A Retrospective Chart Review of UK Patients With Relapsed/Refractory Acute Lymphoblastic Leukaemia Treated With Inotuzumab Ozogamicin, a Real World Research Study
Conditions: Precursor Cell Lymphoblastic Leukemia-Lymphoma
Sponsor: Pfizer

INOTUZUMAB 
X9001222 NON-INTERVENTIONAL STUDY PROTOCOL 
V1.0, 18 July 2019 
 
PFIZER CONFIDENTIAL  
 
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NON-INTERVENTIONAL (NI) STUDY PROTOCOL 
Study information 
Title 
A retrospective chart review of UK patients 
with relapsed/refractory acute lymphoblastic 
leukaemia treated with inotuzumab 
ozogamicin, a real world research study 
Protocol number 
X9001222 
Protocol version identifier 
V1.0 
Date  
18 July 2019 
Active substance 
Inotuzumab ozogamicin 
Medicinal product 
BESPONSA® 
Research question and objectives 
 
 
 
 
 
The purpose of this study is to describe the 
demographics and clinical characteristics, 
treatment pathway, and effectiveness and 
safety of inotuzumab ozogamicin in patients 
with relapsed/refractory B-cell acute 
lymphoblastic leukaemia treated with 
inotuzumab ozogamicin in the real-world. 
The objectives of the study are as follows:  
Primary objective 
• To describe the baseline demographic, 
clinical (including previous treatment) and 
laboratory characteristics of patients with 
relapsed/refractory B-cell acute 
lymphoblastic leukaemia at initiation of 
treatment with inotuzumab ozogamicin.  
Secondary objectives  
• 
To describe the inotuzumab ozogamicin 
treatment pathway, including 
inotuzumab ozogamicin doses, dose 
modifications and number of cycles of 
treatment; and concomitant medications.  
• To summarise complete remission or 
complete remission with incomplete 

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haematological recovery rates following 
treatment with inotuzumab ozogamicin, 
overall and stratified according to the 
number of salvage therapies (0, 1, ≥2) 
received prior to inotuzumab ozogamicin 
initiation. 
• To summarise minimal residual disease 
negativity rates following initiation of 
inotuzumab ozogamicin, and describe the 
number of cycles of inotuzumab 
ozogamicin needed to attain minimal 
residual disease negativity. 
• To describe overall survival, and cause of 
death; in all patients and in patient with or 
without follow-up hematopoietic stem-cell 
transplantation. 
• To describe relapse-free-survival; in all 
patients and in patient with or without 
follow-up hematopoietic stem-cell 
transplantation. Additionally, to describe 
non-relapse mortality in patients 
undergoing follow-up hematopoietic stem-
cell transplantation. 
• To describe the treatments for acute 
lymphoblastic leukaemia and responses to 
treatment post-inotuzumab ozogamicin, 
including hematopoietic stem cell 
transplantation, chemotherapy regimens 
and chimeric antigen receptor T-cell 
therapy. 
• To describe the occurrence of safety 
events including veno-occlusive disease 
/sinosuidal obstruction syndrome, grade 
3/4 treatment-related adverse events 
(lung/cardiac/kidney) and other liver 
dysfunction following inotuzumab 
ozogamicin initiation; in all patients and in 
patients with or without follow-up 
hematopoietic stem-cell transplantation. In 
addition, to evaluate associations between 
risk factors identified in the INO-VATE 
acute lymphoblastic leukaemia trial and 
risk for veno-occlusive disease /sinosuidal 

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PFIZER CONFIDENTIAL  
 
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1. TABLE OF CONTENTS 
1. TABLE OF CONTENTS .......................................................................................................4 
2. LIST OF ABBREVIATIONS ................................................................................................6 
3. RESPONSIBLE PARTIES ....................................................................................................8 
4. ABSTRACT ...........................................................................................................................9 
5. AMENDMENTS AND UPDATES .....................................................................................14 
6. MILESTONES .....................................................................................................................14 
7. RATIONALE AND BACKGROUND ................................................................................14 
8. RESEARCH QUESTION AND OBJECTIVES .................................................................16 
9. RESEARCH METHODS ....................................................................................................17 
9.1. Study design ............................................................................................................17 
9.2. Setting ......................................................................................................................18 
9.2.1. Inclusion criteria .........................................................................................20 
9.3. Variables ..................................................................................................................20 
9.4. Data sources ............................................................................................................26 
9.5. Study size ................................................................................................................26 
9.6. Data management ....................................................................................................27 
7.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic Data 
Record ........................................................................................................................28 
7.6.2. Record Retention ..................................................................................................28 
9.7. Data analysis ...........................................................................................................29 
9.8. Quality control .........................................................................................................30 
9.9. Limitations of the research methods .......................................................................31 
9.10. Other aspects .........................................................................................................32 
10. PROTECTION OF HUMAN SUBJECTS ........................................................................32 
10.1. Patient Information ................................................................................................32 
10.2. Patient Consent ......................................................................................................33 
10.3. Patient Withdrawal ................................................................................................33 
10.4. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............33 
10.5. Ethical Conduct of the Study ................................................................................33 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................33 

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11.1. Single Reference Safety Document .......................................................................36 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS .......36 
13. REFERENCES ..................................................................................................................38 
14. LIST OF TABLES .............................................................................................................40 
15. LIST OF FIGURES ...........................................................................................................40 
16. ANNEX 1. LIST OF STAND ALONE DOCUMENTS ...................................................40 
17. ANNEX 2. ADDITIONAL INFORMATION ...................................................................41 
 

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PFIZER CONFIDENTIAL  
 
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GDPR 
European Union General Data Protection Regulation 
AE 
Adverse Event 
NI 
Non Interventional 
AEM 
Adverse Event Monitoring 
SRSD 
Single Reference Safety Document  
STROBE 
Strengthening The Reporting of Observational 
studies in Epidemiology 
ICMJE 
International Committee of Medical Journal Editors 

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4. ABSTRACT 
A retrospective chart review of United Kingdom (UK) patients with relapsed/refractory acute 
lymphoblastic leukaemia treated with inotuzumab ozogamicin, a real world research study.  
Inotuzumab ozogamicin (InO) is a CD22 monoclonal antibody that was shown to improve 
outcomes of patients with relapsed/refractory B-cell acute lymphoblastic leukaemia (ALL) or 
Philadelphia chromosome positive ALL. In the phase III INO-VATE ALL study, patients 
receiving InO versus standard chemotherapy achieved significantly higher complete 
remission (CR) rates and minimal residual disease (MRD)-negativity rates. Veno-occlusive 
disease (VOD) / sinusoidal obstruction syndrome (SOS) was reported in INO-VATE ALL as 
a treatment related adverse event (TRAE), on average two weeks after end of treatment with 
InO, and especially in patients who had follow-up hematopoietic stem cell transplant (HSCT) 
therapy.  
InO was approved by the European Medicines Agency (EMA) in June 2017. InO recently 
gained recommendation from the National Institute for Health and Care Excellence (NICE) 
in the United Kingdom (UK) in line with the licensed indication on 9th August 2018, and is 
now available in routine care practice throughout the UK. Prior to NICE approval, InO was 
made available to UK patients through a compassionate use program (CUP) run by Pfizer 
Inc. between June 2016 and October 2017, and via private purchase. As part of the CUP 
alone, approximately 75 patients were treated across 31 National Health Service (NHS) 
Trusts, each Trust treating between 1 and 15 patients. Patient level data is available in 
medical records, enabling a retrospective chart review to be conducted. 
There is a paucity of information on clinical outcomes in UK patients with 
relapsed/refractory B-cell ALL treated with InO outside of the context of clinical trials. The 
number of patients enrolled in INO-VATE ALL from the UK was limited. In this context, a 
retrospective chart review evaluating real world effectiveness and safety of InO for ALL 
when administered in routine care in the UK is of interest to clinicians and patients. 
The purpose of this study is to describe the demographics and clinical characteristics, 
treatment pathway, and effectiveness and safety of InO in patients with relapsed/refractory 
B-cell ALL treated with InO in the UK. 
The objectives of the study are as follows: 
Primary objective: 
• To describe the baseline demographic, clinical (including previous treatment) and 
laboratory characteristics of patients with relapsed/refractory B-cell ALL at initiation of 
treatment with InO.  

