Non-Interventional Study Protocol

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 1 of 62

NON-INTERVENTIONAL STUDY PROTOCOL

TITLE Clinical Presentation, Treatment, and Outcomes of Grade 2-4 Acute Graft Versus Host Disease (GVHD) Patients after Allogeneic Hematopoietic Stem Cell Transplants (HSCT): A Multi -Center Chart Audit Study - AGHOS

PROTOCOL/STUDY NO. INCB -EUMA-GVHD-001

VERSION Version: 1.0 28 th June 2019

CLIENT Incyte Biosciences International Sàrl , Route de la Corniche 1, Bâtiment Terrasse, 1066 Epalinges, Switzerland

CONDUCTED BY IQVIA Technology and Services AG, Theaterstrassen 4, 4051 Basel, Switzerland

This protocol contains confidential information that should only be disclosed to those persons responsible for execution and organization of the study and on condition that all such persons agree not to further disseminate it.

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Copyright © 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. DocuSign Envelope ID: B72AA6FE-63A8-4550-9584-69676F907FFF

Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 2 of 62 TABLE OF CONTENTS

INVESTIGATOR SIGNATURE PAGE ...... 4 CLIENT SIGNATURE PAGE...... 5 INFORMATIONAL CONTACTS...... 6 STUDY SYNOPSIS...... 10 DOCUMENTATION OF PROTOCOL AMENDMENTS ...... 20 1. BACKGROUND...... 21 2. RATIONALE...... 24 3. OBJECTIVES...... 24 4. STUDY DESIGN ...... 25 4.1 Study Description...... 25 4.2 Study Population ...... 28 Inclusion Criteria...... 28 Exclusion Criteria...... 29 Study Enrollment...... 29 4.3 Exposure Definition and Measures ...... 31 4.4 Outcome Definition and Measures...... 31 Clinical Outcome Measures ...... 31 Other Measures at patient level ...... 31 4.5 Data Sources and Collection ...... 32 Data collected at site level...... 33 Data collected at patient level ...... 34 5. STATISTICAL METHODS...... 40 5.1 Sample Size ...... 40 5.2 Data Analyses...... 41

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 3 of 62 General Considerations ...... 41 Planned Analyses ...... 42 Handling of Missing Data ...... 46 Limitations of Research Methods...... 47 Interim Analysis and Reporting ...... 48 Final Analyses and Reporting ...... 48 6. STUDY MANAGEMENT ...... 48 6.1 Data Entry/Electronic Data Capture...... 48 6.2 Source Documents...... 48 6.3 File Retention and Archiving ...... 49 6.4 Quality Assurance and Monitoring ...... 49 6.5 Data Management...... 50 6.6 Changes to the Protocol...... 50 6.7 Publication Policy...... 51 7. SAFETY REPORTING ...... 51 7.1 Definitions...... 51 7.2 Procedures for Reporting Adverse Events (AEs) to Incyte Biosciences International ...... 54 8. ETHICAL AND REGULATORY CONSIDERATIONS...... 56 8.1 Guiding Principles...... 56 8.2 Patient Information and Informed Consent ...... 56 8.3 Patient Confidentiality...... 57 8.4 Independent Ethics Committee (IEC)/Institutional Review Board (IRB)...... 58 9. REFERENCES ...... 59 10. APPENDICES...... 61

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 4 of 62 Investigator Signature Page Study Title: Clinical Presentation, Treatment, and Outcomes of Grade 2-4 Acute Graft Versus Host Disease (GVHD) Patients after Allogeneic Hematopoietic Stem Cell Transplants (HSCT): A Multi- Center Chart Audit Study. Protocol version 1.0 dated 28 th June 2019 I have read and understand the protocol and agree that it contains the ethical, legal and scientific information necessary to participate in this study. My signature confirms the agreement of both parties that the study will be conducted in accordance with the protocol and all applicable laws and regulations including, but not limited to good pharmacoepidemiology practices (GPP), and the ethical principles that have their origins in the Declaration of Helsinki and applicable privacy laws. I will provide copies of this protocol as needed to all physicians, nurses, and other professional personnel responsible to me who will participate in the study. I will discuss the protocol with them to assure myself that they are sufficiently informed regarding the conduct of the study. I am aware that this protocol will need to be approved by an appropriate institutional review board (IRB) or independent ethics committee (IEC) prior to any patients being enrolled and that I am responsible for verifying whether that requirement is met. I agree to adhere to the attached protocol and if requested to provide copies of medical information for the purpose of verification of submitted information, I will comply. Since the information in this protocol is confidential, I understand that its disclosure to any third parties, other than those involved in approval, supervision, or conduct of the study is prohibited. I will ensure that the necessary precautions are taken to protect such information from loss, inadvertent disclosure, or access by third parties. Investigator:

Print Name

Signature Date

Print Name of Institution or Practice and Location

RETURN ORIGINAL TO IQVIA RETAIN COPY

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28th June 2019 INCB-EUMA-GVHD-001 Page 5 of 62 Client Signature Page Reviewed and Approved by:

Signature Title Date

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28th June 2019 INCB-EUMA-GVHD-001 Page 6 of 62 Informational Contacts Client The Marketing Authorisation Holder (MAH) will serve as the Client of this study. It is the responsibility of the MAH to ensure proper monitoring of the study and compliance with all applicable regulatory guidelines and laws.

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 7 of 62 List of Abbreviations

ADR Adverse drug reaction AE Adverse event ALL Acute Lymphocytic Leukemia AML Acute Myeloid leukemia ATG Antithymocyte globulin BKV BK virus BMI Body mass index BTK Bruton’s tyrosine kinase CIBMTR Center for International Blood and Marrow Transplant Research CLL Chronic Lymphocytic Leukemia CML Chronic myeloid leukemia CMV Cytomegalovirus CRO Clinical research organization CTT Clinical trial technician DLBCL Diffuse Large B-cell Lymphoma DLI Donor Lymphocyte Infusion DRI Disease Risk Index EBMT European Society for Blood and Marrow EBV Epstein-Barr virus ECOG Eastern Cooperative Oncology Group Performance Status ECP Extracorporeal photopheresis eCRFs Electronic case report forms EDC Electronic data capture EMA European Medicines Agency ER Emergency room FL Follicular Lymphoma GI Gastrointestinal GITMO Gruppo Italiano Trapianto Midollo Osseo GPP Good pharmacoepidemiology practices GVHD Graft versus host disease HCRU Healthcare resource utilization HCT-CI Hematopoietic Cell Transplantation-Comorbidity Index HL Hodgkin Lymphoma

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 8 of 62 HLA Human leukocyte antigen HSCT Hematopoietic Stem Cell Transplant HSV herpes simplex virus IBMTR International Bone Marrow Transplantation Registry IEC Independent ethics committee ICF Informed consent form ICMJE International Committee of Medical Journal Editors ICU Intensive care unit IRB Institutional review board ISPE International Society for Pharmacoepidemiology ITK Interleukin-2-inducible T cell kinase KPS Karnofsky Performance Status MAGIC Mount Sinai Acute GVHD International Consortium MAH Marketing authorization holder MCL Mantle Cell Lymphoma MDS Myelodysplastic syndrome MedDRA Medical dictionary for regulatory activities MMF Mycophenolate mofetil MPN Myeloproliferative neoplasm mTOR Mammalian target of rapamycin MM Multiple Myeloma NHI National Institutes of Health Q1 First quarter Q2 Second quarter Q3 Third quarter Q4 Fourth quarter RAEB-1 Refractory anemia with excess blasts type 1 RAEB-2 Refractory anemia with excess blasts type 2 SAE Serious adverse event SAP Statistical analysis plan SLL Small Lymphocytic Lymphoma SR Steroid-refractory STROBE STrengthening the Reporting of OBservational studies in Epidemiology TCF Transplant center form UK United Kingdom Template No.: RWI_TP_EPI0011 Revision 1 Reference: RWI_WI_EPI0005

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 9 of 62 VZV Varicella zoster virus

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Study Synopsis

Full Study Title : Clinical Presentation, Treatment, and Outcomes of Grade 2-4 Acute Graft Versus Host Disease (GVHD) Patients after Allogeneic Hematopoietic Stem Cell Transplants (HSCT): A Multi -Center Chart Audit Study

Phase: Non -interventional study Type: Observational

Number of Patients : 307 Duration of Patient Participation : Retrospective

Number of Sites : approximately 25 sites from 4 Duration of study : Approximately 16 months since European countries protocol development until study report including 2-3 months for data abstraction per site

Background: Graft-versus-host disease (GVHD) is a clinical syndrome caused by the response of transplanted donor allogeneic cells to histocompatibility antigens expressed on tissues of the transplantation recipient. It is the most serious complication of allogeneic hematopoietic stem cell transplant (HSCT) 1. Acute GVHD is classically defined as GVHD that develops within 100 days of transplant, while chronic GVHD occurs beyond 100 days. Treatment for GVHD depends on disease grade, affected tissue and whether the disease is acute or chronic. There is good evidence in support of first-line therapy with corticosteroid therapy (prednisone / methylprednisolone). However, up to 50% of all patients will be unresponsive to steroids. In patients who develop steroid-resistant disease, second-line treatment remains controversial. The choice of treatment is complicated by the heterogeneous nature of the patient characteristics, including organ involvement, age, conditioning regimens, GVHD prophylaxis and type of HSCT. Treatment options include cyclosporine, tacrolimus, mycophenolate mofetil (MMF), Anti-thymocyte Globulin (ATG), pentostatin, interleukin-2 receptor antagonists (denileukin, daclizumab, inolimomab, basiliximab), antitumor necrosis factor antibodies (infliximab, etanercept), extracorporeal photopheresis, mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), methotrexate, anti-CD52 monoclonal antibodies (alemtuzumab), other monoclonal antibodies (muromonab, visilizumab), mesenchymal stem cells, and anti-IL6 receptor targeted therapies, among others 2. A variety of novel agents are also under development, including JAK inhibitors (ruxolitinib), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), S1P receptor modulators (fingolimod, ponesimod), CTLA4-Ig fusion proteins (abatacept), Bruton’s tyrosin e kinase (BTK) and Interleukin-2-inducible T cell kinase (ITK) inhibitors (ibrutinib), Syk inhibitors (fostamatinib), NE inhibitor (AZD9668), and hedgehog inhibitors (vismodegib, sonidegib) 3. Supportive care that includes antimicrobial/antibiotic prophylaxis is also an important part of GVHD treatment.

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 11 of 62 The evaluation of GVHD treatments is challenged by heterogeneous patient characteristics, the lack of a clear definition of steroid-refractory (SR) disease and inconsistent treatment endpoints. Therefore, treatment regimens across transplant centers are varied and often depend on financial considerations, the availability of different treatments, and physician preference.

Rationale: Given a lack of understanding and consensus about real-world treatment patterns, and a lack of robust clinical evidence in support of the most effective treatment options, the objectives of this study are to describe the clinical presentation, treatment patterns, clinical outcomes and healthcare utilization among patients who developed a grade 2-4 acute GVHD based on the Mount Sinai Acute GVHD International Consortium (MAGIC) criteria [or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the International Bone Marrow Transplantation Registry (IBMTR) criteria] after allogeneic HSCT in 4 European countries: Germany, Italy, Sweden and Finland. The present study will be conducted in parallel but operationally independently in France and in the UK.

