Not for publication or presentation · To promote studies of hematopoietic cell transplantation and other cellular therapies for autoimmune disease and to more broadly investigate

Not for publication or presentation

A G E N D A CIBMTR AUTOIMMUNE DISEASES AND CELLULAR THERAPY WORKING COMMITTEE Grapevine, TX Wednesday, February 26, 2014, 12:15 pm – 2:15 pm Co‐Chair: David McKenna, MD; University of Minnesota Medical Center;

Phone: 612‐624‐5736, Fax: 612‐624‐1777, E‐mail: [email protected] Co‐Chair: Ian Lewis, MD, Royal Adelaide Hospital, Adelaide, Australia Phone: 6‐18‐8222‐3328, Fax: 6‐18‐8222‐3162,

E‐mail: [email protected] Co‐Chair: Mitchell Cairo, MD, Columbia University Medical Center, New York, NY Phone: 212‐305‐8316; Fax: 212‐305‐8428; E‐mail: [email protected] Co‐Chair: Paulo Muraro, MD, PhD, Imperial College London, UK

Telephone: +44 (0) 207‐594‐6670; Fax: +44 (0) 207‐594‐6548 E‐mail: [email protected] Co‐Chair: Steven Pavletic, MD, National Cancer Institute, NIH, Bethesda, MD Telephone: 301‐402‐4899; Fax: 301‐451‐5578 E‐mail: [email protected] Statisticians: Jessie Huang, MS, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414‐805‐0686; Fax: 414‐805‐0714; E‐mail: [email protected]

Kwang Woo Ahn, PhD, CIBMTR Statistical Center, Milwaukee, WI Telephone 414‐456‐7387; Fax: 414‐456‐6530; E‐mail: [email protected] Scientific Director: Marcelo Pasquini, MD, MSc, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414‐805‐0700; Fax: 414‐805‐0714; E‐mail: [email protected]

1. Introduction a. Minutes of Autoimmune Disease Tandem 2013 Meeting (Attachment 1) b. New appointed co‐chair: Stefanie Sarantopoulos, MD, Duke University Medical Center,

Durham, NC; Phone: (919) 688‐4383; Email: [email protected]

2. Mission statement To promote studies of hematopoietic cell transplantation and other cellular therapies for autoimmune disease and to more broadly investigate novel uses of cellular therapies for both malignant and non‐malignant indications.

3. Committee merging: overview and rationale (Marcelo Pasquini)

4. Accrual summary (Attachment 2)

5. Presentations, published or submitted papers AD09‐01 P Muraro, R Saccardi, M Pasquini, M Sormani, X Zhong, S Pavletic. Long‐term follow‐up for autologous transplant in multiple sclerosis. Presentation at EBMT Meetings in London, UK, April 2013.

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Not for publication or presentation

6. Studies in progress (Attachment 3) a.

AD09‐01 Long‐term follow‐up for autologous transplant in multiple sclerosis (P Muraro)

Manuscript Preparation

b. CT10‐01 DLI vs 2nd allo tx for relapse (Noelle Frey/Alison Loren/David Porter) Manuscript Preparation c. AD13‐01 HCT for Systemic Lupus Erythematous (Sarfaraz Hasni/Steven

Pavletic) Data Collection

d. AD12‐01 The Effect of Allogeneic Hematopoietic Cell Transplantation on the Activity and Progression of Multiple Sclerosis (G Georges)

Protocol Development

e. CT13‐01 Utility of DLI for infection treatment in AlloHCT (Gorgun Akpek) Protocol Development

7. New study proposals a. PROP 1311‐04 G‐CSF Mobilized versus Unmobilized Donor Leukocyte Infusions following Disease Relapse after Allogeneic Hematopoietic Cell Transplantation (Betty Ky Hamilton/ Navneet Majhail) (Attachment 4) b. PROP 1312‐14 Long Term Outcomes after Autologous Hematopoietic Cell Transplantation for Rapidly Progressive Systemic Scleroderma (Dominique Farge) (Attachment 5)

8. Presentations a. Report from the SOSS on HCT for non‐malignant diseases (Harry Atkins) b. Report from the SOSS on Cellular Therapy (Helen Heslop)

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Not for publication or presentation Attachment 1

MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR AUTOIMMUNE DISEASES Salt Lake City, Utah Wednesday, February 13, 2011, 2:45 pm – 4:45 pm Co‐Chair: Paulo Muraro MD, PhD, Imperial College London, UNITED KINGDOM

Telephone: +44 (0) 207‐594‐6670; Fax: +44 (0) 207‐594‐6548; E‐mail: [email protected]

Co‐Chair: Steven Pavletic, MD, National Cancer Institute, NIH, Bethesda, MD Telephone: 301‐402‐4899; Fax: 301‐451‐5578; E‐mail: [email protected] Statisticians: Tony X. Zhong, MS, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414‐805‐0567; Fax: 414‐805‐0714; E‐mail: [email protected] Kwang Woo Ahn, PhD, CIBMTR Statistical Center, Milwaukee, WI

Telephone 414‐456‐7387; Fax: 414‐456‐6530; E‐mail: [email protected] Scientific Director: Marcelo Pasquini, MD, MSc, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414‐456‐8325; Fax: 414‐456‐6530; E‐mail: [email protected] 1. Introduction

The meeting started at 2:45pm. The Committee Chairs (Paolo Muraro, MD and Steve Pavletic, MD) and the Scientific Director (Marcelo Pasquini, MD) welcomed the committee and started the meeting. After the brief introduction, Dr. Muraro reminded the group that there are 2 listed proposals in the voting sheet. However, only one of them has submitted the literal proposal to ADWC by the time of the Tandem. The other one submitted by Dr. Dominique Farge is lack of proposal but only have a topic. We provide accrual summary for both the proposal. The minutes from the 2012 meeting in San Diego were then approved by the committee.

2. Accrual Summary

There was no formal presentation or review of the accrual summary. However Dr. Pavletic briefly went through 2 page slides of accrual summary in 2012. The CIBMTR have already started to collect data of autoimmune disease in 2012 and most of the information focusing on registration level data. About 520 cases have been reported to CIMBTR in this level since 1995, most of these centers are in USA and the most frequent indication is Multiple Sclerosis (MS) and Systemic Lupus Erythematosis (SLE).

3. Published/submitted studies and presentations

a. AD06‐03 Pasquini MC, Voltarelli J, Atkins HL, Hamerschlak N, Zhong X., Ahn KW, Sullivan KM,

Carrum G, Andrey J, Bredeson CN, Cairo M, Gale RP, Hahn T, Storek J, Horowitz MM, McSweeney, PA, Griffith LM, Muraro PA, Pavletic SZ, Nash RA. Overview of Hematopoietic stem cell transplantation for autoimmune diseases performed in North and South America and reported to CIBMTR. Biology of Bone Marrow Transplantation 18(10):1471‐1478, 2012. Dr. Pasquini announced to all the working committee members that the first formal

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publication in ADWC has been published in BBMT on October 2012. The study presents the information of Hematopoietic Cell transplant for autoimmune disease performed in North and South America and report to CIBMTR. The news was welcomed by applause from the committee members.

