A Retrospective Analysis of Inotuzumab Ozogamicin (InO) Usage in Adult Patients With Relapsed/Refractory (R/R) B-cell Acute Lymphoblastic Leukemia (ALL)
Conditions: Adult Relapsed/Refractory B Cell Acute Lymphoblastic Leukemia
Sponsor: Pfizer

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“NON-INTERVENTIONAL (NI) STUDY PROTOCOL”
Study information
Title
A retrospective analysis of Inotuzumab ozogamicin
(InO) usage in adult patients with 
relapsed/refractory (R/R) B-cell Acute 
Lymphoblastic leukemia (ALL)
Study Design
A multicentric retrospective cohort analysis of adult 
R/R B-cell ALL patients treated with Inotuzumab 
ozogamicin at tertiary care institutions.
Protocol number
B1931043
Protocol version identifier
Version 1.0
Date
14 November 2022
Active substance
Antineoplastic agents, other Antineoplastic agent,
monoclonal antibodies, ATC code: L01XC26
Inotuzumab Ozogamicin
Medicinal product
Inotuzumab Ozogamicin
Research question and 
objectives
We aim to carry out a multicentric retrospective 
cohort analysis with data of approximately 55
patients treated with Inotuzumab ozogamicin 
monotherapy to provide clinical outcomes in real-
world clinical practice in India.
Author
PPD

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This document contains confidential information belonging to Pfizer.  Except as otherwise 
agreed to in writing, by accepting or reviewing this document, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by 
applicable law) or use it for unauthorized purposes.  In the event of any actual or suspected 
breach of this obligation, Pfizer must be promptly notified.
PPD

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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................3
2. LIST OF ABBREVIATIONS................................................................................................5
3. KEY DEFINITIONS .............................................................................................................7
4. RESPONSIBLE PARTIES....................................................................................................8
5. ABSTRACT.........................................................................................................................10
6. MILESTONES.....................................................................................................................11
7. RATIONALE AND BACKGROUND................................................................................12
8. RESEARCH QUESTION AND OBJECTIVES .................................................................13
9. RESEARCH METHODS ....................................................................................................14
9.1. Study design /Setting...............................................................................................14
9.1.1. Inclusion criteria .........................................................................................14
9.1.2. Exclusion criteria........................................................................................14
9.1.3. Primary endpoint ........................................................................................15
9.1.4. Secondary endpoints...................................................................................15
9.2. Data sources ............................................................................................................15
9.3. Study size ................................................................................................................16
9.4. Data management....................................................................................................16
9.4.1. Collection, Monitoring, Processing of Data and Archiving: ......................16
9.4.2. Case report forms (CRFs)/Data collection tools (DCTs) ...........................17
9.4.3. Record Retention ........................................................................................17
9.5. Data analysis ...........................................................................................................18
9.6. Quality control.........................................................................................................18
9.6.1. Monitoring and Quality Control:................................................................18
9.6.2. Reporting and Publication of Data: ............................................................19
9.7. Limitations of the research methods .......................................................................19
10. PROTECTION OF HUMAN SUBJECTS ........................................................................19
10.1. PATIENT INFORMATION .................................................................................20
11. INSTITUTIONAL REVIEW BOARD (IRB)/INDEPENDENT ETHICS COMMITTEE 
(IEC)....................................................................................................................................20
11.1. Ethical conduct of the study..................................................................................20

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12. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................21
13. SAFETY REPORTING.....................................................................................................22
14. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........23
15. ANNEX 1. LIST OF STAND ALONE DOCUMENTS ...................................................23
16. REFERENCES: .................................................................................................................23

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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
ADC
antibody-drug conjugate
AE
adverse event
AEM
adverse event monitoring
allo-HCT
allogeneic hematopoietic stem cell transplantation
CNS
central nervous system
CR
complete remission
Cri
complete remission with incomplete hematologic 
recovery
CRF
case report form
DOR
duration of remission
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HSCT
haematopoietic stem cell transplantation
IEC
Independent Ethics Committee
ICMJE
International Committee of Medical Journal Editors
InO
Inotuzumab ozogamicin
IQR
interquartile range
IRB
Institutional Review Board
MoAb
monoclonal antibody 
MRD 
minimal residual disease
NIS
non-interventional study
OS 
overall survival 

