Shin Mineishi, MD, University of Alabama at Birmingham, … · 2016. 1. 25. · Treated with...

Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR REGIMEN-RELATED TOXICITY AND SUPPORTIVE CARE Honolulu, HI Friday, February 19, 2016, 2:45 – 4:45 pm

Co-Chair: Andrew Artz, MD, MS, University of Chicago School of Medicine, Chicago, IL; Telephone: 773-834-8980; E-mail: [email protected]

Co-Chair: Alison Loren, MD, MSCE, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Telephone: 215-615-3138; E-mail: [email protected]

Co-Chair: Shin Mineishi, MD, University of Alabama at Birmingham, Birmingham, AL; Telephone: 205-975-7664; E-mail: [email protected]

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

Statistical Director: Brent Logan, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-456-8849; E-mail: [email protected]

Statistician: Xiaochun Zhu, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0649; E-mail: [email protected]

1. Introduction a. Minutes and Overview Plan from February 2015 meeting (Attachment 1)

2. Accrual summary (Attachment 2)

3. Presentations, published or submitted papers

a. RT07-01a Sorror ML, Logan BR, Zhu X, Rizzo JD, Cooke KR, McCarthy PL, Ho VT, Horowitz MM, Pasquini MC. Prospective validation of the predictive power of the hematopoietic cell transplantation comorbidity index: a Center for International Blood and Marrow Transplant Research study. Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation. 2015 Aug 1; 21(8):1479-1487.

b. RT09-01 Olsson RF, Logan BR, Chaudhury S, Zhu X, Akpek G, Bolwell BJ, Bredeson CN, Dvorak CC, Gupta V, Ho VT, Lazarus HM, Marks DI, Ringdén OTH, Pasquini MC, Schriber JR, Cooke KR. Primary graft failure after myeloablative allogeneic hematopoietic cell transplantation for hematologic malignancies. Leukemia. 2015 Aug 1; 29(8):1754-1762.

c. RT09-04/IB09-06 a) Hahn T, Sucheston-Campbell LE, Preus L, Zhu X, Hansen JA, Martin PJ, Yan L, Liu S,

Spellman S, Tritchler D, Clay A, Onel K, Pasquini M, McCarthy PL. Establishment of definitions and review process for consistent adjudication of cause-specific mortality after allogeneic unrelated-donor hematopoietic cell transplantation. Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation. 2015 Sep 1; 21(9):1679-1686.

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d. RT11-01 Chen Y-B, Lane AA, Logan BR, Zhu X, Akpek G, Aljurf MD, Artz AS, Bredeson CN, Cooke KR, Ho VT, Lazarus HM, Olsson RF, Saber W, McCarthy PL, Pasquini MC. Impact of conditioning regimen on outcomes for patients with lymphoma undergoing high-dose therapy with autologous hematopoietic cell transplantation. Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation. 2015 Jun 1; 21(6):1046-1053.

e. RT12-01 Holter-Chakrabarty JL, Pierson N, Zhang M-J, Zhu X, Akpek G, Aljurf MD, Artz AS, Baron F, Bredeson CN, Dvorak CC, Epstein RB, Lazarus HM, Olsson RF, Selby GB, Williams KM, Cooke KR, Pasquini MC, McCarthy PL. The sequence of cyclophosphamide and myeloablative total body irradiation in hematopoietic cell transplantation for patients with acute leukemia. Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation. 2015 Jul 1; 21(7):1251-1257.

f. RT10-01 Artz AS, Logan B, Zhu X, Akpek G, Bufarill RM, Gupta V, Lazarus HM, Litzow M, Loren A, Majhail N, Maziarz R, McCarthy PL, Popat U, Saber W, Spellman S, Ringden O, Wickrema A, Pasquini MC, Cooke K. The Prognostic Value of Serum C-reactive Protein (CRP), Ferritin, and Albumin prior to Allogeneic Hematopoietic Cell Transplantation for AML and MDS. Submitted.

g. RT09-04/IB09-06 b) Sucheston-Campbell LE, Preus L, McCarthy PL, Pasquini MC, Onel K, Zhu X, Spellman S, Haiman C, Stram D, Pooler L, Sheng X, Zhu Q, Yan L, Liu Q, Hu Q, Liu S, Clay A, Battaglia S, Tritchler D, Hahn T. Combined Donor and Recipient non-HLA Genotypes show Evidence of Genome- Wide Association with Transplant Related Mortality (TRM) after HLA-Matched Unrelated Donor Blood and Marrow Transplantation (URD-BMT) (DISCOVeRY- BMT study). Oral presentation at the 2015 the American Society of Hematology Conference in Orlando, FL, December 2015.

h. RT09-04/IB09-06 c) Hahn T, Preus L, McCarthy PL, Pasquini MC, Onel K, Zhu X, Spellman S, Haiman C, Stram D, Pooler L, Sheng X, Zhu Q, Yan L, Liu Q, Hu Q, Liu S, Clay A, Battaglia S, Tritchler D, Sucheston-Campbell L. Genome-Wide Association Study of Overall and Progression-Free Survival after HLA-Matched Unrelated Donor Blood and Marrow Transplantation (DISCOVeRY-BMT study). Oral presentation at the 2015 the American Society of Hematology Conference in Orlando, FL, December 2015.

i. RT09-04/IB09-06 d) Clay A, Hahn T, Preus L, Onel K, Zhu Q, Haiman C, Stram DO, Pooler L, Sheng X, Weisdorf D, Yan L, Liu Q, Hu Q, Liu S, Battaglia S, Zhu X, Block A, Sait S, Ambrosone CB, Tritchler D, Spellman S, Pasquini MC, McCarthy P, Sucheston-Campbell LE. Evidence for Heterogeneous Genetic Associations with Acute Lymphoblastic Leukemia (ALL) By Cytogenetics and Sex in High Risk Patients Treated with Matched Unrelated Donor Allogenic Blood or Marrow Transplant (URD-BMT). Poster presentation at the 2015 the American Society of Hematology Conference in Orlando, FL, December 2015.

j. RT12-03 Muffly L, Pasquini MC, Martens M, Brazauskas R, Zhu X, Adekola K, Aljurf M, Ballen KK, Bajel A, Battiwalla M, Beitenjaneh A, Cahn JY, Carabasi M, Chen YB, Chhabra S, Ciurea S, Copelan E, D’Souza A, Edwards J, Freytes C, Fung HC, Gale RP, Giralt S, Hashmi SK, Hildebrandt G, Ho V, Jakubowski A, Lazarus H, McCarthy P, Olin R, Olsson R, Rezvani A, Rizzieri D, Seftel M, Seo S, Sorror M, Szer J, Wood WA, Artz A. Transplant in older adults: is it feasible in those 70 years and older? Oral presentation at the annual BMT Tandem Meeting, Honolulu, HI, February 2016.

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4. Studies in progress (Attachment 3) a. RT07-01b Prospective validation of the impacts of the hematopoietic cell transplantation co-morbidity

index, alone and combined with aging on hematopoietic cell transplantation outcomes (M Sorror/M Thakar) Manuscript preparation

b. RT12-03 Transplant in older adults: is it feasible in those 70 years and older? (L Muffly/A Artz) Manuscript preparation

c. RT13-01 In-hospital mortality among allogeneic hematopoietic cell transplant recipients that develop critical illness in the early post-transplantation period: a nationwide temporal trend analysis (1998 - 2010) (S Kadri/ S Hohmann) Data file preparation

d. RT14-03 Multicenter cohort identification of transplant-related risk-factors for infection, organ failure, and mortality among pediatric hematopoietic stem cell transplant patients requiring intensive care unit admission (C Dvorak/M Zinter/A Sapru) Data file preparation

e. RT15-01 Comparison of outcomes for myeloablative conditioning regimens combining busulfan with either cyclophosphamide or fludarabine (A Harris/J Levine) Data file preparation

f. RT13-02 Safety of high-dose total body irradiation followed by an allogeneic hematopoietic cell transplant for hematologic malignancies (M Sabloff) Protocol development

g. RT14-01 Trends and risk factors for infant mortality following allogeneic hematopoietic cell transplant: Case-Control study (P Satwani/S Parikh) Protocol development

h. RT14-02 Endothelial injury complications after allogeneic hemotapoietic cell transplantation (S Davies/ W Chinratanalab/S Jodele/M Ramanathan/B Laskin) Protocol development

i. RT15-02 Association of anti-epileptic medication with outcomes after conditioning with targeted busulfan followed by cyclophosphamide before allogeneic hematopoietic cell transplantation (PJ Martin/ JS McCune) Protocol development

5. Future/proposed studies a. PROP 1510-07 Prediction of outcomes of patients undergoing T-cell replete haploidentical donor

transplantation using post-transplant cyclophosphamide using the HCT-CI. (M Perales) (Attachment 4) b. PROP 1511-89 Effect of BEAM dose adjustments on the outcomes of patients with lymphoma. (C

Brunstein/ J Rogosheske/ M Perales) (Attachment 5) c. PROP 1511-105 Evaluation of outcome of lung transplantation for non-infectious pulmonary

complications following allogeneic stem cell transplant. (A Saad/K Minagawa/S Mineishi) (Attachment 6) d. PROP 1511-106 Evaluation of lung toxicity following allogeneic stem cell transplant with

fludarabine/total body irradiation conditioning regimen. (A Saad/K Minagawa/Y Kanda/S Mineishi) (Attachment 7)

e. Prop 1511-57 & 1509-03 (combined) Reduced intensity conditioning compared with Myeloablative conditioning using Haploidentical Donor transplants with post-transplant Cyclophosphamide in patients with AML or MDS. (N Shah/M Kharfan-Dabaja/M Hamadani/P Hari) (Attachment 8)

Dropped proposed studies a. PROP 1508-01 The change in incidence of sinusoidal obstruction syndrome (SOS) over time and factor

analysis. Dropped due to overlap with current study RT14-01 b. PROP 1511-12 Effect of Donor Weight/BMI on Recipient Outcomes and Survival. Dropped due to overlap

with current study GV15-01 c. PROP 1511-132 Defining the changing incidence and emerging risk factors for veno-occlusive disease

(VOD/SOS)/Sinosidal obstructive syndrome (SOS) in children undergoing allogeneic hematopoietic stem cell transplantation (HSCT) in the current era. Dropped due to overlap with current studies RT14-01/RT14-02

d. PROP 1511-135 Impact of timing of drug administration on treatment related toxicity and engraftment success in allogeneic hematopoietic stem cell transplantation. Dropped due to feasibility

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6. Other Business

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Not for publication or presentation Attachment 1

MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR REGIMEN-RELATED TOXICITY AND SUPPORTIVE CARE San Diego, CA Saturday, February 14, 2015, 2:45 – 4:45 pm

Co-Chair: Philip L. McCarthy, MD, Roswell Park Cancer Institute, Buffalo, NY; Telephone: 716-845-4074; Fax: 716-845-3272; E-mail: [email protected]

Co-Chair: Andrew Artz, MD, MS, University of Chicago School of Medicine, Chicago, IL; Telephone: 773-834-8980; Fax: 773-702-3163; E-mail: [email protected]

Co-Chair: Alison Loren, MD, MSCE, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Telephone: 215-615-3138; Fax: 215-615-5887; E-mail: [email protected]

Statisticians: Brent Logan, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-456-8849; Fax: 414-955-6513; E-mail: [email protected] Xiaochun Zhu, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0649; Fax: 414-805-0714; E-mail: [email protected]

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

1. Introduction Dr. Artz announced the CIBMTR Regimen-Related Toxicity and Supportive Care Committee (RRTWC) meeting started at 2:45 pm on Saturday, February 14th, 2015. He introduced the leadership of RRTWC. Dr. Shin Mineishi was welcomed to RRTWC as the incoming chair starting from March 2015. The outgoing chair Dr. Philip L. McCarthy was acknowledged for his services from the CIBMTR. Dr. Artz explained working committee’s membership to all attendees that CIBMTR working committees are open to any individual willing to take an active role in study development and completion. All members who attend the working committee meetings during the Tandem BMT meeting are automatically added to the working committee membership.