4. Studies in progress a. AD06‐01 Hematopoietic Cell Transplantation for Autoimmune Cytopenias (M. Pasquini and

H. Atkins) This study was dropped. Dr. Pasquini explained to the working committee member that since the existing data do not provide enough information to support this study, this study was dropped from ADWC for the time being.

b. AD06‐02 The Effect of Hematopoietic Cell Transplantation on Systemic Lupus Erythematous when Present as a Coexistent Disease at Time of Transplantation (R. Nash) This study was dropped. Dr. Pasquini explained to the working committee member that since the existing data do not provide enough information to support this study, this study is presently closed.

c. AD09‐01 Long Term Follow‐up Analysis of Patients with MS after Auto Hematopoietic cell

Transplantation (P. Muraro, M. Pasquini, and R. Saccardi) Dr. Muraro updated the committee on the status of the project. This is a collaborative study between the EBMT and CIBMTR which will use MS data from US, Canada, Brazil, Asia and Europe. The main aim of the study is to evaluate and describe then long term outcomes among MS patients who are alive beyond five years after auto transplant for MS. During the last year, both CIBMTR and EBMT data are collected and combined to analyze. The primary results has been summarized into an abstract and submitted to EBMT annual meeting in London 2013. It was announced to the committee that the project won the Van Bekkum award in EBMT 2013 and will have an oral presentation during the opening session of the conference. The main investigators will focus on complete the detailed analysis and manuscript in 2013. After that, the manuscript will be submitted to a scientific journal.

d. AD11‐01 Identification of HLA Functional Motifs Associated with Severe Systemic Sclerosis

and Sclerotic‐GVHD: the Shared Epitopes of Fibrosis (Del Galdo) Dr. Pasquini explained the study was originally proposed to identify the HLA functional motifs associated with skin fibrosis by bio‐informatics meta‐analysis of the HLA typing data from sclerotic‐chronic graft versus host disease patients and systemic sclerosis patients that required hematopoietic stem cell transplantation because of severe skin fibrosis. The key of moving this study is to obtain the blood sample for study cohort and the process of getting approval is difficult, the leadership members decided to defer the study.

e. AD12‐01 Invited presentation: Allogeneic HCT in Multiple Sclerosis patients: international

registry AI120 (George E. Georges) Dr. Georges from Fred Hutchinson Cancer Research Center gave a presentation on study AD1201, which is a planned study the outcomes of transplant from 37 MS patients who underwent allogeneic HCT. Among those 37 patients, 14 identified via Fred Hutchinson Cancer Research Center and 23 identified from CIBMTR database. Some committee members asked about the funding in support of the long term follow‐up of the patients and Dr. Georges explained that the funding is available to support travel expenses of patients wishing to participate in the study.

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5. Autoimmune Disease EBMT Registry presentation

Dr. Ricardo Saccardi gave a short presentation on the Autoimmune Disease EBMT Registry. Information given to committee members included number of transplants, demographical information, transplant indications, cases by year and country. Lastly, Dr. Saccardi also showed a bar chart of centers which reported more than 20 cases in EBMT registry. This presentation opened a window for working committee interested in knowing the autoimmune disease information in EBMT registry.

6. Future/ Proposed studies a. PROP 1212‐07 Hematopoietic Cell Transplant for Systemic Lupus Erythematosus: efficacy

and adverse effects (Steve Pavletic and Sarfaraz A. Hasni) Dr. Steve Pavletic from NIH presented the proposal. The study aims to analyze the outcomes of hematopoietic cell transplant for SLE. There are 35 patients with SLE reported to CIBMTR with transplant between 1996 and 2010, which are 5 allogeneic transplant and 30 autologous. All these patients will be included in the study. Some of the members ask that how many patients are still alive and are able to contact. Dr. Pavletic explained that there are 4 out of 5 allogeneic recipients alive and 19 out of 30 autologous recipients alive at the time of the proposal completed.

b. PROP 1212‐08 Outcome of Autologous Transplants for Scleroderma (Dominique Farge) Dr. Muraro simply introduced the idea proposed by Dr. Dominique Farge, which consists of using the data in CIBMTR and EBMT and possibly retrieve additional disease‐specific data, following the same process pioneered by the AI0901 study in MS, to study the long‐term outcome of autologous transplant for Scleroderma patients. By the time of the Tandem meeting started, no formal materials had been received by the ADWC leadership members. Based on the policy of CIBMTR ADWC, the proposal will not be voted in the meeting of this year and Dr Farge will be invited to submit a full proposal for future consideration.

PROP 1112‐07 was accepted as new study AD13‐01 after voting. PROP 1212‐08 was dropped. 7. Ongoing initiatives under then ADWC.

Dr. Pasquini thanked all the committee members for their participation in the research of Autoimmune Disease Working Committee. Dr. Pasquini explained that the major difficulty in this working committee is collecting data from centers. In order to make it better, an Autoimmune Disorders and Cellular Therapy workshop for all the researchers in this field will be held in April 2013. This is a very good chance for all the researchers to communicate and improve this group and will be open for registration right after Tandem meeting. Dr. Pasquini encouraged all the members to register in the workshop and to pass around the information to their Colleagues and potentially interested researchers. All the committee members are appreciated for their support to this study group.

Working Committee Overview Plan for 2013‐2014

a. AD09‐01 Long Term Follow‐up Analysis of Patients with MS after Auto Hematopoietic cell

Transplantation. This study will be presented orally at EBMT London 2013 on April 7. Before the presentation, we will aim to complete all the additional analysis for the presentation.

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After the EBMT annual meeting, we will aim at writing the manuscript and submit it by the early summer.

b. AD12‐07: Hematopoietic Cell Transplant for Systemic Lupus Erythematosus: efficacy and adverse effects. PI will be informed the acceptance on Marc. Draft protocol is anticipated receiving on July and we will start working on the protocol. Draft protocol with descriptive table will be submit to CIBMTR STAT meeting and try to get approval on Sep/Oct, 2013. We anticipate finalizing the protocol on Oct/Nov, 2013 and completing the data file on Jan/Feb, 2014. After that we will do the analysis on March/April, 2014 and then work on the manuscript. The manuscript is anticipate completing on June/July, 2014. After that we will submit the manuscript for peer‐review.

Work Assignments for Working Committee Leadership (February 2013)

Paulo Muraro AD09‐01 Long Term Follow‐up Analysis of Patients with MS after

Autologous Hematopoietic cell Transplantation

Steve Pavletic AD13‐01 Hematopoietic Cell Transplant for Systemic Lupus Erythematosus: efficacy and adverse effects

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MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR CELLULAR THERAPIES Salt Lake City, Utah Friday, February 15, 2013, 2:45 pm – 4:45 pm Co‐Chair: Mitchell Cairo, MD, Children’s and Women’s Physicians of Westchester,

Vahalla, NY Telephone: 914‐594‐3650; Fax: 914‐594‐3650;

E‐mail: [email protected]

Co‐Chair: Armand Keating, MD, Princess Margaret Hospital, Toronto, CANADA Telephone: 416‐946‐4595; Fax: 416‐946‐4530;

E‐mail: [email protected] Co‐Chair: Ian Lewis, MD, Royal Adelaide Hospital, Adelaide, AUSTRALIA Telephone: +6‐18‐8222‐3328; Fax: +6‐18‐8222‐3162;

E‐mail: [email protected] Statisticians: Sandy Korman, MS, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414‐805‐0682; Fax: 414‐805‐0714; E‐mail: [email protected]

John Klein, PhD, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414‐456‐8379; Fax: 414‐456‐6530; E‐mail: [email protected]

Scientific Director: Marcelo Pasquini, MD, MS, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414‐805‐0700; Fax: 414‐805‐0714; E‐mail: [email protected]

1. Introduction The CIBMTR Working Committee for Cellular Therapies on Friday, February 15, 2013 at 2:45 pm. Minutes from the 2012 Tandem meeting in San Diego were approved. The new chair, David McKenna, from University of Minnesota Medical Center was introduced and the retiring chair, Armand Keating, was thanked for his contributions to the committee. The CIBMTR guidelines for assigning priority/scientific merit for existing studies and proposals were reviewed.