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Secondary objectives: 
 To describe the InO treatment pathway, including InO doses, dose modifications and 
number of cycles of treatment; and concomitant medications.  
 To summarise CR or CR with incomplete haematological recovery (CR/CRi) rates 
following initiation of InO, overall and stratified according to the number of salvage 
therapies (0, 1, ≥2) received prior to InO initiation. 
 To summarise MRD negativity rates following initiation of InO, and describe the number 
of cycles of InO needed to attain MRD negativity. 
 To describe overall survival (OS) and cause of death; in all patients and in patient with or 
without follow-up HSCTTo describe relapse-free-survival (RFS) in all patients and in 
patients with or without follow-up HSCT. Additionally, to describe non-relapse mortality 
(NRM) in patients undergoing follow-up HSCT.   
 To describe the treatments for ALL and responses to treatment post InO, including HSCT, 
chemotherapy regimens and chimeric antigen receptor (CAR) T-cell therapy  
 To describe the occurrence of safety events including documented diagnoses of 
VOD/SOS, grade 3/4 TRAEs (lung/cardiac/kidney) and other liver dysfunction following 
InO initiation; in all patients and in patients with or without follow-up HSCTIn addition, 
to evaluate associations between risk factors identified in the INO-VATE ALL trial and 
risk for VOD/SOS in patients with follow-up HSCT. 
This is a UK, multi-centre, retrospective, non-interventional cohort study based on secondary 
use of hospital medical records (paper-based and/or electronic, as appropriate). 
Key definitions 
 The index date: the date of initiation of the first cycle of InO. 
 The baseline period: period from 6 months prior to index date to index date. The closest 
observation recorded during the baseline period and closest to index date will be used as 
baseline data (when more than one observations are available). 
 Pre-index observation period: period from the date of ALL diagnosis to the index date. 
 Post-index observation period: period from the index date until the date of death, or date 
of latest visit at the time of data collection, whichever is soonest.  
 CR/CRi rate: number of patients who achieve CR/CRi divided by the total number of 
patients completing treatment with InO (defined as patients with a  recorded date of 
discontinuation of InO).  

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 MRD negativity rate: proportion of patients in whom MRD-negative status is observed, 
among patients in whom MRD negativity status has been assessed, at any time until the 
end of treatment with InO (defined as the date of recorded discontinuation of InO).   
 OS:  time from index date to death. 
 RFS: time from index date to the earliest date of the following events: death, progressive 
disease (including objective progression, relapse from CR/CRi, treatment discontinuation 
due to global deterioration of health status), and start of new induction therapy or post-
therapy HSCT without achieving CR/CRi.  
 NRM:  Time from the date of follow-up HSCT until death without disease progression or 
relapse. Deaths from any cause without prior progression are events. Events related to the 
disease such as relapse, progression are competing events, loss to follow‐up are censored 
 
Patients will be observed from the start of the pre-index observation period until the end of 
the post-index observation period. Patients who have not completed 1 year of follow-up after 
index date and are still alive will be censored at the latest visit date at the time of data 
collection. 
The source population for this study is adult patients treated with InO at the selected sites and 
who accessed InO via NHS commissioning, via the CUP or via private purchase between 
June 2016 and date of data collection (to be confirmed). The NICE recommendation is as an 
option for treating relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic 
leukaemia in adults; and patients with relapsed or refractory Philadelphia chromosome 
positive disease should have had at least 1 tyrosine kinase inhibitor. The eligibility criteria 
for inclusion into the CUP is provided in Section 14 Annex 1.  
Patients will be eligible for inclusion in the present study if they fulfill all of the following 
criteria: 
Inclusion criteria 
 Patients with relapsed/refractory ALL. 
 Patients who initiated InO between 1st of June 2016 and date of data collection (to be 
confirmed). 
 Patients who accessed InO treatment via NHS commissioning, via the CUP, or via private 
purchase.  
 Patients aged ≥18 years old at initiation of InO treatment  
 
 Exclusion criteria 
 Patients initiated on treatment with InO at a different hospital than the ones selected in this 
study. 

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 Patients with <3 months of follow-up since index date, unless death occurs <3 months 
from index date. 
Consent will not be required as all identifiable patient data (from surviving and deceased 
patients) will be extracted by the patient’s direct medical care team. Eligible patients will be 
selected by chronological order and with a priority given to patients treated via NHS 
commissioning, where possible. 
Dataset 
The following data will be collected from patients medical records in order to address the 
objectives of the study: 
 Patient demographics and clinical and laboratory characteristics (including details of age, 
sex, Eastern Cooperative Oncology Group (ECOG), ALL diagnosis, type and stage, liver 
disease history, ALL-related  treatment history,  hematological and biochemical 
laboratory evaluations) 
 InO treatment pathway (including details of InO doses, dose modifications, treatment 
duration, number of cycles and duration of each cycle, reason for interruption of cycle) 
 Azole antifungal therapy concomitant to InO treatment  
 InO treatment outcomes (including details of treatment response assessments, disease 
progression, death) 
 Treatments post-InO (including new chemotherapy regimen, HSCT, CAR-T) and 
responses to treatment (CR, CRi, stable disease, progressive disease)  
 Safety events (including details of documented diagnoses of VOD/SOS, grade 3/4 TRAEs 
and other liver dysfunction and risk factors for VOD/SOS) and treatment for those events. 
Data will be collected retrospectively from patients’ hospital medical records (paper-based 
and electronic) by members of the direct care team. Data will be collected using a 
pseudonymised electronic case report form designed specifically for the study. Participants 
will be identified in all study records by a unique participant identification number to allow 
data management queries to be resolved with reference to source medical records while 
preserving patient confidentiality. 
Three to five of the 31 NHS Trusts participating in the CUP that individually treated the 
largest number of patients with InO as part of the CUP (total number of patients including 
private purchase to be confirmed), will initially be selected for this study to achieve a target 
sample size of approximately 25 patients (the number of sites may be expanded at a later 
date).  

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5. AMENDMENTS AND UPDATES 
None 
6. MILESTONES 
 
Milestone 
Planned date 
Start of data collection 
01 September 2019 
End of data collection 
15 January 2020 
Final study report 
01 March 2020 
 
7. RATIONALE AND BACKGROUND 
Acute lymphoblastic leukaemia (ALL) is an acute form of leukemia which affects the white 
blood cells (B cells or T cells), that is aggressive and progresses rapidly, requiring immediate 
treatment. The incidence of ALL in the UK is 1.5 per 100,000 in males and 2 per 100,000 in 
females1.  
ALL is a disease characterised by malignant transformation and proliferation of lymphoid 
progenitor cells in the bone marrow, blood and extramedullary sites2. Patients with relapsed 
or refractory acute ALL have less than 50% chance of achieving a complete remission (CR), 
with a median relapse-free survival (RFS) of only 5.2 months3. The 5-year overall survival 
rate has been estimated as 7% overall, and is higher in younger patients: 12% in patients aged 
under 20 years versus 3% in patients over 50 years4.    
Several novel therapies have been recently approved for relapsed/refractory B-cell ALL with 
the aim to maintain remission and prolong survival5. Antibody-drug conjugates (ADC) are a 
class of novel emerging therapies that target the cell surface or intracellular antigens specific 
for leukaemic cells, thus sparing cell death in the normal and off target tissues5. Inotuzumab 
ozogamicin (InO) is a CD22 monoclonal antibody that was shown to improve outcomes of 
patients with relapsed/refractory B-cell ALL or Philadelphia chromosome positive ALL.  
In the phase III INO-VATE ALL study, patients receiving InO versus standard chemotherapy 
achieved significantly higher response (CR rate was 80.7% [95% confidence interval [CI], 
72%–88%] vs 29.4% [95% CI, 21%–39%]) and minimal  residual disease (MRD)-negativity 
rates (78.4% [95% CI, 68%–87%] vs 28.1% [95% CI, 14%–47%])6. Progression-free 
survival (median was 5.0 [95% CI, 3.7–5.6] vs 1.8 [95% CI, 1.5–2.2] months) and overall 
survival (median was 7.7 (95% CI, 6.0–9.2) vs 6.7 (95% CI, 4.9–8.3) months) were also 

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prolonged in patients treated with InO versus standard chemotherapy6.  
 
