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OGBIMI, A., G. OYEYINKA, and A. OMU. "ABO blood group incompatibility and infertility in Nigerian couples." Immunology Letters 14, no. 4 (April 1987): 299–301. http://dx.doi.org/10.1016/0165-2478(87)90008-3.
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Siqi, Cheng, Baolin Tang, Xiaoyu Zhu, Huilan Liu, Kaidi Song, Xiang Wan, Wen Yao, Jian Wang, and Zimin Sun. "Impact of ABO Blood Group Incompatibility on Outcomes after Single-Unit Umbilical Cord Blood Transplantation for Malignant Hematological Disease." Blood 134, Supplement_1 (November 13, 2019): 2055. http://dx.doi.org/10.1182/blood-2019-130699.
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Objective In contrast to solid organ transplantation, ABO blood group incompatibility was acceptable in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, reports of the effect of donor-recipient ABO incompatibility on long-time survival, graft-versus-host disease (GVHD), and relapse after allo-HSCT were controversial. Relatively few reports existed on the effects of ABO incompatibility after umbilical cord blood transplantation (UCBT). The aim of this study was to investigate the role of major ABO incompatibility on RBC transfusion burden, hematologic recovery, GVHD, transplant-related mortality (TRM), relapse, and overall survival (OS) in UCBT for malignant disease. Methods This retrospective study included 587 malignant hematonosis patients who received myeloablative single-unit unrelated donor UCBT at our center between May 2008 and June 2018. Median follow-up time of the patients alive was 40.7 months (range: 12.0-134.6 months). A total of 230 (39.2%) patients received an ABO-identical transplant, and 357 (60.8%) received ABO-mismatched transplants, including 161 (27.4%) minor, 141 (24.0%) major, and 55 (9.4%) bidirectional ABO-incompatible UCBTs. All patients received myeloablative conditioning regimens and cyclosporine A (CsA) combined with mycophenolate mofetil (MMF) as a GVHD prophylaxis. Results A comparison of ABO compatibility and incompatibility demonstrated no significant differences (P>0.05) in the cumulative incidence of neutrophil, platelet, and red blood cell engraftment . There was no significant difference in the cumulative incidence of grades Ⅱ to Ⅳ aGVHD (P= .527) and Ⅲ to Ⅳ aGVHD (P= .949) among the 4 groups (Figure A , B). In univariate analysis, ABO blood group incompatibility was not associated with cumulative incidence of 180d TRM (Figure C, P= .602). The overall 3-year survival had no statistically significant differences among the 4 groups (Figure D; P= .384). Further, 11 patients were excluded from the analysis of post-UCBT RBC transfusion burden because of missing data and non-red blood cell engraftment. Of the remaining 576 patients, the median number of RBC transfusions during transplant days 0 to 60 was 4 (range, 0 to 106). There was no significant difference in the transfusion burden among all ABO blood type mismatch groups (Table 1, P = .069). Furthermore, none of the patients developed pure red aplastic anemia (PRCA) after UCBT. Conclusion The results showed that ABO blood group incompatibility had no significant impact on hematologic engraftment, the occurrence of GVHD, and the survival of malignant hemoblastosis. Patients with myeloablative single-unit UCBT may not develop PRCA; Donor-recipient ABO incompatibility may not be the major consideration in the selection of umbilical cord blood. Disclosures No relevant conflicts of interest to declare.
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Kahwaji, Joseph, Ashley A. Vo, and Stanley C. Jordan. "ABO blood group incompatibility: a diminishing barrier to successful kidney transplantation?" Expert Review of Clinical Immunology 6, no. 6 (November 2010): 893–900. http://dx.doi.org/10.1586/eci.10.78.
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Maria Elfving, A., Bengt A. Lindberg, M. Landin-Olsson, Christine S. Hampe, Åke Lernmark, and Sten-A. Ivarsson. "Islet Cell Autoantibodies in Cord Blood from Children with Blood Group Incompatibility or Hyperbilirubinemia." Autoimmunity 36, no. 2 (January 2003): 111–15. http://dx.doi.org/10.1080/0891693031000073109.
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Tsuji, Masanori, Atsushi Wake, Naoyuki Uchida, Kazuya Ishiwata, Nobuaki Nakano, Shinsuke Takagi, Hisashi Yamamoto, et al. "Impact of ABO Imcompatibility On Acute GvHD and Thrombotic Microangiopathy After Reduced-Intensity Cord Blood Transplantation." Blood 114, no. 22 (November 20, 2009): 2298. http://dx.doi.org/10.1182/blood.v114.22.2298.2298.
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Abstract Abstract 2298 Poster Board II-275 Introduction: Althouth ABO blood type is one of two antigen system for transplantation, the effect of ABO incompatibility on transplantation outcome still remains controversy. Furthermore, there is little data about ABO incompatibility on the outcome of unrelated cord blood transplantation following reduced-intensity conditioning (RI-CBT). Design and Methods: We retrospectively analyzed data of 155 patients who underwent RI-CBT performed at Toranomon Hospital from January 2005 to December 2008. The patients include 45 ABO-identical, 47 minor, 43 major, and 20 bidirectional ABO mismatched. All patients were performed using fludarabine-based reduced-intensity conditioning, and 114 patients (74%) were performed using TBI-containing regimen. Median age were 57 years-old and 94 patients (61%) were over 55 years-old. We evaluated the association between ABO incompatibility and neutrophil engraftment, one-year overall survival (OS) ; one-year non-relapsed mortality (NRM) ; and one-year relapse rate. We also analyzed the incidence of pre-engraftment immune reaction (PIR), acute graft-versus-host disease (GvHD) including severity, and thrombotic microangiopathy (TMA). Results: There were no significant differences in neutrophil-engraftment time, reticulocyte-engraftment time, and the incidence of PIR. The incidence of acute GvHD and grade 2-4 acute GvHD were significantly higher in major/bidirectional ABO-incompatible group than ABO-identical/minor ABO-incompatible group (respectively P=0.0008 and P=0.0116). The incidence of TMA tended to be higher in minor/bidirectional ABO-incompatible group than ABO-identical/major ABO-incompatible group (P=0.0637). There were no significant differences in one-year OS, NRM, and relapse rate. In multivariate analysis, risk factors of acute GvHD were age over 55, TBI-containing regimen, CD34-positive cells>0.7×10e5/kg, and major/bi-directional ABO incompatibility, and those of TMA were grade 3-4 acute GvHD and minor/bi-directional ABO incompatibility. Discussion: This study showed major-directional ABO incompatibility setting increased the incidence of acute GvHD. Sex incompatibility and HLA incompatibility were not significantly influenced the incidence of acute GvHD. The use of steroid for severe GvHD and the expression of ABO antigen on the surface of vascular endothelial cell may influence pathogenesis of TMA. Further studies including larger patients numbers are required to elucidate the impact of ABO incompatibility on the clinical outcome of RI-CBT. Disclosures: No relevant conflicts of interest to declare.
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Obukhova, P. S., A. V. Kachanov, N. A. Pozdnyakova, and M. M. Ziganshina. "AB0-incompatibility of mother and fetus: the role of anti-glycan alloantibodies in the hemolytic disease of newborns." Medical Immunology (Russia) 23, no. 1 (March 1, 2021): 17–34. http://dx.doi.org/10.15789/1563-0625-aom-1977.
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The mother and fetus incompatibility due to Rh-factor, blood group or other blood factors can lead to hemolytic disease of the fetus and newborn (HDN). HDN is a clinical disease condition of the fetus and newborn as a result of hemolysis, when maternal IgG alloantibodies cross the placenta and destroy the red blood cells of the fetus and newborn. The child disease begins in utero and can dramatically increase immediately after birth. As a result, hyperbilirubinemia and anemia develop, that can lead to abortions, serious complications, or death of the neonates in the absence of proper therapy. The range of HDN has changed significantly now compared to previous decades. Half a century ago, HDN was considered an almost complete synonym of RhD-alloimmunization, and this was a frequent problem for newborns. By now due to the high effective of Rh-conflict prevention, immunological AB0-conflicts have become the most common cause of HDN. The review aimes to one of the main causes of jaundice and anemia in neonates at present, i.e. HDN due to immunological AB0-conflict of mother and newborn (AB0-HDN). The main participants of the AВ0- incompatibility mother and child are considered, namely A- and B-glycans, as well as the corresponding anti-glycan alloantibodies. Close attention is paid to the structure features of glycan alloantigens on the red blood cells of the fetus and adult. The possible correlation of the frequency and severity of HDN with the blood group of mother and child, as well as with the titer of maternal alloantibodies, has been considered. The influence of immunoglobulin G subclasses on the AB0-HDN development has been evaluated. In most cases, AB0-HDN appear when the mother has the blood group 0, and the fetus has the group A (subgroup A1) or the group B. Other rare incidences of AB0-incompatibility with severe course are occurred. As a whole the etiology of AB0-HDN is complex and the HDN severity is influenced by many factors. The authors have analyzed statistical data, as well as the prevalence of AB0-incompatibility and AB0-HDN in various regions of the world. Current approaches to the diagnosis of AB0-HDN are discussed in addition. By now the problems of AB0- HDN occurrence and developing of ways to overcome this disease remain relevant.
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Curtis, Brian R., Janice G. McFarland, Andrea Fick, Andrew J. Lochowicz, Robert H. Ball, and Aster H. Richard. "Neonatal Alloimmune Thrombocytopenia (NATP) Associated with Maternal-Fetal Incompatibility for Blood Group B." Blood 106, no. 11 (November 16, 2005): 955. http://dx.doi.org/10.1182/blood.v106.11.955.955.
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Abstract In most individuals, A and B blood group antigens are weakly expressed on platelets, allowing ABO incompatible platelets to be tolerated when transfused. However, in a minority of normal subjects (high expressers, H-Exp), platelets carry 10–20 times the usual number of A or B epitopes (up to 20,000/platelet, Blood2000;96:1574). Post-transfusion survival of incompatible H-Exp platelets has not been systematically studied. We recently encountered a family in which NATP in two infants appears to have been caused by maternal anti-B reacting with H-Exp fetal platelets inherited from a father with the group B H-Exp trait. The first two children (C1 and C2) born to a G4P2 group O mother and A2B father were positive for blood group B, and had neonatal thrombocytopenia (TP) (C1 = 33K/μL, C2 = 61K/μL), anemia, positive direct antiglobulin test, elevated reticuloytes and hyperbilirubinemia requiring phototherapy. C1 required 3 platelet transfusions and RBC transfusion, and C2 required RBC transfusion. Both recovered in the immediate neonatal period. A third child (C3) inherited blood group A2 from the father and was born with a normal platelet count. The parents were incompatible for HPA-2b and -3b, but no platelet-specific antibodies were detected in maternal serum. High titer IgG antibodies were detected in maternal serum against father’s platelets in both flow cytometry and modified antigen capture ELISA. This activity was completely removed by absorption with normal, washed group B RBCs. When tested by flow cytometry with monoclonal anti-B and anti-A, the father’s platelets were shown to carry 17 times the normal level of B antigen, and only trace amounts of A antigen. We previously showed that the potent glycosyltransferase activity associated with the H-Exp trait causes essentially all H antigen on platelets and RBCs to be converted to A and/or B antigen. Consistent with this, father’s platelets and RBCs were found to express no detectable H. Quantitation of B and H antigens on platelets and RBCs from C1 and C2 is pending receipt of samples. Findings made in this family indicate that maternal anti-B (and presumably anti-A) IgG antibodies can cause NATP in infants with the ABO “high expresser” trait. Maternal-fetal ABO incompatibility should be considered as a cause of NATP when maternal antibodies against platelet-specific antigens cannot be demonstrated. The possibility that ABO incompatibility can aggravate thrombocytopenia caused by antibodies against recognized platelet-specific antigens also deserves consideration.
