Independence in Umbilical Cord Blood and Allogeneic
Peripheral Blood Hematopoietic Cell Transplants
Melhem Solh,
1Claudio Brunstein,
1Shanna Morgan,
2Daniel Weisdorf
1Allogeneic hematopoietic cell transplantation (HCT) recipients have substantial transfusion requirements. Factors associated with increased transfusions and the extent of blood product use in umbilical cord blood (UCB) recipients are uncertain. We reviewed blood product use in 229 consecutive adult recipients of allogeneic HCT at the University of Minnesota: 147 with leukemia, 82 lymphoma or myeloma; 58% received unrelated UCB and 43% sibling donor peripheral blood stem cell (PBSC) grafts. Although neutrophil recov-ery was prompt (UCB median 17, range: 2-45 days, and PBSC 14, range: 3-34 days), only 135 of 229 (59% cumulative incidence) achieved red blood cell (RBC) independence and 157 (69%) achieved platelet independence by 6 months. Time to platelet independence was prolonged in UCB recipients (median UCB 41 versus PBSC 14 days) and in patients who had received a prior transplant (median 48 versus 32 days). Patients who received UCB grafts required more RBC through day 60 post-HCT (mean UCB 7.8 (95% confidence interval [CI] 6.7-8.9) versus PBSC 5.2 (3.7-6.7) transfusions,P5.04), and more platelet transfusions (mean 25.2 (95% CI 22.1-28.2) versus 12.9 (9.4-16.4),P\.01) compared to PBSC recipients.
Patients receiving myeloablative (MA) conditioning required more RBC and platelet transfusions during the first 2 months post-HCT compared to reduced-intensity conditioning (RIC) (7.4 versus 6.2,P 5.30 for RBC; 23.2 versus 17.5,P5.07 for platelets). Despite prompt neutrophil engraftment, UCB recipients had delayed platelet recovery as well as more prolonged and costly blood product requirements. Enhanced approaches to accelerate multilineage engraftment could limit the transfusion-associated morbidity and costs accompanying UCB allotransplantation.
Biol Blood Marrow Transplant 17: 710-716 (2011)Ó2011 American Society for Blood and Marrow Transplantation
KEY WORDS: Hematopoietic cell transplatation, Blood products in HCT, Platelet transfusion, RBC transfusion
INTRODUCTION
Over the past decade, there has been an increase in the use of allogeneic hematopoietic stem cell trans-plants (HCT) to treat hematologic malignancies and life-threatening nonmalignant hematologic disorders. This increase is attributable to newer techniques, safer preparative regimens, and expanded use of peripheral blood stems cells (PBSC) and umbilical cord blood (UCB) as graft sources [1]. Even using newer, less
intensive regimens, patients undergoing HCT will receive frequent blood products as part of their sup-portive therapy [2]. In light of substantial cost and some risk associated with blood product use, we pur-sued a detailed study of red blood cell (RBC) and plate-let (PLT) transfusion needs during an HCT course. Limited available data on the extent of blood product utilization after HCT include Osterwalder et al. [2]
reporting 39 HCT patients needing a range of 1 to 32 RBC and 1 to 11 PLT transfusions, and Pihlstedt et al.[3]describing 182 allogeneic transplants patients receiving 1 to 63 RBC and 2 to 394 PLT transfusions. We reviewed the blood product use in 229 consecutive patients at our institution and assessed factors associ-ated with greater transfusion needs.
MATERIALS AND METHODS Patients and Methods
Using prospectively collected data from the Uni-versity of Minnesota Blood and Marrow Transplant Database, we reviewed demographics and HCT
From the1Division of Hematology, Oncology, and Transplantation;
and 2Department of Laboratory Medicine and Pathology,
University of Minnesota, Minneapolis, Minnesota.
Financial disclosure:See Acknowledgments on page 715.
Correspondence and reprint requests: Daniel Weisdorf, MD, Blood and Marrow Transplant Program,Division of Hematology, On-cology and Transplantation,University of Minnesota, Mayo Mail Code 480; 420 Delaware Street SE, Minneapolis, MN 55455 (e-mail:weisd001@umn.edu).
