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A G E N D A CIBMTR WORKING COMMITTEE FOR GRAFT SOURCES & MANIPULATION San Diego, CA Thursday, February 12, 2015, 12:15 – 2:15 pm
Co-Chair: Daniel Fowler, MD, NIH-NCI Experimental Transplantation and Immunology Branch, Bethesda, MD; Telephone: 301-435-8641; 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] Co-Chair: Vanderson Rocha, MD, PhD, Churchill Hospital, Oxford, United Kingdom; Telephone: 44 1865 572326; Fax: 44 1865 235260; E-mail: [email protected] Statisticians: Mei-Jie Zhang, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-456-8375; Fax: 414-456-6513; 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, MBBS, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0700: Fax: 414-805-0714; E-mail: [email protected]
1. Introduction
a. Minutes and Overview Plan from February 2014 meeting (Attachment 1) b. Introduction of incoming Co-Chair: Asad Bashey, MD, PhD; The Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA. Email: [email protected]
2. Accrual Summary (Attachment 2)
3. Presentations, published or submitted papers
a. GS05-01 Karen K. Ballen, Brent R. Logan, Mary J. Laughlin, Wensheng He, Daniel R. Ambruso, Susan E. Armitage, Rachel L. Beddard, Deepika Bhatla, William Y.K. Hwang, Joseph E. Kiss, Gesine Koegler, Joanne Kurtzberg, Arnon Nagler, David Oh, Lawrence D. Petz, Thomas H. Price, Ralph R. Quinones, Voravit Ratanatharathorn, J. Douglas Rizzo, Kathleen Sazama, Andromachi Scaradavou, Michael W. Schuster, Leonard S. Sender, Elizabeth J. Shpall, Stephen R. Spellman, Millicent Sutton, Lee Ann Weitekamp, John R. Wingard, Mary Eapen. Effect of Cord Blood Processing on Transplant Outcomes after Single Myeloablative Umbilical Cord Blood Transplantation. Biol Blood Marrow Transplant, In press, 2015.
b. GS08-01 Craig Kollman, Stephen R. Spellman, Mei-Jie Zhang, Anna Hassebroek, Claudio Anasetti, Joseph H. Antin, Richard E. Champlin, Dennis Confer, John DiPersio, Marcelo Fernandez-Vina, Robert Hartzman, Mary M Horowitz, Carolyn K Hurley, Chatchada Karanes, Martin Maiers, Carlheinz Mueller, Michelle Setterholm, Ann Woolfrey, Neng Yu, Mary Eapen. The Effect of Donor Characteristics on Survival after Unrelated Donor Transplantation for Hematologic Malignancy. Submitted.
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c. GS13-01 Doris M. Ponce, Rodney Sparapani, Junfang Chen, Vanderson Rocha, Daniel H. Fowler, Mary Eapen, Juliet N. Barker, Migule-Angel Perales. Comparable 3-Year Disease-Free Survival Regardless of Anti-Thymocyte Globulin Inclusion in Pediatric Myeloablative Cord Blood Transplantation for Acute Lymphoblastic Leukemia. Presented at the 56th annual meeting of the American Society of
Hematology, San Francisco, CA, December 2014 (Poster presentation).
d. SC11-02b Mary Eapen, Brent R. Logan, Fredrick R. Appelbaum, Joseph H. Antin, Claudio Anasetti, Daniel R. Couriel, Junfang Chen, Richard T. Maziarz, Philip L. McCarthy, Ryotaro Nakamura, Voravit Ratanatharathorn, Ravi Vij, Richard E. Champlin. Long-Term Survival after Transplantation of Unrelated Donor Peripheral Blood or Bone Marrow Hematopoietic Cells for Hematologic Malignancy. Biol Blood Marrow Transplant. 21(1): 55-59 2015.
e. SC11-02a Mary Eapen, Brent R. Logan, Mary M. Horowitz, Xiaobo Zhong, Miguel Angel Perales, Stephanie J. Lee, Vanderson Rocha, Robert J. Soiffer, Richard E. Champlin. Bone Marrow or Peripheral Blood for Reduced Intensity Conditioning Unrelated Donor Transplantation. J Clin Oncol. In press, 2014.
f. GS12-01 Johan Törlén, Olle Ringdén, Jennifer Le Rademacher, Minoo Batiwalla, Junfang Chen, Tom Erkers, Vincent Ho, Partow Kebriaei, Carolyn Keever-Taylor, Tamila Kindwall-Keller, Hillard M. Lazarus, Mary J. Laughlin, Michael Lill, Tracey O’Brien, Miguel-Angel Perales, Vanderson Rocha, Bipin N. Savani, David Szwajcer, David Valcarcel, Mary Eapen. Low CD34 Dose Is Associated with Poor Survival after Reduced-Intensity Conditioning Allogeneic Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome. Biol Blood Marrow Transplant 20 (9): 1418-1425 2014.
g. GS12-03 Daniel Weisdorf, Mary Eapen, Annalisa Ruggeri, Mei-Jie Zhang, Xiaobo Zhong, Claudio Brunstein, Celalettin Ustun, Vanderson Rocha, Eliane Gluckman. Alternative Donor Transplantation for Older Patients with Acute Myeloid Leukemia in First Complete Remission: a Center for International Blood and Marrow Transplant Research-Eurocord Analysis. Biol Blood Marrow Transplant 20 (6): 816- 822 2014.
h. GS14-01a Stefan Ciurea, Mei-Jie Zhang, Andrea Bacigalupo, Asad Bashey, Fredrick Appelbaum, Philippe Armand, Joseph Antin, Omar Altijwa, Junfang Chen, Steve Devine, Daniel Fowler, Ryotaro Nakamura, Miguel-Angel Perales, Ravi Pingali, David Porter, Marcie Riches, Olle Ringden, Vanderson Rocha, Ravi Vij, Daniel Weisdorf, Richard Champlin, Ephraim Fuchs, Mary Eapen. Survival after T-cell Replete Haplo-identical Related Donor Transplant with Post-transplant Cyclophosphamide Compared with Matched Unrelated Donor Transplant for Acute Myeloid Leukemia. Presented at the 56th annual meeting of the American Society of Hematology, San Francisco, CA, December 2014 (Oral presentation).
4. Studies in progress (Attachment 3)
a. GS13-02 Matching between UCB units in double CB HCT (C Brunstein) Protocol Development b. GS14-01a Haploidentical vs. matched unrelated HCT (S Ciurea/ O Ringden/E Manuscript Preparation Fuchs/A Bacigalupo) c. GS14-01b Haploidentical vs. CB HCT (A Mussetti /M Perales) Data File Preparation d. GS14-02 Association between recipient and donor sex and clinical Analysis outcomes after allogeneic HCT (P Armand/H Kim)
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5. Future/proposed studies
a. PROP 1410-01/1410-12/1411-26/1411-95/1412-12 Selecting the best Haplo-identical donor (Attachment 4) b. PROP 1411-98 DRI-guided Graft Source Selection for Allogeneic Hematopoietic Cell Transplantation in Adults with Leukemia and Lymphoma (N Bejanyan/D Weisdorf) (Attachment 5) c. PROP 1411-40 Likelihood of survival for patients with acute leukemia who are alive and disease-free at 3, 6, & 12 months post-transplant: Are there differences by donor source? (W Hwang) (Attachment 6) d. PROP 1412-03 What should be the minimum required stem cell dose for successful autologous peripheral blood HCT after myeloablative conditioning? (G Akpek) (Attachment 7) e. PROP 1412-24 What is the optimal stem cell source (peripheral blood versus bone marrow) for recipients aged ≥20 years with HLA-matched sibling donors? (George Chen) (Attachment 8)
6. Other Business
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MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR GRAFT SOURCES & MANIPULATION Grapevine, TX Thursday, February 27, 2014, 2:45-4:45 pm
Co-Chair: Daniel H. Fowler, MD, National Cancer Institute, Bethesda, MD Telephone: 301-435-8641; 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] Co-Chair: Vanderson Rocha, MD, PhD; Churchill Hospital, Oxford, UK Telephone: 44-1865-572326; Fax: 44-1865-235260; E-mail: [email protected] Statisticians: Mei-Jie Zhang, PhD, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414-955-8375; Fax: 414-955-6513; 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
Dr. Fowler opened the meeting at 2:45 pm by welcoming the working committee members for attending the Graft Sources and Manipulation working committee (GSWC). He then briefly introduced the GSWC’s leadership, goals, expectations and limitations. He also presented the voting process, rule of membership/ authorship, and working committee evaluation information. The minutes of the February 2013 meeting were approved as written. Members were referred to the accrual summary, which reflects potentially eligible cases when considering submitting study proposals to this committee.