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Rao, Latha B., Zohaib Ahmed, and Bulent Ozgonenel. "The Clinical Spectrum of ABO Incompatibility and Hemolytic Disease in the Newborn." Blood 120, no. 21 (November 16, 2012): 1182. http://dx.doi.org/10.1182/blood.v120.21.1182.1182.
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Abstract Abstract 1182 Introduction: ABO hemolytic disease of the newborn occurs almost exclusively in infants of blood group A or B who are born to group O mothers. Although ABO incompatibility is common, its related hemolytic disease has been reported to be low. In this study, we aimed to investigate the rate of direct anti-globulin test (DAT) positivity and clinical events, such as hyperbilirubinemia or anemia in infants born to group O mothers. Methods: Using the charge code for cord blood evaluation, we were able to identify all cord blood evaluations from January 1, 2006 - December 31, 2007, and then select out the ABO incompatible births from group O mothers. We then reviewed the electronic medical records for demographic, clinical and laboratory information. Clinical events (anemia, jaundice, hemolytic disease) were investigated only in babies born at 37 weeks or higher gestation. Chi-square tests were used to cross-tabulate clinical events, demographic parameters (gender, ethnicity), and laboratory parameters (AO versus BO incompatibility, DAT-positivity). Results: There were 10,891 live births during the two-year period and 1519 (14%) of these were ABO incompatible. ‘Black’ ethnicity was registered in 80% of these babies. AO and BO incompatibility comprised 57.8% and 42.2% of the cases, respectively. 5.3% of the cases had concomitant Rh incompatibility. DAT was positive in 16.7% of the cases: 13.8% weakly or 1+ positive, and 2.9% 2+ or 3+ positive. DAT was more commonly positive among BO-incompatible cases compared to AO-incompatible cases (21.7% versus 13.1%). Among blacks, DAT-positivity in BO incompatibility was more common (24.9% among blacks compared to 7.8% among non-blacks, p<0.001). Concomitant Rh incompatibility did not affect DAT positivity rate. Among AO-incompatible babies, DAT-positivity was more frequent among females (15.5% in females vs 10.8% in males, p=0.045). 1299 babies were born at term (3 37 weeks gestation).of these infants, hyperbilirubinemia (defined as indirect bilirubin 3 8 mg/dL) was detected in 17.3% of babies. This was significantly associated with DAT positivity (40.6% in DAT-positive cases vs 12.3% in DAT-negative cases, p<0.001) and BO incompatibility (p=0.001). Hemolytic anemia (defined as hematocrit £ 45% and reticulocyte count 3 250,000/mm3 in the first week of life) was noted in 3.4% of cases, and was significantly associated with DAT positivity (13.2% in DAT-positive cases vs 1.1% in DAT-negative cases, p<0.001); BO incompatibility (p=0.001); and black ethnicity (p=0.001). Discussion: Our study indicated that cord blood DAT was positive in 16.7% of ABO incompatible pregnancies. BO-incompatible cases were more likely to be DAT-positive in blacks. AO-incompatibility was more common among girls, consistent with earlier studies that had shown a stronger A antigen expression among female newborns. DAT-positive cases were more likely to develop hyperbilirubinemia or hemolytic anemia. In addition, black ethnicity and BO incompatibility conferred significantly increased risk of hemolytic anemia in our study. Despite this strong association, the sensitivity of the positive DAT was 41.3% for hyperbilirubinemia and 70.5% for hemolytic anemia in ABO incompatibility. Disclosures: No relevant conflicts of interest to declare.
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Chen, Yang, Huiru Wang, Zimin Sun, Wen Yao, Huilan Liu, Xiaoyu Zhu, and Dongyao Wang. "Abo不相容性和抗a / B异凝集素滴度对血液恶性肿瘤清髓处理后输血需求和无关脐带血移植的早期结果的影响." Blood 136, Supplement 1 (November 5, 2020): 26. http://dx.doi.org/10.1182/blood-2020-143297.
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Abstract Background:ABO incompatibility is not considered a main contraindication to allogeneic hematopoietic stem cell transplantation (aHSCT). However, it has been associated with a number of immunohematological complications. The effects of ABO incompatibility on aHSCT remain controversial.The change of isoagglutinin titers and early clinical outcomes were analyzed after unrelated cord blood transplantation (UCBT) with ABO-incompatibility donor. Methods:252 patients with hematological malignant diseases and other hematological disorders who underwent unrelated UCBT from January 2019 to April 2020 were retrospectively analyzed in this research. Patients were studied in identical, major, minor and bidirectional mismatch groups. Immunoglobulin m (IgM) isoagglutinin titers were tested one day before the transplant (-1 day), 2 weeks post-transplant, 4 weeks post-transplant and 6 weeks post-transplant. R esults:76 match,71 major mismatch, 70 minor mismatch and 35 bidirectional unrelated UCBT were identified. The median neutrophil, PLT and red blood cell (RBC) recovery days were 18, 38 and 22, respectively. ABO mismatch did not influence the neutrophil, PLT and RBC engraftment. The median of RBC transfusion in 30 days were 5 units and PLT were 6 units. There were no statisitcal difference in 0-30 days RBC and PLT transfusion after UCBT. 31-100 days transfusion was similar to in 30 days transfusion. No patients developed pure red cell anemia (PRCA). -1day IgM titers ≥1:16 did not develop higher risk of grade II-IV aGVHD when compared with titers≤1:8 group. However, we detected a marginal higher PLT transfusion in 30 days after transplant at antibody titers ≥1:16 group when compared with titers≤1:8 (P=0.051). In the major and bidirectional groups, we found that group O IgM anti-donor antibodies were displayed a significant higher than the group B anti-A titer (p<0.001) in setting the time one day before the transplant, but no significant with group A. 2 weeks after the transplant, group B anti-A was still showed significant lower than the group O anti-A (p<0.001). 4 weeks after the UCBT, we observed a modest, but no statistical significant lower titers of group B anti-A antibodies as compared with O group (P=0.097). 6 weeks after the transplant, there were no statistical significant among group O, A and B. In the multivariable Cox regression model, transfusion of ≥5 RBC units in 30 days after UCBT (HR=1.727, 95%CI=1.020-2.926, P=0.042) and PLT engraftment ≥38 days (HR=1.964, 95%CI=1.134-3.401, P=0.016) were correlated to greater risk of grade severe aGVHD. Conclusion:This study showed that ABO mismatch did not influence the neutrophil, PLT and RBC recovery time.Group O IgM anti-donor isoagglutinins in recepients showed a higher titers than the group B in setting with the time (-1 days pre-transplant, 2 weeks post-transplant, 4 weeks post-transpant). Pre-transplant higher anti-donor isoagglutinins were associated with more PLT transfusion requirements after UCBT. More RBC transfusion (≥5 units) and longer PLT recovery time (≥38 days) showed a higher incidence of severe aGVHD. Disclosures No relevant conflicts of interest to declare.
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Yoshida, H., K. Ito, T. Kusakari, K. Ida, Y. Ihara, T. Mori, and M. Matsumura. "Removal of maternal antibodies from a woman with repeated fetal loss due to P blood group incompatibility." Transfusion 34, no. 8 (August 1994): 702–5. http://dx.doi.org/10.1046/j.1537-2995.1994.34894353467.x.
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Shin, Milljae, and Sung-Joo Kim. "ABO Incompatible Kidney Transplantation—Current Status and Uncertainties." Journal of Transplantation 2011 (2011): 1–11. http://dx.doi.org/10.1155/2011/970421.
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In the past, ABO blood group incompatibility was considered an absolute contraindication for kidney transplantation. Progress in defined desensitization practice and immunologic understanding has allowed increasingly successful ABO incompatible transplantation during recent years. This paper focused on the history, disserted outcomes, desensitization modalities and protocols, posttransplant immunologic surveillance, and antibody-mediated rejection in transplantation with an ABO incompatible kidney allograft. The mechanism underlying accommodation and antibody-mediated injury was also described.
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Neil, Stuart J. D., Áine McKnight, Kenth Gustafsson, and Robin A. Weiss. "HIV-1 incorporates ABO histo-blood group antigens that sensitize virions to complement-mediated inactivation." Blood 105, no. 12 (June 15, 2005): 4693–99. http://dx.doi.org/10.1182/blood-2004-11-4267.
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Abstract ABO histo-blood group antigens have been postulated to modify pathogen spread through the action of natural antibodies and complement. The antigens are generated by a polymorphic glycosyl-transferase encoded by 2 dominant active and a recessive inactive allele. In this study we investigated whether ABO sugars are incorporated into the envelope of HIV-1 virions. HIV vectors derived from cells expressing ABO antigens displayed sensitivity to fresh human serum analogous to ABO incompatibility, and ABO histo-blood group sugars were detected on the viral envelope protein, glycoprotein 120 (gp120). Moreover, lymphocyte-derived virus also displayed serum sensitivity, reflecting the ABO phenotype of the host when cultured in autologous serum due to adsorption of antigens to cell surfaces. Serum sensitivity required both active complement and specific anti-ABO antibodies. Thus, incorporation of ABO antigens by HIV-1 may affect transmission of virus between individuals of discordant blood groups by interaction with host natural antibody and complement. (Blood. 2005;105:4693-4699)
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Topcuoglu, Pervin, Mutlu Arat, Tugce Bolukbasi, Ender Soydan, Yesim Ozer, Muhit Ozcan, Gunhan Gurman, et al. "The Comparison of Myeloablative Versus Reduced Intensity Conditioning Regimen in ABO Mismatched Allogeneic Hematopoietic Cell Transplantation." Blood 104, no. 11 (November 16, 2004): 5146. http://dx.doi.org/10.1182/blood.v104.11.5146.5146.
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Abstract Recently, in an effort to reduce the transplant related mortality, AHCT with reduced intensity conditioning (RIC) have been developed. It has been reported that patients receiving RIC from an ABO-mismatched donor had more transplant-associated complications compared to ablative AHCT (BMT2001;28: 315, Transfusion2002; 42:1293, Transfusion2003; 43: 1153). In this single center, retrospective, historical case-matched study, we aimed to analyze the influence of ABO-incompatibility on transplant-related morbidity and mortality between ablative and RIC. Between 1988 and 2003, 39 patients underwent AHCT with RIC and only 14 were ABO-incompatible. Ten patients with ABO-incompatibility and having a regular follow-up for blood group typing were evaluated for immuno-hematological complications, such as acute or delayed-type hemolysis (DTH), pure red cell aplasia (PRCA), thrombotic thrombocytopenic purpura (TTP) and early transplant-related complications, were compared to 20 case control recipients having matched pretransplant characteristics and similar follow up, but myeloablative regimen, either bone marrow (BM) or peripheral blood (PB) stem cells infused. Patients’ characteristics are shown in table below. All the recipients and donors underwent a detailed pretransplant work up and all the recipients were followed twice a week post transplant by a transfusion specialist according to guidelines (BMT, 2001;28:315). Median follow-up was 195 days (range, 51–538d). We did not observe any acute hemolysis, but 11 experienced DTH. No significant differences were encountered among the three groups in terms of DTH (p=0.356). In all recipients having a major ABO incompatibility, the blood group switched to donor type, but 50% of the patients with minor ABO-incompatibility still had either their antigen persistency or the appearance of donor-derived isoagglutinins. We observed mild (n=1, BM group) and severe pure red cell aplasia (n=1, RIC group) in two patients having a major ABO-incompatibility. TTP was developed in one patient with major ABO-incompatibility. In conclusion, we did not observe any difference between ablative AHCT and RIST in ABO incompatible patients in terms of immuno hematological complications in contrast to published case series. In addition, we could not show any negative impact of ABO-incompatibility on the severity of acute GVHD and the rate of early transplant related mortality. Table Conditioning Ablative Reduced Intensity Source (patients) PB (n=10) BM (n=10) PB (n=10) Gender (M/F) 2/8 6/4 5/5 Median age (range) 34 (16–45) 31 (17–46) 33 (21–47) Diagnosis CML (2), AML (7), other (1) CML (2), AML (6), other (2) CML (4), AML (1), other (5) ABO-incompatibility Major 5 6 5 Minor 5 4 5 Delayed type hemolysis 5 (50%) (22,23,55,90,120) 2 (20%) (18,27) 4 (40%)(20,130,165,188) RBC transfusion (100 days) 3 (0–15) 4 (0–10) 5 (0–10) Median days of the independence from pRBC 7 (0–31) 18 (0–41) 7 (0–28) Median follow-up (days) 195 (90–538) 194 (63–467) 200 (51–511) Acute GVHD (grade II–IV) n (%) 3 (30%) 4 (40%) 4 (40%) TRM 100, n (%) 1 (%10) 1 (%10) 1 (%10)
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Chapuy, Claudia I., Richard M. Kaufman, Edwin P. Alyea, and Jean M. Connors. "Daratumumab for Delayed Red Cell Engraftment after Hematopoietic Stem Cell Transplant." Blood 132, Supplement 1 (November 29, 2018): 2545. http://dx.doi.org/10.1182/blood-2018-99-111880.
