Churchill Hospital [email protected] · GS06-01b Passweg JR, Zhang MJ, Rocha V, Kan F, Eapen M. Donor characteristics affecting graft failure, graft vs. host disease and survival

Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR GRAFT SOURCES & MANIPULATION Salt Lake City, Utah Friday, February 15, 2013, 12:15 pm – 2:15 pm Co-Chair: Mary Laughlin, MD, University of Virginia, Charlottesville, VA Telephone: 434-982-6406; Fax: 434-243-0064; E-mail: [email protected] Co-Chair: Daniel H. Fowler, MD, National Cancer Institute, Bethesda, MD Telephone: 301-480-4354; Fax: 301-480-4354; E-mail: [email protected] Co-Chair: Miguel-Angel Perales, MD, Memorial Sloan-Kettering Cancer Center, New

York, NY Telephone: 212-639-8682; Fax: 212-717-3500; E-mail: [email protected] Statisticians: Mei-Jie Zhang, PhD, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414-456-8375; Fax: 414-456-6530; E-mail: [email protected] Junfang Chen, MS, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414-805-0711; Fax: 414-805-0714; E-mail: [email protected] Scientific Director: Mary Eapen, MD, MS, Medical College of Wisconsin, Milwaukee, WI Telephone: 414-805-0700; Fax: 414-805-0714; E-mail: [email protected]

1. Introduction

a. Minutes of February, 2012 meeting (Attachment 1)

b. Newly appointed Co-Chair: Vanderson Rocha, MD, PhD; Churchill Hospital, Oxford, UK; Email: [email protected]

2. Accrual summary (Attachment 2)

3. Published or submitted papers

a. GS09-03 Brunstein CG, Eapen M, Ahn KW, Appelbaum FR, Ballen KK, Champlin RE, Cutler C, Kan F, Laughlin MJ, Soiffer RJ, Weisdorf DJ, Woolfrey A, Wagner JE. Reduced intensity conditioning transplantation in acute leukemia: the effect of source of unrelated donor stem cells on outcomes. Blood 119(23):5591-5598, 2012.

b. GS08-05/R04-88 Scaradavou A, Brunstein C, Eapen M, Le-Rademacher J, Barker J, Spellman S, Kan F, Laughlin MJ, Kurtzberg J, Wagner JE, Shpall EJ. Umbilical cord blood transplantation for adults with acute leukemia: impact of single vs double cord blood units on transplantation outcomes. In Press.

c. GS08-02 Alousi AM, Le-Rademacher J, Saliba RM, Appelbaum FR, Artz A, Benjamin J, Divine SM, Kan F, Laughlin MJ, Lazarus HM, Liesveld J, Perales M, Maziarz RT, Sabloff M, Waller EK, Eapen M, Champlin RE. Who is the better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer? In Press.

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Not for publication or presentation

4. Studies in progress (Attachment 3)

a. HC03-01 Graft contamination (R Champlin) Analysis b. GS05-01 UCB processing and thawing techniques on MA CB HCT

outcomes (K Ballen) Analysis

c. GS07-01 PBPC vs. BM in unrelated RIC transplants (R Champlin) Analysis

d. GS08-01 Reassessment of impact donor age on outcome after URD HCT (C Kollman)

Manuscript Preparation

e. GS09-02 Allele-level HLA-matching and outcomes after UCB transplants (M Eapen / V Rocha / S Spellman)


f. GS10-03 Outcomes using a cryopreserved adult URD graft in URD HCT (N Frey / H Lazarus)

Protocol Pending

g. GS11-01 Unrelated UCB vs. PBSC/BM for ALL in CR1/CR2 in adults (D Marks)


h. GS12-01 Stem cell dose in RIC HCT for AML, MDS and ALL (J Törlén/T Erkers/O Ringdén)

Protocol Pending

i. GS12-03 Survival after URD AML for patients ≥ 50 in CR1 (D Weisdorf/E Gluckman)

Analysis

j. SC11-02 Long-term survival after URD BM and PBPC for hematologic malignancy (M Eapen/B Logan)

Analysis

5. Future / proposed studies a. PROP 0912-03 Who is the better donor for older adult hematopoietic transplant recipients: an

older-aged sibling or unrelated double UCB? (M Laughlin/C Brunstein/J Barker) (Attachment 4) b. PROP 1112-55 Comparison of cord blood transplantation outcomes according to the inclusion of

anti-thymocyte globulin (ATG) in pre-transplant conditioning (DM Ponce/JN Barker/ MA Perales) (Attachment 5)

c. PROP 1112-67 Matching between UCB units in double UCB transplantation (C Brunstein) (Attachment 6)

d. PROP 1112-19 Cord blood unit release testing criteria and the impact on transplantation outcome (D Regan) (Attachment 7)

6. Other business

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Not for publication or presentation Attachment 1

MINUTES CIBMTR WORKING COMMITTEE FOR GRAFT SOURCES & MANIPULATION San Diego, California Thursday, February 2, 2012, 12:15 pm – 2:15 pm Co-Chair: Richard Champlin, MD, UT MD Anderson Cancer Center, Houston, TX Telephone: 713-792-3618; Fax: 713-792-4346;

E-mail: [email protected] Co-Chair: Mary Laughlin, MD, University of Virginia, Charlottesville, VA Telephone: 434-982-6406; Fax: 434-243-0064; E-mail: [email protected] Co-Chair: Daniel H. Fowler, MD, National Cancer Institute, Bethesda, MD Telephone: 301-480-4354; Fax: 301-480-4354; E-mail: [email protected] Statisticians: Mei-Jie Zhang, PhD, Medical College of Wisconsin, Milwaukee, WI Telephone: 414-456-8375; Fax: 414-456-6530; E-mail: [email protected] Tanya L. Pedersen, MPH, CIBMTR Minneapolis, MN Telephone: 612-884-8607; Fax: 612-884-8661; E-mail: [email protected] Scientific Director: Mary Eapen, MD, MS, Medical College of Wisconsin, Milwaukee, WI Telephone: 414-805-0700; Fax: 414-805-0714; E-mail: [email protected]

1. Introduction

Richard Champlin called the meeting to order at 12:16 pm. Drs. Champlin, Laughlin, and Fowler chaired the meeting. Richard Champlin reviewed the upcoming forms revisions process. The form which collects graft manipulation and processing data (Form 2006) is scheduled to be revised this year. The form is available to review online at www.cibmtr.org. Comments and suggestions from the committee are encouraged. The comment period extends from now until March 2. Please send suggestions for revisions to Emilie Meissner at [email protected]. Joanne Kurtzberg made a motion to accept the minutes from the 2011 committee meeting. David Marks seconded. The minutes were approved as written. Mary Eapen thanked Richard Champlin for his strong leadership and guidance as Co-Chair of the committee, and welcomed incoming Co-Chair Miguel-Angel Perales, MD.