2. Published papers Dr. Perales reviewed publications (shown below), and summarized the findings and conclusions of on-going studies described below. There were two presentations at the 2013 American Society of Hematology meetings and one, at the 2013 European Group for Blood and Marrow Transplantation meeting.
a. GS08-02 Alousi AM, Le-Rademacher J, Saliba RM, Appelbaum FR, Artz A, Benjamin J, Devine SM, Kan F, Laughlin MJ, Lazarus HM, Liesveld J, Perales MA, 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? Blood 121(13):2567-73, 2013.
b. GS09-02 Eapen M, Klein JP, Ruggeri A, Spellman S, Lee SJ, Anasetti C, Arcese W, Barker JN, Baxter-Lowe LA, Brown M, Fernandez-Vina MA, Freeman J, He W, Iori AP, Horowitz MM,
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Locatelli F, Marino S, Maiers M, Michel G, Sanz GF, Gluckman E, Rocha V. Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy. Blood 123(1):133-40, 2014.
c. GS11-01 Marks DI, Ahn KW, Xiaobo Z, Appelbaum, Bachanova V, Barker JN, Brunstein CG, Gibson J, Kebriaei P, Lazarus HM, Olsson R, Perales, Pidala J, Savani B, Rocha V, Eapen M. Unrelated umbilical cord blood transplant for adult acute lymphoblastic leukemia in first and second complete remission: a comparison with allografts from adult unrelated donors. Haematologica 99(2):322-328, 2014.
3. Studies in Progress
Four studies were completed in 2013 and manuscripts circulated to writing committee members with submission planned in the next 6-8 weeks. These studies are summarized below:
a. GS05-01: The effect of cord blood processing and thawing techniques on transplant outcomes after single myeloablative umbilical cord blood (UCB) transplantation (KK Ballen). UCB banking practices were separated into four groups based on whether processing was manual or automated, units were plasma/ red cell reduced or plasma reduced and whether hespan was added to the bag. Neutrophil recovery at day-28 was significantly lower after transplantation of units that were manually processed and plasma reduced. However, this did not affect day-100 mortality.
b. GS08-01: Effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy (C Kollman). In this dataset of almost 7000 donor-recipient pairs, we identified three donor characteristics associated with better survival: 1) donors aged 32 years or younger, HLA-matched at HLA-A, -B, -C and –DRB1 and blood group ABO matched. Importantly, each of these donor characteristics had an independent prognostic value. Transplantation of grafts from male donor or female nulliparous donors were associated with lower risks of chronic GVHD; donor sex was not associated with survival. Donor CMV seropositivity was also not associated with survival.
c. GS12-01: Low CD34 cell dose is associated with higher non-relapse and overall mortality after reduced intensity HCT for AML and MDS (J Thörlén/O Ringden). CD34 dose was associated with overall mortality and non-relapse mortality but the dose threshold differed by donor source. Peripheral blood grafts that contained less than 4 x 106/kg was associated with higher risks of overall mortality and non-relapse mortality after HLA-matched sibling donor transplants. In the setting of unrelated donor transplantation, grafts that contained CD34 dose less than 6 x 106/kg were associated with higher overall and non-relapse mortality. CD34 dose was not associated with acute or chronic GVHD risks.
d. GS12-03: Alternative donor transplantation for older patients with acute myeloid leukemia in 1st complete remission (D Wesidorf). This is a joint study with Eurocord. UCB grafts were associated with slower hematopoietic recovery and lower rates of chronic GVHD. Compared to HLA-matched unrelated donor transplant, leukemia-free and overall survival was lower after UCB transplants. Nevertheless, for those without a fully matched adult unrelated donor, UCB transplants extend leukemia-free survival for over a third of patients. This paper is now in press (Biol Blood Marrow Transplant; 2014).
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Studies in Progress: Analysis
e. GS13-01: Comparison of cord blood transplantation outcomes testing for an effect of anti- thymocyte globulin to transplant conditioning regimen (D Ponce/ M Perales/J Barker). The study will compare outcomes after single or double UCB transplantation for AML, ALL and MDS patients testing for the effect of ATG on outcomes. Patient age, use to ATG and regimen intensity are confounding factors. Therefore, we will conduct two separate analyses. The first, in a pediatric population (n = 588), that received myeloablative transplant conditioning. Results of analyses confirmed lower risks of acute and chronic GVHD with regimens that included ATG. However, there were no differences in non-relapse mortality, relapse, disease-free or overall survival. The members suggested we study the effect of ATG on hematopoietic recovery and grade 3-4 acute GVHD. V Rocha has questioned that the effect of ATG on the incidence of GVHD and not impact on survival can be related to higher incidence of infection. Infections related death should be investigated. The CIBMTR captures data on infections within the first 3 months; thereafter infection related data are not collected consistently as patients may not be followed up regularly at the tertiary center (transplant center). Studying causes of death using data submitted to an observation registry is challenging and unreliable. While these data can be reviewed, past precedence suggests this to be of low scientific merit. The second part of the study will focus on adults who received reduced intensity regimens and test the effect of ATG. This analysis is ongoing.
Studies in Progress: Protocol Development
f. GS13-02: Matching between cord blood units in double cord blood unit transplantation – Does this affect hematopoietic recovery, acute GVHD and early survival? (C Brunstein).
4. New study proposals Dr. Rocha has conducted the discussion of the new proposals, reinforcing that the committee would select proposals with high impact score and have greatest impact on clinical practice.
a. PROP 1309-01/1310-23/1311-71 All three proposals are seeking to study outcomes after transplantation of haplo-identical donor transplants to HLA-matched unrelated adult donor transplantation or umbilical cord blood transplantation. Prop 1309-01 was presented by S Ciurea in collaboration with investigators at Johns Hopkins, Genova and Atlanta. Prop 1310-23 was presented by O Ringden and Prop 1311-71, Alberto Mussetti and Miguel Perales. As haplo- identical donor transplants are relatively recent, the study population will be limited to 2007- 2012 and adult patients with AML. The study will be limited to adults and when possible, we will identify transplant packages. There are few patients with ALL, who received haplo-identical donor or UCB transplants. The haplo-identical donor transplant group will be divided into CD34 selected grafts and post-transplant cyclophosphamide. Further, we will make appropriate adjustments for transplant conditioning regimen intensity. These proposals will be combined together for efficiency. The committee was keen to conduct these analyses and assigned a high priority score. It is likely that there will be two separate publications, one comparing outcomes after haplo-identical donor transplantation to that after unrelated donor transplantation and the second, comparing outcomes after haplo-identical donor transplantation to that after cord blood transplantation. Within the committee, we have prioritized this proposal over GS13-02.
