8.5 GRAFT SOURCES AND MANIPULATION WORKING COMMITTEE
Co-Chair: Daniel Fowler, MD, NIH NCI Experimental Transplantation and Immunology
Branch
Email: [email protected]
Co-Chair: Miguel-Angel Perales, MD, Memorial Sloan Kettering Cancer Center
Email: [email protected]
Co-Chair: Vanderson Rocha, MD, PhD, Churchill Hospital
Email: [email protected]
Scientific Director: Mary Eapen, MBBS, MS, CIBMTR Milwaukee
Email: [email protected]
PhD Statistician: Mei-Jie Zhang, PhD, CIBMTR Milwaukee
Email: [email protected]
MS Statistician: Junfang Chen, MS, CIBMTR Milwaukee
Email: [email protected]
RECENTLY COMPLETED STUDIES
Study # GS05-01
Journal Citation: Ballen KK, Logan BR, Laughlin MJ, He W, Ambruso DR, Armitage SE, Beddard
RL, Bhatla D, Hwang WYK, Kiss JE, Koegler G, Kurtzberg J, Nagler A, Oh D, Petz LD, Price TH, Quinones RR, Ratanatharathorn V, Rizzo JD, Sazama K,
Scaradavou A, Schuster MW, Sender LS, Shpall EJ, Spellman SR, Sutton M, Weitekamp LA, Wingard JR, Eapen M. Effect of cord blood processing on
transplant outcomes after single myeloablative umbilical cord blood
transplantation. Biology of Blood and Marrow Transplantation: Journal of the
American Society for Blood and Marrow Transplantation. doi:10.1016/j.bbmt.2014.12.017. Epub 2014 Dec 24.
Abstract: Variations in cord blood manufacturing and administration are common, and the optimal practice is unknown. We compared processing and banking practices at 16 public cord blood banks (CBB) in the US, and assessed transplant outcomes on 530 single UCB MA transplantations for hematologic malignancies, facilitated by these banks. UCB banking practices were separated into three mutually exclusive groups based on whether processing was automated or manual; units were plasma and red blood cell reduced or buffy coat production method or plasma reduced. Compared to the automated processing system for units, the day-28 neutrophil recovery was significantly lower after transplantation of units that were manually processed and plasma reduced (red cell replete) (OR 0.19, p=0.001) or plasma and red cell reduced (OR 0.54, p=0.05). Day-100 survival did not differ by CBB. However, day-100 survival was better with units that were thawed with the dextran-albumin wash method compared to the “no wash” or “dilution only” techniques (OR 1.82, p=0.04). In conclusion, CBB processing has no significant effect on early (day 100) survival despite differences in kinetics of
CIBMTR Progress Report 2014 8.5 GRAFT SOURCES AND MANIPULATION WORKING COMMITTEE
neutrophil recovery implying advances in supportive care have in part overcome early mortality associated with slower neutrophil recovery.
Study # GS12-01
Journal Citation: Törlén J, Ringdén O, Le Rademacher J, Batiwalla M, Chen J, Erkers T, Ho V,
Kebriaei P, Keever-Taylor C, Kindwall-Keller T, Lazarus HM, Laughlin MJ, Lill M, O'Brien T, Perales M-A, Rocha V, Savani BN, Szwajcer D, Valcarcel D, Eapen M. Low CD34 dose is associated with poor survival after reduced-intensity
conditioning allogeneic transplantation for acute myeloid leukemia and myelodysplastic syndrome. Biology of Blood and Marrow Transplantation:
Journal of the American Society for Blood and Marrow Transplantation. 2014 Sep 1; 20(9):1262-1273. doi:10.1016/j.bbmt.2014.05.021. Epub 2014 Jun 2. PMC4127369.