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Abstract Allogeneic stem cell transplantation represents a curative treatment option for patients with malignant hematologic diseases, including myelodysplastic syndrome (MDS). In 25-50% of transplants, HLA-matched allogeneic stem cell donors have some degree of ABO incompatibility with the recipient. Major ABO incompatibility is caused by recipient antibodies directed against donor red blood cells (RBCs) and may lead to delayed RBC recovery and transient pure red cell aplasia (PRCA). We describe a case of treatment-refractory pure red cell aplasia following a major ABO-mismatchedallogeneic stem cell transplant successfully treated with daratumumab. The 72-year-old patient with MDS received a matched unrelated donor transplant with a major ABO incompatibility, recipient blood group O from blood group A donor. Despite prompt engraftment with WBC and platelet recovery he remained anemic and RBC transfusion dependent. Bone marrow biopsy showed <1% erythroid elements concerning for post-transplant PRCA. 200 days post-transplant he had persistent circulating anti-A antibodies and no signs of red cell recovery. Standard treatments including tapering of immunosuppression, steroids, rituximab and erythropoiesis stimulating agents had no effect. The patient remained transfusion dependent with 1-2 units per week. Following treatment with daratumumab 390 days post transplant, he achieved transfusion-independence promptly within one week of treatment with daratumumab and continues to have normal erythropoiesis 10 months after daratumumab treatment. Anti-A antibodies became undetectable. The patient tolerated daratumumab well and no signs of GVHD or opportunistic infections were observed. We describe the use of daratumumab in patients with PRCA after major ABO mismatch allogeneic stem cell transplant. We hypothesized that a selective treatment targeting the CD38 positive plasma cells would decrease anti-A antibody production and allow for RBC recovery. Our findings suggest that direct targeting of residual host plasma cells with an anti-CD38 targeted agent such as daratumumab might be a valid treatment option that needs to be considered for patients refractory to standard treatments. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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Prokopchuk-Gauk, Oksana, Joanna McCarthy, Peter Duggan, Meer-Taher Shabani-Rad, and Nicole L. Prokopishyn. "Impact of ABO Incompatibility on Engraftment in Allogeneic Hematopoietic Stem Cell Transplantation." Blood 128, no. 22 (December 2, 2016): 3394. http://dx.doi.org/10.1182/blood.v128.22.3394.3394.
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Abstract Introduction: The selection of an allogeneic hematopoietic stem cell transplant (allo-HSCT) donor is highly dependent on human leukocyte antigen (HLA) allele profile matching with that of the intended recipient to minimize graft-related complications and improve post-transplant outcomes. Although ABO compatibility simplifies recipient transfusion needs, transplantation of an ABO incompatible graft has been identified not to have a significant impact on marrow engraftment or recipient survival. We completed an audit of adult allo-HSCT recipients of the Alberta Bone Marrow and Blood Cell Transplant Program to evaluate the impact of ABO incompatibility on engraftment in our allo-HSCT recipient population. Methods: A retrospective review including all adult allo-HSCT recipients between January 1, 2008 and January 1, 2015 was performed. Data was obtained from review of cellular therapy laboratory electronic records, with blood group confirmation by the transfusion medicine laboratory information system. Statistical calculations were completed using the unpaired t test. Results:A total of 513 adult patients underwent 528 allo-HSCT procedures (493 peripheral blood, 12 marrow, 23 cord blood). The mean HSCT recipient age was 46 (range 17-66) with 291 (57%) male recipients. The most common HSCT indication was acute myeloid leukemia. All allo-HSCT recipients received myeloablative conditioning. A total of 91% of recipients were conditioned with a regimen of Fludarabine-Busulfan-ATG, with or without total body irradiation. ABO compatibility status for allo-HSCT procedures included the following: 264 (50%) ABO identical grafts, 125 (24%) grafts with a minor incompatibility, 113 (21%) grafts with a major incompatibility, and 26 (5%) grafts with bidirectional incompatibility. HLA matching data was available for 447 allo-HSCT procedures. A total of 350 (78%) patients were recipients of fully HLA matched grafts (340 peripheral blood, 9 marrow, 1 cord blood). Taking into consideration ABO compatibility status, 10/10 HLA matched peripheral blood or marrow grafts were provided to 89% of ABO identical graft recipients, 77% of recipients each with a minor or major incompatibility, and 65% of recipients with a bidirectional incompatibility. Cellular engraftment including the number of days until absolute neutrophil count (ANC) > 1.0 x 106/L and platelet count > 20 x 109/L was available for 496 (94%) of all transplant procedures. A total of 34 transplant recipients did not successfully engraft one or both cell lines. A summary of recipient engraftment data for each category of ABO matching according to stem cell source appears in Table 1. Conclusion:In our study population, the risk of non-engraftment is lowest in recipients of ABO identical peripheral blood or marrow source donor stem cells. Time to cellular engraftment following allo-HSCT transplant with peripheral blood or marrow source stem cells of minor or major ABO incompatibility is similar to that of an ABO identical donor, while platelet engraftment appears to be prolonged in the setting of a bidirectional incompatibility. However, the small number of recipients of grafts with a bidirectional incompatibility and the large standard deviation affects our confidence in this result. The impact of ABO matching on engraftment appears to be the greatest in cord blood transplants. The risk of cellular non-engraftment is variable among all ABO compatibility categories, though the time to platelet engraftment is significantly prolonged in recipients of grafts with major ABO or bidirectional incompatibility. These findings are limited by our small cord blood recipient population and the presence of some degree of HLA mismatching in nearly all recipients of cord blood transplants evaluated. Further study is required in larger populations of cord blood transplant recipients to better understand the impact of ABO compatibility status on marrow engraftment, together with variables including the cellular composition of the cord blood graft and host immune factors. Table 1 Rate of non-engraftment and days to neutrophil and platelet engraftment following allo-HSCT according to ABO compatibility, including standard deviation and statistical calculation (*indicates statistically significant value). Table 1. Rate of non-engraftment and days to neutrophil and platelet engraftment following allo-HSCT according to ABO compatibility, including standard deviation and statistical calculation (*indicates statistically significant value). Disclosures No relevant conflicts of interest to declare.
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Andrews, GA, PS Chavey, JE Smith, and L. Rich. "N-glycolylneuraminic acid and N-acetylneuraminic acid define feline blood group A and B antigens." Blood 79, no. 9 (May 1, 1992): 2485–91. http://dx.doi.org/10.1182/blood.v79.9.2485.2485.
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Abstract Blood group incompatibility causes transfusion reactions and neonatal isoerythrolysis in cats. We investigated the molecular nature of the blood group antigens from cats that had blood type A, B, and AB erythrocytes. Naturally occurring anti-type B antibodies, Triticum vulgaris lectin, monoclonal antibody (MoAb) 32–27, and MoAb R-24 were used in agglutination tests, Western blots, and thin-layer chromatography (TLC) enzyme immunostaining. Type A erythrocytes had NeuGc-NeuGc-Galactose-Glucose-Ceramide ([NeuGc]2GD3) where NeuGc represents N-glycolylneuraminic acid, and NeuAc-NeuGc-GD3, where NeuAc represents N-acetylneuraminic acid, and may have [NeuGc]2 disialylparagloboside and NeuAc-NeuGc-disialylparagloboside. Type B erythrocytes only had [NeuAc]2GD3. Type AB erythrocytes had [NeuGc]2GD3, NeuAc-NeuGc-GD3, and [NeuAc]2GD3. Blood group antigens were also found on a 50-Kd membrane protein. We conclude that type B erythrocytes are characterized by [NeuAc]2GD3 as the only form of this ganglioside and the presence of NeuAc on a 50-Kd membrane protein. NeuGc is the major determinant of the A antigen; specifically, [NeuGc]2GD3 is the major glycolipid form. The A antigen is also present on a 50-Kd membrane protein.
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Andrews, GA, PS Chavey, JE Smith, and L. Rich. "N-glycolylneuraminic acid and N-acetylneuraminic acid define feline blood group A and B antigens." Blood 79, no. 9 (May 1, 1992): 2485–91. http://dx.doi.org/10.1182/blood.v79.9.2485.bloodjournal7992485.
Full textAbstract:
Blood group incompatibility causes transfusion reactions and neonatal isoerythrolysis in cats. We investigated the molecular nature of the blood group antigens from cats that had blood type A, B, and AB erythrocytes. Naturally occurring anti-type B antibodies, Triticum vulgaris lectin, monoclonal antibody (MoAb) 32–27, and MoAb R-24 were used in agglutination tests, Western blots, and thin-layer chromatography (TLC) enzyme immunostaining. Type A erythrocytes had NeuGc-NeuGc-Galactose-Glucose-Ceramide ([NeuGc]2GD3) where NeuGc represents N-glycolylneuraminic acid, and NeuAc-NeuGc-GD3, where NeuAc represents N-acetylneuraminic acid, and may have [NeuGc]2 disialylparagloboside and NeuAc-NeuGc-disialylparagloboside. Type B erythrocytes only had [NeuAc]2GD3. Type AB erythrocytes had [NeuGc]2GD3, NeuAc-NeuGc-GD3, and [NeuAc]2GD3. Blood group antigens were also found on a 50-Kd membrane protein. We conclude that type B erythrocytes are characterized by [NeuAc]2GD3 as the only form of this ganglioside and the presence of NeuAc on a 50-Kd membrane protein. NeuGc is the major determinant of the A antigen; specifically, [NeuGc]2GD3 is the major glycolipid form. The A antigen is also present on a 50-Kd membrane protein.
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Zimin, Sun, Ji Mengmeng, Yao Wen, Zheng Changcheng, Tong Juan, Liu Huilan, Geng Liangquan, et al. "Impact Of ABO Incompatibility On Overall Survival After Unrelated Cord Blood Transplantation a Single Institute Experience In China." Blood 122, no. 21 (November 15, 2013): 5535. http://dx.doi.org/10.1182/blood.v122.21.5535.5535.
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Abstract Umbilical cord blood transplantation (UCBT) has now become a more common treatment for patients with hematologic malignancies who lack matched related or unrelated donors. However, few reports have addressed the impact of ABO incompatibility on the clinical outcomes, such as engraftment, transfusion requirements and survival after UCBT. Therefore, we retrospectively analyzed the impact of ABO mismatching on the clinical outcomes of 121 patients, including 51 ABO-identical, 23 minor, 39 major, and 8 bidirectional ABO-incompatible recipients after UCBT. With a median follow-up of 11 months (range, 5-151 months), the disease-free survival (DFS) rates among the ABO-identical, minor, major, and bidirectional ABO-incompatible groups were 71.7%, 60.0%, 37.1%, and 71.4%, respectively (P=0.014), whereas the OS did not differ significantly among the four groups (76.1%, 65.0%, 48.6%, and 71.4%, respectively; P=0.078). The DFS (68.2%, 42.9%; P=0.009) and OS estimates (72.7%, 52.4%; P=0.031) of the ABO identical/minor incompatible group also differed significantly from the ABO major/bidirectional incompatible group. These results were confirmed in the multivariate analysis. No significant differences in the engraftment times, transfusion requirements, graft-versus-host disease (GVHD), relapse, and non-relapse mortality (NRM) were noted among the groups. Severe immune hemolysis or pure red cell aplasia did not occur among these patients. These results indicate that ABO incompatibility somewhat affects the DFS and OS in UCBT, but further studies are still required. Disclosures: No relevant conflicts of interest to declare.