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b. PROP 1310-21 Trends in HLA haplo-identical allogeneic hematopoietic stem cell transplantation for hematologic malignancies: a CIBMTR analysis (G Akpek). The purpose of the study is to compare trends and transplant outcomes among 5 cohorts of patients who received haplo- identical allo-transplants for hematologic malignant diseases based on their year of transplantation from the 1980s to current. The primary outcome of interest is transplant- related mortality at day+100 and 1 year. However, transplant strategies and supportive care have evolved over the decades making it impossible to attribute survival differences to transplant strategy alone. This proposal received a low priority score. Therefore the proposal was dropped.
c. PROP 1311-18 Association between recipient and donor sex and chronic GVHD, relapse and survival after allogeneic hematopoietic stem cell transplantation (P Armand/ H Kim). The aim of the study is to determine whether recipient gender or recipient/donor gender match is associated with clinical outcomes after allogeneic HSCT, and whether this association varies by disease. Drs. Armand and Kim will utilize an existing dataset that they have worked on to validate the disease risk index developed by this group. The DRI index was predictive for overall survival. They would like to extend to other outcomes – relapse and GVHD. We are unable to study acute GVHD for the entire population as registration level data does not capture the date of onset of acute GVHD. Therefore acute GVHD will be evaluated in a subset for whom we have organ staging and date of onset. The proposal received a high priority score; we will update the existing dataset for Drs. Armand and Kim.
d. PROP 1311-53 Peripheral stem cell graft composition of female donors and transplant outcome (J Schetelig/ A Nagler/ A Shimoni/ G Ehninger). Dr. Schetelig presented the proposal. The aim of this study is to challenge the preferential activation of unrelated male peripheral blood stem cell (PBSC) donors, and to describe the effect of sex mismatch in matched unrelated donor- recipient peripheral blood stem cell transplantation (PBSCT). The research question is whether donor-recipient mismatch (female donor/male recipient) is associated with a higher incidence of GVHD, non-relapse mortality and disease-free survival compared to transplantation from male donors to male or female recipients or female donors to female recipients in the setting of HLA-matched unrelated adult PBPC transplants. The investigators are interested in CD34 and CD3 dose; the later is not reported for about 60% of eligible HLA-matched sibling donor transplants. The NMDP does not collect CD3 dose – the CIBMTR does not collect graft characteristics for transplants facilitated by the NMDP. On the other hand, CD3 dose is available for DKMS facilitated transplants in the US. Study population will include patients with AML, ALL or MDS. The committee was interested in pursuing this proposal further but we are unsure as to whether we will be able to identify a cohort for whom we have CD34 and CD3 dose. The proposal was conditionally approved to assess feasibility – which will require the CIBMTR prepare a study file and thereafter identify those transplants facilitated by the DKMS through the NMDP. We will test feasibility and only if feasible will we proceed to protocol development.
e. PROP 1311-66 The impact of graft T-cell subset doses on the outcomes of allogeneic peripheral blood stem-cell transplants after reduced intensity conditioning in patients with hematologic malignancies (R Reshef/ D Porter). The purpose of the study is to assess the impact of CD3, CD4 and CD8 cell doses on overall survival, relapse-free survival, acute and chronic GVHD and,
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treatment-related mortality in patients with hematologic malignancies undergoing allogeneic peripheral blood stem-cell transplantation with reduced-intensity conditioning. Only T-cell replete transplants will be included. As with the above-mentioned proposal, CD3 dose is not readily available but if obtained for the above study we would use those data for this proposal. However, CD8 counts are not routinely performed in the US; a show of hands at the meeting concluded only 3 centers report CD8 dose. Although this proposal is interesting it is not feasible. As Drs. Reshef and Potter have pilot data from their institution, they will discuss with investigators at the two other centers for a collaborative study.
f. PROP 1312-11 Using landmark analysis to provide updated relapse and leukemia-free survival estimates to patients after umbilical cord blood transplantation (C Brunstein/ S Lee). Dr. Brunstein presented this proposal, which is similar to the recent publication by Drs. Lee and Weisdorf. It is clear there are very few long-term survivors because adult UCB transplant is relatively recent and it would take several hundreds of adult UCB transplant with long-term follow-up to undertake this study. The purpose of presentation was to gauge interest within the committee. There is enthusiasm from the committee members – consequently, Dr. Brunstein will present a separate proposal in a few years.
Meeting adjourned at 4:38 PM.
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Working Committee Overview Plan for 2014-2015
a. GS13-01: Comparison of cord blood transplantation outcomes testing for an effect of anti- thymocyte globulin to transplant conditioning regimen. Manuscript submission June 2014.
b. GS13-02: Matching between cord blood units in double cord blood unit transplantation – Does this affect hematopoietic recovery, acute GVHD and early survival? Data file preparation/data analysis January 2015; Manuscript submission June 2015.
c. GS14-01 (PROP 1309-01/1310-23/1311-71): Evaluation of three alternative donor strategies for AML. This study is a priority – we anticipate developing a protocol and study file by July 2014 and plan on submitting abstracts to the 2014 American Society of Hematology meeting. Manuscript submission June 2015
d. GS14-02 (PROP 1311-18): Association between recipient and donor sex and clinical outcome after allogeneic hematopoietic stem cell transplantation. Updating the existing study file will be completed by September 2014. Manuscript submission December 2014.
e. GS14-03 (PROP 1311-53): Peripheral stem cell graft composition of female donors and transplant outcome. We will determine feasibility by June 2014; if feasible we will proceed with protocol development thereafter and plan to complete analysis January 2015; manuscript submission June 2015.
Working Assignments for Working Committee Leadership (March 2014)
Miguel Perales GS13-01: Comparison of cord blood transplantation outcomes testing for an effect of anti-thymocyte globulin to transplant conditioning regimen.
Vanderson Rocha GS13-02: Matching between cord blood units in double cord blood unit transplantation – Does this affect hematopoietic recovery, acute GVHD and early survival?
Mary Eapen GS14-01: Evaluation of three alternative donor strategies for AML.
Mary Eapen GS14-02: Association between recipient and donor sex and clinical outcome after allogeneic hematopoietic stem cell transplantation.
Daniel Fowler GS14-03: Peripheral stem cell graft composition of female donors and transplant outcome.