2. Accrual Summary The accrual tables were referenced and reviewed briefly but not formally presented.

3. Studies in Progress Marcelo Pasquini provided updates of the studies in progress.

a. CT09‐02 Cellular therapy for regenerative medicine: 2008 activity survey in US and Canada (M Pasquini) The objective of this study is 1) to identify centers in the United States and Canada with active cellular therapy, and 2) to assess the indications and cellular products utilized for regenerative medicine in the region for the year 2008. This study currently includes data from six centers and may be expanded to include data from the Production Assistance for Cellular Therapies (PACT)

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Group. Preparation of manuscript for this study is underway.

b. CT09‐01 Follow‐up of subject receiving genetically modified cell products post‐transplant (H Heslop) Status: Dropped due to inability to track some of the cases that were not reported initially to the CIBMTR and some of the long term follow up analysis were published separately.

c. CT10‐01 Donor leukocyte infusion versus second allogeneic hematopoietic stem cell transplantation for disease relapse after first allogeneic stem cell transplantation (N Frey/A Loren/D Porter) The purpose of this study is to describe and compare outcomes for recipients of second allogeneic hematopoietic stem cell transplantation (HCT) versus donor leukocyte infusion (DLI) when administered for disease relapse after first allogeneic HCT. The study includes 3,180 patients: 427 recipients of a second allogeneic HCT, 646 recipients of a DLI, and 2,106 with no cellular intervention. The CIBMTR has been contacting centers to resolve inconsistencies in transplantation and infusion dates. The dataset for this study is being finalized.

4. Future/Proposed Studies a. PROP 1112‐29 Utility of Donor Leukocyte Infusion (DLI) for the Treatment of Drug‐resistant Viral

or Fungal Infections in Allogeneic HCT Recipients: A CIBMTR Analysis (G Akpek) Gorgun Akpek presented this proposed study. The purpose of this study is to describe clinical outcomes after DLI in allogeneic HCT recipients with drug‐resistant viral or fungal infections and, if an adequate sample size is available, identify variables that are associated with successful outcomes. The primary outcome for this study is overall survival. Secondary outcomes include infection response and incidence of acute and chronic GVHD. There are currently 53 patients eligible for inclusion in this study; research‐level data are available for a subset of 17 of these patients. Bone marrow, peripheral blood, and cord blood were the graft sources for 32%, 55%, and 13% of the HCT, respectively. Eighty‐seven percent of the patients received DLI for a viral infection and 4% received DLI for a fungal infection, the type of infection for which the remaining 9% of the patients received DLI was not reported. During discussion point was raised that it may be possible to identify additional patients eligible for inclusion in this study by contacting CIBMTR‐reporting centers. This study was approved.

b. PROP 1112‐66 Prognostic Implications of Prior Graft‐versus‐Host Disease in Patients undergoing Donor Leukocyte Infusion for Relapse after Allogeneic Hematopoietic Cell Transplantation (S Nikiforow) This proposal was not presented at the working committee meeting but brought to the attention of the committee after the BMT Tandem Meetings. The purpose of this study is to determine if the presence and grade of acute and/or chronic GvHD prior to DLI impacts outcome after DLI (subsequent GvHD, response and survival) when administered for relapse following allogeneic stem cell transplantation. Outcomes to be evaluated include response, overall survival, treatment related mortality, disease free survival, and overall survival. This study has been approved and will be combined with the Acute Leukemia Working Committee Study LK02‐09 (Evaluation of DLI to treat relapsed hematologic malignancies after related and unrelated donor myeloablative allogeneic HCT) into a new study, CT13‐02.

5. Update on the CIBMTR data collection on Cellular Therapies Marcelo Pasquini provided this update. Most of the data collected through this form are provided by

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cell processing centers. A task force was established to evaluate the goals of the Cellular Therapies Data Collection Form. The form is currently being revised.

6. Other Business Presentations were given by three invited speakers:

a. Helen Heslop presented results from the Survey of Cellular Therapy Approaches

b. Ed Horowitz discussed the biology of mesenchymal stromal cells

c. Bob Lindblad provided an update of recent PACT activities

Ian Lewis thanked all the committee members for their participation in the research of Cellular Therapies Working Committee and adjourned the meeting at 4:45pm.

Working Committee Overview Plan for 2013‐2014

a. CT09‐02 Cellular therapy for regenerative medicine: 2008 activity survey in US and Canada.

Manuscript will be submitted for publication by June 2013.

b. CT10‐01 Donor leukocyte infusion versus second allogeneic hematopoietic stem cell transplantation for disease relapse after first allogeneic stem cell transplantation. We anticipate finishing analyses by June 2013 submitting a manuscript for publication by June 2014.

c. CT12‐01 (PROP 1112‐29) Utility of Donor Leukocyte Infusion (DLI) for the Treatment of Drug‐resistant Viral or Fungal Infections in Allogeneic HCT Recipients: A CIBMTR Analysis. The draft protocol is expected to be received by June 2013. We anticipate finishing data file preparation by June 2014.

d. CT12‐02 (PROP1112‐66) Prognostic Implications of Prior Graft‐versus‐Host Disease in Patients undergoing Donor Leukocyte Infusion for Relapse after Allogeneic Hematopoietic Cell Transplantation. We anticipate finishing data file preparation by June 2014.

Work Assignments for Working Committee Leadership (February 2013)

Marcelo Pasquini CT09‐02: Cellular therapy for regenerative medicine: 2008 activity survey in US and Canada

Mitchell Cairo CT10‐01: Donor leukocyte infusion versus second allogeneic hematopoietic stem cell transplantation for disease relapse after first allogeneic stem cell transplantation

Ian Lewis CT12‐02: Prognostic Implications of Prior Graft‐versus‐Host Disease in Patients undergoing Donor Leukocyte Infusion for Relapse after Allogeneic Hematopoietic Cell Transplantation

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David McKenna CT12‐01: Utility of Donor Leukocyte Infusion (DLI) for the Treatment of Drug‐resistant Viral or Fungal Infections in Allogeneic HCT Recipients: A CIBMTR Analysis

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Accrual Summary for Autoimmune Disorders and Cellular Therapy Working Committee

Recipients of first transplant for Autoimmune Disorders registered to the CIBMTR, 2008‐2013

Characteristics Allogeneic Autologous

Number of patients 33 112Number of centers1 23 36Age at transplant, years

median age (range) 15 (<1‐61) 37 (6‐70) 0‐18 24 (73) 11 (10) 18‐30 7 (21) 77 (69) 30‐40 1 (3) 19 (17) 40‐50 1 (3) 5 (4)Region US 25 (76) 70 (63) Canada 1 (3) 11 (10) Europe 3 (9) 2 (2) Asia 0 10 (9) Australia/New Zealand 1 (3) 2 (2) Mideast/Africa 0 3 (3) Central/South America 3 (9) 14 (13)Gender Male 17 (52) 44 (39) Female 16 (48) 68 (61)Karnofsky Score, % ≥90 9 (27) 23 (21) <90 21 (64) 86 (77) Missing 3 (9) 3 (3)Graft type BM 17 (52) 0 PB 8 (24) 111 (99) UCB 8 (24) 1 (<1)Donor type HLA‐identical sibling 13 (39) ‐‐ Unrelated donor 19 (58) ‐‐ Other relative 1 (3) ‐‐Disease Multiple sclerosis 1 (3) 43 (38) System Scleroderma 9 (27) 40 (36) Systemic lupus erythematosis (SLE) 1 (3) 6 (5) Rheumatoid arthritis 0 1 (<1) Psoriatic arthritis or psoriasis 0 1 (<1) Polymyositis‐dermatomyositis 0 1 (<1) Antiphospholipid syndrome 0 2 (2) Other Connective tissue disease 2 (6) 2 (2) Juvenile idiopatic arthritis 1 (3) 0 Other neurologic disorder 0 10 (9) Hemolytic anemia 4 (12) 0 Evan syndrome 2 (6) 0 Other autoimmune cytopenia 7 (21) 0

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Characteristics Allogeneic Autologous

Crohns disease 2 (6) 6 (5) Ulcerative colitis 1 (3) 0 Other immunodeficiencies, specify 1 (3) 0 Other bowel disorder 2 (6) 0Conditioning regimen TBI+CY+‐others 6 (18) 23 (21) BU+CY+‐others 5 (15) 0 CY+ATG+‐others 5 (15) 48 (43) CY+‐others 3 (9) 9 (8) BU+‐others 5 (15) 0 LPAM+‐others 7 (21) 32 (29) ATG+‐others 2 (6) 0GVHD prophylaxis T‐cell depletion +‐others 1 (3) ‐‐ CD34 selection +‐others 0 ‐‐ FK506 + MMF +‐ others 9 (27) ‐‐ FK506 + MTX +‐ others 4 (12) ‐‐ FK506 +‐ others (Not MTX/MMF) 3 (9) ‐‐ CSA + MMF +‐ others 5 (15) ‐‐ CSA + MTX +‐ others 6 (18) ‐‐ CSA +‐ others (Not MTX/MMF) 3 (9) ‐‐ Unknown 2 (6) ‐‐Time from diagnosis to transplant <12 months 10 (30) 13 (12) 12‐24 months 4 (12) 19 (17) 24‐36 months 5 (15) 12 (11) >36 months 14 (42) 68 (61)Year of transplant 2008‐2009 12 (36) 46 (41) 2010‐2011 9 (27) 46 (41) 2012‐20132 12 (36) 20 (18)Median follow‐up of survivors (range), months 37 (3‐62) 25 (3‐62)

1. Cases from Northwestern Memorial Hospital were excluded. 2. Cases continue to be registered to CIBMTR for 2012 and 2013.