Objectives: The primary objective of the present study is to describe the clinical presentation, treatment patterns, and clinical outcomes of patients aged 18 or older who developed a grade 2-4 acute GVHD based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria) stratifying by country. Specifically, the objectives of the present study will be to: 1. Describe the clinical presentation of patients with grade 2-4 acute GVHD based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria). 2. Describe treatment patterns (e.g. first and second-line therapies, duration of therapy, and time to second - line therapy) among patients with grade 2-4 acute GVHD based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria) 3. Describe clinical outcomes (e.g. response to therapy, non-relapse mortality) among patients with grade 2-4 acute GVHD based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria), at 6 and 12 months after acute GVHD diagnosis and until death or last data available. 4. Describe the characteristics of participating transplant centers. 5. Describe healthcare resource utilization (HCRU) (e.g. hospitalizations) among patients with grade 2-4 acute GVHD based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria).

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 12 of 62 Secondary objectives The present study aims to describe clinical presentation, treatment patterns and clinical outcomes at 6 and 12 months after acute GVHD diagnosis and until death or last data available of patients with grade 2-4 acute GVHD based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria)stratifying according to the following variables: - SR status - Severity grade (based on the most common index used to grade included patients) - Donor type

Study design: This is a non -interventional, retrospective chart audit study in Germany, Italy, Sweden and Finland. Adult patients who received an allogeneic HSCT between January 1, 2016 and June 30, 2017 and were diagnosed with grade 2 -4 acute GVHD based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria) at least 12 months before the data collection will be retrospectively included. The diagnosis of acute GVHD (early onset acute, classical acute, or late onset acute) may occur at any time since HSCT transplant until 12 months prior to the data collection. The present study will be conducted in parallel but operationally independently in France and in the United Kingdom ( UK). The patient identification period starts on June 30, 2017 and ends on January 1, 2016. The index date is the day the patient received the allogeneic HSCT. Overall, centers will be asked to include approximately between 4 and 25 eligible patients. The specific number of patients included per center will be defined at site level based on the total number of transplants performed during the patient identification period. Patients will be included retrospectively and consecutively, starting with those who received a HSCT on June 30, 2017 and developed aGVHD and going backwards until January 1, 2016 or until the sample size has been reached, whatever occurs first . The patients’ chart will be reviewed since index date until the day of data collection or u ntil death or loss to follow -up, whichever occurs first. Time from the allogeneic HSCT (index date) till the end of follow-up is defined as the follow-up period.

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 13 of 62 1st Jan 31 st March 30 th Jun 30 th Sep 31 st Dec 31 st March 30 th Jun 2016 2016 2016 2016 2016 2017 2017

RETROSPECTIVE IDENTIFICATION OF PATIENTS 1st January 2016 Data collection

Minimum 12 months follow up

Patient 1 Patient 2 Patient 3 Patient 4

Baseline: Allogenic HSCT Event: Acute GVHD Follow up event : end of follow-up, loss to follow-up or death.

Study population: The study will aim to enroll approximately 307 patients from a total of approximately 25 centers in Germany, Italy , Sweden and Finland . Sites will be specialized institutions that routinely perform allogenic HSCT and are members of the European Society for Blood and Marrow (EBMT). Based on data currently available from the E BMT registry and additional information retrieved through an initial feasibility questionnaire including specialized sites from all three countries, the patient distribution across countries and the approximate number of sites which are estimated to partic ipate in each country is presented below:

Approx. Number of Approx. Total approx. number Country patients Number of sites of patients per site

Germany 137 8 5-25

Italy 130 13 4-25

Sweden 20 2 5-15

Finland 20 2 5-15

Inclusion criteria

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 14 of 62 The following criteria must be met in order to be enrolled in the study:

· Patient who received a first allogeneic HSCT between January 1 , 2016 and June 30, 2017, from any donor source using bone marrow, peripheral blood stem cells, or cord blood. · Patient diagnosed with acute GVHD (including early onset acute, classical acute or late onset acute) graded 2-4 based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria) any time since transplant to 12 months prior to the data collection. · Patient aged 18 years and older at the time of acute GVHD development. Patient with clinical records containing the main clinical characteristics related with the original disease requiring allogenic HSCT, and clinical information on acute GVHD presentation and treatment Exclusion criteria Patients meeting ANY of the following criteria are not eligible for participation: · Patient who have received more than one HSCT · Patient participating in a GVHD prophylaxis trial with a primary completion date later than 31 Dec 2018 or in any GVHD treatment trial at any point of the data collection period (from January 2016 until time of data collection, death or loss to follow up). · Patients who experience disease progression before the first acute GVHD episode. · Patients who experience an acute GVHD following a Donor Lymphocyte Infusion (DLI). Data collection/Data Sources: Patient data will be collected from the patient’s medical records and entered into the electronic Case Report Forms ( eCRF). For each eligible patient, data will be collected from transplant to patient death, or the end of data availability (or most recent follow-up visit).

Data collection will be standardized using an eCRF that will allow to capture: · Data at site level: A Transplant Center Form (TCF) will be used to obtain transplant center information. · Data at patient level: this will allow to collect c omprehensive data, including patient demographics, transplant characteristics, clinical presentation of acute GVHD, acute GVHD treatments, clinical outcomes, and healthcare resource utilization.

Data collected at site level · Geographic location of transplant center · Type of center, including whether academic/community center and if conduct pediatric HSCTs · Number of physicians dedicated to allotransplant activity for more than 90% of the working time are employed at the institution (current) · Number of adult allogeneic HSCTs conducted between January 1, 2016 and June 30, 2017 · Type of transplants conducted between January 1, 2016 and June 30, 2017 (first HSCT, autologous, allogenic)

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 15 of 62 · Existence of a long-term follow-up or GVHD clinic Approximate percentage of patients regularly followed up at outpatient/inpatient setting after HSCT · Criteria used to grade acute GVHD · Protocols and therapies used to treat acute GVHD · Definition used to classify SR status for acute GVHD · Proportion of patients who develop severe acute GVHD and approximate range of patients treated for severe acute GVHD at the institution · Month and year when cyclophosphamide was introduced for the prophylaxis of acute GVHD and type of patients it was approved for based on donor relationship

Patient demographic and general characteristics · Patient still alive at the time of data collection (yes/no) o For patients still alive, ICF signature date (if applicable) o For deceased patients § ICF required according to local regulation (yes/no), if not necessary, date of death § Next of kin consent obtained (yes/no), if obtained, date of signature and date of death § Requirement for anonymous data collection due to local regulation (yes/no), if required, year of death · Year of birth · Sex (not collected in case of anonymous data collection) · Weight at transplant (Kg) · Height at transplant (cm) · Body Mass Index (BMI) (in Kg/m²) (directly calculated from height and weight, if available)

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 16 of 62 o Date of transplant (only month and year for anonymous data collection) o Donor sex and age o Stem cell source o Donor type o Donor and recipient Cytomegalovirus (CMV) status o Degree of human leukocyte antigen HLA match, location of HLA mismatch (if applicable) o Level of chimerism achieved and dates for each determination available (for coded data collection) and maximum level of chimerism (for anonymous data collection) o Transplant conditioning regimen o Transplant conditioning regimen type · Prophylaxis therapy for acute GVHD: treatment received, start date (only month and year for anonymous data collection), and stop date (not collected in anonymous data collection), treatment duration (only for anonymous data collection), start dose, units, frequency, route and highest dose received and units and whether treatment was received as part of an interventional clinical trial (yes/no) o Ex-vivo T-cell depletion o In-vivo T-cell depletion (ATG, Alemtuzumab, other) o Cyclosporine o Steroid o Tacrolimus-based o Cyclophosphamide o Methotrexate o Mycophenolate o Sirolimus o Extracorporeal photophoresis (ECP) o Other Clinical characteristics, treatment and outcomes of acute GVHD · Date of diagnosis (only month and year for anonymous data collection) · ECOG or KPS score at acute GVHD diagnosis · Biopsies performed (yes/no) to skin, GI (lower/upper), liver or other · Acute GVHD stage (MAGIC, Glucksberg, Keystone, and/or IBMTR, if available) at diagnosis · Organ symptom involvement at diagnosis based on MAGIC (skin, GI lower/upper and liver) · Development of infections: type of infection [fungal, viral (varicella zoster virus infection, CMV active infection without organ disease, CMV active infection with organ disease, asymptomatic CMV DNAemia, Other), parasitic], date of infection diagnosis (not collected for anonymous data collection). · Treatment of acute GVHD: variables to be collected for each line of therapy: o Reason for treatment initiation (only for second and subsequent lines and if different from treatment discontinuation)

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 17 of 62 o Medication prescribed and date of first response to treatment and whether the patient was SR for corticosteroids o Start and stop dates (not collected in anonymous data collection), treatment duration (only for anonymous data collection) and whether these are continued in subsequent treatment lines for each drug o Dose and highest dose administered, units and frequency for each drug (only for first and second line) o Route of administration for each drug (only for first and second lines) o Date (for anonymous data collection, treatment duration will be collected instead of date) and reason for discontinuation (Disease resolved, No response, Partial response, Primary malignancy relapse, Infection, Patient decision, Death, Other Adverse Events (AEs), Worsening of acute GVHD, development of GVHD in another organ, Worsening of acute GVHD, Development of acute GVHD in another organ, Other, Unknown) for each drug o Best overall response based on physician’s clinical criteri a and date (complete response, very good partial response, partial response, mixed response, progressive disease, no response, not assessed, other) o Acute GVHD stage at initiation and finalization of each line of therapy o Organ symptom involvement based on MAGIC (skin, GI lower/upper and liver) at initiation and finalization of each line of therapy (only for first and second line of therapy) · Clinical outcomes of acute GVHD at 6 and 12 months (± one month) since acute GVHD onset and at most recent follow up: o Reason for death (related /non-related with GVHD for deceased patients only) and time from acute GVHD to death (only for anonymous data collection) o Date of most recent follow up prior to data collection (not collected for anonymous data collection) time from acute GVHD and most recent follow up (only for anonymous data collection) o Acute GVHD stage (Glucksberg, Keystone, MAGIC and/or IBMTR, if available) at 6 and 12 months (± one month) since acute GVHD onset and at most recent follow up o Reoccurrence of acute GVHD, date (not collected for anonymous data collection), time from acute GVHD and development of chronic GVHD (only for anonymous data collection) and action taken (re-started steroid, maintained steroid, increased steroid dose, added another therapy, other) o Development of chronic GVHD, date (not collected for anonymous data collection), time from acute GVHD and development of chronic GVHD (only for anonymous data collection) and severity o Development of overlap syndrome and date o Overall acute GVHD response at 6 and 12 months (±one month) and at most recent follow up (complete response, very good partial response, partial response, mixed response , progressive disease, no response, not assessed, other) o Presence of symptoms at 6 and 12 months (± one month) and at most recent follow up

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 18 of 62 o Organ symptom involvement (skin, GI lower/upper and liver) based on M at 6 and 12 months (±one month) and at most recent follow up

Health Related Resource Utilization since acute GVHD · Hospitalizations/inpatient admissions: o Date of admission and date of discharge (not collected in anonymous data collection) or length of hospitalization (for anonymous data collection) o Reason for hospitalization (transplant that lead to the development of acute GVHD, related to acute GVHD or other) o ICU stay during hospitalization (length of ICU stay) · Outpatient and Emergency (ER) department visits: o Date (if available) o Type of visit (outpatient/emergency) o Reason for the visit (related to acute GVHD or other)

Data Management and Quality Assurance: Before data collection begins, a data management plan (DMP) will be developed. The DMP will describe all functions, processes, and specifications for data collection, cleaning and validation and will be aligned to the DMP developed for the studies implemented in France and in the UK to ensure consistency between the electronic data capture (EDC) system s used by each CRO to collect the data. The eCRFs will include programmable edit checks to obtain immediate feedbac k if data are missing, out of range, illogical or potentially erroneous that will also be aligned between the different EDC systems to ensure consistency of the data collected in each country so that it can be pooled and analyzed together . Concurrent manual data review will be performed, and ad hoc queries will be generated within the EDC systems and followed-up for resolution. High data quality standards will be maintained, and processes and procedures utilized to repeatedly ensure that the data are as clean and accurate as possible when presented for analysis. Data quality will be enhanced through a series of programmed data quality checks that automatically detect out of range or anomalous data .