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Link, H., MA Boogaerts, AA Fauser, S. Slavin, J. Reiffers, NC Gorin, AM Carella, F. Mandelli, S. Burdach, and A. Ferrant. "A controlled trial of recombinant human erythropoietin after bone marrow transplantation." Blood 84, no. 10 (November 15, 1994): 3327–35. http://dx.doi.org/10.1182/blood.v84.10.3327.3327.
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Abstract Recombinant human erythropoietin (rHuEPO) stimulates erythropoietic bone marrow cells and increases erythrocyte production. This prospective study was designed to evaluate the effects of rHuEPO on regeneration of erythropoiesis after allogeneic or autologous bone marrow transplantation (BMT). Seventeen centers participated in this randomized, double-blind, placebo-controlled multicenter trial. The randomization was performed centrally for each center and stratified according to allogeneic or autologous BMT and major ABO-blood group incompatibility. One hundred and six patients received rHuEPO after allogeneic BMT and 109 patients received placebo. After autologous BMT, 57 patients were treated with rHuEPO and 57 with placebo. Patients received either 150 IU/kg/day C127 mouse-cell-derived rHuEPO or placebo as continuous intravenous infusion. Therapy started after bone marrow infusion and lasted until independence from erythrocyte transfusions for 7 consecutive days with stable hemoglobin levels > or = 9 g/100 mL or until day 41. After allogeneic BMT, the reticulocyte counts were significantly higher with rHuEPO from day 21 to day 42 after BMT. The median time (95% confidence intervals) to erythrocyte transfusion independence was 19 days (range, 16.3 to 21.6) with rHuEPO and 27 days (range, 22.3 to > 42) with placebo (P < .003). The mean (+/- SD) numbers of erythrocyte transfusions until day 20 after BMT were 6.6 +/- 4.8 with rHuEPO and 6.0 +/- 3.8 with placebo. However, from day 21 to day 41, the rHuEPO-treated patients received 1.4 +/- 2.5 (median, 0) transfusions and the control group received 2.7 +/- 4.0 (median, 2) transfusions (P = .004). In the follow-up period from day 42 up to day 100, 2.4 +/- 5.6 transfusions were required with rHuEPO and 4.5 +/- 9.6 were required with placebo (P = .075). A multivariate analysis (ANOVA) showed that acute graft-versus-host disease (GVHD), major ABO-blood group incompatibility, age greater than 35 years, and hemorrhage significantly increased the number of transfusions. However, after day 20, rHuEPO significantly reduced the number of erythrocyte transfusions in these patient groups, as well as reducing incompatibility in the major ABO-blood group. For the whole study period, rHuEPO reduced the transfusion requirements in GVHD III and IV from 18.4 +/- 8.6 to 8.5 +/- 6.8 U (P = .05). After autologous BMT, there was no difference in the time to independence from erythrocyte transfusions and in the regeneration of reticulocytes. Marrow purging strongly increased the requirement for transfusions as well as the time to transfusion independence.
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Link, H., MA Boogaerts, AA Fauser, S. Slavin, J. Reiffers, NC Gorin, AM Carella, F. Mandelli, S. Burdach, and A. Ferrant. "A controlled trial of recombinant human erythropoietin after bone marrow transplantation." Blood 84, no. 10 (November 15, 1994): 3327–35. http://dx.doi.org/10.1182/blood.v84.10.3327.bloodjournal84103327.
Full textAbstract:
Recombinant human erythropoietin (rHuEPO) stimulates erythropoietic bone marrow cells and increases erythrocyte production. This prospective study was designed to evaluate the effects of rHuEPO on regeneration of erythropoiesis after allogeneic or autologous bone marrow transplantation (BMT). Seventeen centers participated in this randomized, double-blind, placebo-controlled multicenter trial. The randomization was performed centrally for each center and stratified according to allogeneic or autologous BMT and major ABO-blood group incompatibility. One hundred and six patients received rHuEPO after allogeneic BMT and 109 patients received placebo. After autologous BMT, 57 patients were treated with rHuEPO and 57 with placebo. Patients received either 150 IU/kg/day C127 mouse-cell-derived rHuEPO or placebo as continuous intravenous infusion. Therapy started after bone marrow infusion and lasted until independence from erythrocyte transfusions for 7 consecutive days with stable hemoglobin levels > or = 9 g/100 mL or until day 41. After allogeneic BMT, the reticulocyte counts were significantly higher with rHuEPO from day 21 to day 42 after BMT. The median time (95% confidence intervals) to erythrocyte transfusion independence was 19 days (range, 16.3 to 21.6) with rHuEPO and 27 days (range, 22.3 to > 42) with placebo (P < .003). The mean (+/- SD) numbers of erythrocyte transfusions until day 20 after BMT were 6.6 +/- 4.8 with rHuEPO and 6.0 +/- 3.8 with placebo. However, from day 21 to day 41, the rHuEPO-treated patients received 1.4 +/- 2.5 (median, 0) transfusions and the control group received 2.7 +/- 4.0 (median, 2) transfusions (P = .004). In the follow-up period from day 42 up to day 100, 2.4 +/- 5.6 transfusions were required with rHuEPO and 4.5 +/- 9.6 were required with placebo (P = .075). A multivariate analysis (ANOVA) showed that acute graft-versus-host disease (GVHD), major ABO-blood group incompatibility, age greater than 35 years, and hemorrhage significantly increased the number of transfusions. However, after day 20, rHuEPO significantly reduced the number of erythrocyte transfusions in these patient groups, as well as reducing incompatibility in the major ABO-blood group. For the whole study period, rHuEPO reduced the transfusion requirements in GVHD III and IV from 18.4 +/- 8.6 to 8.5 +/- 6.8 U (P = .05). After autologous BMT, there was no difference in the time to independence from erythrocyte transfusions and in the regeneration of reticulocytes. Marrow purging strongly increased the requirement for transfusions as well as the time to transfusion independence.
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Igarashi, Takehito, Jason Wynberg, Ramprasad Srinivasan, Brian Becknell, J. Phillip McCoy, Yoshiyuki Takahashi, Dante A. Suffredini, W. Marston Linehan, Michael A. Caligiuri, and Richard W. Childs. "Enhanced cytotoxicity of allogeneic NK cells with killer immunoglobulin-like receptor ligand incompatibility against melanoma and renal cell carcinoma cells." Blood 104, no. 1 (July 1, 2004): 170–77. http://dx.doi.org/10.1182/blood-2003-12-4438.
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Abstract Cellular inactivation through killer immunoglobulin-like receptors (KIRs) may allow neoplastic cells to evade host natural killer (NK) cell–mediated immunity. Recently, alloreactive NK cells were shown to mediate antileukemic effects against acute myelogenous leukemia (AML) after mismatched transplantation, when KIR ligand incompatibility existed in the direction of graft-versus-host disease (GVHD). Therefore, we investigated whether solid tumor cells would have similar enhanced susceptibility to allogeneic KIR-incompatible NK cells compared with their KIR-matched autologous or allogeneic counterparts. NK populations enriched and cloned from the blood of cancer patients or healthy donors homozygous for HLA-C alleles in group 1 (C-G1) or group 2 (C-G2) were tested in vitro for cytotoxicity against Epstein-Barr virus–transformed lymphoblastic cell lines (EBV-LCLs), renal cell carcinoma (RCC), and melanoma (MEL) cells with or without a matching KIR-inhibitory HLA-C ligand. Allogeneic NK cells were more cytotoxic to tumor targets mismatched for KIR ligands than their KIR ligand–matched counterparts. Bulk NK populations (CD3–/CD2+/CD56+) expanded 104-fold from patients homozygous for C-G1 or C-G2 had enhanced cytotoxicity against KIR ligand–mismatched tumor cells but only minimal cytotoxicity against KIR ligand–matched targets. Further, NK cell lines from C-G1 or C-G2 homozygous cancer patients or healthy donors expanded but failed to kill autologous or KIR-matched MEL and RCC cells yet had significant cytotoxicity (more than 50% lysis at 20:1 effector-target [E/T] ratio) against allogeneic KIR-mismatched tumor lines. These data suggest immunotherapeutic strategies that use KIR-incompatible allogeneic NK cells might have superior antineoplastic effects against solid tumors compared with approaches using autologous NK cells.
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Kimura, Fumihiko, Ken Sato, Shinichi Kobayashi, Takashi Ikeda, Hiroki Torikai, Yukiko Ohsawa, Hitoshi Ohto, Makoto Hirokawa, and Kazuo Motoyoshi. "Impacts of ABO-Blood Type Incompatibility on Outcome of Unrelated Bone Marrow Transplantation through the Japan Marrow Donor Program." Blood 108, no. 11 (November 16, 2006): 173. http://dx.doi.org/10.1182/blood.v108.11.173.173.
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Abstract ABO incompatibility between donor and recipient is not a barrier for successful allogeneic hematopoietic stem cell transplantation, but conflicting data still exist concerning its influence on transplant outcome, graft-versus-host disease (GVHD), relapse, and survival. We retrospectively analyzed the data of patients who underwent UR-BMT through the Japan Marrow Donor Program between January 1993 and September 2005, with complete data on ABO-blood group compatibility, age, and gender in donors and recipients. A total of 4,970 patients were transplanted with marrow from ABO-matched (M; n=2,513, 50.6%), major incompatible (MA; n=1,254, 25.2%), minor incompatible (MI; n=1,081, 21.8%), and bidirectional incompatible donors (IA; n=122, 2.5%), and were followed up over a median period of 325 days. Among these four groups, excluding age, there was no significant difference in the gender of patients and donors, number of transplantations, conditioning regimen, GVHD prophylaxis, and performance status before transplantation by the likelihood ratio test. The 5-year overall survival of any ABO-incompatible group was significantly lower compared to an identical group (Wilcoxon test, p<0.0001); the estimates for each group were 50.0% (M), 44.7% (MA), 46.7% (MI), and 41.3% (IA). Even in HLA-matched transplantation (n=2,608), a similar difference in overall survival was observed among the four groups (p=0.0124). In ABO-mismatched transplantation, the processing of bone marrow is necessary to prevent hemolysis of donor or recipient red blood cells as a result of the infusion of ABO-incompatible red blood cells or plasma contained within it. This procedure may reduce the number of hematopoietic stem cells. In fact, the mean number of total infused cells in each group was 3.10 (M), 1.52 (MA), 2.87 (MI), and 1.33 (IA) x108 per patient body weight (kg), with a significant difference in 4,210 patients in which data on the infused cell number were available (M; n=2,310, MA; n=996, MI; n=802, IA; n=102). To examine whether the difference in overall survival depended on the transplanted cell number, we used time-dependent Cox proportional hazards modeling to compare identical and major incompatible groups in terms of overall survival. Whereas the disease (standard and high-risk malignant disease, and benign disease; p=0.0000), patient age (p=0.0000), and ABO compatibility (p=0.0311) were elucidated to be significant risk factors, the number of infused cells was not (p=0.0603). Engraftment of red blood cells, white blood cells, and platelets were significantly delayed in major ABO mismatch in comparison with ABO identity (p<0.0001). Univariate analysis revealed a small but significant difference in the rate of grade III and IV GVHD among the four groups (p=0.0204). Patients with major and minor ABO incompatibility had a higher incidence of severe GVHD compared to ABO identity (21.9%, 20.4% vs 16.2%). There was no significant difference in GVHD of the skin and gut, but major and minor mismatch developed a higher incidence of moderate to severe hepatic GVHD compared to ABO match (p<0.0001, p=0.0010, respectively). ABO incompatibility had no significant effect on relapse, but the incidence of rejection was significantly higher with ABO-incompatible transplantation (p=0.0219).