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Cellular Therapies for Regenerative Medicine (CTRM) number of complete forms submitted to CIBMTR since implementation of CTRM data collection form (Form 4000) in January 2011

Characteristics N (%)

Number of infusions 389Number of centers reporting 6Year of infusion 2002 4 ( 1) 2003 3 ( 1) 2004 3 ( 1) 2005 7 ( 2) 2006 7 ( 2) 2007 16 ( 4) 2008 39 (10) 2009 103 (26) 2010 87 (22) 2011 93 (24) 2012* 26 ( 7) 2013* 1 (<1)Indication

Neurologic Cerebral Palsy 223 (57) Congenital Hydrocephalus 81 (21) Developmental Delay 15 ( 4) Hemiparesis 14 ( 4) Periventricular leukomalacia; encephalomalacia 12 ( 3) HIE 9 ( 2) Brain Injury 8 ( 2) Partial agenesis of corpus callosum 3 ( 1) Perinatal hypoxic ischemic event 1 (<1) Spastic Quadriplegia 1 (<1)Cardio and peripheral vascular Chronic coronary artery disease 13 ( 3) Acute myocardial infarction 3 ( 1) Thromboangitis obliterans 1 (<1)Autoimmune disease Diabetes mellitus type 1 2 ( 1)Musculoskeletal Avascular Necrosis of Femoral Head 1 (<1)Other Acute kidney injury following cardiac surgery 2 ( 1)

Tissue source Cord blood unit 367 (94)Bone marrow 18 ( 5)Pancreatic tissue 2 ( 1)Peripheral blood 1 (<1)Umbilical cord 1 (<1)

Cell Type Infused Cord blood unit 367 (94)Unselected mononuclear cells 12 ( 3)

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Characteristics N (%)

AMR‐001 (bone‐marrow‐derived selected CD34+ cell product) 3 ( 1)Mesenchymal stromal cells 2 ( 1)Islet cells 2 ( 1)Human umbilical cord perivascular cells 1 (<1)CD34+ peripheral blood stem cells 1 (<1)Stem cells from bone marrow 1 (<1)

* Several centers first collect certain data required for the completion Form 4000 at 1‐year post infusion and cannot submit Form 4000 to the CIBMTR until this time. Cases continue to be registered for 2012 and 2013; data for these years are incomplete.

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TO: Autoimmune Disorders and Cellular Therapy Working Committee FROM: Marcelo Pasquini, MD, MS

Scientific Director for Autoimmune Disorders and Cellular Therapy Working Committee RE: Studies in Progress Summary

AUTOIMMUNE DISEASES

AD09‐01: Long Term Outcome after Autologous Hematopoietic Cell Transplantation for Multiple Sclerosis (P Muraro/R Saccardi): This study is being done in collaboration with the Autoimmune Working Party from the EBMT. The objective is to analyze long term outcomes after autologous hematopoietic cell transplantation for multiple sclerosis (MS). Manuscript preparation is underway. AD12‐01: The Effect of Allogeneic Hematopoietic Cell Transplantation on the Activity and Progression of Multiple Sclerosis (G. Georges): This study proposes to examine the impact of allogeneic hematopoietic cell transplantation (HCT) on multiple sclerosis (MS) disease activity when it is present as a coexisting autoimmune disease. Protocol development is underway. AD13‐01: HCT for Systemic Lupus Erythematous (S Hasni/S Pavletic): The study proposes to analyze the effectiveness of hematopoietic cell transplantation (HCT) for the treatment of systemic lupus erythematosus (SLE) and further exploration of use of HCT as a viable option in a subset of patients with recalcitrant SLE. Data collection is underway. CELLULAR THERAPIES CT10‐01: Donor leukocyte infusion versus second allogeneic hematopoietic stem cell transplantation for disease relapses after first allogeneic stem cell transplantation (N Frey/A Loren/D Porter): The study proposes to compare outcomes among patients with relapsed hematologic malignancies after allogeneic hematopoietic stem cell transplant (HCT) who receive either a second allogeneic HCT, donor leukocyte infusion (DLI) or no cellular intervention. Factors associated with overall survival for DLI and second HCT are also of interest. Manuscript preparation is underway. CT13‐01: Utility of Donor Leukocyte Infusion (DLI) for the Treatment of Drug‐resistant Viral or Fungal Infections in Allogeneic HCT Recipients: A CIBMTR Analysis (PI: G Akpek; MS: Sandy Korman): This objective of the study is to describe clinical outcomes after DLI in allogeneic HCT recipients with drug‐resistant viral or fungal infections and to identify variables that are associated with successful outcome, (only if the number of subjects identified in CIBMTR database is adequate). Protocol development is underway.

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Study Proposal 1311‐04 Study Title: G‐CSF Mobilized versus Unmobilized Donor Leukocyte Infusions following Disease Relapse after Allogeneic Hematopoietic Cell Transplantation Betty Ky Hamilton, MD, Cleveland Clinic, [email protected] Navneet Majhail, MD, MS, Cleveland Clinic, [email protected] Specific Aims: 1. To compare incidence, severity, and type of graft versus host disease in G‐CSF mobilized versus

unmobilized donor leukocyte infusion (DLI) for the treatment of relapse after allogeneic HCT. 2. To compare treatment‐related mortality (TRM), leukemia‐free survival (LFS) and overall survival (OS)

in patients receiving mobilized versus unmobilized DLI for treatment of disease relapse after allogeneic HCT.

Scientific Justification: Leukemic relapse is still a major cause of treatment failure after allogeneic hematopoietic cell transplant (HCT) for acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL). Although outcomes are still poor, donor leukocyte infusions (DLI) are currently still one of the more commonly used treatment strategies to treat relapse after HCT by intending to exert a strong graft‐versus‐leukemia (GVL) effect by immune reactions against leukemia antigens.1‐4 While DLI was originally studied in, and has been effective in, inducing remissions in chronic myelogenous leukemia (CML) in chronic phase5, it has been less successful in patients with acute leukemia and myelodysplasia, where patients may progress rapidly before a GVL effect can take place.2, 6 Given the often rapid pace of leukemia, and the time it takes for a GVL effect to occur, many have used DLI in combination with or as consolidation after chemotherapy to induce remission.6‐9 DLI has traditionally involved the collection of peripheral blood lymphocytes form the donor for treatment of post‐HCT relapse, however, with the use of chemotherapy, more recent studies have also used growth factor (G‐CSF) stimulated mobilized hematopoietic stem cells, given at the nadir of chemotherapy.7, 9, 10 There is some data that suggests exposure of donor cells to G‐CSF skews the T cells toward a Th2 cytokine profile, thus making them less alloreactive.11 When given with chemotherapy, G‐CSF mobilized cells may help support hematopoietic recovery as well. There is, unfortunately, great variability in the way and manner in which DLI is given, however, and limited data regarding the comparative efficacy and toxicity of traditional DLI versus mobilized‐DLI for treatment of relapse post‐HCT. A small retrospective study evaluated 67 patients given either GCSF‐mobilized or conventional DLI and found similar incidence of GVHD, engraftment, and survival, however, this study was limited by the variability in disease and use of chemotherapy.12 We thus propose to evaluate and compare outcomes of traditional DLI versus mobilized‐DLI in the treatment of post‐HCT disease relapse. Patient Eligibility Population: The study population will include all patients from 2000‐2011 with the diagnosis of acute myeloid leukemia, myelodysplasia or acute lymphoblastic leukemia treated with a first donor lymphocyte infusion for leukemic relapse >3 months after first allogeneic hematopoietic cell transplant from an HLA‐identical sibling or unrelated donor. Patients with identical twin, cord blood, or haploidentical donor will be excluded. Patients defined as having receiving second allogeneic HCT will be excluded. Patients recorded to have progressive relapsed disease who are not in remission will be excluded. Patients with active disease but have been specified to have received cytoreductive therapy may be considered to be included in the analysis.

