GRASPA (Erythrocytes Encapsulating L-asparaginase) in Pat... | NCT01518517

Label	Type	Description	Intervention Names
GRASPA	Experimental	Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles)	Drug: GRASPA
reference L-asparaginase	Active Comparator	For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles).	Drug: L-asparaginase

Name	Type	Description	Arm Group Labels	Other Names
GRASPA	Drug	one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	GRASPA

Measure	Description	Time Frame
Duration of Asparaginase Activity >100 U/L During Induction	Co-primary efficacy endpoint: duration in days of asparaginase activity >100 U/L in whole blood during the induction treatment phase: last available date/time of activity >100 UI/L before activity drops below 100 U/L - date/time of first activity >100 UI/L. Asparaginase activity is compared for GRASPA versus native ASNase to demonstrate the non-inferiority of GRASPA.	Induction treatment period (i.e. 28 days)
Allergic Reaction During Induction Phase	Co-primary safety endpoint: allergic reaction regardless of grade during induction phase. Only those reactions that were reported in relation to the treatment to which the patient was randomised were counted.	Induction treatment period (i.e. 28 days)

Measure	Description	Time Frame
Complete Remission (CR)	CR is defined as, no physical evidence of leukemia, normal CBC, cytologic remission: normally regenerating bone marrow, with <5% leukemic blasts and the absence of detectable CNS or extramedullary disease, evaluated with physical examination and CSF findings, at the end of induction	Induction treatment period (i.e. 28 days)

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Patient from 1 to 55 years old (Children and adolescents from 1 to 17 years/ Adults from 18 to 55 years)
Patients with 1st ALL relapse, which could be either isolated bone marrow relapse, or combined (medullary and extra-medullary) relapse, or extra-medullary isolated relapse; or lymphoblastic lymphoma (excepted Burkitt lymphoma) OR Failure to ALL first line treatment (no complete remission obtained)
Patient previously treated with free E.Coli L-asparaginase form or pegylated one
Performance Status ≤ 2 (WHO score)
Patient informed and consent provided (the 2 parents need to consent when children are below 18)

Exclusion Criteria:

ALL t(9;22) and/or BCR-ABL positive (Philadelphia chromosome positive)
Patient with 2nd relapse and over
Women of childbearing potential without effective contraception as well as pregnant or breast feeding women
Patient unable to receive treatments used in global chemotherapy protocols, due to general or visceral conditions such as:Severe cardiac impairment (NYHA grade 3 or 4 cardiomyopathy)/Serum creatinine 2 x ULN unless related to ALL /ALT or AST 5 x ULN unless related to ALL /Pancreatitis history /Other malignancy that ALL / Severe Infection, HIV positive, active hepatitis related to B or C virus infection / Trisomy 21 / Other serious conditions according to investigator's opinion
Known grade 4 allergic reaction to E.Coli L-asparaginase (according NCI-CTCAE, Version 3.0)
History of grade 3 transfusional incident
Presence of specific anti-erythrocyte antibodies preventing from getting a compatible erythrocyte concentrate for the patient
Patient under concomitant treatment likely to cause hemolysis
Patient undergoing yellow fever vaccination
Patient under phenytoin treatment
Patient included in previous clinical study less than 6 weeks ago

Name	Affiliation	Role
Yves Bertand, MD		Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Hopital Des Enfants Reine Fabiola		Brussels			Belgium
Chr de La Citadelle

ID	Title	Description
FG000	GRASPA (Non Allergic Population)	Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy

Arm/Group Information

ID	Title	Description
BG000	GRASPA (Non Allergic Population)	Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
BG001	Reference L-asparaginase (Non Allergic Population	For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy
BG002	GRASPA (Allergic Population)	Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
BG003	Total	Total of all reporting groups

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Duration of Asparaginase Activity >100 U/L During Induction

Co-primary efficacy endpoint: duration in days of asparaginase activity >100 U/L in whole blood during the induction treatment phase: last available date/time of activity >100 UI/L before activity drops below 100 U/L - date/time of first activity >100 UI/L. Asparaginase activity is compared for GRASPA versus native ASNase to demonstrate the non-inferiority of GRASPA.

Only non allergic population evaluated for efficacy (i.e. 2 randomized arms). Only patient receiving treatment are considered.

Posted

Mean

95% Confidence Interval

days

Induction treatment period (i.e. 28 days)

ID	Title	Description
OG000	GRASPA Non Allergic	Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
OG001	Reference L-asparaginase	For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy

Units	Counts
Participants	OG00026 OG00128

Title

Denominators

Categories

Title	Measurements
	OG00018.9(16.7 to 21.0) OG0018.5(6.0 to 11.1)

Primary

Allergic Reaction During Induction Phase

Co-primary safety endpoint: allergic reaction regardless of grade during induction phase. Only those reactions that were reported in relation to the treatment to which the patient was randomised were counted.