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Mehta, Pallavi, Stalin Ramprakash, C. Raghuram, Deepa Trivedi, Priya Marwah, Rajpreet Soni, Rakesh Dhanya, Rajat Kumar Agarwal, and Lawrence Faulkner. "In-Vivo Adsorption of Iso-Haemagglutinin (IHA) Antibodies By Donor Type Red Cell Transfusion during Conditioning Is a Safe and Effective Method to Overcome Major ABO Incompatibility-Related Acute Hemolytic Reactions in Stem Cell Transplant Using Bone Marrow As Stem Cell Graft Source." Blood 134, Supplement_1 (November 13, 2019): 4467. http://dx.doi.org/10.1182/blood-2019-131118.
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Introduction: ABO blood group incompatibility is not a barrier to performing allogeneic stem cell transplant, but may result in life-threatening acute hemolytic reactions as well as pure red cell aplasia. As stem cell product manipulation is cumbersome and may entail cell loss, attempts have been made in the past to reduce IHA titers in-vivo either by donor type red cell transfusion or using frozen plasma in peripheral blood stem cell (PBSC) transplants (Scholl et al. Transfusion 2005; Damodar et al. BMT 2005). The efficacy of such strategies have not been described in Bone marrow transplant (BMT) setting. We are reporting the effectiveness and safety of donor type red cell infusion during conditioning as a method of reducing acute hemolytic reaction during transplant while using unmanipulated marrow as stem cell source (BMT). Materials and Methods: We retrospectively analyzed 241 consecutive allogeneic BMTs for beta thalassemia major, between August 2015 and July 2019 out of which 82 were ABO mismatched transplants, either major (n=30) or minor (n=40), or bidirectional (n =12) mismatched. Infusion of donor type red blood cell during conditioning after the infusion of Anti-thymocyte globulin (ATG) and post-transplant complication of acute hemolysis were determined by retrospective review of individual medical records. When there is a major ABO incompatibility and IHA titers against the donor were > 1:64, a single unit of donor type Packed Red Blood cell (PRBC) was divided into 4 aliquots, irradiated and administered over 4 days at increasing incremental volumes once daily over 4 days if tolerated (Day 1 - 5 ml, Day 2 - 10ml, Day 3- 20-30 ml, Day 4 - 40-60 ml) (Fig.1). Patients were watched carefully for febrile reactions and hemoglobinuria and mild reactions were tolerated. If no clinical evidence of severe hemolytic reaction, bone marrow was infused without manipulation on the day of transplant. Results: Out of 30 patients with major ABO incompatibility, 13 patients had titers more than 1:64 (highest was 1:2048) and hence received donor type PRBC infusion in small incremental doses. Eight patients showed evidence of some hemolysis (4 during infusion of donor type PRBC aliquot and 4 showed increase in indirect bilirubin with marrow infusion) which was managed conservatively with hydration. None of the patients developed severe hemolytic or anaphylactic reaction at the time of marrow infusion. Post infusion of donor type blood, titers were checked in 7 patients. 6 patients had significant reduction in titers (all were less than 1:32) except for 1(titers increased to 1:4096), which was not considered clinically relevant as he tolerated 100mls of donor type PRBC. He also tolerated marrow infusion without any evidence of severe hemolytic reaction. Four more patients with bidirectional mismatch had IHA titers against the donor more than 1:64, hence the same procedure was followed. One of them had mild hemoglobinuria during donor type PRBC infusion and 3 patients had mild hemoglobinuria with rise in indirect bilirubin at the time of marrow infusion. All patients were managed conservatively with hydration. Conclusion: Our experience demonstrated that donor-type PRBC infusion as a method of in-vivo adsorption of IHA antibodies against donor is safe and effective in preventing acute hemolysis in major ABO-mismatched stem cell transplants even in the context where bone marrow is used as graft source. This simple method in addition to avoiding the problems related to product manipulation can also be safely and easily performed in resource limited settings. Disclosures No relevant conflicts of interest to declare.
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Yazdanbakhsh, Karina, Stanley Kang, Daniel Tamasauskas, Dorothy Sung, and Andromachi Scaradavou. "Complement receptor 1 inhibitors for prevention of immune-mediated red cell destruction: potential use in transfusion therapy." Blood 101, no. 12 (June 15, 2003): 5046–52. http://dx.doi.org/10.1182/blood-2002-10-3068.
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AbstractActivation of complement cascade via the antibody-mediated classical pathway can initiate red blood cell (RBC) destruction, causing transfusion reactions and hemolytic anemia. In the present study, we have assessed the ability of a human recombinant soluble form of complement receptor 1 (sCR1) to inhibit complement-mediated RBC destruction in vitro and in vivo. Using an in vitro alloimmune incompatibility model, sCR1 inhibited complement activation and prevented hemolysis. Following transfusion of human group O RBCs into mice lacking detectable pre-existing antibodies against the transfused RBCs, systemic coadministration of 10 mg/kg sCR1, a dose well tolerated in human subjects for prevention of tissue injury, completely inhibited the in vivo clearance of the transfused RBCs and surface C3 deposition in the first hour after transfusion, correlating with the half-life of sCR1 in the circulation. Treatment with sCR1 increased the survival of transfused human group A RBCs in the circulation of mice with pre-existing anti-A for 2 hours after transfusion by 50%, reduced intravascular hemolysis, and lowered the levels of complement deposition (C3 and C4), but not immunoglobulin G (IgG) or IgM, on the transfused cells by 100-fold. We further identified potential functional domains in CR1 that can act to limit complement-mediated RBC destruction in vitro and in vivo. Collectively, our data highlight a potential use of CR1-based inhibitors for prevention of complement-dependent immune hemolysis.
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Chan, Esther HL, Thiow Christofer, Susan TT Lim, Lip Kun Tan, and Michelle Poon. "Evaluation of Blood Group Conversion Following ABO-Incompatible Hematopoietic Stem Cell Transplantation (HCT)." Blood 124, no. 21 (December 6, 2014): 1557. http://dx.doi.org/10.1182/blood.v124.21.1557.1557.
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Abstract Title: Evaluation of blood group conversion following ABO-incompatible Hematopoietic Stem Cell Transplantation (HCT). Background: While there have been a number of reports concerning the influence of AB0 incompatibility on hematopoietic transplantation (HCT) outcomes, data evaluating post-HCT blood group conversions following ABO incompatible transplants remains extremely limited. Methods: We performed a single centre retrospective analysis of 97 patients undergoing major or minor or bidirectional ABO-mismatched bone marrow (BM), peripheral blood (PB), and cord blood (CB) hematopoietic stem cell transplantation (HCT) between January2005 – April 2014, in whom engraftment had occurred and blood group data was available. The aim of the study was to analyse the red cell ABO phenotype (forward grouping) and levels of anti-A/B antibodies (reverse grouping) in these patients following the ABO-mismatched transplants. Results: 97 patients transplanted between January 2004 and April 2014 were included in the analysis. There were 40 (41%) matched sibling, 32 (33%) matched unrelated and 25 (26%) CB transplants. Indications for HSCT included both haematological malignancies (n=87) and benign conditions (n=10). Of these donor recipient pairs, there were 44 (45%) minor, 39 (40%) major and 14 (15%) bidirectional ABO mismatches. All patients had achieved full donor type chimerism at the time of analysis. Analysis of post –HCT blood group conversion was performed in each of the three groups. Amongst the major mismatch patients (n=39), all had conversion of RBC phenotype to donor ABO phenotype and loss of their host derived anti-donor ABO antibodies. Interestingly, in the minor mismatch patients who were tested (n=44), all the patients had conversion of their RBC phenotype, but 43 out of 44 patients failed to produce recipient directed anti-ABO antibodies. Similarly in the bidirectional mismatch group, all 14 patients converted to donor ABO phenotype, but none produced recipient directed anti-ABO antibodies. Conclusion: In one of the largest study looking at this issue, our study demonstrated the lack of a development of recipient directed anti A/B antibodies despite complete donor chimerism in the majority (1 out of 58) of patients undergoing minor or bidirectional ABO-mismatched HSCT. We postulate that this phenomenon may be due to the donor B cell tolerance against host ABO antigen due to the presence of host A and B antigens within other body tissues. Disclosures No relevant conflicts of interest to declare.
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Liao, Jianyun, Zhiyong Peng, Huaying Liu, Yuelin He, and Chunfu Li. "Rituximab Combined with Donor Lymphocyte Infusion Cured Immunohemolysis after Refractory Hematopoietic Stem Cell Transplantation." Blood 132, Supplement 1 (November 29, 2018): 5745. http://dx.doi.org/10.1182/blood-2018-99-120163.
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Abstract Background Immuno-hemolytic anemia is a severe complication after allogeneic hematopoietic stem cell transplantation (HSCT). Primary or secondary reaction between recipient lymphocytes and donor RBC antigens was considered as one of cause of post-transplantation immune-hemolysis (PTI). Different treatments can be administered according to the donor cell chimeric status and antibody titer of blood types of the donor in recipient. Objective: To find the ways of treatment of PTI after HSCT. Methods: A retrospective analysis about the complications of 707 patients underwent HSCT in our center from January 2010 to July 2017 was made. Of them, PI occurred in 28 patients with positive direct Coomb's test. By donor cell chimerism status, the 28 patients with PTI were divided into two groups. In group 1 (n=11), the patients presented full donor chimerism and received rituximab or/and steroid treatment only; In group 2 (n=17), the patients presented mixed chimerism and received rituximab and gradually decreasing immunosuppressive agents with/without, thereafter, donor lymphocyte infusion (DLI). Results: A total of 28 patients was cured after treatment. Of 11 cases in group 1, five patients developed grade 1-2 acute GVHD and four of which developed pancytopenia. Of 17 patients with mixed chimerism (75-99.5%) in group 2, four had post-HSCT pure red blood cell aplasia and the major blood type incompatibility between the donor and recipients. In group 2, six patients with PTI were cured by rituximab and gradually decreasing immunosuppressive therapy only; 11 patients had no respond to the treatment of these treatments, and were cured after combined with DLI. Conclusion: When PTI occurred, chimerism status may help us to determine how to treat PTI. For patients with full donor cell chimerism, it may be fit to give rituximab and to reduce immunosuppressive agent gradually. DLI may be given to the patients with mixed chimerism and no responding to the combined therapy of rituximab and immunosuppressive agent reduction. Disclosures No relevant conflicts of interest to declare.
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Hefazi, Mehrdad, Mark Litzow, William Hogan, Dennis Gastineau, Eapen Jacob, Moussab Damlaj, Shahrukh Hashmi, Aref Al-Kali, and Mrinal M. Patnaik. "ABO blood group incompatibility as an adverse risk factor for outcomes in patients with myelodysplastic syndromes and acute myeloid leukemia undergoing HLA-matched peripheral blood hematopoietic cell transplantation after reduced-intensity conditioning." Transfusion 56, no. 2 (October 7, 2015): 518–27. http://dx.doi.org/10.1111/trf.13353.
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Prokopchuk-Gauk, Oksana, Nicole L. Prokopishyn, Joanna McCarthy, and Meer-Taher Shabani-Rad. "Red Cell Alloimmunization Rates in Allogeneic Hematopoietic Stem Cell Transplant Recipients." Blood 128, no. 22 (December 2, 2016): 3402. http://dx.doi.org/10.1182/blood.v128.22.3402.3402.