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Data Requirements:

Data to be analyzed will be from data collected in the CIBMTR Report Forms. No additional data will be needed. Patient, disease and transplant variables include: Patient‐related:

Age

Gender

Karnofsky performance score Disease‐related:

Disease status at time of transplant

Cytogenetic/molecular risk group

Blast count at time of relapse

Time from HCT to relapse Transplant‐related:

Preparative regimen/type of transplant

Donor relationship

Donor‐recipient gender match

Donor cell source DLI/Chemotherapy characteristics:

Disease status

Use of cytoreductive chemotherapy

CD34 dose

CD3 cell dose

Escalated versus non‐escalated (if available) Outcomes:

Time to hematopoietic recovery (if available)

Incidence of aplasia (if available)

Incidence of grade 2‐4 and grade 3‐4 acute GVHD

Incidence of chronic GVHD

Transplant‐related mortality

Leukemia‐free survival

Overall Survival

Cause of Death Sample Requirements: N/A Study Design: This is a retrospective comparative cohort study comparing outcomes after G‐CSF mobilized versus conventional DLI for the treatment of relapsed leukemia after allogeneic HCT. The outcomes studied will be incidence of grade 2‐4 and grade 3‐4 acute GVHD13, any chronic GVHD, transplant‐related mortality, leukemia‐free survival and overall survival. Categorical variables will be summarized as frequency counts and percentages and compared between GVHD prophylaxis groups using the Chi‐Square test. Continuous variables are summarized as the mean, standard deviation, median, minimum, and maximum and compared using the Mann‐Whitney test. Transplant‐related mortality (TRM) will be

17


summarized as cumulative incidence estimate with relapse/progression as the competing risk. Leukemia‐free survival (LFS) will be defined as time to relapse or death from any cause and overall survival (OS) is time to death from any cause. Surviving patients will be censored at time of last follow up. Probabilities of LFS and OS will be calculated using Kaplan‐Meier methods and compared between regimens using the log‐rank test. Multivariate analyses will be performed using proportional hazards models for OS, LFS, TRM, GVHD and relapse using Cox model. Potential imbalances of disease status and use of cytoreductive chemotherapy given prior to DLI will be analyzed. References: 1. Loren AW, Porter DL. Donor leukocyte infusions for the treatment of relapsed acute leukemia

after allogeneic stem cell transplantation. Bone marrow transplantation 2008; 41(5): 483‐93. 2. Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W et al. Graft‐versus‐

leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1995; 86(5): 2041‐50.

3. Porter DL. Donor leukocyte infusions in acute myelogenous leukemia. Leukemia 2003; 17(6): 1035‐7.

4. Schmid C, Labopin M, Nagler A, Bornhauser M, Finke J, Fassas A et al. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem‐cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2007; 25(31): 4938‐45.

5. Porter DL, Roth MS, McGarigle C, Ferrara JL, Antin JH. Induction of graft‐versus‐host disease as immunotherapy for relapsed chronic myeloid leukemia. The New England journal of medicine 1994; 330(2): 100‐6.

6. Collins RH, Jr., Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1997; 15(2): 433‐44.

7. Levine JE, Braun T, Penza SL, Beatty P, Cornetta K, Martino R et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem‐cell transplantation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2002; 20(2): 405‐12.

8. Choi SJ, Lee JH, Lee JH, Kim S, Seol M, Lee YS et al. Treatment of relapsed acute myeloid leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G‐CSF‐primed donor leukocyte infusion: a high incidence of isolated extramedullary relapse. Leukemia 2004; 18(11): 1789‐97.

9. Alessandrino EP, Bernasconi P, Caldera D, Colombo A, Malcovati L, Martinelli G et al. Chemotherapy and donor peripheral blood progenitor cells for acute leukemia in early relapse after allogeneic bone marrow transplantation. Bone marrow transplantation 1999; 23(6): 607‐12.

10. Lee JH, Lee KH, Kim S, Seol M, Kim SH, Kim WK et al. Combination chemotherapy of intermediate‐dose cytarabine, idarubicin, plus etoposide and subsequent mobilized donor leukocyte infusion for relapsed acute leukemia after allogeneic bone marrow transplantation. Leukemia research 2001; 25(4): 305‐12.

11. Klangsinsirikul P, Russell NH. Peripheral blood stem cell harvests from G‐CSF‐stimulated donors contain a skewed Th2 CD4 phenotype and a predominance of type 2 dendritic cells. Experimental hematology 2002; 30(5): 495‐501.

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12. Abbi KK, Zhu J, Ehmann WC, Epner E, Carraher M, Mierski J et al. G‐CSF mobilized vs conventional donor lymphocytes for therapy of relapse or incomplete engraftment after allogeneic hematopoietic transplantation. Bone marrow transplantation 2013; 48(3): 357‐62.

13. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus Conference on Acute GVHD Grading. Bone marrow transplantation 1995; 15(6): 825‐8.

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Characteristics of patients who relapsed prior to receiving a DLI after a first HLA‐matched sibling or unrelated donor HCT for AL in CR or MDS with <5% blasts in blood reported to the CIBMTR from 2000

through 2012

Donor received treatment to

enhance cell collectionCharacteristic No Yes

Total N 237 139Year of HCT, N (%) 2000 ‐ 2002 33 (14) 14 (10)2003 ‐ 2005 51 (22) 36 (26)2006 ‐ 2008 90 (38) 53 (38)2009 ‐ 2011 57 (24) 34 (24)2012 6 ( 3) 2 ( 1)Age at transplant, years, N (%) <10 13 ( 5) 4 ( 3)10‐19 27 (11) 10 ( 7)20‐29 35 (15) 12 ( 9)30‐39 29 (12) 20 (14)40‐49 45 (19) 25 (18)50‐59 53 (22) 48 (35)60‐69 32 (14) 20 (14)70+ 3 ( 1) 0Age at transplant, years, Median (Range) 44 (<1‐76) 49 (2‐69)Patient sex, N (%) Male 126 (53) 90 (65)Female 111 (47) 49 (35)Karnofsky score, N (%) 90‐100% 59 (25) 29 (21)<90% 162 (68) 99 (71)Missing 16 ( 7) 11 ( 8)Disease, N (%) AML 153 (65) 106 (76)ALL 52 (22) 17 (12)MDS 32 (14) 16 (12)Disease status at transplant, acute leukemia only, N (%) AML CR1 105 (69) 77 (73) CR2 47 (31) 28 (26) CR3+ 1 ( 1) 1 ( 1) ALL CR1 33 (63) 12 (71) CR2 18 (35) 5 (29) CR3+ 1 ( 2) 0Blasts in blood at transplant, MDS only, N (%) None 28 (88) 13 (81)1% 2 ( 6) 1 ( 6)2% 2 ( 6) 1 ( 6)3% 0 1 ( 6)

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Recipeint/Donor CMV, N (%)

Recipient ‐ / Donor ‐ 67 (28) 31 (22)