2. Dr. McCarthy updated the members on some studies recently submitted, published or presented.

a. RT09-01 Richard F. Olsson, Brent R. Logan, Sonali Chaudhury, Xiaochun Zhu, Görgün Akpek, Brian J. Bolwell, Christopher N. Bredeson, Christopher C. Dvorak, Vikas Gupta, Vincent T. Ho, Hillard M. Lazarus, David I. Marks, Olle T.H. Ringdén, Marcelo C. Pasquini, Jeffrey R. Schriber, Kenneth R. Cooke. Primary Graft Failure after Myeloablative Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies. Submitted. Currently under review at Leukemia.

b. RT07-01a Mohamed L. Sorror, Brent R. Logan, Xiaochun Zhu, J. Douglas Rizzo, Kenneth R. Cooke, Philip L McCarthy, Vincent T. Ho, Mary M. Horowitz, and Marcelo C. Pasquini. Prospective Validation of the Predictive Power of the Hematopoietic Cell Transplantation Comorbidity Index: A CIBMTR Study. Second submission to BBMT.

c. RT11-01 Yi-Bin Chen, Andrew A. Lane Brent Logan, Xiaochun Zhu, Görgün Akpek, Mahmoud Aljurf, Andrew Artz, Christopher N. Bredeson, Kenneth R. Cooke, Vincent T. Ho, Hillard M. Lazarus, Richard Olsson, Wael Saber, Philip McCarthy, Marcelo C. Pasquini. Impact of Conditioning Regimen on

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mailto:[email protected]







Outcomes for Patients with Lymphoma Undergoing High-Dose Therapy with Autologous Hematopoietic Cell Transplantation. Accepted by BBMT (2015) right before Tandem meeting.

d. RT12-04 Hong S, Le-Rademacher J, Artz A, McCarthy PL, Logan BR, Pasquini MC. Comparison of nonmyeloablative conditioning regimens for lymphoproliferative disorders. Published BBMT 2014.

e. RT12-01 Jennifer L. Holter-Chakrabarty, Namali Pierson, Mei-Jie Zhang, Xiaochun Zhu, Görgün Akpek, Mahmoud D. Aljurf, Andrew S. Artz, Frédéric Baron, Christopher N. Bredeson, Christopher C. Dvorak, Robert B. Epstein, Hillard M. Lazarus, Richard F. Olsson, George B. Selby, Kirsten M. Williams, Kenneth R. Cooke, Marcelo C. Pasquini, and Philip L. McCarthy. The Sequence of Cyclophosphamide and Myeloablative Total Body Irradiation in Hematopoietic Cell Transplant for Patients with Acute Leukemia. Submitted. Currently under review at BBMT.

f. RT10-01 Andrew Artz, Brent Logan, Xiaochun Zhu, Gorgun Akpek, Rodrigo Martino Bufarill, Vikas Gupta, Hillard M. Lazarus, Mark Litzow, Alison Loren, Navneet Majhail, Richard Maziarz, Philip McCarthy, Udat Popat, Wael Saber, Spellman, Olle Ringden, Kenneth Cooke, Marcelo C. Pasquini. Pre-transplant C-reactive protein (CRP), ferritin and albumin as biomarkers to predict transplant related mortality (TRM) after allogeneic hematopoietic cell transplant (HCT). Presentation at ASH 2014. Currently under manuscript preparation.

3. Studies in progress

Dr. Pasquini briefly summarized the studies that were in progress but not presented. Due to several studies in manuscript stage, the activities during the second semester of 2014 were dedicated in submission and re-submission of all these manuscripts. Other studies in protocol or dataset stages were pushed for this semester.

a. RT07-01b Prospective validation of the impacts of the hematopoietic cell transplantation comorbidity index, alone and combined with aging on hematopoietic cell transplantation outcomes (M Sorror/M Thakar). The current status is manuscript preparation.

b. RT10-01 Pre-transplant C-reactive protein (CRP), ferritin and albumin as biomarkers to predict transplant related mortality (TRM) after allogeneic hematopoietic cell transplant (HCT) (A. Artz). Presentation at ASH 2014. PI is working on manuscript.

c. RT12-03 Transplant in older adults: is it feasible in those 70 years and older? (L Muffly/A Artz). The current status is protocol development.

d. RT13-01 In-hospital mortality among allogeneic hematopoietic cell transplant recipients that develop critical illness in the early post-transplantation period: a nationwide temporal trend analysis (1998 - 2010) (S Kadri/ S Hohmann). The protocol development was completed and activities were stalled during the dataset stage. This study requires data merge with UHC to obtain certain diagnosis or procedure codes that could help define a critical illness or ICU care. These data are collected by UHC. However, UHC is quality database and not necessarily built for research utilization as patients are not specifically consented. Thus after several discussions, UHC felt that they could not share this data directly with CIBMTR. One alternative is to the request through the centers directly as a supplemental data collection. The plan is to run this in two sites first in order to understand and verify this process.

e. RT13-02 Safety of high-dose total body irradiation followed by an allogeneic hematopoietic cell transplant for hematologic malignancies (M Sabloff). The current status is protocol development.

f. RT14-01 Trends and risk factors for infant mortality following allogeneic hematopoietic cell transplant: Case-Control study (P Satwani/S Parikh). The current status is protocol development.

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g. RT14-02 Endothelial injury complications after allogeneic hemotapoietic cell transplantation (S Davies/ W Chinratanalab/S Jodele/M Ramanathan/B Laskin). The current status is protocol development.

h. RT14-03 Multicenter cohort identification of transplant-related risk-factors for infection, organ failure, and mortality among pediatric hematopoietic stem cell transplant patients requiring intensive care unit admission (C Dvorak/M Zinter/A Sapru). The current status is protocol development.

4. Future/Proposed studies

Drs. Loren and McCarthy led this section. The proposals were the following:

a. PROP 1407-01 Association of anti-epileptic medication with outcomes after conditioning with targeted busulfan followed by cyclophosphamide before allogeneic hematopoietic cell transplantation. (PJ Martin/JS McCune) Dr. Martin presented the proposal. The proposal plans to evaluate the safety of using levetiracetam as a replacement for phenytoin in preventing seizures caused by busulfan when followed by CY 60 mg/kg on two successive days as the conditioning regimen before allogeneic hematopoietic cell transplantation. Safety will be evaluated primarily through measures of hepatic toxicity and secondarily through measures of non-relapse mortality, relapse or progression of malignant disease and overall survival. The study requires a center survey to determine anti-seizure prophylaxis practices and time windows. However, it would be important to understand if there are sufficient amount of centers that are still using phenytoin in order to make this study feasible. Additionally, the information related to PK as prescribed in the eligibility of this proposal might require additional information from centers. One alternative is to request PK results directly from centers. This proposal was approved by the committee.

b. PROP 1410-02 Scoring system to predict major outcomes after hematopoietic cell transplantation in elderly population. (C Ustun/D Weisdorf) Dr. Ustun presented the proposal. The proposal is 1) to develop a scoring system (SS) to predict their major outcomes for older patients receiving alloHCT for hematologic malignancy (leukemias, lymphomas, myeloma); 2) to validate this SS (training on 2/3; validation on 1/3); 3) to develop a user-friendly web-based calculator (to be used by health care providers) to predict estimated outcomes for individual patients; 4) to evaluate the differences between 60-69yo and 70+ patients; 5) to evaluate survival, TRM, relapse, acute and chronic GVHD. The main concern was the age scoring system could not be easily distinguished from other scoring systems, e.g. HCT-CI, DRI. The proposal was not approved due to low impact score from committee members voting and input from the committee leadership.

c. PROP 1411-11 Prediction of Allogeneic Hematopoietic Stem Cell Transplantation Outcomes: Development and Validation of Machine Learning Based Models. (R Shouval/A Nagler/B Savani) Dr. Shouval presented the proposal. The proposal is to 1) validate of the – Alternating Decision Tree (ADT) ML based prediction model for day 100 NRM. The model was developed on the registry of the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT); 2) develop ML based prediction models for long term allogeneic (allo) transplant related outcomes: NRM, overall survival (OS), leukemia free survival (LFS), Relapse incidence (RI); 3) establish a data driven decision support systems for allo-HSCT candidate selection, in patients with hematologic malignancies, eligible for transplantation; 4) Introduce the data mining approach as a tool for HSCT data analysis.

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http://www.ebmt.org/

http://www.ebmt.org/


Dr. Shouval explained the basic concepts to all members. Main concerns were: 1) how much effort need to clean large number of missing data; 2) although random forest was chosen appropriately for this study, it is unclear whether how much more information related to predictors of TRM this approach would provide in comparison to current standard methods. The proposal was not approved due to low impact score from committee members.

d. PROP 1411-21 A case control study of health care utilization associated with hepatic veno-occlusive disease in pediatric patients receiving hematopoietic cell transplant: a subanalysis of CIBMTR study RT14-02. (S Arnold/P Satwani)

Dr. Arnold presented the proposal. The proposal is 1) to identify outcomes of VOD management with and without defibrotide; 2) to determine HCU associated with VOD.

A member concerned that it is difficult to identify patients who got severe VOD. The proposal was not approved due to low impact score from committee members.

e. PROP 1411-50 Body Mass Index and Reduced Intensity Conditioning Hematopoietic Cell Transplantation (HCT) Regimens for Acute Myeloid Leukemia (AML) (C Yuen/SA Hopps/JH Chakrabarty) Dr. Yuen presented the proposal. The proposal is to compare differences in overall survival, nonrelapse mortality, relapse, progression, progression-free survival, acute and chronic graft- versus-host disease (GVHD) and transplant-related mortality (TRM) after hematopoietic cell transplantation with reduced-intensity conditioning regimens for Acute Myeloid Leukemia (AML) of differing weight groups. Dr. Pasquini commented the actual/adjusted weight and dosing/intend regimen intensity in the CIBMTR data collection forms. A member raised a question if the hypothesis is true how the result will change the practice of transplant. Dr. Yuen responded that either prior transplant intervention can be done by reducing body weight or alternative treatment can be considered for high risk group of patients. The proposal was not approved due to low impact score from committee members.

f. PROP 1411-63 Comparison of outcomes for myeloablative conditioning regimens combining busulfan with either cyclophosphamide or fludarabine. (A Harris/JE Levine). Dr. Harris presented the proposal. The primary aims of the proposal are: 1) to compare regimen- related toxicity (e.g., SOS, IPS, hemorrhagic cystitis) between children receiving myeloablative conditioning regimens consisting of fludarabine/busulfan and those receiving busulfan/cyclophosphamide; 2) to compare transplant-related complications (primary graft failure, acute GVHD, infections, chronic GVHD) between children receiving myeloablative conditioning regimens consisting of fludarabine/busulfan and those receiving busulfan/cyclophosphamide; 3) to compare overall outcomes (non-relapse mortality, overall survival) at 2 years post-transplant between children receiving myeloablative conditioning regimens consisting of fludarabine/busulfan and those receiving busulfan/cyclophosphamide. The second aim is to compare relapse rates for the subset of patients receiving HCT for AML in CR between children receiving myeloablative conditioning regimens consisting of fludarabine/busulfan and those receiving busulfan/cyclophosphamide. Currently 80% of pediatric busulfan-based transplants use Bu/Cy conditioning regimen. A member pointed out that more practices in Europe recommend using Flu/Bu in pediatric. Another important issue was raised related to limit the analysis to malignant disease due to the heterogeneity of the nonmalignant disease and the conditioning regimens used in this setting. The PI agreed with that approach. This proposal was approved by the committee.