Received July 16, 2010; accepted August 21, 2010
Ó2011 American Society for Blood and Marrow Transplantation 1083-8791/$36.00
doi:10.1016/j.bbmt.2010.08.017 710
complications in 229 consecutive adult patients who underwent allogeneic HCT. This was supplemented with complete and detailed transfusion data for the initial 3 months after HCT. We also detailed the pre-parative regimen, gender, race, and number of prior transplants to determine associated factors that may have altered their blood product utilization, RBC and PLT engraftment, and time to transfusion inde-pendence. The patients were divided into 4 groups based on the underlying disease: leukemia (n5147), lymphoma/myeloma (n582), nonmalignant disorders (43), and Fanconi anemia (7). The formal analysis was limited to the more homogeneous subset of patients with either leukemia or lymphoma/myeloma (N5229). The patients received a preparative regimen classified as either myeloablative (MA) plus filgrastim-mobilized sib-ling donor PBSC, reduced-intensity conditioning (RIC) plus sibling donor PBSC, UCB MA, or UCB RIC. Patients were given prophylaxis for graft-versus-host disease (GVHD) and supportive care based on the de-fined institutional guidelines and active investigational protocols.
Transfusion Support and Endpoints
Prophylactic platelet transfusions were adminis-tered to nonbleeding patients at a pretransfusion trigger of\10,000/mL unless additional risks of bleeding (eg, mucositis, plasma coagulation disorder, sepsis) were present. Treatment for therapeutic bleeding followed WHO guidelines. Red blood cell transfusions were administered for Hb\8 g/dL. All products were irradi-ated in vitro with 25 Gy prior to transfusion.
Transfusion independence was defined as the day of the last post-HCT PLT transfusion with no PLT transfusions in the following 7 days. RBC transfusion independence was defined as the day of the last RBC transfusion with no transfusion in the following 30 days. The total number of transfusion episodes and the total transfused PLT and RBC units during the transplant period were determined. Incidence and time to hematologic and RBC independence was de-termined for the total (N 5 229) and separately for the leukemia (n 5 147) and lymphoma/myeloma (n582) subgroups.
Statistical Analysis
Comparison of patients’ characteristics used thec2 test or Fisher’s exact test for categoric variables, and Wilcoxon’s rank-sum test for continuous variables. The cumulative incidence of RBC and PLT indepen-dence was used by treating deaths from other causes as competing risks. Univariate analysis was performed for differences in PLT independence and RBC indepen-dence, whereas risk factor analysis of time to RBC trans-fusion independence and time to PLT transtrans-fusion independence was performed using competing risk
regression analysis. Risk factors considered included: donor and graft source, conditioning regimen (myeloablative versus RIC), race, gender, and HCT number for those with a prior HCT. AllP values re-ported were 2-sided andPvalues\.05 were considered statistically significant. Marginal mean was used to report on the monthly and total number of PLT and RBC units used. Marginal mean is defined as the weighted average of the conditional means, with weights equal to the probability of being in the subgroup deter-mined by the corresponding value of the conditioning variable. Data analysis was performed using SAS soft-ware, version 8.0. The University of Minnesota institu-tional review board approved the data collection and analysis.
RESULTS
Patient Characteristics
We studied 229 consecutive allogeneic adult HCT recipients with hematologic malignancies receiving either PBSC or UCB grafts (Table 1). Of these, 140 were males (61%), 196 were Caucasian (86%), 131 (57%) received UCB, and 98 (43%) PBSC grafts. One hundred eighteen (52%) received RIC and 111 (48%) MA conditioning. Thirty-nine (17%) had a previous (38 autologous; 1 allogeneic) HCT. In the entire group, hematopoietic reconstitution manifest as sustained neutrophil recovery was prompt (UCB median 17, range: 2-45 days, and PBSC median 14, range: 3-34 days).