Only patient receiving treatment are considered.

Posted

Number

reactions

Induction treatment period (i.e. 28 days)

ID	Title	Description
OG000	GRASPA (Non Allergic Population)	Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
OG001	Reference L-asparaginase (Non Allergic Population)	For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy

Secondary

Complete Remission (CR)

CR is defined as, no physical evidence of leukemia, normal CBC, cytologic remission: normally regenerating bone marrow, with <5% leukemic blasts and the absence of detectable CNS or extramedullary disease, evaluated with physical examination and CSF findings, at the end of induction

Posted

Count of Participants

Participants

Induction treatment period (i.e. 28 days)

ID	Title	Description
OG000	GRASPA (Non Allergic Population)	Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
OG001	Reference L-asparaginase (Non Allergic Population)	For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy

Secondary

Overall Survival (OS)

OS is defined as the time from randomisation or date of inclusion (allergic arm) until death due to any cause. Patients who did not die were censored at 36 months of follow-up or the date of the patient's last visit, whichever was earlier.

Entries given below are number of patients dying in each group

Posted

Count of Participants

Participants

Overall trial period to 36 months

ID	Title	Description
OG000	GRASPA (Non Allergic Population)	Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
OG001	Reference L-asparaginase (Non Allergic Population)	For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy

Secondary

Event Free Survival

EFS is defined as the time from randomisation until the first documented sign of disease relapse or death due to any cause. In line with CHMP guidance (CHMP, 2016), patients who did not achieve CR at the end of the induction period were considered to have had an event at time 0. For the patients enrolled in the GRASPA allergic arm, EFS is defined from the date of inclusion in the study.

Patients who achieved CR at the end of induction and who did not have a documented relapse or death due to any cause were censored at 36 months of follow-up or the date of the patient's last visit, whichever was earlier.

Entries below are the numbers of patients with events in each treatment group

Posted

Count of Participants

Participants

Overall trial period to 36 months

ID	Title	Description
OG000	GRASPA (Non Allergic Population)	Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
OG001	Reference L-asparaginase (Non Allergic Population)	For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	GRASPA (Non Allergic Population)	Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	9	26	23	26	26	26
EG001	Reference L-asparaginase (Non Allergic Population)	For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy	12	28	26	28	28	28
EG002	GRASPA (Allergic Population)	Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	14	26	23	26	26	26

