressed at low levels on immature B cells

CD22

CD22 is expressed at higher levels on mature B cells

Overall, most circulating IgM-positive, IgD-positive human B cells (including activated B cells

and memory B cells) strongly express CD22, whereas differentiated plasma cells do not

CD22 is absent from differentiated plasma cells

B-lymphocyte precursor

Pro B Pre B Immature B

IgM

Transitional B

IgM IgD

Mature B

IgM IgD Memory B cell

Plasmablast Plasma cell

Shor B et al. Mol Immunol 2015;67;107–116; Blüml S et al. Arthritis Res Ther 2013;15 (Suppl 1):S4

CD22: role and therapeutic target Ø  CD22 is a 135-kDa B-cell-specific adhesion molecule preferentially expressed on

mature B lymphocytes Ø  normal function of CD22 is to regulate signal transduction of the surface

immunoglobulin receptors on B cells.

Ricard AD. Clin Cancer Res 2011;17(20):6417–6427 Gudowius S, et al. Klin Padiatr 2006;218(6):327–333

Why is CD22 a

good target?

expressed on the cells of

the majority of B-lymphocyte malignancies In a study of 181

patients with B-cell precursor

ALL, CD22 was expressed on the surface of >90% of leukemic blast

one of the better internalizing molecules

among several B-lymphoid

lineagespecific surface antigens

not shed into the

extracellular environment

Memory B cells do not

express CD22.

not expressed on

hematopoietic stem cells or

normal tissues

Inotuzumab Ozagamicin (IO) in ALL Ø  On the basis of promising pre-clinical data of dose-dependent apoptotic effect on B-ALL

cell lines and primary ALL cells IO has been studied in clinical trials in 2 dosing strategies at MDACC:

Ø  IO 1.8 mg/m2 IV every 3-4 weeks

Ø  IO weekly dosing schedule (0.8 mg/m2 day 1, 0.5 mg/m2 day 8 and 15) every 3-4 weeks; same cumulative dose

MONTHLY SCHEDULE à up to 8 cycles Cycle 1 Cycle 2 IO 1.8 mg/m2 IO 1.8 mg/m2 D1 D8 D15 D22 D29 D8 D15 D22 WEEKLY SCHEDULE à up to 8 cycles Cycle 1 Cycle 2 IO 0.8 mg/m2 IO 0.5 mg/m2 IO 0.5 mg/m2 IO 0.8 mg/m2 IO 0.5 mg/m2 IO 0.5 mg/m2 D1 D8 D15 D22 D29 D8 D15 D22

Kantarjan et al. Lancet Oncol 2012; 13: 403–11 Kantarjan et al. Cancer 2013;

Inotuzumab in R/R ALL

ü  Phase 2, single-center trial

ü  Short course of steroid or cytoreduction with hydroxyurea was admitted before cycle

ü  Premedication to IO: 650 mg paracetamol orally, 10–25 mg diphenhydramine, and 25 mg hydrocortisone intra venously

ü  Suitability for alloSCT was assessed

ü  Patients who achieved a CR or bone marrow CR afer 1 – 2 course were allowed 2 additional courses. Maximum of 4 cycles. 68% ≥ S2

Kantarjian H et al. Cancer 2013;119:2728-2736

Inotuzumab in R/R ALL – MDAACC results

Kantarjian H et al. Cancer 2013;119:2728-2736

Response Single dose n°=49

Weekly n°=41

Overall n°=90

CR 9 (18) 8 (20) 17 (19)

CRp 14 (29) 13 (32) 27 (30)

CRi, bone marrow CR 5 (10) 3 (7) 8 (9)

PR 0 0 0

Resistant 19 (39) 15 (37) 34 (38)

Death < 4 weeks 2 (4) 2 (5) 4 (4)

ORR 28 (57) 26 (59) 52 (58)

•  Response rates weekly vs monthly similar •  Median CRD 5 - 6 months Median survival 5 - 7.3 months à responde duration was brief •  Best RR in S1 e S2 •  ORR 58% MRD 72%

Deep molecular remissions allow opportunity to transplant

Survival by salvage status

Kantarjian H et al. Cancer 2013;119:2728-2736

Survival by achievement of MRD

Kantarjian H et al. Cancer 2013;119:2728-2736

Adverse eventes weekly vs monthly

Weekly Single-dose

G1-2 G3-4 G1-2 G3-4

Day 1-2 drug-related fever 3 6 20 9

Day 1-2 drug-related hypotension 6 0 12 1

↑ bilirubin 2 0 12 2

↑ AST/ALT 9 2 27 1

↑amylase/lipase 1 0 0 1

ü  Less frequent toxicity with weekly dose probably related to peak levels

ü  Peak levels not associated with worse response

ü  Weekly IO as effective and less toxic

Targeting CD22 in R/R ALL phase I/II

Job bag #

Phase I/II B1931010 trial (multi-institution)2,3

N=35 • Patients with R/R ALL • CD22-positive • Second and later salvage settings

Part 1 Inotuzumab ozogamicin*

0.8–2.0 mg/m2 per cycle

(2–3 weekly doses per 28-day cycle for a maximum of six

cycles)

Part 2 Inotuzumab ozogamicin*

1.8 mg/m2 per cycle (3 weekly doses per 28-day cycle for a maximum of six

cycles)