Safety: This is a non -interventional study based on secon dary use of data collected from healthcare professionals or consumers for other purposes. No administration of any therapeutic or prophylactic agent is required in this protocol, and there are no procedures required as part of this protocol.

As the colle ction of information concerns secondary use of data only, AEs should not be actively submitted to the Sponsor in this study. All AEs /reactions collected for this study will be captured in the eCRF and summarized in the final study analysis report.

There are certain circumstances in which individual AEs may need to be reported following local legislation. In addition, for Incyte’s products only, any spontaneous AEs, other safety information (special situations), or quality complaint relating to an Incyte medicinal product(s), should be reported to Incyte within 24 hours of the

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 19 of 62 date first becoming aware of such AE, safety information or quality complaint (e-mail: [email protected], and/or via phone: +800 000 27423 (EU Universal Toll Free) or +41 (0) 445834495 (Swiss Local Toll Paid)).

Statistical Considerations: All disease diagnosis (e.g. comorbidities) and medical procedures’ verbatim terms will be recorded and coded using the Medical Dictionary for Regulatory Activities (MedDRA). The same dictionary version will be used across the EDC systems used in this study. All computations and generation of tables, listings and data for figures will be performed using SAS ® version 9.2 or higher (SAS Institute, Cary, NC, USA). The analysis plan will be fully described in a written and approved statistical analysis plan (SAP). Descriptive analyses will be performed to gain an understanding of the qualitative and quantitative nature of the data collected and the characteristics of the sample s tudied. Continuous variables will be reported as mean (and standard deviation [SD] ) or median and range where appropriate. Categorical variables will be summarized as number and proportion of the total study population, and by subgroups where appropriate. Descriptive data will be reported at the study population level and stratified by country, not at center -level. In addition, tables will be also reported for the subsample of patients who are SR. SR patients will be those receiving more than one line of c orticosteroids. Frequencies and proportions will be used to describe categorical variables, while mean, median, range and SD will be calculated for continuous variables. Survival and other time -relevant variables may be assessed using Kaplan-Meyer survival analysis. HCRU (e.g. hospitalization) will also be descriptively assessed in the total sample, stratified by country and the subsample of patients who are SR.

Sample size This study is descriptive and is not designed to test a hypothesis. Therefore, sample size has been calculated in order to describe continuous and categorical variables with a predefined precision level. For continuous variables a coefficient of variation (standard deviation/mean) of 0.5 has been considered, a confidence level of 95%, a precision level of 0.06 and 13% as the maximum percentage of patients with non-available data due to the retrospective data collection. Based on these estimations and the fact that this is a descriptive study, a sample of 307 patients is expected to reach a precision level of 6%. If the sample is lower than expected the precision level will be that reported in the table below.

Precision level 6% 6.5% 7% 7.5% 8% 8.5%

Sample 307 262 226 197 173 153

Interim and final Analyses:

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 20 of 62 An interim analysis may be performed when approximately 60% of the patient target population has been included (n=185 patients), approximately 3 -4 months after first patient inclusion. A final report will be prepared at closure of the study database, when all data collection procedures are completed. The final report will encompass all planned analyses, including a description of the complete study population, clinical outcomes, treatment patterns, HCRU and center characteristics as described in the written SAP.

Ethical and Regulatory Considerations: This non -interventional study will be conducted in accordance with the protocol and all applicable laws and regulations including, but not limited to good pharmacoepidemiology practices (GPP) 4, and the ethical principles that have their origins in the Declaration of Helsinki and applicable privacy laws 5. Data protection and p rivacy regulations will be strictly observed in capturing, forwarding, processing, and storing patient data. Every effort will be made to protect participant confidentiality according to the Directive 95/46/EC on the protection of individuals, and in compl iance with Safe Harbor privacy principles. An Institutional review board / Independent ethics committee (IRB/IEC) must review and approve the protocol before any patients are enrolled. If required by local regulation, before any protocol -directed data coll ection is performed, the patient must sign and date the IRB/IEC -approved informed consent form 4-6. In those countries where next of kin consent or ICF waiver for unreachable patients is not acceptable for deceased patients, according to local regulation, data collection will be performed fully anonymized.

DOCUMENTATION OF PROTOCOL AMENDMENTS Not applicable (original protocol).

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 21 of 62 1. BACKGROUND

Graft-versus-host disease (GVHD) is a clinical syndrome caused by the response of transplanted donor allogeneic cells to histocompatibility antigens expressed on tissues of the transplantation recipient. It is the most serious complication of allogeneic hematopoietic stem cell transplant (HSCT) 1. Acute GVHD is classically defined as GVHD that develops within 100 days of transplant, while chronic GVHD occurs beyond 100 days. It is now recognized that clinical features of each disease occur outside of this time range, and that features of the two types may coexist, known as overlap syndrome 7. Depending on patient- and transplant-related variables, the incidence of acute GVHD ranges from 10% to 80% among patients who receive allogeneic HSCT, whereas, chronic GVHD is estimated to affect 30% to 70% of allogeneic HSCT recipients surviving beyond 100 days, with a median onset of 4 to 6 months after HSCT 2. GVHD contributes significantly to transplant-related morbidity and mortality, and transplant-related mortality is estimated to range from 28% in Grade 0 acute GVHD, to 92% in Grade 4 acute GVHD 8. Depending on the onset of Acute GVHD, these can be classified as: · Classic: first episode of acute GVHD occurs within the first 100 days after the HSCT · Late: first episode of acute GVHD occurs after the first 100-days period after the HSCT · Recurrent: Recurrence of acute GVHD occurs beyond day 100, after a period of acute GVHD control, inactivity or resolution · Persistent: acute GVHD signs persist beyond day 100 from a prior active classic acute GVHD Risk factors for developing GVHD after allogeneic HSCT include the degree of human leukocyte antigen (HLA) mismatch between donor and recipient, gender mismatch, older age, type of GVHD prophylaxis, the conditioning regimen, the stem cell source, whether the donor/recipient has ever been pregnant, and whether the donor/recipient has ever had cytomegalovirus (CMV) or Epstein-Barr virus. GVHD prophylactic regimens are standard for HSCT patients and aim to either suppress donor T-cell function with immunomodulatory agents (e.g. cyclosporine, methotrexate, tacrolimus, mycophenolate mofetil [MMF]), or deplete donor T cells before or after stem-cell infusion 9-11 .

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 22 of 62 With regards to the clinical manifestations, according to the most recent European Society for Blood and Marrow (EBMT) - NIH (National Institutes of Health) - CIBMTR (Center for International Blood and Marrow Transplant Research) GVHD Task Force 1, acute GVHD refers to the appearance of an allogeneic inflammatory response in exclusively three organs: the skin (inflammatory maculopapular erythematous skin rash), the liver (hyperbilirubinemia due to cholestatic jaundice), and the gastrointestinal (GI) tract (upper and/or lower GI tract manifestations: anorexia with weight loss, nausea, vomiting, diarrhea, severe pain, GI bleeding and/or ileus) 1. The diagnosis must occur in the absence of manifestations of chronic GVHD and should ideally be supported by positive histological findings, but this is not strictly necessary if no alternative etiology is present 1. The severity of acute GVHD has a large impact on clinical outcomes and treatment response. The Glucksberg acute GVHD classification was first proposed in the 1970s and it stage skin, lower GI tract and liver on a scale of 0 (absent) to 4 (severe) points, to provide a final overall Grade of I (mild) to IV (life-threatening) 12 . The Glucksberg classification was reviewed 20 years later to provide a modified Glucksberg or “Keystone” criteria (Table 1)13 , a couple of years later the CIBMTR proposed the International Bone Marrow Transplantation Registry (IBMTR) classification, which was based on similar raw organ staging and resulted in a final Grade of A−D ( Table 1). Most recently, the Mount Sinai Acute GVHD International Consortium (MAGIC) has revisited these criteria and recommended more precise definitions for Grade IV acute GVHD 14 (Table 1) According to the EBMT - NIH - CIBMTR GVHD Task Force, the MAGIC criteria are considered the most current and detailed criteria to diagnose and score the severity of acute GVHD 1. Table 1. Comparison of the different guidelines available for acute GvHD assessment: overall severity grading

Overall Modified Overall Glucksberg Original Glucksberg Glucksberg MAGIC IBMTR IBMTR / MAGIC criteria 12 or “Keystone criteria 14 criteria 15 Grade Grade criteria” 13 no organ involvement (skin=0; and liver=0; and GI=0) corresponds to the absence of 0 0 acute GVHD skin=1, skin=1 or 2, without liver/GI skin=1 or 2, without liver/GI without I involvement or decrease in A involvement liver/GI performance status/fever involvement