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Accrual Summary for Graft Sources and Manipulation Working Committee
Characteristics of patients reported to the CIBMTR between 2000 and 2014
Registration Research Characteristics N (%) N (%) Number of cases 140327 47775 Donor type HLA-identical sibling donor HCT 62078 15318 Bone marrow 17888 (29) 4256 (28) Peripheral blood 43761 (70) 10890 (71) Umbilical cord blood 429 ( <1) 172 ( 1)
Identical twin donor HCT 862 373 Bone marrow 138 (16) 66 (18) Peripheral blood 719 (83) 305 (82) Umbilical cord blood 5 (<1) 2 (<1)
HLA mismatched related donor HCT 9348 2498 Bone marrow 3262 (35) 924 (37) Peripheral blood 6000 (64) 1455 (58) Umbilical cord blood 86 ( 1) 119 ( 5)
Unrelated donor HCT 68039 29586 Bone marrow 18521 (27) 8878 (30) Peripheral blood 38232 (56) 13932 (47) Umbilical cord blood 11286 (17) 6776 (23)
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TO: The Members, Graft Sources and Manipulation Working Committee
FROM: Mary Eapen, MD, MS; Scientific Director for the Graft Sources Working Committee
RE: Summary of the Committee’s Activities for 02/2014 – 02/2015
Completed Studies: 02/2014 – 02/2015
GS13-01: Comparable 3-Year Disease-Free Survival Regardless of Anti-Thymocyte Globulin Inclusion in Pediatric Myeloablative Cord Blood Transplantation for Acute Lymphoblastic Leukemia (D Ponce/M Perales/J Barker): This study compared outcomes after cord blood transplantation testing the effect of in vivo T-cell depletion. The inclusion of anti-thymocyte globulin (ATG) in pediatric cord blood transplantation (CBT) is controversial. We evaluated outcomes according to ATG inclusion in 297 children and adolescents with acute lymphoblastic leukemia (ALL) who received myeloablative total body irradiation-based conditioning and either single (74%) or double-unit (26%) grafts. Ninety-two patients (31%) received ATG and 205 (69%) did not. Patients were in first, second, or third complete remission (CR) at transplantation. Non-ATG recipients were more likely to be cytomegalovirus seropositive and to receive double-unit grafts. With a median 3-year follow-up, day 100, grade II-IV acute GVHD (30% versus 54%, p = 0.0002), and 3-year chronic GVHD (22% versus 43%, p = 0.0008) were decreased in ATG recipients. However, day 100 grade III-IV acute GVHD was comparable: 11% in ATG and 17% in non-ATG recipients, p = 0.15. The 3-year rates of transplant-related mortality (16% versus 17%, p = 0.98), relapse (17% versus 27%, p = 0.12), and leukemia-free survival (66% versus 55%, p = 0.23) in ATG and non-ATG recipients were similar. Leukemia-free survival was better for those transplanted in first CR and those who were cytomegalovirus seronegative. Leukemia-free survival in pediatric myeloablative CBT for ALL is similar regardless of ATG inclusion.
SC11-02a: Bone Marrow or Peripheral Blood for Reduced Intensity Conditioning Unrelated Donor Transplantation (M Eapen/B Logan): Background: There have been no randomized trials that have compared peripheral blood (PB) to bone marrow (BM) grafts in the setting of reduced intensity conditioning transplants for hematologic malignancy. As immune modulation plays a significant role in sustaining clinical remission after reduced intensity conditioning, we hypothesize that higher graft versus host disease associated with PB transplantation may offer a survival advantage. Methods: The primary outcome evaluated was overall survival. Cox regression models were built to study outcomes after transplantation of PB (N = 887) relative to BM (N = 219) for patients with acute myeloid leukemia, myelodysplastic syndrome and non- Hodgkin lymphoma, the three most common indications for unrelated reduced intensity conditioning transplantation. Transplants were performed in the United States between 2000 and 2008. Conditioning regimens consisted of an alkylating agent and fludarabine and GVHD prophylaxis involved a calcineurin inhibitor (CNI) with either methotrexate (MTX) or mycophenolate (MMF). Results: After adjusting for age, performance score, donor-recipient HLA-match, disease and disease status at transplantation, factors associated with overall survival, there were no significant differences in 5-year
11 Not for publication or presentation Attachment 3 rates of survival after transplantation of PB compared to BM; 34% versus 38%, with CNI-MTX and 27% versus 20% with CNI-MMF GVHD prophylaxis. Conclusion: Survival after transplantation of PB and BM are comparable in the setting of non-irradiation RIC regimens for hematologic malignancy. The effect of GVHD prophylaxis on survival merits further evaluation.
SC11-02b: Long-Term Survival after Transplantation of Unrelated Donor Peripheral Blood or Bone Marrow Hematopoietic Cells for Hematologic Malignancy (M Eapen/B Logan): We sought to determine whether differences in chronic graft versus host disease (GVHD) rates would lead to survival differences comparing 2463 peripheral blood (PB) and 1713 bone marrow (BM) hematopoietic cell transplant recipients. Patients had acute leukemia, chronic myeloid leukemia (CML) or myelodysplastic syndrome, received myeloablative conditioning regimens and calcineurin-inhibitor GVHD prophylaxis. There were no significant differences in long-term survival after transplantation of PB and BM except first chronic phase CML. For these patients, 5-year rate of survival was lower after transplantation of PB compared to BM (35 % vs. 56%, p=0.001). Although mortality risks were higher in patients with chronic GVHD after both PB (HR 1.58; p<0.001) and BM (HR 1.73; p<0.001) transplants, its effect on mortality did not differ by graft (p=0.42). BM is the preferred graft for first chronic phase CML where as either graft is suitable for other leukemia.
GS14-01a: Haploidentical vs. matched unrelated HCT (S Ciurea/O Ringden/E Fuchs/A Bacigalupo): This study compared transplant outcomes of 2,174 adults with acute myeloid leukemia (AML) after haploidentical and 8/8 HLA-matched unrelated donor transplantation. All haploidentical transplant recipients received post-transplant cyclophosphamide; n=104 received myeloablative (MAC) and 88, reduced intensity conditioning (RIC) regimens. Among unrelated donor transplant recipients n=1,245 received MAC and 737, RIC regimens. The primary endpoint was overall survival. The 3-year probabilities of overall survival were 50% (95% CI 47-53) after MAC unrelated donor compared with 45% (95% CI 36-54) after haploidentical transplants (p=0.38). The corresponding rates after RIC transplants were 44% (95% CI 0.40-47) and 46% (95% CI 35-56), respectively (p=0.71). However, other outcomes differed: Day-30 neutrophil recovery was 97% after MAC unrelated donor compared with 90% haploidentical transplants (p=0.02). The corresponding rates after RIC transplants were 96% and 93%, respectively (p=0.25). In the MAC setting, 3-month grade 2-4 acute graft-versus-host disease (GVHD) (33% versus 16%; p<0.0001) and 3-year chronic GVHD (53% versus 30%, p<0.0001) were higher after unrelated donor compared with haploidentical transplants. A similar trend was observed after RIC transplants, 28% versus 19%, p=0.05 and 52% versus 34%, p=0.002, respectively. In conclusion, in this retrospective analysis, the available data suggest that survival for AML patients after haploidentical transplantation was comparable with HLA-matched unrelated donor transplantation.
Studies: Active
GS13-02: Matching between UCB units in double UCB transplantation (C Brunstein): This study will explore whether better matching between two mismatched units in the setting of double umbilical cord blood transplantation affects early transplant outcomes.
GS14-01b: Haploidentical vs. CB HCT (A Mussetti /M Perales): This study will compare outcomes after unrelated cord blood (UCB) transplantation with outcomes of haplo-identical donor transplantation using post-transplant cyclophosphamide (PT/Cy). This study is currently under analysis.
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GS14-02: Association between recipient and donor sex and clinical outcomes after allogeneic HCT (P Armand/H Kim): This study will explore whether recipient gender or recipient/donor gender match is associated with clinical outcome after allogeneic HSCT, and whether this association varies by disease. This study is currently under analysis.
