A G E N D A CIBMTR WORKING COMMITTEE FOR ......Not for publication or presentation A G E N D A...

Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR INFECTION AND IMMUNE RECONSTITUTION Salt Lake City, Utah Thursday, February 22, 2018, 12:15 – 2:15 pm

Co-Chair: Jeffery Auletta, MD, Nationwide Children’s Hospital, Columbus, OH; Telephone: 614-722-3553; E-mail: [email protected]

Co-Chair: Caroline Lindemans, MD, PhD, University Medical Center Utrecht, Utrecht, Netherlands; Telephone: +31 622879245; E-mail: [email protected]

Co-Chair: Krishna Komanduri, MD, University of Miami; Miami, FL; Telephone: 305-243-5302; E-mail: [email protected];

Scientific Director: Marcie Riches, MD, MS, The University of North Carolina at Chapel Hill, Chapel Hill, NC; Telephone: 919-966-3048; E-mail: [email protected]

Statistical Directors: Kwang Woo Ahn, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-456-7387; E-mail: [email protected] Soyoung Kim, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-955-8271; E-mail: [email protected]

Statistician: Min Chen, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0710; E-mail: [email protected]

1. Introductiona. Welcome and introductionb. Welcome to Dr. Jan Styczynski, Chair EBMT Infectious Diseases Working Partyc. Introduction of incoming Co-Chair: Dr. Miguel-Angel Perales, Memorial Sloan Kettering

Cancer Centerd. Minutes and Overview Plan from February 2017 meeting (Attachment 1)

2. Accrual summary (Attachment 2)

3. Studies submitted/Preliminary resultsa. IN07-01/IN11-01(a) Bacterial bloods stream infection (BSI), particularly post-engraftment

BSI, are associated with increased mortality after allogeneic hematopoietic cell transplantation (C Ustun/ JA Young). Submitted to BBMT.

b. IN07-01/IN11-01(b) Bloodstream infection (BSI) due to Vancomycin-resistant Enterococcus (VRE) and mortality after hematopoietic cell transplantation. A multicenter retrospective cohort study (GA Papanicolaou).

c. IN13-01 Bacterial and fungal infections in patients undergoing allogeneic hematopoietic cell transplantation following nonmyeloablative and myeloablative regimens (C Ustun).

d. IN14-01 Post allogeneic hematopoietic transplant Epstein Barr Virus related Lymphoproliferative disorder following conditioning with Antithymocyte globulin or Alemtuzumab (S Naik/ C Bachier/ P Shaughnessy/ P Hari/ R Kamble). (Attachment 3)

e. IN16-01 Viral Encephalitis in Hematopoietic Stem cell Transplant Recipients, 2007-2013(M Abidi/ P Hari). (Attachment 4)

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Not for publication or presentation

4. Studies in progress (Attachment 5)a. IN16-02 Determination of the burden of mucosal barrier injury-laboratory confirmed

bloodstream infections (MBI-LCBI) in the first 100 days after stem cell transplant (C Dandoy/ P Daniels) Data file preparation (Attachment 6)

b. IN17-01 Incidence and impact of cytomegalovirus and other viral infections, on post-transplant outcomes following HLA-haploidentical hematopoietic cell transplantation compared to other donor sources. (Rizwan Romee/ Anurag Singh/ Randy Allison Taplitz) Protocol development (Attachment 7)

5. Future/proposed studiesa. PROP 1707-01 Comparison of Early (d100) Infections after Haplo HCT between patients

receiving Cy-based vs other GVHD prophylaxis (C Ustun/ G Papanicolaou) (Attachment 8)b. PROP 1710-06 Posa v Vori prophylaxis in patients with Allo HCT (S Farhan/ N Janakiraman/ E

Peres) (Attachment 9)c. PROP 1711-57 Incidence and impact of C diff infection by day 100 on allo HCT outcomes (M

Ramanathan/ B Savani) (Attachment 10)d. PROP 1711-74 AlloHCT is feasible and effective for HIV positive patients with heme

malignancies (SR Pingali/ A Mukherjee/ KUA Adekola) (Attachment 11)

Dropped proposed studies a. PROP 1710-13 Comparison of Cipro vs Levo in patients with AlloHCT. Dropped due to

feasibility-the data just started being requested Jan 2017.b. PROP 1711-17 Changing epidemiology of invasive pneumococcal infx since PCV vaccines.

Dropped due to feasibility –We do not have the data to answer these questions.c. PROP 1711-62 Risk of CMV reactivation in Haplo patients with PTCY. Dropped due to overlaps

with ongoing study IN1701d. PROP 1711-73 Association between respiratory viral infection and rates of GVHD by 2 years

after HCT. Dropped due to feasibilitye. PROP 1711-76 Impact of TMP/SMX prophy on rates of bacterial infection and NRM following

allogeneic HCT. Dropped due to feasibility-no data for duration of prophylaxis.

6. Other Business

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Not for publication or presentation Attachment 1

MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR INFECTION AND IMMUNE RECONSTITUTION Orlando, FL Saturday, February 25, 2017, 12:15 – 2:15 pm

Co-Chair: Jeffery Auletta, MD, Nationwide Children’s Hospital, Columbus, OH; Telephone: 614-722-3553; E-mail: [email protected]

Co-Chair: Caroline Lindemans, MD, PhD, University Medical Center Utrecht, Utrecht, Netherlands; Telephone: +31 622879245; E-mail: [email protected]

Co-Chair: Krishna Komanduri, MD, University of Miami; Miami, FL; Telephone: 305-243-5302; E-mail: [email protected];

Scientific Director: Marcie Riches, MD, MS, The University of North Carolina at Chapel Hill, Chapel Hill, NC; Telephone: 919-966-3048; E-mail: [email protected]

Statistical Directors: Kwang Woo Ahn, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-456-7387; E-mail: [email protected] Soyoung Kim, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-955-8271; E-mail: [email protected]

Statistician: Min Chen, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0710; E-mail: [email protected]

1. Introductiona. Welcome and introduction

Dr. Jeffery Auletta moderated the introduction of the working committee followed by whichall the attending co-chairs and the statisticians were introduced.

Dr. Auletta reviewed the goal of the working committee is to publish high impact studies in atimely manner. The expectations of the meeting are review of the current status of ongoingstudies and timelines and for members to assess and select proposals that will have a highimpact on the field. The working committee is limited by the complicated nature of infectiondata (Best before day 100) including data regarding infection prophylaxis.

The working committee members were asked to vote on a level of scientific impact score, 1 isthe highest impact and 9 is the lowest impact score for the new proposals based on thefeasibility and impact on the transplant community. Due to limited statistical hours and on-going work in the INWC, only one proposal will be accepted this year.

Dr. Auletta mentioned the working committee’s membership is open to any individual willingto take an active role in study development and completion. He emphasized the rules ofAuthorship: 1. substantial and timely contributions to conception and design, acquisition ofdata, or analysis and interpretation of data; 2. drafting the article or revising it critically forimportant intellectual content; 3. final approval of the version to be published. All three

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conditions must be met. The studies that are closest to submission will receive highest priority. Last, Dr. Auletta introduced sources of HCT data in the CIBMTR. Dr. Marcie Riches emphasized infection information only available in CRF forms, which is a subset of reported patients based upon an internally reviewed selection algorithm.

b. Minutes and Overview Plan from February 2016 meeting The minutes and overview plan from the 2016 Tandem meeting held in Honolulu, Hawaii were reviewed and approved by committee members.

2. Published papers Dr. Jeffery Auletta reported that the infection working committee has published four papers in the past year.

a. IN10-01 Karen Ballen, Kwang Ahn , Min Chen , Dr. Hisham Abdel-Azim , Ibrahim Ahmed , Dr. Mahmoud Aljurf , Dr. Joseph Antin , Ami Bhatt , Michael Boeckh , George Chen , Dr. Christopher Dandoy , Dr. Biju George , Mary Laughlin , Dr. Hillard Lazarus , Dr. Margaret MacMillan , David Margolis , Prof. David Marks , Dr. Maxim Norkin , Dr. Joseph Rosenthal , Ayman Saad , Prof. Bipin Savani , Dr. Harry Schouten , Jan STOREK , Paul Szabolcs , Dr. Celalettin Ustun , Dr. Michael Verneris , Dr. Edmund K Waller , Dr. Daniel Weisdorf , Dr. Kirsten Williams , John Wingard , Baldeep Wirk , Tom Wolfs , Jo-Anne Young , Jeffery Auletta , Dr. Krishna Komanduri , Dr. Caroline Lindemans , Dr. Marcie Riches: Infection Rates among Acute Leukemia Patients receiving Alternative Donor Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 22(9):1036-1645

b. IN09-01 Richard Maziarz, Dr. Ruta Brazauskas , Min Chen , Dr. Aleksandra McLeod , Dr. Rodrigo Martino , John Wingard , Dr. Mahmoud D Aljurf , Minnoo Battiwalla , Dr. Christopher Dvorak , Prof. Biju George , Dr. Eva Guinan , Dr. Gregory Hale , Dr. Hillard Lazarus , Prof. Jong Wook Lee , Dr. Jane Liesveld , Dr. Muthalagu Ramanathan , Dr. Vijay Reddy , Prof. Bipin Savani , Dr. Franklin Smith , Dr. Lynne Strasfeld , Dr. Randy Taplitz , Dr. Celalettin Ustun , Dr. Michael Boeckh , Dr. Juan Gea-Banacloche , Dr. Caroline Lindemans , Jeffery Auletta , Dr. Marcie Riches : Outcomes of allogeneic HSCT for patients with hematologic malignancies (AML, ALL, MDS, CML) with and without pre-existing fungal infections- pre-existing invasive fungal infection is not a contraindication for subsequent HSCT: a CIBMTR® study. Bone Marrow Transplantation. doi:10.1038/bmt.2016.259. Epub 2016 Dec 19.

c. IN12-01a Pierre Teira, Minoo Battiwalla, Muthalagu Ramanathan, Kwang Woo Ahn, Min Chen, Jaime Green, Ayman Saad, Joseph H. Antin, Bipin N. Savani, Hillard M. Lazarus, Matthew Seftel, Wael Saber, Carolyn Behrendt, David Marks, Mahmoud Aljurf, Maxim Norkin, John R. Wingard, Caroline A. Lindemans, Michael Boeckh, Marcie L. Riches, Jeffery J. Auletta: Early Cytomegalovirus reactivation remains associated with increased transplant related mortality in the current era: a CIBMTR analysis. Blood 127(20):2427-2438

d.

IN12-01b Muthalagu Ramanathan , Pierre Teira , Minnoo Battiwalla , Dr. A. Barrett , Kwang Ahn , Min Chen , Carolyn Behrendt , Jaime Green , Mary Laughlin , Dr. Hillard Lazarus , Prof. David Marks , Ayman Saad , Dr. Matthew Seftel , Dr. Wael Saber , Prof. Bipin Savani , Dr. Edmund K Waller , John Wingard , Jeffery Auletta , Dr. Caroline Lindemans , Michael Boeckh , Dr. Marcie Riches : Impact of Early Cytomegalovirus Reactivation in Cord blood Stem Cell Recipients in the Current Era. Bone Marrow Transplant 51(8):1113-1120

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3. Studies with Preliminary Results Dr. Jeffery Auletta also introduced two studies with preliminary results.

a. IN07-01/IN11-01 Early Bacterial infection in patients undergoing allogeneic HCT (M Robien/G Papanicolaou/Celalettin Ustun/ JA Young) Two manuscripts are under preparation based on this study. One of them has been accepted as a poster in this tandem meeting.

b. IN13-01 Bacterial and fungal infections in patients undergoing allogeneic hematopoietic cell transplantation following nonmyeloablative and myeloablative regimens (C Usten) The final analysis has been circulated to the writing comment for comments and the manuscript is under preparation.

4. Studies in progress Dr. Krishna Komanduri mentioned the ongoing studies.

a. IN14-01 Post allogeneic hematopoietic transplant Epstein Barr Virus related Lymphproliferative disorder following conditioning with Antithymocyte globulin or Alemtuzumab (S Naik, C Bachier, P Shaughnessy, P Hari, R Kamble) Date file preparation Dr. Jeffery Auletta updated the study on behalf of the PIs. The specific aims of this study are: to describe the characteristics of patients with post-transplant lymphoproliferative disorders (PTLD) following allogeneic hematopoietic cell transplantation (allo HCT); To determine morbidity and outcomes associated with Epstein Barr virus (EBV) positive and EBV negative PTLD. The current population has 236 EBV positive patients and 34 EBV negative patients. 190 path reports have been reviewed. Comments from Working Committee:

- Campath may effect EBV. Dr. Riches mentioned few patients received Campath in the current population.

- Assessment of prior use of Rituximab in the conditioning regimen. It was noted that since the patients included did not have B-cell lymphoma as the disease for transplant, it was unlikely that patients had received Rituximab during the conditioning regimen.

b. IN16-01 Viral Encephalitis in Hematopoietic Stem cell Transplant Recipients, 2007-2013

(M Abidi, P Hari) Protocol development Dr Abidi Maheen updated the study. The objectives of the study are: to describe the frequency and significance of viral DNA detection in cerebrospinal fluid (CSF) in hematopoietic stem cell transplant (HCT) recipients screened for viral encephalitis; to determine the OS of patients with viral encephalitis after HCT. The primary endpoint will be overall survival of patients developing EBV positive and EBV negative PTLD. The secondary endpoints will be time to onset of PTLD. Factors at transplant impacting outcomes following diagnosis of EBV positive PTLD. There are 118 patients in the current population. Dr. Komanduri expressed surprise by how much HHV6 dominated the infections in this study. The lack of viremia may due to some centers do not test viremia routinely until recently. Dr.

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Riches pointed out, during the time period, cord blood transplants were over selected and it may potentially skew the data. Additional issues raised by the working committee:

1. Limitations include: no clear systematic evaluation of patients, unknown symptomatology triggering LP, inability to determine HHV6 latency in the study, inability to have a control cohort that also had an LP - These limitations may result in erroneous conclusions

2. Discussion of unpublished data from NIH suggesting a low level of HHV-6 in the CSF when tested in patients receiving intrathecal chemotherapy

3. Should we address the season of the year for the encephalitis? c. IN16-02 Determination of the burden of mucosal barrier injury-laboratory confirmed

bloodstream infections (MBI-LCBI) in the first 100 days after stem cell transplant (C Dandoy, P Daniels) Protocol development Dr. Christopher Dandoy updated the study. This study hypothesizes that patients in the first 100 days after stem cell transplant who develop mucosal barrier injury laboratory confirmed bloodstream infections (MBI-LCBI) have increased transplant related mortality (TRM) and decreased overall survival (OS) compared to those with no infection or an infection not classified as an MBI-LCBI. The Specific Aims of the study are: compare TRM and OS post-SCT between patients who develop a MBI-LCBI versus those with no infection or a non-MBI-LCBI in the first 100 days; Determine the incidence of MBI-LCBIs in the first 100 days post SCT; Determine the risk factors for development of a MBI-LCBI in the first 100 days; and determine the timing of MBI-LCBI after SCT. The outcomes of the study are: overall survival; transplant related mortality (TRM); Incidence of MBI-LCBI within the first 100 days; and Incidence of bloodstream infections (bacterial and fungal) not meeting criteria for MBI-LCBI; and infection as primary or secondary cause of death by day 100 and by 1 year. A bloodstream infection will be classified as a MBI-LCBIs if it meets both the organism criteria and the patient criteria from the NHSN. Study strengths are: Large sample size, Contemporary, Reflects the global reality of HSCT by including all centers, Identify MBI-LCBI burden for public health reporting, Public health implications and should target major public health journal such as JAMA. Comments:

- Important topic for hospital epidemiology/infection control - Consider inclusion of autologous transplants

5. Future/proposed studies

Dr Caroline Lindemans reported that 9 proposals were received this year and 4 will be presented. Since there is significant overlap of Prop 1611-02, Porp1611-117 and Prop1611-134, we propose to merge the three proposals into one study to maximize efficiency and statistical hours.

a. PROP1605-01 Clinical outcomes for patients with invasive fungal infections undergoing hematopoietic stem cell transplant, (Myeloablative vs. Nonmyeloablative/Reduced intensity stem cell transplant) in the era of newer anti-fungals, 2009-2015 (Maheen Abidi/