2. Accrual summary Mary Eapen briefly reviewed the accrual summary for the committee.

3. Published or submitted papers

a. GS05-02 Chu R, Brazauskas R, Kan F, Bashey A, Bredeson C, Camitta B, Chiang KY, Frangoul H, Gale RP, Gee A, George B, Goldman FD, Gross TG, Gupta V, Hale GA, Isola L, Ispizua AU, Lazarus H, Marsh J, Russell J, Sabloff M, Waller EK, Eapen M. Comparison of outcomes after transplantation of G-CSF stimulated bone marrow grafts versus bone marrow or peripheral blood

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grafts from HLA-matched sibling donors for patients with severe aplastic anemia. Biol Blood Marrow Transplant 17:1018-1024, 2011.

b. GS06-01b Passweg JR, Zhang MJ, Rocha V, Kan F, Eapen M. Donor characteristics affecting

graft failure, graft vs. host disease and survival after unrelated donor transplantation with reduced intensity conditioning for hematologic malignancies. Biol Blood Marrow Transplant 17:1869-1873, 2011.

c. GS08-03 Soiffer RJ, LeRademacher J, Ho V, Kan F, Artz A, Champlin RE, Devine S, Isola L,

Lazarus HM, Marks DI, Porter DL, Waller EK, Horowitz MM, Eapen M. Impact of immune modulation with anti-T cell antibodies on the outcome of reduced intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Blood 117:6963-6970, 2011.

d. GS06-02 Eapen M, Klein JP, Sanz GF, Spellman S, Ruggeri A, Anasetti C, Brown M, Champlin

RE, Garcia-Lopez J, Hattersely G, Koegler G, Laughlin MJ, Michel G, Nabhan S, Smith FO, Horowitz MM, Gluckman E, Rocha V. Effect of donor-recipient HLA matching at HLA A, B, C, and DRB1 on outcomes after umbilical cord transplantation for leukaemia and myelodysplastic syndrome: a retrospective analysis. Lancet Oncol 12:1214-1221, 2011.

e. GS09-03 Brunstein C, Eapen M, Ahn KW, Appelbaum F, Ballen KK, Champlin RE, Cutler C,

Kan F, Laughlin MJ, Soiffer RJ, Weisdorf DJ, Woolfrey A and Wagner JE. Reduced Intensity Conditioning (RIC) Transplantation in Acute Leukemia: the Effect of Source of Unrelated Donor Stem Cells on Outcomes. Submitted.

4. Studies in progress a. HC03-01: Prevalence of microbially contaminated hematopoietic stem cell products (RE

Champlin): The manuscript for this study is being prepared. The dataset and analysis will be updated to include recently reported cases.

b. GS05-01: Effect of cord blood processing and thawing techniques on transplant outcomes after single umbilical cord blood transplantation for acute leukemia and myelodysplastic syndromes (K Ballen): Karen Ballen presented an overview of the study design. The hypothesis is that single, myeloablative outcomes are not dependent on processing, storage, or thawing techniques. The study will compare outcomes of single UCBT using red cell vs. plasma depletion, and different thawing techniques, as well as evaluate the length of storage time on single UCBT outcomes. The study population will be restricted to US banks and US patients and include both adult and pediatric patients. The primary outcome will be neutrophil recovery. Secondary outcomes include platelet recovery, transplant-related mortality, overall and disease-free survival, post-infusion adverse events, recovery of TNC, viability of cells, CFU and sterility post thaw, and donor chimerism. Most data will be available in the NMDP’s Cord Link database, but supplemental data collection may be required. This was considered a very high priority study by the committee.

c. GS07-01: Peripheral blood vs. bone marrow for non-myeloablative stem cell transplantation (RE Champlin): Richard Champlin presented the results of this study. The objective of the study was to determine differences in GVHD or overall survival in patients with hematologic malignancy receiving reduced-intensity unrelated donor HCT using either peripheral blood (n=535; 85%) or bone marrow (n=88; 15%) grafts. Patients were transplanted between 1999 and 2007. The majority (70%) of patients had AML. 70% of donor-recipient pairs were matched at HLA-A, -B, -C, and –DRB1 using high-resolution typing, and one-third of patients were older than 50 years. Conditioning regimens included non TBI containing regimes of Bu/Mel/Cy ± Flu, and TBI

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containing regimens of 200cGY. In vivo T cell depletion was commonly used across the graft sources. GHVD prophylaxis was either CSA or FK506 based. Multivariate analysis revealed no differences between peripheral blood or bone marrow grafts on TRM, relapse, disease-free survival or mortality. Factors influencing mortality risk include: HLA mismatch, poor performance score, diagnosis of AML/MDS compared to CLL, active disease at transplantation, and GVHD prophylaxis regimen containing CSA. In a recently completed prospective NMDP study with ablative transplants, PBPC was associated with more cGVHD than BM; in this study in nonmyeloablative transplants, no difference in cGVHD was found. This issue will be further analysed to consider all the factors potentially contributing to chronic GVHD The manuscript for this study is being prepared.

d. GS08-01: Reassessment of impact of donor age on outcome after unrelated donor hematopoietic cell transplantation (HCT) (C Kollman): Mary Eapen presented the results of this study. The objective of this study was to determine whether unrelated donor age has an effect on transplant outcomes that is not explained by other donor factors such as HLA-match, graft type, ethnicity or gender, or other patient, disease and treatment factors. It is a reexamining of the earlier NMDP analysis which found a higher risk of death with older donors. 6,349 leukemia and MDS patients, transplanted between 1988 and 2006 were included. Median donor age was 36 years, and median recipient age was 37 years. Approximately 60% of donor-recipient pairs were matched at HLA-A, -B, -C, and –DRB1 using high-resolution typing. There was no a priori assumption of how to categorize donor age. Donor age categories were determined to be: 18-32 years (baseline), 33-49 years, and 50+ years. Older age increased risk of mortality and acute GVHD, but did not influence engraftment or chronic GVHD. Other donor factors that increased mortality risk included: HLA-mismatch, and ABO mismatch (both minor and major). No effect of donor ethnicity, CMV status or graft type was observed. To explain the relationship of donor age, HLA mismatch, and ABO mismatch, further analyses would have to be performed to determine a “donor risk score.” The committee was asked whether these analyses should be performed, and the vote was unanimous to conduct this analysis as a high priority.

e. GS08-02: Should an older-aged patient receive a transplant from his older-aged sibling or a young HLA-matched unrelated donor? (A Alousi / R Champlin / R Saliba): The manuscript for this study is being prepared.

f. GS08-05/R04-88: Similar outcomes after single and double umbilical cord blood transplantation for adults with acute leukemia (EJ Shpall): The manuscript for this study is being prepared.

g. GS09-02: Association between cell dose and HLA match on outcomes after UCBT (M Eapen / V Rocha / S Spellman): The protocol for this study is being developed.

h. GS10-03: Outcomes using a cryopreserved donor graft in unrelated allogeneic stem cell transplantation (N Frey / S Goldstein / H Lazarus): The protocol for this study is being developed.

i. GS11-01: The outcome of myeloablative and reduced intensity unrelated donor cord blood transplants for acute lymphoblastic leukaemia in CR1 and CR2 in adults. A comparison with unrelated donor marrow and peripheral blood transplantation (D Marks): The protocol for this study is being developed.