Veno-occlusive disease (VOD; also known as sinusoidal obstruction syndrome [SOS]) was 
reported in INO-VATE ALL as a treatment related adverse event (TRAE) occurring on 
average 16 days after the last dose of InO, and especially in patients who proceeded onto 
hematopoietic stem cell transplant (HSCT) therapy after InO treatment 6,7. Occurrence of 
VOD/SOS was 13% in patients receiving InO versus <1% in patients receiving standard of 
care, and 22% versus 3%, respectively, in patients with  follow-up HSCT7. Additional 
characteristics at initiation of treatment with InO and at follow-up HSCT were also tested by 
Kantarjian et al. that may help identify patients with follow-up HSCT most at risk of 
developing VOD/SOS7. Non-haematologic TRAEs were also observed which affected the 
lung, cardiac system and kidney6,8.  
InO was approved by the European Medicines Agency (EMA) in June 2017 for the treatment 
of adults with relapsed/refractory CD22-positive B-cell ALL and for adults with Philadelphia 
chromosome positive relapsed/refractory B-cell ALL who have failed previous treatment, to 
be marketed as BESPONSA®. BESPONSA® is administered in 3- to 4- week cycles at doses 
of 1.5 mg/m2 to 1.8 mg/m2 for a total duration of  2-3 cycles in patients proceeding to HSCT 
(third cycle added for patients  not achieving CR/CRi and MRD negativity), and up to 6 
cycles otherwise 6.  
InO recently gained recommendation from the National Institute for Health and Care 
Excellence (NICE) in the United Kingdom (UK) in line with the licensed indication on 9th 
August 20189 (see Annex 1), and is now available in routine care practice throughout the 
UK. Prior to NICE approval, InO was made available to UK patients through a 
compassionate use program (CUP) run by Pfizer Inc. between June 2016 and October 2017 
(see Annex 1), and via private purchase. As part of the CUP alone, approximately 75 patients 
were treated across 31 National Health Service (NHS) Trusts, each Trust treating between 1 
and 15 patients. Patient level data is available in medical records, enabling a retrospective 
chart review to be conducted. 
There is a paucity of information on the descriptive characteristics, treatment patterns and 
clinical outcomes in patients with relapse/refractory B-ALL treated with InO outside of the 
context of clinical trials9. The number of patients enrolled in INO-VATE ALL was also 
relatively limited 6. In this context, and considering that InO is the only ADC currently 
available to ALL patients in the European Union (EU), a retrospective chart review 
evaluating real world effectiveness and safety of InO for ALL when administered to adult 
patients in routine care in the UK is of interest to clinicians and patients. 
 

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8. RESEARCH QUESTION AND OBJECTIVES 
The purpose of this study is to describe the demographics and clinical characteristics, 
treatment pathway, and effectiveness and safety of InO in patients with relapsed/refractory 
B-cell ALL treated with InO in the real-world. 
The objectives of the study are as follows. 
Primary objective: 
• To describe the baseline demographic, clinical (including previous treatment) and 
laboratory characteristics of patients with relapsed/refractory B-cell ALL at initiation of 
treatment with InO.  
Secondary objectives: 
 To describe the InO treatment pathway, including InO doses, dose modifications and 
number of cycles of treatment; and concomitant medications.  
 To summarise CR or CR with incomplete haematological recovery (CR/CRi) rates at 
completion of treatment with InO, overall and stratified according to the number of 
salvage therapies (0, 1, ≥2) received prior to InO initiation. 
 To summarise MRD negativity rates in patients assessed for MRD negativity, at 
completion of treatment with InO, and describe the number of cycles of InO needed to 
attain MRD negativity. 
 To describe overall survival (OS), and cause of death; in all patients and in patient with or 
without follow-up HSCT. 
 To describe RFS; in all patients and in patient with or without follow-up HSCT. 
Additionally, to describe non-relapse mortality (NRM) in patients undergoing follow-up 
HSCT.  
 To describe the treatments for ALL and responses to treatment post InO, including HSCT, 
chemotherapy regimens and chimeric antigen receptor T-cell therapy  
 To describe the occurrence of safety events including documented diagnoses of 
VOD/SOS, grade 3/4 TRAEs (lung/cardiac/kidney) and other liver dysfunction following 
InO initiation; in all patients and in patients with or without follow-up HSCT. In addition, 
to evaluate associations between risk factors identified in the INO-VATE ALL trial and 
risk for VOD/SOS in patients with follow-up HSCT. 
 

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9. RESEARCH METHODS  
9.1. Study design  
This is a UK, multi-centre, retrospective, non-interventional cohort study based on secondary 
use of hospital medical records (paper-based and/or electronic, as appropriate). Three to five 
out of the 31 NHS Trusts that treated the largest number of patients with InO as part of the 
CUP will be initially selected for this study (the number of centres may be further expanded).  
A retrospective design has been selected as data have already been recorded into medical 
records and are available for data collection. The study is non-interventional as all patients 
received InO as part of routine clinical care, either via enrolment into the CUP or via private 
purchase. 
Endpoints related to the primary objective are as follows and will be further described in 
Section 7.3: 
 Summary measures of demographic characteristics (age and sex) 
 Summary measures of clinical characteristics, including date of disease, stage of disease , 
C22-positive/negative, ALL cytogenetics, and Eastern Cooperative Oncology Group 
(ECOG) performance status, number of relapses prior to InO initiation. 
 Summary measures of ALL-related treatments prior to InO initiation, and response to 
treatment. 
 Baseline laboratory measurement including: blood indicators (full blood counts, platelets 
and absolute neutrophil counts [ANC]), liver function tests alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), bilirubin, albumin 
and gamma glutamyl transferase (GGT).   
 
Endpoints related to the secondary objective are as follows and will be further described in 
Section 7.3: 
 Summary measures of InO treatment including: duration, number of cycles per patient, 
dose at initiation, dose modifications and discontinuation status (including reasons). 
 Summary measures of azole antifungal therapy concomitant to InO treatment.  
 Summary measures of CR, CRi and CR/CRi rates at end of InO cycles of treatment; 
overall and according to the number of salvage therapies in the pre-index observation 
period (0, 1, ≥2).  
 Summary measures of MRD negativity at the end of InO cycles of treatment; and the 
number and proportion of patients attaining MRD negativity overall and according to the 
number of completed cycles of InO at the time of attainment (after 1, 2, ≥3 cycles of InO). 
 The number and proportion of patients surviving at 3, 6 and 12 months after InO 
initiation, and cause of death; overall and in patients with and without HSCT. 

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 MRD negativity rate: proportion of patients in whom MRD-negative status is observed, 
among patients in whom MRD negativity status has been assessed, at any time until the 
end of treatment with InO (defined as the date of recorded discontinuation of InO).   
 OS:  time from index date to death. 
 RFS: time from index date to the earliest date of the following events: death, progressive 
disease (including objective progression, relapse from CR/CRi, treatment discontinuation 
due to global deterioration of health status), and start of new induction therapy or post-
therapy HSCT without achieving CR/CRi.  
 NRM:  Time from the date of follow-up HSCT until death without disease progression 
 
Patients will be observed from the start of the pre-index observation period until the end of 
the post-index observation period. For the purpose of identifying risk factors for VOD/SOS 
and replicating the findings by Kantarjian et al.7, follow-up will be defined as the post-index 
observation period, and patients will be censored at the date of the last recorded clinic visit 
prior to data collection. 
Figure 1: Study design and observation periods 
 
 
Three to five of the 31 NHS Trusts participating in the CUP that treated the largest number of 
patients with InO as part of the CUP (total number of patients including private purchase to 
be confirmed) will initially be selected for this study to achieve a target sample size of 
approximately 25 patients (the number of sites may be expanded at a later date). The list of 
selected sites will be maintained in a stand-alone document. Sites will be selected on the 
basis that:  
 Their cancer service participated in the CUP. 
 They treated at least 1 adult patient with InO via the CUP. 
 They have an interest in taking part in the study. 

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 They have appropriate and sufficient personnel available locally to identify eligible 
patients, collect the required data from medical records and to appropriately conduct the 
study in accordance with applicable legal and regulatory requirements. 
 
9.2.1. Inclusion criteria 
The source population for this study is adult patients treated with InO at the selected sites and 
who accessed InO via NHS commissioning, via the CUP or via private purchase between 
June 2016 and February 2019 The NICE recommendation is as an option for treating 
relapsed or refractory CD22- positive B-cell precursor ALL in adults; and patients with 
relapsed or refractory Philadelphia chromosome positive disease should have had at least 1 
tyrosine kinase inhibitor9 (see Annex 1 for NICE eligibility criteria).  The eligibility criteria 
for inclusion in the CUP are provided in Annex 1.  
Patients will be eligible for inclusion in the present study if they fulfill all of the following 
criteria: 
Inclusion criteria 
 Patients with relapsed/refractory ALL. 
 Patients who initiated InO between 1st of June 2016 and date of data collection. 
 Patients who accessed InO treatment via NHS commissioning, via the CUP, or via private 
purchase. 
 Patient aged ≥18 years old at initiation of InO treatment 
 Exclusion criteria 
 Patients initiated on treatment with InO at a different hospital than the ones selected in this 
study. 
 Patients with <3 months of follow-up since index date, unless death occurs <3 months 
from index date. 
Eligible patients will be selected by chronological order and with a priority given to patients 
treated via NHS commissioning, if possible. 
9.3. Variables 
The endpoints associated with each of the study objectives are described below, along with 
the variables that will be collected in order to address the objectives. Response options for 
each variable will be further detailed in the electronic case report form (eCRF). A list of data 
items to be collected and operational definitions for clinical endpoints are provided in Annex 
2.  