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Study Proposals 1410-01/1410-12/1411-26/1411-95/1412-12
Combined Study Title: Selecting the best haplo-identical donor
Study proposal 1410-01: Title: Influence of donor selection on outcomes after T-cell replete haploidentical hematopoietic stem cell transplantation followed by high-dose posttransplant cyclophosphamide PI: Maxim Norkin, John Reed Wingard
Study proposal 1410-12: Title: Does the Extent of HLA Mismatching Affect Outcomes In Haploidentical Transplantation? PI: Natasha Kekre, Joseph H Antin
Study proposal 1411-26: Title: Optimal graft and donor selection for patients undergoing T-cell replete haploidentical donor transplantation using post-transplant cyclophosphamide PI: Christina Cho, Miguel-Angel Perales, Asad Bashey
Study proposal 1411-95: Title: Effect of donor choice donor in T-cell HLA Haplo-mismatch related hematopoietic cell Transplantation (Haplo-HCT) PI: Rabi Hanna
Study proposal 1412-12: Title: Bone marrow cells or peripheral blood in post Cyclophosphamide haplo-identical transplants, which is the best graft source and cell dose to improve outcomes? PI: Robert Danby, Vanderson Rocha
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Characteristics of patients who underwent first allogeneic haplo-identical transplantations with post- transplant cyclophosphamide in US and report to the CIBMTR, 2008-2013
Variable N (%) Number of patients 616 Number of centers 41 Patients related Recipient age at transplant, years 18 - 30 83 (13) 31 - 50 200 (32) ≥ 50 333 (54) Disease AML 235 (38) ALL 66 (11) CML 35 (6) MDS 50 (8) NHL 169 (27) HL 61 (10) Transplant related Conditioning regimen MAC 195 (32) NMA/RIC 421 (68) Graft type BM 514 (83) PB 102 (17) Donor related Donor gender Male 343 (56) Female 273 (44) Donor CMV serostatus Negative 308 (50) Positive 308 (50)
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Study Proposal 1411-98
Study Title: DRI-guided Graft Source Selection for Allogeneic Hematopoietic Cell Transplantation in Adults with Leukemia and Lymphoma
Nelli Bejanyan, MD, University of Minnesota, Minneapolis, MN, [email protected] Daniel Weisdorf, MD, University of Minnesota, Minneapolis, MN, [email protected]
Study Hypothesis: The choice of graft source for allogeneic hematopoietic cell transplantation (alloHCT) can be best informed by DRI
Specific Aims: 1. Primary endpoint: a) To study the effect of graft source on disease-free survival (DFS) of adult allograft recipients with hematological malignancies based on DRI assignment. b) To stratify DRI-based models of graft choice by disease-group (leukemia and lymphoma). 2. Secondary endpoints: To study neutrophil recovery, platelet recovery, acute and chronic GVHD, treatment-related mortality (TRM), malignancy relapse and overall survival (OS).
Scientific Justification: AlloHCT is commonly used therapy for adults with various hematological malignancies. HLA-identical sibling donor is the preferred graft source that provides the best clinical outcomes of alloHCT.1 However, this graft source is only available to1/3 of the adults undergoing transplantation, and the remaining large group of patients commonly receives allograft from adult HLA-matched unrelated (MUD), mismatched unrelated donor (MMUD), umbilical cord blood (UCB) or haploidentical related donor. Several studies examined the effect of the graft source on alloHCT outcomes in specific diseases or disease categories.2-8 However, while some studies included only patients with disease in first complete remission (CR1),4 others had no restriction regarding the disease remission status (stage risk).2,3,7 There were also large inter-study disease risk assignment variations with some including ≥ CR2 into “advances risk” category, while others restricting this category to only persistent, progressive or relapse disease. Most recently disease risk index (DRI) has been developed to stratify patients undergoing alloHCT by disease risk, which incorporates both disease type and status.9 This has been independently validated in large CIBMTR registry study and was identified to be the strongest prognostic factor for overall survival after transplantation.10 Since persistent disease before allograft is a well-recognized independent prognostic factor for malignancy recurrence and treatment failure of alloHCT, we hypothesize that the choice of graft source for alloHCT can be best informed by DRI. Therefore, CIBMTR’s large dataset will help us guide with the preferred graft source based on DRI assignment among adult patients with no available HLA-identical sibling undergoing alloHCT for leukemia or lymphoma.
Patient Eligibility Population: Inclusion criteria: Adult patients (≥18 years old) with hematological malignancies who underwent alloHCTat participating CIBMTR centers between 2008 and 2013 Both MA and RIC transplants
Exclusion criteria: Patients with myeloproliferative neoplasms and multiple myeloma
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Data Requirements: All necessary study data are available for extraction from the disease‐specific CIBMTR data collection forms Demographic and clinical characteristics (Supplementary Table 1) and DRI assessment (Supplementary Table 2; A and B) will be abstracted from the CIBMTR data forms. As possible, data sets utilized will include already analyzed (and/or published) HCT outcomes to minimize the need for subsequent data re-review and cleanup.
Sample Requirements: None
Study Design: We propose an observational retrospective study of adult recipients of alloHCT with leukemia and lymphoma. Chi-square test for categorical variables and the Wilcoxon two sample tests for continuous variables will be used to compare patient, disease and transplant related characteristics between graft sources (MRD vs. MUD vs. MMUD vs. UCB vs. Haplo). Cumulative incidence estimator will be used to calculate probabilities of neutrophil engraftment, platelet engraftment, acute and chronic GVHD, TRM and relapse. The Kaplan-Meier method will be used to estimate DFS and OS probabilities. Cox proportional hazards regression model would be used to study the association between treatment groups and outcomes. Multivariate models will be built using the forward step-wise selection process considering variables in Table 1. The graft source groups will be included in all steps of model building (reference group; MRD), regardless of level of significance. The effect of the graft source will be examined across all DRI categories (low, intermediate, high and very high). The Cox regression model will be used to estimate adjusted probability of DFS and OS.
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Characteristics of patients receiving alloHCT from 2008-2013
Variables : Patient Related Characteristics: Age Median (range) <40 40-49 50-64 ≥65 Gender Male Female Karnofsky score <90% ≥90% Unknown Disease Related Characteristics: Leukemia group AML Favorable cytogenetics* Intermediate/unavailable cytogenetics* Adverse cytogeneics* CR1 CR2 CR3 Relapse/induction failure MDS Low-risk# High-risk# Intermediate/unavailable cytogenetics§ Adverse cytogeneics§ Untreated CR Improved but not CR Relapsed/no response/progression ALL CR1 CR2 CR3 Relapse/induction failure CML Chronic phase Accelerated phase Blast crisis Lymphoid Group CLL/SLL CR