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Ph
Philadelphia chromosome 
R/R B cell ALL
Relapsed/Refractory/ B Cell Acute lymphoblastic 
leukemia
RFS
relapse free survival
SD
standard deviation
SDV
source data verification
SOS
sinusoidal obstruction syndrome
TKI
tyrosine kinase inhibitor
TRAE
treatment-related adverse event
US
United States
VOD
veno-occlusive disease
YRR
your reporting responsibilities

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3. KEY DEFINITIONS
Index date: The date of initiation of the first cycle of InO.
Baseline period: Period from 6 months before index date to the 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).
CR/CRi rate: Number of patients who achieve complete remission/complete remission with 
incomplete hematologic recovery (CR/Cri) divided by the total number of patients completing 
treatment with InO (defined as patients with a recorded date of discontinuation of InO).
Complete remission (CR): is defined as 5% bone marrow blasts, no evidence of disease in the bone 
marrow, and recovery of peripheral blood count (platelet count of > 100 x 109/L and absolute 
neutrophil count of > 1 x 109/L). 
CR with incomplete count recovery (CRi): is defined as 5% bone marrow blasts and no evidence of 
disease in the bone marrow, but with incomplete recovery of peripheral blood count. Minimal 
residual disease (MRD) will be assessed at each participating institution by multicolor flow 
cytometry.
MRD negativity rate: Proportion of patients in whom minimal residual disease (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), or the start of new induction therapy or posttherapy haematopoietic 
stem cell transplantation (HSCT) without achieving CR/CRi.
EMD: Extramedullary disease is the presence of leukemic cell aggregates in the form of solid tumor
outside that of bone marrow.i
LBL: lymphoblastic lymphoma, is a clonal hematopoietic stem cell disorder of B or T cell originii

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4. RESPONSIBLE PARTIES
Name
Job Title
Affiliation
E-Mail
Principal Investigator(s) of the Protocol
Name, 
degree(s)
Job Title
Affiliation
Address
PPD
PPD

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PPD

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5. ABSTRACT
    None

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6. MILESTONES
Milestone
Planned date
Start of data collection
01 December 2022
End of data collection
28 March 2023
Final study report
15 June 2023

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7. RATIONALE AND BACKGROUND
B-cell acute lymphoblastic leukemia (ALL) is a malignant transformation and proliferation of 
lymphoid progenitor cells in the bone marrow, blood,and extramedullary sites. Only 20% of ALL 
occurs in adult patients.iii Incidence data on adult B-cell ALL in India is lacking.iv The regimens used 
for pediatric patients with B-cell ALL are mostly used for the treatment of adult patients with B-cell 
ALL. The treatment of B-cell ALL in adults is mostly based on regimens developed for pediatric 
patients.
Most chemotherapy regimens used to treat adults with B-cell ALL in India consists of multi-agent 
induction, intensification or consolidation, and maintenance phases, together with central nervous 
system (CNS) prophylaxis using intrathecal chemotherapy, with or without cranial irradiation. 
Commonly used cytotoxic agents in first line treatment protocol for adult patients with B-cell ALL 
are cyclophosphamide, vincristine, daunorubicin, L-asparaginase and prednisolone. The prognosis of 
R/R B-cell ALL has historically been dismal with complete remission (CR) rates of 20-40%, median OS 
of 6 months, and cure rates of < 10% even with intensive salvage chemotherapy and HSCTv.
R/R B-cell ALL in adults is a challenging disease, with high mortality resulting from refractory disease 
or toxicity from intensive chemotherapy regimens. The only curative option in this subset of patients 
is CR after salvage therapy followed by allo-HCT. Even salvage regimens in case of relapse are mostly 
composed of old agents used in first-line protocols. Although second remissions are possible, with 
these salvage regimes, these are of short duration unless an allogeneic stem cell transplant is 
feasible.vi The data on the outcomes of salvage therapy in adult patients with B-cell ALL is lacking 
from India. However, Novel therapies such as InO have improved the outcomes of this subset of 
patients, with more patients experiencing CR and minimal residual disease negativity, thus 
becoming eligible for allo-HCT. The real-world data on the use of Ino monotherapy in cases of adult 
R/R B cell ALL is limited in Indian settings with knowledge gaps relating to diagnostic and treatment 
practices. Currently, only a single study is available with CUP data from 8 patients. 
InO is an antibody-drug conjugate consisting of a recombinant, humanized IgG4 antibody (G544) 
covalently bound to a semi synthetic derivative of calicheamicin. Calicheamicin, a cytotoxic natural 
product produced by microbial fermentation that is significantly more potent than conventional 
cytotoxic chemotherapeutic agents, binds to the DNA minor groove and causes cell death by 
inducing double strand DNA breaks. The targeting agent in InO, (G544) specifically recognizes human 
CD22, which is expressed on the malignant cells of the majority of B-lymphocyte malignancies, 
including on the surface of blasts in >90% of patients with B cell ALL.vii In 2017, the United States 
(US) Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved InO for 
the treatment of adult with R/R B-cell precursor B-cell ALL.viii,ix
            Inotuzumab: mode of action and literature evidence 
ALL is the second most common acute leukemia in adults. The characteristic features are 
chromosomal abnormalities and genetic alterations involved in differentiation and proliferation of 
lymphoid precursor cells. The backbone of therapy remains multi-agent chemotherapy with 