CR + CRi: 65.7%

MRD -: 78%

1. Dahl J et al. Expert Rev Hematol 2016 [Epub]; 2. Advani AS et al. ASH 2014 (abstract 2255)

*Fractionated dosing only

INO-VATE ALL: IO vs chemo in ALL salvage

•  Phase 3 multi-center study •  INO-VATE ALL: NCT 01564784

Relapsed/Refractory CD22positive ALL

Ph+/Ph- Eligible for 1st or 2nd salvage therapy

Inotuzumab Ozagamicin IO IO maximum dose 1.8 mg/m2 per cycle

(21-28 day cycle)

- Day 1 IO 0.8 mg/m2

- Day 8 and day 22 IO 0.5 mg/m

Investigator’s choice - SOC: - FLAG: Fludarabine, cytarabine and G-

CSF up to 4 cycles - Cytarabine and mytoxantrone for up to 4

cycle HIDAC: high dose cytarabine up to 12

doses

Randomization 1:1

Stratification: •  Duration of 1st remission >12 mos

vs <12 months •  S1 vs S2 •  Age >55 vs <55y

DeAngelo D et al. EHA 2015 (abstract LB2073).

Allogenic stem cell transplant encouraged afetr CR/CRi

INO-VATE results Primary end-points: • CR/CRi • OS Secondary end-points: • MRD negativity in patients achieving CR/CRi (<0.01% FCM) • Safety • PFS • Duration of remission • AllogenicSCT rate

CR/CRia: 80.7% (95% CI: 72-88)

MRD – neg in pts with CR/CRi: 78.4% (95% CI: 68-87)

CR/CRia: 33.3% (95% CI: 24-44)

MRD – neg in pts with CR/CRi: 28.1% (95% CI: 14-47)

Inotuzumab ozogamicin weekly dosing:

Investigator’s choice: FLAG or Cytarabine + mitoxantrone or HiDAC (high-dose Ara-C)

DeAngelo D et al. EHA 2015 (abstract LB2073).

•  Most common grade ≥3 AEs were haematological cytopenias

•  Grade ≥3 hepatobiliary AEs occurred in 9% of the inotuzumab arm vs 3% in the SOC arm

•  Any grade veno-occlusive liver disease occurred in 15 vs 1 patients, respectively

IO and alloSCT – VOD risk

•  Monthly INO: VOD suspected in 6 pts (23%): 2 cases confirmed by biopsy; 2 pts were receiving 2nd SCT; 5 cases were fatal (19%)

•  Weekly INO: 1 case of VOD confirmed by Doppler, resolved

•  SCT Conditioning for 5 VOD cases •  • BU/Clo (n=1), BU/Clo/thiotepa (n=2), flu/mel/thiotepa (n=2)

•  Interval between INO and SCT did not appear to influence VOD risk: median, 40 d in VOD group vs. 36 d in non-VOD group.

•  No apparent correlation between # INO courses and VOD

•  VOD Risk Factors during SCT after monthly INO

1.  2 alkylating agents 5/13 2.  1 alkylating agent 1/19 P = .02

Kebriaei P et al. Clinical Lymphoma, Myeloma & Leukemia, 2013

IO in association with chemotherapy

ü  Frontline Inotuzumab Ozogamicin in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) for Older Patients with Acute Lymphoblastic Leukemia (ALL)

ü  Patients ≥60 years with newly-diagnosed B-ALL ü  Study design:

Mini-HyperCVAD

Mini-MTX-ARAC

Inotuzumab: first 6 pts received 1.3 mg/m2 for cycle 1 followed by 0.8 mg/m2 for subsequent cycles; Pts 7 onwards received 1.8 mg/m2 for Cycle 1 followed by 1.3 mg/m2 for subsequent cycles.

IO with low-intensity mini-hyper-CVD chemotherapy is safe and shows encouraging results (97% CR/CRp) in the frontline setting in older patients with ALL

Jabbour, Blood ASH 2015

Conclusions

ü  The cell surface antigen, CD22 is highly expressed in B-cell ALL

ü  CD22 exhibits features that make it an ideal therapeutic target in ALL, particularly its ability to internalise on antibody binding

ü  Inotuzumab Ozagamicin is being investigated in ALL with promising results both as single agent and in association with chemotherapy

ü  Role of Inotuzumab and VOD in allogenic stem cell transplant remains an issue

Acknowledgments

Clinical  Team                                                                                                                                                                      Cris%na  Papayannidis  Stefania  Paolini  Sarah  Parisi  Maria  Chiara  Abbenante  

Molecular  Biology  Team                                                                                                                                                          Emanuela  O;aviani  Simona  Soverini  Anna  Ferrari  Viviana  Guadagnuolo  Claudia  Venturi  Margherita  Perricone  Valen%na  Robustelli  Eugenia  Franchini  Elisa  Zuffa  Giorgia  SimoneE  Caterina  de  BenediEs  Teresa  Bocchicchio  Antonella  Padella  Andrea  Ghiselli  

Data  Managers/Project  Managers  Federica  FrabeE  Elena  Ten%  Cinzia  Bonajuto  

Prof  Giovanni  Mar;nelli  

Cytogene;cs  Nicole;a  Testoni  Carmen  Baldazzi  Simona  LuaE  Giulia  Marzocchi                                                                                                Prof  Michele  Cavo