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Table 1: List of endpoints and variables required to address the objectives of the study 
Endpoint to address the primary objective 
Dataset required to address the 
primary objective 
Primary objective: To describe the baseline demographic, clinical (including previous treatment) 
and laboratory characteristics of patients with relapsed/refractory B-cell ALL at initiation of 
treatment with InO. 
Summary measures of: 
 
Demographic characteristics: 
o Age at index date 
o Sex 
 
Clinical characteristics: 
o ECOG performance status at 
baseline. 
o Date of ALL diagnosis. 
o Phase of disease at index date: 
CR, 1st relapse, 2nd relapse , 3rd 
relapse, 4th or greater relapse 
o CD22 expression: percentage of 
positive cell blasts 
o ALL cytogenetics; mixed lineage 
leukaemia (MLL)-AF4; BCR-
ABL; low hypodiploidy/near 
triploidy; complex karyotype  
o Number of ALL relapses prior to 
index date 
o History of liver diseases prior to 
index date (before or after 
diagnosis), and whether they 
were ongoing or resolved at 
index date. 
 
 
Laboratory characteristics at baseline 
o Full blood counts, including: 
platelets and ANC 
o Liver function tests including: 
alanine aminotransferase (ALT), 
aspartate aminotransferase 
(AST), alkaline phosphatase 
(ALP), bilirubin, albumin, 
gamma glutamyl transferase 
(GGT).   
 
Dates are DD/MM/YYYY unless specified 
 
Date of InO initiation  
 
Date of birth (MM/YY) 
 
M/F  
 
Date of initial diagnosis of ALL. 
Recorded during baseline period and closest prior 
to index date:  
 
ECOG performance status results 
 
Phase of disease at index date: CR, 1st relapse, 
2nd relapse , 3rd relapse, 4th or greater relapse 
 
Pre-existing liver disease ongoing/resolved 
(Y/N). 
 
Percentage of positive cell blasts (CD22 
expression test) 
 
Result for test for ALL cytogenetics: MLL-
AF4; BCR-ABL; low hypodiploidy/near 
triploidy; complex karyotype  
 
ALL relapses prior to index date: dates 
 
Results and date of liver function tests results 
including: ALT, AST, ALP, bilirubin, albumin, 
GGT. 
 
Results and date of full blood counts results 
including: platelets and ANC  
 
Anytime between initial diagnosis of ALL and InO 
initiation: 
 
1st line chemotherapy according to 
national trial or treatment guideline  
 
Number of lines of salvage therapy 
 
Number of prior HSCT, conditioning regimen 
for each HSCT (high-dose myeloablative, 
reduced-intensity, nonmyeloablative)  
 
Treatment with blinatumomab: yes/no 
 
Number of CAR T-cell treatments 

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 
ALL-related treatment prior to InO 
initiation: 
o 1st line chemotherapy according 
to national trial or treatment 
guideline  
o Summary of number of patients 
by; 
 
number of lines of 
salvage therapy: 0, 1, 2, 
≥3 
 
number of prior HSCT 
(0, 1, 2, ≥3) and by type 
of  conditioning regimen 
for each HSCT (high-
dose myeloablative, 
reduced-intensity, 
nonmyeloablative 10)  
 
Treated with 
blinatumomab 
 
Number of CAR T-cell 
therapies: 0, 1, ≥2 
 
Endpoints to address the secondary 
objectives 
Dataset required to address the secondary 
objectives 
Secondary objective: To describe the InO treatment pathway, including InO doses, dose 
modifications and number of cycles of treatment; and concomitant medications. 
Summary measures of: 
 
Total duration of treatment with InO 
 
Number of cycles of InO per patient 
 
Interrupted cycles of InO, including 
reasons (liver toxicity TRAEs, other 
AEs, tolerance, treatment failure, and 
course complete). 
 
Doses of InO prescribed 
 
Modification of doses of InO, including 
reasons (liver toxicity TRAEs, other 
AEs, tolerance, treatment failure, and 
course complete). 
 
Azole antifungal therapy concomitant to 
InO treatment  
Dates are DD/MM/YYYY unless specified 
 
InO treatment: start date and end date of each 
cycle, cycle completed / interrupted (if 
interrupted provide reason for discontinuation) 
 
Azole antifungal therapy including 
fluconazole, voriconazole, itraconazole and 
posaconazole (and other indicated in the 
medical records): date started, date end. 
 
Secondary objective:  To summarise CR/CRi rates following initiation of InO, overall and 
according to the number of salvage therapies received prior to InO initiation. 

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Summary measures of: 
 
CR, CRi and CR/CRi response rates by 
the end of InO treatment, overall and 
according to the number of salvage 
therapies in the pre-index observation 
period (0, 1, ≥2).  
 
Median time to CR/CRi (95% CI) 
Dates are DD/MM/YYYY unless specified 
 
Date of start and stop  of InO treatment (stop 
date is date of discontinuation) 
 
Response to InO treatment first recorded after 
end of treatment: date, response (CR, CRi, 
stage disease, progression) 
 
 
Number of salvage therapies for ALL prior to 
index date. 
Secondary objective: To summarise MRD negativity rates following initiation of InO, and describe 
the number of cycles of InO needed to attain MRD negativity. 
 
Number and proportion of patients 
achieving MRD negativity overall and by 
the number of completed cycles of InO 
(after 1, 2, ≥3 cycles of InO) in patients 
evaluated by flow-cytometry/ molecular 
assessment / both. 
 
Dates are DD/MM/YYYY unless specified 
 
Date of InO initiation 
 
Start and stop date of each cycle of InO 
 
Date of discontinuation of InO 
 
MRD negativity recorded: Y/N. If Y test 
performed (flow cytometry, molecular 
assessment, both), result: negative / positive, 
date of test.  
 
 
 
Secondary objective: To describe OS, and cause of death; in all patients and in patient with or 
without follow-up HSCT. 
Summary measures of, in all patients, and 
separately in patients with and without 
follow-up HSCT: 
 
The number and proportion of patients 
surviving at 3, 6 and 12 months after InO 
initiation 
 
Cause of death 
 
Median OS (95% CI) 
Dates are DD/MM/YYYY unless specified 
 
Date of InO initiation 
 
Patient with follow-up HSCT: Yes/No 
 
Patient alive at data collection (Y/N) 
 
For deceased patients: date and cause of death 
leukaemia or TRM 
 
For surviving patients: date of last visit before 
data collection 
Secondary objective: To describe RFS in all patients and in patients with or without follow-up 
HSCT. Additionally, to describe NRM in patients undergoing follow-up HSCT. 
Summary measures of, in all patients, and 
separately in patients with and without 
follow-up HSCT: 
 
The number and proportion of patients 
who are relapse-free at 3, 6 and 12 
months after InO initiation 
 
Median RFS (95% CI) 
In patients undergoing follow-up HSCT:  
Dates are DD/MM/YYYY unless specified 
 
Date of InO initiation 
 
Patient with follow-up HSCT: Yes/No 
 
Patient alive at data collection (Y/N) 
 
For deceased patients: date and cause of death 
 
For surviving patients: date of last visit before 
data collection.  