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vincristine, corticosteroids and an anthracycline with allogeneic stem cell transplantation for eligible 
candidates.x
The advent of moAb targeting CD22 (InO) and CD19 (blinatumomab), have dramatically improved 
the outcome of adults with R/R B cell ALL. These have shown significant survival benefits against 
standard therapies and expanded the armamentarium of ALL.xi
InO is an anti-CD22 moAb conjugated to the cytotoxic antibiotic calicheamicin. Based on promising 
phase I/II data, InO was compared to standard salvage chemotherapy in Phase 3 multicenter trial 
(INO-VATE) of 218 adult patients with CD22+ B cell ALL. The overall response and MRD negativity 
rates among responders were significantly higher with InO compared with chemotherapy (81% 
versus 29%, p < 0.001, and 78% versus 28%, p < 0.001, respectively). More patients who received 
InO were able to undergo HSCT (41% versus 11%; p < 0.001). The median remission duration and 
progression-free survival were significantly longer with InO (4.6 versus 3.1 months; p = 0.03, and 5.0 
versus 1.8 months; p < 0.001, respectively). The median OS was 7.7 versus 6.7 months (p = 0.04). 
This was later confirmed with longer follow-up on 326 patients showing 2-year OS rates of 23% 
versus 10% (p = 0.01) in favor of InO [24]. Predictors for better survival included achievement of CR, 
MRD negativity, and consolidative HSCT. Patients who achieved MRD negativity derived more 
benefits regardless of the number of prior therapies.xii
InO is an ADC comprising of a moAb targeting CD22,xiii a cell surface antigen expressed on 
approximately 90% of B-cell malignancies,xiv linked to a cytotoxic agent.
CD22 is an important modulator of B-cell lymphocyte function and survival,xv and is expressed on 
mature B-cells, which may allow for targeted delivery of the cytotoxic agent.xvi
When InO binds to the CD22 antigen on malignant B-cells, it is absorbed into the cell, at which point 
the cytotoxic agent calicheamicin is released to destroy the cell.xvii
Adding an ADC targeting CD22, such as InO, to existing treatments options, may provide additional 
anti-tumor activity.xviii
8. RESEARCH QUESTION AND OBJECTIVES
We aim to carry out a multicentric retrospective cohort analysis study with data from approximately 
55 patients to observe clinical outcomes among patients treated with InO monotherapy in real-
world clinical practice in India. 