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 23 of 62 skin=2; skin=1 or 2 and (liver and/or and/or GI involvement=1 or 2) with skin=3; and/or liver=1; and/or II liver=1 or 2; B mild decrease in performance GI=1 and/or GI=1 status or 2 (skin and/or liver and/or skin=3; liver=2 or 3; GI=2, 3 or 4) with marked liver=2 or 3; and/or III and/or GI=2, C decrease in perfor mance and/or GI=2 or 3 liver=3; 3 or 4 a status and/or GI=3 (skin and/or liver and/or skin=4; and/or skin=4; and/or liver=4; and/or IV GI=2, 3 or 4) with Karnofsky D liver=4 b GI=4 <30% GI: Gastrointestinal; GVHD: Graft versus host disease; IBMTR: International Bone Marrow Transplantation Registry; MAGIC: Mount Sinai Acute GVHD International Consortium Treatment for GVHD depends on disease grade, affected tissue and whether the disease is acute or chronic. There is good evidence in support of first-line therapy with corticosteroid therapy (prednisone/methylprednisolone). However, up to 50% of all patients will be unresponsive to steroids. Although the definition of steroid-refractory (SR) remains debated, it is generally accepted that when acute GVHD worsens in any organ after 3 days of treatment, or there is no response in 5 to 14 days, secondary therapy should be considered 2. The initiation of second-line therapy may be earlier in patients with more severe disease 16 . Failure to respond to steroid therapy is also a significant predictor of non-relapse mortality 17 . In patients who develop SR disease, second-line treatment remains controversial. The choice of treatment is complicated by the heterogeneous nature of the patient characteristics, including organ involvement, age, conditioning regimens, GVHD prophylaxis and type of HSCT. Treatment options include cyclosporine, tacrolimus, MMF, antithymocyte globulin (ATG), pentostatin, interleukin-2 receptor antagonists (denileukin, daclizumab, inolimomab, basiliximab), antitumor necrosis factor antibodies (infliximab, etanercept), extracorporeal photopheresis, mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), methotrexate, anti-CD52 monoclonal antibodies (alemtuzumab), other monoclonal antibodies (muromonab , visilzumab), mesenchymal stem cells, and anti-IL6 receptor targeted therapies, among others 2. A variety of novel agents are also under development, including JAK inhibitors (ruxolitinib), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), S1P receptor modulators (fingolimod, ponesimod), CTLA4-Ig fusion proteins (abatacept), Bruton’s tyrosin e kinase (BTK) and Interleukin-2-inducible T cell kinase (ITK) inhibitors (ibrutnib), Syk inhibitors (fostamatinib), NE inhibitor (AZD9668), and hedgehog

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 24 of 62 inhibitors (vismodegib, sonidegib) 3. Supportive care that includes antimicrobial/antibiotic prophylaxis is also an important part of GVHD treatment. The evaluation of GVHD treatments is challenged by heterogeneous patient characteristics, the lack of a clear definition of SR disease and inconsistent treatment end points. Therefore, treatment regimens across transplant centers are varied and often depend on financial considerations, the availability of different treatments, and physician preference.

2. RATIONALE Given a lack of understanding and consensus about real world treatment patterns, and a lack of robust clinical evidence in support of the most effective treatment options, the objectives of this study are to describe the clinical presentation, treatment patterns, clinical outcomes and healthcare utilization among patients who developed a grade 2-4 acute GVHD based on MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria) after allogeneic HSCT in 4 European countries: Germany, Italy, Sweden and Finland. The present study will be conducted in parallel but operationally independently in France and in the United Kingdom (UK).

3. OBJECTIVES Primary objectives The primary objective of the present study is to describe the clinical presentation, treatment patterns, and clinical outcomes of patients aged 18 years or older who developed a grade 2-4 acute GVHD based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria) stratifying by country. Specifically, the objectives of the present study will be to: 1. Describe the clinical presentation of patients with a grade 2-4 acute GVHD based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria). 2. Describe treatment patterns (e.g. first and second-line therapies, duration of therapy, and time to second-line therapy) among patients with a grade 2-4 acute GVHD based on the

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 25 of 62 MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria). 3. Describe clinical outcomes (e.g. response to therapy, non-relapse mortality) among patients with a grade 2-4 acute GVHD based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria), at 6 and 12 months after acute GVHD diagnosis and until death or last data available. 4. Describe the characteristics of participating transplant centers. 5. Describe healthcare resource utilization (HCRU) (e.g. hospitalizations) among patients with a grade 2-4 acute GVHD based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria). Secondary objectives The present study aims to describe clinical presentation, treatment patterns and clinical outcomes at 6 and 12 months after acute GVHD diagnosis and until death or last data available of patients with grade 2-4 acute GVHD based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria)stratifying according to the following variables: - SR status - Severity grade (based on the most common index used to grade included patients) - Donor type

4. STUDY DESIGN

4.1 Study Description This is a non-interventional, retrospective chart audit study in Germany, Italy, Sweden and Finland. Adult patients who received an allogeneic HSCT between January 1, 2016 and June 30, 2017 and were diagnosed with a grade 2-4 acute GVHD based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 26 of 62 criteria or a B-D according to the IBMTR criteria) at least 12 months before the data collection will be retrospectively included. The diagnosis of acute GVHD (early onset acute, classical acute, or late onset acute) may occur at any time since HSCT transplant until 12 months prior to the data collection. The patient identification period starts on June 30, 2017 and ends on January 1, 2016. The index date is the day the patient received the allogeneic HSCT. Overall, centers will be asked to include approximately between 4 and 25 eligible patients. The specific number of patients included per center will be defined at site level based on the total number of transplants performed during the patient identification period. Patients will be included retrospectively and consecutively, starting with patients who received a HSCT on June 30, 2017 and developed aGVHD and going backwards until January 1, 2016 or until the sample size has been reached. (Figure 1).

Q2 2017 Q1 2017 Q4 2016 Q3 2016 Q2 2016 Q1 2016

30% 30% 10% 10% 10% 10%

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1st Jan 31 st March 30 th Jun 30 th Sep 31 st Dec 31 st March 30 th Jun 2016 2016 2016 2016 2016 2017 2017

RETROSPECTIVE IDENTIFICATION OF PATIENTS 1st January 2016 Data collection

Minimum 12 months follow up

Patient 1 Patient 2 Patient 3 Patient 4

Baseline: Allogenic HSCT Event: Acute GVHD Follow up event : end of follow-up, loss to follow-up or death.

Figure 1. Summary of the study design

The patients’ chart will be reviewed since index date until the day of data collection or until death or loss to follow-up, whichever occurs first. Time from the allogeneic HSCT (index date) till the end of follow-up is defined as the follow-up period. This follow-up period will allow for data collection on clinical characteristics, treatment patterns and outcomes of patients receiving an allogeneic HSCT and suffering an acute GVHD. The end of the study period will be defined as the date of the last data collection time point of the last patient in the study. Study observation period will last from January 1, 2016 through approximately 4th quarter 2019. Data collection is expected to be performed between second quarter 2019 and first quarter 2020, approximately. Only retrospective data available in medical records will be collected. The observation period will be equal or before patient’s inclusion in the study. A summary of the study design is shown in Figure 1.

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 28 of 62 4.2 Study Population The study will aim to enroll approximately 307 patients from a total of approximately 25 centers in Germany, Italy, Sweden and Finland. Sites will be specialized institutions that routinely perform allogenic HSCT and are members of the EBMT. Based on data currently available from the EBMT registry and additional information retrieved through an initial feasibility questionnaire including specialized sites from all three countries, the patient distribution across countries and the approximate number of sites which are estimated to participate in each country is presented in Table 2. Table 2. Sample size distribution and approximate number of sites per country

Approx. number of Approx. Number of Total approx. number of Country patients sites patients per site

Germ any 137 8 5-25

Italy 130 13 4-25

Sweden 20 2 5-15

Finland 20 2 5-15

The study investigators will be mainly hematologists and medical oncologists, among other specialties, experienced in the management of acute GVHD. The participating investigators or their delegate(s) will be responsible for abstracting the data from the patients’ medical records directly into a secure online database, electronic case record forms (eCRFs). If necessary, the completion of the eCRFs may be performed by an assigned Clinical trial technician (CTT) delegated by the sponsor depending on the site capabilities and resources. In the event that CTTs external to site are required, they will be provided specific instructions containing explicit guidelines for completion of the study forms in a step by step fashion. All personnel from the site and external to the site involved in the study will be instructed on the eCRFs.

Inclusion Criteria The following criteria must be met in order to be enrolled in the study:

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 29 of 62 · Patient who received a first allogeneic HSCT between January 1, 2016 and June 30, 2017, from any donor source using bone marrow, peripheral blood stem cells, or cord blood.

· Patient diagnosed with acute GVHD (including early onset acute, classical acute or late onset acute) graded 2-4 based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria) any time since transplant to 12 months prior to the data collection

· Patient aged 18 years and older at the time of acute GVHD development.

· Patient with clinical records containing the main clinical characteristics related with the original disease requiring allogenic HSCT, and clinical information on acute GVHD presentation and treatment

Exclusion Criteria Patients meeting ANY of the following criteria are not eligible for participation:

· Patient who have received more than one HSCT

· Patient participating in a GVHD prophylaxis trial with a primary completion date later than 31 Dec 2018 or in any GVHD treatment trial at any point of the data collection period (from January 2016 until time of data collection, death or loss to follow up).

· Patients who experience disease progression before the first acute GVHD episode.

· Patients who experience an acute GVHD following a Donor Lymphocyte Infusion (DLI).

Study Enrollment Hematologists and medical oncologists, among other specialties, who are routinely involved in the care and treatment of patients with acute GVHD will be targeted for recruitment. Site selection criteria will include: minimum number of first allogenic HSTS over the identification window period (January 2016-June 2017), out of this, minimum number patients who developed an acute GVHD since January 2016 until June 2018 and acceptance

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 30 of 62 of rules and responsibilities related to the study (Table 3). To the extent possible, representative sites reflective of the treatment patterns within each country will be recruited. Selection criteria and basic site information (e.g. site size, investigator specialty, site type) will be collected via a site qualification survey. Prior to study enrollment, centers that conduct HSCTs will be pre-screened using a site feasibility questionnaire. Screening criteria will include the number of allogeneic HSCTs conducted during the study period and the number of patients diagnosed with acute GVHD during the study period who meet study criteria. Eligibility requirements to be assessed in this questionnaire for each country are displayed in Table 3.

Table 3. Eligibility requirements to be assessed in the site feasibility questionnaire in order to be eligible to participate in the study for each country

Germany Italy Sweden Finland

Minimum number of first allogenic HSCT over the 10 8 3 3 identification window period (January 2016-June 2017)

Out of the patients defined above, minimum number patients who developed an acute GVHD since January 4 4 1 1 2016 until June 2018

Acceptance of rules and responsibilities related to the Yes Yes Yes Yes study

GVHD: Graft versus host disease; HSTC: Hematopoietic stem cell transplant

No clinic visits are required as part of participation in this study. All assessments are intended to be performed at the time of a routine clinical encounter or by referencing the medical record. All patients who received an allogenic HSCT between January 1, 2016 and June 30, 2017 will be retrospectively assessed for eligibility according to the defined selection criteria and all eligible patients will be consecutively enrolled in the study.

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 31 of 62 4.3 Exposure Definition and Measures This is an observational study of real-world treatment practices in this patient population. This protocol does not recommend the use of any specific treatments. No study medication is provided as part of participation.

4.4 Outcome Definition and Measures Outcomes and measures definition are summarized in sections 4.4.1 and 4.4.2. More detail will be given in the Statistical Analysis Plan (SAP).