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Mark R. Litzow/M. Rizwan Sohail/Randall C. Walker) Dr. Maheen Abidi presented the proposal. The objectives of this proposal are: 1. Study period 2010-2015 in era of newer antifungals; compare results with outcomes of IFIs that underwent HSCT 1995-2009 (IN09-01); 2. Determine outcomes & mortality rates of patients with leukemia & other hematologic malignancies with & without IFIs that undergo HSCT; 3. Determine the relationship between IFIs and the incidence & severity of GVHD & on relapse rates. Dr. Riches answered the question regarding why limited the patients with 2046 and 2146 form (fungal supplemental forms) only, since the requested information is available only in the 2046/2146 form. Dr. Komanduri suggested adding time from diagnosis to transplant, or time of remission. Since delay of transplant will increase the relapse mortality. Committee Discussion:

- Inability to determine if the fungal infection is possible/probable/proven - Lack of information of the status of the infection at the time of transplant

b. PROP 1611-02 The Incidence of Cytomegalovirus Viremia and Disease following HLA-

Haploidentical Hematopoietic Cell Transplantation Compared to HLA-Matched Related Donor, Matched Unrelated Donor, and Umbilical Cord Blood Transplantation (Rizwan Romee / Ephraim Fuchs/ Asad Bashey/ Stefan Ciurea) Dr. Scott Goldsmith presented the proposal. The hypotheses of the study are: Incidence of CMV reactivation and disease higher after haploHCT with PTCy compared to MUD/MRD/UCB; CMV reactivation does not promote decreased relapse, or longer DFS or OS in haploHCT. The Inclusion criteria are: Heme malignancy, age ≥ 18 years, and HCT between 2008-2015; HaploHCT w/ PTCy, UCB, 8/8 MUD, MRD. The exclusion criteria are: Ex-vivo T-cell depletion; HaploHCT for benign condition; Lack of donor/recipient CMV serostatus. The Primary Endpoint are: Compare incidence of CMV reactivation and disease between haploHCT w/ PTCy to MRD/MUD/UCB. Secondary Endpoints: Determine association of CMV donor/recipient serostatus with CMV disease; Compare DFS, relapse, NRM, GVHD and GRFS between the groups (Association with CMV reactivation; Association with CMV donor/recipient serostatus; Subset analysis for patients with AML).

c. PROP 1611-117 Impact of CMV Reactivation on Relapse of Hematological Malignancies after Haploidentical HSCT: a CIBMTR Analysis (Anurag Singh/ Siddhartha Ganguly) (Attachment 11) Dr. Anurag Singh presented the proposal. The specific aim of the study is to describe the effect of early CMV reactivation on relapse in the setting of haploidentical transplant. The Inclusion criteria are: patients receiving a first allogeneic transplantation for any AML, MDS, ALL and lymphomas from a haploidentical donor between 2000 and 2015 and reported to the CIBMTR. The exclusion criteria are: Second transplant or more; lack of day 100 follow-up forms capturing CMV reactivation data. The statistical methods are: Patient-, disease-, and transplant-related factors will be compared among groups using the Pearson χ2 test for discrete variables and the Kruskal-Wallis test for continuous variables.

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d. PROP 1611-134 Incidence and Outcomes of individuals with and without viral infections in recipients of haploidentical versus other allogeneic hematopoietic stem cell transplantation for patients with hematologic malignancies (Randy Allison Taplitz/ Carolyn Mulroney/ Richard Maziarz) (Attachment 12) Dr. Randy Allison Taplitz presented the proposal. This study hypothesizes that outcomes of treatment related mortality, overall survival, relapse rate, GVHD, diagnosis of bronchiolitis obliterans/COP, leukemia-free survival and presence of co-infection in patients with any viral infections after transplant will be inferior in those patients receiving haploidentical donors vs some other donor type transplant (compared separately – cord and mismatched unrelated, matched transplants; and as a group). Characteristics of patient who underwent first Allo transplant with AML, ALL, MDS, CML, CLL, NHL, HL, plasma cell disorders and severe aplastic anemia reported to the CIBMTR from 2010-2015 Dr. Marcie Riches mentioned, if we decide this combined proposal proceed forward, we have to redefine the population. Dr. Komanduri is concerned the testing methods change overtime, so some compromise has to be made.

Committee Discussion (for proposals b – d) - Issues of Haploidentical with post-transplant cyclophosphamide vs without PTCy - Issues of PTCy in donors other than Haploidentical - Consideration of including an lymphocyte recovery data at day 100 - Limited data/events for viruses other than CMV - Can we include information on duration of CMV reactivation (data not available)

and treatment of CMV (data not available)

Chairs discussion: Is there a way to collaborate with the EBMT to increase the Haplo population?

Dropped proposed studies a. PROP 1611-72 CMV exposure of cord blood donor- Impact on CMV reactivation in the

recipient. Dropped due to feasibility-low number of patients. b. PROP 1611-151 Immune Reconstitution and its relation with Infectious Morbidity Post

Autologous Peripheral Blood Stem Cell Transplantation (PBSCT). Dropped due to feasibility -the CIBMTR does not capture the data required to answer the hypothesis.

c. PROP 1611-122 Outcomes from progressive multifocal leukoencephalopathy in hematopoietic stem cell transplant patients Dropped due to feasibility-low number of patients

d. PROP 1611-54 The Effect of Antibacterial Prophylaxis on Early Post-transplant Mortality in Patients with Multiple Myeloma and Lymphoma Undergoing High-dose Chemotherapy and Autologous Stem Cell Transplantation. Dropped due to feasibility

e.

PROP 1611-01 Infection Density per Donor Type and Conditioning Intensity and Their Association with NRM in 3 different time points (0-33, 34-66, and 67-100 days) within 100 days after alloHCT. Dropped due to low scientific impact

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6. Other Business Dr. Marcie Riches presented the infection form updates. The following sections have/will be updated:

1. Infection Prophylaxis data (activated Jan 2017) 2. PostHCT infection data capture revisions (activated Jan 2017) 3. Revised organism lists focusing on viral and fungal infections (activated Jan 2017) 4. 2046/2016 form (fungal infection form) (anticipated July 2017) 5. 2149 form (Respiratory Virus form) (anticipated July 2017) 6. 2150 form (CMV/EBV/ADV/HHV-6 form) (anticipated July 2107)

Working Committee Overview Plan for 2017-2018

a. IN07-01/IN11-01 Early bacterial infection in patients undergoing allogeneic HCT (C Ustun /J-A Young/M Robien/G Papanicolaou).

i. VEP vs LEP BSI: Plan to submit to Blood by June 2017. We anticipate the paper is published by June 30, 2018. (Hour to completion: 60; Allocated by Jun 30, 2017: 60)

ii. VRE vs Other BSI: Plan to submit to Blood by June 2017. We anticipate the paper is published by June 30, 2018. (Hour to completion: 60; Allocated by Jun 30, 2017: 60)

b. IN 13-01 Bacterial and fungal infections in patients undergoing allogeneic hematopoietic cell transplantation following nonmyeloablative and myeloablative regimens (C Usten). Plan to submit to BBMT by July 2017. We anticipate paper is published by June 30, 2018. (Hour to completion: 70; Allocated by Jun 30, 2017: 70)

c. IN 14-01 (PROP 1303-03/PROP1311-19): Post allogeneic hematopoietic transplant Epstein Barr Virus related lymphproliferative disorder following conditioning with antithymocyte globulin or alemtuzumab (R Kamble/ P Hari/S Naik /C Bachier/P Shaughnessy). We anticipate paper is submitted by June 30, 2018

(Hour to completion: 150; Allocated by Jun 30, 2017: 150)

d. IN16-01 Viral encephalitis in hematopoietic stem cell transplant recipients, 2007-2013 (Maheen Abidi/ Parameswaran Hari) (PROP1510-16). We anticipate paper is published by June 30 2018. (Hour to completion: 230; Allocated by Jun 30, 2018: 230)

e. IN16-02 Determination of the burden of mucosal barrier injury-laboratory confirmed bloodstream infections in the first 100 days after stem cell transplant (Christopher Dandoy/ Paulina Daniels) (PROP 1511-85). We anticipate receiving the paper for submission by June 30, 2018. (Hour to completion: 300; Allocated by Jun 30, 2018: 300)

f. IN17-01 Incidence and Outcomes of individuals with and without viral infections in recipients of haploidentical versus other allogeneic hematopoietic stem cell transplantation for patients with hematologic malignancies (Rizwan Romee/ Ephraim Fuchs/ Asad Bashey/ Stefan Ciurea/ Anurag Singh/ Siddhartha Ganguly/ Randy Allison Taplitz/ Carolyn Mulroney/ Richard Maziarz). We anticipate data file ready for analysis by June 30, 2018. (Hour to completion: 310; Allocated by Jun 30, 2018: 160)

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Work Assignments for Working Committee Leadership (March 2017)

Jeffery Auletta IN07-01/IN11-01: Early bacterial infection in patients undergoing allogeneic HCT

Caroline Lindemans

IN13-01 Bacterial and fungal infections in patients undergoing allogeneic hematopoietic cell transplantation following nonmyeloablative and myeloablative regimens.

Jeffery Auletta IN14-01 Post allogeneic hematopoietic transplant Epstein Barr Virus related lymphproliferative disorder following conditioning with antithymocyte globulin or alemtuzumab (R Kamble/ P Hari/S Naik /C Bachier/P Shaughnessy)

Krishna Komanduri

IN16-01 Viral encephalitis in hematopoietic stem cell transplant recipients, 2007-2013 (Mhaeen Abidi/ Parameswaran Hari)

Caroline Lindemans and Jeffery Auletta

IN16-02 Determination of the burden of mucosal barrier injury-laboratory confirmed bloodstream infections in the first 100 days after stem cell transplant (Christopher Dandoy/ Paulina Daniels)

Caroline Lindemans and Krishna Komanduri

IN17-01 Incidence and Outcomes of individuals with and without viral infections in recipients of haploidentical versus other allogeneic hematopoietic stem cell transplantation for patients with hematologic malignancies(Rizwan Romee/ Ephraim Fuchs/ Asad Bashey/ Stefan Ciurea/ Anurag Singh/ Siddhartha Ganguly/ Randy Allison Taplitz/ Carolyn Mulroney/ Richard Maziarz). (PROP 1611-02/1611-117/1611-134)

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Accrual Summary for Infection and Immune Reconstitution Working Committee Donor-recipient and Infection information reported to the CIBMTR after 2008

Characteristics of Patients Allogeneic

N(%) Autologous

N(%) Number of Patients Infection 24706 10595 Infection Donor/recipient CMV status

-/- 5604 (23) N/A +/- 2773 (11) -/+ 6302 (26) +/+ 8379 (34) Missing/not tested 1648 ( 7)

Donor/recipient hepatitis B status -/- 9160 (37) N/A +/- 281 ( 1) -/+ 384 ( 2) +/+ 107 (<1) Missing/not tested 14774 (60)

Donor/recipient hepatitis C status -/- 9437 (38) N/A +/- 63 (<1) -/+ 97 (<1) +/+ 6 (<1) Missing/not tested 15103 (61)

Fungal Infection history No 22686 (92) 10483 (99) Yes 1994 ( 8) 110 ( 1) Missing 26 (<1) 2 (<1)

Fungal Infection after starting of conditioning No 19553 (79) 9262 (87) Yes 4679 (19) 613 ( 6) Missing 474 ( 2) 720 ( 7)

Infection prophylaxis after starting of conditioning No 326 ( 1) 227 ( 2) Yes 24112 (98) 10143 (96) Missing 268 ( 1) 225 ( 2)

Immune Reconstitution IgG at 100 day

Data not available 9038 (37) 4401 (42) Data available 15668 (63) 6194 (58)

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N(%) Autologous

N(%) IgM at 100 day

Data not available 16414 (66) 5086 (48) Data available 8292 (34) 5509 (52)

IgA at 100 day Data not available 16416 (66) 5039 (48) Data available 8290 (34) 5556 (52)

CD3 at 100 day Lymphocyte analyses were not performed 14239 (58) 9356 (88) Data not available 4297 (17) 694 ( 7) Data available 6170 (25) 545 ( 5)



CD20 at 100 day Lymphocyte analyses were not performed 14239 (58) 9356 (88) Data not available 8829 (36) 1118 (11) Data available 1638 ( 7) 121 ( 1)

CD56 at 100 day Lymphocyte analyses were not performed 14239 (58) 9356 (88) Data not available 6542 (26) 1010 (10) Data available 3925 (16) 229 ( 2)

Infection Prophylaxis Antibiotics

No 8450 (34) 3914 (37) Yes 15988 (65) 6456 (61) Missing 268 ( 1) 225 ( 2)

Antifungal agent No 9496 (38) 6658 (63) Yes 14942 (60) 3712 (35) Missing 268 ( 1) 225 ( 2)

Amphotericin No 20741 (84) 9142 (86) Yes 1626 ( 7) 71 (<1) Missing 2339 ( 9) 1382 (13)

Caspofungin

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N(%) Autologous

N(%) No 21221 (86) 9158 (86) Yes 1156 ( 5) 55 (<1) Missing 2329 ( 9) 1382 (13)

Fluconazole No 14845 (60) 6563 (62) Yes 8291 (34) 3481 (33) Missing 1570 ( 6) 551 ( 5)

Itraconazole No 21937 (89) 9172 (87) Yes 403 ( 2) 42 (<1) Missing 2366 (10) 1381 (13)

Micafungin No 19328 (78) 9093 (86) Yes 3333 (13) 133 ( 1) Missing 2045 ( 8) 1369 (13)

Posaconazole No 19712 (80) 9181 (87) Yes 2795 (11) 35 (<1) Missing 2199 ( 9) 1379 (13)

Ravuconazole No 22151 (90) 9013 (85) Yes 23 (<1) 5 (<1) Missing 2532 (10) 1577 (15)

Voriconazole No 16597 (67) 9047 (85) Yes 5989 (24) 169 ( 2) Missing 2120 ( 9) 1379 (13)

Other systemic antifungal agent No 21854 (88) 9148 (86) Yes 569 ( 2) 66 (<1) Missing 2283 ( 9) 1381 (13)

Antiviral agent No 4651 (19) 1732 (16) Yes 19787 (80) 8638 (82) Missing 268 ( 1) 225 ( 2)

Acyclovir No 7310 (30) 2492 (24) Yes 16399 (66) 7377 (70) Missing 997 ( 4) 726 ( 7)

Foscarnet

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N(%) Autologous

N(%) No 21461 (87) 8992 (85) Yes 714 ( 3) 26 (<1) Missing 2531 (10) 1577 (15)

Ganciclovir No 20931 (85) 9028 (85) Yes 1448 ( 6) 36 (<1) Missing 2327 ( 9) 1531 (14)

Valganciclovir No 20477 (83) 8956 (85) Yes 1853 ( 8) 112 ( 1) Missing 2376 (10) 1527 (14)

Valacyclovir No 17304 (70) 7161 (68) Yes 5298 (21) 2063 (19) Missing 2104 ( 9) 1371 (13)

Other antiviral agent No 21522 (87) 8904 (84) Yes 801 ( 3) 160 ( 2) Missing 2383 (10) 1531 (14)

Pneumocystis agent No 3002 (12) 4134 (39) Yes 21436 (87) 6236 (59) Missing 268 ( 1) 225 ( 2)

Other prophylaxis agent No 19397 (79) 8274 (78) Yes 2778 (11) 743 ( 7) Missing 2531 (10) 1578 (15)

Disease Acute Leukemia/MDS 17888 (72) 171 ( 2) Chronic Leukemia 812 ( 3) 0 Non-Hodgkin Lymphoma 1502 ( 6) 2593 (24) Hodgkin Lymphoma 103 (<1) 842 ( 8) Solid tumors 19 (<1) 771 ( 7) Myeloma/Plasma Cell Disorder 145 (<1) 6156 (58) Non-malignant disorders 4237 (17) 62 (<1)

Year of transplant 2008 3316 (13) 2281 (22) 2009 3008 (12) 937 ( 9) 2010 1899 ( 8) 425 ( 4) 2011 1365 ( 6) 512 ( 5)

14



N(%) Autologous

N(%) 2012 1447 ( 6) 543 ( 5) 2013 2687 (11) 1239 (12) 2014 3573 (14) 1325 (13) 2015 3528 (14) 1477 (14) 2016 3130 (13) 1480 (14) 2017 753 ( 3) 376 ( 4)

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IN14-01 Abstract

Title: Outcomes of Allogeneic Hematopoietic Cell Transplants with EBV Positive or EBV Negative Post-Transplant Lymphoproliferative Disorder (PTLD).