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9. RESEARCH METHODS
This research is designed as a multicenter, retrospective study. Site investigators, namely 
hematologists /oncologists who are experienced in treating hematological malignancies in India will 
drive this research. 
9.1. Study design /Setting
The study is classified as a Non-interventional study (NIS) secondary data collection- unstructured 
review with sites/investigators.
R/R B-cell ALL patients who are 18 years old at the time of InO initiation and those who received the 
drug outside of clinical trials will be evaluated. 
Data will be collected retrospectively from patients hospital medical records (paper-based ) by 
members of the direct care team (investigators).  We intend to have 7- 10 sites across India using 
InO monotherapy including patients with both private purchase and compassionate use to reach a 
cohort of approximately 55. If needed, more sites will be enrolled to meet the target cohort. Data 
will be reviewed and analyzed from all the sites. 
Medical records will be reviewed to collect demographic, patient-related, disease-related, and 
clinical outcome data. These patients will be evaluated for response (CR/CRi), MRD status, duration 
of remission (DOR), Dosage patterns, Rate of transplant, Overall survival in all patients including 
Survival rate at 6 months and 12 months in transplanted patients & non transplanted patients,
Relapse free survival (RFS), Rate of VOD (Total, during study treatment and post HSCT if any patient 
underwent HSCT), safety/tolerability, Other adverse effects (including hematological toxicities and 
raised liver enzymes), No of cycles to achieve MRD negativity in responders & CR/CRi in EMD/LBL.
9.1.1. Inclusion criteria

Patients must meet all of the following inclusion criteria to be eligible for inclusion in the study:

Patient Population -

Patients aged ≥18 years old at the initiation of InO treatment

Patients with relapsed/refractory B-cell ALL

Patients who initiated InO monotherapy between Feb’2017 and Feb’2022 and are CD22 positive 

Ph+ patients who have failed treatment with at least 1 TKI
9.1.2. Exclusion criteria

Patient not completing at least 1 cycle of InO therapy

Patient on InO in combination with chemotherapy

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Following local legislation, informed consent won’t be signed by the patients since this is a 
retrospective study and they are not getting enrolled in a prospective clinical trial. All data 
points mentioned in the inclusion criteria should be available which are necessary to analyze
protocol endpoints for the selected patient cohort who has undergone the full treatment of the 
drug in question. Ethics Committee approval of study protocol will be taken to access medical 
records.
9.1.3. Primary endpoint
Complete remission or complete remission with incomplete hematological recovery following 
treatment with InO, by the number of salvage therapies (0, 1, ≥2) received before InO initiation.
9.1.4. Secondary endpoints

MRD Negativity following initiation of Ino

Number of cycles of InO needed to attain CR/CRi

DOR

Dosage pattern: InO doses, dose modifications, and the number of cycles of treatment; 

Concomitant medications

Rate of transplant (No of patients who proceeded to transplant)

Survival rate at 6 months & 12 months (transplanted patients & non transplanted patients, in 
both who achieved CR/CRi and MRD negativity)

Cause of death

Relapse-free-survival; in all patients and patients with or without follow-up HSCT.

Rate of VOD (Total, during study treatment and post HSCT, if any patient underwent HSCT) in 
transplanted & non transplanted patients.

Occurrence of Grade 3/4 treatment-related adverse events in lung/cardiac/kidney/liver etc 
following InO initiation; in all patients and patients with or without follow-up HSCT & 
hematological toxicities

CR/CRi in EMD/LBL 
All these parameters will be assessed in the following subgroups –

1st salvage and later lines

High burden and Low burden disease (<50%; 50-90%; >90%)

Ph +ve and Ph – ve patients

Elderly patients> 65 years
9.2. Data sources
Data for this study will be collected through retrospective data collection from 7-10 sites for patients 
in India who received Inotuzumab for the indication of adult R/R B Cell ALL between the time period 
Feb’2017 –  Feb’2022. Additional centers may be added at a later stage if the target sample size is 
not achieved.