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5. Future / proposed studies

a. PROP 1011-03 Lack of engraftment by day 30 following umbilical cord blood transplant in children with malignant and non-malignant diseases will result in poor EFS, OS, and higher TRM compared to engraftment before day 30 (P Satwani / M Bhatia) (Attachment 4) This proposal could not be voted on since it was not presented.

b. PROP 1111-09 Role of stem cell dose in reduced-intensity conditioning transplants for

AML/MDS and ALL. (J Törlén / T Erkers / O Ringdén) Olle Ringdén presented the proposal. The aim of the study is to evaluate the role of nucleated and CD34 cell dose in RIC transplants. Outcomes to be analyzed include engraftment, graft failure, GVHD, TRM, relapse, overall and disease-free survival. Study population includes allogeneic HCT recipients with acute leukemia or MDS. The study is important since it is necessary to give an optimal cell dose to each patient but the role of cell dose in RIC transplants has not been analyzed in a large study. Suggestions from the committee include examining for a center effect, include ATG as a variable in the multivariate model, and analyze bone marrow and peripheral blood grafts separately. According to preliminary numbers, there are appear to be sufficient cases for analysis. Based on the voting results, this proposal was accepted and will proceed to protocol development.

c. PROP 1111-25 Evaluation of the long term impact of mixed donor-donor chimerism in double umbilical cord blood transplantation (D Szwajcer) David Szwajcer presented the proposal. The aim of the study is to determine if mixed donor-donor chimerism is associated with increased risk of relapse and GVHD when compared to single full donor chimerism among patients who received double umbilical cord blood transplant. The study would analyze chimerism at 90 days post-transplant (± 30 days). There was extensive discussion of the proposal. This was considered an important question, but the methods used for assessing chimerism vary among institutions and chimerism is not being consistently assessed at given timepoints. Based on the voting results, the proposal was not accepted due to lack of feasibility given the complexity of chimerism data.

d. PROP 1111-65 Investigation of the development of autoimmune hemolytic anemia in patients

with immune deficiency following allogeneic hematopoietic stem cell transplant (M McManus / M Pulsipher) Megan McManus presented the proposal. The aim of the study is to determine the influence of cord blood HCT on the development of autoimmune hemolytic anemia (AIHA) in patients with immune deficiencies. The secondary aims are to determine the incidence, risk factors and outcomes of the development of AIHA. It is important to understand the impact of AIHA on outcome because patients who develop AHIA have significantly higher rates of mortality, and longer duration of immunosuppressive therapy which leads to increased rates of infection. According to preliminary numbers, there are very few cases of AIHA identified in the database. Most cases were identified from review of the “Other, specify” fields. AIHA may be underreported as a result. Based on the results of the voting, the proposal was not accepted due to insufficient numbers.

The meeting was adjourned at 1:35 pm.

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Accrual Summary for Graft Sources and Manipulation Working Committee

Characteristics of patients reported to the CIBMTR between 1989 and 2012

Characteristics TED

N (%) Research

N (%)Number of cases 165509 73235Donor type HLA-identical sibling donor HCT 86272 30111 Bone marrow 45390 (53) 18529 (62) Peripheral blood 39712 (46) 11239 (37) Peripheral blood + bone marrow 631 (<1) 112 (<1) Umbilical cord blood 539 ( <1) 231 (<1) Identical twin donor HCT 1408 662 Bone marrow 576 (41) 307 (46) Peripheral blood 820(58) 350 (53) Peripheral blood + bone marrow 8 (<1) 2 (<1) Umbilical cord blood 4 (<1) 3 (<1) Other related donor HCT 14240 7243 Bone marrow 8647 (61) 5692 (79) Peripheral blood 5262 (37) 1453 (20) Peripheral blood + bone marrow 225 ( 2) 51 (<1) Umbilical cord blood 106 (<1) 47 (<1) Unrelated donor HCT 63589 35219 Bone marrow 28012 (44) 18224 (52) Peripheral blood 25732 (40) 10901 (31) Peripheral blood + bone marrow 146 (<1) 124(<1) Umbilical cord blood 9699 (15) 5970 (17)

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TO: Graft Sources and Manipulation Working Committee Members FROM: Mary Eapen, MD, MS, Scientific Director for the Graft Sources and Manipulation WC RE: Studies in Progress Summary HC03-01: Prevalence of microbially contaminated hematopoietic stem cell products (R Champlin): This study will examine the potential of microbially contaminated hematopoietic stem cell products to produce morbidity and mortality in transplant recipients. The study is currently under analysis. GS05-01: Effect of cord blood processing and thawing techniques on transplant outcomes after single myeloablative umbilical cord blood transplantation (K Ballen): This study will compare the clinical and graft-related outcomes of cord blood transplants using different thawing, storage, and processing methods. The study is currently under analysis. GS07-01: Peripheral blood versus bone marrow for non-myeloablative stem cell transplantation (R Champlin): This study will address the role of graft source for reduced intensity transplants in adults with acute and chronic leukemia and NHL. The study is currently under analysis. GS08-01: Reassessment of impact of donor age on outcome after unrelated donor hematopoietic cell transplantation (HCT) (C Kollman): This study will determine the effect of donor age on risk for mortality, graft-versus-host disease, and relapse after unrelated donor hematopoietic cell transplantation. The draft manuscript is being prepared. GS09-02: The effect of better HLA matching on survival after umbilical cord blood transplants (M Eapen /V Rocha /S Spellman): This study will examine the relative importance of donor-recipient allele-level matching at HLA-A, -B, -C and HLA-DRB1 on outcomes after umbilical cord blood transplantation for acute leukemia and myelodysplastic syndrome. The draft manuscript is being prepared. GS10-03: Outcomes using a cryopreserved donor graft in unrelated allogeneic HCT (N Frey /H Lazarus): This study will determine if recipients of cryopreserved unrelated donor grafts have different outcomes compared with recipients of fresh unrelated donor grafts. Protocol is pending. GS11-01: The outcome of myeloablative and reduced intensity unrelated donor cord blood transplants for ALL in CR1 and CR2 in adults. A comparison with unrelated donor marrow and peripheral blood transplantation (D Marks): This study will compare cord blood transplants against adult donor transplants to see if they do the same in outcomes. The draft manuscript is being prepared. SC11-02: Compare long-term disease-free and overall survival after unrelated donor bone marrow and peripheral blood transplants for leukemia (M Eapen/B Logan): This study will determine whether there are long-term survival differences after PBPC and BM transplantation in adults with hematologic malignancy. The study is currently under analysis.