Transfusion Independence
Time to transfusion independence by donor type and conditioning regimen subgroups is shown in
Table 2. RBC independence occurred at a median of 44 (range: 7-141) days and PLT independence at a me-dian of 33 (range: 11-172) days after HCT. Although
Table 1. Patient Demographics and Graft Source
N Percent
Total 229 100%
Graft source and conditioning intensity
PBSC RIC 46 20% PBSC myeloablative 52 23% UCB RIC 72 31% UCB myeloablative 59 26% Sex Male/female 140/89 61%/39% Race White/other 196/31 86%/14% Transplant number 1 190 83% >1 39 17% Diagnosis Leukemia 147 64% Lymphoma/myeloma 82 36%
PBSC indicates peripheral blood stem cell; RIC, reduced-intensity conditioning; UCB, umbilical cord blood.
median time to RBC independence did not differ based upon donor source or HCT number, it was somewhat longer after MA conditioning (median 55 [range: 9-141] days versus 42 [7-127] days,P5.43) and among women (56 days versus 42 days,P5.26). The time to PLT independence was prolonged in UCB recipients compared to PBSC, although it did not reach statisti-cal significance (41 [range: 18-172] days versus 14 [11-161] days,P5.52) and in recipients of second HCT (48 days versus 32 days, P5.09). By 6 months after HCT, only 76 of 131 (58%) UCB recipients versus. 59 of 98 (60%) PBSC recipients were independent of RBC transfusions, and 92 of 131(70%) UCB and 65 of 98 (66%) PBSC were independent of PLT support.
Transfusion Independence within Disease Subgroups
Because either diagnosis or prior therapies con-founded the assessment of transfusion needs, we analyzed the cumulative transfusion requirements of patients with leukemia and with myeloma/lymphoma separately. Of 147 patients with leukemia, 98 (67%) received UCB grafts, 90 (62%) received MA conditioning regimen, and 126 patients (86%) had no prior transplant. Eighty-three patients (56%) achieved RBC indepen-dence within 6 months of transplant with a median time to RBC independence of 49 (range: 11-160) days. Time to RBC independence was somewhat longer in fe-males (63 versus 43 days,P5.27) and after MA condi-tioning (56 versus 43 days,P5 .21) but did not reach statistical significance. Ninety-five patients (65%) achieved PLT independence by 6 months with a median time of 35 days. Time to PLT independence was longer yet not significant after UCB (43 versus 25 days,P5.43) and in recipients of second transplants (57 days versus 34 days,P5.16). However, within the leukemia group, we observed no statistically significant differences in the time to PLT transfusion independence based on donor source (Figure 1), conditioning regimen, race, gender, or num-ber of transplants. Among the patients who received
RIC conditioning, median times to RBC and PLT trans-fusion independence in the UCB subgroup were 41.5 and 39 days and were not different from the PBSC subgroup (58 and 12 days).
Of 82 patients with lymphoma/myeloma, 32 (39%) had UCB grafts, 21 (26%) had MA conditioning, and 18 (22%) had received a prior transplant. Fifty-two patients (63%) achieved RBC independence by 6 months, with a median time to independence of 43 days. The median time to RBC independence was somewhat longer in females (52 versus 35 days,P5.27), recipients of UCB (40 versus 10 days,P5.10), those with prior HCT (54 versus 35 days,P5.02), and fol-lowing MA conditioning (47 versus 41 days,P5.03). Sixty-two patients (75%) achieved PLT independence by 6 months, with a median time of 21 days. The time to PLT independence was longer yet not statistically significant in recipients of UCB versus PBSC (40 ver-sus 10 days, P5 .16) and also in those with a prior transplant (48 versus 15 days, P5 .01). There were no differences in time to PLT independence based on conditioning regimen (21 days for myeloablative versus 20 days for RIC) or other clinical factors.
Multivariate Regression Analysis of Transfusion Independence
Using competing risk regression analysis, we eval-uated factors influencing the time to platelet or RBC independence in the different disease subgroups. In the lymphoma/myeloma group, there was a statistically significant longer time to RBC independence using myeloablative conditioning (P 5 .03) and following second HCTs (P5.02). Similarly, time to PLT inde-pendence was significantly longer after MA condition-ing (P5.01) and second HCT (P5.009). There was no significant difference based on the graft source (UCB versus PBSC, P 5 .16). However, within the larger subgroup of patients with leukemia, no factors were independently associated with the time to achieve either RBC or PLT independence.