Abstract: RIC/NMA regimens are increasingly used in allogeneic HCT. Reports have shown CD34+ dose to be important for transplant-outcome using MAC. The role of CD34+ dose of PBPCs has not been previously analyzed in a large population undergoing RIC/NMA HCT. We studied 1,054 patients aged 45-75 years, with AML or MDS transplanted between 2002 and 2011. Results of multivariate analysis showed that PBPC from HLA-matched siblings containing <4x106
CD34+/kg were associated with higher NRM (HR 2.03, p=0.001), overall mortality (HR 1.48, p=0.008), and lower neutrophil (OR 0.76, p=0.03) and platelet (OR 0.76, p=0.03) recovery. PBPCs from unrelated donors with CD34+ dose <6x106
CD34+/kg were also associated with higher NRM (HR 1.38, p=0.02) and overall mortality (HR 1.20, p=0.05). In contrast to reports after myeloablative HCT, CD34+ dose did not affect relapse or GVHD with either donor type. An upper cell dose limit was not associated with adverse outcomes. These data suggest that PBPC CD34+ dose >4x106 CD34+/kg and >6x106 CD34+/kg are optimal for HLA-
matched sibling and unrelated donor HCT, respectively.
Study # GS12-03
Journal Citation: Weisdorf D, Eapen M, Ruggeri A, Zhang M-J, Zhong X, Brunstein C, Ustun C,
Rocha V, Gluckman E. 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. Biology of Blood
and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation. 2014 Jun 1; 20(6):816-822.
doi:10.1016/j.bbmt.2014.02.020. Epub 2014 Feb 26. PMC4085692.
Abstract: We studied AML patients over age 50 in CR1 after adult URD (n 441 8/8 and n=94 7/8 HLA-matched) or UCB (n=205) transplantations. UCB recipients less often achieved CR1 within 8 weeks and more often received RIC and cyclosporin- based GVHD prophylaxis. Neutrophil recovery was slower in UCB (69% by day 28) vs 8/8 URD (97%) and 7/8 (91%) (p<0.001). Three-year TRM was higher and LFS lower with UCB (35% and 28%, respectively) vs 8/8 URD (27% and 39%). TRM was higher in 7/8 URD (41%, p=0.01), but LFS similar (34%, p=0.39). Three- year chronic GVHD was least in UCB (28%) vs 53% and 59% in 8/8 and 7/8 URD recipients. Three-year survival was 8/8 URD 43% (95% CI 38-48), UCB 30% (95%
8.5 GRAFT SOURCES AND MANIPULATION WORKING COMMITTEE CIBMTR Progress Report 2014
CI 23-37) (p=0.002) and 7/8 URD 37% (95% CI 27-46). AlloHCT for AML in CR1 with any of these grafts extends LFS for over a third of older patients. In the absence of an 8/8 HLA-matched URD or when transplantation is needed
urgently, UCB can provide extended survival. Less frequent chronic GVHD with UCB transplantation may be of particular value for older patients.
Study # SC11-02a
Journal Citation: Eapen M, Logan BR, Horowitz MM, Zhong X, Perales M, Lee SJ, Rocha V, Soiffer
RJ, Champlin RE. Bone marrow or peripheral blood for reduced-intensity
conditioning unrelated donor transplantation. Journal of Clinical Oncology.
doi:10.1200/JCO.2014.57.2446. Epub 2014 Dec 22.
Abstract: Background: There have been no randomized trials that have compared PB to BM grafts in the setting of RIC transplants for hematologic malignancy. As immune modulation plays a significant role in sustaining clinical remission after RIC, we hypothesize that higher GVHD associated with PB transplantation may offer a survival advantage. Methods: The primary outcome evaluated was OS. Cox regression models were built to study outcomes after transplantation of PB (N=887) relative to BM (N=219) for patients with AML, MDS, and NHL, the three most common indications for unrelated RIC transplantation. Transplants were performed in the US between 2000 and 2008. Conditioning regimens consisted of an alkylating agent and fludarabine and GVHD prophylaxis involved a CNI with either MTX or 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 rates of survival after transplantation of PB compared to BM: 34% vs 38% with CNI-MTX and 27% vs 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.
Study # SC11-02b
Journal Citation: Eapen M, Logan BR, Appelbaum FR, Antin JH, Anasetti C, Couriel DR, Chen J,
Maziarz RT, McCarthy PL, Nakamura R, Ratanatharathorn V, Vij R, Champlin RE. Long-term survival after transplantation of unrelated donor peripheral
blood or bone marrow hematopoietic cells for hematologic malignancy.
Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation. 2015 Jan 1; 21(1):55-59.
doi:10.1016/j.bbmt.2014.09.006. Epub 2014 Sep 22. PMC4272909.