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Data will be collected in anonymized form on Paper/excel based CRF 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.
Medical records will be reviewed from secondary data sources to collect demographic, patient-
related, disease-related, and clinical outcome data & AE’s. These patients will be evaluated for 
response, duration of response (DOR), OS from the time of InO initiation till 6 months or 1 year of 
therapy and toxicity
Data to be verified in accordance with Protocol standards. Before obtaining the data from the 
selected sites across the nation, the necessary regulatory approval will be ensured.
9.3. Study size
This is a descriptive study and there is no prior hypothesis specified, therefore a formal power 
calculation is not required. The sample size of approximately 55 patients has been based on the 
number of patients expected to be available at these 7-10 sites that individually treated the largest 
number of patients with InO
The study will include information on approximately 55 patients as per the availability of data from 
7-10 sites.
9.4. Data management 
9.4.1. Collection, Monitoring, Processing of Data and Archiving:
Data pertaining to all fields required to fulfill the primary and secondary endpoints of the study will 
be captured in a paper Case Report Form (CRF). Data from the paper CRF will then be transferred to 
an excel master managed by Insignia. Data entry, data query generation & resolution, source 
document verification & database lock will be performed as per standard GCP guidelines.
Rules for completing CRFs
Print legibly using preferably a black/blue ballpoint pen. Ensure that all questions are answered and
that no empty data blocks exist. Ensure that no information is recorded outside the data blocks.
If the question is irrelevant (eg, is not applicable) indicate this by writing “NA” (not applicable) in the 
respective ensure that all information derived from source documentation is consistent with the 
source information. By signing the affirmation statement, the Investigator confirms that the 
information answer field. 
The investigator staff must is complete and correct.
Corrections to CRFs:
Corrections to the data on the CRFs must only be made by drawing a straight line through the 
incorrect data and by writing the correct value next to data that has been crossed out.  Each 
correction must be initialed, dated and explained by the Investigator or the Investigator’s authorised 
staff.

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Monitoring of CRFs:
Filled case report forms will be checked for accuracy by designated staff before sending them to 
Insignia for data entry, validation and analysis.  The case report forms will be checked and collected 
in a mutually agreed frequency. Investigator will be responsible for the retention of patient notes for 
1 year from the study closeout
9.4.2. Case report forms (CRFs)/Data collection tools (DCTs)
As used in this protocol, the term CRF should be understood paper-based case report form for 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 paper case report 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.
The source documents are the hospital or the physician's chart.  In these cases, data collected on the 
CRFs must match those charts. 
9.4.3. 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), 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 telephone call reports).  The records 
should be retained by the investigator according to local regulations or as specified in the clinical 
study agreement (CSA), whichever is longer.  The investigator must ensure that the records continue 
to be stored securely for as 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 

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records must be transferred to a designee acceptable to Pfizer, such as another investigator, 
another institution, or an independent third party arranged by Pfizer. 
Study records must be kept for a minimum of 15 years after completion or discontinuation of the 
study, unless Insignia Communications Pvt Ltd and Pfizer have expressly agreed to a different period 
of retention via a separate written agreement.  Record must be retained for longer than 5 years or 
as required by applicable local regulations. 
The investigator & Insignia Communications must obtain Pfizer's written permission before 
disposing of any records, even if retention requirements have been met.
9.5. Data analysis 
All qualitative outcomes will be summarized by frequency and percentage. The quantitative 
outcome will be summarized by mean and SD if data is symmetric, otherwise median, and IQR. The 
outcomes will also be classified and compared across different demographic and relevant clinical 
factors. External validity will be assessed by t-test/ANOVA or chi-square test of indepdence 
depending on the nature of the outcome. However, observations will be generalized for the 
population the selected patients would represent. p-value<0.05 will be considered statistical 
significance. A standard statistical software will be used for data analysis.
9.6. Quality control
9.6.1. Monitoring and Quality Control:
Insignia representative or delegate will:
Establish the adequacy of the facilities and the investigator’s capability to appropriately select the 
sample.
Discuss with the investigator(s) (and other personnel involved with the study) their responsibilities 
with regard to protocol compliance, and the responsibilities of Insignia or its representatives.  
During the study, the Insignia representative or delegate can implement different activities to assure 
compliance with Insignia’s standards of quality. These activities could include but are not limited to:
Contacts with the sites to:
Provide information and support to the investigator(s).
Ensure that the research team is complying with the protocol and that data are being accurately 
recorded in the CRFs.
Ensure that the CRFs are completed properly and with adequate quality.
Post-entry pre-analysis data validation will be performed, and if any information is missing or 
incorrect, the sites will be contacted.
Monitoring activities for:
Checking that patients exist in medical records (a sample)
The extent and nature of monitoring will be mutually decided. If the study in charge is suspicious of 
a potential non-optimal level of protocol compliance by the site investigator, specific measures 
should be adopted to evaluate the situation, identify the issue and implement specific action plans 
to correct the situation.