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 
Median NRM (95% CI) from the date of 
follow-up HSCT 
 
 
Dates of the following events: death, 
progressive disease (including objective 
progression, relapse from CR/CRi, treatment 
discontinuation due to global deterioration of 
health status), and start of new induction 
therapy or post-therapy HSCT without 
achieving CR/CRi; as documented in medical 
records (if unavailable, infer using definitions 
above).   
Secondary objective: 
To describe the treatments for ALL and responses to treatment post-InO, 
including HSCT, chemotherapy regimens and CAR T-cell therapy 
For each treatment post-InO including: new 
chemotherapy (blinatumomab, other), HSCT, 
CAR T cell therapy, report:  
 
number and proportion of patients 
initiated on treatment (for HSCT report 
number of HSCT)  
 
response to treatment: CR, CRi, 
progressive disease, stable disease 
 
Survival: number of patients alive / dead 
at completion of treatment 
Dates are DD/MM/YYYY unless specified 
 
Stop date of InO treatment  
 
List of treatments started post-InO: new 
chemotherapy (blinatumomab, other), HSCT 
(record if several HSCT), CAR-T cell therapy  
 
Response to treatments post InO: CR, CRi, 
progressive disease, stable disease  
 
Survival: whether alive / dead at completion of 
treatment 
Secondary objective: To describe the occurrence of safety events including documented diagnosis 
of VOD/SOS, grade 3/4 TRAEs (lung/cardiac/kidney) and other liver dysfunction following InO 
initiation; in all patients and in patients with or without follow-up HSCT. In addition, to evaluate 
associations between risk factors identified in the INO-VATE ALL trial and risk for VOD/SOS in 
patients with follow-up HSCT. 
Summary measures of, in all patients, and 
separately in patients with and without 
follow-up HSCT: 
 
Number and proportion of patients 
experiencing a documented diagnosis of 
VOD/SOS during the post-index 
observation period, overall, by grade, and 
in the subsets of patients (1) with follow-
up chemotherapy after completion of 
chemotherapy, and (2) with follow-up 
HSCT after HSCT 
 
Treatments received for documented 
diagnoses of VOD/SOS including 
defibrotide and heparin and survival 
following treatment (patient alive / dead, 
cause of death) 
Dates are DD/MM/YYYY unless specified 
 
Date of InO initiation 
 
Date of InO discontinuation and reason 
 
Date of birth (MM/YY) 
 
Documented diagnosis of VOD/SOS 
diagnosis: Y/N, if Y: start and end dates, 
grade, treatment for VOD/SOS including 
defibrotide and ursodeoxycolic acid  
 
Treatment for documented diagnosis of 
VOD/SOS: list (defibrotide, ursodeoxycolic 
acid, other[specify]), patient alive / dead at end 
of treatment (cause of death) 
 
Grade 3/4 TRAEs (lung/cardiac/kidney) 
diagnoses: start and end dates, grade 
 
Dates and results for liver function tests 
including ALT, AST and bilirubin immediately 

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 Identified using univariate logistic regression: 
o Conditioning regimen with two alkylating agents (two versus one) prior to follow-
up HSCT 
o Busulfan-containing regimen (yes versus no) prior to follow-up HSCT 
o Last bilirubin concentration (≥Upper limit of normal [ULN] vs <ULN) measured 
prior to follow-up HSCT  
o Age (≥55 years vs <55 years)  
 Identified using multivariate logistic regression: 
o Conditioning regimen with two alkylating agents (two vs one) prior to follow-up 
HSCT 
o Last bilirubin concentration (≥ULN vs <ULN) measured prior to follow-up 
HSCT. Last AST or ALT concentration (>1.5 × ULN vs ≤1.5 × ULN) measured 
prior to follow-up HSCT 
 
9.4. Data sources  
Data for this study will be initially collected through retrospective data collection from three 
to five NHS Trust cancer services in the UK which were part of the CUP (additional centres 
may be added at a later stage if the target sample size is not achieved).  
Data on patient demographic and clinical characteristics, treatment patterns, outcomes, and 
AEs will be collected from paper based and/or electronic hospital medical records (as 
applicable at each site) by members of the patient’s direct care team in anonymised-coded 
form.  
Data will be collected using anonymized-coded eCRFs designed specifically for the study. 
Participants will be identified in all study records by a unique participant identification 
number to allow data management queries to be resolved with reference to source medical 
records while preserving patient confidentiality. 
9.5. Study size 
This is a descriptive study and there is no a priori hypothesis specified, therefore a formal 
power calculation is not required. The sample size of approximately 25 patients has been 
based on the number of patients expected to be available at three centres that individually 
treated the largest number of patients with InO.  
 
For the assessment of risk factors for VOD/SOS in patients with follow-up HSCT, the 
following rationale applies regarding sample size. Usually, 10 events per variable are 
required to be able to fit a Cox proportional hazard model with sufficient accuracy11. The 
Kantarjian analysis identified 4 risk factors in a univariate analysis and 2 risk factors in the 

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multivariate analysis (See section 7.3). In addition, 47% of patients (77 out of 164 patients) 
had follow-up HSCT and VOD/SOS occurred in 22% of patients with follow-up HSCT in the 
INO-VATE ALL trial7. Therefore, it derives that for the univariate analysis (i.e., a model 
which fits one variable at a time), 45 patients with follow-up HSCT and 96 patients overall 
would be needed to be enrolled into the study. For the multivariate analysis fitted with the 2 
significant risk factors previously identified, 90 patients with HSCT and 192 patients overall 
would be need to be enrolled. Therefore, considering the sample size of the study, if risk 
factors cannot be estimated using a multivariate model, all factors will be assessed using a 
univariate model, if possible.  
 
9.6. Data management  
Data management and handling of data will be conducted according to the study specific data 
management plan and in accordance with European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance (ENCePP)/ International Society for 
Pharmacoepidemiology (ISPE)/ General Data Protection Regulation (GDPR) guidance. Data 
for the study will be collected via an electronic data capture system using a standardised 
eCRF designed specifically for the study in accordance with this protocol. All data will be 
collected from hospital medical records by members of the NHS direct care team.  
 
Before the start of data collection, NHS staff collecting data from patients’ hospital medical 
records will be trained in data entry into the eCRFs by study management staff from pH 
Associates and consistency checks will be built into the eCRF to ensure data quality.  
 
Patients will be identified in all study records by a unique study code to link multiple study 
records for each participant (if applicable) and preserve patient confidentiality. 
 
Data management for eCRFs will be carried out using MACRO™, a data management 
system which has a secure web-based data entry interface and is fully validated and 
compliant with Food and Drug Administration Information Governance standard 21 Code of 
Federal Regulations part 11. The MACRO™ system has restricted access permissions for 
data entry and data management, and records an audit trail of all changes to data and activity 
in the system in line with 21 Code of Federal Regulations part 11. Access to the study in 
MACRO™ will be restricted (by password protection) to only those members of staff 
directly involved with the study and assigned access permissions will control the level of 
access to that required for the role of each individual working on the study. If corrections are 
needed to an eCRF, queries will be raised in the electronic data capture system by the study 
data manager and these will be resolved by the responsible investigator (or designee) by 
reference to the source records. 

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After obtaining the appropriate local approvals for data release, the anonymised-coded study 
data will be collated and transferred securely to pH Associates, who will be the Data 
Processor for data management, analysis and reporting on behalf of Pfizer, the Data 
Controller.  
 
7.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic form and will be password 
protected or secured in a locked room to prevent access by unauthorized third parties. 
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases the source documents are the hospital or the physician's chart.  In these cases, 
data collected on the CRFs must match those charts.  
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.  
7.6.2. Record Retention 
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, e.g., CRFs and hospital records), all copies of all 
CRFs, safety reporting forms, source documents, detailed records of treatment disposition, 
and adequate documentation of relevant correspondence (e.g. letters, meeting minutes, and 

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telephone call reports).  The records should be retained by the investigator according to local 
regulations or as specified in the clinical study agreement, whichever is longer.  The 
investigator must ensure that the records continue to be stored securely for so long as they are 
retained. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 5 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.  
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met. 
9.7. Data analysis  
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a separate statistical analysis plan (SAP), which will be dated, filed and 
maintained by the sponsor.  The SAP may modify the plans outlined in the protocol; any 
major modifications of primary endpoint definitions or their analyses would be reflected in a 
protocol amendment. 
Analyses will be performed by pH Associates using Stata (StataCorp LLC) and R statistical 
software (version 3.4.1 or later). Data from all participating centres will be pooled for 
analysis. 
Descriptive statistics (number, percentages, means, standard deviations, medians, quartiles, 
minimum, maximum, number of missing and non-missing values), as appropriate to the data 
collected, will be used to describe baseline demographic and clinical characteristics for the 
overall study. Treatment patterns, treatment outcomes and TRAEs will also be reported using 
descriptive characteristics.  Frequency and percentages will be used to describe categorical 
variables. All percentages will be reported to the nearest whole number; therefore, in 
reporting study results in tables, figures and associated text, percentages may not add up to 
100% due to rounding. Means, standard deviations, medians, quartiles, minimum, and 
maximum, will be used to describe continuous variables. Patients who are still alive and have 
not progressed at the last visit date without clinical evidence of progression will be censored.  
Kaplan-Meier plots will be used to describe data related to OS, RFS and time to CR/CRi. A 
summary table of the number of events and censored patients at each monthly interval will 
also be included. 