Table 2. Time to RBC and Platelet Transfusion Independence
RBC Independence Platelet Independence
N RBC Independent by 6 months (n) Median time to independence (range, days) Platelet Independent by 6 months (n) Median time to independence (range, days) Total 229 135 44 (7-141) 157 33 (11-172) Graft source UCB 131 76 44.5 92 41 PBSC 98 59 44 65 14 Conditioning RIC 118 68 41.5 80 29 Myeloablative 111 67 55 77 35 Transplant number >1 39 17 44 21 48 1 190 118 44.5 136 32
Transfusion Requirements in Patients with Leukemia
Patients in the larger leukemia subgroup were further studied to detail the number of transfusions re-quired during each of the first 3 months after HCT. The marginal mean number of RBC and PLT transfu-sions received in each month was compared in cohorts defined by the graft source (UCB versus PBSC) and con-ditioning regimen intensity (MA versus RIC) (Table 3). Compared to PBSC, UCB recipients required a greater number of RBC transfusions during each of the first 3 months posttransplantation, and this reached statistical significance for months 2 and 3. Patients who received MA conditioning also had a greater need for PLT transfusions (Table 3). Similarly, during each of the first 3 months post-HCT, UCB recipients re-quired significantly more PLT transfusions than PBSC (P\.01). The marginal mean and total number of both PLT and RBC transfusions were significantly higher in UCB recipients during the first 3 months
post-HCT (Figure 2). MA conditioning was associated with significantly increased PLT requirements during month 1, and a similar trend in months 2 and 3, but RBC requirements were similar in both conditioning groups.
DISCUSSION
Recipients of HCT often have substantial transfusion requirements, particularly in the minority with either delayed recovery of hematopoiesis, alloimmunization to PLTs, or GVHD. Even using standard thresholds for blood product administration such as RBC for Hb\8 g/dL or PLT for a count\10,000/mL, transfusion needs vary substantially. The PLADO trial questioned the ne-cessity of PLT prophylactic transfusions by noting that major bleeding episodes are infrequent and not clearly associated with PLT counts, even in the severely throm-bocytopenic patient [4]. The majority of hospitalized allogeneic HCT recipients are vulnerable to infections or febrile, have added risks of bleeding because of muco-sitis, plasma coagulation abnormalities, or similar com-plications that suggest a need for a higher PLT count trigger for transfusion. We restricted our detailed analy-sis of total blood product usage and time to transfusion independence in allogeneic HCT patients with leukemia because they are usually multiply transfused and possibly alloimmunized prior to HCT.
Transfusion guidelines in HCT patients are tradi-tionally extrapolated from other subgroups of pancyto-penic patients, as specific data from HCT are less well defined[5-8]. The threshold for PLT transfusion in HCT recipients has changed over time, with earlier guidelines suggesting 20,000/mL as an acceptable threshold for prophylaxis[9]. Several reports showed that a platelet threshold of less than 20,000/mL can be safely used in acute leukemia and HCT recipients
[10-12]. In some reports, lowering the transfusion
Figure 1. Time to RBC and platelet independence. In leukemia pa-tients, shown is the cumulative incidence of the time to transfusion in-dependence (untransfused Hb.8 g/dL; PLT.20,000/mL) in recipients of UCB or sibling donor PBSC grafts.
Table 3. Marginal Mean RBC and Platelet Transfusions (HCT for Leukemia)
Month 1 Month 2 Month 3
N Mean 95% CI P* Mean 95% CI P Mean 95% CI P*
All 146 RBC 4.5 (4.0-5.0) 7.0 (6.0-7.9) 7.7 (6.6-8.8) Platelets 14.5 (13.6-15.7) 21.2 (18.7-23.8) 23.7 (20.2-27.2) Graft source UCB 98 RBC 4.8 (4.2-5.4) .18* 7.8 (6.7-8.9) .04 8.9 (7.5-10.2) .02 PBSC 48 3.9 (3.1-4.8) 5.2 (3.7-6.7) 5.4 (3.7-7.0) UCB Platelets 16.1 (14.7-17.6) <.01 25.2 (22.1-28.2) <.01 28.5 (24.1-32.8) <.01 PBSC 11.0 (8.7-13.2) 12.9 (9.4-16.4) 13.6 (9.3-17.9) Conditioning intensity Myeloablative 90 RBC 4.8 (4.3-5.4) .16 7.4 (6.3-8.5) .30 8.4 (7.0-9.8) .17 RIC 56 4.0 (3.1-4.9) 6.2 (4.6-7.8) 6.4 (4.6-8.3) Myeloablative Platelets 15.8 (14.5-17.2) <.01 23.2 (20-26) .07 26.4 (22.2-30.6) .07 RIC 12.1 (9.6-14.6) 17.5 (12.9-22.2) 18.4 (12.5-24.2)
CI indicates confidence interval; RIC, reduced-intensity conditioning; RBC indicates red blood cells; PBSC, peripheral blood stem cells; UCB, umbilical cord blood; HCT, hematopoietic cell transplant.