Abstract: We sought to determine whether differences in chronic GVHD rates would lead to survival differences comparing 2,463 PB and 1,713 BM HCT recipients. Patients had acute leukemia, CML, or MDS; received MAC regimens and CNI 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
CIBMTR Progress Report 2014 8.5 GRAFT SOURCES AND MANIPULATION WORKING COMMITTEE
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 whereas either graft is suitable for other leukemias.
PRELIMINARY RESULTS
Study # GS08-01
Title: Reassessment of impact of donor age on outcomes after unrelated / related donor hematopoietic cell transplantation
Study Chair: Craig Kollman (Jaeb Center for Health Research)
MS Statistician: Mike Haagenson ([email protected])
PhD Statistician: Mei-Jie Zhang ([email protected]) Study Status: Submitted
Abstract: We analyzed 6,349 adult unrelated donor transplantations performed in 1988– 2006 to reexamine the effect of donor age and other donor characteristics
including donor-recipient HLA matching on transplant outcomes. Patients had a hematologic malignancy (ALL, AML, CML, MDS) and approximately 40% were in first complete remission or first chronic phase. 93% of transplantations used donors younger than 50 (median 35.8, range 18-61). The majority of patients received MA preparative regimens (88%) and BM grafts (62%). All patients received CNI-containing GVHD prophylaxis, and 20% received in vivo T cell depletion. We identified three donor characteristics associated with overall survival: donor age, high resolution donor-recipient HLA-match, and ABO blood group match. Risk adjusted 5-year survival rates were 37%, 33%, and 29% with donors aged 18-32, 33-50, and >50 years, respectively (p<0.0001). Corresponding hazard ratios were 1.13 (p=0.0004) for donors aged 33–50 years and 1.29 (p<0.001) for donors >50 years compared with donors aged 18-32 years. Mortality risks were higher with one (HR 1.24, p<0.0001) and two (HR 1.62, p<0.0001) HLA- mismatches compared with HLA-matched transplants and minor (HR 1.10, p=0.002) or major (HR 1.13, p=0.001) ABO blood group mismatch compared with ABO-matched transplants. A sub-analysis investigated the possibility that the association with donor age may be due to underlying genetic disparity between donor and recipient. That is, recipients with rare HLA genotypes tend to have fewer matched donors to choose from and thus more likely to receive a graft from an older donor. Recipient genotypes were assigned to quartiles using frequency data from 4 million NMDP donors as a reference. The lowest frequency quartile was associated with donors older than 50 (p<0.0001) and higher rates of HLA mismatching (p<0.001), but no association was found between genotype frequency and overall mortality. Acute GVHD risks were associated with donor age and HLA match and donor parity, the only donor characteristic associated with chronic GVHD. In summary, the data recommend the consideration of donor age and ABO blood group match to maximize
8.5 GRAFT SOURCES AND MANIPULATION WORKING COMMITTEE CIBMTR Progress Report 2014
survival when selecting among comparably HLA-matched adult unrelated stem cell donors for treatment of a hematologic malignancy.
Study # GS13-01
Title: Comparable 3-year disease-free survival regardless of anti-thymocyte globulin inclusion in pediatric myeloablative cord blood transplantation for acute lymphoblastic leukemia
Study Chairs: Doris Ponce (Memorial Sloan Kettering Cancer Center) Juliet Barker (Memorial Sloan Kettering Cancer Center)
Miguel-Angel Perales (Memorial Sloan Kettering Cancer Center)
MS Statistician: Junfang Chen ([email protected])
PhD Statistician: Rodney Sparapani ([email protected]) Study Status: Manuscript preparation
Abstract: Background: CB is routinely used as an alternative stem cell source for the treatment of children with acute leukemia and has been associated with high rates of DFS. However, one controversial issue in pediatric CB transplantation is the role of ATG as immunoprophylaxis. While inclusion of ATG in the
conditioning may decrease the risk of GVHD, it could potentially abrogate GVL effects and increase the risk of opportunistic infections. Thus, we compared outcomes in a uniform group of pediatric patients with ALL who underwent MA CB transplantation with or without ATG. Methods: Patients with ALL in