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a. RT07-01b Prospective validation of the impacts of the hematopoietic cell transplantation comorbidity index, alone and combined with aging on hematopoietic cell transplantation outcomes. We anticipate finalizing manuscript, circulating to writing committee in April 2015, submitting to peer-review journal in June 2015.

b. RT10-01 Pre-transplant C-reactive protein (CRP), ferritin and albumin as biomarkers to predict

transplant related mortality (TRM) after allogeneic hematopoietic cell transplant (HCT). We anticipate finalizing manuscript, circulating to writing committee in April 2015, submitting to peer- review journal in June 2015.

c. RT12-03 Transplant in older adults: is it feasible in those 70 years and older? We will finalized data

analysis by March 2015 and prepare manuscript by June 2015.

d. RT13-01 In-hospital mortality among allogeneic hematopoietic cell transplant recipients that develop critical illness in the early post-transplantation period: a nationwide temporal trend analysis (1998 - 2010). We will finalized data analysis by March 2015 and complete analysis by June 2015.

e. RT13-02 Safety of high-dose total body irradiation followed by an allogeneic hematopoietic cell

transplant for hematologic malignancies. We will finalized data analysis by March 2015 and complete analysis by June 2015.

f. RT14-01 Trends and risk factors for infant mortality following allogeneic hematopoietic cell

transplant: Case-Control study. We will finalize protocol April 2015 and start data file preparation by June 2015.

g. RT14-02 Endothelial injury complications after allogeneic hemotapoietic cell transplantation. We will

finalize protocol April 2015 and data file by May 2015. Analysis will be in June 2015.

h. RT14-03 Multicenter cohort identification of transplant-related risk-factors for infection, organ failure, and mortality among pediatric hematopoietic stem cell transplant patients requiring intensive care unit admission. We will finalize protocol April 2015 and start data file preparation by June 2015.

i. RT15-01 (proposal 1411-63) Comparison of outcomes for myeloablative conditioning regimens

combining busulfan with either cyclophosphamide or fludarabine. We anticipate to have a draft protocol by June 2016.

j. RT15-02 (proposal 1407-01) Association of anti-epileptic medication with outcomes after

conditioning with targeted busulfan followed by cyclophosphamide before allogeneic hematopoietic cell transplantation. Propose a survey to assess antiepileptic uses by centers to assess the feasibility of this study. We anticipate to have a draft protocol by June 2016.

Working Committee Overview Plan for 2015-2016

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Alison Loren RT14-01 Trends and Risk Factors for Infant Mortality Following Allogeneic Hematopoietic Cell Transplant: Case-Control study.

RT14-02: Endothelial injury complication after allogeneic hematopoitic cell transplantation.

Philip McCarthy RT07-01b: Prospective validation of the impacts of the hematopoietic cell transplantation co-morbidity index, alone and combined with aging on hematopoietic cell transplantation outcomes.

Andrew Artz RT12-03 Transplant in older adults: is it feasible in those 70 years and older?

RT14-03 Multicenter cohort identification of transplant-related risk- factors for infection, organ failure, and mortality among pediatric hematopoietic stem cell transplant patients requiring intensive care unit admission

Shin Mineishi RT13-02 Safety of high-dose total body irradiation followed by an allogeneic hematopoietic cell transplant for hematologic malignancies.

RT15-01 Comparison of outcomes for myeloablative conditioning regimens combining busulfan with either cyclophosphamide or fludarabine.

Marcelo Pasquini RT13-01: In-hospital mortality among allogeneic hematopoietic stem cell transplant recipients that develop critical illness in the early post- transplantation period - a nationwide temporal trend analysis

RT15-02 Association of anti-epileptic medication with outcomes after conditioning with targeted busulfan followed by cyclophosphamide before allogeneic hematopoietic cell transplantation.

Oversight Assignments for Working Committee Leadership (March 2015)

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Accrual Summary for the Regimen-Related Toxicity and Supportive Care Working Committee

Characteristics of recipients of autologous transplant reported to the CIBMTR between 2000 and 2015 in research retrieval

Characteristics of patients Research AUTO TX Number of patients 17657 Number of centers 322 Age, median (range), years 55 (<1 - 83) Sex

Male 10569 (60) Female 7088 (40)

Disease AML 704 ( 4) ALL 63 (<1) Other leukemia 39 (<1) CML 13 (<1) MDS/MPS 36 (<1) NHL 4753 (27) HD 1568 ( 9) PCD/MM 8760 (50) Other Malignancies 1609 ( 9) SAA 5 (<1) Inherited abnormalities erythrocyte differention or function 2 (<1) SCID and other immune system disorders 7 (<1) Histiocytic disorders 1 (<1) Autoimmune Diseases 89 (<1) Other, specify 8 (<1)

IPn or ARDS/IPS No 16250 (92) Yes 927 ( 5) Missing 480 ( 3)

Bronchiolitis obliterans No 2196 (12) Yes 127 (<1) Missing 15334 (87)

Pulmonary hemorrhage No 1413 ( 8) Yes 123 (<1) Missing 16121 (91)

Cryptogenic organizing pneumonia No 839 ( 5)

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Characteristics of patients Research AUTO TX Yes 28 (<1) Missing 16790 (95)

VOD/SOS No 1394 ( 8) Yes 204 ( 1) Missing 16059 (91)

Renal failure severe enough to warrant dialysis No 5088 (29) Yes 968 ( 5) Missing 11601 (66)

Year of transplant 2000-2001 2477 (14) 2002-2003 1978 (11) 2004-2005 2766 (16) 2006-2007 2668 (15) 2008-2009 3430 (19) 2010-2011 1084 ( 6) 2012-2013 1859 (11) 2014-2015 1395 ( 8)

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Characteristics of recipients of allogeneic transplant reported to the CIBMTR between 2000 and 2015 in research retrieval

Characteristics of patients Research ALLO TX Number of patients 51380 Number of centers 401 Age, median (range), years 40 (<1 - 83) Sex

Male 30157 (59) Female 21223 (41)

Disease AML 16187 (32) ALL 7666 (15) Other leukemia 1520 ( 3) CML 3804 ( 7) MDS/MPS 7385 (14) NHL 4541 ( 9) HD 830 ( 2) PCD/MM 1242 ( 2) Other Malignancies 371 (<1) SAA 2610 ( 5) Inherited abnormalities erythrocyte differention or function 2117 ( 4) SCID and other immune system disorders 1557 ( 3) Inherited abnormalities of platelets 75 (<1) Inherited disorders of metabolism 851 ( 2) Histiocytic disorders 513 (<1) Autoimmune Diseases 40 (<1) Other, specify 71 (<1)

IPn or ARDS/IPS No 43274 (84) Yes 7270 (14) Missing 836 ( 2)

Bronchiolitis obliterans No 16227 (32) Yes 1487 ( 3) Missing 33666 (66)

Pulmonary hemorrhage No 5277 (10) Yes 1269 ( 2) Missing 44834 (87)

Cryptogenic organizing pneumonia No 3321 ( 6)

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Characteristics of patients Research ALLO TX Yes 192 (<1) Missing 47867 (93)

VOD/SOS No 10182 (20) Yes 2967 ( 6) Missing 38231 (74)

Renal failure severe enough to warrant dialysis No 20943 (41) Yes 5241 (10) Missing 25196 (49)

Year of transplant 2000-2001 7135 (14) 2002-2003 7375 (14) 2004-2005 8347 (16) 2006-2007 7887 (15) 2008-2009 7571 (15) 2010-2011 3809 ( 7) 2012-2013 4798 ( 9) 2014-2015 4458 ( 9)

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TO: Regimen-Related Toxicity and Supportive Care Working Committee Members FROM: Marcelo C. Pasquini, MD, MS; Scientific Director for the Regimen-Related Toxicity and

Supportive Care Working Committee RE: Studies in Progress Summary RT07-01b: Prospective validation of the impacts of the hematopoietic cell transplantation co-morbidity index, alone and combined with aging on hematopoietic cell transplantation outcomes (M Sorror/M Thakar) This study are 1) to investigate the interaction between comorbidities, aging and the addition of age intervals to the HCT-CI to form composite scores using retrospective data collected from 6 collaborative academic institutions; 2) to validate the comorbidities ± aging scores on HCT outcomes using data from the Center for International Bone Marrow Transplantation Registry (CIBMTR). The study is in the manuscript preparation phase. RT12-03: Transplant in older adults: is it feasible in those 70 years and older? (L Muffly/A Artz) This study are 1) to describe the baseline characteristics of patients 70 years and older receiving an allogeneic hematopoietic cell transplant (HCT) reported to the CIBMTR; 2) to detail the secular trend in absolute numbers and proportion of all transplanted patients for adults 70 years and older undergoing HCT from 2000 to 2013, describe 1 year mortality rates and incidence of graft failure over time; 3) first Subset Analysis: To examine factors associated with survival outcomes post transplant in patients older than 70y with malignant disease from 2008 to 2013; 4)second Subset analysis: To assess TRM, disease relapse or progression, OS, DFS and GVHD among patients with early and intermediate acute leukemia/MDS and chemotherapy sensitive NHL at time of transplant from 2008 to 2013. Analyze factors associated with TRM and overall mortality in this second subset. The study is in the manuscript preparation phase. RT13-01: Survival from Critical Illness After Allogeneic Hematopoietic Stem Cell Transplantation – A Nationwide Temporal Trend Analysis (1998 – 2010) (S Kadri/S Hohmann) The aims are 1) to determine and trend the annual proportion of adults that develop critical illness following Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT) on the same hospitalization between 1998 and 2012; 2) to determine and trend ICU, in-hospital, 100 day, 200 day and 1 year mortality and readmission rates for each year’s cohort between 1998 and 2012 and identify predictors of mortality and short and long term survival; 3) to determine the incidence (and grade) of Acute and Chronic Graft Versus Host Disease (GVHD) following critical illness that develops in the early post Allo-HSCT period; 4) to assess the impact of graft source, donor/HLA status, underlying disease and regimen intensity on the development of critical illness and on short and long term survival following critical illness; 5) to understand the importance of clinical data points in transplantation that reflect critical illness, critical care utilization and outcomes to allow potentially valuable additions to CIBMTR data record forms. The study is data file preparation stage.