threshold from 20,000 to 10,000/mL in stable marrow transplant recipients did not increase severe bleeding or death because of bleeding, but reduced PLT use by about 25% [13]. The current threshold of 10,000/mL is used by most centers to initiate prophylactic PLT transfusions[5,8,14].
The demand for RBC transfusion in HCT has de-creased in recent years. This could be related to the use of less intensive regimens and implementing granulo-cyte colony stimulating factor (G-CSF) into the trans-plant process, hence decreasing oral or gastrointestinal bleeding episodes related to prolonged mucositis[15]. A transfusion trigger of Hb\8 g/dL is used at our and most centers, although higher thresholds are indi-cated for patients with cardiovascular comorbidities
[16]. Higher thresholds have also been suggested for transplant recipients with acute GVHD (aGVHD),
delayed engraftment, major ABO incompatibility, and high-risk malignancies[3].
RIC has been more widely used in recent years be-cause of the decreased risk of associated toxicities and the reliance on a more pronounced graft-versus-tumor effect for cancer control[17]. Prebet et al.[18]reported data on PLT recovery and transfusion needs in 145 adult allogeneic sibling donor HCT recipients with RIC. PLT recovery (.20,000/mL) was seen at a median of 9 days with 68% of the patients demonstrating a PLT count.100,000/mL by day1100. A lower PLT count prior to conditioning and the presence of aGVHD (grade III-IV) significantly influenced day1100 PLT recovery and PLT transfusion needs. Similarly, the me-dian time to PLT independence in our RIC cohort is 14 days, even with 61% receiving UCB grafts, which may delay engraftment compared to other donor sources
[19]. Other unrelated donor sources and MA condition-ing are also associated with delayed PLT recovery.
Median time to more robust PLT recovery (.50,000/mL) in UCB HCT has been reported to be as late as day190; and the success was related to the patient’s age, diagnosis, graft cell dose infused, post-HCT infection, and the development of GVHD
[20]. Although the incidence of PLT transfusion inde-pendence at 6 months did not differ, we observed that UCB grafts led to delayed PLT independence com-pared to other donor sources [21] and an overall greater transfusion burden. Delayed engraftment, a precursor to PLT recovery in UCB recipients, has been associated with a lower CD341cell dose, recipi-ent weight, and HLA disparity[22].
We also observed less frequent and later transfu-sion independence in recipients having a prior HCT. In our cohort of 39 repeat HCT recipients, this delay could be because of the graft source, prior marrow stromal damage from extensive prior treatment, or their specific diagnoses (most often secondary acute myelogenous leukemia [AML]/myelodysplastic syn-drome [MDS]), although we could not fully character-ize the pathogenesis of delayed PLT recovery in this small subgroup. In comparison, Baron et al. [23] re-ported on 147 patients receiving a very low-intensity, nonmyelablative regimen followed by either matched related (n 5 62) or unrelated (n 5 85) allogeneic RIC HCT because of disease relapse after a prior autologous or allogeneic transplant who needed only a median of 0 and 4 for PLT and RBC transfusions, re-spectively. Martino et al.[24]reported a median of 11 days to obtain a PLT count of.20,000/mL in a similar group of sibling donor RIC HCT recipients who had relapsed after a prior autologous transplant.