Authors: Seema Naik, MD1, Rammurti T. Kamble, MD2, Parameswaran Hari, MD3, Soyong Kim4, Min Chen, MS4, Krishna V. Komanduri, MD5, Caroline A Lindemans6, Jeffery J. Auletta, MD7 and Marcie L. Riches, MD8, (1)Hematology Oncology, PennState Cancer Institute, Hershey, PA, (2)Division of Hematology andOncology, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, (3)Department ofMedicine, Medical College of Wisconsin, Milwaukee, WI, (4)CIBMTR (Center for International Blood andMarrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI,(5)Adult Stem Cell Transplant Program, University of Miami Hospital and Clinics, SylvesterComprehensive Cancer Center, Miami, FL, (6)Pediatric Blood and Bone Marrow TransplantationProgram, Wilhelmina Children's Hospital, Utrecht, Netherlands, (7)Hematology, Oncology and BoneMarrow Transplant, Nationwide Children's Hospital, Columbus, OH, (8) Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC

Abstract: Background: PTLD following allogeneic hematopoietic cell transplant (alloHCT) is associated with significant mortality and can be either EBVpos or EBVneg. Between 2002 and 2014, 267 cases (EBVpos=222, 81%; EBVneg=45, 19%) of PTLD were identified in 26,710 eligible alloHCT patients reported to the CIBMTR. This study aimed to determine survival following EBVpos and EBVneg PTLD and to define donor, recipient, and transplant characteristics affecting survival following PTLD. Methods: Data [age; Karnofsky performance score (KPS); donor type; HLA match (M) or mismatch (MM); disease type (malignant (MAL)/non-malignant (NonMAL); use of alemtuzumab (CAM)/ATG, TBI, and myeloablative (MAC)/reduced intensity (RIC) conditioning; and occurrence of CMV viremia, EBV viremia, and/or GvHD prior to PTLD] were obtained from the CIBMTR database. Descriptive statistics compared EBVpos and EBVneg patients. Kaplan-Meier curves estimated overall survival from PTLD and a Cox model for survival was fit with EBVpos and EBVneg as the main effect variable. Results: Patient characteristics were similar between the EBVpos and EBVneg cohorts. Median ages for EBVpos and EBVneg PTLD patients were 32 (0-76) and 47 (1–70) years, respectively. Most PTLD patients were male (60%), Caucasian (79%), and had KPS ≥ 90 % (73%) at HCT. Most received alloHCT for MAL (70%) or aplastic anemia (19%). Donors were related (M=15%, MM=4%) and unrelated BM/PBSC (M=32%, MM=16%, Unk=5%) or cord (28%). Median onset for PTLD did not differ by EBV association [EBVpos, 3 mo (<1-102); EBVneg 5 mo (1-110), p=0.1]. Occurrence of aGVHD, cGVHD, CMV or EBV viremia prior to PTLD were similar between PTLD groups; however, CMV viremia occurred earlier in EBVpos vs EBVneg PTLD [32d (5-95) vs. 47d (10-70), p=0.016]. For 167 (63%) cases with available pathology, frequencies of monomorphic disease were similar [EBVpos=88 (65%), EBVneg=21 (66%); p=0.19]. Also Ki67, CD20, BCL6, and BCL2 markers were similar; significant missing data (30-70% reports) precluded comparisons. At median follow-up of 62 mo (3-167) and 94 mo (6-121) from HCT for EBVpos and EBVneg PTLD survivors, 1-yr OS from PTLD was 55% (95% CI 48-61%) and 44% (95% CI 29-58), respectively (Figure). Multivariate analysis for OS is shown in the Table. Conclusions: One-year OS after PTLD is poor, regardless of EBV association. PTLD developing in the context of in vivo T-cell depletion or RIC+TBI conditioning for malignant disease is associated with inferior OS.

16


Results of Multivariable Analysis for Overall Survival

RR of death P-value PTLD EBVneg vs. EBVpos 1.42 (0.94-2.15) 0.098 Disease/Conditioning <0.001 Mal/MAC+TBI 1.00 Mal/MAC no TBI 1.42 (0.91-2.21) 0.128 Mal/RIC+TBI 2.06 (1.11-3.82) 0.022 Mal/RIC no TBI 1.49 (0.91-2.44) 0.117 NonMal+TBI 0.42 (0.21-0.82) 0.011 NonMal no TBI 0.72 (0.42-1.23) 0.234 In Vivo TCD ATG/CAM vs. no ATG/CAM 2.09 (1.34-3.26) 0.0012

17

https://bmt.confex.com/data/abstract/tandem/2018/Paper_10728_abstract_14109_0.png


IN16-01 Abstract

Title: Viral isolates in the Cerebrospinal fluid of Hematopoietic Stem Cell Transplant Recipients, 2007-2015.

Authors: Abidi MZ1, Chen M2, Soyoung K2, Auletta J3, Lindemans C4, Riches M5. 1Division of Infectious Disease, University of Colorado Denver, 2Medical College of Wisconsin, 3Division of Hematology and Oncology, Nationwide Children’s Hospital, 4Pediatric Blood and Bone Marrow Transplantation Program, Wilhelmina Children’s Hospital, 5Division of Hematology and Oncology, University of North Carolina

Abstract: Background: Limited data exists on the epidemiology and survival following central nervous system viral infections (CNS-VI) in allogeneic hematopoietic stem cell transplant (alloHCT) recipients. Querying the CIBMTR database, 165 alloHCT patients were reported to have a CNS virus isolated within the first 6 months after HCT. Median age for this patient cohort was 43 years (range 1–76); and most patients were male (61%) and received myeloablative conditioning (65%) for malignant disease (87%) as well as umbilical cord blood stem cells (53%). Median follow-up for survivors was 49 months (3–100). Results: Detected viruses predominantly included human herpes virus-6 (HHV6) (73%), followed by Epstein-Barr virus (EBV, 10%), cytomegalovirus (CMV, 3%), varicella zoster virus (VZV, 3%), herpes simplex virus (HSV, 3%) and adenovirus (ADV, 3%). Three patients (4%) had more than one CNS viral isolate. Median time for isolating CNS virus was 31 (12–180) days, but isolating CNS HHV6 was shorter compared to other CNS viral isolates (28 days vs. 80 days). Concurrent viremia, defined as the same virus also being detected in the blood within 14 days of the CNS viral isolate, occurred in 52% patients. Notably, 123 CNS viral isolates occurred within the first 60 days after alloHCT; and the majority were HHV6 (n=111). Beyond day 60, other viral isolates predominated (Table). Amongst the 121 patients with CNS HHV6, isolated CNS involvement occurred in 63 patients (52%). Several patients had CNS HHV6 in addition to other sites including viremia (n=52, 43%) alone, another site alone (n=2, 2%), and viremia plus another site (n=4, 3%). Overall survival after detecting a CNS virus was poor as only 50% (95% CI 42–57) patients were alive at 6 months (Figure). Conclusions: Viral CNS isolates were primarily HHV6 within the first 2 months after alloHCT. Mortality following detection of CNS virus is high, but significant concurrent viremia suggests a possible marker for early intervention to prevent associated viral-related morbidity and mortality.

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Frequency of viral detection in cerebrospinal fluid by time period

Time period of viral detection in CSF

Day 0 – 30

Day 31 – 60

Day 61 – 100

Day 101 - 180

Total Infections

HHV-6 77 31 8 6 122 Cytomegalovirus 0 3 2 3 8 Epstein Barr Virus 3 4 8 4 19 Adenovirus 0 1 1 2 4 Varicella Zoster Virus 1 0 3 1 5 Herpes Simplex Virus 0 1 1 2 4 Polyoma Virus 0 2 0 4 6

Total infections

81

42

23

23

168*

*3 patients had multiple viruses

Figure 1: Overall survival for 165 allogeneic HCT patients after diagnosis of CNS-VI

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TO: Infection and Immune Reconstitution Working Committee Members

FROM: Marcie Riches, MD, MS, Scientific Director for the Infection and Immune Reconstitution Working Committee

RE: Studies in Progress Summary

Studies submitted IN07-01/IN11-01: Early bacterial infection in patients undergoing allogeneic HCT (C Ustun /J-A Young /M Robien /G Papanicolaou). This study aims to enumerate bacterial infections occurring early (from day 0 until 14 days after neutrophil engraftment) after hematopoietic cell transplantation (HCT) by site and causative organisms over a 10 year period; Study the impact of bacterial infections on long term overall survival; Study the impact of microbiologic and transplant related factors (such as stem cell source) in relation to survival. Manuscript preparation is underway for two manuscripts: 1) very early versus later infections within the first 100 days, and 2) VRE BSI versus other BSI in the first 100 days. IN07-01/IN11-01a: Bacterial bloods stream infection (BSI), particularly post-engraftment BSI, are associated with increased mortality after allogeneic hematopoietic cell transplantation. Submitted to BBMT.

Studies with Preliminary Results IN07-01/IN11-01b: Bloodstream infection (BSI) due to Vancomycin-resistant Enterococcus (VRE) and mortality after hematopoietic cell transplantation. A multicenter retrospective cohort study. Plan to submit to Blood by June 2018.

IN13-01: Bacterial, viral and fungal infections in patients undergoing allogeneic hematopoietic cell transplantation (Allohct) following nonmyeloablative and myeloablative (C Ustun) This study is to compare bacterial and fungal infections between patients undergoing allogeneic hematopoietic cell transplantation (AlloHCT) following NMAR, RIC, and MAR. Manuscript preparation is underway. Plan to submit by July 2018.

IN14-01: Post allogeneic hematopoietic transplant Epstein Barr Virus related Lymphoproliferative disorder following conditioning with Antithymocyte globulin or Alemtuzumab (S Naik/ C Bachier/ P Shaughnessy/ P Hari/ R Kamble) This study is to describe the characteristics and transplant outcomes of patients with EBV-positive and EBV negative PTLD following allogeneic transplant. Furthermore, it assesses the characteristics present at transplant that impact OS from the time of diagnosis of PTLD. Data presented as poster at Tandem 2018. Plan to submit by July 2018.

IN16-01: Viral Encephalitis in Hematopoietic Stem cell Transplant Recipients, 2007-2013 (M Abidi/ P Hari) This study is to describe the frequency and significance of CNS viral isolates in hematopoietic stem cell transplant (HCT) recipients and to assess the impact of viral isolates on OS following allogeneic HCT. Data presented as poster at Tandem 2018. Plan to submit by July 2018.

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Studies in Progress IN16-02: Determination of the burden of mucosal barrier injury-laboratory confirmed bloodstream infections (MBI-LCBI) in the first 100 days after stem cell transplant (C Dandoy/ P Daniels). This study is to compare TRM and OS post-SCT between patients who develop a MBI-LCBI versus those with no infection or a non-MBI-LCBI in the first 100 days; To determine the incidence of MBI-LCBIs in the first 100 days post SCT; To determine the risk factors for development of a MBI-LCBI in the first 100 days; To determine the timing of MBI-LCBI after SCT. The study is under data file preparation. IN17-01: Incidence and impact of cytomegalovirus and other viral infections on post-transplant outcomes following HLA-haploidentical HCT compared to other sources (R Romee/ A Singh/ RA Taplitz). This is a combined study from 2 different proposals and will include 3 analyses to assess 1) the impact of donor/recipient CMV serostatus following Haploidentical transplant with and without post-transplant cyclophosphamide; 2) to assess the impact of CMV reactivation on transplant outcomes for patients receiving Haploidentical transplant; and 3) to describe the frequency of other viral infections comparing haploidentical, matched adult donor, and UCB donors. The study protocol is under development.

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MEMORANDUM TO: INWC working committee

STUDY PIs: Christopher Dandoy, Paulina Daniels

DATE: December, 2017

RE: CIBMTR Study # IN16-02: Determination of the burden of mucosal barrier injury-laboratory confirmed bloodstream infections (MBI-LCBI) in the first 100 days after stem cell transplant

Draft protocol for review: next step Data file preparation

1. Specific Aims:• Compare TRM and OS post-SCT between patients who develop a MBI-LCBI versus those

with no infection or a non-MBI-LCBI BSI in the first 100 days• Determine the incidence of MBI-LCBIs in the first 100 days post SCT• Determine the risk factors for development of a MBI-LCBI in the first 100 days• Determine the timing of MBI-LCBI after SCT

2. Selection criteria

Selection Criteria Removed RemainFirst allo transplant 2009-2016 23BM, PM or CB only 300 230

BM+UCB,n=54 PB+UCB, n=199 Other, specify, n=3 BM+Other, n=2 PB+other, n=14 UCB+other, n=26 BM+PB+other, n=2

Excluded if twin or multiple donor 222 228Twin, n=212 Multi donor(other than CB), n=10

Excluded if no consent 868 219Excluded embargo centers 505 214Excluded if no 100 day follow up form 313 21

22


Additional exclusion Excluded if other leukemia, CML, NHL, HL, PCD/MM or other malignancies Other leukemia, n=552 2977 18167

CML, n=612

NHL, n=1365

HL, n=242

PCD/MM, n=192

Other malignancies, n=14

Excluded if conditioning regimen intensity missing

15 18152 Excluded centers with "no GVHD prophylaxis"' high (>15%) 191 17961 Excluded patients if reported "no GVHD prophylaxis"

430 17531

The control and/or BSI have to be from the same centers of MBI 421 17110

Completeness index as of 3/1/2017

Follow up MBI-LCBI and other BSI MBI-LCBI only BSI only Control

Number of patients 726 1494 3113 12315 @1 year 99 97 99 98 @3 year 94 91 93 92 3. Groups definition:

MBI-LCBI group: Certain BSI in blood by 100 days after transplant: Organisms include Candida (200 – 209), Enterococcus (135, 177), Strep Viridans (167), Enterobacteriacecae (130, 134, 136, 146, 155, 160, 161), or Anaerobes (122, 124, 123, 129, 131, 139, 147, 148, 154, 166) and Site in Bloodstream/Central line draw (1, 60, 61) • Infection occurs 14 days before or 60 days after GI (stage3 or stage4) aGVHD; or • Infection occurs and ANC criteria met:

o ANC >500 never achieved o Before ANC>=500 or 7 days after ANC>=500 o For ANC reach ANC500 or never dropped and then declined: infection occurred 7 days before or 7 days after decline

BSI group: Any fungal or bacteria in blood by 100 days after transplant which is not in MBI-LCBI Controls group : All other transplants with infection documented

4. Notes from discussions: Discussion 10-27-17 (INWC Monthly Chairs Meeting)

- Patients: Exclude other leukemia, CML, NHL, HL, MM o Rationale: Small patient numbers and varied rates of relapse impact data cleaning significantly when estimating TRM

- Add subset analysis for RISK FACTORS for MBI o AML/ALL/MDS cohorts

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Discussion 11-01-17 (Biweekly INWC Stats Call) - Issues of early death due to infection must be accounted for as this will impact events - Plan:

o Current: Proceed with analysis similar to IN0701/1101 o To Do: Kwang Woo/Soyoung will discuss with Brent and Mei-Jie potential

alternative statistical methods that will allow a univariate description of outcomes from time of transplant for patients who develop early infection still allowing for control outcomes to be measured

Stats Call 12-19-17

- Exclude patients with No GVHD prophylaxis o Review the # of Centers with patients with no GVHD prophylaxis o Send MR list of centers for these patients and # of patients (by group) for each

center as may start by deleting centers since data suspect - Please provide a x-tab of MBI patients by reason for MBI (Neutropenia only vs GVHD only

vs Neutropenia+GVHD) o Rationale: Given the increased risk of TRM with GI stage 3/4 aGVHD, may skew

outcomes o May need to analyze separately depending upon numbers

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CIBMTR IN16-02

Determination of the burden of mucosal barrier injury-laboratory confirmed bloodstream infections (MBI-LCBI) in the first 100 days after stem cell transplant

DRAFT PROTOCOL

Study Chair(s): Christopher Dandoy, MD, MSc Assistant Professor of Clinical Pediatrics Cincinnati Children’s Hospital Medical Center 3333 Burnet Avenue, MLC 11027

Cincinnati, Ohio 45229-3039 Telephone: (513) 636-7287 E-mail: [email protected]

Paulina Daniels, DO Bone Marrow Transplant Physician Cincinnati Children’s Hospital Medical Center 3333 Burnet Avenue, MLC 11027

Cincinnati, Ohio 45229-3039 Telephone: (513) 636-7287 E-mail: [email protected] Statistical Directors: Kwang Woo Ahn, PhD Associate Professor

8701 Watertown Plank Road Milwaukee, WI 53226 Telephone: 414-955-7387 Fax: 414-955-6513 E-mail: [email protected] Soyoung Kim, PhD, 8701 Watertown Plank Road Milwaukee, WI 53226 Telephone: 414-955-8271 E-mail: [email protected]

Study Statistician: Min Chen, MS CIBMTR Statistical Center 9200 W. Wisconsin Ave. CLCC, Suite C5500 Milwaukee, WI 53226 Telephone: (414) 805-0710 E-mail: [email protected]

25

mailto:[email protected]



Scientific Director: Marcie Riches, MD, MS University of North Carolina at Chapel Hill Associate Professor Division of Hematology/Oncology 170 Manning Drive, POB 3, #7305 Chapel Hill, NC 27599 Telephone: 919-966-3048 Fax: 919-966-7748 E-mail: [email protected] Working Committee Chairs: Jeffery Auletta, MD Nationwide Children’s Hospital Department of Hematology/Oncology and BMT 700 Children’s Drive Columbus, OH 43205 Telephone: (614) 722-3553 E-mail: [email protected]

Caroline Lindemans, MD, PhD. Wilhelmina Children's Hospital University Medical Center Utrecht Telephone: 31-61-4026510 E-mail: [email protected] Krishna Komanduri, MD; University of Miami Sylvester Cancer Center 1475 NW 12th Ave Miami; Miami, FL 33136; Telephone: (305) 243-5302 E-mail: [email protected]

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1. Hypothesis: Patients in the first 100 days after stem cell transplant (SCT) who develop mucosal barrier injury laboratory confirmed bloodstream infections (MBI-LCBI) have increased transplant related mortality (TRM) and decreased overall survival (OS) compared to those with no infection or an infection not classified as an MBI-LCBI.