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Study Proposal 0912-03 Study Title: Who is the better donor for older adult hematopoietic transplant recipients: an older-aged sibling or unrelated double UCB? Mary Laughlin, MD, University of Virginia Health System, Charlottesville, VA., [email protected] Claudio Brunstein, MD, University of Minnesota Medical Center, Fairview, Minneapolis, MN, [email protected] Juliet Barker, MD, Memorial Sloan Kettering Cancer Center - Adults, New York NY, [email protected] Specific Aims:

‐ To compare event free survival (EFS) and overall survival (OS) in patients with malignant hematologic disorders (AML, MDS, ALL) receiving either dual unrelated UCB or older-aged (>50 years) histocompatible sibling donors.

‐ To compare treatment related mortality at day +100 and +365 in patients with malignant hematologic disorders (AML, MDS, ALL) receiving either dual unrelated UCB or older-aged (>50 years) histocompatible sibling donors.

Scientific Justification: Recent retrospective analyses of transplant outcomes in adult patients with malignant hematologic disorders receiving older-aged (>50 years) histocompatible sibling donor (MRD) grafts vs. unrelated young adult donors (MUD’s) revealed lower overall survival, and increased treatment related mortality in recipients of unrelated young adult donor grafts. Further, these differences in OS and TRM were attributable in part to higher incidence of acute and chronic graft vs. host disease. Rates of acute GVHD grade II-IV, III-IV and chronic GVHD were higher in MUD’s by multivariate analysis (hazard ratio (HR), 1.63; 95% CI, 1.41-1.89, p<0.001; HR, 1.85; 95% CI, 1.54-2.23, p<0.001 and HR, 1.48; 95% CI, 1.29-1.70, p<0.0001, respectively) which translated into worse non-relapse mortality and over-all survival. Based on these data, the investigators indicate that preference should be for a MRD over a MUD in patients >50 years of age. Older patients are increasingly undergoing allogeneic hematopoietic transplants. Previous reports have found donor age to impact graft-versus-host disease (GVHD) rates. A relevant question is whether outcomes can be improved by use of dual unrelated umbilical cord blood grafts rather than an older- aged matched sibling. There has been a progressive increase in the age of recipients undergoing AHCT, primarily due to the use of reduced intensity and non-myeloablative preparative regimens. Patients over 50 years now represent the largest growing age group, including a marked rise in the subset of patients over 60 years. Most centers attempt to identify an HLA-matched sibling before considering an adult volunteer unrelated donor. For older-age patients, use of similarly aged sibling donor can be problematic due to the common presence of co-morbidities as well as concerns regarding the regenerative potential of stem and immune cells from older donors. Several studies have also found donor age to be a risk factor for the development of acute and chronic GVHD, with higher rates seen with the use of older donors(2-4)

Unrelated UCB partially HLA matched to the recipient at 4 of 6 class I/II loci has been shown to elicit lower incidences of gr II-IV aGVHD and cGVHD.(5, 6) A recent study in Japan compared procedure outcomes after an unrelated cord blood (UCB) unit or a related donor with a 1-antigen mismatch at the HLA-A, HLA-B or HLA-DR locus in the graft-versus-host direction (RD/1AG-MM-GVH) for patients without an HLA-matched related/unrelated donor. This was a retrospective study using national registry data on patients with leukemia or myelodysplastic syndrome who received transplantation using a single UCB (n=2288) unit or an RD/1AG-MM-GVH (n=525). These investigators found that the survival rate in the UCB group was comparable to that in the RD/1AG-MM-GVH group, although the RD/1AG-MM-GVH group with an HLA-B mismatch showed significantly higher overall and non-relapse mortality.

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Neutrophil and platelet engraftment were significantly faster, whereas the incidence of acute or chronic graft-versus-host disease (GVHD) was significantly higher in the RD/1AG-MM-GVH group. The incidence of acute or chronic GVHD in the RD/1AG-MM-GVH group with in vivo T-cell depletion was comparable to that in the UCB group, which translated into a trend toward better overall survival, regardless of the presence of an HLA-B mismatch. These investigators concluded that UCB and RD/1AG-MM-GVH are comparable for use as an alternative donor, except for RD/1AG-MM-GVH involving an HLA-B mismatch.(7) Further recent studies have included a comparison of transplant outcomes after HLA-matched sibling and unrelated donor transplantation for children with high-risk Acute Lymphoblastic Leukemia.(8) Although nonrelapse mortality was higher after transplantation of mismatched unrelated donor BM and cord blood, there were no differences in leukemia-free survival (LFS) between HLA-matched sibling and any of the unrelated donor transplantations. The 3-year probabilities of LFS were 50% after HLA-matched sibling and 44% after matched unrelated BM, and 44% after mismatched unrelated BM and 43% after cord blood transplantation. These observations support transplantation of BM or cord blood from a suitably matched unrelated donor or cord blood for patients without an HLA-matched sibling with ALL in second CR. In summary, an important question for older recipients is whether outcomes are improved with a matched sibling donor who are generally about the same age, or dual UCB unrelated donor. The goal of this study will be to answer this question in order to guide donor selection for transplant recipients over the age of 50 years. Patient Eligibility Population:

Included are patients aged 50 years and older reported to the Center for International Blood and Marrow Research and transplanted during the time period 2004 – 2011 for a hematologic malignancy. Two cohorts are included: 1) recipients of an HLA-matched transplantation with donors aged 50 years or older (MRD > 50 years) and 2) recipients of two HLA-mismatched unrelated UCB grafts.

Excluded are recipients of prior autologous and allogeneic transplants, recipients of mismatched related donor transplants and ex vivo T-cell depleted grafts

Data Requirements:

Patient-related data: - Age - Gender - Performance score

Disease-related data: ‐ Disease: ALL vs. AML vs. MDS ‐ Disease status at time of transplant: Early vs. intermediate vs. advanced ‐ Acute leukemia:

‐ AML: FAB subtype ‐ ALL: Immunophenotype

‐ WBC at diagnosis: <25 x 109/L, 25-50 x 109/L, 50-100 x 109/L, >100 x109/L ‐ Duration of CR1 (for patients beyond CR1): <6 months, 6-12 months, >12 months ‐ Time from remission to transplant (for patients in CR1): <3 months, 3-6 months, >6 months. ‐ Cytogenetics:

‐ AML: good vs. intermediate vs. poor prognosis vs. no abnormalities ‐ ALL: No abnormalities vs. hyperdiploid vs. hypodiploid/ t(9;22)/ t(4;11)/ t(8;14) vs. other

abnormalities ‐ MDS: RA/RARS vs. RAEB/RAEBt

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Transplant-related: ‐ Donor type: MRD vs. UCB ‐ Source of stem cells: bone marrow vs. peripheral blood stem cells ‐ Donor-recipient sex matching ‐ Donor-recipient CMV status (-/- vs. -/+ vs. +/- vs. +/+) ‐ Conditioning regimens: categories will be determined by the most common regimens used, RIC, Flu/Bu, Flu/Mel, Flu/Cy, Flu/Treo and NMA protocols, Flu + 2 Gy. ‐ Immunosuppression: categories will be determined by the most commonly used, for instance

CyA + MTX, tacrolimus + MTX, CyA + MMF, etc. ‐ Year of transplant

Supplemental data is not required.