RBC transfusion needs in the first 60 days after allogeneic HCT were observed at a median of 4 RBC units for RIC and 12 units for MA conditioning
[25]; slightly more in patients with leukemia (6 units for RIC and 13 units for MA). Another report
Figure 2. Marginal mean of platelet (A) and RBC (B) transfusion over time. Shown are the marginal means of cumulative PLT (A) and RBC (B) transfusions over the first 6 months post-HCT for patients with leuke-mia. UCB recipients have significantly greater mean PLT (P\.01) and RBC (P5.02) transfusion needs compared to PBSC.
described infusion of only 2 RBC units after RIC[26]. Factors associated with increased RBC transfusion requirements include aGVHD, ABO incompatible donor, and high-risk malignancy [3]. Our data show that both MA conditioning and UCB grafts are associ-ated with higher transfusion requirements.
We previously analyzed the increased cost for UCB compared to matched related or unrelated donor HCT with 11% to 14% of the costs in different HCT settings attributable to transfusion product needs[27]. Our cur-rent data show that patients receiving UCB grafts required a mean of 15 extra PLT transfusions and 4 extra RBC transfusions during the first 3 months post-HCT. Based on costs from the Centers for Medicare and Med-icaid Services 2007 reimbursement report on blood transfusion (leukoreduced irradiated RBC unit: $227; apheresis PLT irradiated leukoreduced: $614), the in-crease in transfusion requirements seen with UCB grafts augmented transfusion-associated costs by approxi-mately $11,000 during the first 3 months post-HCT, equating to $122 per day, plus additional costs for pre-medications, infusion supplies, and the nursing effort for transfusion and monitoring.
Our observations suggest that RBC and PLT trans-fusion requirements are somewhat increased with UCB grafts, although are moderated by RIC HCT. The use of UCB as a donor source may delay transfusion inde-pendence and modestly increase the overall costs of HCT as well. Additional efforts to improve transfusion practices and augment hematopoietic recovery may limit both the transfusion burden and the costs of prolonged RBC and PLT transfusions.
ACKNOWLEDGMENTS
Financial disclosure:No financial conflict of interest related to this study.
REFERENCES
1. Hiemenz JW. Management of infections complicating alloge-neic hematopoietic stem cell transplantation.Semin Hematol. 2009;46:289-312.
2. Osterwalder B, Gratwohl A, Reusser P, Tichelli A, Speck B. Hematological support in patients undergoing allogenetic bone marrow transplantation.Recent Results Cancer Res. 1988;108:44-52. 3. Pihlstedt P, Paulin T, Sundberg B, Nilsson B, Ringden O. Blood transfusion in marrow graft recipients.Ann Hematol. 1992;65: 66-70.
4. Slichter SJ, Kaufman RM, Assmann SF, et al. Dose of prophylac-tic platelet transfusions and prevention of hemorrhage.N Engl J Med. 362:600–613.
5. Diedrich B, Remberger M, Shanwell A, Svahn BM, Ringden O. A prospective randomized trial of a prophylactic platelet transfu-sion trigger of 1010(9) per L versus 3010(9) per L in allo-geneic hematopoietic progenitor cell transplant recipients.
Transfusion. 2005;45:1064-1072.
6. Klumpp TR, Herman JH, Innis S, et al. Factors associated with re-sponse to platelet transfusion following hematopoietic stem cell transplantation.Bone Marrow Transplant. 1996;17:1035-1041.
7. Nevo S, Fuller AK, Zahurak ML, et al. Profound thrombocyto-penia and survival of hematopoietic stem cell transplant patients without clinically significant bleeding, using prophylactic platelet transfusion triggers of 1010(9) or 2010(9) per L.
Transfusion. 2007;47:1700-1709.
8. Nevo S, Fuller AK, Hartley E, Borinsky ME, Vogelsang GB. Acute bleeding complications in patients after hematopoietic stem cell transplantation with prophylactic platelet transfusion triggers of 1010(9) and 2010(9) per L.Transfusion. 2007; 47:801-812.
9. Gaydos LA, Freireich EJ, Mantel N. The quantitative relation between platelet count and hemorrhage in patients with acute leukemia.N Engl J Med. 1962;266:905-909.
10. Rebulla P, Finazzi G, Marangoni F, et al. The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto.N Engl J Med. 1997;337:1870-1875.