Clinical Outcome Measures The following clinical outcome measures will be used in order to meet Objective 3: · Time to acute GVHD diagnosis from transplant · Time to first response and overall best response to acute GVHD treatment. In case a full response is not reached, a description of system organ involvement will be performed at 6 and 12 months since acute GVHD development and overall · Proportion of patients presenting non-relapse mortality at 6 and 12 months since acute GVHD development and overall · Proportion of patients developing acute GVHD reoccurrence and chronic GVHD at 6 and 12 months since acute GVHD development and overall · Time to recurrence and chronic GVHD development, severity and action taken · Proportion of patients reaching symptoms resolution of acute and chronic GVHD at 6 and12 months since acute GVHD development and overall · Time to symptomatic resolution of acute and chronic GVHD

Other Measures at patient level Other measures that will allow meeting objectives 1, 2 and 5 include: · Patient demographics · Patient general clinical characteristics · Clinical characteristics of the primary disease

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 32 of 62 · Donor type · Conditioning regimen · Transplant clinical characteristics · Acute GVHD characteristics · Acute GVHD prophylaxis · Acute GVHD treatment · HCRU: hospitalizations, Intensive care unit (ICU) stays and emergency and outpatient visits

4.5 Data Sources and Collection Patient data will be collected from the patient’s medical records and entered into the eCRFs. For each eligible patient, data will be collected from transplant to patient death, or the end of data availability (or most recent follow-up visit).

Data collection will be standardized using an eCRFs that will allow to capture: · Data at site level: A Transplant Center Form (TCF) will be used to obtain transplant center information. · Data at patient level: this will allow to collect comprehensive data, including patient demographics, transplant characteristics, clinical presentation of acute GVHD, acute GVHD treatments, clinical outcomes, and healthcare resource utilization.

Table 4. Summary of the Data Collection Schedule

Variables Variables collected at patient level collected at site level General At HSCT and At acute GVDH onwards and onwards

Transplant Center Form X

Demographics X

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 33 of 62 Clinical characteristics XXX

Prophylaxis treatment for X acute GVHD

Treatment for acute X GVHD

Overall c linical outcomes X

Clinical outcomes at 6 X and 12 months

HCRU XX GVHD: Graft versus host disease; HCRU: Healthcare resource utilization; HSCT: Hematopoietic stem cell transplant

Data collected at site level

The following data will be collected at site level within the TCF: · Geographic location of transplant center · Type of center, including whether academic/community center and if conduct pediatric HSCTs · Number of physicians dedicated to allotransplant activity for more than 90% of the working time are employed at the institution (current) · Number of adult allogeneic HSCTs conducted between January 1, 2016 and June 30, 2017 · Type of transplants conducted between January 1, 2016 and June 30, 2017 (first HSCT, autologous, allogenic) · Existence of a long-term follow-up or GVHD clinic (yes/no) · Criteria used to grade acute GVHD (Glucksberg, modified Glucksberg or Keystone, MAGIC, IBMTR, other) · Protocols and therapies used to treat acute GVHD (Institutional, Mayo Clinic, EBMT, Gruppo Italiano Trapianto Midollo Osseo (GITMO), German-Austrian-Swiss Consensus, other)

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 34 of 62 · Definition used to classify SR status for acute GVHD o Progression in any organ within 3-5 days of therapy onset with ≥2 mg/kg/day o Failure to improve within 5-7 days of treatment initiation o Incomplete response after more than 28 days of immunosuppressive treatment including steroids o Incomplete response after 14 days of therapy o Use of an additional immunosuppressive agent o Other · Proportion of patients who develop severe acute GVHD and approximate range of patients treated for severe acute GVHD at the institution (<20%, 21-40%, 41-60%, 61-80%,>80%) · Month and year when cyclophosphamide was introduced for the prophylaxis of acute GVHD and type of patients it was approved for based on donor relationship

Data collected at patient level The following data will be collected for all enrolled patients: Patient demographic and general characteristics · Patient still alive at the time of data collection (yes/no) o For patients still alive, ICF signature date (if applicable) o For deceased patients § ICF required according to local regulation (yes/no), if not necessary, date of death § Next of kin consent obtained (yes/no), if obtained, date of signature and date of death § Requirement for anonymous data collection due to local regulation (yes/no), if required, year of death · Year of birth · Sex (not collected in case of anonymous data collection) o Male o Female · Weight at transplant (Kg) · Height at transplant (cm)

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 35 of 62 · Body Mass Index (BMI) (in Kg/m²) (directly calculated from height and weight, if available)

Patient clinical characteristics at transplant · Characteristics of primary diagnosis for transplant: o Date of diagnosis (age at diagnosis for anonymous data collection) o Primary diagnosis that led to HSCT, stage [complete remission (cytological standard), partial remission, active relapse or progressive disease, induction failure or no response, untreated patient, unknown, other] cytogenetic risk (favorable, adverse, intermediate, unknown – not for anonymous data collection) and disease risk index (DRI) (low, intermediate, high, very high, unknown): § Acute Lymphocytic Leukemia (ALL) § Acute myeloid leukemia (AML) § Myelodysplastic syndrome (MDS) and morphologic risk [ >5% of blasts - Myelodysplastic syndromes other than refractory anemia with excess blasts (low risk) or ≤5% of bla sts - refractory anemia with excess blasts type 1 or type 2 (RAEB-1 or RAEB-2) (high risk)] § Chronic myeloid leukemia (CML) § Non-CML Myeloproliferative neoplasm (MPN) § B-Cell lymphoma [Chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), Follicular lymphoma (FL), Diffuse large B-cell lymphoma (DLBCL), Mantle cell lymphoma (MCL), Other B-Cell Lymphoma] § T-Cell Lymphoma § Hodgkin Lymphoma (HL) § Multiple Myeloma (MM) § Other malignancy · Eastern Cooperative Oncology Group Performance Status (ECOG) or Karnofsy Performance Status (KPS) at transplant · Presence of clinically relevant comorbidities at transplant o Diagnosis

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 36 of 62 o Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) or Sorror Score at transplant (if available) · Transplant characteristics: o Date of transplant (only month and year for anonymous data collection) o Donor sex and age o Stem cell source § Bone marrow § Peripheral blood (PBSC) § Umbilical cord blood o Donor type § Related donor (HLA matched, HLA mismatch, fully HLA matched twin) § Unrelated donor (HLA matched, HLA mismatched) o Donor and recipient CMV status o Degree of HLA match, location of HLA mismatch (if applicable) o Level of chimerism achieved and dates for each determination available Transplant conditioning regimen: § Myeloablative § Reduced intensity § Nonmyeloablative § Sequential o Transplant conditioning regimen type: § Total body irradiation (TBI)-based regimens and dose (Gy) and number of fractions received § Fludarabine-Based Conditioning § Busulfan-Based Conditioning § Other · Prophylaxis therapy for acute GVHD: treatment received, start date (only month and year for anonymous data collection), stop date (not collected in anonymous data collection) and treatment duration (only for anonymous data collection) start dose, units, frequency, route and highest dose received and units and whether treatment was received as part of an interventional clinical trial (yes/no) o Ex-vivo T-cell depletion

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 37 of 62 o In-vivo T-cell depletion (ATG, Alemtuzumab, other) o Cyclosporine o Steroid o Tacrolimus o Cyclophosphamide o Methotrexate o Mycophenolate o Sirolimus o Extracorporeal photophoresis (ECP) o Other Clinical characteristics, treatment and outcomes of acute GVHD · Date of diagnosis (only month and year for anonymous data collection) · ECOG score at acute GVHD diagnosis · Biopsies performed (yes/no) to skin, GI (lower/upper), liver or other · Acute GVHD stage (MAGIC, Glucksberg, Keystone and/or IBMTR, if available) at diagnosis · Organ symptom involvement at diagnosis (skin, GI lower/upper and liver according to the MAGIC classification) · Development of infections: type of infection [fungal, viral (varicella zoster virus infection, CMV active infection without organ disease, CMV active infection with organ disease, asymptomatic CMV DNAemia, Other), parasitic, bacterial], and date of infection diagnosis (not collected for anonymous data collection). · Treatment of acute GVHD: variables to be collected for each line of therapy: o Reason for treatment initiation (only for second and subsequent lines and if different from treatment discontinuation) o Medication prescribed: § ABX-CBL § Alemtuzumab § ATG § Basiliximab

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 38 of 62 § Bortezomib § Carfilzomib § Cyclosporine § Daclizumab § Denileukin diftitox § ECP § Etanercept § Everolimus § Fingolimod § Fostamatinib § Infliximab § Inolimomab § Ixazomib § Methotrexate § Methylprednisolone [if selected, date of first response (for anonymous data collection, time to first response will be collected instead of date) to treatment and whether the patient was SR according to physician’s criteria] § Muromomab § Muromomab-CD3 § Mycophenolate mofetil § Pentostatin § Ponesimod § Ruxolitinib § Sirolimus § Sonidegib § Tacrolimus § Triamcinolone [if selected, date of first response (for anonymous data collection, time to first response will be collected instead of date) to treatment and whether the patient was SR according to physician’s criteria] § Visilizumab § Visiluzmab

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 39 of 62 § Vismodegib § Other corticosteroids (specify and indicate first response to treatment and whether the patient was SR according to physician’s criteria ) § Other (specify) o Start and stop dates (not collected in anonymous data collection) and treatment duration (only for anonymous data collection) and whether these are continued in subsequent treatment lines for each drug o Start dose and highest dose administered, units and frequency for each drug (only for first and second line only) o Route of administration for each drug (only for first and second line) o Date (for anonymous data collection, treatment duration will be collected instead of date) and reason for discontinuation (Disease resolved, No response, Partial response, Primary malignancy relapse, Infection, Patient decision, Worsening of acute GVHD, development of GVHD in another organ, Death, Other Adverse Events (AEs), Worsening of acute GVHD, development of GVHD in another organ Other, Unknown) for each drug o Best overall response based on physician’s criteria and date (complete response, very good partial response, partial response, mixed response, progressive disease, no response, not assessed, other) o Acute GVHD stage at initiation and finalization of each line of therapy o Organ symptom involvement (skin, GI lower/upper and liver based on MAGIC) at initiation and finalization of each line of therapy (only for first and second line of treatment) · Clinical outcomes of acute GVHD at 6 and 12 months (± one month) since acute GVHD onset and at most recent follow up: o Reason for death (related /non-related with GVHD for deceased patients only) and time from acute GVHD to death (only for anonymous data collection) o Date of most recent follow up prior to data collection (no collected for anonymous data collection), time from acute GVHD and most recent follow up (only for anonymous data collection) o Acute GVHD stage (Glucksberg, Keystone, MAGIC and/or IBMTR, if available) at 6 and 12 months (± one month) since acute GVHD onset and at most recent follow up

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 40 of 62 o Reoccurrence of acute GVHD, date (not collected for anonymous data collection), time from acute GVHD and development of chronic GVHD (only for anonymous data collection) and action taken (re-started steroid, maintained steroid, increased steroid dose, added another therapy, other) o Development of chronic GVHD, date (not collected for anonymous data collection), time from acute GVHD and development of chronic GVHD (only for anonymous data collection) and severity o Development of overlap syndrome and date o Overall acute GVHD response at 6 and 12 months (± one month) and at most recent follow up (complete response, very good partial response, partial response, mixed response, progressive disease, no response, not assessed, other) o Presence of symptoms at 6 and 12 months (±one month) and at most recent follow up o Organ symptom involvement (skin, GI lower/upper and liver based on MAGIC) at 6 and 12 months (±one month) and at most recent follow up Health Related Resource Utilization since acute GVHD · Hospitalizations/inpatient admissions: o Date of admission and discharge (not collected in anonymous data collection), length of hospitalization (for anonymous data collection) o Reason for hospitalization (related to acute GVHD or other) o ICU stay during hospitalization (length of stay) · Outpatient and Emergency (ER) department visits: o Date (if available) (not collected for anonymous data collection) o Type of visit (outpatient/emergency) o Reason for the visit (related to acute GVHD or other)

5. STATISTICAL METHODS

5.1 Sample Size This study is descriptive and is not designed to test a hypothesis. Therefore, sample size has been calculated in order to describe continuous and categorical variables with a predefined precision level. For continuous variables a coefficient of variation (standard deviation/mean) of 0.5 has been considered, a confidence level of 95%, a precision level of 0.06 and 13% as

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 41 of 62 the maximum percentage of patients with non-available data due to the retrospective data collection. These assumptions correspond to a 95% confidence interval for continuous variables (i.e. time to acute GVHD diagnosis from transplant) corresponding to 0.128 standard deviations. Based on these estimations and the fact that this is a descriptive study, a sample of 307 patients is expected to reach a precision level of 6%. If the sample is lower than expected the precision level will be that reported in the table below.