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9.6.2. Reporting and Publication of Data:
Insignia will prepare a Study report within 2 months after the completion of the last patient.
If a report of the study is published, the contribution of participating doctors will be duly 
acknowledged.
Insignia is obliged to analyze and report all study data as described in the protocol. 
In accordance with the Declaration of Helsinki, both authors and publishers have ethical obligations. 
In publication of the results of the study, the authors are obliged to preserve the accuracy of the 
results.  Negative as well as positive results should be published or otherwise publicly available.  
Insignia endeavors to publish the results of study and is committed to ensure that the data are 
reported in a responsible and coherent manner.
Insignia seeks to ensure that publications in biomedical journals follow the guidelines established by 
the International Committee of Medical Journal Editors (ICMJE) and published in its Uniform 
Requirements of Manuscripts Submitted to Biomedical Journals. 
Insignia is committed to ensuring that authorship for all publications should comply with the criteria 
defined by the ICMJE.  These state that: "Each author should have participated sufficiently in the 
work to take public responsibility for the content."
9.7. Limitations of the research methods

The medical records may not be available for each & every data points provided in the CRF, from 
the aspect of the clinician or the patient.

Patients may be lost to follow-up due to the occurrence of AEs, lack of efficacy or other reasons.

This could be due to censoring events, that is, information on time to outcome event may not 
available for all study participants. Patient/s in such cases will be marked as "censored" when 
such information on time to event is not available due to loss to follow-up or non-occurrence of 
outcome events before the end of the study. 

For such patients (censored because of lost to follow-up due to the occurrence of AEs, lack of 
efficacy or other reasons), the use of Kaplan-Meier curves will be obtained as estimates of 
median OS, RFS and time to CR/Cri taking 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, Source data verification (SDV) will be employed to identify and correct 
abstraction errors.
10. PROTECTION OF HUMAN SUBJECTS
In this retrospective study, the anonymity of patients is of utmost importance. Several measures are 
taken to ensure the confidentiality of the collected information. Reviewers, monitors and data 
analysts are under a confidentiality agreement with the CRO to maintain the secrecy of the 

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information. Study personnel would never contact individual patients or physicians. During the data 
collection, the records would never be left unattended and will always be stored in a locked room. 
Approval from the institutional review board and ethics committee, the custodians of patient data 
privacy, will be obtained.
Patient identifiers will be kept in a dataset separately from the primary database. 
10.1. PATIENT INFORMATION 

All parties will comply with all applicable laws, including laws regarding the implementation of 
organizational and technical measures to ensure the 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 e-CRF excel 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 
personal data can be recovered in the event of a disaster.  In the event of a potential personal 
data breach, the study site shall be responsible for determining whether a personal data breach 
has occurred and, if so, providing breach notifications as required by law.

To protect the rights and freedoms of natural persons concerning 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.
10.2. Institutional review board (IRB)/Independent ethics committee (IEC)
There must be prospective approval of the study protocol, protocol amendments, and other 
relevant documents (e.g., informed consent forms if applicable) from the relevant IRBs/IECs.  All 
correspondence with the IRB/IEC must be retained.  Copies of IRB/IEC approvals must be forwarded 
to Pfizer. 
IRBs/IEC review and approval for each site will be obtained for access to anonymized patient 
medical records. 
10.3. Ethical conduct of the study
The study will be performed following ethical principles that are consistent with the Declaration of 
Helsinki, ICH GCP, ICMR, and the applicable legislations. The Investigator will perform the study in 
accordance with the regulations and guidelines governing medical practice and ethics in the country 

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of the study and in accordance with currently acceptable techniques and know-how and in 
accordance to the below mentioned guidelines.
1.
Guidelines for Good Pharmacoepidemiology Practices (GPP). Public Policy Committee,
International Society of Pharmacoepidemiology. Pharmacoepidemiology and Drug Safety
2.
Good Practices for Outcomes Research issued by the International Society for
Pharmacoeconomics and Outcomes Research (ISPOR)
3.
Good practices for real-world data studies of treatment and/or comparative effectiveness:
Recommendations from the joint ISPOR-ISPE Special Task Force on real-world evidence in
health care decision making
4.
European Medicines Agency (EMA) European Network of Centres for
Pharmacoepidemiology and Pharmacovigilance (ENCePP) Guide on Methodological
Standards in Pharmacoepidemiology
5.
FDA Guidance for Industry and FDA Staff: Best Practices for Conducting and Reporting
Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS 

All AEs will be captured from the medical records. 