morphologic remission (CR1 n=106, CR2 n=146, CR3 n=45) aged ≤ 20 years transplanted between 01/2007-12/2011 with high-dose TBI-based conditioning and single or double unit CB grafts were eligible for analysis. CB units were 4-6/6 HLA-A,-B at the antigen-level, -DRB1 allele matched to the recipient, and had CB unit with cryopreserved total nucleated cell dose of ≥2.5x107/kg/unit. Cox
regression models were built to evaluate potential differences in outcome in ATG versus non-ATG CB transplant recipients. The primary endpoint was three-year DFS. Results: Of 297 patients, 92 received ATG and 205 did not. Age and disease status were similar in each group whereas ATG recipients were less likely to be CMV seropositive and more likely to receive single unit CB grafts. While
neutrophil engraftment was similar in each group, the risk of day 100 grade II-IV acute GVHD [30% (95% CI 21-40) vs 54% (95% CI 47-61), p=0.0002] and 3-year chronic GVHD [22% (95% CI 14-31) vs 43% (95% CI 36-50), p=0.0008] were decreased in ATG recipients. However, day 100 grade III-IV acute GVHD was comparable: 11% (95% CI 5-18) in ATG vs 17% (95% CI 12-23) in non-ATG recipients, p=0.15]. The 3-year TRM was similar in both groups: 16% (95% CI 10- 25) in ATG vs 17% (95% CI 13-23) in non-ATG recipients (p=0.98). Relapse was also similar in ATG and non-ATG recipients: 17% (95% CI 10-23) vs 27% (95% CI 21-34, p=0.12), respectively. In multivariate analysis, negative CMV serostatus was associated with reduced TRM risk [HR 0.55 (95% CI 0.30-0.98), p=0.004] whereas remission status CR2 or CR3 significantly increased relapse risk [HR 2.18 (95% CI 1.22-3.89), p=0.008], but inclusion of ATG had no effect on either outcome. With a median follow-up of survivors of 36 months (range 5-72), the 3- year DFS was 66% (95% CI 56-76) and 55% (95% CI 48-62) in ATG and non-ATG
CIBMTR Progress Report 2014 8.5 GRAFT SOURCES AND MANIPULATION WORKING COMMITTEE
recipients, respectively (p=0.23). The distribution of causes of death was similar in each group. In multivariate analysis, treatment failure risk was increased in patients transplanted in CR2 or CR3, but the inclusion of ATG had no effect (p=0.24). Conclusion: Inclusion of ATG in pediatric myeloablative CB transplant for ALL is associated with a decreased risk of grade II-IV acute GVHD and chronic GVHD but not severe grade III-IV acute GVHD. There was no difference in three-year DFS in each group, and multivariate analysis revealed ATG
inclusion had no impact upon treatment failure risk. These results indicate that optimization of both ATG and non-ATG conditioning platforms are needed in order to further improve CB transplantation survival in children with ALL. Unanswered questions include the impact of the formulation, dose, and timing of ATG administration. These findings cannot be extrapolated for other diagnoses, reduced intensity conditioning, or adults.
STUDIES IN PROGRESS
Study # GS13-02
Title: Matching between umbilical cord blood units in double umbilical cord blood transplantation
Study Chair: Claudio Brunstein (University of Minnesota Medical Center)
MS Statistician: Junfang Chen ([email protected])
PhD Statistician: TBD
Study Status: Protocol development
Study # GS14-01
Title: Outcomes after T-cell replete haploidentical and matched related and unrelated donor hematopoietic stem cell transplantation
Study Chairs: Olle Ringdén (Karolinska University Hospital, Centre for Allogeneic Stem Cell Transplantation)
Ephraim Fuchs (Johns Hopkins University Sidney Kimmel Cancer Center) Stefan Ciurea (The University of Texas MD Anderson Cancer Center) Sai Ravi Pingali (The University of Texas MD Anderson Cancer Center) Alberto Mussetti (Memorial Sloan Kettering Cancer Center)
Miguel-Angel Perales (Memorial Sloan Kettering Cancer Center)
MS Statistician: Junfang Chen ([email protected])
PhD Statistician: Mei-Jie Zhang ([email protected]) Study Status: Analysis in progress
8.5 GRAFT SOURCES AND MANIPULATION WORKING COMMITTEE CIBMTR Progress Report 2014 Study # GS14-02
Title: Association between recipient and donor sex and clinical outcome after allogeneic hematopoietic stem cell transplantation
Study Chairs: Philippe Armand (Dana Farber Cancer Institute) Haesook Kim (Dana Farber Cancer Institute)
MS Statistician: Junfang Chen ([email protected])
PhD Statistician: TBD