11. Wandt H, Frank M, Ehninger G, et al. Link, safety and cost ef-fectiveness of a 1010(9)/L trigger for prophylactic platelet transfusions compared with the traditional 2010(9)/L trigger: a prospective comparative trial in 105 patients with acute mye-loid leukemia.Blood. 1998;91:3601-3606.
12. Aderka D, Praff G, Santo M, Weinberger A, Pinkhas J. Bleeding due to thrombocytopenia in acute leukemias and reevaluation of the prophylactic platelet transfusion policy.Am J Med Sci. 1986; 291:147-151.
13. Gil-Fernandez JJ, Alegre A, Fernandez-Villalta MJ, et al. Clinical results of a stringent policy on prophylactic platelet transfusion: non-randomized comparative analysis in 190 bone marrow transplant patients from a single institution. Bone Marrow Transplant. 1996;18:931-935.
14. Zumberg MS, del Rosario ML, Nejame CF, et al. A prospective randomized trial of prophylactic platelet transfusion and bleed-ing incidence in hematopoietic stem cell transplant recipients: 10,000/L versus 20,000/microL trigger. Biol Blood Marrow Transplant. 2002;8:569-576.
15. Nevo S, Vogelsang GB. Acute bleeding complications in patients after bone marrow transplantation.Curr Opin Hematol. 2001;8:319-325.
16. Gajewski JL, Johnson VV, Sandler SG, Sayegh A, Klumpp TR. A review of transfusion practice before, during, and after hema-topoietic progenitor cell transplantation. Blood. 2008;112: 3036-3047.
17. Niederwieser D, Maris M, Shizuru JA, et al. Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unre-lated donors and postgrafting immunosuppression with cyclo-sporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases.Blood. 2003;101:1620–1609.
18. Prebet T, Ladaique P, Ferrando M, et al. Platelet recovery and transfusion needs after reduced intensity conditioning alloge-neic peripheral blood stem cell transplantation.Exp Hematol. 38:55–60.
19. Brunstein CG, Barker JN, Weisdorf DJ, et al. Intra-BM injec-tion to enhance engraftment after myeloablative umbilical cord blood transplantation with two partially HLA-matched units.Bone Marrow Transplant. 2009;43:935-940.
20. Rubinstein P, Carrier C, Scaradavou A, et al. Outcomes among 562 recipients of placental-blood transplants from unrelated donors.N Engl J Med. 1998;339:1565-1577.
21. Wagner JE, Rosenthal J, Sweetman R, et al. Successful trans-plantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease.Blood. 1996;88:795-802. 22. Matsuno N, Wake A, Uchida N, et al. Impact of HLA disparity
in the graft-versus-host direction on engraftment in adult patients receiving reduced-intensity cord blood transplantation.
Blood. 2009;114:1689-1695.
23. Baron F, Storb R, Storer BE, et al. Factors associated with outcomes in allogeneic hematopoietic cell transplantation with
nonmyeloablative conditioning after failed myeloablative hema-topoietic cell transplantation.J Clin Oncol. 2006;24:4150-4157. 24. Martino R, Caballero MD, de la Serna J, et al. Low transplant-related mortality after second allogeneic peripheral blood stem cell transplant with reduced-intensity conditioning in adult patients who have failed a prior autologous transplant. Bone Marrow Transplant. 2002;30:63-68.
25. Ivanov V, Faucher C, Mohty M, et al. Decreased RBCTs after re-duced intensity conditioning allogeneic stem cell transplantation: predictive value of prior Hb level.Transfusion. 2004;44:501-508.
26. Weissinger F, Sandmaier BM, Maloney DG, Bensinger WI, Gooley T, Storb R. Decreased transfusion requirements for patients receiving nonmyeloablative compared with conventional peripheral blood stem cell transplants from HLA-identical siblings.Blood. 2001;98:3584-3588.
27. Majhail NS, Mothukuri JM, Brunstein CG, Weisdorf DJ. Costs of hematopoietic cell transplantation: comparison of umbilical cord blood and matched related donor transplantation and the impact of posttransplant complications. Biol Blood Marrow Transplant. 2009;15:564-573.