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Leukaemia recurrent	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (17.1)	Systematic Assessment	EG0009 events8 affected26 at risk EG0019 events9 affected28 at risk EG0028 events7 affected26 at risk
drug hypersensitivity	Immune system disorders	MedDRA (17.1)	Systematic Assessment	EG0003 events3 affected26 at risk EG0017 events7 affected28 at risk EG0023 events3 affected26 at risk
Mucosal inflammation	Respiratory, thoracic and mediastinal disorders	MedDRA (17.1)	Non-systematic Assessment	EG0003 events3 affected26 at risk EG0014 events4 affected28 at risk EG0025 events5 affected26 at risk
lung disorder	Respiratory, thoracic and mediastinal disorders	MedDRA (17.1)	Non-systematic Assessment	EG0000 events0 affected26 at risk EG0012 events2 affected28 at risk EG0020 events0 affected26 at risk
Febrile bone marrow aplasia	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment	EG00023 events11 affected26 at risk EG00110 events7 affected28 at risk EG0027 events5 affected26 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected26 at risk EG0010 events0 affected28 at risk EG0023 events3 affected26 at risk
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment	EG0004 events4 affected26 at risk EG0019 events5 affected28 at risk EG0027 events4 affected26 at risk
Cerebral haemorrhage	Nervous system disorders	MedDRA (17.1)	Non-systematic Assessment	EG0000 events0 affected26 at risk EG0010 events0 affected28 at risk EG0021 events1 affected26 at risk
Mucosal inflammation	General disorders	MedDRA (17.1)	Non-systematic Assessment	EG00015 events15 affected26 at risk EG0018 events8 affected28 at risk EG0026 events6 affected26 at risk
Pancreatitis	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected26 at risk EG0013 events3 affected28 at risk EG0021 events1 affected26 at risk
Intestinal ischaemia	Gastrointestinal disorders	MedDRA (17.1)	Non-systematic Assessment	EG0000 events0 affected26 at risk EG0011 events1 affected28 at risk EG0020 events0 affected26 at risk
Renal failure	Renal and urinary disorders	MedDRA (17.1)	Non-systematic Assessment	EG0001 events1 affected26 at risk EG0011 events1 affected28 at risk EG0020 events0 affected26 at risk
Sepsis	Infections and infestations	MedDRA (17.1)	Non-systematic Assessment	EG0004 events4 affected26 at risk EG0012 events2 affected28 at risk EG0020 events0 affected26 at risk
Anal Abscess	Infections and infestations	MedDRA (17.1)	Non-systematic Assessment	EG0000 events0 affected26 at risk EG0012 events2 affected28 at risk EG0020 events0 affected26 at risk
Bacteraemia	Infections and infestations	MedDRA (17.1)	Non-systematic Assessment	EG0000 events0 affected26 at risk EG0010 events0 affected28 at risk EG0022 events2 affected26 at risk
Septic shock	Infections and infestations	MedDRA (17.1)	Non-systematic Assessment	EG0003 events3 affected26 at risk EG0011 events1 affected28 at risk EG0021 events1 affected26 at risk
Staphylococcal sepsis	Infections and infestations	MedDRA (17.1)	Non-systematic Assessment	EG0003 events3 affected26 at risk EG0011 events1 affected28 at risk EG0020 events0 affected26 at risk
Fusarium infection	Infections and infestations	MedDRA (17.1)	Non-systematic Assessment	EG0000 events0 affected26 at risk EG0010 events0 affected28 at risk EG0021 events1 affected26 at risk
Human herpesvirus 6 infection	Infections and infestations	MedDRA (17.1)	Non-systematic Assessment	EG0000 events0 affected26 at risk EG0010 events0 affected28 at risk EG0021 events1 affected26 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Haematoma	Vascular disorders	MedDRA (17.1)	Systematic Assessment	EG0002 events2 affected26 at risk EG0010 events0 affected28 at risk EG0020 events0 affected26 at risk
Drug hypersensitivity	Immune system disorders	MedDRA (17.1)	Systematic Assessment	EG0008 events7 affected26 at risk EG00121 events18 affected28 at risk EG00221 events17 affected26 at risk
Graft versus host disease	Immune system disorders	MedDRA (17.1)	Systematic Assessment	EG0002 events2 affected26 at risk EG0012 events2 affected28 at risk EG0020 events0 affected26 at risk
Pyrexia	General disorders	MedDRA (17.1)	Systematic Assessment	EG0003 events2 affected26 at risk EG0010 events0 affected28 at risk EG0024 events4 affected26 at risk
Asthenia	General disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected26 at risk EG0010 events0 affected28 at risk EG0022 events2 affected26 at risk
Depression	Psychiatric disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected26 at risk EG0012 events2 affected28 at risk EG0021 events1 affected26 at risk
Allergic transfusion reaction	Injury, poisoning and procedural complications	MedDRA (17.1)	Systematic Assessment	EG0002 events2 affected26 at risk EG0012 events2 affected28 at risk EG0022 events2 affected26 at risk
Transaminases increased	Investigations	MedDRA (17.1)	Systematic Assessment	EG00040 events16 affected26 at risk EG00133 events16 affected28 at risk EG00221 events15 affected26 at risk
Hypokalaemia	Investigations	MedDRA (17.1)	Systematic Assessment	EG00013 events13 affected26 at risk EG00112 events11 affected28 at risk EG00212 events9 affected26 at risk
Antithrombin III decreased	Investigations	MedDRA (17.1)	Systematic Assessment	EG0007 events4 affected26 at risk EG00144 events20 affected28 at risk EG00211 events9 affected26 at risk
Gamma-glutamyltransferase increased	Investigations	MedDRA (17.1)	Systematic Assessment	EG00020 events8 affected26 at risk EG00115 events14 affected28 at risk EG00216 events7 affected26 at risk
Blood albumin decreased	Investigations	MedDRA (17.1)	Systematic Assessment	EG0005 events5 affected26 at risk EG00115 events11 affected28 at risk EG0027 events6 affected26 at risk
Hyponatraemia	Investigations	MedDRA (17.1)	Systematic Assessment	EG0006 events6 affected26 at risk EG00119 events10 affected28 at risk EG0028 events7 affected26 at risk