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PR Relapse/induction failure Hodgkin lymphoma CR PR Relapse/induction failure Indolent B-cell NHL CR PR Relapse/induction failure Aggressive B-cell NHL CR PR Relapse/induction failure Mantle cell lymphoma CR PR Relapse/induction failure T-cell lymphoma CR PR Relapse/induction failure Burkitt’s lymphoma CR PR Relapse/induction failure Transplant Related Characteristics: Year of Transplant Median (range) 2008-2013 DRI Low Intermediate High Very high HCT-Cl♮ 0 1-2 ≥3 Unavailable Donor relation Matched Related Donor (MRD) Matched Unrelated Donor (MUD = 8/8 URD) Mismatched Unrelated Donor (MMUD = 7/8 URD) UCB Donor Haplo Donor (= mismatched relative) Graft source
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Marrow PBSC UCB CMV Serostatus Recipient-negative and donor-negative Recipient-negative and donor-positive Recipient-positive and donor-negative Recipient-negative and donor-positive Recipient or donor unknown Conditioning regimen Myeloablative Nonmyeloablative/RIC In vivo T cell depletion Yes No Not reported GVHD prophylaxis Tacrolimus + mycophenolate Tacrolimus + methotrexate Tacrolimus alone Cyclosporine + mycophenolate Cyclosporine + methotrexate Cyclosporine alone Follow up for survivors, months Median (range) * Classified according to Armand et al.11 # Low-risk MDS refers to MDS with ≤5% blasts (RA, RARS and RSMD); high-risk MDS refers to MDS with >5% blasts (RAEB-1 and RAEB-2) §Classified according to Armand et al 12 Indolent B-cell NHL includes follicular lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma ♮Classified according to Sorror et al 13
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Supplementary Table 2. A. DRI assignment for leukemia and lymphoma Diagnosis Disease Risk Stage Risk DRI Assignment AML favorable cytogenetics CR CML chronic phase CLL/SLL CR/PR Low Indolent NHL CR/PR Hodgkin lymphoma CR Mantle cell lymphoma CR CML accelerated phase AML intermediate cytogenetics CR MDS intermediate cytogenetics Low-risk/High risk Early Low-risk Advanced
MDS adverse cytogenetics Low-risk Early Intermediate ALL CR1 CLL Advanced Indolent NHL Advanced Hodgkin lymphoma PR Mantle cell lymphoma PR Aggressive NHL CR/PR T-cell NHL CR/PR AML favorable/ intermediate cytogenetics Advanced AML adverse cytogenetics CR MDS intermediate cytogenetics High risk Advanced MDS adverse cytogenetics Low-risk/High risk Advanced
High risk Early High ALL CR2/CR3 Hodgkin lymphoma Advanced Mantle cell lymphoma Advanced Aggressive NHL Advanced T-cell NHL Advanced Burkitt’s lymphoma CR CML blast phase AML adverse cytogenetics Advanced ALL Advanced Very high Aggressive NHL Advanced Burkitt’s lymphoma PR
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B. DRI assignment for leukemia and lymphoma separately Diagnosis Disease Risk Stage Risk DRI Assignment AML favorable cytogenetics CR Low CML chronic phase CML accelerated phase AML intermediate cytogenetics CR MDS intermediate cytogenetics Low-risk/High risk Early Low-risk Advanced Intermediate MDS adverse cytogenetics Low-risk Early
ALL CR1 AML favorable/ intermediate cytogenetics Advanced AML adverse cytogenetics CR Leukemia MDS intermediate cytogenetics High risk Advanced MDS adverse cytogenetics Low-risk/High risk Advanced High High risk Early ALL CR2/CR3 CML blast phase AML adverse cytogenetics Advanced Very high ALL Advanced CLL/SLL CR/PR Indolent NHL CR/PR Low Hodgkin lymphoma CR Mantle cell lymphoma CR CLL Advanced Indolent NHL Advanced Intermediate
Hodgkin lymphoma PR Mantle cell lymphoma PR Aggressive NHL CR/PR T-cell NHL CR/PR Lymphoma Hodgkin lymphoma Advanced Mantle cell lymphoma Advanced Aggressive NHL Advanced High T-cell NHL Advanced Burkitt’s lymphoma CR Aggressive NHL Advanced Very high Burkitt’s lymphoma PR
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References: 1. Alousi AM, Le-Rademacher J, Saliba RM, et al. Who is the better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer? Blood;121:2567-2573. 2. Brunstein CG, Gutman JA, Weisdorf DJ, et al. Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood. Blood;116:4693-4699. 3. Eapen M, Rocha V, Sanz G, et al. Effect of graft source on unrelated donor haemopoietic stem- cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol;11:653-660. 4. Weisdorf D, Eapen M, Ruggeri A, et al. Alternative donor transplantation for older patients with acute myeloid leukemia in first complete remission: a center for international blood and marrow transplant research-eurocord analysis. Biol Blood Marrow Transplant;20:816-822. 5. Laughlin MJ, Eapen M, Rubinstein P, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med. 2004;351:2265-2275. 6. Rocha V, Labopin M, Sanz G, et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med. 2004;351:2276-2285. 7. Raiola AM, Dominietto A, di Grazia C, et al. Unmanipulated haploidentical transplants compared with other alternative donors and matched sibling grafts. Biol Blood Marrow Transplant;20:1573-1579. 8. Chen YB, Aldridge J, Kim HT, et al. Reduced-intensity conditioning stem cell transplantation: comparison of double umbilical cord blood and unrelated donor grafts. Biol Blood Marrow Transplant;18:805-812. 9. Armand P, Gibson CJ, Cutler C, et al. A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood;120:905-913. 10. Armand P, Kim HT, Logan BR, et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood;123:3664-3671. 11. Armand P, Kim HT, Zhang MJ, et al. Classifying cytogenetics in patients with acute myelogenous leukemia in complete remission undergoing allogeneic transplantation: a Center for International Blood and Marrow Transplant Research study. Biol Blood Marrow Transplant;18:280-288. 12. Armand P, Deeg HJ, Kim HT, et al. Multicenter validation study of a transplantation-specific cytogenetics grouping scheme for patients with myelodysplastic syndromes. Bone Marrow Transplant;45:877-885. 13. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912- 2919.
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Characteristics of adult patients who underwent first allogeneic transplantation in US and reported to the CIBMTR, 2009-2012
HLA-identical HLA-matched HLA-matched Cord sibling unrelated 8/8 unrelated 7/8 Blood BM PB BM PB BM PB Variable N (%) N (%) N (%) N (%) N (%) N (%) N (%) Number of patients 388 5519 796 4517 226 1053 1329 Number of centers 65 138 100 120 69 101 94 Age at transplant, years 18 - 30 118 (30) 549 (10) 142 (18) 466 (10) 51 (23) 138 (13) 274 (21) 31 - 50 112 (29) 1699 (31) 253 (32) 1229 (27) 80 (35) 361 (34) 468 (35) ≥ 50 158 (41) 3271 (59) 401 (50) 2822 (62) 95 (42) 554 (53) 587 (44) Disease AML 174 (45) 2496 (45) 427 (54) 2239 (50) 117 (52) 534 (51) 704 (53) ALL 101 (26) 902 (16) 139 (17) 579 (13) 43 (19) 162 (15) 248 (19) MDS 49 (13) 750 (14) 132 (17) 719 (16) 39 (17) 145 (14) 144 (11) NHL 52 (13) 1138 (21) 75 (9) 845 (19) 21 (9) 174 (17) 186 (14) HL 12 (3) 233 (4) 23 (3) 135 (3) 6 (3) 38 (4) 47 (4) Conditioning regimen MAC 326 (84) 3402 (62) 613 (77) 2478 (55) 146 (65) 639 (61) 777 (58) NMA/RIC 62 (16) 2117 (38) 183 (23) 2039 (45) 80 (35) 414 (39) 552 (42)
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Study proposal 1411-40
Study Title: Likelihood of survival for patients with acute leukemia who are alive and disease-free at 3, 6, & 12 months post-transplant: Are there differences by donor source?
William Hwang, MBBS, MRCP, MMed, FAMS, Singapore general Hospital, Singapore [email protected]
1. Long term outcomes of 100-day survivors of hematopoietic stem cell transplant by cell source Hypothesis: cord blood transplant recipients have better long term outcomes if they have survived the first 100 days of transplant.
Methods: analysis of overall survival, progression free survival (and possibly presence of chronic gvhd, performance score, and other medical issues) of 100-day survivors of HSCT. Comparison between sources of stem cell - matched sib, mud, cord, haplo. Cord further stratified by level of match and cell dose.