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CCI

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and further training provided by pH Associates if required. If any subsequent issues are 
identified related to quality, accuracy or consistency of data collection, a random check of a 
further 10% of data collected by that data collector will be undertaken. Should any further 
issues be identified, 100% SDV will be undertaken at the centre. It is the Investigator's 
responsibility at each centre to ensure the accuracy of the data entered into the CRFs. 
 
A ‘back-to-back’ SDV monitoring methodology will be performed with a member of the 
direct care team. This will involve the direct care team member at the centre reciting data 
from the patient notes to the pH Associates study monitor so that they can verify the data in 
the eCRF without the need to look directly at the identifiable source records. All people 
performing SDV will be trained by pH Associates. 
 
All clinical data submitted will be checked for eligibility, completeness and accuracy and 
queries will be raised by the pH Associates data management team using agreed manual and 
programmed validation checks. Study centres will be required to co-operate with the data 
management team in the resolution of these queries.  
 
Analysis of the primary endpoint will be independently reviewed by a member of the Data 
Analysis team at pH Associates who was not involved in the analysis of the final study data. 
No additional analysis checks will be carried out. 
 
9.9. Limitations of the research methods 
 
Several sources of selection bias may be introduced in the study:  
o Patients treated as part of the CUP may differ from patients treated via private 
purchase and patients treated via NHS commissioning.  
o Patients were recruited from larger centres enrolled in the CUP, which may 
differ from smaller centres in terms of demographic and clinical 
characteristics, and therefore may not be representative of all real-world 
patients treated with InO.  
 
Patients may be lost to follow-up due to the occurrence of AEs, lack of efficacy or other 
reasons. The use of Kaplan-Meier curves to obtain estimates of median OS, RFS and 
time to CR/Cri takes into account patients’ attrition. 
 
The interpretation of data collected retrospectively will be dependent on the 
completeness and quality of the medical records and the reliability of the abstraction of 
data from the medical records. However, SDV will be employed to identify and correct 
abstraction errors. 

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 
This is a descriptive study and no analyses to control for confounding will be carried out; 
therefore, no definitive causal relationships between InO and study endpoints can be 
made. 
 
The overall sample size of the study is relatively small, and therefore CR/CRi rates and 
MRD negativity rates may be estimated with relative imprecision, and 95% CIs may be 
relatively wide. In addition, the small sample size may not allow the conduct of 
univariate and multivariate Cox modelling to estimate the risk of VOD/SOS in patients 
with follow-up HSCT. 
9.10. Other aspects 
Not applicable.  
10. PROTECTION OF HUMAN SUBJECTS 
10.1. Patient Information  
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws.  
 
The personal data will be stored at the study site in encrypted electronic form and will be 
password protected or secured in a locked room to ensure that only authorized study staff has 
access.  The study site will implement appropriate technical and organizational measures to 
ensure that the personal data can be recovered in the event of disaster.  In the event of a 
potential personal data breach, the study site shall be responsible for determining whether a 
personal data breach has in fact occurred and, if so, providing breach notifications as required 
by law. 
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, patient names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, patient-specific code.  
The investigator site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity.  In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal data 
consistent with the Clinical Study Agreement and applicable privacy laws. 

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10.2. Patient Consent 
The direct care team for each patient will be involved in extracting data and will produce 
pseudo-anonymized records from identifiable patient’s records which will be collected for 
the purpose of this study, at all time preserving confidentiality. As this study involves 
pseudo- anonymized structured or unstructured data, which according to applicable legal 
requirements do not contain data subject to privacy laws, obtaining informed consent from 
patients by Pfizer is not required.   
10.3. Patient Withdrawal 
Not applicable 
10.4. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
This study does not require IRB/IEC approval and an IRB/IEC review is not required as all 
confidential data will only be accessed via the direct care team. This protocol will be 
submitted for approval to the Health Research Authority.  
10.5. Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the 
International Society for Pharmacoepidemiology (ISPE13), European Medicines Agency 
(EMA), European Network of Centres for Pharmacoepidemiology and Pharmacovigilance 
(ENCePP13), and EU General Data Protection Regulation (GDPR14), as appropriate.  
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS  
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal 
product. The definition of an AE includes worsening of a pre-existing medical condition. A 
serious AE is any adverse drug reaction as defined above that:  
 is fatal 
 is life threatening (places the subject at immediate risk of death) 
 requires in-patient hospitalisation or prolongation of existing hospitalisation 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
 other significant medical hazard. 

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A serious adverse drug reaction is a serious adverse event that is considered related to the 
medicinal product. 
A hospitalisation meeting the regulatory definition for “serious” is any inpatient hospital 
admission that includes a minimum of an overnight stay in a healthcare facility. “Other 
significant medical hazards” refer to important medical events that may not be immediately 
life-threatening or result in death or hospitalisation, but may jeopardise the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above. 
Examples of such events could include allergic bronchospasm, convulsions, and blood 
dyscrasias, drug-induced liver injury, events that necessitate an emergency room visit, 
outpatient surgery, or other events that require other urgent intervention.  
All AEs related to any Pfizer product(s) shall be reported to Pfizer Pharmacovigilance, Pfizer 
Limited, Walton Oaks, Dorking Road, Tadworth, Surrey KT20 7NS. Email Transmission: 
GBR.AEReporting@pfizer.com; 
Facsimile 
Transmission: 
0800 
015 
6401 
(toll 
free);Telephone Contact: 0845 300 8031 (toll-free)  or 0845 300 8032 (toll), by the 
Principal Investigator at each centre or pH Associates within 24 hours of discovery or 
notification.  AE information must be recorded on the AE form emailed and/or faxed to 
Email Transmission: GBR.AEReporting@pfizer.com Facsimile Transmission Pfizer 
Pharmacovigilance; 0800 015 6401 (toll free) or 0845 300 8032 (toll) Telephone Contact: 
0845 300. 
Adverse drug reactions for non-Pfizer products should be notified by the Principal 
Investigator at each centre to the appropriate Marketing Authorisation Holder and/or to the 
Medicines and Healthcare Regulatory Authority (MHRA). 
All pregnancies occurring in female patients while taking Pfizer products, and all 
pregnancies occurring in female partners of male patients taking Pfizer products should be 
reported 
to 
Email 
Transmission: 
GBR.AEReporting@pfizer.com; 
Facsimile 
Transmission: 0800 015 6401 (toll free), 0845 300 8032 (toll) Telephone Contact: 0845 
300 8031 (toll-free)  or 0845 300 8032 (toll). Pfizer Pharmacovigilance, Pfizer Limited, 
Walton 
Oaks, 
Dorking 
Road, 
Tadworth, 
Surrey 
KT20 
7NS 
Email: 
GBR.AEReporting@Pfizer.com. 
This study protocol requires human review of patient-level unstructured data; unstructured 
data refer to verbatim medical data, including text-based descriptions and visual depictions of 
medical information, such as medical records, images of physician notes, neurological scans, 
X-rays, or narrative fields in a database.  The reviewer is obligated to report AEs with 
explicit attribution to any Pfizer drug that appear in the reviewed information (defined per the 
patient population and study period specified in the protocol).  Explicit attribution is not 
inferred by a temporal relationship between drug administration and an AE, but must be 

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based on a definite statement of causality by a healthcare provider linking drug 
administration to the AE. 
 
The requirements for reporting safety events on the non-interventional study (NIS) adverse 
event monitoring (AEM) Report Form to Pfizer Safety are as follows: 
 All serious and non-serious AEs with explicit attribution to any Pfizer drug that 
appear in the reviewed information must be recorded on the eCRF and reported, 
within 24 hours of awareness, to Pfizer Safety using the NIS AEM Report Form. 
 Scenarios involving drug exposure, including exposure during pregnancy, exposure 
during breast feeding, medication error, overdose, misuse, extravasation, lack of 
efficacy, and occupational exposure associated with the use of a Pfizer product must 
be reported, within 24 hours of awareness, to Pfizer Safety using the NIS AEM 
Report Form. 
For these AEs with an explicit attribution or scenarios involving exposure to a Pfizer product, 
the safety information identified in the unstructured data reviewed is captured in the Event 
Narrative section of the report form, and constitutes all clinical information known regarding 
these AEs.  No follow-up on related AEs will be conducted. 
 