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RT14-03: Multicenter cohort identification of transplant-related risk-factors for infection, organ failure, and mortality among pediatric hematopoietic stem cell transplant patients requiring intensive care unit admission (C Dvorak/M Zinter/A Sapru) The specific aims are: 1) to identify transplant-related risk factors for PICU mortality through multivariate regression; 2) to identify transplant-related risk factors for life-threatening infections in the PICU, including sepsis, gram-positive and gram-negative bacterial infections, fungal infections, and viral infections; 3) to identify transplant-related risk factors for organ dysfunction and life-saving interventions both on PICU admission and throughout PICU stay. The study is data file preparation stage. RT15-01 Comparison of outcomes for myeloablative conditioning regimens combining busulfan with either cyclophosphamide or fludarabine (A Harris/J Levine) The specific aims are 1) to compare regimen-related toxicity (e.g., SOS, IPS, hemorrhagic cystitis) between children receiving myeloablative conditioning regimens consisting of busulfan/fludarabine and those receiving busulfan/cyclophosphamide; 2) to compare transplant-related complications (primary graft failure, acute GVHD, infections, chronic GVHD) between children receiving myeloablative conditioning regimens consisting of busulfan/fludarabine and those receiving busulfan/cyclophosphamide; 3) to compare outcomes (non-relapse mortality, overall survival) post-transplant between children receiving myeloablative conditioning regimens consisting of busulfan/fludarabine and those receiving busulfan/cyclophosphamide; 4) to compare relapse rates for the subset of patients receiving HCT for AML in CR between children receiving myeloablative conditioning regimens consisting of busulfan/fludarabine and those receiving busulfan/cyclophosphamide. The study is data file preparation stage. RT13-02: Safety of high-dose tbi followed by an allogeneic stem cell transplant for hematologic malignancies (M Sabloff) The specific aims are 1) To describe the toxicity profile of those patients receiving high dose TBI (>12Gy) compared to those who had a myeloablative transplant with TBI ≤12, with or without chemotherapy. To study if any pre BMT characteristics might have an influence on the type of toxicity in either group; 2) To compare the toxicity profile of those patients who received high dose TBI (>12Gy) with chemotherapy to those who received high dose TBI (>12Gy) without chemotherapy. To study if any pre BMT characteristics might have an influence on the type of toxicity in either group; 3) To describe the overall and progression free survival of those receiving high dose TBI (>12Gy) compared to patients who received a myeloablative transplant with TBI ≤ 12, with or without chemotherapy; 4) To describe the overall and progression free survival of those receiving high dose TBI (>12Gy) with chemotherapy to patients who received conditioning with high dose TBI (>12Gy), without chemotherapy. The study protocol is under development. RT14-01: Trends and Risk Factors for Infant Mortality Following Allogeneic Hematopoietic Cell Transplant: A Case-Control study (P Satwani/ S Parikh) The primary objectives are 1) to compare transplant related mortality in infants (<1 year old) following allogeneic hematopoietic stem cell transplant (AlloHCT) between the period of 2001-2005 and 2006-2011; 2) to compare the transplant related mortality in infants (<1 year old) vs. children >1-10 years old following AlloHCT between the period of 2001-2005 and 2006-2011. The secondary objectives are 1) to compare the incidence of day+30, +100 and 1 year TRM between two-time periods for patients <1 year at the time of start of conditioning. Measure the incidence of TRM in patients receiving AlloHCT for malignant (ALL, AML and MDS/MPS) and non-malignant diseases (SCID, HLH & other immune system disorders, metabolic disorders) between the period of 2001-2005 and 2006-2011; 2) to compare the incidence of day+30, +100 and 1 year TRM between patients <1 year vs. >1-10 years. Measure the incidence of TRM in patients receiving AlloHCT for malignant (ALL, AML and MDS/MPS) and non-malignant diseases (SCID,

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HLH & other immune system disorders, metabolic disorders) between the period of 2001-2005 and 2006-2011; 3) to calculate the incidence of acute and chronic graft versus host disease, incidence of veno-occlusive disease (VOD), pulmonary toxicity and graft failure; 4) to identify risk factors associated with transplant-related mortality in infants following AlloHCT. The study is under protocol development stage. RT14-02: Endothelial injury complications after allogeneic hemotapoietic cell transplantation (S Davies/ W Chinratanalab/S Jodele/M Ramanathan/B Laskin) The specific aims are 1) to report outcomes of children and adults who developed transplant-associated thrombotic microangiopathy (TA-TMA) after allogeneic and autologous HSCT in comparison to HCT patients without TMA; 2) to study the risk factors for VOD in the current era of reduced intensity conditioning regimens and reduced toxicity myeloablative conditioning regimens. The study is under protocol development stage. RT15-02 Association of anti-epileptic medication with outcomes after conditioning with targeted busulfan followed by cyclophosphamide before allogeneic hematopoietic cell transplantation (PJ Martin/ JS McCune) The specific aims is to evaluate the safety of using levetiracetam as a replacement for phenytoin in preventing seizures caused by high-dose busulfan (BU)when followed by high-dose cyclophosphamide (CY) 60 mg/kg on two successive days as the conditioning regimen before allogeneic hematopoietic cell transplantation. Safety will be evaluated through measures of hepatic toxicity, interstitial pneumonia, renal failure requiring dialysis, non-relapse mortality, relapse or progression of malignant disease, and overall survival. The study is under protocol development stage.

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Proposal 1510-07 Title: Prediction of outcomes of patients undergoing T-cell replete haploidentical donor transplantation using post-transplant cyclophosphamide using the HCT-CI Miguel-Angel Perales, MD, Memorial Sloan Kettering Cancer Center, [email protected] Hypothesis: The HCT-CI may help predict outcomes in patients undergoing T-cell replete haploidentical donor transplantation using post-transplant cyclophosphamide (Haplo-post-HCT-CY ), which in turn can help select appropriate patients for transplant using this approach. Specific aims: The specific aims are:

1. Assess the ability of the HCT-CI and HCT-CI/age predict outcomes in patients undergoing Haplo-post-HCT-CY.

2. General Outcomes to be examined include: 3. Engraftment (neutrophil, platelet), graft failure 4. NRM 5. acute GVHD (II-IV and II-IV) 6. chronic GVHD 7. relapse/progression 8. PFS/DFS 9. OS 10. Outcomes to be examined in correlation with HCT-CI and HCT-CI/Age: 11. NRM 12. PFS/DFS 13. OS

Scientific justification: Availability of an HLA-identical sibling (MRD) or suitably matched unrelated donor (MUD) has historically been a limiting factor in the application of allogeneic hematopoietic transplantation. Although almost all patients have an HLA-haploidentical family donor, it has only been recently with the introduction of by the Johns Hopkins group of the use of T-cell replete grafts and post-transplant cyclophosphamide (Haplo-post-HCT-CY) that this approach has yielded consistently positive outcomes (1-6). NRM rates of <10% are usual and rapid reconstitution of immunity leads to a low rate of post-transplant infections. Although there has been significant uptake in the use of Haplo-post-HCT-CY, questions remain. In particular, risk stratification of patients using this approach has not been reported. Patient selection plays a key role in transplant success. The Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), initially proposed by Sorror and colleagues,(7) has become a widely validated tool to predict outcomes in many transplant settings including children,(8) and adults undergoing allo-HCT for various diseases,(9-11) and receiving different conditioning regimens.(12) This model was initially developed to predict non-relapse mortality (NRM), although it has been proved to stratify patients for the risk of other outcomes including overall survival (OS),(9) and GVHD.(13) Additionally, Sorror et al. have recently proposed a modification of the HCT-CI, named HCT-CI/age, that adds an extra point for patients older than 40 years to the classic HCT-CI.(14) In a recent report from Kasamon et al on 271 patients aged > 50

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who underwent Haplo-post-HCT-CY with NMA conditioning, higher HCT-CI risk categories were not statistically significantly associated with greater NRM by predefined risk categories (low, intermediate, or high risk).(15) The authors did state that there was a statistically significant effect with HCT-CI score treated as a continuous variable, with an effect predominantly confined to HCT-CI scores of 5 relative to lower scores. In a second report from the same that included 372 patients older than 18 undergoing NMA Haplo-post-HCT-CY,(McCurdy Blood 2015) HCT-CI was not predictive when analyzed as predefined risk categories. The goal of the present study is to expand on this data and determine the impact of comorbidities in the setting of Haplo-post-HCT-CY, by validating the classical HCT-CI and the HCT-CI/age score in this population. Patient eligibility: Population This study will include adult patients > 18 with hematologic malignancies who received a first allogeneic using a haploidentical donor and post-transplant CY between 01/2008 and 12/2014. Inclusion criteria

• first allo-HCT between 2008 and 2014 • Age > 18 • HLA-haploidentical only • Graft manipulation with PT/Cy only • GVHD prophylaxis (tacrolimus/CSA + MMF only) – exclude ATG

Data requirements: Utilizing data collected by CIBMTR from pre and post HCT, which includes pre-transplant essential data form #2400, post-transplant essential data form #2450, chimerism studies form #2451, selective post-transplant selective data form #2455 and 100 day post-HSCT data form #2100. The parameters to be assessed are outlined in table 1 below. Table 1 Data Requirements:

Type of data Data point Specific data Patient Specific

Patient specific characteristics

Age at transplant (Date of birth) Gender Race Significant comorbidities Primary disease type (AML, ALL, CLL, MDS, NHL, HL) Disease risk (high risk or standard) Prior autologous transplant Remission status (CR1, CR2, etc) HCT-CI HCT-CI/age

Transplant Specific

Transplant date Transplant date Preparative regimen used

Myeloablative Reduced Intensity/ non-myeloablative

GVHD prophylaxis Calcineurin inhibitor based (cyclosporin, tacrolimus) Sirolimus Corticosteroids Other

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Graft characteristic Donor-recipient HLA match Outcome Measures

Engraftment Time to absolute neutrophil count >500 cells/mm3 for 3 consecutive laboratory readings Time to unsupported platelets >20 x 109 cells/L and >50 x 109

cells/L Donor-recipient chimerism Graft failure (primary and secondary)

GVHD Acute GVHD (aGVHD) Incidence of grade II-IV acute GVHD (aGVHD) (subset evaluating grade III-IV aGVHD) Time to aGVHD GVHD after day 100 Incidence of chronic GVHD (cGVHD) Severity of GVHD after day 100

Mortality Time to mortality Day 100, 6 months and 1 year mortality Treatment related mortality at 6 months and 1 year Cause of mortality

Disease relapse Incidence of disease relapse Time to disease relapse

Study design: A retrospective study will be conducted utilizing CIBMTR data. Patients will be eligible for inclusion if they are > 18 and who received a first allogeneic HCT using a haploidentical donor and post-transplant CY between 01/2008 and 12/2014 for a hematologic malignancy. The objectives of this analysis are to determine whether the HCT-CI and HCT-CI/age predict outcomes in patients undergoing Haplo-post-HCT-CY. HCT outcomes will include NRM, DFS/PFS and OS according to baseline HCT-CI and HCT-CI/Age. HCT-CI and HCT-CI/age will be analyzed as pre-defined risk categories and continuous variables. Potential Pitfalls: The main pitfall is whether the study will be powered to answer these questions with registry data. As the number of transplants using this approach has increased significantly over the past few years, we expect that we will be able to address these important questions either now or in the near future. References: 1. O'Donnell PV, Luznik L, Jones RJ, Vogelsang GB, Leffell MS, Phelps M et al. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2002; 8(7): 377-86. 2. Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M 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): 641-50. 3. Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J et al. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood 2011; 118(2): 282-8.