2. Specific Aims: • Compare TRM and OS post-SCT between patients who develop a MBI-LCBI versus those with no

infection or a non-MBI-LCBI in the first 100 days • Determine the incidence of MBI-LCBIs in the first 100 days post SCT • Determine the risk factors for development of a MBI-LCBI in the first 100 days • Determine the timing of MBI-LCBI after SCT

3. Scientific Justification

Patients undergoing SCT are at increased risk of a bacterial infection. The majority of patients have a central venous catheter (CVC) for medication administration, transfusions and frequent blood draws. Central line-associated bloodstream infections (CLABSIs) are among the most serious complications in SCT patients and lead to prolonged hospitalization, intensive care admissions, prolonged antibiotic treatment and increased mortality1-3. CVC maintenance care has been shown to be effective in reducing CLABSIs4-6. Recently, concern has been raised regarding immunocompromised patients including SCT patients who are at risk of developing blood stream infections classified as CLABSIs that do not result from the presence of the central line but instead from other mechanisms, such as translocation of bacteria through non-intact mucosa7,8. On the basis of literature review and expert opinion, the Centers for Disease Control and Prevention developed a modification of the CLABSI definition, termed “mucosal barrier injury laboratory-confirmed bloodstream infection” (MBI-LCBI). This definition was recently integrated into National Healthcare Safety Network (NHSN) methods for primary blood stream infection surveillance to aid in identifying a subset of blood stream infections reported as CLABSIs that are likely related to mucosal barrier injury and not the presence of a central line7. Unlike CLABSIs, MBI-LCBIs are not prevented by improved CVC maintenance care. A blood stream infection is defined as an MBI-LCBI if: (1) it resulted from 1 or more of a group of selected organisms known to be commensals of the oral cavity or gastrointestinal tract and (2) occurred in a patient with certain signs or symptoms compatible with the presence of mucosal barrier injury such as gastrointestinal graft-versus-host disease and/or neutropenia7. There is very little data describing MBI-LCBIs. There is no data on the incidence, risk factors, and/or outcome of patients that develop an MBI-LCBI after SCT. Currently, SCT is a known risk factor for MBI-LCBIs, but there is little investigation in risk stratification and prevention of these infections. This study will determine the burden of MBI-LCBIs after SCT by comparing the outcome of patients who develop a MBI-LCBI to patients with no infection or with an infection that is not classified as a MBI-LCBI. Additionally, we will determine the risk factors for MBI-LCBI development.

4. Patient Eligibility Population: The following patients will be included in this study

27


• All patients (pediatric and adult) undergoing first allogeneic stem cell transplant reported to the CIBMTR between 2009 and 2016

• Any stem cell source including bone marrow, peripheral or cord blood • Any source including matched or mismatched related and unrelated donors • An MBI-LCBI requires patients meeting both organism and patient criteria from NHSN9:

i. Organism Criteria: Eligible organisms include Candida species, Enterococcus species, Enterobacteriaceae, viridans group, Streptococcus species, and certain anaerobes without isolation of additional recognized pathogens or common commensal organisms.

ii. Patient Criteria: Stage 3-4 lower gastrointestinal graft versus host diseases Or BSI occurring +/- 7 days of an ANC ≤500

• Patients will be limited to centers in which at least 1 MBI-LCBI patient is identified and either 1 control patient or 1 other BSI patient is present

5. Outcomes

• Overall survival: Time to death, patients will be censored at last follow-up. • Transplant related mortality (TRM): time to death without evidence of disease

relapse/progression. This event will be summarized as cumulative incidence estimate with relapse/progression as the competing risk.

• Incidence of MBI-LCBI within the first 100 days: This will be assessed as the cumulative incidence function with death and relapse/progression as competing risks.

• Incidence of bloodstream infections (bacterial and fungal) not meeting criteria for MBI-LCBI: This will be assessed as the cumulative incidence function with death and relapse as competing risks.

• Cumulative incidence of chronic GVHD: death/relapse as competing risk. • Infection as primary or secondary cause of death by day 100 and by 1 year.

6. Variables to be described

i. Patient-related variables • Age at transplant (continuous) and by decades • Gender: male vs. female • Lansky/Karnofsky performance status: <80% vs 80 – 89% vs >90%

ii. Transplant related • Disease • Donor/Recipient HLA Match • Graft type: BM vs. PBSC vs. CB • Conditioning: Myeloablative (malignant disease) vs. RIC/non-ablative (malignant disease) vs.

conditioning for non-malignant disease • GVHD prophylaxis: CSA +/- others vs. FK-506 +/- others vs. T cell depletion vs. others • ATG use at transplant: yes vs. no • Year of Transplant

iii. Infection type iv. Time dependent variables

• Acute GVHD grades 2-4 post-transplant: yes or no • Neutrophil engraftment

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7. Study Design: For description, patients will be categorized into 4 groups based on event occurring by day 100:

i. MBI-LCBI only as defined in section 4 ii. BSI: Patients with a bacterial or fungal BSI not meeting criteria for MBI-LCBI

iii. MBI-LCBI + BSI: Includes patients with both an MBI-LCBI and another BSI during the first 100 days

iv. Controls: Patients without either an MBI-LCBI or a BSI by day 100

The Kaplan-Meier method will be used to estimate the probability of overall survival after day 100. The cumulative incidence will be calculated for treatment related mortality after day 100. The Log-Rank test will be used to assess differences in survival and Gray’s test for competing risks will be used for differences in TRM (treating relapse and death from disease as competing risks) among the groups. Incidence of MBI-LCBI and bloodstream infections with in the first 100 days will be calculated using the cumulative incidence. Descriptive tables of patient-, disease-, and transplant-related factors will be prepared. These tables will list median and range for continuous variables and percent of total for categorical variables. Multivariable Cox regression analysis will be used to evaluate for potential risk factors and their interactions for development of MBI-LCBI/other BSI following transplant in OS and TRM. The main effect will be added as time-dependent covariate. The proportional hazards (PH) assumption will be tested. The covariates that violate the PH assumption will be added as time-dependent covariates. A stepwise selection procedure will be used to identify the final model. Because early infections will likely impact later outcomes but the comparator cohorts are determined by events occurring by day 100, univariate outcomes of TRM and OS will be calculated separately from the time of transplant for the 4 cohorts for all patients transplanted as well as only those patients alive at day 100 as done in a prior similar study IN0701/1101. For assessment of risk factors for development of an MBI-LCBI, a subset of patients will be analyzed. This subset will include only patients with Acute Leukemia (AML/ALL) and MDS. A limited number of variables will be tested in the MVA for risk factors.

29


8. References:

1. Wilson MZ, Rafferty C, Deeter D, Comito MA, Hollenbeak CS. Attributable costs of central line-associated bloodstream infections in a pediatric hematology/oncology population. Am J Infect Control. 2014;42(11):1157-1160.

2. Cecinati V, Brescia L, Tagliaferri L, Giordano P, Esposito S. Catheter-related infections in pediatric patients with cancer. Eur J Clin Microbiol Infect Dis. 2012;31(11):2869-2877.

3. Poutsiaka DD, Price LL, Ucuzian A, Chan GW, Miller KB, Snydman DR. Blood stream infection after hematopoietic stem cell transplantation is associated with increased mortality. Bone Marrow Transplant. 2007;40(1):63-70.

4. Bundy DG, Gaur AH, Billett AL, et al. Preventing CLABSIs among pediatric hematology/oncology inpatients: national collaborative results. Pediatrics. 2014;134(6):e1678-1685.

5. Pronovost P, Needham D, Berenholtz S, et al. An intervention to decrease catheter-related bloodstream infections in the ICU. N Engl J Med. 2006;355(26):2725-2732.

6. Miller MR, Griswold M, Harris JM, et al. Decreasing PICU catheter-associated bloodstream infections: NACHRI's quality transformation efforts. Pediatrics. 2010;125(2):206-213.

7. See I, Iwamoto M, Allen-Bridson K, Horan T, Magill SS, Thompson ND. Mucosal barrier injury laboratory-confirmed bloodstream infection: results from a field test of a new National Healthcare Safety Network definition. Infect Control Hosp Epidemiol. 2013;34(8):769-776.

8. Freeman JT, Elinder-Camburn A, McClymont C, et al. Central line-associated bloodstream infections in adult hematology patients with febrile neutropenia: an evaluation of surveillance definitions using differential time to blood culture positivity. Infect Control Hosp Epidemiol. 2013;34(1):89-92.

9. Central Line–Associated Bloodstream Infection (CLABSI) Event. National Healthcare Safety Network website: http://www.cdc.gov/nhsn/PDFs/pscManual/4PSC_CLABScurrent.pdf.

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Table 1 Characteristics of patients who underwent first ALLO transplants with MBI-LCBI and without MBI-LCBI by day 100 after transplant, reported to the CIBMTR, from 2009 to 2016

Variable

MBI-LCBI and other

BSI N(%) MBI-LCBI only N(%)

BSI only N(%)

Control N(%)

Patient related

Number of patients 711 1458 3052 11889 Number of centers 151 177 180 186

Gender Male 403 (57) 841 (58) 1802 (59) 6847 (58) Female 308 (43) 617 (42) 1250 (41) 5042 (42)

Age, median(range), years 39 (<1 - 77) 42 (<1 - 82) 43 (<1 - 79) 49 (<1 - 83) Age at transplant, years

<=10 148 (21) 304 (21) 653 (21) 1850 (16)

11-20 77 (11) 172 (12) 326 (11) 1161 (10) 21-30 68 (10) 104 ( 7) 231 ( 8) 956 ( 8) 31-40 67 ( 9) 110 ( 8) 237 ( 8) 904 ( 8)

41-50 83 (12) 195 (13) 309 (10) 1233 (10) 51-60 130 (18) 252 (17) 587 (19) 2223 (19) 61-70 113 (16) 284 (19) 589 (19) 2910 (24)

>70 25 ( 4) 37 ( 3) 120 ( 4) 652 ( 5) Karnofsky performance pre-Preparative Regimen

<80 93 (13) 166 (11) 357 (12) 1339 (11)

80-89 169 (24) 339 (23) 703 (23) 2717 (23) >=90 439 (62) 928 (64) 1945 (64) 7651 (64) Missing 10 ( 1) 25 ( 2) 47 ( 2) 182 ( 2)

Disease-related Disease

AML 293 (41) 604 (41) 1210 (40) 4839 (41) ALL 132 (19) 275 (19) 487 (16) 1607 (14) MDS 154 (22) 330 (23) 768 (25) 3380 (28)

Severe aplastic anemia 41 ( 6) 70 ( 5) 134 ( 4) 620 ( 5) Inherited abnormalities erythrocyte differentiation or function

23 ( 3) 58 ( 4) 139 ( 5) 637 ( 5)

SCID and other immune system disorders 31 ( 4) 62 ( 4) 151 ( 5) 487 ( 4) Inherited abnormalities of platelets 1 (<1) 2 (<1) 8 (<1) 16 (<1)

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Variable

MBI-LCBI and other


BSI only N(%)

Control N(%)

Inherited disorders of metabolism 24 ( 3) 30 ( 2) 93 ( 3) 165 ( 1) Histiocytic disorders 10 ( 1) 22 ( 2) 52 ( 2) 125 ( 1)

Autoimmune Diseases 1 (<1) 2 (<1) 5 (<1) 7 (<1) Other, specify 1 (<1) 3 (<1) 5 (<1) 6 (<1)

Transplant-related

Graft type Bone Marrow 129 (18) 305 (21) 685 (22) 2640 (22) Peripheral blood 306 (43) 611 (42) 1525 (50) 7255 (61)

Cord blood 276 (39) 542 (37) 842 (28) 1994 (17) Donor/recipient HLA match

Cord blood 276 (39) 542 (37) 842 (28) 1994 (17)

HLA-identical siblings 128 (18) 342 (23) 700 (23) 3608 (30) matched related 3 (<1) 9 (<1) 32 ( 1) 148 ( 1)

Mismatched related, mismatch=1 0 3 (<1) 1 (<1) 10 (<1) Mismatched related, mismatch>=2 28 ( 4) 57 ( 4) 120 ( 4) 388 ( 3) Mismatched related, mismatch missing 25 ( 4) 31 ( 2) 82 ( 3) 280 ( 2)

8/8 unrelated 171 (24) 332 (23) 927 (30) 4130 (35) 7/8 unrelated 55 ( 8) 92 ( 6) 223 ( 7) 856 ( 7) <=6/8 unrelated 4 (<1) 8 (<1) 13 (<1) 28 (<1)

Unrelated (HLA match information missing) 21 ( 3) 42 ( 3) 112 ( 4) 447 ( 4) Conditioning regimen intensity

Myeloablative 421 (59) 849 (58) 1657 (54) 5736 (48)

RIC/NMA 158 (22) 360 (25) 808 (26) 4090 (34) Non Malignancies 132 (19) 249 (17) 587 (19) 2063 (17)

GVHD prophylaxis

Ex vivo T-cell depletion 12 ( 2) 12 (<1) 34 ( 1) 102 (<1) CD34 selection 10 ( 1) 31 ( 2) 48 ( 2) 245 ( 2) Cyclophosphamide 60 ( 8) 125 ( 9) 202 ( 7) 723 ( 6)

TAC/CSA + MMF +- others 292 (41) 537 (37) 1145 (38) 3559 (30) TAC/CSA + MTX +- others 258 (36) 548 (38) 1230 (40) 5649 (48) TAC/CSA + others (except MTX, MMF) 56 ( 8) 145 (10) 277 ( 9) 1017 ( 9)

TAC/CSA alone 10 ( 1) 45 ( 3) 78 ( 3) 398 ( 3) MMF +/- Other 3 (<1) 4 (<1) 9 (<1) 42 (<1)

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Variable

MBI-LCBI and other


BSI only N(%)

Control N(%)

MTX +/- Other 2 (<1) 2 (<1) 4 (<1) 39 (<1) SIRO +/- others (Not TAC/CSA) 5 (<1) 8 (<1) 24 (<1) 91 (<1)

Steroids alone 0 0 0 13 (<1) Other GVHD prophylaxis* 3 (<1) 1 (<1) 1 (<1) 11 (<1)

ATG

No 482 (68) 999 (69) 2010 (66) 8139 (68) Yes 229 (32) 459 (31) 1042 (34) 3750 (32)

Year of transplant

2009 160 (23) 234 (16) 601 (20) 1415 (12) 2010 90 (13) 167 (11) 348 (11) 993 ( 8) 2011 58 ( 8) 103 ( 7) 234 ( 8) 751 ( 6)

2012 48 ( 7) 116 ( 8) 216 ( 7) 864 ( 7) 2013 74 (10) 182 (12) 378 (12) 1661 (14)

2014 88 (12) 234 (16) 435 (14) 2209 (19) 2015 100 (14) 245 (17) 462 (15) 2151 (18) 2016 93 (13) 177 (12) 378 (12) 1845 (16)