Recipient ‐ / Donor + 30 (13) 10 ( 7)

Recipient + / Donor ‐ 60 (25) 28 (20)

Recipient + / Donor + 71 (30) 59 (42)

Recipient ‐ / Donor unknown 3 ( 1) 1 ( 1)

Recipient + / Donor unknown 4 ( 2) 5 ( 4)

Recipient and donor unknown 2 ( 1) 5 ( 4)

Recipeint/Donor Sex, N (%)

Recipient M / Donor M 61 (26) 46 (33)

Recipient F / Donor F 40 (17) 14 (10)

Recipient M / Donor F 38 (16) 24 (17)

Recipient F / Donor M 56 (24) 25 (18)

Recipient M / Donor unknown 27 (11) 20 (14)

Recipient F / Donor unknown 15 ( 6) 10 ( 7)

Donor Type, N (%)

HLA‐identical sibling 132 (56) 92 (66)

Unrelated donor 105 (44) 47 (34)

Graft Source, N (%)

Bone Marrow 93 (39) 22 (16)

PBSC 144 (61) 117 (84)

Conditioning Regimen Intensity, N (%)

Myeloablative 168 (71) 106 (76)

Non‐myeloablative/Reduced intensity 69 (29) 33 (24)

ATG or Campath prior to transplant, N (%)

ATG 61 (26) 32 (23)

Campath 17 ( 7) 6 ( 4)

No ATG or Campath 159 (67) 101 (73)

GVHD Prophylaxis, N (%)

CsA/FK506 + MTX 156 (66) 115 (83)

CsA/FK506 + MMF 34 (14) 11 ( 8)

Other 43 (18) 11 ( 8)

Missing 4 ( 2) 2 ( 1)

Interval from Dx to HCT, months, Median

(Range)

6 (2‐109) 5 (2‐96)

Interval from HCT to DCI, months, Median (Range) 10 (4‐76) 10 (3‐70)

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Reason for DCI, N (%)

Relapse 175 (74) 95 (68)

Stable, mixed chimerism 2 ( 1) 2 ( 1)

Loss of/decreased donor T‐cell chimerism 1 (<1) 4 ( 3)

Treatment for GVHD 0 1 ( 1)

Other 3 ( 1) 3 ( 2)

Missing 56 (24) 34 (24)

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Patient selection criteria:

For patients reported using CIBMTR data collection forms

N Excluded Reason Excluded

Selection Criteria

Missing/Unknown

Value Other Value Total Excluded N

Included

Initial criteria ◦ Diseases: AML, ALL, MDS ◦ First allogeneic HCT ◦ Year of HCT: 2000 ‐ 2012

22,759

AL only (n=19201): Disease status at HCT ‐ CR 283 4406 4689 18,070

MDS only (n=3558): <5% blasts in blood at HCT 749 257 1006 17,064

HLA‐matched sibling or unrelated donor 46 445 491 16,573

Graft sources: Bone marrow or PBSC 3 2,634 2,637 13,936

Patient received a DCI after first HCT 139 12,735 12,874 1,062

Exclude if missing data regarding donor treatment prior to donation

506* 0 506 556

Patient relapsed after first HCT 11 110 121 435

Exclude if patient first relapsed after DCI 12 59 71 364

Exclude if patient relapsed <3 months post‐HCT 0 62 62 302

Exclude if patient has <100 days of follow‐up 0 0 0 302

Exclude if patient did not consent to research 0 1 1 301

* NMDP legacy cases, n=244; Transplant performed prior to 2002 (i.e. prior to introduction of DCI form), n=62; Data not provide (i.e. data collection field left blank), n=186; Reason for missingness TBD, n=14

For patients reported using IBMTR “legacy” data collection forms

N Excluded Reason Excluded

Selection Criteria

Missing/Unknown Value Other Value Total Excluded

N Included

Initial criteria ◦ Diseases: AML, ALL, MDS ◦ Second HCT ◦ Transplant type: DCI ◦ Year of DCI ≥ 2000

374

Exclude if missing data regarding donor treatment prior to donation 60a 0 60 314

Patient relapsed after first HCT 45 19 64 250

Exclude if patient first relapsed after DCI 41b 52 93 157

Exclude if patient relapsed <3 months post‐HCT 0 46 46 111

Exclude if patient has <100 days of follow‐up 0 0 0 111

Exclude if patient did not consent to research 0 0 0 111

Criteria applied based on data reported for first HCT

AL only (n=98): Disease status at HCT ‐ CR 0 23 23 88

MDS only (n=13): <5% blasts in blood at HCT 3 2 5 83

HLA‐matched sibling or unrelated donor 0 8 8 75

Graft sources: Bone marrow or PBSC 0 0 0 75

Data not provide (i.e. data collection field left blank), n=45; Reason for missingness TBD, n=48. Date of DCI is unknown, n=41

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Study Proposal 1312‐14

Study Title: Long Term Outcomes after Autologous Hematopoietic Cell Transplantation for Rapidly Progressive Systemic Scleroderma Principal Investigator: Dominique Farge, MD, PhD Saint Louis Hospital

Internal Medicine and Vascular Diseases Unit Paris, France Email: dominique.farge‐[email protected]

Study Co‐Chair : Marcelo Pasquini, MD, MS

CIBMTR 9200 W. Wisconsin Ave, CCC5500 Milwaukee, WI 53226 Tel: 414‐805‐0700 Fax: 414‐805‐0714 E‐mail: [email protected]

Specific Objectives: The objective of this study is to evaluate long term outcomes from autologous hematopoietic cell transplantation (HCT) for rapidly progressive systemic sclerosis (SSc) from time of transplant to three and five years after transplantation:

- Analyze overall survival, event free survival (same definition as ASTIS) , progression‐free survival (criteria to be discussed not the one of ASTIS) transplant related mortality, response to AHSCT,

- Describe late effects (malignancies, late toxicities, secondary autoimmunity), in patients who underwent autologous HCT for treatment of SSc. Scientific Jusitification: Systemic Sclerosis is a heterogeneous disease, characterised by the excessive production and deposition of collagen in the skin, blood vessels and organs, with a limited (lc) and a diffuse cutaneous form (dc) 1. Severe forms of SSc, especially the rapidly progressing diffuse cutaneous form with organ involvement appearing within the first 4 years of disease onset, are associated with significant mortality (approximately 40 – 50% 5‐year survival rate) as a consequence of lung, heart and kidney involvement. 2‐6 The treatment of individual organ manifestations has been improved over the last few years with the introduction of new therapeutic substances. Treatment with endothelin receptor antagonists, phosphodiesterase inhibitors and intravenous or inhaled prostaglandins leads to a reduction in pulmonary arterial pressure with additional effects on the digital ulcers 7‐12. Proton pump inhibitors reduce reflux symptoms in patients with oesophageal motility disorders and ACE‐inhibitors probably have a beneficial effect on renal involvement 13‐14. Although each type of immunosuppressive drugs has successively been tested for the treatment of scleroderma (Methotrexate 15‐16, D‐penicillamine 17, alpha‐interferon 18, rituximab 19,20,