Precision level 6% 6.5% 7% 7.5% 8% 8.5%

Sample 307 262 226 197 173 153

In addition, the same sample will allow to describe categorical variables, taking into account that for a given variable 50% of the respondents chose a given response option (value requiring the highest sample size), with a precision level of 6% and using a confidence level of 95% and 13% of non-evaluable sample. These assumptions will derive to the estimation of response options (i.e non-relapse mortality at 6 and 12 months since acute GVHD) with a maximum 95% confidence interval of ±6% (corresponding to an estimation of 50%, for lower percentages of responses smaller confidence intervals will be reached).

5.2 Data Analyses

General Considerations All disease diagnosis (e.g. comorbidities) and medical procedures’ verbatim terms will be recorded and coded using the Medical Dictionary for Regulatory Activities (MedDRA). All computations and generation of tables, listings and data for figures will be performed using SAS ® version 9.2 or higher (SAS Institute, Cary, NC, USA). The analysis plan will be fully described in a written and approved statistical analysis plan (SAP). Descriptive analyses will be performed to gain an understanding of the qualitative and quantitative nature of the data collected and the characteristics of the sample studied. Continuous variables will be reported as mean (and standard deviation) or median and range where appropriate. Categorical variables will be summarized as number and proportion of the total study population, and by subgroups where appropriate.

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 42 of 62 Descriptive data will be reported at the study population level and stratified by country, not at center-level. Frequencies and proportions will be used to describe categorical variables, while mean, median, range and standard deviations will be calculated for continuous variables. Survival and other time-relevant variables may be assessed using Kaplan-Meyer survival analysis. Healthcare resource utilization (e.g. hospitalization) will also be descriptively assessed in the total sample, stratified by country and the subsample of patients who are SR. Data retrieved in the present study will be pooled and analyzed together with that retrieved from the studies conducted in parallel in France and in the UK.

Planned Analyses

Objective 1. To describe the clinical presentation of patients with grade 2-4 acute GVHD based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria)Glucksberg Severity Index 2-4 (or alternatively, a 2-4 severity index according to the Keystone or the MAGIC criteria or a B-D according to the IBTMR criteria) acute GVHD. In order to meet objective 1, demographic and general, transplant- and acute GVHD-related clinical characteristics will be described for the overall population and stratified by country. These will include the following variables: · Demographics: age at transplant and at acute GVHD and sex. · General Clinical characteristics: weight, height, BMI, presence of comorbidities (Sorror score at transplant); primary diagnosis for transplant; remission status at transplant; ECOG at transplant and acute GVHD. In case sites indicate DRI is unknown, it will be classified as “low”, “intermediate”, “high”, “very high” or “unknown” based on the primary diagnosis, stage at transplant and cytogenetics as described by Armand et al 18,19 . · Transplant clinical characteristics: donor age and sex; stem cell source; donor type; donor and recipient CMV status; degree and location of HLA mismatch; transplant conditioning regimen;

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 43 of 62 · Acute GVHD clinical characteristics: biopsies performed for acute GVHD diagnosis and location; acute GVHD stage at diagnosis (MAGIC, Glucksberg, Keystone and IBMTR, if available), development of infections (type, microbiologically documented and recurrence). Objective 2. To describe treatment patterns (e.g. first and second-line therapies, duration of therapy, and time to second-line therapy) among patients with grade 2-4 acute GVHD based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria) In order to meet objective 2, the following variables will be described for the overall sample, and stratified by country: · Acute GVHD prophylaxis: o Proportion of patients receiving each agent o Dose, time to treatment initiation and treatment duration for each drug received for GVHD prophylaxis · Acute GVHD treatment: o For each treatment line: reason for line initiation, time to treatment initiation (since acute GVHD for first-line and finalization of prior line for subsequent lines), treatment duration, severity grade of acute GVHD at initiation and finalization and best overall response of the treatment line. o For each drug: Dose, frequency, route or administration, time to treatment initiation, treatment duration, highest and last dose received and reason for discontinuation o Total duration of therapy for acute GVHD Treatment sequencing will be presented from acute GVHD diagnosis to end of data availability. Treatment pathways will be analyzed regarding sequences of newly initiated GVHD therapy. The results will be illustrated using a Sankey diagram to describe sequences depending on prior pathways. Time to each line therapy will be assessed using Kaplan-Meyer survival analysis, right-censored at the end of data availability.

Objective 3. To describe clinical outcomes (e.g. response to therapy, non-relapse mortality ) among patients with grade 2-4 acute GVHD based on the MAGIC criteria (or alternatively,

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 44 of 62 a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria)Glucksberg Severity Index 2-4 acute GVHD (or alternatively, a 2-4 severity index according to the Keystone or the MAGIC criteria or a B- D according to the IBMTR criteria), at 6 and 12 months after acute GVHD diagnosis and until death or last data available. In order to meet Objective 3, the clinical outcomes described below will be descriptively assessed in the total sample, stratified by country and among patients who are SR. Because the duration of medical recording will vary across patients, the following time-to-relevant outcomes will also be assessed using Kaplan-Meyer survival analysis in the total sample and by subgroups. Analyses will be right-censored at the end of data availability. The following variables will be described: · Time to acute GVHD diagnosis from transplant · Time to first response and overall best response to acute GVHD treatment (using Kaplan-Meyer survival analysis). In case a full response is not reached, a description of system organ involvement will be performed at 6 and 12 months and end of follow-up since acute GVHD development · Proportion of patients presenting non-relapse mortality at 6 and 12 months and end of follow-up since acute GVHD development · Proportion of patients developing acute GVHD reoccurrence and chronic GVHD at 6 and 12 months and end of follow-up since acute GVHD development · Time to recurrence and chronic GVHD development (using Kaplan-Meier survival analysis), severity and action taken · Proportion of patients reaching symptoms resolution of acute and chronic GVHD at 6 and 12 months and end of follow-up since acute GVHD development · Time to symptomatic resolution of acute and chronic GVHD (using Kaplan-Meier survival analysis).

Objective 4. To describe the characteristics of participating transplant centers. In order to meet Objective 4, the following variables will be described overall and stratifying

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 45 of 62 by country: · Proportion of sites corresponding to each geographic region and type of center; · Number of Bone Marrow Transplant physicians; · Number of allogeneic HSCTs conducted between January 1, 2016 and June 30, 2017, and proportion of each type of transplants conducted between January 1, 2016 and June 30, 2017 (first HSCT, autologous, allogenic); · Proportion of centers with long-term follow-up or GVHD clinic, using each GVHD severity grade scale (Glucksberg, modified Glucksberg or Keystone, MAGIC, IBMTR, other), following each type of protocol/guideline, using each type of SR definition; and · Percentage of patients developing chronic and acute GVHD and treated at the institution

Objective 5. To describe healthcare resource utilization (HCRU) (e.g. hospitalizations) among patients with grade 2-4 acute GVHD based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria)Glucksberg Severity Index 2-4 acute GVHD (or alternatively, a 2-4 severity index according to the Keystone or the MAGIC criteria or a B- D according to the IBTMR criteria). In order to meet Objective 5, HCRU since the development of the acute GVHD until the end of follow up will be described. For each health care resource, the percentage of patients using it and the number of times that patients have used the resource on annual basis will be described using descriptive measures for categorical and continuous variables, respectively. Number of resources used per year will be calculated dividing the number of times that patients have used each resource by the number of years of follow-up (calculated as the difference between acute GVHD diagnosis and end of follow-up). The following variables will be described overall, stratified by countries and in the SR subgroup · Hospitalizations and inpatient admissions ICU stay, and length of ICU stay · Outpatient and emergency visits and reason

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 46 of 62 Secondary objectives: to describe clinical presentation, treatment patterns and clinical outcomes at 6 and 12 months after acute GVHD diagnosis and until death or last data available of patients with grade 2-4 acute GVHD based on the MAGIC criteria (or alternatively, a 2-4 severity grade according to the Glucksberg Severity Index or the Keystone criteria or a B-D according to the IBMTR criteria) stratifying according to the following variables: - SR status - Severity grade (based on the most common index used to grade included patients) - Donor type In order to meet the secondary objectives, analyses performed in order to meet objective 1, 2 and 3 will be replicated stratifying according to the following variables: - SR (yes/no): SR patients will be those receiving more than one line of corticosteroids. - Severity grade (2/3/4 or B/C/D depending on the most common index used to grade included patients) - Donor type (HLA matched-related / HLA mismatch-related / HLA matched-unrelated / HLA mismatch-unrelated)

Handling of Missing Data It is optimal to prevent missing data, to the extent possible, through strategies set forth in the design and conduct of a study. For the current study, we will aim to minimize missing information by: · ensuring that primary variables of interest are those that are routinely collected as part of real-world clinical care and are available via medical charts, physician and/or patient/caregiver reporting, as appropriate · collecting only critical data elements (e.g. variables aligned with the study objectives) to minimize site/participant burden · requiring important variables · including "not applicable", "not done" on case report forms to differentiate these from values that are truly unknown

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 47 of 62 · training of sites and data abstractors regarding data collection; setting reporting windows around a target timepoint Should missing data occur, the data will be analyzed as they are recorded in the study eCRFs. However, the number of missing values for data elements will be reported, and we will assess the likely impact of missing data on the analysis and the pattern of the missing information. Depending upon the amount of missing data, and whether there is evidence of bias in the missing data (e.g. differences between patients with and without missing data), an imputation strategy, such as multiple imputations, may be performed. If an imputation strategy is undertaken, a sensitivity analysis will be carried out comparing the results from the complete case analysis (where records with missing data will be dropped) and the full set analysis including the imputed data. Full details on handling of missing data will be described in detail in the SAP.