Median follow-up of survivors, months 47 (3 - 100) 35 (3 - 98) 36 (3 - 102) 29 (2 - 103) Abbreviations: ALL=acute lymphoblastic leukemia; AML=acute myelogenous leukemia; MDS =myelodysplastic syndromes; HLA=human leukocyte antigen;

FK506 = tacrolimus; CSA = cyclosporine; MTX = methotrexate; TBI = total body irradiation; MMF=mycophenolate mofetil; CSA= cyclosporine A; ATG=anti-thymocyte globulin; COR=corticosteroids; ECP=extra-corporeal photopheresis; KGF=kepivance; MAB=in vivo monoclonal antibody; IVIM=in vivo immunotoxin; SIRO=sirolim us; URSO=ursodiol; OTH=other agent

Footnote: *GVHD_prophylaxis gvhdlist MBI-LCBI and other BSI MBI-LCBI only BSI only Control total

Other GVHD prophylaxis Missing 3 0 1 3 7

atg 0 0 0 3 (38) 3

urso 0 0 0 3 (38) 3

bltr 0 1 0 0 1

mab 0 0 0 1 (13) 1

oth 0 0 0 1 (13) 1

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Table 2 Infection and time dependent variables

Variable

MBI-LCBI and other BSI

N(%) MBI-LCBI only N(%)

BSI only N(%) Control N(%)

Number of patients 711 1458 3052 11889

Infection-related Candida (not mutually exclusive)

No 651 (92) 1382 (95) 3015 (99) 11889

Yes 60 ( 8) 76 ( 5) 37 ( 1) 0 Enterococcus (not mutually exclusive)

No 441 (62) 1100 (75) 2866 (94) 11889

Yes 270 (38) 358 (25) 186 ( 6) 0 Strep all except pneumoniae (not mutually exclusive)

No 525 (74) 1052 (72) 2965 (97) 11889

Yes 186 (26) 406 (28) 87 ( 3) 0 Enterobacteriaceae (not mutually exclusive)

No 436 (61) 829 (57) 2719 (89) 11889

Yes 275 (39) 629 (43) 333 (11) 0 Anaerobes (not mutually exclusive)

No 609 (86) 1331 (91) 2955 (97) 11889

Yes 102 (14) 127 ( 9) 97 ( 3) 0 Time from transplant to MBI-LCBI/BSI, median(range), days

9 (<1 - 97) 8 (<1 - 98) 38 (<1 - 100) N/A

Time dependent variable ANC>500 days

Yes 620 (87) 1289 (88) 2935 (96) 11543 (97) No 90 (13) 169 (12) 100 ( 3) 307 ( 3)

Missing 1 (<1) 0 17 (<1) 39 (<1)

Time from transplant to ANC>500, days 18 (<1 - 149) 18 (1 - 122) 16 (<1 - 73) 15 (<1 - 125) Acute GVHD grade II-IV

No 376 (53) 866 (59) 1665 (55) 7591 (64)

Yes 332 (47) 580 (40) 1347 (44) 4165 (35) Missing 3 (<1) 12 (<1) 40 ( 1) 133 ( 1) Time from transplant to aGVHD, days 27 (7 - 174) 33 (7 - 169) 29 (7 - 176) 34 (7 - 178)

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Distribution of continuous variables Variable N Min 1% 5% 25% 50% 75% 95% 99% Max

Patient age (years)

MBI-LCBI and other BSI 711 0.10 0.25 1.13 13.81 39.29 57.55 68.75 72.81 76.61

MBI-LCBI only 1458 0.08 0.48 1.61 14.09 42.43 58.81 68.76 73.07 81.55

BSI only 3052 0.07 0.25 0.98 13.32 43.28 59.16 69.28 73.10 79.14

Control 11889 0.04 0.33 2.03 19.64 49.03 62.04 70.23 73.83 83.42

Time from HCT to death/last follow-up date (months)


MBI-LCBI only 1458 0.07 0.33 0.89 3.45 11.88 32.76 72.47 94.38 98.39

BSI only 3052 0.03 0.69 1.55 4.80 12.14 35.54 72.53 95.46 102.30

Control 11887 0.03 0.59 2.01 6.32 13.09 35.79 72.57 95.10 102.53

Time from HCT to first BSI (days)


MBI-LCBI only 1458 0.00 0.00 2.00 6.00 8.00 13.00 68.00 87.00 98.00

BSI only 3052 0.00 0.00 3.00 11.00 38.00 69.00 94.00 99.00 100.00

Variable N Min 1% 5% 25% 50% 75% 95% 99% Max

Time from HCT to ANC>500 days


MBI-LCBI only 1289 1.00 9.00 10.00 14.00 18.00 23.00 39.00 64.00 122.00

BSI only 2935 0.00 1.00 9.00 12.00 16.00 20.00 29.00 41.00 73.00

Control 11543 0.00 1.00 8.00 12.00 15.00 19.00 28.00 42.00 125.00

Variable N Min 1% 5% 25% 50% 75% 95% 99% Max

Time between transplant and 2-4 acute GVHD, months


MBI-LCBI only 580 0.23 0.30 0.39 0.69 1.09 1.58 3.09 4.51 5.56

BSI only 1347 0.23 0.26 0.36 0.66 0.95 1.48 3.36 5.03 5.79

Control 4165 0.23 0.30 0.39 0.76 1.12 1.81 3.88 5.36 5.86

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CIBMTR IN17-01

Incidence and impact of cytomegalovirus and other viral infections, on post-transplant outcomes following HLA-haploidentical hematopoietic cell transplantation compared to fully matched donors.

DRAFT PROTOCOL Study Chair(s): Scott Goldsmith, MD

[email protected], Washington University in Saint Louis

Ephraim Fuchs, MD [email protected] Johns Hopkins School of Medicine

Asad Bashey, MD, PhD [email protected] Northside Hospital, Atlanta

Stefan Ciurea, MD [email protected] MD Anderson Cancer Center

Anurag Singh, MD [email protected] University of Kansas Medical Center

Siddhartha Ganguly, MD [email protected] University of Kansas Medical Center

Randy Allison Taplitz, MD [email protected] University of California, San Diego

Carolyn Mulroney,MD [email protected] University of California, San Diego

Richard Maziarz,MD [email protected] Oregon Health and Sciences University

Rizwan Romee, MD [email protected] Washington University in Saint Louis

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Statistical Directors: Soyoung Kim, PhD,

8701 Watertown Plank Road Milwaukee, WI 53226 Telephone: 414-955-8271 E-mail: [email protected] Kwang Woo Ahn, PhD

Associate Professor 8701 Watertown Plank Road Milwaukee, WI 53226 Telephone: 414-955-7387 Fax: 414-955-6513 E-mail: [email protected]

Study Statistician: Min Chen, MS CIBMTR Statistical Center 9200 W. Wisconsin Ave. CLCC, Suite C5500 Milwaukee, WI 53226 Telephone: (414) 805-0710 E-mail: [email protected] Scientific Director: Marcie Riches, MD, MS University of North Carolina at Chapel Hill Associate Professor Division of Hematology/Oncology 170 Manning Drive, POB 3, #7305 Chapel Hill, NC 27599 Telephone: 919-966-3048 Fax: 919-966-7748 E-mail: [email protected] Working Committee Chairs: Jeffery Auletta, MD Nationwide Children’s Hospital Department of Hematology/Oncology and BMT 700 Children’s Drive Columbus, OH 43205 Telephone: (614) 722-3553 E-mail: [email protected]

Caroline Lindemans, MD, PhD. Wilhelmina Children's Hospital University Medical Center Utrecht Telephone: 31-61-4026510 E-mail: [email protected]

37






Krishna Komanduri, MD; University of Miami Sylvester Cancer Center 1475 NW 12th Ave Miami; Miami, FL 33136; Telephone: (305) 243-5302 E-mail: [email protected]

38


1.0 Hypothesis: We hypothesize that the viral infection incidence and impact on transplant outcomes differ between fully matched adult donor transplants (MRD/MUD) and Haploidentical (HaploHCT) transplants with further differences associated with use of post-transplant cyclophosphamide (PTCy).

2.0 Specific aims:

2.1 Assess the impact of donor/recipient CMV serostatus on transplant outcomes 2.1.1 Relapse 2.1.2 Non-relapse mortality 2.1.3 GVHD 2.1.4 GVHD Relapse free survival 2.1.5 DFS 2.1.6 OS

2.2 Assess the impact of CMV reactivation occurring by day 100 on transplant outcomes 2.2.1 Relapse 2.2.2 Non-relapse mortality 2.2.3 GVHD 2.2.4 GVHD Relapse free survival 2.2.5 DFS 2.2.6 OS

2.3 Describe the frequency and identify risk factors for development of non-CMV viral infections

3.0 Scientific impact/ justification: Cytomegalovirus has long been associated with increased morbidity and mortality following allogeneic hematopoietic cell transplantation (alloHCT).1–3 A recent CIBMTR analysis demonstrated that even in the current era of preemptive surveillance and treatment protocols, early CMV reactivation was associated with significantly increased non-relapse mortality (NRM) among recipients of alloHCT for AML, ALL, MDS, and CML, which translated to decreased overall survival (OS) among those with AML and ALL.4 The association of CMV reactivation and improvement in relapse-free survival (RFS) is a well-published phenomenon among patients who received HLA-matched alloHCT for hematologic malignancies, however this CIBMTR study failed to identify any effect of CMV reactivation on relapse.5,6,4,7 This registry study was incredibly impactful, however Haploidentical hemaotpoeitic cell transplantation (haploHCT) were underrepresented, and less than 1% of all patients from the registry had received post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis. This is likely due to the fact that the records utilized in this registry study were of those who underwent alloHCT prior to 2010, and the utilization of haploHCT has really only accelerated on an international level over the past five years.8,9 It is unknown if there are differences in the incidence of CMV reactivation and disease among recipients of haploHCT with PTCy in comparison to other non haplo alloHCT (MRD, MUD, and UCB) and haploHCT receiving other GVHD prophylaxis. Identification of a higher incidence of disease and/ or earlier reactivation would allow design of more aggressive CMV surveillance and preemptive treatment protocols better suited to the specific immunosuppressive aspects of haploHCT with PTCy.

39


Additionally, determination if CMV reactivation has any effect on relapse and mortality especially in the context of haploHCT, which would help provide prognostic information. Recently we conducted a single-center, retrospective cohort study out of Washington University in St. Louis on 138 patients who underwent haploHCT with PTCy, receiving T-cell replete PBSC grafts, and did not detect a significant difference in cumulative incidence of relapse (CIR) or overall survival (OS) between those who did and those who did not have CMV viremia.10 Notably, our viremia cohort experienced very early CMV viremia (median time to viremia of 24d), and an incidence of CMV disease that was higher than expected in the era of preemptive antiviral strategies. A large, registry study with similar endpoints would assess the validity of these results, and identify whether there is fundamental difference between HLA-haploidentical and other allogeneic transplantation, or a factor related to PTCy, that would predispose haploHCT with PTCy recipients to a higher risk of CMV disease and negate the relapse protection seen previously with CMV reactivation. Such results could lead to tailoring of preemptive treatment strategies and aid in prognosis of disease relapse. In addition to CMV, we aim to describe the incidence of other viral infections, their specific end-organ effects, and their impact on relapse and mortality outcomes in recipients of haploHCT with PTCy in comparison to non-PTCy haploHCT and other alloHCT (MRD, MUD, and UCB). An understanding of the occurrence of these viruses will help identify specific risk factors following haploHCT as well as aid in the design of specific surveillance and treatment protocols tailored to this unique population. High rates of viral infections in general have been reported after haploHCT, particularly in the setting of PTCy. There have been a few single-center studies describing the incidence of viral infections following haploHCT with PTCy, but multicenter, comparative data is lacking. Infection rates in this setting have been reported in the range of 70% at 100 days and 77% at 1 year for viral infections. CMV reactivation has been reported in up to 76% of recipients, and polyomavirus associated cystitis 19%. The CIBMTR database provides an ideal opportunity to take a broader look at viral infections after haploidentical transplants, particularly in recipients of PTCy, and identify the burden of viral and other infectious diseases, risk factors and outcomes.

4.0 Study population:

Inclusion Criteria: • Patients receiving first allogeneic HCT for AML, ALL, and MDS between 2008 – 2016 • Age ≥ 2 years

Exclusion Criteria: • Patients who received UCBT • Patients with a mismatched unrelated peripheral blood or marrow donor • Patient information that lacks post-transplant infection information • Center restriction: Patients transplanted at centers which have no reported haploHCT patients

Patient cohorts for analysis are as follows: • HaploHCT with PTCy • HaploHCT with other GVHD prophylaxis • MRD/MUD with PTCy • MRD/MUD with other GVHD prophylaxis (Control)

40


5.0 Outcomes • Relapse: death is the competing risk. • Overall survival: time to death. Death from any cause is an event. Surviving patients are

censored at time of last follow-up. • Disease Free survival: time to relapse or death from any cause. • Non-relapse mortality: death without evidence of disease relapse. Relapse is the competing

risk. • aGVHD grade 2 – 4: Death is the competing risk • cGVHD, any severity: Death is the competing risk • Total number of inpatient hospital days within first 100 days (LOS) (Aim 2.1 ) • Co-infection (yeast/mold/bacteria): Presence/absence of co-infection of any type ± 30 days

of viral infection. (Aim 2.2 and 2.3 only) • GVHD Free relapse free survival (GFRS): defined as patients alive and without active GVHD

(Aim 2.1 and 2.2 only) • Non-CMV viral infection

1) Analysis 1 (Aim 2.1):

Comparisons based upon donor/recipient CMV serostatus at time of transplant across the 4 cohorts

2) Analysis 2 (Aim 2.2): Comparisons based on the presence/absence of CMV reactivation occurring by day 100 post-transplant. This will be a left-truncated analysis starting at day 100

3) Analysis 3 (Aim 2.3) Examined based upon the development (or not) of a non-CMV viral infection.

6.0 Variables to be described: Patient related • Patient age at transplant (in decades ≤ 10, 11-20, 21-30, 31-40, 41-50, 51-60, ≥ 60) • Patient gender • Patient race/ethnicity • Karnofsky performance at transplant: <90% vs. ≥90%

Disease/Transplant Related • Disease • Time from hematologic diagnosis to HCT • Recipient HCT-CI • Disease risk index (low vs intermediate vs high risk) • Donor gender • Donor age (related donors only) • Conditioning intensity (myeloablative vs. reduced-intensity/non-ablative) • TBI-based conditioning (yes vs. no) • T cell depletion (in vivo/ex vivo) vs. no • Stem cell source (peripheral blood vs. marrow vs. UCB)

41


Cell counts • Total nucleated cell dose (TNC), CD34 +/kg-bw and CD3+/kg-bw cell doses • Day 100 total white cell count and absolute lymphocyte count (when reported)

CMV related (Aims 2.1 and 2.2) • CMV reactivation by day 100: Yes/No [Analysis 2 variable defining groups] • Time to CMV reactivation from transplant • Time to CMV end-organ disease (if developed) • Recipient and donor cytomegalovirus serostatus (positive versus negative) [Analysis 1 variable

defining groups]

Other viral infections (Aim 2.3) • Type of viral infection (parainfluenza virus, influenza virus, RSV, adenovirus, hMPV, BK, EBV,

HHV-6, VZV, and HSV) • Time to viral infection • End-organ manifestations/viral disease versus viral detection only • HSV-1 and HSV-2 Ab seropositive pre-transplant

7.0 Study design:

As noted, this study will have multiple analyses which will be performed separately using the same cohort of patients. Analyses 1 and 2 will follow the previously published IN1201 study.

Patient-, disease- and transplant- related factors will be compared between groups using the Chi-square test for categorical variables and the Wilcox on two sample test for continuous variables. The probabilities of progression-free and overall survival will be calculated using the Kaplan Meier estimator, with the variance estimated by Greenwood’s formula. Values for other endpoints will be generated using cumulative incidence estimates to account for competing risks. Cox proportional hazards regression will be used for each outcome. . The variables to be considered in the multivariable regression models are listed. The assumption of proportional hazards for each factor in the Cox model will be tested using time-dependent covariates. When this indicates differential effects over time (non-proportional hazards), models will be constructed breaking the post-transplant time course into two periods, using the maximized partial likelihood method to find the most appropriate breakpoint. The stepwise variable selection method will be used to identify significant risk factors which associated with the outcomes. Factors significantly associated with the outcome variable at a 5% level will be kept in the final model. Interactions between main effect and significant covariates will be tested. Epidemiologic changes in incidence will be reported descriptively. For Aim 2.2, CMV reactivation will be added as a time-dependent covariate. Center effects will be tested.