Sample Requirements: To be determined by CIBMTR statistician Study Design: Patient, disease and transplant-related characteristics for the two cohorts will be compared using chi-

square statistics for categorical variables and the Kruskal-Wallis test for continuous variables. The probability of overall survival (OS) will be calculated using the Kaplan-Meier estimator. The probabilities of acute and chronic GVHD, NRM and relapse will be calculated using the

cumulative incidence estimator to accommodate competing risks. For NRM, relapse is the competing risk and for relapse, the competing risk is NRM. For hematopoietic recovery and chronic GVHD, death without the event is the competing risk. For acute GVHD, death without the event or disease recurrence prior to onset of acute GVHD is the competing risk. For analysis of OS, death from any cause is considered an event. In all analyses, data on patients without an event is censored at last follow-up.

Cox proportional hazard regression models will be constructed for acute and chronic GVHD, NRM, relapse and overall mortality. Results will be expressed as hazard ratio (HR) with 95% confidence interval (CI). Multivariate models are built using stepwise selection procedure. All variables significant at level ≤0.01 are included in the final models. Proportional-hazards assumption is tested for all variables considered in multivariate analysis. Final models are stratified by variables that failed to meet the proportional hazards assumption.

The main effect term, donor source (MRD; HLA-matched sibling donor aged ≥50 years versus UCB) will be held in all steps of model building, regardless of level of significance. First order interactions between the main effect and the other variables will be tested in multivariate models; when significant, an interaction term was built and retained in models. Other variables to be tested include: patient age (50 – 59 vs. 60 – 69 vs. ≥70 years), performance score (90 – 100 vs. ≤80), disease (acute myeloid leukemia [AML] vs. acute lymphoblastic leukemia [ALL] vs. myelodysplastic syndrome [MDS] vs. chronic myeloid leukemia [CML] vs. non-Hodgkin lymphoma [NHL] vs. chronic lymphocytic leukemia [CLL]), disease status at transplantation (remission vs. relapse), interval from diagnosis to transplantation (≤12 vs. >12 months), conditioning regimen (ablative vs. reduced intensity/non-ablative), in vivo T-cell depletion (yes vs. no), GVHD prophylaxis (cyclosporine-containing vs. tacrolimus-containing), graft source (bone marrow vs. peripheral blood progenitor cells vs. UCB), donor-recipient sex match (female donor – male recipient vs. others), donor-recipient CMV sero-status (donor/recipient negative vs. donor positive / recipient negative vs. donor negative /recipient positive vs. donor / recipient positive) and year of transplant (2001– 2004 vs. 2005 – 2009).

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References: 1. Abbott, W. G., Geursen, A., Fraser, J. D., Marbrook, J., Skinner, M. A., and Tan, P. L. (1995)

The influence of a maternal chronic hepatitis B virus infection on the repertoire of transcribed T-cell receptor beta chain variable region genes in human cord blood. Hepatology 22, 1034-1039

2. Flowers, M. E., Inamoto, Y., Carpenter, P. A., Lee, S. J., Kiem, H. P., Petersdorf, E. W., Pereira, S. E., Nash, R. A., Mielcarek, M., Fero, M. L., Warren, E. H., Sanders, J. E., Storb, R. F., Appelbaum, F. R., Storer, B. E., and Martin, P. J. (2011) Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood 117, 3214-3219

3. Kollman, C., Howe, C. W., Anasetti, C., Antin, J. H., Davies, S. M., Filipovich, A. H., Hegland, J., Kamani, N., Kernan, N. A., King, R., Ratanatharathorn, V., Weisdorf, D., and Confer, D. L. (2001) Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood 98, 2043-2051

4. Nademanee, A., Schmidt, G. M., Parker, P., Dagis, A. C., Stein, A., Snyder, D. S., O'Donnell, M., Smith, E. P., Stepan, D. E., Molina, A., and et al. (1995) The outcome of matched unrelated donor bone marrow transplantation in patients with hematologic malignancies using molecular typing for donor selection and graft-versus-host disease prophylaxis regimen of cyclosporine, methotrexate, and prednisone. Blood 86, 1228-1234

5. Spellman, S. R., Eapen, M., Logan, B. R., Mueller, C., Rubinstein, P., Setterholm, M. I., Woolfrey, A. E., Horowitz, M. M., Confer, D. L., and Hurley, C. K. (2012) A perspective on the selection of unrelated donors and cord blood units for transplantation. Blood 120, 259-265

6. Lazarus, H. M. (2012) Acute leukemia in adults: novel allogeneic transplant strategies. Hematology 17 Suppl 1, S47-51

7. Kanda, J., Ichinohe, T., Kato, S., Uchida, N., Terakura, S., Fukuda, T., Hidaka, M., Ueda, Y., Kondo, T., Taniguchi, S., Takahashi, S., Nagamura-Inoue, T., Tanaka, J., Atsuta, Y., Miyamura, K., and Kanda, Y. (2012) Unrelated cord blood transplantation vs related transplantation with HLA 1-antigen mismatch in the graft-versus-host direction. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K

8. Zhang, M. J., Davies, S. M., Camitta, B. M., Logan, B., Tiedemann, K., and Eapen, M. (2012) Comparison of Outcomes after HLA-Matched Sibling and Unrelated Donor Transplantation for Children with High-Risk Acute Lymphoblastic Leukemia. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 18, 1204-1210

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Number of patients over 50 years of age that received an allogeneic HLA-identical sibling donor or cord blood transplant for AML, ALL or MDS reported to the CIBMTR between 2004 and 2011

with research-level data available

HLA-matched SiblingsN (%)

Cord blood N (%)

Number of patients 1709 468

Disease, N (%)

ALL 163 (10) 53 (11)

AML 1167 (68) 342 (73)

MDS 379 (22) 73 (16)

Year of transplant, N (%)

200 -2007 824 (48) 104 (22)

2008-2011 885 (52) 364 (78)

Region, N (%)

United States 1341 (78) 439 (94)

Canada 29 (2) 0

Europe 168 (10) 19 (4)

Asia 82 (5) 9 (2)

Australia/New Zealand 40 (2) 1 (<1)

Mideast/Africa 26 (2) 0

Central/South America 23 (1) 0

13


Characteristics of AML, ALL, and MDS patients aged ≥ 50 who underwent first allogeneic HCT and reported to CIBMTR, 2004-2011.