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Abstract Introduction: Donor selection for allogeneic hematopoietic stem cell transplant (allo-HSCT) is dependent on matching with the intended recipient HLA allele profile, but not blood group compatibility. Red blood cell (RBC) phenotype matching is not considered, even if recipient alloantibodies are present pre-HSCT. Historically, up to 3.7% of allo-HSCT recipients have been found to develop new RBC alloantibodies following allo-HSCT. We completed an audit of all adult and pediatric allo-HSCT recipients of the Alberta Bone Marrow and Blood Cell Transplant Program to define the rate of RBC alloimmunization, and evaluate the impact of this RBC alloantibody presence on donor marrow engraftment in our allo-HSCT recipient population. Methods:A retrospective review was completed including all allogeneic pediatric and adult HSCT recipients between January 1, 2007 and January 1, 2015. Data was obtained from review of cellular therapy laboratory electronic records with red cell alloantibody information extracted manually from the transfusion medicine laboratory information system. Results: A total of 674 patients, including 104 pediatric recipients (<18 years old), underwent 697 allo-HSCT procedures (591 peripheral blood, 45 marrow, 61 cord blood). The mean HSCT recipient age was 40 (range 0-66) and most common HSCT indication was acute myeloid leukemia. Myeloablative conditioning was given to all adults and 86% of pediatric recipients. Fully HLA matched grafts were provided to 77% of recipients. ABO compatibility status of allo-HSCT procedures included the following: 362 (52%) ABO identical grafts, 154 (22%) grafts with a minor incompatibility, 143 (21%) grafts with a major incompatibility, and 38 (5.0%) grafts with bidirectional incompatibility. Rh mismatches were present in 165 (24%) of donor-recipient pairs. A total of 47 allo-HSCT recipients, including 3 pediatric and 44 adult patients, were found to have RBC alloantibodies before or after allo-HSCT. A total of 45 (6.4%) of allo-HSCT recipients had detectable RBC alloantibodies pre-HSCT, with 69 individual alloantibodies identified. The most common RBC alloantibody was anti-E (30%). Antibody screen results available on the day of or following HSCT in 43 allo-HSCT recipients found: 12 (28%) with antibody disappearance pre-HSCT and a negative screen on the date of allo-HSCT, 15 (35%) with antibody waning to disappearance after allo-HSCT, and 11 (26%) with persistence of pre-HSCT antibodies following allo-HSCT. New post-HSCT RBC alloantibodies were detected in 3 adult recipients of peripheral blood collected stem cell grafts (anti-D; anti-Kpa; anti-K plus anti-E), with an overall rate of 0.4%. These patients all received myeloablative conditioning and grafts which were ABO identical or had a minor ABO incompatibility. The anti-D antibody developed post-transplant in an Rh positive recipient of an Rh negative graft. Thus, the calculated overall rate of anti-D development in Rh mismatched HSCT recipients was 0.6%. There was no observed impact on neutrophil and platelet engraftment comparing adult allo-HSCT recipients who did and did not have pre-HSCT RBC alloantibodies. Conclusion: The risk of post-HSCT RBC alloantibody development is very low, even in Rh mismatched donor-recipient pairs. ABO incompatibility does not affect the risk of post-HSCT alloantibody development. Allo-HSCT recipients infrequently have pre-HSCT RBC alloantibodies, which may disappear after myeloablative conditioning. The presence of RBC alloantibodies pre-HSCT does not appear to impact donor marrow engraftment. The results of our retrospective study are limited by the availability, timing and frequency of post-HSCT antibody screen investigations. The decision to perform an antibody screen post-HSCT is a clinical one, typically dependent on recipient transfusion needs. Further prospective research is required to more accurately determine the rate of new post-HSCT alloantibody development and duration of alloantibody persistence or disappearance in allo-HSCT recipients. Results of these studies may also help guide RBC transfusion decisions in HSCT recipients known to have pre-HSCT RBC alloantibodies with proven engraftment and a negative post-HSCT antibody screen. Disclosures No relevant conflicts of interest to declare.
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Gajewski, JL, LD Petz, L. Calhoun, S. O'Rourke, EM Landaw, NR Lyddane, LA Hunt, GJ Schiller, WG Ho, and RE Champlin. "Hemolysis of transfused group O red blood cells in minor ABO- incompatible unrelated-donor bone marrow transplants in patients receiving cyclosporine without posttransplant methotrexate." Blood 79, no. 11 (June 1, 1992): 3076–85. http://dx.doi.org/10.1182/blood.v79.11.3076.3076.
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Abstract Hemolysis most commonly occurs following bone marrow transplant when there is “minor” ABO blood group incompatibility between donor and recipient. The hemolysis has been attributed to destruction of the patient's incompatible erythrocytes by donor-derived anti-A and/or anti- B antibody produced from “passenger” immunocompetent donor lymphocytes. Extraordinary transfusion requirements of group O erythrocytes in a series of patients receiving unrelated minor ABO-incompatible marrow grafts led us to investigate whether this mechanism could account for the extent of hemolysis observed. In seven consecutive minor ABO- incompatible unrelated-donor bone marrow transplant recipients receiving cyclosporine without posttransplant methotrexate, we observed excessive hemolysis. For cases in this index group, a strongly reactive donor-derived ABO blood group antibody was identified coincident with development of hemolysis. Transfusion requirements in the first three patients (26 U of group O erythrocytes each) greatly exceeded the recipient's volume of incompatible erythrocytes, indicating that lysis of transfused group O erythrocytes was also occurring. Pretransplant erythrocyte exchange transfusion with group O erythrocytes performed in the four subsequent patients decreased the severity of hemolysis, but did not prevent it. Among minor ABO-incompatible marrow graft recipients, an analysis of variance demonstrated effects on transfusion requirements due to donor-recipient relationship being unrelated (P less than .002) and the use of posttransplant methotrexate (P = .0001), and there was interaction between these two factors (P less than .001). Bone marrow transplants from unrelated donors resulted in an exaggerated immune response to ABO blood group antigens, which was associated with hemolysis of transfused group O erythrocytes, as well as the patient's ABO-incompatible erythrocytes. This serious complication may be prevented by posttransplant immunosuppression with methotrexate.
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Gajewski, JL, LD Petz, L. Calhoun, S. O'Rourke, EM Landaw, NR Lyddane, LA Hunt, GJ Schiller, WG Ho, and RE Champlin. "Hemolysis of transfused group O red blood cells in minor ABO- incompatible unrelated-donor bone marrow transplants in patients receiving cyclosporine without posttransplant methotrexate." Blood 79, no. 11 (June 1, 1992): 3076–85. http://dx.doi.org/10.1182/blood.v79.11.3076.bloodjournal79113076.
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Hemolysis most commonly occurs following bone marrow transplant when there is “minor” ABO blood group incompatibility between donor and recipient. The hemolysis has been attributed to destruction of the patient's incompatible erythrocytes by donor-derived anti-A and/or anti- B antibody produced from “passenger” immunocompetent donor lymphocytes. Extraordinary transfusion requirements of group O erythrocytes in a series of patients receiving unrelated minor ABO-incompatible marrow grafts led us to investigate whether this mechanism could account for the extent of hemolysis observed. In seven consecutive minor ABO- incompatible unrelated-donor bone marrow transplant recipients receiving cyclosporine without posttransplant methotrexate, we observed excessive hemolysis. For cases in this index group, a strongly reactive donor-derived ABO blood group antibody was identified coincident with development of hemolysis. Transfusion requirements in the first three patients (26 U of group O erythrocytes each) greatly exceeded the recipient's volume of incompatible erythrocytes, indicating that lysis of transfused group O erythrocytes was also occurring. Pretransplant erythrocyte exchange transfusion with group O erythrocytes performed in the four subsequent patients decreased the severity of hemolysis, but did not prevent it. Among minor ABO-incompatible marrow graft recipients, an analysis of variance demonstrated effects on transfusion requirements due to donor-recipient relationship being unrelated (P less than .002) and the use of posttransplant methotrexate (P = .0001), and there was interaction between these two factors (P less than .001). Bone marrow transplants from unrelated donors resulted in an exaggerated immune response to ABO blood group antigens, which was associated with hemolysis of transfused group O erythrocytes, as well as the patient's ABO-incompatible erythrocytes. This serious complication may be prevented by posttransplant immunosuppression with methotrexate.
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Klink, Anne, Christoph Kasper, Sebastian Scholl, Lars-Olof Muegge, Kristina Schilling, Anja Markusch, Klaus Hoeffken, and Herbert G. Sayer. "First Report of a Prospective Randomised Controlled Trial of Recombinant Human Erythropoietin after Allogeneic Blood Stem Cell Transplantation." Blood 104, no. 11 (November 16, 2004): 1833. http://dx.doi.org/10.1182/blood.v104.11.1833.1833.
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Abstract Recombinant human erythropoietin (rHuEPO) stimulates progenitor cells of erythropoiesis and increases erythrocyte production. This prospective, placebo-controlled, double-blind trial was designed to evaluate the use of erythropoietin versus red blood cell transfusions (RBC) to evade detrimental effects of anaemia during the first weeks after allogeneic peripheral blood stem cell transplantation (alloPBSCT). Between 4/2002 and 4/2004, 52 patients recieved either 10.000 units rHuEPO [Erypho(R)] 3 times a week subcutaneously or placebo, stratified according to AB0-incompatibility. Applications were started after stem cell transfusion (day +1) and lasted up until in mean day +39.5 [range: 29–50] or until haematocrit (HC) levels reached 0.38. Both groups underwent identical supportive care and RBC transfusion policy. Need for transfusion was defined by HC< 0.27. At time of transplantation, 18 (35%) patients were in remission, and 34 (65%) in advanced stage of their disease. Within the 22 female and 30 male patients (median age: 44.5 years [range:17–64]) 52 % (n=27) received for conditioning treatment a total body irradiation-based regimen, 4% (n=2) high dose treosulfan and cyclophosphamid, and 48 % (n=25) a dose reduced conditioning including fludarabine, busulfan/melphalan and anti-thymocyte globuline, respectively. Thirteen (25 %) patients received transplant from HLA-identical family donors, 26 (50%) from HLA-matched unrelated and 13 (25 %) from mis-matched alternative donors. The two study groups were well balanced regarding age, gender, disease status, graft characteristics, and conditioning regimens. Two patients were excluded from the study due to graft failure on day 21 and one patient refused further treatment on day 37. Eight side effects were observed in the rHuEPO group (3 x local haematoma, 3 x bone/muscle pain, 1 x dizziness, 1 x headache), whereas one was reported in the placebo group (1x headache). No serious adverse event related to study drug was noted. The mean numbers of RBC transfusions were 10.8 ± 5.5 [range: 4–18] with placebo and 9.9 ± 4.2 [range: 6–19] with rHuEPO up to day +50. These effects were identical in the unrelated donor group (n=24) with 11.4 ± 5.7 versus 10.4 ± 4.1, and in the HLA-identical family donor group (n=28) 10.8 ± 5.5 versus 9.4 ± 2.4. Interestingly, in the minor AB0-group (n=15) the rHuEPO arm needed 8.1 ± 3.4 as compared to 12.4 ± 4.2 RBC transfusion in the placebo arm. No differences were observed in the major AB0 group (n=12). Reticulocytes, by similar lab counts on day 0 in both groups, were significantly enhanced on day +30 in the rHuEPO arm. (62.6 ± 18.9 versus 29.3 ± 14.3; p < 0.001). Mean HC on day + 30 was 0.28 ± 0.03, on day + 50 0.33 ± 0.05 in the placebo arm, 0.31 ± 0.03 and 0.36 ± 0.04 in the rHuEPO arm, respectively. Overall survival of the total group after the first 100 days was 49/52 (94,2%).One (3.8%) patient died in placebo-group, and 2 (7.7%) patients in the rHuEPO-group. Further clinical parameters like engraftment, acute graft-versus-host disease (GvHD) and relapse rate were not different between the two treatment groups so far. After alloPBSCT rHuEPO can be given without initial clinical relevant side effects. We conclude that the reconstitution of erythropoiesis seems to be accelerated by early treatment with rHuEPO and reduces number of RBC-transfusions in AB0 minor incompatibility situation after alloPBSCT.