Number of Participants Who Experienced a Documented Diagnosis of Veno-occlusive Disease 
(VOD)/Sinusoidal Obstruction Syndrome (SOS) Post InO Treatment. 

Number of Participants Who Survived Following Treatment For Documented Diagnoses of Veno-
occlusive Disease (VOD)/Sinusoidal Obstruction Syndrome (SOS).

Number of Participants With Interrupted InO Treatment Due to VOD/SOS.

Number of Participants Who Experienced Grade 3 and Grade 4 (Lung/Cardiac/Kidney/Liver) 
Treatment-Related Adverse Event (TRAE) Following InO initiation.

All hematological AEs: Neutropenia, febrile neutropenia, and thrombocytopenia

Being NIS secondary data collection– This study involves retrospective patients treated with InO 
for R/RB-cell ALL data that exist as unstructured data by the time of study start or a combination 
of existing unstructured data, which will be converted to structured form during the 
implementation of the protocol solely in an excel using CRF template.

It is not possible to link (ie, identify a potential association between) a particular product and 
medical event for any individual. Thus, the minimum criteria for reporting an AE (ie, identifiable 
patient, identifiable reporter, a suspect product, and event) cannot be met.

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12. SAFETY REPORTING

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 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 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 case report form & AE reporting form 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 exposure during pregnancy in studies of pregnant women, data on the exposure to InO
during pregnancy, are not reportable unless associated with serious or non-serious adverse 
events. 

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 (eg, 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.   

All research staff members must complete the following Pfizer training requirements:   
“Your Reporting Responsibilities (YRR) Training for Vendors.”
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. 

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13. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable competent 
authority in any area of the world, or if the investigator is aware of any new information which 
might influence the evaluation of the benefits and risks of a Pfizer product, Pfizer should be 
informed immediately.
14. ANNEX 1. LIST OF STAND ALONE DOCUMENTS
         None
15. REFERENCES:
i Shah H, Halpern J and Sakellis C. Extramedullary Leukemia - A Pictorial Atlas. Journal of Nuclear Medicine 
2021; 62 (supplement 1): 2036
ii Kaseb H, Tariq MA, Gupta G. Lymphoblastic Lymphoma. [Updated 2022 Oct 11]. In: StatPearls [Internet]. 
Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: 
https://www.ncbi.nlm.nih.gov/books/NBK537237/
iii Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 
update. Blood Cancer J. 2017;7(6):e577. Published 2017 Jun 30
iv Samra B, Jabbour E, Ravandi F, Kantarjian H, Short NJ. Evolving therapy of adult acute lymphoblastic 
leukemia: state-of-the-art treatment and future directions. J Hematol Oncol. 2020;13(1):70.
v Samra B, Jabbour E, Ravandi F, Kantarjian H, Short NJ. Evolving therapy of adult acute lymphoblastic 
leukemia: state-of-the-art treatment and future directions. J Hematol Oncol. 2020;13(1):70.
vi Boni J et al. Modeling the Pharmacokinetic/Pharmacodynamic Platelet Response of Inotuzumab 
Ozogamicin, a Novel Antibody Drug Conjugate, Administered Alone or in Combination with Rituximab 
in Patients with Non-Hodgkin’s Lymphoma. Accepted Poster Presentation at the European Society of 
Medical Oncology 2010 Annual Meeting, October 8-12, 2010. Milan, Italy
vii Leonard J et al. Epratuzumab, a Humanized Anti-CD22 Antibody, in Aggressive Non-Hodgkin’s Lymphoma: 
a Phase I/II Clinical Trial Results. Clinical Cancer Research. 2004; 10: 5327-5334.
viii Dorner T. Targeting CD22 as a Strategy for treating systemic autoimmune diseases. Therapeutics and 
Clinical Risk Management. 2007; 3: 953-959.
ix DiJoseph J et al. Antibody-Targeted Chemotherapy with CMC-544: a CD22 Targeted Immunoconjugate of 
Calicheamicin for the Treatment of B-Lymphoid Malignancies. Blood. 2004; 1-3: 1807- 1814
                                                