All the demographic fields on the NIS AEM Report Form may not necessarily be completed, 
as the form designates, since not all elements will be available due to privacy concerns with 
the use of secondary data sources.  While not all demographic fields will be completed, at the 
very least, at least one patient identifier (e.g., gender, age as captured in the narrative field of 
the form) will be reported on the NIS AEM Report Form, thus allowing the report to be 
considered a valid one in accordance with pharmacovigilance legislation.  All identifiers will 
be limited to generalities, such as the statement “A 35-year-old female...” or “An elderly 
male...”  Other identifiers will have been removed.       
Additionally, the onset/start dates and stop dates for “Illness”, “Study Drug”, and “Drug 
Name” may be documented  in month/year (mmm/yyyy) format rather than identifying the 
actual date of occurrence within the month /year of occurrence in the day/month/year 
(DD/MMM/YYYY ) format.” 
 
All research staff members must complete the following Pfizer training requirements:    
  “YRR Training for Vendors Working on Pfizer Studies (excluding interventional 
clinical studies and non-interventional primary data collection studies with 
sites/investigators)”.  

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These trainings must be completed by research staff members prior to the start of data 
collection.  All trainings include a “Confirmation of Training Certificate” (for signature by 
the trainee) as a record of completion of the training, which must be kept in a retrievable 
format.  Copies of all signed training certificates must be provided to Pfizer.  
Re-training must be completed on an annual basis using the most current Your Reporting 
Responsibilities training materials. 
 
11.1. Single Reference Safety Document 
The InO Summary of Product Characteristics 15 will serve as the Single Reference Safety 
Document (SRSD) during the course of data collection part of the study, which will be used 
by Pfizer safety to assess any safety events reported to Pfizer Safety by the investigator 
during the course of this study.  
The SRSD should be used by the investigator for prescribing purposes and guidance. 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
The study will be reported according to the requirements of Strengthening the reporting of 
observational studies in epidemiology (STROBE)16. 
Authorship of publications arising from the study will follow the 2015 guidelines proposed 
by the International Committee of Medical Journal Editors (ICMJE)17.  All authors will meet 
the criteria for authorship, and all people who meet the criteria will be authors.  Potential 
conflicts of interest will be disclosed.  All authors will have:  
 made substantial contributions to conception or design or acquisition of data, or 
analysis and interpretation of data; AND 
 participated in drafting the article or revising it critically for important intellectual 
content; AND  
 approved the final version to be published. 
Each author will meet all of these conditions and all individuals meeting these criteria will be 
authors.  Acquisition of funding, collection of data, or general supervision of the research 
group does not justify authorship.  Each author will have participated sufficiently in the work 
to take public responsibility for appropriate portions of the content. 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 

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information which might influence the evaluation of the benefits and risks of a Pfizer 
product, Pfizer should be informed immediately.   
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this NI study protocol that the investigator becomes aware of. 
 
 

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13. REFERENCES 
1.  Redaelli A, Laskin BL, Stephens JM, et al. A systematic literature review of the clinical 
and epidemiological burden of acute lymphoblastic leukaemia (ALL). European Journal 
of Cancer Care 2005; 14: 53–62. 
2.  Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review 
and 2017 update. Blood Cancer J 2017; 7: e577. 
3.  Tavernier E, Boiron J-M, Huguet F, et al. Outcome of treatment after first relapse in 
adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. 
Leukemia 2007; 21: 1907–1914. 
4.  Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute 
lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 2007; 
109: 944–950. 
5.  Thota S, Advani A. Inotuzumab ozogamicin in relapsed B-cell acute lymphoblastic 
leukemia. European Journal of Haematology 2017; 98: 425–434. 
6.  Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab Ozogamicin versus Standard 
Therapy for Acute Lymphoblastic Leukemia. N Engl J Med 2016; 375: 740–753. 
7.  Kantarjian HM, DeAngelo DJ, Advani AS, et al. Hepatic adverse event profile of 
inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic 
leukaemia: results from the open-label, randomised, phase 3 INO-VATE study. Lancet 
Haematol 2017; 4: e387–e398. 
8.  European Medicines Agency - Find medicine - Besponsa, 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/00411
9/human_med_002109.jsp&mid=WC0b01ac058001d124 (accessed 2 July 2018). 
9.  Inotuzumab ozogamicin for treating relapsed or refractory acute lymphoblastic 
leukaemia [ID893] | Guidance and guidelines | NICE, 
https://www.nice.org.uk/guidance/gid-ta10091/documents/html-content (accessed 15 
August 2018). 
10.  Giralt S, Ballen K, Rizzo D, et al. Reduced-Intensity Conditioning Regimen Workshop: 
Defining the Dose Spectrum. Report of a Workshop Convened by the Center for 
International Blood and Marrow Transplant Research. Biology of Blood and Marrow 
Transplantation 2009; 15: 367–369. 
11.  Concato J, Peduzzi P, Holford TR, et al. Importance of events per independent variable 
in proportional hazards analysis I. Background, goals, and general strategy. Journal of 
Clinical Epidemiology 1995; 48: 1495–1501. 

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12.  Resources - International Society for Pharmacoepidemiology, 
https://www.pharmacoepi.org/resources/guidelines_08027.cfm (accessed 7 June 2018). 
13.  ENCePP Home Page, http://www.encepp.eu/index.shtml (accessed 7 June 2018). 
14.  European Union. General Data Protection Regulation, http://eugdpr.org/the-
regulation.html (25 May 2018, accessed 6 April 2018). 
15.  IBRANCE 75 mg hard capsules - Summary of Product Characteristics (SmPC) - (eMC), 
https://www.medicines.org.uk/emc/product/4449/smpc (accessed 28 June 2018). 
16.  STROBE Statement: Available checklists, https://www.strobe-
statement.org/index.php?id=available-checklists (accessed 7 June 2018). 
17.  International Committee of Medical Journal Editors (ICMJE). ICMJE uniform 
requirements for manuscripts, http://www.icmje.org/about-icmje/faqs/icmje-
recommendations/ (2017, accessed 6 September 2017). 
18.  Chatterjee T, Mallhi RS, Venkatesan S. Minimal residual disease detection using flow 
cytometry: Applications in acute leukemia. Med J Armed Forces India 2016; 72: 152–
156. 
 
 
 

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14. LIST OF TABLES  
Table 2: List of endpoints and variables required to address the objectives of the study 
Table 3. Dataset to be collected according to study time points 
 
15. LIST OF FIGURES 
Figure 1. Schematic of study design 
 
16. ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
Number 
Document reference 
number 
Date 
Title 
1 
B193 
InO_Incl_Excl_criteria 
15 08 2018 
Inclusion and exclusion criteria for InO 
CUP 
2 
INO1_Inotuzumab_rr_
Phpos and neg_Bcell_A
06 09 2018 
Inclusion and exclusion criteria for InO 
NHS Commissioning for adults 
 
 
 

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17. ANNEX 2. ADDITIONAL INFORMATION 
Table 4. Dataset to be collected according to study time points 
Variables 
Study time points 
Pre-index 
observation 
period 
Baseline 
 
Index 
date  
Post-
initiation 
observat
ion 
period  
Other  
Date of birth (MM/YY) 
 
 
 
 
 
M/F 
 
 
 
 
 
ECOG performance status 
 
 
 
 
 
InO first cycle:  
 
dates of infusion 
 
doses administered at each date, if 
dose is modified add reason for 
modification 
 
date of end of cycle  number 
 
if decision taken to discontinue 
treatment: date discontinuation, 
reasons 
 
 
 
 
 
InO second cycle:  
 
dates of infusion 
 
doses administered at each date, if 
dose is modified add reason for 
modification 
 
date of end of cycle  number 
 
if decision taken to discontinue 
treatment: date discontinuation, 
reasons 
 
 
 
 
 
InO additional cycles:  
 
cycle number  
 
dates of infusion 
 
doses administered at each date, if 
dose is modified add reason for 
modification 
 
date of end of cycle  number 
 
if decision taken to discontinue 
treatment: date discontinuation, 
reasons 
 
 
 
 
 
Response to InO treatment: 
 
Treatment cycle number  
 
Date response recorded 
 
number of days into cycle 
response recorded 
 
 
 
 
 

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Variables 
Study time points 
Pre-index 
observation 
period 
Baseline 
 
Index 
date  
Post-
initiation 
observat
ion 
period  
Other  
 
CR, CRi, no response, progression  
 
MRD negative, MRD positive 
If CR/CRi response to InO 
treatment is not recorded in 
patient’s medical notes for a specific 
cycle, then collect the following at 
time closest to the end of cycle to be 
able to infer CR/CRi and MRD 
negativity (see Annex 2 for 
operational definition): 
 
Cycle number 
 
platelets levels  
 
ANC levels  
 
peripheral leukaemic blasts 
 
bone marrow blasts 
 
Ongoing extramedullary disease 
in the visceral organs, lymph 
nodes, and the central nervous 
system: Yes/No (interval from 
date started to date resolved needs 
to include date of end of cycle)  
 
 
 
 
 
If MRD negativity response to InO 
treatment is not recorded in 
patient’s medical notes for a specific 
cycle, then collect the following at 
time closest to the end of cycle to be 
able to infer CR/CRi and MRD 
negativity (see Annex 2 for 
operational definition): 
 
Cycle number 
 
PCR results providing percentage 
of leukaemic cells in bone marrow 
nucleated cells 
 
Or alternatively, 
immunophenotyping by flow-
cytometry results  providing 
percentage of leukaemic cells in 
bone marrow nucleated cells 
 
 
 
 
 
ALL diagnosis: 
 Date of first diagnosis. 
 