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Oseni, BashiruS, and OluseunF Akomolafe. "The frequency of ABO blood group maternal-fetal incompatibility, maternal iso-agglutinins, and immune agglutinins quantitation in Osogbo, Osun State, South-West of Nigeria." Asian Journal of Transfusion Science 5, no. 1 (2011): 46. http://dx.doi.org/10.4103/0973-6247.75998.
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Ahlen, Maria T., Mette K. Killie, Anne Husebekk, Jens Kjeldsen-Kragh, Martin L. Olsson, and Bjorn Skogen. "The Development of Severe Anti-HPA 1a-Related Neonatal Alloimmune Thrombocytopenia Is Influenced by the Maternal ABO Type." Blood 110, no. 11 (November 16, 2007): 2093. http://dx.doi.org/10.1182/blood.v110.11.2093.2093.
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Abstract About 100 000 pregnant women were included in a screening and intervention program aimed to reduce morbidity and mortality related to neonatal alloimmune thrombocytopenia (NAIT). NAIT due to HPA 1a immunization have many features in common with hemolytic disease of the newborn (HDN) caused by RhD immunization. Platelets express blood group A and B antigens, and as described in HDN, ABO incompatibility between mother and fetus could possibly protect against immunization against HPA 1a. The aim of the study was to describe the ABO distribution among the immunized mothers and examine whether ABO status of the mother influenced the severity of thrombocytopenia in the newborn. ABO typing of HPA 1a immunized women was routinely performed by serological methods during the screening. ABO genotyping resolving the major alleles (A1, A2, B, O1, O1v or O2 alleles) of the women and their newborns was performed by PCR-RFLP methods. The ABO distribution among the immunized HPA 1a negative women was found to be similar to the normal distribution in the Norwegian population, which may indicate that the ABO type does not influence the immunization mechanism. However, we find that HPA 1a immunized women of blood group A have a higher risk of delivering a child with severe NAIT (platelet count < 50×109/L) than women with blood group O. Twenty percent of the immunized women with blood group O gave birth to children with severe NAIT, compared to 46% among the immunized blood group A mothers, resulting in a relative risk of 0.43 (95% CI 0.25–0.76). The ABO type of the newborn was not found to influence development of severe NAIT. The O1/O1v allele distribution among the immunized women with blood group O resembles the distribution reported for a Swedish population. However, only 2/22 (9.1%) pregnancies among the O1v negative blood group O mothers resulted in a newborn with severe NAIT, compared to 10/34 (29.4%) among the O1v-positive blood group O women, resulting in a relative risk of 0.31 (95% CI 0.07–1.28). The observation that the immune response against HPA 1a may have different consequences depending on the ABO blood group of the mother is interesting. O1v, also termed O02, constitutes a separate but ancient allelic lineage at the ABO locus and we are now in the process of examining if our observation is related to linkage disequilibrium between the ABO gene and one or more pregnancy-related immunoregulatory genes.
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Willemze, Roelof, Celso arrais Rodrigues, Myriam Labopin, Guillermo Sanz, Gerard Michel, Gerard Socié, Bernard Rio, et al. "KIR-Ligand Incompatibility in the Graft-Versus-Host Direction Is Associated with Better Outcomes after Unrelated Cord Blood Stem Cell Transplantation for Acute Leukemia in Complete Remission." Blood 112, no. 11 (November 16, 2008): 156. http://dx.doi.org/10.1182/blood.v112.11.156.156.
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Abstract HLA class I, killer-cell immunoglobulin-like receptor (KIR) ligands which are missing in the recipient may trigger cytotoxicity of donor NK cells leading to graft-versus- host disease (GvHD) and/or graft-versus-leukemia reactions. Donor KIR(-ligand) incompatibility in the graft-versus-host (GvH) direction is associated with decreased relapse incidence (RI) and improved disease-free survival (DFS) in haplo-identical and HLA-mismatched unrelated hematopoietic stem cell transplantation (HSCT). Since it is unknown whether KIR-ligand mismatching impacts outcomes in unrelated cord blood stem cell transplantation (UCBT), we studied patients reported to Eurocord Registry with acute leukemia in complete remission (CR) with available high resolution typing of HLA-A, -B and -C in recipient/donor pairs who received a single UCBT. Patients and donors were categorized to their KIR-ligand groups by determining whether or not they expressed: HLA-C group 1 or 2, HLA-Bw4 and HLA-A3 or -A11. A total of 218 patient-donor pairs met the eligibility criteria. The patients had ALL (n=124) or AML (n=94) and were transplanted in 1st CR (n=105), 2nd CR (n=91) or >2nd CR (n=22). Median age was 13.4 yrs, weight 49 kg, and nucleated cell dose infused was 3.0×10E7/kg. The cord blood was HLA identical (6/6) in 21, 5/6 in 91, 4/6 in 91 and <4/6 in 15. Conditioning was myeloablative (84%) or reduced intensity (16%), and included ATG in 80%. Forty-one donors were HLA-C, 12 HLA-Bw4 and 22 HLA-A3/-A11 KIR-ligand mismatched in the GvH direction with the patient whereas fifty-one patients were HLA–C group 1 or 2, 19 HLABw4 and 18 HLA-A3/-A11 KIR-ligand mismatched in the HvG direction with the donor. When studying only donor-patient pairs in the GvH direction a total of sixty-nine patients had a KIR-ligand mismatched (KIR+) donor and 149 had not (KIR−). There were no statistical differences for patient-, disease- and transplantion-related factors between the KIR+ and KIR− group, except for more cytogenetically bad risk AML patients in the KIR+ group. HLA-C group 1 and 2, and HLA-A3/-A11, KIR-ligand incompatible UCBT showed independently a trend to improved DFS (p=0.09 and p=0.13, respectively). Analysis of the combined HLA-A, -B and -C KIR-ligand (mis)matches showed no statistical association with neutrophil recovery (81±4% KIR+, 79±3% KIR− group, p=0.21), non-relapse mortality (25±6% KIR+, 32±4% KIR−, p=0.34), acute GvHD (27±5% KIR+, 29±3% KIR−, p=0.82) and chronic GvHD (18±4% KIR+, 14±3% KIR−, p=0.38). However, differences were shown in RI (20±6% KIR+, 37±4% KIR−, p=0.03), DFS (55±7% KIR+, 31±4% KIR−, p=0.005) and overall survival (57±7% KIR+, 40±4% KIR−, p=0.02). In multivariate analysis, donor KIR-ligand incompatibility was associated with decreased RI (HR=0.53, p=0.05), increased DFS (HR=2.05, p=0.016) and overall survival (HR=2, p=0.004). In subgroup analysis for AML: RI for KIR+ vs KIR− was 5±4% vs 36±7% (p=0.005) and DFS 73±10% vs 38±7% (p=0.012); and for ALL: RI was 29±8% vs 37±6% (p=0.71) and DFS 44±9% vs 27±6% (p=0.10), respectively. The use of KIR-ligand incompatible donors in UCBT resulted in a lower RI and increased DFS and overall survival, especially in AML. If these results are confirmed in a larger series of patients KIR-ligand incompatibility in the GvH direction might be considered as a criterion of cord blood donor choice.
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Kotecha, Ritesh, Xin Tian, Jennifer Wilder, Nicole Gormley, Hahn Khuu, David Stroncek, Susan F. Leitman, et al. "NK Cell KIR Ligand Mismatches Influence Engraftment Following Combined Haploidentical and Umbilical Cord Blood (UCB) Transplantation In Patients With Severe Aplastic Anemia (SAA)." Blood 122, no. 21 (November 15, 2013): 2038. http://dx.doi.org/10.1182/blood.v122.21.2038.2038.
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Abstract Background Allogeneic hematopoietic stem cell transplant (HSCT) is curative for patients (pts) with severe aplastic anemia (SAA). For SAA pts who lack HLA-identical donors, we explored a HSCT approach that co-infuses PBSCs enriched for CD34+ cells from a haplo-identical relative combined with a single umbilical cord blood unit (UCB). Although most pts undergoing this approach had early haplo-myeloid engraftment that was eventually supplanted by the UCB unit, engraftment patterns were highly variable; in some pts full cord myeloid chimerism was delayed greater than one year, while others had loss of cord engraftment with sustained full haplo-donor myeloid chimerism. Here, we investigated the impact of various patient, UCB, and haplo-donor characteristics, as well as NK cell KIR ligand mismatches between graft sources, on engraftment kinetics following haplo-cord HSCT. Methods Pts with SAA or SAA evolved to MDS unresponsive to immunosuppressive therapy with severe neutropenia (ANC<500), who lacked an HLA-matched donor and had an available haploidentical family member, and had at least one ≥ 4/6 matched UCB unit with a minimum TNC dose ≥1.5x107 cells/kg were eligible for HSCT. Pts were conditioned with cyclophosphamide (120 mg/kg), fludarabine (125 mg/m2), equine-ATG (160 mg/kg) and 200 cGy of total body irradiation. On Day 0, pts received a CD34 selected (Miltenyi CliniMacs) G-CSF mobilized haplo-donor allograft combined with a single UCB. Tacrolimus and MMF were given for GVHD prophylaxis. Results 16 pts (median age: 18.9 yrs, range: 4.5-27.9) including 13 SAA and 3 with SAA evolved to MDS underwent haplo-cord transplant. Ten pts received a 4/6, and six pts received a 5/6 HLA-matched UCB unit. A median 3.6x107 TNC/kg (range: 1.96-6.93) from the UCB unit, and 3.3x106CD34+ cells/kg (range: 3.0-4.1) from the haplo-donor were transplanted. All 16 pts had sustained engraftment with 15/15 pts evaluable past day 100 having transfusion independence. At a median follow-up of 570 days (range: 55-1826), 14/16 pts survive for an overall survival rate of 81.8%. Two pts died at day 414 and 402 post-HSCT from viral related complications (CMV pneumonitis and limbic encephalopathy). Neutrophil and platelet recovery occurred at a median 10 (range: 9-22), and 21 (range: 10-213) days post-HSCT, respectively. By post-HSCT day 11, 15/16 pts had neutrophil recovery. Cord myeloid engraftment (cord ANC>500, calculated from chimerism data) occurred in 13/16 pts at a median 42 days. 3/16 did not achieve a cord ANC>500 but had sustained haplo-donor engraftment. The cumulative incidence of acute grade II-IV GvHD was 38.1%. Engraftment profiles were highly variable among pts; 12 achieved full cord chimerism in all cell lineages, 2 remained mixed haplo-cord chimeras, and 2 failed to have UCB engraftment but had sustained 100% haplo-donor myeloid chimerism. Higher degrees of HLA matching (out of 10 alleles) between recipient and UCB unit were associated with faster rates of full cord engraftment (p=0.006) and a higher probability of complete loss of haplo-donor chimerism (p=0.018). KIR ligand incompatibility in the haplo vs. cord direction (defined as the presence of a KIR ligand in the haplo-donor graft that is absent in the UCB unit at HLA epitopes Bw4, HLA-C Group 1 & 2, HLA-A3, and HLA-A11) negatively impacted cord myeloid engraftment. 5/5 (100%) pts who failed to achieve full cord myeloid chimerism by post-HSCT day 400 had haplo vs. cord KIR ligand incompatibility. Moreover, both pts who failed to have UCB engraftment and had sustained haplo-donor chimerism had haplo vs. cord KIR ligand incompatibility. In contrast, only 3/11 (27%) pts who achieved full cord myeloid chimerism post-HSCT by day 231 had haplo vs. cord KIR ligand incompatibility (p=0.026). KIR ligand incompatibility in the cord vs. haplo direction showed no significant effect on haplo-donor myeloid engraftment. Conclusion These results show that haplo-cord HSCT is an effective treatment option for pts with SAA who lack an HLA-matched donor. Further, these results suggest that NK cell alloreactivity, occurring as a consequence of KIR ligand mismatch between the two graft sources, may have a negative impact on cord engraftment when haplo vs. cord KIR ligand incompatibility is present. In summary, this study highlights a novel factor that should be considered during graft selection for haplo-cord transplantation. Disclosures: No relevant conflicts of interest to declare.