24


mycophenolate 21‐23., imatinib 24‐26, Cyclophosphamide 27‐31) none of them has proven any efficacy in prospective randomised trials. Therefater, metanalysis of randomized controlled trials and observational prospective cohort studies on cyclophosphamide effects on pulmonary function in SSC patients did not show any benefit from its use in this setting. In this context, AHSCT for rapidly progressive SSc with internal organ involvement within the first 4 years of disease onset or for cyclophosphamide‐refractory cases has recently emerged as the best proven effective therapy 32. Indeed, several European 33‐34 and North‐American 35‐37 open phase I‐II studies using AHSCT for SSc showed rapid and durable fall in skin score 38, improved functional status, stable lung function and regression of fibrosis extent on skin histology 36,38 and on lung imaging 39. Even normalisation of pathological capillary changes (nailfold capillary),40‐41 was shown. While gaining experience 42‐43, Transplant‐Related‐Mortality (TRM) decreased to 3‐5% 43, an acceptable risk regarding spontaneous disease evolution 2‐6, Regular data registers on this activity have been published 34,42‐43, while a center‐effect related to centre activity was demonstrated 43‐44. Various treatment schemes for mobilisation and conditioning have been applied worldwide. Schemes with total body irradiation are avoided because of their high pulmonary toxicity 44. The same applies for avoiding busulfan. In‐vitro treatment of the stem cells before retransfusion (purging and/or CD34 selection) appears reasonable here to return as few autoaggressive T‐cells as possible and to avoid early relapse of the autoimmune disease 45. However, in‐vitro manipulation is also associated with an increased susceptibility to infection. Results of 3 adequate randomized trials conducted in the mean time with comparable eligibility criteria and control arms are emerging 46‐48. Two of them used either non myeloablative regimen (cyclophosphamide and rabbit ATG) with CD34+ selection for the European multicenter ASTIS (Autologous Stem Cell Transplantation International Scleroderma’) trial, or without, for the American single center ASSIST trial in Chicago, and the third one the US multicenter SCOT trial used a TBI myeloablative regimen. Recruiting in these trials has been challenging, because SSc is a rare Autoimmune Disease (AD) (prevalence 7–50/Million) and AHSCT a well validated procedure, rather than a new drug to be tested. ASSIST46, the first phase II study randomized trial comparing cyclophosphamide pulse therapy and AHSCT for SSc was stopped earlier due to the impressive short term clinical superiority (ASSIST) of AHSCT in 10 SSc patients, who showed rapid and significant regression of skin score, a strong predictor of outcome, and of volume of lung disease on CT scan plus improved functional status on SF 36, whereas 9 patients under cyclophosphamide (6 iv bolus monthly) progressed or failed to improve after one year. The ASSIST trial, originally designed to enroll 60 patients, allowed crossover for 8 controls who progressed, of whom 7 with no contraindication could switch for AHSCT. All 17 AHSCT patients, without TRM, improved on the same parameters, with rather short follow‐up: at least 2 years for 11 cases. Stopping rules for significant differences in outcome between the two arms, i.e. failure to achieve equipoise, allowed earlier trial termination and solved the dilemma of sustained randomization in ASSIST, the Chicago single center study. Initial results from the ASTIS phase III stem cell transplant trial recently presented at EULAR 2012, the Annual Congress of the European League Against Rheumatism 48, demonstrate that haematopoietic stem cell transplantation (HSCT) results in fewer deaths than IV cyclophosphamide in patients with poor prognosis early diffuse cutaneous systemic sclerosis. In January 2014, about 300 patients with SSc treated by AHSCT have been reported to the EBMT database.and xx patients to the CIBMTR. In this context, use of AHSCT has become the best treatment

25


option that can be proposed to patients with severe or rapidly progressive forms of SSc, as long as it will be performed after careful pretransplant evaluation of organ involvement 49, especially heart evaluation 50, respect of contra indications and performed in experienced centers. It is estimated that more than xx patients with SSc underwent autologous HCT worldwide. The CIBMTR includes xx patients with SSc who received an autologous HCT from 1996 to 2011 from registering centers in North and South America. The European Group for Blood and Marrow Transplantation (EBMT) registry includes 140 patients who received an autologous HCT from 1994 to 2011 for SSc. This study has the objective of combining data from CIBMTR and EBMT databases and update follow up with current disease status in surviving patients to analyze long term outcomes. Eligibility Criteria:

Identification of participating Centers: All registering centers with CIBMTR and EBMT that had performed at least one autologous HCT for SSc from 1996 to December 2011 will be invited to participate. The availability of a minimum set of data/patient will be considered a pre‐requisite to enter each patient into the trial. (do we need a minimum set of data to participate in the study ?)

The proposed data set includes the following items: - Conditioning Regimen - Graft manipulation - At least one follow‐up visit/report after transplantation

Patient Eligibility: All Patients (irrespective of age) who underwent an autologous HCT for the treatment of SSc from January 1994 to December 2011and not included in ASTIS or in SCOTT

Eligibility for the landmark analysis: all patients who are alive at 3 and 5 years after autologous HCT will be included in the landmark analysis.

Study Endpoints: (from NIS):

Primary end point: Overall survival (OS),

Secondary end points: 100‐day Treatment related mortality (TRM) defined as any death during 100 day

following transplant that cannot be attributed to progression or relapse of the disease.

Safety: Treatment related toxicity throughout the study period using WHO toxicity parameters (expressed as maximum grade toxicity per organ system, see appendix)

- Incidence of Adverse Events (AE) and Serious Adverse Events (SE) - Neutrophil and platelet engraftment, defined as first day after

transplantation with absolute neutrophil count > 500 cells/μL and >20.000 platelets/μL without platelet transfusion, respectively

Event Free Survival defined as survival since Baseline (the 1st day of mobilisation) without event‐free survival defined as the time in days from the day of randomization until the occurrence of death due to any cause or the development of persistent major organ failure (heart, lung, kidney) defined as left ventricular ejection fraction (LVEF) <30% by echocardiography (or MUGA), resting arterial oxygen tension (PaO2) <8 kPa (<60 mmHg) and/or resting arterial carbon dioxide

26


tension (PaCO2) >6.7 kPa (>50 mmHg) without oxygen supply, or the need for renal replacement therapy.

Response to treatment Response to treatment within 1 year following autologous HSCT, defined as

25% improvement in mRSS and/or

≥10% improvement in DLCO or FVC as compared to baseline without need of further immunosuppression

Late effects:

- Malignancies - Late non‐neoplastic toxicities - Secondary autoimmune diseases:

‐Autoimmune thrombocytopaenia ‐Autoimmune thyroid disease ‐Autoimmune haemolytic anaemia ‐Evans’ syndrome ‐Acquired haemophila ‐Myasthenia gravis ‐Ulcerative colitis ‐Crohn’s disease ‐Psoriasis ‐Rheumatoid arthritis/ spondyloarthropathy ‐Lupus erythematosus ‐Vasculitis

‐Autoimmune hepatitis ‐ Other: specify

Variables to be analyzed:

Patient‐related: - Age - Gender

Transplant‐related: - Use of chemotherapy for hematopoietic cell mobilization - Year of Transplant - Conditioning regimen - Graft manipulation - Cause of death for transplant related mortality

Disease‐related: - mRSS prior to mobilization - mRSS prior to conditioning regimen - …..

Study Design: TO BE DISCUSSED and ADAPTED ACCORDING TO ABOVE AND final agreement on the end points once we shall have worked together

27


Statistical analysis This study will be a retrospective cohort study on autologous HSCT for treatment of SSc. Data collected from both the EBMT and CIBMTR as described below (Data collection, 6.1) will be summarized in descriptive tables of demographic information of all the population. Continuous variables will be reported as medians and ranges, while categorical variables will be reported as absolute numbers and percent of total patients. The probabilities of Overall survival and Event Free survival will be calculated using the Kaplan‐Meier Estimator(11). Others outcomes listed in section 4 will be generated using cumulative incidence estimates to account for competing risk. The endpoints listed in section 4 will be analyzed using Cox proportional hazards regression models. The proportionality assumption of Cox models will be tested by adding a time‐dependent covariate for each covariate factor. The associations between each endpoint and potential prognostic variables will be evaluated using a stepwise approach. Variables significantly associated with each outcome event will be included as covariate factors in the subsequent comparisons. Adjusted probabilities of progression‐free and overall survival will be generated from the final Cox models stratified on weighted averages of covariate values using the sample proportion as the weight function. These adjusted probabilities estimate likelihood of outcomes in populations with similar prognostic factors. Two landmark analyses are planned for this study, at three and five years, respectively. The latter will depend on the number of eligible patients. Live patients and without disease progression at 3 and 5 years will enter the landmark analysis. Outcomes listed in section 4 will be analyzed starting at 3 and 5 year time points.