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4. Kasamon YL, Luznik L, Leffell MS, Kowalski J, Tsai HL, Bolanos-Meade J et al. Nonmyeloablative HLA-haploidentical bone marrow transplantation with high-dose posttransplantation cyclophosphamide: effect of HLA disparity on outcome. Biol Blood Marrow Transplant 2010; 16(4): 482-9. 5. Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK 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: results of a prospective phase II trial. Biol Blood Marrow Transplant 2012; 18(12): 1859-66. 6. Bashey A, Zhang X, Sizemore CA, Manion K, Brown S, Holland HK 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): 1310-6. 7. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005; 106(8): 2912-9. 8. Smith AR, Majhail NS, MacMillan ML, DeFor TE, Jodele S, Lehmann LE et al. Hematopoietic cell transplantation comorbidity index predicts transplantation outcomes in pediatric patients. Blood 2011; 117(9): 2728-34. 9. Sorror ML, Giralt S, Sandmaier BM, De Lima M, Shahjahan M, Maloney DG et al. Hematopoietic cell transplantation specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC experiences. Blood 2007; 110(13): 4606-13. 10. Sorror ML, Sandmaier BM, Storer BE, Maris MB, Baron F, Maloney DG et al. Comorbidity and disease status based risk stratification of outcomes among patients with acute myeloid leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation. J Clin Oncol 2007; 25(27): 4246-54. 11. Pollack SM, Steinberg SM, Odom J, Dean RM, Fowler DH, Bishop MR. Assessment of the hematopoietic cell transplantation comorbidity index in non-Hodgkin lymphoma patients receiving reduced-intensity allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2009; 15(2): 223-30. 12. Barba P, Pinana JL, Martino R, Valcarcel D, Amoros A, Sureda A et al. Comparison of two pretransplant predictive models and a flexible HCT-CI using different cut off points to determine low-, intermediate-, and high-risk groups: the flexible HCT-CI Is the best predictor of NRM and OS in a population of patients undergoing allo-RIC. Biol Blood Marrow Transplant 2010; 16(3): 413-20. 13. Sorror ML, Martin PJ, Storb RF, Bhatia S, Maziarz RT, Pulsipher MA et al. Pretransplant comorbidities predict severity of acute graft-versus-host disease and subsequent mortality. Blood 2014; 124(2): 287-95. 14. Sorror ML, Storb RF, Sandmaier BM, Maziarz RT, Pulsipher MA, Maris MB et al. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol 2014; 32(29): 3249-56. 15. Kasamon YL, Bolanos-Meade J, Prince GT, Tsai HL, McCurdy SR, Kanakry JA et al. Outcomes of Nonmyeloablative HLA-Haploidentical Blood or Marrow Transplantation With High-Dose Post-Transplantation Cyclophosphamide in Older Adults. J Clin Oncol 2015; 33(28): 3152-61.

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Characteristics of patients with age≥18 years old who received haplo-identical related first allogeneic transplant reported to the CIBMTR between 2008 and 2014

Characteristics of patients N (%)

Number of patients 363 Number of centers 57

Age, median (range), years 55 (18 - 77) 10 thru 19 8 ( 2)

20 thru 29 38 (10) 30 thru 39 37 (10) 40 thru 49 54 (15)

50 thru 59 95 (26) 60 thru 69 106 (29) ≥70 25 ( 7)

Sex Male 220 (61) Female 143 (39)

Race Caucasian 248 (68) African-American 83 (23)

Asian 16 ( 4) Pacific islander 3 (<1) Native American 1 (<1)

Unknown 12 ( 3) Ethnic groups

Caucasian, non-Hispanic 220 (61)

African-American, non-Hispanic 81 (22) Asian, non-Hispanic 16 ( 4)

Pacific islander, non-Hispanic 3 (<1) Native American, non-Hispanic 1 (<1) Hispanic, Caucasian 28 ( 8)

Hispanic, African-American 2 (<1) Unknown 12 ( 3)

Karnofsky performance score

<90% 50 (14) 90-100% 135 (37)

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Missing 178 (49) Disease

AML 170 (47) ALL 45 (12) CLL 13 ( 4)

MDS 51 (14) NHL 69 (19) HD 15 ( 4)

HCT-CI 0 119 (33) 1-2 110 (30)

≥3 134 (37) Donor-recipient sex match

MM 138 (38)

FM 82 (23) MF 79 (22) FF 64 (18)

Donor-recipient CMV status +/+ 130 (36) +/- 46 (13)

-/+ 94 (26) -/- 85 (23)

Missing 8 ( 2) Graft source

Bone marrow 232 (64)

Peripheral blood 131 (36) Conditioning regimen intensity

Myeloablative 84 (23)

RIC 41 (11) NMA 237 (65) TBD (regimens under review) 1 (<1)

GVHD prophylaxis Cyclophosphamide 239 (66) TAC + MMF +- other(s) 120 (33)

CSA + MMF +- other(s) 4 ( 1)

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Year of transplant 2008 37 (10)

2009 35 (10) 2010 20 ( 6) 2011 7 ( 2)

2012 12 ( 3) 2013 103 (28) 2014 149 (41)

Median follow-up of survivors, range, months 13 (3 - 74)

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Title: Effect of BEAM dose adjustments on the outcomes of patients with lymphoma Hypothesis: Adjustments to the dose of chemotherapy drugs in the BEAM regimen for obese patient results in lower toxicity and similar efficacy. Claudio G. Brunstein, MD University of Minnesota John Rogosheske, PharmD University of Minnesota Miguel-Angel Perales, MD Memorial Sloan Kettering Cancer Center Specific aims: By querying the transplant centers: Determine the practices being used for dose adjustment Determine the incidence of regimen related toxicity stratified by dose adjustment practices using re-hospitalization/hospitalization, number of days hospitalized (day zero to day +30), need to TPN, prevalence of neutropenic fevers as surrogates. Determine the incidence of TRM stratified by dose adjustment practices Determine overall survival at days +30, +100 and 1 yr, stratified by dose adjustment practices Justification: Guidelines for the adjustment of the dose of chemotherapy drugs based on weight and/or BMI have been recently published. However, most of these guidelines are based on standard dose chemotherapy for the treatment of hematological malignancies and solid tumors. Evidence to support chemotherapy dose adjustments in patients undergoing HCT in the context high BMI are lacking. Transplant centers tend to have uniform practice on either adjusting the dose for elevated weight and/or BMI or not. Thus, individual center data is unlikely to address our research the question above. Demonstrating that dose adjustments to BEAM chemotherapy drugs, in this case dose reduction, for patients with elevated BMI results in similar efficacy with similar or less toxicity would potentially improve the therapeutic window for patients with high BMI undergoing autologous transplant for lymphoma with BEAM conditioning regimen. Eligibility: Patients undergoing autologous transplant for lymphoma with BEAM conditioning regimen Time period to be defined after querying the data base for patient numbers Variables: Patient age, sex, weight, height, BMI, IBW, dose adjustments to chemotherapy (yes vs no, and criteria used), creatinine/dialysis, diagnosis, disease stage at transplantation, DRI, HCT-CI, previous radiation therapy, KPS, CMV serostatus, year of transplant, CD34+ cell dose, TNC, re-hospitalization/hospitalization, use of TPN, infections from day 0 to +30.

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Characteristics of patients with lymphoma who received autologous transplant and BEAM conditioning regimen reported to the CIBMTR between 2008 and 2014



Age, median (range), years 58 (18 - 79) 18 thru 19 8 (<1) 20 thru 29 65 ( 6)

30 thru 39 96 ( 9) 40 thru 49 151 (14) 50 thru 59 312 (28)

60 thru 69 387 (35) ≥70 90 ( 8)

Sex

Male 654 (59) Female 455 (41)

BMI, median (range) 28 (16 - 61)

BMI≤18.5 16 ( 1) 18.5<BMI≤25 274 (25) 25<BMI≤30 389 (35)

30<BMI≤35 254 (23) BMI>35 175 (16) Missing 1 (<1)

Karnofsky performance score <90% 284 (26) 90-100% 509 (46)

Missing 316 (28) HTC-CI

0 409 (37) 1-2 340 (31) ≥3 356 (32)

Missing 4 (<1) Disease

NHL 907 (82)

HD 202 (18)

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Graft source Bone marrow 8 (<1) Peripheral blood 1101 (99)

Year of transplant 2008 434 (39) 2009 177 (16)

2010 29 ( 3) 2011 47 ( 4) 2012 49 ( 4)

2013 192 (17) 2014 181 (16)


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Proposal 1511-105 Title: Evaluation of outcome of lung transplantation for non-infectious pulmonary complications following allogeneic stem cell transplant Ayman Saad, MD, University of Alabama at Birmingham, USA , [email protected] Kentaro Minagawa, MD, University of Alabama at Birmingham, USA, [email protected] Shin Mineishi, MD, University of Alabama at Birmingham, USA , [email protected] Hypothesis: Lung transplantation (LT) may improve survival of patients with non-infectious pulmonary complications such as bronchiolitis obliterans syndrome (BOS) following allogeneic stem cell transplant. Specific aims: Identification of the frequency of lung transplantation for non-infectious pulmonary complications after allogeneic stem cell transplant (allo HCT). Evaluation of the impact of lung transplantation on overall survival in these patients. Identification of favorable factors associated with better survival after lung transplantation. Identification of complications of lung transplantation (infections, secondary cancer, and recurrence of lung disease). Scientific justification: Non-infectious lung complication is a well-recognized complication of allo HCT.1-3 BOS, in particular, has been considered a manifestation of chronic graft versus host disease (cGVHD)4 and it is one of the most difficult complications to treat.5 BOS does not respond well to immunosuppressive therapy and disease process is typically progressive. There are reports of responsive disease to anti-inflammatory/inhaled steroid therapy6 and extracorporeal photopheresis7, however, outcome is often dismal with very poor survival. There are several other factors that can result in lung damage after allo HCT, such as prior chemotherapy (bleomycin, BCNU) or lung irradiation. Lung transplantation has been tried sporadically in some cases. A retrospective analysis of 70 cases who underwent lung transplantation (for BOS, lung fibrosis, and pulmonary hypertension) after allo HCT showed that lung transplantation was done after a median of 10 years and the median survival was 4 years, but overall long term survival was not favorable.8 We do not currently have adequate data to indicate which patients subset may benefit from lung transplantation for lung complications after allo HCT. Patient eligibility population: Study population: Patients who had allo HCT with reported non-infectious lung complications between 1995 and 2015. Variables to be described and analyzed (comparing patients who had lung transplantation versus no lung transplantation): Lung complications

• Type of lung complication • Bronchiolitis obliterans syndrome (BOS) • Cryptogenic organizing pneumonia (COP) • Idiopathic pneumonia syndrome (IPS)

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• Other non-infectious complications. • Timing of lung complication • Before day +30 • Between day +30 and +100. • After day +100 • After one year • Timing of lung transplantation • Relative to diagnosis of pulmonary complication. • Relative to allo HCT.

Patient-related: • Age at transplant. • Gender. • Race. • Body mass index. • Karnofsky performance status at HCT and at time of lung transplantation. • HCT-CI = comorbidity index. • DLCO parameters (according to the HCT-CI) at HCT and at time of lung transplantation. • Pulmonary co-morbidity (including prior pneumonia) prior to HCT.