Variable

HLA-matched sibling

N (%)

Cord blood

N (%)

Number of patients 1278 422

Age at Transplant, Years

50-59 788 (62) 227 (54)

60-69 455 (36) 178 (42)

70-83 35 ( 3) 17 ( 4)

Disease

AML 847 (66) 308 (73)

ALL 97 ( 8) 39 ( 9)

MDS 334 (26) 75 (18)

Conditioning regimens

Myeloablative 567 (44) 117 (28)

Non-myeloablative/RIC 711 (56) 305 (72)

Year of Transplant

2004-2005 360 (28) 23 ( 5)

2006-2007 280 (22) 72 (17)

2008-2009 409 (32) 167 (40)

2010-2011 229 (18) 160 (38)

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Study Proposal: 1112-55 Study Title: Comparison of cord blood transplantation outcomes according to the inclusion of anti-thymocyte globulin (ATG) in pre-transplant conditioning Doris M. Ponce, MD, Memorial Sloan-Kettering Cancer Center, New York, NY, [email protected] Juliet N. Barker, MBBS, Memorial Sloan-Kettering Cancer Center, New York, NY, [email protected] Miguel Angel Perales, MD, Memorial Sloan-Kettering Cancer Center, New York, NY, [email protected] Specific Aims: To compare cord blood transplantation (CBT) outcomes after myeloablative or reduced intensity/ non-myeloablative conditioning with or without the inclusion of ATG in patients with hematologic malignancies after CBT as to the following: Engraftment (neutrophil recovery; platelet recovery, donor chimerism) Acute graft-versus-host disease (GVHD) Chronic GVHD Basic measures of Immune reconstitution Epstein-Barr virus post-transplant lymphoproliferative disease Disease relapse or progression Transplant-related mortality Overall survival Progression-free survival Cause of death

Scientific Justification: In hematopoietic stem cell transplantation (HSCT) of adult donor, the inclusion of ATG after myeloablative conditioning has been associated with lower incidence and severity of chronic GVHD1,2 and reduced late mortality risk1. In contrast, after reduced intensity/ non-myeloablative conditioning, a large CIBMTR analysis demonstrated a higher relapse risk and lower disease-free survival and overall survival with the inclusion of ATG3. This has lead to a recommendation to eliminate ATG from pre-transplant conditioning at least in the reduced intensity/ non-myeloablative setting. In CBT, the inclusion of ATG is controversial. CBT recipients usually have a high risk disease and, therefore, abrogation of graft-versus-tumor effect is not desirable and the incidence of chronic GVHD has been reported low4. While MacMillan et al. demonstrated that the omission of ATG was a risk factor for grade II-IV acute GVHD5 and Ponce at el reported GVHD as the second most common cause of transplant-related mortality6, Brunstein et al. identified the inclusion of ATG associated with a higher risk of transplant-related mortality7. Therefore, the role of ATG in survival outcomes after CBT is yet to be elucidated and in the absence of randomize clinical trial, a large registry analysis is indicated to further evaluate for these questions. Patient Eligibility Population: This study will include adult patients of 0-70 years that have received CBT between 01/2005 and 12/2010 of least 4/6 donor-recipient HLA-match CB unit (either single-unit or double-unit) after a reduced intensity or myeloablative conditioning and reported to the CIBMTR. Recipients of prior allografts, non-malignant disease, leukemia in morphologic relapse or refractory disease will be excluded.

15


Continued.

Data Requirements: Utilizing data collected by CIBMTR from pre and post HSCT, 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 Weight Infectious serologies (CMV, EBV) Primary disease type (AML, ALL, CLL, MDS, NHL,

HL) Disease risk (high risk or standard) Prior autologous transplant Remission status (CR1, CR2, etc)

Transplant Specific

Transplant date Transplant date Transplant information Single or double unit CBT Preparative regimen used

Myeloablative Reduced Intensity/ non-myeloablative

GVHD prophylaxis Calcineurin inhibitor based (cyclosporin, tacrolimus) Sirolimus Corticosteroids Other ATG (rabbit, equine or none)

Graft characteristic Donor-recipient HLA match (4/6; 5/6; 6/6 HLA-match) Donor-recipient class I allele match if available Infused TNC cell dose (per unit in doubles) Infused CD34+ cell dose (per unit in doubles) Infused CD3+ cell dose (per unit in doubles)

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 For double-unit CBT recipients (initial engraftment of 1

unit vs 2 units) Graft failure (primary and secondary)

GVHD Acute GVHD (aGVHD) o Incidence of grade II-IV acute GVHD

(aGVHD) (subset evaluating grade III-IV aGVHD)

o Time to aGVHD GVHD after day 100

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Type of data

Data point Specific data

o Incidence of chronic GVHD (cGVHD) o 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

Immune reconstitution Incidence of EBV PTLD Recovery of ALC, CD3+4+, CD3+8+ T lymphocytes

Study Design: A retrospective study will be conducted utilizing CIBMTR data. Patients will be eligible for inclusion if they received CBT for the treatment of a hematologic malignancy between the years of 2005 and 2010. Patients will be subsequently excluded if the following criteria were met: 1) Prior allograft; 2) Infused TNC dose <1.5 x 107/kg. Patients will then be stratified into the study according to the use of ATG vs. non-ATG during pre-transplant conditioning. The objective of this analysis is to determine if the abrogation of ATG followed by CBT will impact rates of acute and chronic graft-versus host disease, immune reconstitution, relapse rate, transplant-related mortality, overall survival, PFS and cause of death in the described study population. Incidences of neutrophil and platelet engraftment, donor chimerism, acute and chronic GVHD and relapse will be estimated using the cumulative incidence function. The incidence of engraftment for patients who and did not receive ATG will be compared using a Gray’s test. Similarly, we will compare incidence of both grade II-IV GVHD and grade III-IV GVHD, chronic GVHD and relapse for patients who did and did not deceived ATG nor not. If ATG appears to be significantly associated with any outcome, multivariate models can be implemented to adjust for other known risk factors. PFS and OS will be estimated using Kaplan-Meier methodology, and these curves will be stratified by the use of ATG. A logrank statistics will be used to test for a difference in the survivals for the two groups. If there is any evidence ATG is associated with PFS and or overall survival, a Cox proportional hazards model will be implemented to adjust for other important known risk factors. References: 1. Bacigalupo A, Lamparelli T, Barisione G, et al. Thymoglobulin prevents chronic graft-versus-host

disease, chronic lung dysfunction, and late transplant-related mortality: long-term follow-up of a randomized trial in patients undergoing unrelated donor transplantation. Biol Blood Marrow Transplant. 2006;12(5):560-565.

2. Socie G, Schmoor C, Bethge WA, et al. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood. 2011;117(23):6375-6382.

3. Soiffer RJ, Lerademacher J, Ho V, et al. Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Blood. 2011;117(25):6963-6970.

4. Ponce DM, Gonzales AM, Lubin M, et al. Graft-versus-host disease after double-unit cord blood transplantation (DCBT) targets the gastro-intestinal tract and better engrafting unit recipient HLA-match is protective. ASH Annual Meeting Abstract. 2011;118:3044.

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5. MacMillan ML, Weisdorf DJ, Brunstein CG, et al. Acute graft-versus-host disease after unrelated donor umbilical cord blood transplantation: analysis of risk factors. Blood. 2009;113(11):2410-2415.

6. Ponce DM, Zheng J, Gonzales AM, et al. Reduced late mortality risk contributes to similar survival after double-unit cord blood transplantation compared with related and unrelated donor hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2011;17(9):1316-1326.