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x Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 
update. Blood Cancer J. 2017;7(6):e577. Published 2017 Jun 30
xi Samra B, Jabbour E, Ravandi F, Kantarjian H, Short NJ. Evolving therapy of adult acute lymphoblastic 
leukemia: state-of-the-art treatment and future directions. J Hematol Oncol. 2020;13(1):70
xii Samra B, Jabbour E, Ravandi F, Kantarjian H, Short NJ. Evolving therapy of adult acute lymphoblastic 
leukemia: state-of-the-art treatment and future directions. J Hematol Oncol. 2020;13(1):70
xiii Boni J et al. Modeling the Pharmacokinetic/Pharmacodynamic Platelet Response of Inotuzumab 
Ozogamicin, a Novel Antibody Drug Conjugate, Administered Alone or in Combination with Rituximab 
in Patients with Non-Hodgkin’s Lymphoma. Accepted Poster Presentation at the European Society of 
Medical Oncology 2010 Annual Meeting, October 8-12, 2010. Milan, Italy.
xiv Leonard J et al. Epratuzumab, a Humanized Anti-CD22 Antibody, in Aggressive Non-Hodgkin’s Lymphoma: 
a Phase I/II Clinical Trial Results. Clinical Cancer Research. 2004; 10: 5327-5334.
xv Dorner T. Targeting CD22 as a Strategy for treating systemic autoimmune diseases. Therapeutics and 
Clinical Risk Management. 2007; 3: 953-959
xvi DiJoseph J et al. Antibody-Targeted Chemotherapy with CMC-544: a CD22 Targeted Immunoconjugate of 
Calicheamicin for the Treatment of B-Lymphoid Malignancies. Blood. 2004; 1-3: 1807- 1814.
xvii Boni J et al. Modeling the Pharmacokinetic/Pharmacodynamic Platelet Response of Inotuzumab 
Ozogamicin, a Novel Antibody Drug Conjugate, Administered Alone or in Combination with Rituximab 
in Patients with Non-Hodgkin’s Lymphoma. Accepted Poster Presentation at the European Society of 
Medical Oncology 2010 Annual Meeting, October 8-12, 2010. Milan, Italy
xviii  DiJoseph JF. Antitumor Efficacy of a Combination of CMC-544 (Inotuzumab Ozogamicin), a CD22-
Targeted Cytotoxic Immunoconjugate of Calicheamicin, and Rituximab against Non-Hodgkin’s B-Cell 
Lymphoma. Clin Cancer
Res. 2006; 12: 242-250

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PFIZER CONFIDENTIAL
Staff must always refer to and follow the current official electronic document repository version.
This document was created based on 
CT24-WI-GL02-RF08 3.0 Non-Interventional Study Protocol Administrative Change Letter Checklist 01-Aug-2023
Page 2 of 2
3
6. MILESTONES
Change in Milestones-
Planned Date
Start of data collection - 13
February 2023
End of data collection - 05 July
2023
Final Study report - 10 October 
2023
4
9. RESEARCH 
METHODS 9.3 Study 
size
Sample size changed to
32 subjects
Sample size is changed to 32 
subjects
5
11. MANAGEMENT 
AND REPORTING OF 
ADVERSE 
EVENTS/ADVERSE 
REACTIONS
12. SAFETY 
REPORTING
To clarify the adverse 
event reporting 
requirements for 
structured and 
unstructured data 
components. Also, to 
correct the inconsistency 
with the protocol 
template language.
The last 2 paragraphs of Section 
11 should be moved to the 
beginning of Section 12, Adding
12.1 Structured 
2 paragraphs are pasted and 
revised.
In addition, add a second sub-
12.2 Human Review of 
the 
original content of Section 12.
In the event that this protocol requires substantial changes that apply globally to all sites in the 
future or regulatory authorities request that these changes be incorporated into an updated 
protocol, the administrative changes described in this letter will be incorporated into the 
amended protocol.
Please inform your institutional review board/ ethics committee of these changes, as required.
Sincerely,
Dr. 
cc: NI study master file
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