Disease-related (baseline disease) • Diagnosis. • Disease status at transplant. • Prior chemotherapy regimens (bleomycin or BCNU versus none): Number of regimens and cycles

(if available). • Prior chest irradiation. • Prior autologous HCT. • DRI = Disease Risk Index.

HCT-related: • Year of transplant. • Graft • Type (PB, BM, cord) • CD34 cell dose. • T-cell depletion: ex-vivo or in-vivo (ATG, Alemtuzumab) • Donor • HLA matching (sibling, unrelated, haplo, cord) • Age • Gender and recipient/donor (R/D) gender matching. • CMV status and R/D matching • ABO and R/D matching. • Conditioning regimen • Intensity (myeloablative, reduced intensity, or nonmyeloablative) • Regimen used (FLU/BU, CY/TBI, etc). • TBI in conditioning regimen (yes, no) and TBI dose. • GVHD prophylaxis regimen. • Type of regimen • Post-transplant cyclophosphamide versus none.

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Outcomes measures: The following outcomes measures will be analyzed for patients who received lung transplantation versus no lung transplantation.

1. Complications after lung transplantation (infections, secondary cancer, and recurrence of lung disease). This may require additional data from the transplant centers if not collected by CIBMTR.

2. Incidence of acute and chronic GVHD: Cumulative incidence of grade II-IV acute GVHD (per consensus criteria) at day +100 and +180, with death as competing risk. One-year cumulative incidence of limited and extensive chronic GVHD. Death without GVHD, graft failure, and relapse (because immunosuppression therapy is stopped in most cases) are competing risks for GVHD.

3. CMV reactivation within one year of transplant will be summarized by the cumulative incidence estimate.

4. Non-relapse mortality (NRM): Cumulative incidence of NRM at day 100 and 1 year. NRM is defined as any death within 28 days of transplant, or death after 28 days without evidence of disease relapse/progression. Relapse and progression (after 28 days of transplant) are competing events.

5. Relapse/Progression: Cumulative incidence of disease relapse/progression at 1 and 2 years with NRM as competing event. Death without relapse is a competing risk.

6. Overall survival: time to death from any cause. Event (death due to any cause) will be summarized by a survival curve. Patients are censored at time of last contact (e.g. last follow up visit). There are no competing risks.

7. Disease-free survival: Survival without disease relapse or progression (initial disease before transplant). Relapse or progression of disease and death are events. The event is summarized by a survival curve. Those who survive without recurrence or progression are censored at last contact.

8. Primary cause of death: descriptive only. Study design: Patients who received allo HCT and developed non-infectious pulmonary complication will be analyzed as 2 groups based on whether they received lung transplantation. Patient characteristics, OS, DFS will be compared between cohort with or without lung transplant. A multivariate analysis will be done to identify factors associated with favorable outcome of lung transplantation. References: 1. Cooke KR. Acute lung injury after allogeneic stem cell transplantation: from the clinic, to the bench and back again. Pediatr Transplant 2005; 9 Suppl 7: 25-36. 2. Yoshihara S, Tateishi U, Ando T, Kunitoh H, Suyama H, Onishi Y et al. Lower incidence of Bronchiolitis obliterans in allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning compared with myeloablative conditioning. Bone marrow transplantation 2005; 35(12): 1195-1200. e-pub ahead of print 2005/04/27; doi: 10.1038/sj.bmt.1704985 3. Yoshihara S, Yanik G, Cooke KR, Mineishi S. Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic stem cell transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2007; 13(7): 749-759. e-pub ahead of print 2007/06/21; doi: 10.1016/j.bbmt.2007.05.001 4. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The

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2014 Diagnosis and Staging Working Group report. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2015; 21(3): 389-401.e381. e-pub ahead of print 2014/12/23; doi: 10.1016/j.bbmt.2014.12.001 5. Hildebrandt GC, Fazekas T, Lawitschka A, Bertz H, Greinix H, Halter J et al. Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD. Bone marrow transplantation 2011; 46(10): 1283-1295. e-pub ahead of print 2011/03/29; doi: 10.1038/bmt.2011.35 6. Norman BC, Jacobsohn DA, Williams KM, Au BK, Au MA, Lee SJ et al. Fluticasone, azithromycin and montelukast therapy in reducing corticosteroid exposure in bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: a case series of eight patients. Bone marrow transplantation 2011; 46(10): 1369-1373. e-pub ahead of print 2010/12/07; doi: 10.1038/bmt.2010.311 7. Foss FM, DiVenuti GM, Chin K, Sprague K, Grodman H, Klein A et al. Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host disease: analysis of response and survival incorporating prognostic factors. Bone marrow transplantation 2005; 35(12): 1187-1193. e-pub ahead of print 2005/04/27; doi: 10.1038/sj.bmt.1704984 8. Cheng GS, Edelman JD, Madtes DK, Martin PJ, Flowers ME. Outcomes of lung transplantation after allogeneic hematopoietic stem cell transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2014; 20(8): 1169-1175. e-pub ahead of print 2014/04/15; doi: 10.1016/j.bbmt.2014.04.008

31


Characteristics of patients with non-infectious lung complications who received first allogeneic transplant reported to the CIBMTR between 1994 and 2014



Age, median (range), years 39 (<1 - 82) ≤ 9 1200 (11)

10 thru 19 1335 (12) 20 thru 29 1361 (13) 30 thru 39 1776 (17)

40 thru 49 2285 (21) 50 thru 59 1885 (18) 60 thru 69 847 ( 8)

≥70 73 (<1) Sex

Male 6192 (58)

Female 4570 (42) Karnofsky performance score

<90% 3419 (32)

90-100% 6639 (62) Missing 704 ( 7)

Disease

AML 3101 (29) ALL 1858 (17) Other leukemia 314 ( 3)

CML 1733 (16) MDS/MPS 1435 (13)

Other acute leukemia 75 (<1) NHL 974 ( 9) HD 173 ( 2)

Plasma cell disorder/multiple myeloma 237 ( 2) Other Malignancies 48 (<1) Breast cancer 17 (<1)

SAA 374 ( 3) Inherit.abnorm.erythrocyte diff-funct. 169 ( 2) SCID & oth immune system disorders 208 ( 2)

32



Inherit disorder of metabolism 41 (<1)

Histiocytic disorders 5 (<1) Donor type

Cord blood 1055 (10)

HLA identical sibling 3768 (35) Twin 70 (<1)

Haplo-identical related donor 332 ( 3) HLA-matched/mismatched other relative 385 ( 4) HLA-matched unrelated 2396 (22)

HLA partially matched unrelated 1489 (14) HLA mis-matched unrelated 878 ( 8) Unrelated, HLA-match unknown 374 ( 3)

Multi donor 3 (<1) Missing 12 (<1)

Donor-recipient sex match

MM 3496 (32) FM 2518 (23) MF 2353 (22)

FF 2089 (19) Missing 306 ( 3)

Donor-recipient CMV status

+/+ 2926 (27) +/- 1195 (11) -/+ 2420 (22)

-/- 2780 (26) Missing 1441 (13)

Graft source Bone marrow 5547 (52) Peripheral blood 4160 (39)

Umbilical cord blood 1055 (10) ATG and Campath use

ATG + CAMPATH 4 (<1)

ATG alone 2901 (27) CAMPATH alone 211 ( 2) No ATG or CAMPATH 7493 (70)

Missing 153 ( 1)

33



GVHD prophylaxis

No GVHD prophylaxis 165 ( 2) Ex-vivo T-cell depletion 1159 (11) CD34 selection 205 ( 2)

Cyclophosphamide 113 ( 1) TAC + MMF +- other(s) 861 ( 8)

TAC + MTX +- other(s) 1921 (18) TAC + other(s) 259 ( 2) TAC alone 157 ( 1)

CSA + MMF +- other(s) 768 ( 7) CSA + MTX +- other(s) 4099 (38) CSA + other(s) 609 ( 6)

CSA alone 325 ( 3) Other(s) 102 (<1) Missing 19 (<1)

Year of transplant 1994-2000 5481 (51) 2001-2007 2848 (26)

2008-2014 2433 (23) Post-transplant variables

Bronchiolitis obliterans syndrome (BOS)

No 8877 (82) Yes 1871 (17) Missing 14 (<1)

Cryptogenic organizing pneumonia (COP) No 10569 (98)

Yes 179 ( 2) Missing 14 (<1)

Idiopathic pneumonia syndrome (IPS)

No 7614 (71) Yes 3136 (29) Missing 12 (<1)


34


Proposal 1511-106 Title: Evaluation of lung toxicity following allogeneic stem cell transplant with fludarabine/total body irradiation conditioning regimen Ayman Saad, MD, University of Alabama at Birmingham, USA, [email protected] Kentaro Minagawa, MD, University of Alabama at Birmingham, USA, [email protected] Yoshinobu Kanda, MD, Jichi Medical School, Japan, [email protected] Shin Mineishi, MD, University of Alabama at Birmingham, USA,[email protected] Hypothesis: The conditioning regimen of fludarabine and myeloablative total body irradiation (FLU/TBI) may increase non-infectious lung toxicity following allogeneic hematopoietic stem cell transplantation (allo HCT). Specific aims:

1. Identification of the incidence of non-infectious lung toxicity in patients receiving allo HCT following myeloablative FLU/TBI regimen.

2. Compare the risk of non-infectious lung toxicity in myeloablative FLU/TBI with a matched cohort who received other myelablative or reduced intensity regimens (e.g. FLU/BU or BU/CY).

3. Identify risk factors for development of non-infectious lung toxicity (recipient-, disease-, and transplant-related variables)

4. Identification of the impact of non-infectious lung toxicity on non-relapse mortality. 5. Identification of the impact of non-infectious lung toxicity on overall survival.

Scientific justification: Non-infectious lung complication is an uncommon complication of allo HCT.1-3 It has been postulated that parenchymal lung injury can be a manifestation of graft versus host disease.4, 5 Fludarabine has been shown to be immunosuppressive with favorable toxicity profile and thus often used for the conditioning of allo HCT. Fludarabine has been used as a replacement of Cyclophosphamide (Cy) for reduced intensity and myeloablative conditioning, such as FluBu4 (Fludarabine and myeloablative Busulfan) and has shown to be successful, i.e. FluBu4 is as effective or equally effective as BuCy and less toxic.6 For the same reason, the population which may benefit from high-dose TBI (Such as ALL) but may not quite tolerate to CyTBI or VP16-TBI (because of age or co-morbidity) may benefit from Fludarabine and high dose TBI.7, 8 For these reasons, we started to use Fludarabine and high-dose (myeloablative) TBI regimen in a prospective study at our institution. We noted that a prospective study in Japan as well as data from UAB (prospective study and retrospective data combined) showed above 20% incidence of non-infectious lung complications. These data contrasts with other published data (using fludarabine and myeloablative TBI) that did not report increased lung toxicity with this regimen.7, 9 We propose this study to identify possible correlation between the use of combined Fludarabine and myeloablative (high dose) TBI and risk of non-infectious pulmonary complications. Patient Eligibility Population: Study population: Patients who had allo HCT after myeloablative or reduced intensity conditioning regimen between 2005 and 2015. Prior autologous transplant is allowed. Exclusion criteria:

35


Second allo HCT. Patients who received more than one allo HCT will be excluded from this analysis. Variables to be described and analyzed (comparing cohort with non-infectious lung toxicity versus cohort with no toxicity): Patient-related:

• Age at transplant. • Gender. • Race. • Body mass index. • Karnofsky performance status. • HCT-CI = comorbidity index. • DLCO parameters (according to the HCT-CI). • Pulmonary co-morbidity (including prior pneumonia) prior to transplant.