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Characteristics of adult patients with acute leukemia who were alive and disease free at 3, 6, 12 months after first allogeneic transplant and reported to the CIBMTR, 2003-2012
3 months: HLA identical sibling, HLA-matched PB unrelated 8/8, PB Cord Blood Variable N (%) N (%) N (%) Number of patients 2301 1913 804 Disease AML 1746 (76) 1507 (79) 585 (73) ALL 555 (24) 406 (21) 219 (27) Conditioning regimen MAC 1778 (77) 1338 (70) 505 (63) NMA/RIC 523 (23) 575 (30) 299 (37) Year of transplant 2003 - 2005 823 (36) 537 (28) 59 (7) 2006 - 2008 789 (34) 855 (45) 247 (31) 2009 - 2012 689 (30) 521 (27) 498 (62)
6 months:
HLA identical sibling, HLA-matched PB unrelated 8/8, PB Cord Blood Variable N (%) N (%) N (%) Number of patients 1734 1501 593 Conditioning regimen MAC 1346 (78) 1054 (70) 374 (63) NMA/RIC 388 (22) 447 (30) 219 (37) Year of transplant 2003 - 2005 607 (35) 420 (28) 48 (8) 2006 - 2008 589 (34) 664 (44) 181 (31) 2009 - 2012 538 (31) 417 (28) 364 (61)
12 months:
HLA identical sibling, HLA-matched PB unrelated 8/8, PB Cord Blood Variable N (%) N (%) N (%) Number of patients 1394 1198 427 Conditioning regimen MAC 1086 (78) 860 (72) 279 (65) NMA/RIC 308 (22) 338 (28) 148 (35) Year of transplant 2003 - 2005 471 (34) 331 (28) 33 (8) 2006 - 2008 473 (34) 521 (43) 138 (32) 2009 - 2012 450 (32) 346 (29) 256 (60)
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Study Proposal 1412-03
Study Title: What should be the minimum required stem cell dose for successful autologous peripheral blood HCT after myeloablative conditioning?
Görgün Akpek, Banner MD Anderson Cancer Center, [email protected]
Hypothesis: The study proposed here will analyze CIBMTR data to address the working hypothesis that minimum stem cell dose for successful autologous PBSCT is lower than the dose that is currently recommended, which is 2 x 10^6 CD34+ cells/kg.
Specific Aims: 1. To identify and compare myeloid recovery in different cohort of autologous SCT recipients who received <2, 3-5, 5-8 and >5 x10^6 CD34+ cells kg. 2. Identify the variables that are associated with delayed neutrophil (>14 days) and platelet (>30 days) recovery in low dose (<3 x10^6 CD34+) Primary endpoint: Delayed neutrophil (>14 days) recovery Secondary endpoints: Delayed platelet (>30 days) recovery Hematopoietic recovery (ANC and platelet) Day+100 Transplant-related mortality
Scientific Justification: We aim to collect optimum number of progenitor cells with the minimum number of leukaphereses for autologous HCT following high dose myeloablative chemo + radiotherapy. According to the existing guidelines1 the minimum CD34+ cell dose is 2 x 10^6/kg and recommended dose is 5 x10^6/kg (see table below).
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Using the recommended number of stem cells(>5 million/kg) may reduce both the use of supportive therapies after transplantation and patient inconvenience. Prolongation of neutropenia or thrombocytopenia may delay the administration of further planned chemotherapy or radiotherapy and may increase resource utilization after transplantation. In various published study that compared the outcome of transplantation with different cell doses showed that higher the cell dose more rapid platelet and neutrophil engraftment, which translated in a reduction in hospitalization and antibiotic use, RBC and platelet transfusion, and overall cost saving2.
On the other hand, repeated stem cell mobilizations and collections to reach minimum number of stem cells (2-3 million/kg) could be quite challenging in clinical practice. Although new mobilizing agents have significantly helped our ability to collect adequate stem cell product, we still see patients who are very poor mobilizers despite multiple sessions of collection and multiple attempts of collection. In cases where we don’t have adequate stem cell numbers, we either take them to OR for bone marrow harvest or have to decline them from receiving high dose therapy and stem cell transplantation, which could potentially cure or prolong their life expectancy.
This raises a question of what should be the minimum stem cell dose to be able to proceed with HCT without risking the patient’s lives.
We know that successful transplantation is dependent on the engraftment of reinfused hematopoietic stem cells into the marrow microenvironment. We also know that the function of hematopoietic system is maintained by a relatively small population of stem cells. Theoretically, a single pluripotent hematopoietic stem cell should be able to reconstitute the hematopoietic system after myeloablative anticancer therapy and transplantation. However, clinical and experimental observations demonstrate that it is necessary to transplant numerous stem cells to obtain engraftment3.
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In simulated estimations of the likelihood of complete clonal extinction and hematopoietic engraftment of stem-cell populations of different sizes (see table below), transplantation of a single stem cell (equivalent in humans to a cell dose of 1,000 CD34+ cells to account for loss during homing) will result in total failure of hematopoiesis in 90% of cases after 20 stem-cell cycles. This would be equivalent to a successful engraftment rate of only 10%. According to this simulation model, it would be necessary to transplant the order of 100 stem cells (105 CD34+ cells) to ensure sustained engraftment in 100% of recipients after 20 stem-cell cycles, but even then, 10% of grafts will fail after 100 cycles3 (see table below).
The number of stem cells that are necessary for a successful engraftment has been studied in many different trials as shown in the table below2. Most of these studies focused on the importance of higher number of CD34+ cells/kg in faster neutrophil and platelet engraftment. There were few studies identified that myeloid recovery is delayed but possible if less than <3x10^6 CD34+ cells/kg given in some patients.
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Platelet engraftment was affected more by lower than minimum CD34+ cells than neutrophil engraftment4,5 (see below figures).
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Fig 1. Kaplan-Meier plots of the probability of neutrophil recovery after high-dose chemotherapy with autologous peripheral-blood stem-cell transplantation as a function of the stem-cell dose. Thin solid line: ≥ 8 × 106 CD34+ cells/kg; thick solid line, < 8 but ≥ 5 × 106 CD34+ cells/kg; thick dashed line, < 5 but ≥ 2 × 106 CD34+ cells/kg; thin dashed line, < 2 × 106 CD34+ cells/kg.
There was only 2 day difference in median neutropenia between patients who received <2 x10^6 CD34 cells/kg and those who received 2-5 x10^6 CD34 cells/kg (see table below)5.
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Based on the above literature, I propose a study to revisit the question of what should be the minimum required hematopoietic cell dose to proceed with safe stem cell transplantation. If we demonstrate that CD34+ cell dose lower than 3 but greater than 1x10^6 CD34+ cells is adequate for successful engraftment with no significant delay (>14 days) in neutrophil engraftment, more patients with poor mobilizers can be eligible for transplant with less attempts to collect and/or re-mobilize them.
Patient Eligibility Population: The study population will include all patients who received peripheral blood autologous HCT after myeloablative conditioning between 2000 and 2013.
Data Requirements: This study will use data collected from CIBMTR research centers. No additional data is required.
Sample Requirements: No sample is needed
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Study Design: The goal of this study is to describe the clinical and engraftment outcomes in 4 cohorts defined by the number of stem cells (CD34+ cells/kg) received, <2, 2-3, 3-5, >5 as listed below after HCT.
Medians and ranges will be tabulated for continuous demographic variables and percentages for categorical demographic variables. Patient-related (age, gender, Karnofsky score at transplant), disease- related (disease type and status at transplant) and transplant-related variables (year of transplant, graft type, conditioning regimen, postransplant growth factor use, CD34+ cell dose for PBSCT patients will be analyzed.
Time to NE and PE will be described using cumulative incidence estimates. Patients who died within 21 days after transplant due to other causes before the engraftment (event) will not evaluable for engraftment endpoint. The primary aim of the study was to compare NE and PE after HCT across transplant recipients based on their CD34+ cell dose infused. Logistic regression will be used to analyze engraftment outcome at predetermined time points (day 14, 21, and 28 for NE; day 21, 28 and 60 for PE). Separate logistic regression models at each time point will be used rather than generalized estimating equation (GEE) regression models across multiple time points for simplicity of interpretation because there are many interactions between various covariates including the main effect (CD34+cell dose) and time.