7. Brunstein C, Barker JN, Weisdorf DJ, et al. Umbilical cord blood transplantation after non-myeloablative conditioning: impact on transplant outcomes in 110 adults with hematological disease. Blood. 2007;110(8):3064-3070.

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Characteristics of AML, ALL, MDS, CLL, NHL and HL patients who underwent first allogeneic UCB transplant with Myeloablative conditioning regimen and report to CIBMTR, 2007 - 2011

Variable

ATG

N (%)

No-ATG

N (%)

Number of patients


606 896

<10 317 (52) 268 (30)

10-19 155 (26) 199 (22)

20-29 38 ( 6) 123 (14)

30-39 26 ( 4) 107 (12)

40-49 28 ( 5) 94 (10)

50-59 26 ( 4) 81 ( 9)

60-69 16 ( 3) 24 ( 3)

Disease

AML 274 (45) 399 (45)

ALL 294 (49) 444 (50)

MDS 10 ( 2) 13 ( 1)

CLL 0 1 (<1)

NHL 28 ( 5) 37 ( 4)

HL 0 2 (<1)

Unit of UCB

Single 448 (74) 370 (41)

Double 149 (25) 523 (58)

Missing 9 ( 1) 3( <1)

Year of Transplant

2007 110 (18) 82 ( 9)

2008 131 (22) 178 (20)

2009 122 (20) 194 (22)

2010 124 (20) 206 (23)

2011 119 (20) 236 (26)

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Characteristics of AML, ALL, MDS, CLL, NHL and HL patients who underwent first allogeneic UCB transplant with reduced intensity/non-myeloablative conditioning regimen, 2007 – 2011

Variable

ATG

N (%)

No-ATG

N (%)

Number of patients


159 278

<10 18 (11) 11 ( 4)

10-19 17 (11) 10 ( 4)

20-29 12 ( 8) 23 ( 8)

30-39 16 (10) 26 ( 9)

40-49 17 (11) 44 (16)

50-59 39 (25) 71 (26)

60-69 36 (23) 83 (30)

>=70 4 ( 3) 10 ( 4)

Disease

AML 85 (53) 183 (66)

ALL 37 (23) 53 (19)

MDS 7 ( 4) 3 ( 1)

CLL 3 ( 2) 2 (<1)

NHL 22 (14) 26 ( 9)

HL 5 ( 3) 11 ( 4)

Unit of UCB

Single 33 (21) 40 (14)

Double 114 (72) 235 (85)

Missing 12 ( 8) 3 ( 1)

Year of Transplant

2007 27 (17) 12 ( 4)

2008 31 (19) 39 (14)

2009 26 (16) 69 (25)

2010 41 (26) 80 (29)

2011 34 (21) 78 (28)

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Study Proposal 1112-67 Study Title: Matching between UCB units in double UCB transplantation Claudio Brunstein, MD, University of Minnesota Medical Center, Fairview, Minneapolis, MN, [email protected] Scientific Justification: Double UCB transplant is a strategy used to overcome the cell dose limitation of UCB and allow larger adolescents and adults to proceed to transplant with this donor type. At its inception the University of Minnesota define that in selecting the double UCB graft, each unit could have at most two HLA-mismatches to the recipient and each other, not necessarily at the same loci. The broader utilization of the double UCB platform in our institutions demonstrated that in areas of very ethnically diverse population meeting the selection criteria above limited the ability of finding double UCB grafts for some patients. Thus, many center have now reduce or completely abrogate the requirement the two units match each other. The relative impact of this change in double UCB graft selection on the incidence of engraftment and risk of GVHD is largely unknown. The CIBMT is uniquely positioned to address this question as individual transplant centers follow their own established algorithm and will have only limited number of patients that deviate from their usual practice of HLA-matching between the two units. Selection Criteria: Double cord blood transplants from 2005 – 2010, for AML and ALL. Include all ages, myeloablative and reduced intensity regimens. Outcomes of Interest: Hematopoietic recovery, GVHD and early and later overall survival.

21


Characteristics of AML and ALL patients who underwent first allogeneic UCB HCT and report to CIBMTR, 2005-2010.

Variable MACN (%)

RIC/NMAN (%)

Number of patients Age at Transplant, Years

1224 370

<10 531 (43) 42 (11)10-19 288 (24) 27 ( 7)20-29 140 (11) 27 ( 7)30-39 95 ( 8) 26 ( 7)40-49 84 ( 7) 50 (14)50-59 68 ( 6) 93 (25)60-79 18 ( 1) 105 (28)

Disease AML 636 (52) 282 (76)ALL 588 (48) 88 (24)

Year of Transplant 2005-2006 309 (25) 66 (18)2007-2008 449 (37) 125 (34)

2009-2010 466 (38) 179 (48)

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Study Proposal 1112-19 Study Title: Cord blood unit release testing criteria and the impact on transplantation outcome Donna Regan, M.T., St. Louis Cord Blood Bank, St. Louis, MO, [email protected] Specific Aims: Primary: To determine the impact of umbilical cord blood (UCB) colony forming unit (CFU) testing at the time of release on transplantation outcome. Secondary: To determine potential CFU growth thresholds for release of UCB units for transplantation. Scientific Justification: During the early years of UCB transplantation (UCBTx) standards were developed to characterize the quality of the UCB units (1) and continue to be modified to this day to reflect the introduction of new technologies and processes. Currently, standards define quality through all stages of UCB manufacturing: collection, processing, storage, transport, and infusion. However, about 15-24% of recipients of an UCBTx do not achieve engraftment (2, 3). This may, among other factors, be attributable to the quality of the unit which can be negatively impacted at numerous points during manufacture (4). To identify the quality of UCB, the FDA Guidance for Industry (5) recommends the measurement of UCB potency post processing, but prior to cryopreservation. The following in vitro assays are recommended by the FDA to evaluate potency of UCB: total nucleated cell count (TNC), cell viability, and CD34 analysis. Other assays not listed in the Guidance but performed by cord blood banks include nucleated red blood cell (nRBC) count, white blood cell differential and CFU. Rubinstein et al. (6) at the New York Blood Center were the first to show the link between the results of these in vitro assays and outcomes post UCBTx. In particular, they showed that TNC/kg and total CD34 cells/kg were predictors of engraftment (7). However, more recent studies indicate CFU and CD34 viability of the highest importance when predicting engraftment (8, 9) Because cryopreservation and storage can also affect the quality of the UCB, there is evidence to suggest that the addition of post-cryopreservation quality assessment be conducted (4). The 4th edition of NetCord-FACT International Cord Blood Standards recommends an additional post-cryopreservation CFU to assess these affects (10). However, surveys conducted by the NMDP Cord Blood Advisory Group (CBAG) to determine post-cryopreservation/pre-release quality assessment practices of NMDP member cord blood banks (CBB) indicated little inter-bank consensus on the number of and type of assays performed prior to release of the UCB unit (Table 1). Of the 19 participating CBBs, 84% have established UCB unit release testing criteria. 53% perform CFU, 47% perform TNC, and 37% perform CD34 analysis. 67% perform TNC viability, while 44% perform CD34+ cell viability. A majority (86% of 14 CBBs who answered the question) of CBBs performs overall viability; however, the methodology (7AAD, trypan blue, other) varies between banks. Most CBBs (73%) assay contiguous segments but 50% do not have a validated segment thaw protocol. Of the 12 CBBs that answered the question of whether they have not released a UCB unit based on release testing results, 3 (25%) indicated in the positive. Strikingly, the range of what is considered an acceptable result, if defined at all, varied highly between CBBs for the various assays reported.

