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3734 Evaluation of the Impact of the Presence of Neutralizing L-Asparaginase Antibodies on the Efficacy and Safety of Graspa in Phase 3 Randomized Trial Versus Native L-Asparaginase in Patients with Relapsed Acute Lymphoblastic Leukemia (NCT01518517)

Acute Lymphoblastic Leukemia: Clinical Studies
Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Poster III
Monday, December 7, 2015, 6:00 PM-8:00 PM
Hall A, Level 2 (Orange County Convention Center)

Yves Bertrand, MD, PhD1*, Andre Baruchel, MD2, Xavier Thomas, MD, PhD3, Nicolas Blin, MD4*, Emmanuelle Tavernier, MD5*, Stephane Ducassou, MD6*, Norbert Vey7, Virginie Gandemer, MD, PhD8, Victoria Cacheux, MD9*, Francoise Mazingue, MD10, Emmanuel Raffoux11*, Genevieve Plat, MD12*, Jose Fernandes, MD13*, Maryline Poiree, MD14*, Luc Fornecker, MD15*, Jean-Louis Stephan, MD16*, Mathilde Hunault, MD, PhD17*, Anne Auvrignon, MD18*, Thibault Leguay, MD19*, Dominique Plantaz, MD, PhD20*, Stephane Lepretre, MD21*, Alina Ferster, MD, PhD22, Isabelle Pellier, MD23*, Emmanuel Plouvier, MD24*, Claudine Schmitt25*, Cecile Bonin, Pharm D26*, Yann Godfrin, PhD26 and Iman El Hariry, MD, PhD26*

1Pediatric hematology, CHU Lyon, Lyon, France
2Pediatric Hematology and Immunology Department, Robert Debré Hospital - APHP and University Paris Diderot, Paris, France
3Hematology Department, Hopital Edouard Herriot, Lyon, France
4Department of Hematology, Nantes University Hospital, Nantes, France
5hematology, Institut de cancerologie de la Loire, Saint Priez en jarez, 42271, France
6Pediatric Hematology, CHU de Bordeaux,Hopital des Enfants-Hôpital Pellegrin, Bordeaux, France
7Hematology, Institut Paoli-Calmettes, Marseille, France
8Pediatric Hematology, Centre Hospitalier Universitaire de Rennes, Rennes, France
9Hematology Clermont Ferrand,, CHU Clermont Ferrand, Clermont Ferrand, France
10hematology, CHRU Lille, Lille, France
11Hematology Department, Saint Louis Hospital, Paris, France
12pediatric hematology, CHU Toulouse, Toulouse, France
13Centre Hospitalier Valenciennes Hematology, Valenciennes, France
14CHU Lenval Pediatric Hematology, Nice, France
15Oncology and Hematology, Hopital de Hautepierre, Strasbourg, France
16Hopital Nord - CHU Saint Etienne, Saint Priez en jarez, 42271, France
17Hematology Department, CHU, Angers, France
18Pediatric Hematology, AP-HP,GH-HUEP Trousseau Hospital, PARIS, France
19Department of Hematology, CHU, Bordeaux, Bordeaux,, France
20Pediatric Hematology, CHU Grenoble site Nord, Grenoble, France
21Hematology, CLCC H Becquerel, Rouen, France
22Dept. of Hémato-oncologie pédiatrique, Children's University Hospital Reine Fabiola, Brussels, Belgium
23CHU Angers, Angers Cedex, France
24pediatric hematology, CHRU Besançon, Besançon, France
25Pediatric Hematology, CHU de nancy, Nancy, France
26ERYTECH Pharma, Lyon, France

Background

Asparaginase is a cornerstone in the treatment of ALL, but its utility is limited by toxicities including hypersensitivity. Clinical allergy is associated with inactivation of asparaginase by antibodies, which can also neutralize asparaginase without any clinical signs of hypersensitivity (silent inactivation). GRASPA (eryaspase - proposed INN) is an L-asparaginase encapsulated into the red blood cells. In a recent Phase III trial, it has shown to prolong the asparaginase activity and significantly reduce the incidence of allergic reactions in pts with relapsed ALL.

Methods

This open, randomized international Phase 3 study enrolled pts with relapsed ALL. The co-primary endpoints were the mean duration of asparaginase (ASPA) activity > 100 IU/L and incidence of hypersensitivity reactions during induction phase. Key secondary endpoints were safety, tolerability, complete remission and minimal residual disease rate, PK, and anti-ASPA antibodies (A-Abs) at baseline. Pts (n=80), aged 1-55 years without prior hypersensitivity were randomized to GRASPA (150 IU/kg, n=26, Arm A) or native L-asparaginase (L-ASP, 10,000 IU/m², n= 28, Arm B). Additionally, 26 pts with prior hypersensitivity were treated with GRASPA in a single stratum (Arm C). All pts received COOPRALL protocol as a backbone chemotherapy. Here we report the impact of A-Abs on safety and efficacy of GRASPA. Assessments were performed at Day 4, 13, 18, and 27 (F1/F2 block), Day 6, 15, and 27 (VANDA block), and Day 6, 12 (R2/R1 block).

Results

At baseline, 23%, 25%, and 58% of pts had +ve A-Abs status in Arms A, B, and C, respectively. The mean duration of total ASPA activity (Days) adjusted for baseline antibody status is presented below, and shows that activity slightly differed with positive status; however, GRASPA maintained higher activity compared to L-ASP:

 

 

GRASPA

L-ASP

GRASPA

L-ASP

GRASPA (Arm C)

Antibody status

Negative

Positive

Negative

Positive

N

20

21

6

7

11

15

Mean (SD)

22.4  (3.6)

10.31  (8.1)

14.17  (5.1)

6.5  (4.0)

18.9  (6.8)

18.4  (6.2)

Median

22.4

8.3

12.2

7.0

21.8

21.7

Min; Max

10.2; 30.7

0.0; 25.0

9.8; 21.8

1.9; 14.0

9.1; 27.9

6.9; 25.0

The incidence of hypersensitivity reactions were 0%, 7/21 (33%), and 2/11 (18%) in pts with negative A-Abs, compared to 0%, 6/7 (85.7%), and 1/15 (7%) in pts with positive A-Abs, in arms A, B and C, respectively.

The CR rate during induction was 75%, 48%, and 64% in pts with negative A-Abs, compared to 33%, 14% and 48% in pts with positive A-Abs, in arms A, B and C, respectively.

Conclusion

These results show that about one third of pts without evidence of prior hypersensitivity have silent A-Abs activation. Positive A-Abs appeared to attenuate the clinical activity in all treatments arms. GRASPA consistently demonstrated activity and improved hypersensitivity regardless of A-Abs status, and therefore, GRASPA is a suitable option for patients with relapsed ALL.

Disclosures: Bertrand: ERYTECH Pharma: Consultancy , Membership on an entity’s Board of Directors or advisory committees . Thomas: ERYTECH Pharma: Consultancy . Vey: Celgene: Honoraria ; Roche: Honoraria ; Janssen: Honoraria . Bonin: ERYTECH Pharma: Employment . Godfrin: ERYTECH Pharma: Employment . El Hariry: ERYTECH Pharma: Employment .

*signifies non-member of ASH