Disease-related • Diagnosis. • Disease status at transplant. • Prior chemotherapy regimens (bleomycin or BCNU versus none): Number of regimens and cycles

(if available). • Prior chest irradiation. • Prior autologous HCT. • DRI = Disease Risk Index.

Transplant-related: • Year of transplant. • Time from diagnosis to transplant. • Graft • Type (PB, BM, cord) • CD34 cell dose. • T-cell depletion: ex-vivo or in-vivo (ATG, Alemtuzumab) • Donor • HLA matching (sibling, unrelated, haplo, cord) • Age • Gender and recipient/donor (R/D) gender matching. • CMV status and R/D matching • ABO and R/D matching. • Conditioning regimen • Intensity (MA, or RIC) • Regimen type • TBI in conditioning regimen • GVHD prophylaxis regimen. • Type of regimen • Post-transplant cyclophosphamide versus none.

Outcomes measures:

• The following outcomes measures will be analyzed for patients who developed non-infectious lung complication versus those who did not.

36


Lung complication will be analyzed as follows: • Type of lung complication • Bronchiolitis obliterans syndrome (BOS) • Cryptogenic organizing pneumonia (COP) • Idiopathic pneumonia syndrome (IPS) • Diffuse alveolar hemorrhage (DAH) • Others – non-infectious • Timing of lung complication • Before day +30 • Between day +30 and +100. • After day +100 • After one year 1. Incidence of acute and chronic GVHD: Cumulative incidence of grade II-IV acute GVHD (per

consensus criteria) at day +100 and +180, with death as competing risk. One-year cumulative incidence of limited and extensive chronic GVHD. Death without GVHD, graft failure, and relapse (because immunosuppression therapy is stopped in most cases) are competing risks for GVHD.

2. CMV reactivation within one year of transplant will be summarized by the cumulative incidence estimate.

3. Non-relapse mortality (NRM): Cumulative incidence of NRM at day 100 and 1 year. NRM is defined as any death within 28 days of transplant, or death after 28 days without evidence of disease relapse/progression. Relapse and progression (after 28 days of transplant) are competing events.

4. Relapse/Progression: Cumulative incidence of disease relapse/progression at 1 and 2 years with NRM as competing event. Death without relapse is a competing risk.

5. Overall survival: time to death from any cause. Event (death due to any cause) will be summarized by a survival curve. Patients are censored at time of last contact (e.g. last follow up visit). There are no competing risks.

6. Disease-free survival: Survival without disease relapse or progression. Relapse or progression of disease and death are events. The event is summarized by a survival curve. Those who survive without recurrence or progression are censored at last contact.

7. Primary cause of death: descriptive only. Study design: Patients who received myeloablative or reduced intensity allo HCT will be evaluated for the risk of non-infectious lung complications. A multivariate analysis will be done to identify risk factors for this complication. The effect of conditioning regimen will be evaluated by subgrouping patients as follows: Study Cohort A: Patients with Fludarabine and myeloablative TBI Study Cohort B: Patients with Fludarabine, other chemo (e.g. CY, VP), and myeloablative TBI Comparison Cohort A: Patients with Cyclophosphamide and TBI Comparison Cohort B: Patients with VP-16 and TBI Comparison cohort C: Patients with Fludarabine and Busulfan (myeloablative dose) Comparison cohort D: Patients with BuCy

37


References: 1. Cooke KR. Acute lung injury after allogeneic stem cell transplantation: from the clinic, to the bench and back again. Pediatr Transplant 2005; 9 Suppl 7: 25-36. 2. Yoshihara S, Tateishi U, Ando T, Kunitoh H, Suyama H, Onishi Y et al. Lower incidence of Bronchiolitis obliterans in allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning compared with myeloablative conditioning. Bone marrow transplantation 2005; 35(12): 1195-1200. e-pub ahead of print 2005/04/27; doi: 10.1038/sj.bmt.1704985 3. Yoshihara S, Yanik G, Cooke KR, Mineishi S. Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic stem cell transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2007; 13(7): 749-759. e-pub ahead of print 2007/06/21; doi: 10.1016/j.bbmt.2007.05.001 4. Bolanos-Meade J, Ioffe O, Hey JC, Vogelsang GB, Akpek G. Lymphocytic pneumonitis as the manifestation of acute graft-versus-host disease of the lung. Am J Hematol 2005; 79(2): 132-135. 5. Cooke KR, Yanik G. Acute lung injury after allogeneic stem cell transplantation: is the lung a target of acute graft-versus-host disease? Bone marrow transplantation 2004; 34(9): 753-765. 6. Andersson BS, de Lima M, Thall PF, Wang X, Couriel D, Korbling M et al. Once daily i.v. busulfan and fludarabine (i.v. Bu-Flu) compares favorably with i.v. busulfan and cyclophosphamide (i.v. BuCy2) as pretransplant conditioning therapy in AML/MDS. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2008; 14(6): 672-684. e-pub ahead of print 2008/05/21; doi: 10.1016/j.bbmt.2008.03.009 7. Kanda J, Rizzieri DA, Gasparetto C, Long GD, Chute JP, Sullivan KM et al. Adult dual umbilical cord blood transplantation using myeloablative total body irradiation (1350 cGy) and fludarabine conditioning. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2011; 17(6): 867-874. e-pub ahead of print 2010/09/28; doi: 10.1016/j.bbmt.2010.09.009 8. Stelljes M, Bornhauser M, Kroger M, Beyer J, Sauerland MC, Heinecke A et al. Conditioning with 8-Gy total body irradiation and fludarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia. Blood 2005; 106(9): 3314-3321. e-pub ahead of print 2005/07/16; doi: 10.1182/blood-2005-04-1377 9. Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK et al. Total Body Irradiation-Based Myeloablative Haploidentical Stem Cell Transplantation Is a Safe and Effective Alternative to Unrelated Donor Transplantation in Patients Without Matched Sibling Donors. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2015; 21(7): 1299-1307. e-pub ahead of print 2015/03/24; doi: 10.1016/j.bbmt.2015.03.003

38


Characteristics of patients with malignant disease who received one allogeneic transplant reported to the CIBMTR between 2004 and 2014



Age, median (range), years 48 (<1 - 82) ≤9 1985 ( 8) 10 thru 19 2307 ( 9)

20 thru 29 2560 (10) 30 thru 39 2891 (11) 40 thru 49 4350 (17)

50 thru 59 6469 (25) 60 thru 69 4772 (18) ≥70 579 ( 2)

Sex Male 15078 (58)

Female 10835 (42) Karnofsky performance score

<90% 6582 (25)

90-100% 14964 (58) Missing 4367 (17)

HCT-CI

0 8520 (33) 1-2 3816 (15) ≥3 4648 (18)

Missing 230 (<1) NA, before year 2007 8699 (34)

Disease

AML 10104 (39) ALL 4344 (17) Other leukemia 1041 ( 4)

CML 1637 ( 6) MDS/MPS 4827 (19) Other acute leukemia 250 (<1)

NHL 2599 (10) HD 489 ( 2)

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Plasma cell disorder/multiple myeloma 597 ( 2) Other Malignancies 25 (<1)

Donor type

Cord blood 3821 (15) HLA identical sibling 7056 (27) Twin 170 (<1)

Haplo-identical related donor 676 ( 3) HLA-matched/mismatched other relative 584 ( 2) HLA-matched unrelated 9274 (36)

HLA partially matched unrelated 2766 (11) HLA mis-matched unrelated 528 ( 2) Unrelated, HLA-match unknown 1014 ( 4)

Multi donor 9 (<1) Missing 15 (<1)


MM 8786 (34) FM 5156 (20) MF 5622 (22)

FF 4379 (17) Missing 1970 ( 8)

Donor-recipient CMV status +/+ 7050 (27) +/- 2554 (10)

-/+ 6362 (25) -/- 5925 (23) Missing 4022 (16)

Graft source Bone marrow 4956 (19) Peripheral blood 17136 (66)

Umbilical cord blood 3821 (15) Conditioning regimen and intensity

Flud/TBI - MAC 1611 ( 6)

Flud/TBI - RIC/NMA 2836 (11) Flud/TBI - intensity TBD 2 (<1) Other MAC 14087 (54)

Other RIC/NMA, TBD or missing 7377 (28)

40



ATG and Campath use ATG + CAMPATH 6 (<1) ATG alone 7031 (27)

CAMPATH alone 868 ( 3) No ATG or CAMPATH 17685 (68) Missing 323 ( 1)

GVHD prophylaxis No GVHD prophylaxis 490 ( 2) Ex-vivo T-cell depletion 471 ( 2)

CD34 selection 526 ( 2) Cyclophosphamide 512 ( 2) TAC + MMF +- other(s) 4092 (16)

TAC + MTX +- other(s) 8803 (34) TAC + other(s) 1229 ( 5) TAC alone 601 ( 2)

CSA + MMF +- other(s) 3428 (13) CSA + MTX +- other(s) 4046 (16) CSA + other(s) 796 ( 3)

CSA alone 503 ( 2) Other(s) 312 ( 1)

Missing 104 (<1) Year of transplant

2004-2009 16836 (65)

2010-2014 9077 (35) Post-transplant variable

Non-infectious pulmonary abnormalities

No 19007 (73) Yes 3284 (13) Missing 3622 (14)


41


Combined Proposal 1511-57 & 1509-03 Study Title: Reduced intensity conditioning compared with Myeloablative conditioning using Haploidentical Donor transplants with post-transplant Cyclophosphamide in patients with AML or MDS Nirav N. Shah MD, MSHP, Medical College of Wisconsin, [email protected] Mohamed A. Kharfan-Dabaja, MD, FACP, H. Lee Moffitt Cancer Center and Research Institute,