23


Table 1: UCB release testing criteria practices among NMDP network CBBs

Parameter Sample Sample Handling Acceptable

Results

Yes (%)

No (%)

Segment (%) Vial(%)

Thaw(%)

Thaw andDilute (%)

Thaw and Wash (%)

TNC 9 (47)

10 (53)

5 (56)

4 (44)

5 (63)

3 (37)

0 (0)

>50‐80%

MNC 3 (17)

15 (83)

3 (100)

0 (0)

1 (33)

2 (67)

0 (0)

>80%

CD34+ 7 (37)

12 (63)

5 (71)

2 (29)

4 (57)

2 (29)

1 (14)

>80%

Viability TNC 12 (67)

6 (33)

9 (75)

3 (25)

8 (62)

4 (31)

1 (7)

>40‐75%

Viability CD34+ 8 (44)

10 (56)

6 (75)

2 (25)

5 (56)

2 (22)

2 (22)

>80‐85%

CFU 10 (53)

9 (47)

9 (90)

1 (10)

5 (45)

5 (45)

1 (10)

growth

Other: ALDHbr 1 (6)

16 (94)

1 (100)

0 (0)

0 (0)

0 (0)

1 (100)

>0.1% CFU

It is therefore, important to study the role of post-cryopreservation UCB CFU characteristics on transplant outcomes. This study will focus on the CFU assay because post-thaw growth is indicative of overall unit suitability and approximately 50% of NMDP network CBBs perform the assay pre-release. Primary outcomes analysis will be restricted to neutrophil and platelet engraftment, and day 100 survival. This study will also attempt to define an acceptability threshold for this assay. From the results of this study, recommendations will be made in an effort to standardize UCB unit CFU release testing. Patient Eligibility Population: Patients receiving a first allogeneic myeloablative single cord blood transplantation for AML, ALL or MDS facilitated by the NMDP for which there is recipient consent for research.

24


Data Requirements: Outcomes data is available through the CIBMTR database. CFU release testing practices at the CBBs will be based captured via survey conducted by the NMDP Cord Blood Advisory Group research subcommittee. Sample Requirements: None. Study Design: The following are the variables to be analyzed:

Patient-related: - Age at transplant: group by 10-year increments - Gender: male vs female - Year of transplant

Disease related: - Diagnosis: AML vs ALL vs MDS - Disease status at transplant: early vs. intermediate vs. advanced

UCB related: - Stem cell dose / kg - CD34 cell dose / kg - Donor race: Caucasian vs. others - CBB - Validated release criteria yes/no - Release testing data - TBD

Transplant-related: - Donor-recipient sex match: M/M vs M/F vs F/M vs F/F - Donor-recipient race match - ABO incompatibility: ABO match vs Minor mismatch vs Major mismatch vs Major-minor

mismatch - HLA-matching: 6/6 vs 5/6 vs 4/6 vs less - Conditioning regimen: TBI vs no TBI

o ATG/Campath used in conditioning regimen or GVHD prophylaxis - GVHD prophylaxis: CNI + vs others - Growth factors: G-CSF vs GM-CSF vs none in 1 day pre-Tx to 7 days post-Tx

For this study, each transplanted UCB unit will be categorized into the following groups:

‐ CBB where CFU release testing is performed. ‐ CBB where CFU release testing is not performed based on the CBAG survey. The study will ‐ comparatively analyze engraftment rates along with other outcomes between these two

groups. CBBs that ‐ perform release CFU testing, but release units regardless of the results will be included in the

group that ‐ does not perform CFU release testing.

To examine CFU growth thresholds for release of UCB units for transplant a subset analysis will focus on the UCB units from CBBs where release is determined by the results of post-thaw CFU testing. This analysis will look at the colony counts of the released UCB units and attempt to determine a threshold for release based on outcomes.

25


References: 1. Fraser JK, Cairo MS, Wagner EL, McCurdy PR, Baxter-Lowe LA, Carter SL, et al. Cord Blood

Transplantation Study (COBLT): cord blood bank standard operating procedures. J Hematother. 1998;7:521 – 61.

2. Eapen M, Rocha V, Sanz G, Scaradavou A, Zhang MJ, Arcese W, et al. Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukemia: a retrospective analysis. Lancet Oncol. 2010;11:653 – 60.

3. Eapen M, Rubinstein P, Zhang MJ, Stevens C, Kurtzberg J, Scaradavou A, et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukemia: a comparison study. Lancet 2007;369:1947 – 54.

4. Guidelines for the development and validation of new potency assays for the evaluation of umbilical cord blood.

5. Center for Biologics Evaluation and Research, Rockville, MD. Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications. FDA Guidance for Industry. US Department of Health and Human Services, Food and Drug Administration; 2009. http://www.fda.gov/downloads/

6. BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM187146.pdf. Accessed date: 14 April 2010.

7. Rubinstein DB, Leblanc P, Wright DG, Guillaume T, Strotchevoi A, Boosalis M. Anti-CD34 _ Fabs generated against hematopoietic stem cells in HIV-derived combinatorial immunoglobulin library suggest antigen-selected autoantibodies. Mol Immunol. 1998;35:955 – 64.

8. Migliaccio AR, Adamson JW, Stevens CE, Dobrila NL, Carrier CM, Rubinstein P. Cell dose and speed of engraftment in placental/umbilical cord blood transplantation: graft progenitor cell content is a better predictor than nucleated cell quantity. Blood. 2000;96:2717 – 22.

9. Prasad VK, Mendizabal A, Parikh SH, Szabolcs P, Driscoll TA, Page K, et al. Unrelated donor umbilical cord blood transplantation for inherited metabolic disorders in 159 pediatric patients from a single center: infl uence of cellular composition of the graft on transplantation outcomes. Blood. 2008;112:2979 – 89.

10. Scaradavou A, Smith KM, Hawke R, Schaible A, Abboud M, Kernan NA, et al. Cord blood units with low CD34 _ cell viability have a low probability of engraftment after double unit transplantation. Biol Blood Marrow Transplant. 2010; 16:500 – 8.

11. NetCord-FACT, Omaha, NE. International Standards for Cord Blood Collection, Banking, and Release for Administration. 4th ed. FACT standard D10.5.2. NetCord-FACT; 2010.

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Documents

Churchill Hospital [email protected] · GS06-01b Passweg JR, Zhang MJ, Rocha V, Kan F, Eapen M. Donor characteristics affecting graft failure, graft vs. host disease and survival