blood bilirubin increased	Investigations	MedDRA (17.1)	Systematic Assessment	EG0006 events4 affected26 at risk EG00111 events9 affected28 at risk EG0028 events7 affected26 at risk
Hyperglycaemia	Investigations	MedDRA (17.1)	Systematic Assessment	EG0006 events5 affected26 at risk EG00112 events7 affected28 at risk EG00212 events6 affected26 at risk
Activated partial thromboplastin time prolonged	Investigations	MedDRA (17.1)	Systematic Assessment	EG0002 events1 affected26 at risk EG0017 events4 affected28 at risk EG0025 events5 affected26 at risk
Hypocalcaemia	Investigations	MedDRA (17.1)	Systematic Assessment	EG0003 events3 affected26 at risk EG0014 events4 affected28 at risk EG0023 events1 affected26 at risk
Blood triglycerides increased	Investigations	MedDRA (17.1)	Systematic Assessment	EG0004 events2 affected26 at risk EG0014 events3 affected28 at risk EG0023 events3 affected26 at risk
Prothrombin level decreased	Investigations	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected26 at risk EG0015 events3 affected28 at risk EG0020 events0 affected26 at risk
Blood lactate dehydrogenase increased	Investigations	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected26 at risk EG0012 events2 affected28 at risk EG0021 events1 affected26 at risk
Blood potassium increased	Investigations	MedDRA (17.1)	Systematic Assessment	EG0003 events3 affected26 at risk EG0012 events2 affected28 at risk EG0020 events0 affected26 at risk
C-reactive protein increased	Investigations	MedDRA (17.1)	Systematic Assessment	EG0003 events2 affected26 at risk EG0010 events0 affected28 at risk EG0020 events0 affected26 at risk
Leukopenia	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment	EG00076 events25 affected26 at risk EG00181 events27 affected28 at risk EG00274 events26 affected26 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment	EG00069 events24 affected26 at risk EG00171 events26 affected28 at risk EG00271 events22 affected26 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment	EG00089 events24 affected26 at risk EG00193 events25 affected28 at risk EG00281 events25 affected26 at risk
Lymphopenia	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment	EG00043 events21 affected26 at risk EG00143 events23 affected28 at risk EG00249 events20 affected26 at risk
Febrile bone marrow aplasia	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment	EG00017 events5 affected26 at risk EG00117 events7 affected28 at risk EG00213 events8 affected26 at risk
Hypofibrinogenaemia	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment	EG00011 events9 affected26 at risk EG00137 events19 affected28 at risk EG00212 events11 affected26 at risk
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment	EG0004 events1 affected26 at risk EG0019 events5 affected28 at risk EG0026 events3 affected26 at risk
Anaemia	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment	EG0009 events7 affected26 at risk EG00114 events9 affected28 at risk EG0026 events6 affected26 at risk
Bone marrow failure	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment	EG0002 events2 affected26 at risk EG0014 events3 affected28 at risk EG0021 events1 affected26 at risk
Blood phosphorus decreased	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment	EG0005 events4 affected26 at risk EG0013 events3 affected28 at risk EG0023 events3 affected26 at risk
Pancreatitis	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected26 at risk EG0012 events2 affected28 at risk EG0020 events0 affected26 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0002 events1 affected26 at risk EG0012 events2 affected28 at risk EG0022 events2 affected26 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0003 events3 affected26 at risk EG0013 events2 affected28 at risk EG0022 events2 affected26 at risk
Rectal haemorrhage	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected26 at risk EG0012 events2 affected28 at risk EG0020 events0 affected26 at risk
Vomiting	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0004 events4 affected26 at risk EG0011 events1 affected28 at risk EG0021 events1 affected26 at risk
Hepatotoxicity	Hepatobiliary disorders	MedDRA (17.1)	Systematic Assessment	EG0002 events2 affected26 at risk EG00112 events6 affected28 at risk EG0029 events8 affected26 at risk
Cholestasis	Hepatobiliary disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected26 at risk EG0010 events0 affected28 at risk EG0022 events2 affected26 at risk
renal failure acute	Renal and urinary disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected26 at risk EG0010 events0 affected28 at risk EG0022 events2 affected26 at risk
Drug hypersensitivity	Skin and subcutaneous tissue disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected26 at risk EG0011 events1 affected28 at risk EG0022 events2 affected26 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA (17.1)	Systematic Assessment	EG0002 events2 affected26 at risk EG0013 events2 affected28 at risk EG0020 events0 affected26 at risk
Sepsis	Infections and infestations	MedDRA (17.1)	Systematic Assessment	EG0003 events3 affected26 at risk EG0011 events1 affected28 at risk EG0021 events1 affected26 at risk

ID	Term
D054198	Precursor Cell Lymphoblastic Leukemia-Lymphoma
D012008	Recurrence

ID	Term
D007945	Leukemia, Lymphoid
D007938	Leukemia
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D006402	Hematologic Diseases
D006425	Hemic and Lymphatic Diseases
D008232	Lymphoproliferative Disorders
D008206	Lymphatic Diseases
D007160	Immunoproliferative Disorders
D007154	Immune System Diseases
D020969	Disease Attributes
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms

ID	Term
D000581	Amidohydrolases
D006867	Hydrolases
D004798	Enzymes
D045762	Enzymes and Coenzymes