[email protected] Mehdi Hamadani, MD, Medical College of Wisconsin, [email protected] Parameswaran Hari, MD MS, Medical College of Wisconsin, [email protected] Hypothesis: We hypothesize that patients with AML/MDS receiving haploidentical grafts will have better relapse free and overall survival with myeloablative conditioning regimens compared to when using reduced intensity conditioning. Additionally, we hypothesize that reduced intensity conditioned haplo graft recipients will have lower non-relapse mortality related mortality (NRM) among older patients and those with higher HCT-CI scores. Specific aims: To compare outcomes of patients with AML/MDS undergoing either myeloablative or reduced intensity haploidentical transplant with post-transplant cyclophosphamide. Primary outcomes will be overall survival and progression-free survival Secondary outcomes will include NRM, incidence of acute and chronic graft versus host disease, infectious complications, rates of graft failure/rejection, and engraftment. Scientific justification: Over the past decade there has been increasing utility of alternative donor sources for the purposes of allogeneic stem cell transplantation specifically haploidentical donors and cord-blood donors [1]. New data recently published from the CIMBTR has suggested that haploidentical graft recipients with AML treated with post-transplant Cytoxan for GVHD prophylaxis have outcomes similar to those patients undergoing a matched unrelated donor allograft [2]. In this study, the conditioning intensity was not directly compared among haploidentical recipients but there was a higher non-relapse mortality (12% versus 6%) at 12 months among patients undergoing myeloablative haploidentical transplant and higher rates of relapse at 36 months in patients who received reduced intensity conditioning haplo transplant (58% versus 44%). Several groups have published prospective and retrospective outcomes of phase 2 studies using haploidentical grafts with differing conditioning intensities. There has not been a prospective or retrospective comparison of conditioning intensity in the haploidentical graft setting. Previous studies have evaluated the role of conditioning intensity in the setting of myeloid malignancies but with matched related or unrelated donor grafts. Although several studies have been performed, there has been conflicting results with regards to conditioning intensity. In one randomized control phase 3 trial, direct comparison of conditioning intensity in AML patients aged 18-60 demonstrated no difference in overall survival (OS) or non-relapse mortality (NRM) among patients with matched related or unrelated donors [3]. Supporting the above findings, a retrospective CIBMTR study evaluating conditioning intensity in AML or MDS patients who underwent allogeneic transplant from 1997 to 2004

42


found no difference in disease free survival or OS among reduced intensity and myeloablative regimens [4]. In contrast to these mentioned studies, registry data from the EBMT found that in AML patients younger than the age of 50, a reduced intensity regimen was associated with a higher probability of relapse as compared to a myeloablative regimen, although leukemia free survival was similar [5]. A study from Canada found contrasting results to the EBMT among AML/MDS patients aged 40-60 undergoing allogeneic transplant. In this report, among consecutive patients transplanted between 2002 and 2008, there was no difference in OS, event-free survival, or transplant related mortality. The main variable associated with poorer survival in this study was the disease risk profile entering transplantation [6]. As a result of the above studies, there is sufficient data that suggests that in the unrelated or related donor setting that both a reduced intensity regimen and a myeloablative regimen have efficacy in the treatment of AML/MDS. However, in the setting of alternative donors, there is far less robust data comparing outcomes by conditioning intensity. In the setting of cord blood transplants, a single center analysis evaluated conditioning intensity among patients with AML in complete remission who received an umbilical cord blood transplant between Jan 2001 and Dec 2009. In this small study, 74 patients received a reduced intensity and 45 received a myeloablative conditioning. However, in contrast to the unrelated donor/related donor setting, patients who received a myeloablative conditioning had both improved leukemia free survival and decreased relapse as compared to patients who received a reduced intensity regimen.[7] This suggests that conditioning intensity may play a larger role in patients undergoing alternative donor transplants. Thus a direct comparison of conditioning regimen intensity among haploidentical graft recipients is a question that requires further investigation. Patient eligibility population: Inclusion Criteria:

• Adults>18 years of age between 2007 and 2014 • Diagnosis of AML / MDS • Haploidentical donor PBSC or marrow grafts • Reduced intensity or myeloablative conditioning • Limited to patients using post-transplant cyclophosphamide as GVHD prophylaxis • No in vivo T-cell depleting drugs (ATG, alemtuzumab, moromonab)

Exclusion Criteria: • ≥2nd allogeneic transplantation

Data requirements:

• Data will be captured through CIBMTR collection forms Demographic/patient level variables to be analyzed Main effect:

• MAC vs. RIC Patient-related:

• Age at transplant, Continuous & decades • Gender: male or female • Karnofsky performance status at transplant: < 90% vs. ≥ 90% • HCT comorbidity index at transplant 0, 1, 2, and ≥ 3

43


Donor-related: • Age at transplant, decades • Gender: male or female

Disease-related: • Diagnosis: AML/MDS • Disease status at the time of transplant: CR1, ≥CR2, PIF, vs relapsed disease • Cytogenetics (favorable, normal, intermediate, or poor)

Transplant-related: • Time from diagnosis to haploidentical transplantation: months • Year of transplant: 2007-2011 vs. 2012-2014 • Donor-recipient CMV status: +/+ vs. +/- vs. -/+ vs. -/- • Donor-recipient gender match: male-male vs. male-female vs. female-male vs. female-female

Study Outcomes: Relapse/progression: Progressive disease or recurrences of disease would be counted as events. Treatment related death, defined as death without relapse or progression, is the competing event. Those who survive without recurrence or progression would be censored at the time of last contact. Progression-free survival (PFS): Survival without recurrence or tumor progression. Recurrence of progression of disease and death would be counted as events. Those who survive without recurrence or progression would be censored at the time of last contact. Overall survival (OS): Time to death. Death from any cause will be considered an event. Surviving patients will be censored at the time of last follow up. Acute and chronic GVHD: Occurrence of grades II, III and/or IV acute GVHD, and limited and extensive chronic GVHD. Non-relapse mortality (NRM): Death without relapse or progression, where relapse or progression would be competing risks. Those who survive without recurrence or progression would be censored at the time of last contact. Neutrophil and platelet engraftment: Neutrophil recovery defined as the first of 3 successive days with absolute neutrophil count (ANC) ≥500/µL after post-transplantation nadir. Platelet recovery defined as achieving platelet counts ≥20,000/μL for at least 7 days, unsupported by transfusion. For neutrophil and platelet recovery, death without the event is considered a competing risk. Study design: A retrospective multicenter study will be conducted utilizing CIBMTR dataset involving haploidentical grafts and post-transplant Cytoxan based GVHD prophylaxis. Patients will be eligible if they satisfied the criteria detailed in the patient eligibility section above. Patients will then be stratified according to reduced intensity or myeloablative conditioning regimens. The objective of this analysis is to compare these two approaches for the treatment of AML/ MDS in remission. Chi-square or the Wilcoxon statistic will be used to compare patient, disease and transplantation characteristics between the 2 groups for categorical or continuous variables respectively. PFS and OS will be calculated using the Kaplan-Meier estimator. For neutrophil and platelet recovery, acute GVHD and chronic GVHD, death without the event will be the competing event. For NRM, relapse/progression will be the competing event. For relapse rate, NRM will be the competing event. Data on patients without an event will be censored at last follow up.

44


For univariate analysis, the log-rank test will be used to identify factors influencing cumulative incidence and survival respectively. The association between treatment groups and outcomes will be studied with multivariate Cox regression models. P values are 2 sided and values < 0.05 will be considered significant. The other variables tested will be retained in the final multivariate model if the variable will attain the level of significance set for these analyses. Results will be expressed as hazard ratio (HR) with 95% confidence intervals (CI). Possible interactions within the treatment groups and other variables will be tested. All models will be tested regarding proportional hazard of assumptions (PHA). If the assumption will be violated, time dependent covariates will be constructed. References: 1. Pasquini, M. and Z. Wang. Current use and outcome of hematopoietic stem cell transplantation.

CIBMTR Summary Slides 2013; Available from: http://www.cibmtr.org. 2. Ciurea, S.O., et al., Haploidentical transplant with post-transplant cyclophosphamide versus

matched unrelated donor transplant for acute myeloid leukemia. Blood, 2015. 3. Bornhauser, M., et al., Reduced-intensity conditioning versus standard conditioning before

allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol, 2012. 13(10): p. 1035-44.

4. Luger, S.M., et al., Similar Outcomes Using Myeloablative Versus Reduced Intensity Allogeneic Transplant Preparative Regimens for AML or MDS. Bone Marrow Transplantation, 2012. 47(2): p. 203-211.

5. Ringdén, O., et al., Reduced Intensity Conditioning Compared With Myeloablative Conditioning Using Unrelated Donor Transplants in Patients With Acute Myeloid Leukemia. Journal of Clinical Oncology, 2009. 27(27): p. 4570-4577.

6. Khabori, M.A., et al., Impact of intensity of conditioning therapy in patients aged 40-60 years with AML/myelodysplastic syndrome undergoing allogeneic transplantation. Bone Marrow Transplant, 2011. 46(4): p. 516-22.

7. Oran, B., et al., Effect of conditioning regimen intensity on acute myeloid leukemia outcomes after umbilical cord blood transplantation. Biol Blood Marrow Transplant, 2011. 17(9): p. 1327-34.

45


Characteristics of AML/MDS patients with age≥18 years old who received haplo-identical related first

allogeneic transplant reported to the CIBMTR between 2008 and 2014

CRF TED

Characteristics of patients MA (%) RIC/NMA (%) MA (%) RIC/NMA (%)

Number of patients 41 106 132 182 Number of centers 14 29 11 28

Age, median (range), years 53 (20 - 71) 62 (19 - 76) 47 (19 - 74) 59 (19 - 76) 10 thru 19 2 ( 5) 1 (<1) 3 ( 2) 3 ( 2) 20 thru 29 6 (15) 7 ( 7) 23 (17) 5 ( 3)

30 thru 39 4 (10) 6 ( 6) 20 (15) 21 (12) 40 thru 49 8 (20) 10 ( 9) 31 (23) 27 (15) 50 thru 59 11 (27) 24 (23) 35 (27) 44 (24)

60 thru 69 9 (22) 48 (45) 19 (14) 70 (38) ≥70 1 ( 2) 10 ( 9) 1 (<1) 12 ( 7)

Sex

Male 22 (54) 63 (59) 71 (54) 107 (59) Female 19 (46) 43 (41) 61 (46) 75 (41)

Karnofsky performance score

<90% 5 (12) 12 (11) 38 (29) 46 (25) 90-100% 10 (24) 39 (37) 84 (64) 126 (69) Missing 26 (63) 55 (52) 10 ( 8) 10 ( 5)

Disease AML 32 (78) 82 (77) 112 (85) 146 (80) MDS 9 (22) 24 (23) 20 (15) 36 (20)

HCT-CI 0 9 (22) 30 (28) 54 (41) 61 (34)

1-2 13 (32) 29 (27) 41 (31) 55 (30) ≥3 19 (46) 47 (44) 37 (28) 66 (36)


MM 15 (37) 42 (40) 45 (34) 56 (31) FM 7 (17) 21 (20) 26 (20) 51 (28) MF 11 (27) 25 (24) 33 (25) 39 (21)

FF 8 (20) 18 (17) 28 (21) 36 (20)

46


CRF TED Characteristics of patients MA (%) RIC/NMA (%) MA (%) RIC/NMA (%)

Donor-recipient CMV status +/+ 15 (37) 40 (38) 56 (42) 65 (36) +/- 1 ( 2) 14 (13) 13 (10) 24 (13)

-/+ 13 (32) 27 (25) 32 (24) 46 (25) -/- 12 (29) 23 (22) 28 (21) 43 (24) Missing 0 2 ( 2) 3 ( 2) 4 ( 2)

Graft source Bone marrow 16 (39) 75 (71) 96 (73) 155 (85) Peripheral blood 25 (61) 31 (29) 36 (27) 27 (15)

GVHD prophylaxis Cyclophosphamide 41 106 132 182

Year of transplant

2008-2011 2 ( 5) 21 (20) 56 (42) 87 (48) 2012-2014 39 (95) 85 (80) 76 (58) 95 (52)

Median follow-up of survivors, range, months

12 (3 - 46) 13 (4 - 73) 34 (4 - 65) 37 (7 - 74)

47

Date post:	23-Sep-2020
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Shin Mineishi, MD, University of Alabama at Birmingham, … · 2016. 1. 25. · Treated with...

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