Secondary objectives included 100-day mortality will be calculated using the Kaplan-Meier estimator with variance estimated by Greenwood's formula. Ninety-five percent confidence intervals for this outcome will be calculated across the four groups. We will test the null hypothesis that the probability of each outcome is the same among the four groups by using point-wise chi-square tests.
The covariates that may influence engraftment will be adjusted for using Cox proportional hazards regression models. The proportional hazards assumption will be assessed for each variable using time- dependent or graphical approach. Time-dependent covariates will be used when non proportional hazards are detected. Forward stepwise regression with alpha=0.05 will be used to build models. Two way interactions will be checked between the main effect and other variables in the model.
Outcomes: Hematopoietic recovery: Time to ANC > 0.5 x 109/L sustained for 3 consecutive days. Time to achive platelet count >20 x 109/L independent of platelet transfusion Transplant-related mortality (TRM): Death without progression in the first 100 days post-transplant or death in continuous remission. Relapse of NK-T cell lymphoma is the competing risk. Those who survive without relapse are censored at the time of last contact.
Variables to be Described and Analyzed: Patient related: Patient age, years: continuous Patient gender: male vs. female Race: Caucasian vs. African American vs. Hispanic vs. others Performance score: < 90 vs. ≥90 Disease-related: Time from diagnosis to HCT: continuous/ <12 vs. 12-18 vs. 18-24 vs. >24 mos Number of lines of chemotherapy for first transplant: 1 vs. 2 vs. >2
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Radiation used for initial treatment: yes/no Disease status prior to transplant:CR1, CR-2 or PR or primary refractory Transplant-related: Conditioning regimen Year of transplant: 2000-2004, 2005-2009, 2010-2013 CD34+ cell dose Post-transplant growth factor use
References: 1. Gianni AM: Where do we stand with respect to the use of peripheral blood progenitor cells? Ann Oncol 5:781-784, 1994 2. Siena S, Schiavo R, Pedrazzoli P, et al: Therapeutic relevance of CD34 cell dose in blood cell transplantation for cancer therapy. J Clin Oncol 18: 1360-1377, 2000
3. Gordon MY, Blackett NM: Some factors determining the minimum number of cells required for successful clinical engraftment. Bone Marrow Transplant 15:659-662, 1995 4. Glaspy JA, Shpall EJ, LeMaistre CF, et al: Peripheral blood progenitor cell mobilization using stem cell factor in combination with filgrastim in breast cancer patients. Blood 90:2939-2951, 1997 5. Sezer O, Possinger K, Metzner B, Illiger HJ, et al. Optimal CD34(+) cell dose in autologous peripheral- blood stem-cell transplantation. J Clin Oncol 2000 Sep 15;18(18):3319-20.
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Characteristics of adult patients who underwent first autologous peripheral blood transplant and reported to the CIBMTR, 2008-2013
Variable N (%) Number of patients 3212 Number of centers 138 Age at transplant, years 21 - 30 120 (4) 31 - 50 723 (23) 51-70 2369 (74) Disease NHL 1055 (33) HL 314 (10) MM 1843 (57) CD34 Cell dose x 10^6/kg < 3 895 (28) 3 - 5 917 (29) 5 - 8 628 (20) ≥ 8 557 (17) Unknown 215 (7)
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Study Proposal 1412-24
Study Title: What is the optimal stem cell source (peripheral blood versus bone marrow) for recipients aged ≥20 years with HLA-matched sibling donors?
George Chen, MD Roswell Park Cancer Institute Elm and Carlton Streets Buffalo, New York [email protected] Phone 716 845 8722
Justification and Hypothesis: For children and adolescents aged 8-20, allogeneic transplantation of HLA antigen identical sibling peripheral blood stem cells is associated with higher mortality than bone marrow. (Eapen, et al JCO 2004) In contrast, previous work showed that peripheral blood was superior to bone marrow as a stem cell source for adult and adolescent (aged 12-55) recipients of matched related donor grafts (Bensinger et al N Engl J Med. 2001). The donor age range for preferably using bone marrow as a stem cell source may be higher than 20 years of age, possibly up to 30 to 40 years of age.
Specific Aims: 1. Compare outcomes after bone marrow versus peripheral blood transplant by recipient age (<20 years, 20-39 years, 40-59 years, and >60 years). 2. Determine the recipient age range at which alloHCT clinical outcomes are equivalent for recipients of bone marrow versus peripheral blood grafts.
Inclusion criteria: 1. 6/6 HLA matched related sibling donors 2. AML, ALL, and NHL 3. First allogeneic hematopoietic cell transplants
Exclusion criteria: 1. T cell depletion 2. Cord blood transplants 3. Haploidentical donor transplants
Endpoints: 1. Overall survival 2. Progression free survival 3. Relapse 4. Acute graft versus host disease 5. Chronic graft versus host disease 6. Transplant related mortality (day 100 and 1 year) 7. Time to ANC and platelet recovery 8. Use of growth factor after cellular infusion.
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Other characteristics to study: 1. Total nucleated cell count 2. CD34+ cell count 3. Number of T cells in the grafts.
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Table 1: Characteristics of AML/ALL patients who underwent first allogeneic transplant in US/Canada with HLA identical sibling donor, BM/PB, and reported to the CIBMTR, 2005-2011
BM PB Variable N (%) N (%) Number of patients 212 1594 Number of centers 64 105 Recipient age at transplant, years Median (range), years 24 (10-71) 50 (12-75) 11 - 20 95 (45) 42 (3) 21 - 40 46 (22) 372 (23) 41 - 60 68 (32) 942 (59) ≥ 60 3 (1) 238 (15) Donor age at transplant, years Median (range), years 26 (1-76) 49 (1-82) 1 - 10 25 (12) 6 (<1) 11 - 20 55 (26) 57 (4) 21 - 40 60 (28) 369 (23) 41 - 60 60 (28) 910 (57) ≥ 60 12 (6) 252 (16) Disease AML 152 (72) 1242 (78) ALL 60 (28) 352 (22) TX year 2005 47 (22) 219 (14) 2006 41 (19) 186 (12) 2007 17 (8) 162 (10) 2008 34 (16) 327 (21) 2009 31 (15) 311 (20) 2010 35 (17) 265 (17) 2011 7 (3) 124 (8) Median follow-up of survivors (range), months 61 (2-99) 59 (3-109)
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Table 2: Distribution of recipient age and donor age
Recipient age at transplant, years Donor age at transplant, years Frequency 1-10 11-20 21 - 40 41 - 60 ≥ 60 11 - 20 29 73 35 0 0 21 - 40 1 38 312 65 2 41 - 60 1 1 82 807 119 ≥ 60 0 0 0 98 143
Table 3: Distribution of recipient age and donor age -AML
Recipient age at transplant, years Donor age at transplant, years Frequency 1-10 11-20 21 - 40 41 - 60 ≥ 60 11 - 20 16 45 21 0 0 21 - 40 1 23 195 39 2 41 - 60 1 1 62 654 104 ≥ 60 0 0 0 90 140
Table 4: Distribution of recipient age and donor age -ALL
Recipient age at transplant, years Donor age at transplant, years Frequency 1-10 11-20 21 - 40 41 - 60 ≥ 60 11 - 20 13 28 14 0 0 21 - 40 0 15 117 26 0 41 - 60 0 0 20 153 15 ≥ 60 0 0 0 8 3
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