Limitations of Research Methods Medical records provide a valuable source of data used in the observational study of health outcomes and epidemiology. However, retrospective studies that employ electronic health records face limitations. Limitations include missing data, which can result in bias, where cases with missing information may differ from the other cases. Bias may also be caused by inconsistencies within data abstracters and across abstractors. Potential confounding by variables not available in charts may also exist from one participating site to another site. Although efforts are made to create a balanced sample of physicians and patients, selection bias may occur, given the observational nature of the study. For example, despite instructions, principal investigators may select patient cases that are of particular interest to them, and may differ from the general patient population in severity, complications, etc. The definition of SR may also vary across transplant centers, which may also bias outcomes. Results from the study may not be generalizable to all SR and non-SR acute GVHD patients at each participant country, and treatment patterns may only represent the preferences of physicians who agreed to participate. Bias will be reduced in this study by providing clear instructions to data abstractors and by using a standardized data collection form (eCRFs). However, retrospective chart reviews are important as they reflect real-world clinical practices with average patients and are often less costly than clinical trials. Given the lack of consensus about best practices among patients with GVHD and lack of robust clinical evidence, a greater understanding of real-world treatment patterns and outcomes among patients with acute GVHD is valuable. This study will collect and summarize data on GVHD

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 48 of 62 treatment patterns that would not be otherwise available and analyzed. These data will allow multi-center assessments of the real-world clinical presentation and outcomes among patients with acute GVHD, as well as the variation of GVHD therapies across centers in the 4 European countries.

Interim Analysis and Reporting An interim analysis may be performed when approximately 60% of the patient target population has been included (n=185 patients), approximately 3-4 months after first patient inclusion.

Final Analyses and Reporting A final study report will be generated after all data collection is complete. The final report will encompass all planned analyses, including a description of the complete study population, as described above and in the SAP.

6. STUDY MANAGEMENT IQVIA will manage the study implementation in Germany, Italy, Sweden and Finland. and will receive guidance, input, review and approval of Incyte Biosciences International , including development of materials, recruitment, training and management of sites, electronic data capture and data management and analysis. The study will be independently implemented in France and UK by two different CRO.

6.1 Data Entry/Electronic Data Capture All data forms will be collected and entered directly into an electronic data capture (EDC) system developed by IQVIA. All participating sites from Germany, Italy Sweden and Finland will have access to the data entered regarding the individual site its own enrolled patients. All sites will be fully trained on using the online data capture system and will be provided with eCRFs completion guidelines and help files. Sites will be responsible for entering extracted patient data into secure internet-based EDCs registry databases via the eCRFs. Investigators and site personnel will be able to access their account with a username and password. All eCRFs should be completed by designated, trained personnel or the study coordinator, as appropriate. If necessary, the completion of the eCRFs may be performed by an assigned CTT delegated by the sponsor depending on the site capabilities and resources. In this case, the CTT will also be trained as part of the site personnel. In most cases, the eCRFs should be

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 49 of 62 reviewed, electronically signed, and dated by the Principal investigator. All changes or corrections to eCRFs are documented in an audit trail and an adequate explanation is required.

6.2 Source Documents In most cases, the source documents are contained in the patient’s medical record and data collected on the eCRFs must match the data in the medical records. In some cases, the eCRFs, or part of the eCRFs, may also serve as source documents. All original source documentation is expected to be stored at the site for the longest possible time required by local applicable regulations.

6.3 File Retention and Archiving To enable evaluations and/or audits from regulatory authorities or the Client, the investigator agrees to keep records, including serious adverse event (SAE) forms, source documents and adequate documentation of relevant correspondence (e.g. letters, meeting minutes, telephone calls reports). The records should be retained by the investigator according to local regulations, or as specified in the study contract, whichever is longer. Each site will receive a study site file at study initiation which contains all documents necessary for the conduct of the study and will be updated throughout the study. This file must be available for review in the event the site is selected for monitoring, audits, or inspections and must be safely archived for at least 10 years after the completing participation in the study. Documents to be archived include the patient enrolment log and the signed informed consent forms (ICF), if necessary by local regulation. In the event that archiving of the file is no longer possible at the site, the site will be instructed to notify Incyte.

6.4 Quality Assurance and Monitoring A study monitoring plan, including for-cause monitoring, that is appropriate for the study design will be developed and implemented. During the site initiation visit, the monitor will provide training on the conduct of the study to the Investigator, co-investigator(s), and all site staff involved in the study. In case an external CCT will be necessary to support data collection tasks he/she will be trained as part of the site personnel team. In order to ensure the integrity of the data, sites will be remotely monitored on a regular basis. Site monitoring may be performed by IQVIA to examine compliance with the protocol and adherence to the data collection procedures, to assess the accuracy and completeness of submitted clinical data, and to verify that records and documents are being properly maintained for the duration of the study. The monitor will perform source data verification by review of original patient records for selected patients only when

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 50 of 62 pseudonymized data collection is performed. No source data verification will be done for patients with anonymous data collection. The monitor will close out each site after the last patient’s final follow -up assessment is completed, all data have been entered and all outstanding monitoring issues have been resolved or addressed. All monitoring procedures and frequency of monitoring visits will be described in a monitoring plan. Monitor contact details for each participating site will be maintained in the Investigator Site File. Representatives of the Client ’s quality assurance unit/monitoring team and competent regulatory authorities must be permitted to inspect all study-related documents and other materials at the site, including the Investigator Site File, the completed eCRFs and the patients’ original medical records. Audits may be conducted at any time during or after the study to ensure the validity and integrity of the study data.

6.5 Data Management Before data collection begins, a data management plan (DMP) will be developed by IQVIA. The DMP will describe all functions, processes, and specifications for data collection, cleaning and validation and will be aligned to the DMP developed for the studies implemented in France and in the UK to ensure consistency between the electronic data capture (EDC) systems used by each CRO to collect the data. The eCRFs will include programmable edit checks to obtain immediate feedback if data are missing, out of range, illogical or potentially erroneous that will also be aligned between the different EDC systems to ensure consistency of the data collected in each country so that it can be pooled and analyzed together. Concurrent manual data review will be performed, and ad hoc queries will be generated within the EDC systems and followed-up for resolution. High data quality standards will be maintained, and processes and procedures utilized to repeatedly ensure that the data are as clean and accurate as possible when presented for analysis. Data quality will be enhanced through a series of programmed data quality checks that automatically detect out of range or anomalous data.

6.6 Changes to the Protocol Changes to the protocol will be documented in written protocol amendments. Major (e.g. substantial, significant) amendments will usually require submission to the relevant

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 51 of 62 institutional review board (IRB)/independent ethics committee (IECs) for approval or favorable opinion the Competent Authorities, if applicable. In such cases, the amendment will be implemented only after approval or favorable opinion has been obtained. Minor (non-substantial) protocol amendments, including administrative changes, will be filed by at each participating site and will be submitted to the relevant IRB/IEC or regulatory authorities where required by pertinent regulations. Any amendment that could have an impact on the patient’s agreement to participate in the study requires the patient’s informed consent prior to continued participation in the study.

6.7 Publication Policy Any publication of the results from this study must be consistent with the Client ’s publication policy and guided by the Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication of the International Committee of Medical Journal Editors (ICMJE), updated April 2010 20 . The rights of the investigator and of the Client with regard to publication of the results of this study/registry are described in the investigator contract. All reporting will be consistent with the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) Initiative checklist for cohort studies 21 .

7. SAFETY REPORTING This is a non-interventional study based on secondary use of data collected from healthcare professionals or consumers for other purposes. No administration of any therapeutic or prophylactic agent is required in this protocol, and there are no procedures required as part of this protocol.

As the collection of information concerns secondary use of data only, AEs should not be actively submitted to the Sponsor in this study. All AEs/reactions collected for this study will be captured in the eCRF and summarized in the final study analysis report.

There are certain circumstances in which individual AEs may need to be reported following local legislation. In addition, for Incyte’s pr oducts only, any spontaneous AEs, other safety information (special situations) or quality complaints need to be reported to Incyte within 24 hours of the date first becoming aware.

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 52 of 62 7.1 Definitions Adverse events (AEs) An AE is any untoward medical occurrence in a patient or clinical study subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the product. An AE can therefore, be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. If, according to the Investigator, there is a worsening of a medical condition that was present prior to the administration of the intervention, this should also be considered a new AE and reported (if applicable). Any medical condition present prior to the administration of the intervention that remains unchanged or improved should not be recorded as an AE. Documentation regarding the AE should be made as to the nature, date of onset, end date, severity, relationship to product, action(s) taken, and outcome of any sign or symptom observed by the physician or reported by the patient upon indirect questioning.

Serious adverse events (SAEs) An SAE is any experience that suggests a significant hazard, contraindication, side effect or precaution. An SAE must fulfill at least one of the following criteria at any dose level: · Results in death · Is life-threatening as it occurred Patient was at risk of death at the time of the event. This does not refer to an event which hypothetically might have caused death if it were more severe · Requires inpatient hospitalization or prolongation of existing hospitalization · Results in persistent or significant disability/incapacity Defined as a substantial disruption of a patient's ability to conduct normal life functions · Results in a congenital anomaly or birth defect · Constitutes an important medical event Based upon appropriate medical judgment, event may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed above

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 53 of 62 Other safety information (special situations) Other safety information (special situations) shall include information pertaining to an Incyte medicinal product regarding: · Exposure to drug during pregnancy and pregnancy outcomes (normal or adverse outcome); · AEs during breastfeeding; · overdose (there does not need to be an AE associated with the overdose); · drug abuse; drug misuse (there does not need to be an AE associated with the misuse); · medication errors; · suspected transmission of infectious agents; · reports of lack of efficacy; · reports of falsified product; · possible interactions; · off-label use; · occupational exposure.

Quality complaint Quality complaint refers to any communication that alleges deficiencies relative to the identity, quality, stability, reliability, effectiveness, or performance of an Incyte medicinal product (including packaging and labelling) after it is released for distribution.

Event severity Event severity is defined as a qualitative assessment of the degree of intensity as determined by the investigator or reported to him/her by the patient. The assessment of severity is made irrespective of intervention relationship or seriousness of the event and should be evaluated according to the following scale:

· Mild: The event is noticeable to the patient, but is easily tolerated, and does not interfere with the patient’s daily activities.

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 54 of 62 · Moderate: The event is bothersome, possibly requiring additional therapy, and may interfere with the patient’s daily activities. · Severe: The event is intolerable, necessitates additional therapy or alteration of therapy, and interferes with the patient’s daily activities.

Note: The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE (as in mild, moderate, or severe pain); the event itself may be of relatively minor medical significance (such as a severe he adache). “Serious” is a regulatory definition and is based on patient or event outcome or action criteria usually associated with events that pose a threat to a patient’s life or vital functions.