42


8.0 References: 1. Ariza-Heredia EJ, Nesher L, Chemaly RF. Cytomegalovirus diseases after hematopoietic stem cell

transplantation: A mini-review. Cancer Lett. 2014;342(1):1-8. doi:10.1016/j.canlet.2013.09.004. 2. Ljungman P, Hakki M, Boeckh M. Cytomegalovirus in hematopoietic stem cell transplant

recipients. Infect Dis Clin North Am. 2010;24(2):319-337. doi:10.1016/j.idc.2010.01.008. 3. Mori T, Kato J. Cytomegalovirus infection/disease after hematopoietic stem cell transplantation.

Int J Hematol. 2010;91(4):588-595. doi:10.1007/s12185-010-0569-x. 4. Teira P, Battiwalla M, Ramanathan M, et al. Early cytomegalovirus reactivation remains

associated with increased transplant related mortality in the current era: a CIBMTR analysis. Blood. 2016;127(20):2427-2438. doi:10.1182/blood-2015-11-679639.

5. Elmaagacli AH, Steckel NK, Hegerfeldt Y, et al. Early Cytomegalovirus Replication After Allogeneic Stem Cell Transplantation Is Associated With a Decreased Relapse Risk in Acute Myeloid Leukemia Patients: Evidence for a Putative Virus-Versus-Leukemia Effect. Blood. 2011;118(5):1403-1412. doi:10.1016/j.bbmt.2010.12.034.

6. Takenaka K, Nishida T, Asano-Mori Y, et al. Cytomegalovirus Reactivation after Allogeneic Hematopoietic Stem Cell Transplantation is Associated with a Reduced Risk of Relapse in Patients with Acute Myeloid Leukemia Who Survived to Day 100 after Transplantation. Biol Blood Marrow Transplant. 2015;21(11):2008-2016. doi:10.1016/j.bbmt.2015.07.019.

7. Green ML, Leisenring WM, Xie H, et al. CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. Blood. 2013;122(7):1316-1324. doi:10.1182/blood-2013-02-487074.

8. Bashey A, Zhang X, Sizemore CA, et al. T-Cell-Replete HLA-Haploidentical Hematopoietic Transplantation for Hematologic Malignancies Using Post-Transplantation Cyclophosphamide Results in Outcomes Equivalent to Those of Contemporaneous HLA-Matched Related and Unrelated Donor Transplantation. J Clin Oncol. 2013;31(10):1310-1316. doi:10.1200/JCO.2012.44.3523.

9. Solomon SR, Sizemore C a., Sanacore M, et al. Haploidentical Transplantation Using T Cell Replete Peripheral Blood Stem Cells and Myeloablative Conditioning in Patients with High-Risk Hematologic Malignancies Who Lack Conventional Donors is Well Tolerated and Produces Excellent Relapse-Free Survival: Biol Blood Marrow Transplant. 2012;18(12):1859-1866. doi:10.1016/j.bbmt.2012.06.019.

10. Goldsmith SR, Slade M, DiPersio JF, et al. Cytomegalovirus viremia, disease, and impact on relapse in T-cell replete peripheral blood haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide. Haematologica. 2016. doi:10.3324/haematol.2016.149880.

11. Holtan SG, DeFor TE, Lazaryan A, et al. Composite endpoint of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood. 2015;125(8):1333-1339. doi:10.1182/blood-2014-10-609032.

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1-12-18 INWC Leadership discussion revisions 1. Delete UCBT for the following reasons:

• Clinically, UCBT and haploidentical transplants are mostly done at different transplant centers and this may yield findings based on variance in practices in prophylaxis and screening

• IN1201b, examining the impact of CMV serostatus and CMV reactivation in UCBT, was recently published (BMT 2016, 1113-1120)

• IN101, examining infection rates in alternative donors of UCBT and MMUD, was recently published (BBMT 2016, p1636–1645)

2. Restrict patient population to AML, ALL, and MDS 3. Control Group for Matched Related/Matched Unrelated Donors will be restricted to centers also

having patients in Haploidentical cohort to minimize center bias for prophylaxis and screening

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Table 1 Characteristics of patients who underwent first ALLO transplants with Cy and without Cy conditioning regimen, reported to the CIBMTR, from 2008 to 2016 and will be eligible for inclusion in

analyses

Variable

Mismatch related with Cy

N(%)

Mismatch related

without Cy N(%)

MRD/MUD with Cy

N(%)

MRD/MUD without Cy

N(%) Patient related Number of patients 520 368 447 8552 Number of centers 87 89 74 121 Gender

Male 326 (63) 232 (63) 273 (61) 4942 (58) Female 194 (37) 136 (37) 174 (39) 3610 (42)

Age, median(range), years 59 (3 - 78) 55 (2 - 77) 52 (2 - 75) 56 (2 - 78) Age at transplant, years

<=10 20 ( 4) 32 ( 9) 7 ( 2) 220 ( 3) 11-20 27 ( 5) 42 (11) 18 ( 4) 360 ( 4) 21-30 47 ( 9) 28 ( 8) 59 (13) 625 ( 7) 31-40 32 ( 6) 21 ( 6) 53 (12) 730 ( 9) 41-50 53 (10) 21 ( 6) 63 (14) 1181 (14) 51-60 101 (19) 80 (22) 93 (21) 2237 (26) 61-70 182 (35) 111 (30) 130 (29) 2661 (31) >70 58 (11) 33 ( 9) 24 ( 5) 538 ( 6)

Karnofsky performance pre-Preparative Regimen <80 76 (15) 59 (16) 62 (14) 1106 (13) 80-89 163 (31) 78 (21) 110 (25) 2287 (27) >=90 266 (51) 226 (61) 268 (60) 5046 (59) Missing 15 ( 3) 5 ( 1) 7 ( 2) 113 ( 1)

Race/Ethnicity Caucasian, non-Hispanic 312 (60) 179 (49) 319 (71) 7053 (82) African-American, non-Hispanic 92 (18) 61 (17) 47 (11) 310 ( 4) Asian, non-Hispanic 49 ( 9) 71 (19) 27 ( 6) 430 ( 5) Pacific islander, non-Hispanic 5 (<1) 0 1 (<1) 22 (<1) Native American, non-Hispanic 2 (<1) 1 (<1) 1 (<1) 29 (<1) Hispanic, Caucasian 42 ( 8) 31 ( 8) 36 ( 8) 495 ( 6) Hispanic, African-American 2 (<1) 1 (<1) 2 (<1) 9 (<1) Hispanic, Asian 1 (<1) 0 0 3 (<1) Hispanic, Pacific islander 0 0 0 5 (<1) Hispanic, Native American 1 (<1) 1 (<1) 0 4 (<1) Missing 14 ( 3) 23 ( 6) 14 ( 3) 192 ( 2)

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Variable


N(%)

Mismatch related

without Cy N(%)

MRD/MUD with Cy

N(%)

MRD/MUD without Cy

N(%) Disease-related Disease

AML 267 (51) 189 (51) 252 (56) 4128 (48) ALL 100 (19) 66 (18) 89 (20) 1253 (15) MDS/MPS 153 (29) 113 (31) 106 (24) 3171 (37)

HCT-CI 0 138 (27) 108 (29) 115 (26) 2440 (29) 1 84 (16) 58 (16) 61 (14) 1225 (14) 2 68 (13) 47 (13) 74 (17) 1299 (15) 3 91 (18) 53 (14) 70 (16) 1437 (17) 4 63 (12) 39 (11) 45 (10) 894 (10) 5 75 (14) 49 (13) 81 (18) 1167 (14) Missing 1 (<1) 14 ( 4) 1 (<1) 90 ( 1)

Transplant-related Graft type

Bone Marrow 239 (46) 87 (24) 195 (44) 1278 (15) Peripheral blood 281 (54) 281 (76) 252 (56) 7274 (85)

Donor/recipient HLA match HLA-identical siblings 0 0 311 (70) 3677 (43) matched related 0 0 13 ( 3) 52 (<1) Mismatched related, mismatch=1 2 (<1) 18 ( 5) 0 0 Mismatched related, mismatch>=2 306 (59) 226 (61) 0 0 Mismatched related, mismatch missing 212 (41) 124 (34) 0 0 8/8 unrelated 0 0 123 (28) 4823 (56)

Conditioning regimen intensity Myeloablative 213 (41) 166 (45) 240 (54) 5154 (60) RIC/NMA 307 (59) 202 (55) 207 (46) 3395 (40) Missing 0 0 0 3 (<1)

GVHD prophylaxis Ex vivo T-cell depletion 0 54 (15) 0 55 (<1) CD34 selection 0 43 (12) 0 155 ( 2) Post-CY + other(s) 520 0 432 (97) 0 Post-CY alone 0 0 15 ( 3) 0 TAC/CSA + MMF +- others 0 185 (50) 0 1947 (23) TAC/CSA + MTX +- others 0 61 (17) 0 5394 (63) TAC/CSA + others (except MTX, MMF) 0 3 (<1) 0 679 ( 8) TAC/CSA alone 0 17 ( 5) 0 230 ( 3) Other GVHD prophylaxis 0 5 ( 1) 0 92 ( 1)

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Variable


N(%)

Mismatch related

without Cy N(%)

MRD/MUD with Cy

N(%)

MRD/MUD without Cy

N(%) TBI

No 166 (32) 111 (30) 236 (53) 6111 (71) Yes 354 (68) 256 (70) 211 (47) 2429 (28) Missing 0 1 (<1) 0 12 (<1)

Donor/recipient gender match Male-Male 212 (41) 128 (35) 142 (32) 2384 (28) Male-Female 120 (23) 67 (18) 90 (20) 1623 (19) Female-Male 114 (22) 103 (28) 82 (18) 1380 (16) Female-Female 74 (14) 69 (19) 53 (12) 1164 (14) Missing 0 1 (<1) 80 (18) 2001 (23)

Donor/Recipient CMV status +/+ 229 (44) 162 (44) 135 (30) 2155 (25) +/- 36 ( 7) 42 (11) 40 ( 9) 721 ( 8) -/+ 144 (28) 86 (23) 101 (23) 1872 (22) -/- 86 (17) 60 (16) 84 (19) 1633 (19) Missing 25 ( 5) 18 ( 5) 87 (19) 2171 (25)

Donor age, years Related/Other related 520 368 324 (72) 3729 (44)

18-20 0 0 5 ( 1) 189 ( 2) 21-30 0 0 68 (15) 2303 (27) 31-40 0 0 25 ( 6) 1066 (12) 41-50 0 0 17 ( 4) 590 ( 7) 51-60 0 0 2 (<1) 200 ( 2) >60 0 0 0 6 (<1) Missing 0 0 6 ( 1) 469 ( 5)

Donor age(unrelated only), median(range), years N/A N/A 28 (19 - 52) 28 (18 - 62) Time from diagnosis to transplant

<6 month 197 (38) 124 (34) 199 (45) 3997 (47) 6 month-1Y 138 (27) 108 (29) 125 (28) 2132 (25) 1Y-2Y 87 (17) 71 (19) 60 (13) 1174 (14) >=2Y 98 (19) 64 (17) 63 (14) 1245 (15) Missing 0 1 (<1) 0 4 (<1)

Time from diagnosis to transplant, median(range), months

8 (1 - 172) 8 (<1 - 330) 7 (<1 - 257) 6 (<1 - 522)

Year of transplant 2008 5 (<1) 37 (10) 23 ( 5) 1074 (13) 2009 8 ( 2) 26 ( 7) 16 ( 4) 985 (12) 2010 5 (<1) 3 (<1) 4 (<1) 710 ( 8)

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Variable


N(%)

Mismatch related

without Cy N(%)

MRD/MUD with Cy

N(%)

MRD/MUD without Cy

N(%) 2011 1 (<1) 9 ( 2) 9 ( 2) 513 ( 6) 2012 11 ( 2) 12 ( 3) 9 ( 2) 517 ( 6) 2013 50 (10) 55 (15) 45 (10) 1085 (13) 2014 102 (20) 81 (22) 63 (14) 1442 (17) 2015 138 (27) 73 (20) 136 (30) 1221 (14) 2016 200 (38) 72 (20) 142 (32) 1005 (12)

Median follow-up of survivors, months 20 (2 - 97) 24 (3 - 109) 22 (3 - 97) 37 (2 - 110)

Selection Criteria Removed Remained First allo transplant for hematologic malignancy 2008-2016

23035

Age>=2 338 22697 AML, ALL and MDS only 4344 18353 BM, PM only 3554 14799 Excluded if twin (n=75), multiple donor(n=6), mismatched unrelated donor (n=1505) 1586 13213 Excluded if no consent 487 12726 Excluded quarantine centers from research studies 322 12404 Excluded if no 100 day follow up form 123 12281 Excluded if no GVHD prophylaxis 220 12061 Excluded if cannot be classified in a group (missing in donor HLA or Cy, potential patients) 608 11453

Excluded if patients transplanted at centers which have no reported haplo HCT patients 1566 9887

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Proposal: 1707-01

Title: Comparison of early (By D+100) Infections after haploidentical HSCT between patients receiving Cyclophosphamide-based or other GVHD Prophylaxis

Genovefa Papanicolaou and Celalettin Ustun, Memorial Sloan Kettering Cancer Center and University of Minnesota

Introduction/background: Infections are a common complications of allogeneic hematopoietic cell transplantation (HCT) and are associated with increased morbidity and mortality. . Incidence and type of infections are affected by severity and duration of immunosuppression that depends on graft type, content and intensity of conditioning regimens and GVHD prophylaxis or treatment. The use of Post-transplantation cyclophosphamide (PostCy) has significantly increased over the last few years. Although postCy was first used in haploidentical donor HCT1, its use has been extended to other graft types as well.2 In this study, we like to evaluate the infectious complications of this approach and compare with others.

Objectives: Primary Objectives

• To document the incidence and infection density of 3 types (bacterial, viral, and fungal) ofinfections within 100 days after allogeneic HCT followed by postCy

• To compare these infections with those occurring after allogeneic HCT with othercommon/traditional GVHD prophylaxis (e.g., CNI-based, sirolimus-based, MMF-based)

• To compare these infections with those occurring after allogeneic HCT with T-cell depleted (invivo or in vitro) allogeneic HCT

Secondary Objectives • To compare NRM at 6 months and year 1• To compare OS at year one• To compare acute and cGVHD rates

Study population: The study population will include all patients receiving first allogeneic HCT for any disease between January 2010 and December 2016.

Outcomes: Infections:

• Type (bacterial fungal viral), specific organisms, and onset of infection relative to HSCT. Alldocumented unique infections would be counted regardless of first or second etc.

Non-relapse mortality: • Death without evidence of relapse or progression of underlying malignancy. This will be

estimated using the cumulative incidence function with relapse/progression as the competingrisk. Competing risk methods will also be used for regression analysis.

Causes of Death: • In the event of relapse of disease for transplant, relapse is considered the primary cause of

death.

49


Variables: Patient Related:

• Age • Gender • Performance status: ≥ 90% vs <90% • HCT-CI

Disease Related: • ASBMT RFI classification: low vs intermediate vs high • Time from diagnosis to transplant • Disease, malignant vs. nonmalignant

Transplant Related: • Conditioning regimen intensity: myeloablative vs reduced-intensity/non-myeloablative • Graft type: Sibling, URD, UCB, Haploidentical • Donor age (for unrelated recipients): ≤10y vs. 11-20y vs. 21-30y vs. 31-40y vs. 41-50y vs. >50y • Donor-recipient sex: M-M vs. M-F vs. F-M vs. F-F • Donor-recipient CMV serostatus: -/- vs +/- vs -/+ vs +/+ • Donor-recipient HLA-match:

o Related: Matched versus mismatched o Unrelated: Well-matched versus partially matched vs. mismatched

• GVHD prophylaxis: CNI±other vs. Sirolimus-based, vs. T-cell depletion vs. PostHCT Cytoxan vs. other

• Source of stem cells: BM vs. PBSC vs. CB • Planned therapy with Growth factors (G-CSF or GM-CSF) post-transplant: yes vs. no (defined as

day-3 to day7) • TBI use and dose in conditioning

Infections Related: • Type of bacteria, virus, fungus • Severity (death within a month after infection) • Organ involved in infection • Time from transplant to infection • Year of transplant

Post-transplant event variables: • Time to neutrophil engraftment • Time to graft failure • Time to 2nd Transplant • Onset of grade II – IV acute GVHD • Onset of chronic GVHD • Mortality

References: 1. Luznik L, O'Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow transplantation for

hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14(6):641-650.