 
 
 
 

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Variables 
Study time points 
Pre-index 
observation 
period 
Baseline 
 
Index 
date  
Post-
initiation 
observat
ion 
period  
Other  
 
Phase of disease at receipt of 
Inotuzumab CR, 1st relapse, 2nd 
relapse , 3rd relapse, 4th or greater 
relapse 
 CD22-expression test results: 
positive/negative 
 
Cytogenetic test result: MLL-
AF4; BCR-ABL; low 
hypodiploidy/near triploidy; 
complex karyotype  e 
 Relapsed at index date: Yes/No 
 Refractory at index date: Yes/No 
Liver diseases diagnosed prior to 
index date: 
 
Name 
 
date diagnosis 
 
Diagnosed before/after ALL 
diagnosis 
 
at index date, ongoing / resolved   
 
 
 
 
 
Full blood counts, date, result 
(including unit) for:  
 platelets  
 ANC 
 
 
 
 
 
Liver function tests: date, result and 
ULN for:  
  ALT 
 AST  
 ALP 
 Bilirubin 
 Albumin 
 gamma glutamyl transferase.   
 
 
 
 
 for 
ALT, 
AST and 
bilirubin 
in 
patients 
with 
follow-
up 
HSCT, at 
time of 
follow-
up HSCT 
(up to 3 
months 
before) 
 
Peripheral blood blast counts of 
patients 
 
 
 
 
 in 
patients 
with 
 

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Variables 
Study time points 
Pre-index 
observation 
period 
Baseline 
 
Index 
date  
Post-
initiation 
observat
ion 
period  
Other  
follow-
up 
HSCT, at 
time of 
follow-
up HSCT 
(up to 3 
months 
before) 
ALL relapses prior to InO:  
 
date of relapses 
 
Name, start and stop dates, and 
best response to treatment for 
relapses prior to InO (list to be 
determined and may include: 
fludarabine- and anthracycline-
containing regimens, 
blinatomumab) 
 
 
 
 
 
 
Treatment history for ALL (all since 
diagnosis) prior to InO: 
 
 
1st line chemotherapy 
according to national trial or 
treatment guideline  
 
Blinatumomab treatment 
 
Number of lines of salvage 
therapy 
 
Prior HSCTs: number (0, 1, 2, 
≥3) and type of  conditioning 
regimen for each HSCT: high-
dose myeloablative, reduced-
intensity, nonmyeloablative 
 
CAR T-cell therapies: number 
(0, 1, ≥2) 
  
 
 
 
 
 
ALL refractory prior to InO: 
 
Name, start and stop dates, and 
best response to treatment prior to 
InO 
 
 
 
 
 
 
Concomitant medication to InO 
 
 (if 
 
 
 

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Variables 
Study time points 
Pre-index 
observation 
period 
Baseline 
 
Index 
date  
Post-
initiation 
observat
ion 
period  
Other  
treatment:  
 Azole antifungal therapy including 
fluconazole, voriconazole, 
itraconazole and posaconazole: date 
started, date end 
medicati
on during 
InO 
treatment
) 
AEs: name, date start, date end, grade, 
treatment given and response to 
treatment:  
 Documented diagnoses of VOD/SOS 
 grade 3/4 TRAEs affecting the lung,  
cardiac system, or kidney 
 
 
 
 
 
For each HSCT after initiation of 
InO: 
 
date 
 
InO treatment completed at 
HSCT: Yes / No 
 
Conditioning regimens prior to 
HSCT including Busulfan other 
alkylating agents (names and date 
start, date end); full intensity / 
reduced intensity conditioning 
 
Response to HSCT: CR, CRi, 
progressive disease, stable disease, 
alive/dead after HSCT 
 
 
 
 
 
Chemotherapy treatment after 
initiation of InO:  
 
 name, regimen, start date 
 
Response to chemotherapy 
treatment: CR, CRi, progressive 
disease, stable disease, alive/dead 
at end of treatment 
 
 
 
 
 
CAR-T cell therapy after InO:  
 
start date 
 
response to CAR-T cell therapy: 
CR, CRi, progressive disease, 
stable disease, alive/dead at end of 
treatment 
 
 
 
 
 
Patient status at the end of data 
collection period (alive/dead) 
 date of death / last clinic visit 
 Cause of death 
 If not known (i.e. lost to follow-up), 
 
 
 
 
 

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Variables 
Study time points 
Pre-index 
observation 
period 
Baseline 
 
Index 
date  
Post-
initiation 
observat
ion 
period  
Other  
date of last recorded hospital visit. 
Note: All dates are DD/MM/YYYY for all patients, except for date of birth (MM/YY). If 
dates are not available as DD/MM/YYYY, dates will be recorded as MM/YYYY instead.  
 
 
 

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List 1. Operational definitions for clinical endpoints  
Salvage therapy: therapy initiated in patients in whom initial induction therapy does not 
achieve remission (refractory ALL) or patients who entered remission and then subsequently 
relapsed (relapsed ALL), with the aim to induce remission of ALL. 
Complete Remission (CR): defined as documented in medical records  or (if unavailable in 
the records) as < 5% blasts in the bone marrow and the absence of peripheral blood 
leukaemic blasts, full recovery of peripheral blood counts (platelets ≥ 100 × 109/L and 
absolute neutrophil counts (ANC) ≥ 1 × 109/L) and resolution of any extramedullary disease.  
Complete Remission with incomplete haematological recovery (CRi): defined as 
documented in medical records  or (if unavailable in the records) as < 5% blasts in the bone 
marrow and the absence of peripheral blood leukaemic blasts, incomplete recovery of 
peripheral blood counts (platelets <100 × 109/L and ANC < 1 × 109/L) and resolution of any 
extramedullary disease. 
 Minimal Residual Disease (MRD) negativity: patients with ALL may be in remission 
(CR/CRi) although they may still harbour a large number of undetected malignant cells 
(MRD), and as such may be more susceptible to relapse. MRD describes diseases that can be 
diagnosed by methodology other than conventional morphology, and includes molecular 
methods like PCR, or immunophenotyping by flow-cytometry18. MRD negativity will be 
defined as documented in medical records or (if unavailable in the records) as leukaemic 
cells comprising < 1 × 10-4 (< 0.01%) of bone marrow nucleated cells.  
CR/CRi Rate: proportion of patients who achieve CR/CRi at the end of treatment with InO.  
MRD negativity Rate: the proportion of patients in whom MRD-negative status is observed 
at the end of treatment with InO (2-3 cycles of 3-4 weeks each in patients proceeding to 
follow-up HSCT, and up to 6 cycles of 3-4 weeks each otherwise).  
Overall Survival (OS): time from index date to death. Patients will be censored at the end of 
the post-index observation period.  
Relapse Free survival (RFS): time from index date to earliest date of the following events: 
death, progressive disease (including objective progression, relapse from CR/CRi, treatment 
discontinuation due to global deterioration of health status), and start of new induction 
therapy or post-therapy HSCT without achieving CR/CRi; as documented in medical records 
(if unavailable, infer using definitions above).  Patients will be censored at the end of the 
post-index observation period. 

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Salvage therapy: Therapy initiated in patients in whom initial induction therapy does not 
achieve remission (refractory ALL) or patients who entered remission and then subsequently 
relapsed (relapsed ALL), with the aim to induce remission of ALL.