Relationship to treatment For all events reported in patients exposed to some Incyte’s product , the treating physician or other reporting health care provider will be asked to assess the relationship of the AE/SAEs to this Incyte’s product using the following definitions: · Probable: A causal relationship is clinically/biologically highly plausible, and there is a correlation between the onset of the AE/SAE and administration of the treatment, and between withdrawal of treatment and resolution of the AE/SAE. · Possible: A causal relationship is clinically/biologically plausible and there is a correlation between the onset of the AE/SAE and administration of the treatment. · Unlikely: A causal relationship is improbable, and another documented cause of the AE/SAE is most plausible. · Unrelated: A causal relationship can be definitively excluded, and another documented cause of the AE/SAE is most plausible. An adverse drug reaction (ADR) is defined as a response to a study treatment that is noxious and unintended and that occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease, or for the restoration, correction, or modification of physiological functions.

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 55 of 62 7.2 Procedures for Reporting Adverse Events (AEs) to Incyte Biosciences International All AEs (serious and non-serious), other safety information (special situations) and quality complaints identified during the study considered to be related with some Incyte product need to be notified to Incyte, including the description, seriousness criteria, severity, duration (onset and resolution date), causal relationship with the study treatment, actions taken with the study treatment (dose reduction, withdrawal, etc.), any other required treatment, and outcome. The outcome of each AE (serious or non-serious) other safety information (special situations) and quality complaints related to some Incyte product should be entered with a term such as those described below: · recovered without sequelae · recovered with sequelae · ongoing · change in severity grade (worsening, improving) · died If any of the same AEs occur on several occasions in the same patient, then the AE in question must be documented and assessed each time. In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is considered as the AE rather than the procedure itself. All SAEs and non-serious AEs considered to be related to some Incyte’s product (adverse reactions) identified during the study must be reported to Incyte Pharmacovigilance for purposes of regulatory reporting. Site personnel must complete and submit the appropriate SAE report form and forward it to Incyte Pharmacovigilance within 24 hours of becoming aware of the event. To ensure patient safety, all SAEs and non-serious AEs considered related to some Incyte’s product (adverse reactions) occurring after first exposure to Incyte’s medicinal product and until 30 days after last exposure to the product, should be reported to Incyte Pharmacovigilance within 24 hours of learning of its occurrence. All completed SAE forms should be sent to:

Email: [email protected] Incyte Biosciences International Phone (EU Universal Toll Free) : +800 000 27423 Phone ( Swiss Local Toll Paid): +41 (0) 445834495

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In order to maintain compliance with the European Medicines Agency (EMA) and other international and national regulatory bodies, treating physicians may be further contacted by Incyte Pharmacovigilance in order to collect additional information required to evaluate the potential event. AEs/SAEs will be reported to local and regional health authorities by the Client, when appropriate, in accordance with applicable local and regional regulations. The participating physician is responsible for maintaining compliance with any applicable site- specific requirements related to the reporting of SAEs or other safety information to the local IRB/IEC that approved the study.

8. ETHICAL AND REGULATORY CONSIDERATIONS

8.1 Guiding Principles To ensure the quality and integrity of research, this study will be conducted under the guidelines good pharmacoepidemiology practices (GPPs) issued by the International Society for Pharmacoepidemiology (ISPE) 4, the Declaration of Helsinki and its amendments, and any applicable national guidelines 5.

8.2 Patient Information and Informed Consent If applicable due to local regulation, an ICF must be signed by the patient (or the patient’s legally authorized representative) before his or her participation in the study. The medical file for each patient should document the informed consent process and that written informed consent was obtained prior to participation in the study. A copy of each signed ICF must be provided to the patient or the patient’s legally authorized representative. If applicable, it will be provided in a certified translation of the local language. All signed and dated ICFs must remain in each patient’s study file and must be available for verific ation by study monitors at any time. The ICF should be revised whenever there are changes to procedures outlined in the informed consent or when new information becomes available that may affect the willingness of the patient to participate. For any updated or revised ICFs, the medical file for each patient should document the informed consent process and that written informed consent was obtained for the updated/revised ICF for continued participation in the study. Since this research presents no more than minimal risk of harm to patients and involves no physical procedures with patients, a waiver of informed consent/authorization will be requested

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 57 of 62 for the retrospective collection of non-personally identifiable data, where applicable and in accordance with national regulations. Alternatively, patients will be informed accordingly, and/or will be asked to give their consent on data handling procedures in accordance with national regulations in place in each of the countries included in the study. In those countries where next of kin consent or ICF waiver for unreachable patients is not acceptable for deceased patients, according to local regulation, data collection will be performed fully anonymized

8.3 Patient Confidentiality In order to maintain patient anonymity, each patient will be assigned a unique patient identifier upon study enrolment. This patient identifier will be used in place of patient name for the purpose of data analysis and reporting. Medical record number or other local reference identifiers are not collected as part of the database. All parties will ensure protection of patient personal data and will not include patient names on any study forms, reports, publications, or in any other disclosures, except where required by law. Data protection and privacy regulations will be observed in capturing, forwarding, processing, and storing patient data. Every effort will be made to protect participant confidentiality according to the Directive 95/46/EC on the protection of individuals, and in compliance with Safe Harbor privacy principles. The database will be housed at the IQVIA in a physically and logically secure computer system maintained by the IQVIA in accordance with a written security policy. The system meets approved established standards for the security of health information and is validated. The system also meets the standards of the ICH GCP E6 guideline (revision 2) regarding electronic study data handling and is available for audit upon request. Patient confidentiality will be strictly maintained. Deceased patients for whom data collection needs to be done in a fully anonymized manner, given that next of kin consent or ICF waiver for unreachable patients is not acceptable due to countries ’ local regulation, will not be included in the site log linking the name of the patient with the patient identifier in the study and the CRF will be adapted in order to reduce the risk of de-identification as follows: - Patient’s sex will not be collected

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 58 of 62 - Date of diagnosis of primary diagnosis for transplant will be replaced by age at diagnosis - Only month and year of transplant, GVHD prophylaxis initiation and diagnosis of acute GVHD will be collected instead of full date - Cytogenetic risk will not be collected - Treatments’ start and stop dates will not be collected and treatment duration will be collected instead - Date of hospital and ICU admission and discharge will be replaced by length of stay - Date of first response to corticosteroids will be replaced with time to first response - Date of treatments’ discontinuation will be replaced by time to treatment discontinuation - Date of death will be replaced with year of death and time from GVHD until death - Date of most recent follow-up will be replaced with time since acute GVHD and most recent follow up - Date of reoccurrence of acute GVHD will be replaced with time since acute GVHD and chronic GVHD development - Date of development of chronic GVHD will be replaced with time since acute GVHD and chronic GVHD development

8.4 Independent Ethics Committee (IEC)/Institutional Review Board (IRB) Consistent with local regulations and prior to enrollment of patients at a given site, the study protocol will be submitted together with its associated documents to the responsible IRB/IEC for its review. Patient enrolment will not start at any site before the Client has obtained written confirmation of a favorable opinion/approval from the relevant central or local IRB/IEC. The IRB/IEC will be asked to provide documentation of the date of the meeting at which the favorable opinion/approval was given that clearly identifies the study, the protocol version, and the ICF version reviewed, if applicable. Before implementation of any substantial changes to the protocol, protocol amendments will also be submitted to the relevant IRB/IEC in a manner consistent with local regulations. Pertinent safety information will be submitted to the relevant IECs during the course of the study in accordance with local regulations and requirements. It is the responsibility of the investigator to have prospective approval of the study protocol, protocol amendments and other relevant documents, if applicable, from their local IRB/IEC and provide documentation of approval to IQVIA. All correspondence with the IRB/IEC should be retained in the investigator file.

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 59 of 62 Should the study be terminated early for any unanticipated reason, the investigator will be responsible for informing the IRB/IEC of the early termination.

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 60 of 62 9. REFERENCES

1. Schoemans HM, Lee SJ, Ferrara JL, et al. EBMT-NIH-CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessment. Bone marrow transplantation 2018. 2. Garnett C, Apperley JF, Pavlů J. Treatment and mana gement of graft-versus-host disease: improving response and survival. Therapeutic advances in hematology 2013; 4(6): 366-78. 3. Im A, Hakim FT, Pavletic SZ. Novel targets in the treatment of chronic graft-versus- host disease. Leukemia 2017; 31 (3): 543-54. 4. Guidelines for good pharmacoepidemiology practices (GPP). Pharmacoepidemiology and Drug Safety. 2016; 25: 2-10. 5. Declaration of Helsinki 59th World Medical Association General Assembly, Seoul, October 2008 [Internet]. Available from: http://www.wma.net/en/30publications/10policies/b3/17c.pdf . . 6. Directive 95/46EC of the European Parliament and the council on the protection of individuals with regard to the processing of personal data and on the free movement of such data [Internet]. Available from: http://eur- lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:31995L0046:en:NOT . 7. Pidala J, Vogelsang G, Martin P, et al. Overlap subtype of chronic graft-versus-host disease is associated with an adverse prognosis, functional impairment, and inferior patient- reported outcomes: a Chronic Graft-versus-Host Disease Consortium study. Haematologica 2012; 97 (3): 451-8. 8. Gratwohl A, Hermans J, Apperley J, et al. Acute graft-versus-host disease: grade and outcome in patients with chronic myelogenous leukemia. Working Party Chronic Leukemia of the European Group for Blood and Marrow Transplantation. Blood 1995; 86 (2): 813-8. 9. Hahn T, McCarthy PL, Jr., Zhang M-J, et al. Risk factors for acute graft-versus-host disease after human leukocyte antigen-identical sibling transplants for adults with leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008; 26 (35): 5728-34. 10. Flowers ME, Inamoto Y, Carpenter PA, et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood 2011; 117(11): 3214-9.

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Incyte Biosciences International Clinical characteristics and Outcomes for aGVHD patients Version 1.0 dated 28 th June 2019 INCB-EUMA-GVHD-001 Page 61 of 62 11. Zeiser R, Blazar BR. Pathophysiology of Chronic Graft-versus-Host Disease and Therapeutic Targets. The New England journal of medicine 2017; 377(26): 2565-79. 12. Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18 (4): 295-304. 13. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone marrow transplantation 1995; 15 (6): 825-8. 14. Harris AC, Young R, Devine S, et al. International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2016; 22 (1): 4-10. 15. Rowlings PA, Przepiorka D, Klein JP, et al. IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. British journal of haematology 1997; 97 (4): 855-64. 16. Martin PJ, Rizzo JD, Wingard JR, et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2012; 18 (8): 1150-63. 17. Westin J, Saliba R, De Lima M, et al. Steroid-Refractory Acute GVHD: Predictors and Outcomes. Advances in Hematology 2011; 2011. 18. Armand P, Gibson CJ, Cutler C, et al. A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood 2012; 120(4): 905-13. 19. Armand P, Kim HT, Logan BR, et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood 2014; 123(23): 3664-71. 20. International Committee of Medical Journal Editors (ICMJE) [Internet]. Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication. April 2010. Available from: http://www.icmje.org/urm_full.pdf . 21. STROBE Group [Internet]. STROBE Statement: STrengthening the Reporting of OBservational studies in Epidemiology. March 30, 2008. Available at: http://www.strobe- statement.org/News%20Archive.html .

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