Data collection. - Data collection forms. Participating Centers (identified as described above in

Section 3.1) will be sent Data Collection Forms. The forms will be based on the

minimal essential data “B” forms that has been elaborated either by the EBMT or

CIBMTR. The Study Data Managers designated by the CIBMTR and EBMT

respectively will be responsible for monitoring the completion and return of the

Data Collection Forms from the Participating Centers.

- Study database. A specific database will be set up to input data from the data

collection forms. Data collected in the two Data Management Offices will be

thereafter merged into a study‐specific database.

- Timeline. It is planned to start data collection in april 2014 and to complete it by

october 2014.

Data property rules

- The data collection paper form will bear both the CIBMTR and the EBMT logos and

will be considered as the specific questionnaire to obtain data for this study.

28


- A patient will not be considered as being or becoming an EBMT patient if originally

registered with the CIBMTR and vice versa.

- Only data of patients belonging to the CIBMTR will be stored in the CIBMTR general

registry database and vice versa for the EBMT general registry database.

- Data collected for this study will be merged in one database for the only purpose of

the analysis but will remain property of CIBMTR for patients originally registered

with CIBMTR and of the EBMT for patients originally registered with the EBMT,

respectively.

- The database built for the purpose of this study will bear both the CIBMTR and the

EBMT logos. Both paper forms and database will contain a field allowing to identify

if the patient was originally registered either with the CIBMTR or with the EBMT,

including the patient’s original registration number and name of the centre where

the transplant was performed.

- No further studies will be conducted on the study database or any part of it without

prior approval by the Principal Investigator and by the CIBMTR Working Committee

and EBMT Working Party.

Publication rules

The study will comply with all the guidelines from EBMT (Authorship guidelines for

EBMT publications) and CIBMTR (Authorship V.3 2010‐06‐11) and that are applicable to

a study jointly conducted by CIBMTR and EBMT (as opposed to a study being solely

conducted within each organization).

The PI will have primary responsibility in fulfilling the responsibilities described in

sections II‐VII of the EBMT guidelines and in section 1 (Retrospective studies) of the

CIBMTR Guidelines section 2 (General Guidelines)

A writing group will be formed and Chaired by the PI, and will include the Study Co‐

Chairs and Co‐Investigators who played a substantial role in the acquisition, analysis or

interpretation of the data or individuals of EBMT and CIBMTR who played a critical role

in the organization and conduct of the study and who are prepared to fulfill authorship

role and responsibilities.

The writing group will be chaired by the Principal Investigator who will have a senior

level Authorship (first or last name) in the Authors’ list. Members of the writing group

will be listed as first‐tier Authors, reporting on behalf of the SSc‐HSCT Long‐Term Follow‐

up group (second‐tier Authors). The latter will include data contributors or other

individuals whose contribution does not meet first‐tier Authorship criteria. Minor level

or paid technical contributions which do not meet EBMT and CIBMT or journal

Authorship criteria will be acknowledged if appropriate.

All manuscripts originating from the study should include in the main title (or subtitle if

mandated by the Journal’s title word limits):

29


A joint study from the European Group for Blood and Marrow Transplantation

(EBMT).and from the Center for International Blood&Marrow Research (CIBMTR)

Proposed key Authorship structure:

No data from the study should be published, in preliminary or final form, outside the

arrangements described and without the prior knowledge and approval of the PI and of

the the Chair of the EBMT ADWP and of the scientific director of the CIBMTR WC.

Protocol approval and distribution

The study protocol and subsequent amendments will be submitted for approval by the

PI, by the Chair of the EBMT ADWP, by the Chief Scientific Director of the CIBMTR and

by the President of the EBMT.

The protocol must not be modified in any way or circulated inside or outside the study

team without prior knowledge and agreement of the PI.

References: 1. Gabrielli, Armando, Avvedimento, E.V. & Krieg, Thomas. Scleroderma. The New England Journal of Medicine, 2009, 360(19), p.1989‐2003. 2. Czirjak L, Kumanovics G, Varju C, et al. Survival and causes of death in 366 Hungarian patients with systemic sclerosis. Ann Rheum Dis 2008;67:59‐63. 3. Beretta L, Santaniello A, Cappiello F, et al. Development of a five‐year mortality model in systemic sclerosis patients by different analytical approaches. Clin Exp Rheumatol 2010;28:S18‐27. 4. Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis 2010;69:1809‐15. 5. Scussel‐Lonzetti, L. et al. Predicting mortality in systemic sclerosis: analysis of a cohort of 309 French Canadian patients with emphasis on features at diagnosis as predictive factors for survival. Medicine, 2002,81(2), p.154‐167 6.Fransen J, Popa‐Diaconu D, Hesselstrand R, et al. Clinical prediction of 5‐year survival in systemic sclerosis: validation of a simple prognostic model in EUSTAR centres. Ann Rheum Dis 2011;70:1788‐92. 7.Wigley FM, Seibold JR, Wise RA, McCloskey DA, Dole WP. Intravenous iloprost treatment of Raynaud's phenomenon and ischemic ulcers secondary to systemic sclerosis. J Rheumatol 1992;19:1407‐14. 8.Wigley FM, Wise RA, Seibold JR, et al. Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicenter, placebo‐controlled, double‐blind study. Ann Intern Med 1994;120:199‐206. 9.Matucci‐Cerinic M, Denton CP, Furst DE, et al. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS‐2 randomised, double‐blind, placebo‐controlled trial. Ann Rheum Dis 2011;70:32‐8. 10.Korn JH, Mayes M, Matucci Cerinic M, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 2004;50:3985‐93. 11.Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896‐903. 12.Langleben D, Brock T, Dixon R, Barst R. STRIDE 1: effects of the selective ET(A) receptor antagonist, sitaxsentan sodium, in a patient population with pulmonary arterial hypertension that meets traditional inclusion criteria of previous pulmonary arterial hypertension trials. J Cardiovasc Pharmacol 2004;44 Suppl 1:S80‐4. 13.Steen VD, Medsger TA, Jr. Long‐term outcomes of scleroderma renal crisis. Ann Intern Med 2000;133:600‐3. 14.van Pinxteren B, Sigterman KE, Bonis P, Lau J, Numans ME. Short‐term treatment with proton pump inhibitors, H2‐receptor antagonists and prokinetics for gastro‐oesophageal reflux disease‐like symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev 2010;11:CD002095.

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Appendices: ‐ Accrual Tables ‐ List of Centers ‐ Data Collection Form ‐ Invitation letter template

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Descriptive statistics Characteristics N (%)

Number of patients 88Number of centers 35Age at transplant 42 (8‐61) <18 4 ( 5) 18‐50 63 (72) 50‐60 19 (22) >60 2 ( 2)Sex Male 32 (36) Female 56 (64)KPR ≥90 27 (44) <90 35 (56)Graft type BM 1 ( 1) PB 86 (98) CB 1 ( 1)Conditioning regimens Cyclophosphamide+ATG 24 (27) Cyclophosphamide+ATG+TBI 44 (50) Cyclophosphamide+ATG+Fludarabine 6 ( 7) Cyclophosphamide+TBI 4 ( 5) ARAC+ETOP+Melphalan 2 ( 2) Cyclophosphamide+Fludarabine 2 ( 2) Cyclophosphamide+Buslfan+TBI+ARAC 1 ( 1) TBI+ATG 1 ( 1) Melpahlan+Fludarabine+ATG 1 ( 1) Cyclophosphamide 1 (1) Melphalan 2 ( 2)Time from diagnosis to transplant, median (range), months <12 months 24 (27) 12‐24 months 29 (34) 24‐36 months 12 (14) >36 months 23 (26)Year of transplant 1996‐2000 11 (13) 2001‐2005 29 (33) 2006‐2010 40 (45) 2011‐2012 8 ( 9)Median follow‐up of survivors, median (range), months 46 (9‐62)

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Documents

Not for publication or presentation · To promote studies of hematopoietic cell transplantation and other cellular therapies for autoimmune disease and to more broadly investigate