2. Mielcarek M, Furlong T, O'Donnell PV, et al. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood. 2016;127(11):1502-1508.

50


Table 1. Characteristics of patients who underwent first ALLO transplants with and without Cy as GVHD prophylaxis reported to the CIBMTR, from 2010 to 2016

Characteristics of patients Cy

N(%) Others

N(%) Patient related Number of patients 1064 16088 Number of centers 112 242 Gender

Male 644 (61) 9456 (59) Female 420 (39) 6632 (41)

Age, median(range), years 54 (1 - 82) 48 (<1 - 82) Age at transplant, years

<=10 51 ( 5) 2624 (16) 11-20 71 ( 7) 1573 (10) 21-30 124 (12) 1246 ( 8) 31-40 95 ( 9) 1271 ( 8) 41-50 128 (12) 1717 (11) 51-60 196 (18) 3107 (19) >60 399 (38) 4550 (28)

Disease AML 410 (39) 5433 (34) ALL 144 (14) 2115 (13) Other leukemia 20 ( 2) 411 ( 3) CML 40 ( 4) 414 ( 3) MDS 245 (23) 3979 (25) Other acute leukemia 18 ( 2) 153 (<1) NHL 60 ( 6) 751 ( 5) HL 12 ( 1) 49 (<1) Plasma cell disorder/Multiple Myeloma 1 (<1) 36 (<1) Other Malignancies 4 (<1) 4 (<1) Severe aplastic anemia 55 ( 5) 772 ( 5) Inherited abnormalities erythrocyte differentiation or function

32 ( 3) 828 ( 5)

SCID and other immune system disorders 15 ( 1) 678 ( 4) Inherited abnormalities of platelets 1 (<1) 21 (<1) Inherited disorders of metabolism 2 (<1) 252 ( 2) Histiocytic disorders 5 (<1) 162 ( 1) Autoimmune Diseases 0 9 (<1) Other, specify 0 21 (<1)

Graft type Bone Marrow 438 (41) 3258 (20)

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Characteristics of patients Cy

N(%) Others

N(%) Peripheral blood 624 (59) 9420 (59) Cord blood 2 (<1) 3410 (21)

Donor/recipient HLA match Cord blood 2 (<1) 3410 (21) HLA-identical siblings 342 (32) 4617 (29) matched related 20 ( 2) 183 ( 1) Mismatched related, 1 mismatch 7 (<1) 14 (<1) Mismatched related,>=2 mismatch 315 (30) 337 ( 2) Mismatched related, mismatch unknown 210 (20) 290 ( 2) 8/8 unrelated 121 (11) 5417 (34) 7/8 unrelated 35 ( 3) 1087 ( 7) <=6/8 unrelated 0 39 (<1) Unrelated (HLA match information missing) 12 ( 1) 694 ( 4)

GVHD prophylaxis No GVHD prophylaxis (forms under review) 0 441 ( 3) Ex vivo T-cell depletion 0 154 (<1) CD34 selection 0 332 ( 2) Cyclophosphamide 1064 0 TAC + MMF +- others 0 3001 (19) TAC + MTX +- others 0 5821 (36) TAC + others 0 926 ( 6) TAC alone 0 369 ( 2) CSA + MMF +- others (except TAC ) 0 2525 (16) CSA + MTX +- others (except TAC , MMF) 0 1570 (10) CSA + others (except TAC , MTX, MMF) 0 425 ( 3) CSA alone 0 246 ( 2) Other GVHD prophylaxis 0 278 ( 2)

Year of transplant 2010 15 ( 1) 1789 (11) 2011 14 ( 1) 1302 ( 8) 2012 23 ( 2) 1372 ( 9) 2013 141 (13) 2552 (16) 2014 220 (21) 3294 (20) 2015 376 (35) 3050 (19) 2016 275 (26) 2729 (17)

Median follow-up of survivors, months 23 (1 - 73) 26 (1 - 92)

52


Proposal: 1710-06

Title: Posaconazole vs. voriconazole prophylaxis in patients with allogeneic SCT

Shatha Farhan, MD, [email protected], Henry Ford Health system Nalini Janakiraman, MD, [email protected], Henry Ford Health system Edward Peres, MD, [email protected], Henry Ford Health system

Hypothesis: Both voriconazole and posaconazole are effective in preventing invasive fungal infections (IFI) post SCT but less cost and less administration of other intravenous antifungal therapy with voriconazole

Specific aims: 1. Incidence of proven/probable invasive fungal infection (IFI) within 180 days2. Other outcomes: all-cause mortality, proven/probable Invasive aspergillosis (IA), proven invasive

candidiasis (IC), and administration of other IV antifungal therapy within 180 days3. Cost

Scientific justification: Invasive fungal disease (IFD) is a significant cause of morbidity and mortality in hematopoietic stem cell transplantation (SCT) patients. However, the optimum oral agent for antifungal prophylaxis in allo SCT recipients post-transplant remains uncertain. To our knowledge no single head-to-head randomized clinical trial has directly compared the two widely used posaconazole and voriconazole. A meta-analysis 1could not firmly conclude that specific agents performed better than others in any of the evaluated outcomes, due to the width of credible intervals in the base-case analysis. However, from a medical decision making point of view, the results support the selection of mold-active azoles over fluconazole for the prevention of IFIs in allo SCT recipients post-transplant. In addition, posaconazole and voriconazole may be preferable for protection from IA, itraconazole for protection from IC, and voriconazole for reducing other licensed antifungal therapy.

Patient eligibility population: • Patients with AML/MDS• Age>=18• Matched related and Matched and mismatched unrelated donors and alternative donors• Year of HSCT >=2005• HSCT with myeloablative, reduced intensity regimen and non-myeloablative regimens

Data requirements: • This study will use the following forms:• Acute Myelogenous Leukemia, ALL and MDS/MPN and lymphoid malignancies Pre-HSCT Data• Acute Myelogenous Leukemia, ALL and MDS/MPN and lymphoid malignancies Post-HSCT Data• Pre-Transplant Essential Data• Post-transplant Essential data• Form 2000 and 2100• List of Variables needed: Age of patient at diagnosis, gender of patient, date of diagnosis, date

of HSCT, Donor type, conditioning regimen, GVHD prophylaxis, date of relapse or progression,

53



date of death, presence of neutropenia pre SCT, Myeloid vs other malignancies, date of last follow up.

Study design: Data will be collected and analyzed. We will retrospectively reviewed patients who had allo-HSCT since year 2005. Objectives are to explore the impact of voriconazole vs posaconazole on incidence of proven/probable invasive fungal infection (IFI) within 180 days. In addition to look at all-cause mortality, proven/probable Invasive aspergillosis (IA), proven invasive candidiasis (IC), and administration of other IV antifungal therapy within 180 days and Cost. Demographics, disease-related and transplant-related variables mentioned above will be collected. PFS is defined as the time from HSCT to the time of progression, death or last contact whichever occurred first. OS is defined as the time from HSCT to the time of death or last contact. OS and PFS will be estimated using the Kaplan-Meier method. Proven/probable IFI will be according to the consensus criteria described References: 1. Bow EJ, Vanness DJ, Slavin M, et al. Systematic review and mixed treatment comparison meta-

analysis of randomized clinical trials of primary oral antifungal prophylaxis in allogeneic hematopoietic cell transplant recipients. BMC Infect Dis 2015;15:128.

54


Table 1. Characteristics of patients who underwent first ALLO transplants for AML or MDS/MPS with POSA or VORI reported to the CIBMTR, from 2007 to 2016

Characteristics of patients POSA N(%)

VORI N(%)

Number of patients 482 1101

Number of centers 93 119 Gender

Male 257 (53) 605 (55)

Female 225 (47) 496 (45) Age, median(range), years 59 (18 - 76) 57 (18 - 82) Age at transplant, years

18-20 3 (<1) 17 ( 2) 21-30 23 ( 5) 79 ( 7) 31-40 41 ( 9) 73 ( 7)

41-50 63 (13) 170 (15) 51-60 123 (26) 307 (28) >60 229 (48) 455 (41)

Disease AML 301 (62) 757 (69)

MDS/MPS 181 (38) 344 (31) Graft type

Bone Marrow 48 (10) 165 (15)

Peripheral blood 336 (70) 751 (68) Cord blood 98 (20) 185 (17)

Donor/recipient HLA match

Cord blood 98 (20) 185 (17) HLA-identical siblings 112 (23) 248 (23) matched related 1 (<1) 2 (<1)

Mismatched related, 1 mismatch 1 (<1) 0 Mismatched related,>=2 mismatch 11 ( 2) 33 ( 3) Mismatched related, mismatch unknown 7 ( 1) 25 ( 2)

8/8 unrelated 202 (42) 450 (41) 7/8 unrelated 30 ( 6) 95 ( 9) <=6/8 unrelated 1 (<1) 6 (<1)

Unrelated (HLA match information missing)

19 ( 4) 57 ( 5)

55


Characteristics of patients POSA N(%)

VORI N(%)

Fungal infection after transplant

No 418 (87) 944 (86) Yes 64 (13) 157 (14)

Year of transplant

2007 21 ( 4) 128 (12) 2008 24 ( 5) 123 (11) 2009 25 ( 5) 124 (11)

2010 25 ( 5) 82 ( 7) 2011 18 ( 4) 55 ( 5) 2012 12 ( 2) 64 ( 6)

2013 27 ( 6) 113 (10) 2014 60 (12) 112 (10) 2015 107 (22) 142 (13)

2016 163 (34) 158 (14) Median follow-up of survivors, months 13 (3 - 121) 36 (3 - 124)

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Proposal: 1711-57

Title: Study the Incidence, and impact of C diff infection within 100 days on Transplant outcomes after allogeneic stem cell transplant

Muthalagu Ramanathan, MD, [email protected], University of Massachusetts Medical School and Medical Center, Bipin Savani, MD, [email protected], Vanderbilt University Medical Center

Hypothesis: Clostridium Difficile (C Diff) infection is very common after stem cell transplant due to use of prophylactic antibiotics before and during allogeneic stem cell. Although there are several single institutional reports the incidence, risk factors and impact it has on transplant outcomes has not been clearly defined. Our hypothesis is that Cdiff infection increases risk of acute and chronic graft versus host disease of gut and slows recovery leading to increased transplant related mortality in the elderly.

Specific aims: • Primary purpose of this study will be to determine the incidence, and impact of Cdiff on

allogeneic stem cell transplant outcomes such as acute and chronic GVHD of the gut and TRM.

Scientific impact: • The determination of incidence and impact of C diff on transplant outcomes will further help

develop strategies for prevention and treatment of CDIFF post-transplant. Some of these couldbe how to translate evidence obtained from gut microbiota research4, study the regular use ofprobiotics, prebiotics, fecal transplants etc.

Scientific justification: • Patients undergoing hematopoietic stem cell transplantation (HSCT) appear to be one of the

highest risk populations for this infection, with rates of CDI exceeding 25% in some studies.Clostridium difficile infection (CDI) is reported in 13- 18% of recipients after allogeneichematopoietic stem cell transplantation (HSCT) and 6-8% after autologous stem celltransplants, mainly in the first month post transplantation 1,2,3. Risk factors that have beenidentified are allogeneic stem cell transplant, cord blood as the source of stem cells, acutegraft-versus-host disease (GVHD), total body irradiation (TBI), elderly age, increased use ofprophylactic antibiotics, steroids, PPI, prolonged hospitalizations etc2,3 . There was a strongrelationship noted between early CDI and subsequent development of gastrointestinal tractGVHD in the year following allogeneic HSCT (P < .001)3. Other studies have reported no impacton transplant related mortality 5. The determination of the impact of c diff on transplantoutcomes such as GVHD, TRM, relapse and survival in a multi institutional study is thenecessary first step to develop effective prevention, prophylaxis and treatment strategies for Cdiff.

Patient eligibility population: • Allogenic stem cell transplants since 2010 as we have c diff data and prophylactic antibiotics

data being collected since 2010. Years or forms without infection information will be excluded.

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• If we have enough patients with prophylactic antibiotics usage documented we can restrict to those patients and include autologous stem cell transplants as well.

• All ages, All diseases, Myeloablative and reduced intensity regimens, disease stage. Data requirements:

• Post transplant data form will have all the information with regards to infection and prophylactic antibiotics use.

• No supplemental data collection is planned.

Study design: • To study the impact of c diff infection after allogeneic stem cell transplant determined by C diff

positive reported. Although this will include colonized patients, since routine testing is done only when symptoms of diarrhea are noted we would consider all pcr or toxin positive patients infected.

• Stratify recipients by conditioning myeloablative versus Reduced intensity, auto vs allo if we include auto scts, by age if applicable.

• The primary outcome for this study is TRM based on C diff. • Secondary outcomes of interest are Overall survival, Relapse, the incidence, time of onset, and

severity of acute GVHD, chronic GVHD especially gut. • Number of patients, patient sex, patient age (median), • Degree of HLA matching: matched vs mismatched • Type of donor: related fully matched, related mismatched/haplo, unrelated, cord • Prophylaxis of GVHD : • ATG vs campath vs no • Analysis of OS and EFS (time dependent variable without competing risk) by the product limit

method or by Kalan-Meier method • Analysis of time dependent variables with competing risk, by cause-specific cumulative

incidence rates: • Relapse (competing event death without relapse) • Non relapse mortality (competing event relapse) • Non relapse mortality by infection (competing event relapse, death from non infectious

complication) • aGVH 0-I (competing event death, failure to engraft) • aGVH II-IV (competing event death, failure to engraft) • cGVH limited(competing event death, failure to engraft) • cGVH extensive (competing event death, failure to engraft) • Endpoints: Relapse, NRM, OS and EFS • Covariates: disease stage (0=CR1, 1= CR2 and other stage), GVH prophylaxis (0=no antiT-AB,

1=antiT-AB), sex match (0= female to male, 1=others), conditioning regimen (0=TBI, 1=no TBI). • Disease categories (Malignant=1, non malignant=0) • Nucleated cell dose (0=under the median, 1=over the median), CD34 cell dose ((0=under the

median, 1=over the median) Data Source

• CIBMTR Research Database, CIBMTR Sample Repository.

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References: 1. Clinical Infectious disease 2012 Clostridium difficile infection among hematopoietic stem cell

transplant recipients: beyond colitis.Carolyn D. Alonsoa and Kieren A. Marrb 2. Biol Blood Marrow Transplant. 2014 Oct;20(10):1626-33. doi: 10.1016/j.bbmt.2014.06.025. Epub

2014 Jun 25.Clostridium difficile infection after allogeneic hematopoietic stem cell transplant: strain diversity and outcomes associated with NAP1/027. Kamboj M1, Xiao K2, Kaltsas A3, Huang YT2, Sun J2, Chung D2, Wu S4, Sheahan A2, Sepkowitz K3, Jakubowski AA5, Papanicolaou G3.

3. Clin Infect Dis. 2012 Apr;54(8):1053-63. doi: 10.1093/cid/cir1035. Epub 2012 Mar 12. Epidemiology and outcomes of Clostridium difficile infections in hematopoietic stem cell transplant recipients. Alonso CD1, Treadway SB, Hanna DB, Huff CA, Neofytos D, Carroll KC, Marr KA.

4. Leuk Lymphoma. 2011 Oct;52(10):1844-56. doi: 10.3109/10428194.2011.580476. Epub 2011 Jun 12.Role of gut microbiota in graft-versus-host disease.Murphy S1, Nguyen VH.

5. Pharmacotherapy. 2017 Apr;37(4):420-428. doi: 10.1002/phar.1914. Epub 2017 Mar 30.Evaluation of Risk Factors for Clostridium difficile Infection in Hematopoietic Stem Cell Transplant Recipients.Scardina TL1, Kang Martinez E2, Balasubramanian N3, Fox-Geiman M1, Smith SE4, Parada JP5.

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https://www.ncbi.nlm.nih.gov/pubmed/?term=Alonso%20CD%5BAuthor%5D&cauthor=true&cauthor_uid=23806895

https://www.ncbi.nlm.nih.gov/pubmed/?term=Marr%20KA%5BAuthor%5D&cauthor=true&cauthor_uid=23806895

https://www.ncbi.nlm.nih.gov/pubmed/24973628

https://www.ncbi.nlm.nih.gov/pubmed/?term=Kamboj%20M%5BAuthor%5D&cauthor=true&cauthor_uid=24973628

https://www.ncbi.nlm.nih.gov/pubmed/?term=Xiao%20K%5BAuthor%5D&cauthor=true&cauthor_uid=24973628

https://www.ncbi.nlm.nih.gov/pubmed/?term=Kaltsas%20A%5BAuthor%5D&cauthor=true&cauthor_uid=24973628

https://www.ncbi.nlm.nih.gov/pubmed/?term=Huang%20YT%5BAuthor%5D&cauthor=true&cauthor_uid=24973628

https://www.ncbi.nlm.nih.gov/pubmed/?term=Sun%20J%5BAuthor%5D&cauthor=true&cauthor_uid=24973628

https://www.ncbi.nlm.nih.gov/pubmed/?term=Sun%20J%5BAuthor%5D&cauthor=true&cauthor_uid=24973628

https://www.ncbi.nlm.nih.gov/pubmed/?term=Chung%20D%5BAuthor%5D&cauthor=true&cauthor_uid=24973628

https://www.ncbi.nlm.nih.gov/pubmed/?term=Wu%20S%5BAuthor%5D&cauthor=true&cauthor_uid=24973628

https://www.ncbi.nlm.nih.gov/pubmed/?term=Sheahan%20A%5BAuthor%5D&cauthor=true&cauthor_uid=24973628

https://www.ncbi.nlm.nih.gov/pubmed/?term=Sepkowitz%20K%5BAuthor%5D&cauthor=true&cauthor_uid=24973628

https://www.ncbi.nlm.nih.gov/pubmed/?term=Jakubowski%20AA%5BAuthor%5D&cauthor=true&cauthor_uid=24973628

https://www.ncbi.nlm.nih.gov/pubmed/?term=Papanicolaou%20G%5BAuthor%5D&cauthor=true&cauthor_uid=24973628


https://www.ncbi.nlm.nih.gov/pubmed/?term=Alonso%20CD%5BAuthor%5D&cauthor=true&cauthor_uid=22412059

https://www.ncbi.nlm.nih.gov/pubmed/?term=Treadway%20SB%5BAuthor%5D&cauthor=true&cauthor_uid=22412059

https://www.ncbi.nlm.nih.gov/pubmed/?term=Hanna%20DB%5BAuthor%5D&cauthor=true&cauthor_uid=22412059

https://www.ncbi.nlm.nih.gov/pubmed/?term=Huff%20CA%5BAuthor%5D&cauthor=true&cauthor_uid=22412059

https://www.ncbi.nlm.nih.gov/pubmed/?term=Neofytos%20D%5BAuthor%5D&cauthor=true&cauthor_uid=22412059

https://www.ncbi.nlm.nih.gov/pubmed/?term=Carroll%20KC%5BAuthor%5D&cauthor=true&cauthor_uid=22412059

https://www.ncbi.nlm.nih.gov/pubmed/?term=Marr%20KA%5BAuthor%5D&cauthor=true&cauthor_uid=22412059

https://www.ncbi.nlm.nih.gov/pubmed/21663498/

https://www.ncbi.nlm.nih.gov/pubmed/?term=Murphy%20S%5BAuthor%5D&cauthor=true&cauthor_uid=21663498

https://www.ncbi.nlm.nih.gov/pubmed/?term=Nguyen%20VH%5BAuthor%5D&cauthor=true&cauthor_uid=21663498


https://www.ncbi.nlm.nih.gov/pubmed/?term=Scardina%20TL%5BAuthor%5D&cauthor=true&cauthor_uid=28226419

https://www.ncbi.nlm.nih.gov/pubmed/?term=Kang%20Martinez%20E%5BAuthor%5D&cauthor=true&cauthor_uid=28226419

https://www.ncbi.nlm.nih.gov/pubmed/?term=Balasubramanian%20N%5BAuthor%5D&cauthor=true&cauthor_uid=28226419

https://www.ncbi.nlm.nih.gov/pubmed/?term=Fox-Geiman%20M%5BAuthor%5D&cauthor=true&cauthor_uid=28226419

https://www.ncbi.nlm.nih.gov/pubmed/?term=Smith%20SE%5BAuthor%5D&cauthor=true&cauthor_uid=28226419

https://www.ncbi.nlm.nih.gov/pubmed/?term=Parada%20JP%5BAuthor%5D&cauthor=true&cauthor_uid=28226419

https://www.ncbi.nlm.nih.gov/pubmed/?term=Parada%20JP%5BAuthor%5D&cauthor=true&cauthor_uid=28226419


Characteristics of patients who underwent first ALLO transplants with Clostridium difficile by 100 day, from 2010 to 2016

Characteristics of patients N(%) Number of patients 1653 Number of centers 177 Gender

Male 963 (58) Female 690 (42)

Age, median(range), years 46 (<1 - 82) Age at transplant, years

<=10 282 (17) 11-20 168 (10) 21-30 149 ( 9) 31-40 129 ( 8) 41-50 171 (10) 51-60 299 (18) >60 455 (28)

Disease AML 672 (41) ALL 278 (17) Other leukemia 26 ( 2) CML 36 ( 2) MDS 335 (20) Other acute leukemia 27 ( 2) NHL 66 ( 4) HL 2 (<1) Plasma cell disorder/Multiple Myeloma 3 (<1) Other Malignancies 2 (<1) Severe aplastic anemia 57 ( 3) Inherited abnormalities erythrocyte differentiation or function

51 ( 3)

SCID and other immune system disorders 47 ( 3) Inherited abnormalities of platelets 3 (<1) Inherited disorders of metabolism 34 ( 2) Histiocytic disorders 14 (<1)

Graft type Bone Marrow 351 (21)

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Characteristics of patients N(%)

Peripheral blood 902 (55) Cord blood 400 (24)

Donor/recipient HLA match Cord blood 400 (24) HLA-identical siblings 396 (24) matched related 8 (<1) Mismatched related, 1 mismatch 1 (<1) Mismatched related,>=2 mismatch 87 ( 5) Mismatched related, mismatch unknown 52 ( 3) 8/8 unrelated 556 (34) 7/8 unrelated 97 ( 6) <=6/8 unrelated 6 (<1) Unrelated (HLA match information missing) 50 ( 3)

Systemic antibacterial antibiotics

No 517 (31) Yes 1136 (69)

Year of transplant 2010 182 (11) 2011 146 ( 9) 2012 153 ( 9) 2013 245 (15) 2014 337 (20) 2015 331 (20) 2016 259 (16)

Median follow-up of survivors, months 29 (2 - 79)

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Proposal: 1711-74

Title: Allogeneic hematopoietic cell transplantation is a feasible and effective treatment option for HIV positive patients with advanced hematological disorders.

Sai Ravi Pingali, MD, [email protected], Houston Methodist Hospital, Akash Mukherjee, MD, [email protected], Houston Methodist Hospital, Kehinde U. A. Adekola, MD, MS, [email protected], Robert H. Lurie Comprehensive Cancer Center

Hypothesis: Allogeneic hematopoietic cell transplantation (allo-HCT) is a feasible and effective treatment option for HIV positive patients with advanced hematological disorders and outcomes are similar to non- HIV infected patients receiving allo-HCT.

Specific aims: • Primary aim:

1. To evaluate Non-relapse mortality (NRM), overall survival (OS), progression free survival(PFS) of study cohort compared to non- HIV positive patients at day 100, 1, 3 and 5 years.

• Secondary aim:1. To evaluate engraftment, incidence of acute and chronic GVHD at day 100, 1, 3 and 5 years.2. To evaluate immune-reconstitution at 1-year post transplant.

Scientific Impact: There are no large studies evaluating outcomes of allo-HCT in HIV patients. This study is only feasible with large data sets like CIBMTR data-base. Comparing outcomes of allo-HCT in patients with HIV vs non-HIV infected patients would be very helpful in clinical practice. This study would allow us to effectively compare the outcomes while adjusting for the patient and disease related factors, thereby giving us a better understanding of allo-HCT outcomes in HIV patients.

Scientific justification: With advent of highly active antiretroviral therapy (HAART); the incidence of opportunistic infections have decreased and overall survival of HIV-infected patient has significantly improved with malignancy now being the leading cause of mortality in individuals with HIV infection.1 Patients with HIV have significantly higher incidence of non-Hodgkin lymphoma and Hodgkin lymphoma compared to age and sex matched normal cohorts. Few studies also showing increased risk of acute myeloid leukemia.2,3. Approximately 40,000 new cases of HIV infection occur in US annually4 and as these individuals age, their cancer risk will also continue to rise making it even more important to study the impact of HIV on allo-HCT recipients.

Prior to availability of HAART, HIV infected patients with hematological malignancies were considered ineligible for allo-HCT, however with HAART therapy and improved life expectancy, HIV patients are increasingly being considered for transplant. Few studies with small sample size reported equivalent outcomes compared to non-HIV patients in both autologous and allogeneic setting.5-11. A retrospective study on only 23 HIV positive patients using CIBMTR database who underwent allo-HCT from 1987 to 2003 showed improved survival in HAART era and a feasible intervention for hematological disorders

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but their report was limited by sample size and incomplete information on CD4 counts and HIV viral load on their patients.6. There are no studies evaluating outcomes of allo-HCT in HIV positive patients based on donor type (MRD vs MUD vs MMUD vs Haplo vs Cord), based on their conditioning regimen (Myeloablative vs Reduced intensity conditioning vs T-cell depleting conditioning) and based on their pre-transplant HIV control determined by CD4 count and HIV viral load. HIV infection can affect allo-HCT recipient with hematological malignancy in multiple ways including its CD4 lowering ability affecting CD4 reconstitution post-transplant, myelosuppressive effect from viremia and HAART, increased risk of opportunistic infection, higher incidence of concomitant hepatitis infection, complex drug interactions of CYP450 inhibitors like protease inhibitors with transplant related medications, effect of HIV viremia on bone marrow microenvironment and cytokine mileu, increased risk of GVHD and overall impact on survival in these patients.6

Hence, with this retrospective study, we hope to answer primary and secondary objectives as above mentioned for this cohort. Patient eligibility population: All patients age 18 years or more with HIV positive infection who underwent allo-HCT from 2004 to 2016 regardless of donor type or conditioning regimen or GVHD prophylaxis. Data requirements:

• CIBMTR forms required to carry out this proposed study: • HIV patients Pre-HCT Data • 100 Day Post-HCT Data • Year 1,3,5 Post-HCT Data • Post-Transplant Essential Data • Recipient Death Data

Study design: This is a retrospective study with review of CIBMTR database. Plan will be to analyze all patients with HIV that got an allo-HCT, from year 2004-2016. Variables to be evaluated include the demographics (age, gender, race, etc), disease stage at transplant, transplant characteristics (type of donor, preparative regimen, source of stem cells), outcome data including engraftment and post-transplant outcomes. We will use descriptive statistics, discuss relevant characteristics and discuss the outcomes of patients as related to the donor type. Outcome analysis: Overall survival (OS) is defined as time from HCT to last follow-up. Similarly, non-relapse mortality (NRM) will be computed from time of HCT to last known vital sign. Time-to-progression is defined time of HCT and date of disease progression. Patients who are alive and did not experience progression of disease at the last follow-up date will be censored. The Kaplan-Meier method will be used to estimate OS and DFS and the log-rank test was used to assess differences between specific groups12. NRM and time-to-progression will be determined by the cumulative incidence function using the competing risks method. The cumulative incidence of grade II-IV acute graft vs. host disease (GVHD) and chronic GVHD (cGVHD) (limited and extensive) will also be determined using the competing risks method13. The

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competing risks include disease progression and death, while those patients who do not experience GVHD or progression of disease and alive at the last follow-up will be censored. References: 1. Binnet F, Lewden C, May T, et al. Malignancy related causes of death in human immunodeficiency

virus infected patients in the era of highly active antiretroviral therapy. Cancer. 2004; 10:317-324. 2. Goedert JJ, Cote TR, Virgo P, et al. Spectrum of AIDS associated malignant disorders. Lancet. 1998;

351: 1833-1839. 3. Sutton L, Guenel P, Tanguy ML, et al. Acute myeloid leukemia in human immunodeficiency virus

infected adults: epidemiology, treatment feasibility and outcome. Br J Haematol 2001;112:900-908. 4. Krishnan A. Stem cell transplantation in HIV infected patients. Curr Opin HIV AIDS. 2009 Jan; 4(1):

11-15. 5. Alvarnas JC, Rademacher JL, Wang Y et al. Autologous hematopoietic cell transplantation ofr HIV

related lymphoma: results of the BMT CTN 0803/AMC 071 trial. Blood. 2016; 128(8):1050-1058. 6. Gupta V, Tomblyn M, Pedersen T et al. Allogeneic hematopoietic cell transplantation in HIV-positive

patients with hematological disorders: A report from the Center for International Blood and Marrow Transplant Research (CIBMTR). Biol Blood Marrow Transplant. 2009 July; 15(7): 864-871.

7. Tomonari A, Takahashi S, Shimohakamada Y, et al. Unrelated cord blood transplantation for a human immunodeficiency virus-1 seropositive patient with acute lymphoblastic leukemia. Bone Marrow Transplant 2005;36:261-262.

8. Wolf T, Rickerts V. Staszewski S. et al. First case of successful allogeneic stem cell transplantation in an HIV patient who acquired severe aplastic anemia. Haematologica 2007;92:e56-e58.

9. Kang EM, de Witte M, Malech H, et al. Nonmyeloablative conditioning followed by transplantation of genetically modified HLA-matched peripheral blood progenitor cells for hematologic malignancies in patients with acquired immunodeficiency syndrome. Blood 2002; 99:698-701.

10. Campbell P, Iland H, Gibson J, et al. Syngeneic stem cell transplantation for HIV related lymphoma. Br J Haematol 1999;105:795-798.

11. Bryant A, Milliken S. Successful reduced-intensity conditioning allogeneic HSCT for HIV related primary effusion lymphoma. Biol Blood Marrow Transplant 2008; 14:601-602.

12. Kaplan EL, M. P. " Nonparametric estimation for incomplete observations." J Am Stat Assoc 1958( 53): 457-481.

13. Prentice RL, K. J., Peterson AV "The analysis of failure times in the presence of competing risks." Jr. Biometrics 1978(34(4)): 541-554.

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Table 1. Characteristics of adult patients who underwent first ALLO transplants with negative or positive HIV, from 2008 to 2016

Characteristics of patients HIV positive

N(%) HIV negative

N(%)

Number of patients 39* 5870 Number of centers 28 28

Gender Male 34 (87) 3337 (57) Female 5 (13) 2533 (43)

Age, median(range), years 53 (25 - 66) 56 (18 - 78) Age at transplant, years

18-20 0 66 ( 1)

21-30 1 ( 3) 493 ( 8) 31-40 5 (13) 588 (10) 41-50 10 (26) 945 (16)

51-60 13 (33) 1581 (27) >60 10 (26) 2197 (37)

Disease

AML 18 (46) 2465 (42) ALL 4 (10) 687 (12) Other leukemia 2 ( 5) 246 ( 4)

CML 3 ( 8) 234 ( 4) MDS 5 (13) 1703 (29) Other acute leukemia 1 ( 3) 51 (<1)

NHL 5 (13) 461 ( 8) HL 1 ( 3) 23 (<1)

Graft type Bone Marrow 6 (15) 853 (15) Peripheral blood 30 (77) 4258 (73)

Cord blood 3 ( 8) 759 (13) Donor/recipient HLA match

Cord blood 3 ( 8) 759 (13)

HLA-identical siblings 12 (31) 1761 (30) matched related 0 30 (<1) Mismatched related, 1 mismatch 0 14 (<1)

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Characteristics of patients HIV positive

N(%) HIV negative

N(%)

Mismatched related,>=2 mismatch 1 ( 3) 248 ( 4)

Mismatched related, mismatch unknown 0 89 ( 2) 8/8 unrelated 16 (41) 2301 (39) 7/8 unrelated 6 (15) 446 ( 8)

<=6/8 unrelated 1 ( 3) 28 (<1) Unrelated (HLA match information missing)

0 194 ( 3)

Year of transplant 2008 2 ( 5) 767 (13)

2009 2 ( 5) 708 (12) 2010 3 ( 8) 461 ( 8) 2011 0 319 ( 5)

2012 2 ( 5) 337 ( 6) 2013 5 (13) 734 (13)

2014 8 (21) 915 (16) 2015 7 (18) 877 (15) 2016 10 (26) 752 (13)

Median follow-up of survivors, months 32 (3 - 91) 37 (1 - 109) *32 patients have HIV form 2048 submitted

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