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Rieneck, Klaus, Christoffer Egeberg Hother, Frederik Banch Clausen, Marianne Antonius Jakobsen, Thomas Bergholt, Ellinor Hellmuth, Lene Grønbeck, and Morten Hanefeld Dziegiel. "Next Generation Sequencing-Based Fetal ABO Blood Group Prediction by Analysis of Cell-Free DNA from Maternal Plasma." Transfusion Medicine and Hemotherapy 47, no. 1 (2020): 45–53. http://dx.doi.org/10.1159/000505464.
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Introduction: ABO blood group incompatibility between a pregnant woman and her fetus as a cause of morbidity or mortality of the fetus or newborn remains an important, albeit rare, risk. When a pregnant woman has a high level of anti-A or anti-B IgG antibodies, the child may be at risk for hemolytic disease of the fetus and newborn (HDFN). Performing a direct prenatal determination of the fetal ABO blood group can provide valuable clinical information. Objective: Here, we report a next generation sequencing (NGS)-based assay for predicting the prenatal ABO blood group. Materials and Methods: A total of 26 plasma samples from 26 pregnant women were tested from gestational weeks 12 to 35. Of these samples, 20 were clinical samples and 6 were test samples. Extracted cell-free DNA was PCR-amplified using 2 primer sets followed by NGS. NGS data were analyzed by 2 different methods, FASTQ analysis and a grep search, to ensure robust results. The fetal ABO prediction was compared with the known serological infant ABO type, which was available for 19 samples. Results: There was concordance for 19 of 19 predictable samples where the phenotype information was available and when the analysis was done by the 2 methods. For immunized pregnant women (n = 20), the risk of HDFN was predicted for 12 fetuses, and no risk was predicted for 7 fetuses; one result of the clinical samples was indeterminable. Cloning and sequencing revealed a novel variant harboring the same single nucleotide variations as ABO*O.01.24 with an additional c.220C>T substitution. An additional indeterminable result was found among the 6 test samples and was caused by maternal heterozygosity. The 2 indeterminable samples demonstrated limitations to the assay due to hybrid ABO genes or maternal heterozygosity. Conclusions: We pioneered an NGS-based fetal ABO prediction assay based on a cell-free DNA analysis from maternal plasma and demonstrated its application in a small number of samples. Based on the calculations of variant frequencies and ABO*O.01/ABO*O.02 heterozygote frequency, we estimate that we can assign a reliable fetal ABO type in approximately 95% of the forthcoming clinical samples of type O pregnant women. Despite the vast genetic variations underlying the ABO blood groups, many variants are rare, and prenatal ABO prediction is possible and adds valuable early information for the prevention of ABO HDFN.
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Kumlien, Gunilla, Lisbeth Ullstrom, Amal Ayoub, and Gunnar Tyden3. "Clinical Experience with a New Apheresis Filter That Specifically Depletes ABO Blood Group Antibodies." Blood 104, no. 11 (November 16, 2004): 2722. http://dx.doi.org/10.1182/blood.v104.11.2722.2722.
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Abstract Background: The shortage of organs for transplantation is a well-known problem and one of the means to increase the donor pool is the use of ABO blood group incompatible donors. Presently, in most transplant centers, between 30% and 40% of potential donors are turned down due to ABO blood group incompatibility. Recently a low-molecular carbohydrate column with A or B blood group antigen linked to a sepharose matrix (Glucosorb-ABO, Glycorex Transplantation, Lund, Sweden) that specifically depletes anti-A or anti-B antibodies was registered in Europe and we have had the opportunity to evaluate this device in eleven patients who successfully have received ABO incompatible renal grafts, four of which have been reported earlier (Tyden G, Kumlien G, Fehrman I. Transplantation2003;76:730–731). Method: Pretransplant conditioning was started on day −10 with one infusion of rituximab 375 mg/m2, followed by tacrolimus 0,3 mg/kg, mycophenolate mofetil 3g and prednisolone 30 mg. On day −1 0,5 mg/kg of intravenous immunoglobulin was administered. Patient plasma (1–2 plasma volumes per session) was recirculated through the column using CobeSpectra apheresis machine. Anti-A and anti-B titers were analysed using standard direct (NaCl) and indirect (IAT) agglutination techniques. In the adult or adolescent patients immunoglobulins, including IgG-subclass antibodies and specific antibodies against protein and carbohydrate antigens, were analysed before first apheresis and after last apheresis before renal transplant. Results: ABO blood group antibody titers were lowered up to fours steps per apheresis procedure. No side effects were detected. So far eleven patients including two infants have been successfully transplanted with ABO-incompatible living donors using this protocol. Donor blood groups were: four A1, one A1B, four B and two A2. See Table1 for patient data. IgG, IgG1 and IgM were lowered to slightly subnormal levels pre transplant while IgA, IgG2, IgG3 and IgG4 remained normal. Levels of specific antibodies against protein and carbohydrate antigens were not affected. Since ABO antibodies are of IgG and IgM immunoglobulin class, the decrease is quite logical and the fact that levels of specific antibodies were unchanged confirms the specificity of the column. Conclusion: Our experience shows that ABO-blood group antibodies can be effectively and specifically depleted without any side-effects using the Glucosorb-ABO column and that antibody production can be effectively suppressed without splenectomy. Specific depletion of ABO blood group antibodies is a new apheresis method with significant advantages for patients compared to multiple sessions of plasmapheresis since the patients own plasma is recirculated through the column and no donor plasma or other substitution fluids are needed. Table 1 Patient data Don/Rec blood groups Anti-A or B titers before adsorption (IgG) No of preop adsorptions Anti-A or B titers at transplantation (IgG) No of postop adsorptions Follow-up (months) Serum creatinine levels at follow-up (umol/L) A2/O 1:64 4 1:2 3 34 80 B/O 1:32 4 1:4 3 17 169 B/A 1:16 4 1:1 3 22 120 A1/O 1:64 8 1:1 16 18 108 A2/O 1:64 4 1:4 3 15 179 A1/O 1:128 9 1:2 5 13 93 B/A 1:8 4 1:1 3 9 135 B/O 1:2 0 1:2 3 5 24 A1B/B 1:16 6 1:2 6 4 100 A1/O 1:16 4 1:1 5 3 114 A1/O 1:1 0 1:1 3 2 37
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Yan, Jiawei, Guangyu Sun, Wen Yao, Lei Zhang, Xiang Wan, Baolin Tang, Xiaoyu Zhu, et al. "Impact of ABO Incompatibility on Engraftment , Transfusion Requirement and Survival after Unrelated Cord Blood Transplantation：a Single Institute Experience in China." Blood 124, no. 21 (December 6, 2014): 2586. http://dx.doi.org/10.1182/blood.v124.21.2586.2586.
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Abstract Few reports have focused on the impact of ABO incompatibility on the clinical outcomes, after unrelated cord blood transplantation (UCBT). Therefore, we retrospectively analyzed the impact of ABO mismatching on the clinical outcomes of 177 patients with hematologic malignancies, which underwent single UCBT in Anhui Provincial Hospital from May 2008 to April 2014. The study patients included 86 ABO-identical, 52 minor, 32 major, and 11 bidirectional ABO-incompatible recipients. All of them received a homogeneous intensified myeloablative pre-transplantation conditioning regimen of total body irradiation (TBI)cyclophosphamide (CY) [TBI (total,12 Gy; four fractions) and CY (60 mg/kg daily for 2 days)] (age≥14 years) or BuCY2 [busulfan (0.8 mg/kg every 6 h for 4 days) and CY]. Medians of 3.85×107/kg (range, 1.03-10.43) total nucleated cell (TNC) and 2.0×105/kg (range, 0.45-6.88) CD34+cells were transfused. Of the 177 patients who underwent UCBT, 169 achieved successful neutrophil engraftment. In patients receiving ABO-identical, minor, major, and bidirectional ABO-incompatible UCBT, the cumulative incidences of neutrophil engraftment were 92.7%, 100%, 96.9% and 90.9%, respectively (P=0.509). The median days to achieve neutrophil engraftment were 17, 18, 17, and 20, respectively (P=0.409). The cumulative incidences of platelet engraftment were 81.7%, 86.5% , 87.5% and 63.6%, respectively(P=0.436) .And the median days to achieve platelet engraftment for the 4 groups were 36, 40, 36, and 38, respectively; (P=0.545). All of the data did not show any significant difference among the 4 groups. Neutrophil engraftment(cumulative incidence, 95.5% versus 95.3% , P=0.861; median day, 17 versus 18, P=0.717) also did not differ significantly between the ABO-identical/minor ABO-incompatible and major/bidirectional ABO-incompatible recipients (HR1.08, P=0.680). And platelet engraftment (83.6% versus 81.4%, P=0.964; median day, 38 versus 37, P=0.699) reached the similar result (HR1.104, P=0.621). We investigated the results from a 169-patient population with neutrophil engraftment, the average units of platelets (Plts) and red blood cells (RBCs) transfused during the hospitalization after the UCBT were 0.204 units/kg(range, 0.03-1.45)and 0.159 units/kg (range, 0-1.56).In patients with ABO-identical, minor, major, and bidirectional ABO-incompatible UCBT, the average units of Plts transfused after UCBT were 0.221, 0.202, 0.169, and 0.195 units/kg(P=0.53), respectively, and the average units of RBCs transfused were 0.151, 0.156, 0.163, and 0.221 units/kg (P=0.847), respectively. No significant differences in the transfusion requirements among the 4 groups were noted, so did the comparison between the ABO-identical/minor ABO-incompatible and major/bidirectional ABO-incompatible recipients. With a median follow-up of 12 months (range, 3-74 months), the disease-free survival (DFS) rates among the ABO-identical, minor, major, and bidirectional ABO-incompatible groups were 67.1%, 57.7%, 62.5 % and 54.5%, respectively (P=0.804), and the overall survival (OS) also did not differ significantly among the four groups (68.3%, 61.5%, 65.6%, and 63.6%, respectively; P=0.929). When it came to the comparison between the ABO identical/minor incompatible group and the ABO major/bidirectional incompatible group, the DFS (63.4% versus 60.5%; P=0.995) and OS estimates (65.7% versus 65.1%; P=0.820) were not significantly different, either. What’s more, none of the patients clinical developed severe immune hemolysis or pure red-cell aplasia after transplantation. In summary, the results above indicated that :1) ABO incompatibility did not seem to have a significant impact on clinical outcomes after UCBT, such as engraftment, transfusion requirements and survival. 2) No patients developed pure red-cell aplasia after UCBT. 3) In addition, we also compared the outcomes between the ABO-identical and bidirectional ABO-incompatible groups, even it did not show any significant difference, the former did better on platelet engraftment (81.7% versus 63.6%) and DFS (67.1 versus 54.5%). The reason led to this result may be the lack of bidirectional ABO-incompatible recipients. Therefore, we’d better avoid selecting bidirectional ABO-incompatible in UCBT to improve the patients’ recovery and survival time. Disclosures No relevant conflicts of interest to declare.
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Honna, Hiroko, Kumiko Goi, Kinuko Hirose, Itaru Kuroda, Takeshi Inukai, Keiko Kagami, and Kanji Sugita. "KIRs Expression and Cytotoxic Activities of Cord Blood Natural Killer Cells Against Acute Lymphoblastic Leukemia with MLL Gene Rearrangement." Blood 110, no. 11 (November 16, 2007): 2803. http://dx.doi.org/10.1182/blood.v110.11.2803.2803.
Full textAbstract:
Abstract MLL-rearranged ALL is associated with an extremely poor prognosis despite intensive chemotherapy and hematopoietic stem cell transplantation (SCT). We have reported that MLL-rearranged ALL is resistant to death-inducing ligands TRAIL and FasL expressed on cytotoxic T lymphocytes, and therefore T-cell mediating graft-versus-leukemia (GVL) effect is not expected post allogeneic SCT. We recently demonstrated that MLL-rearranged ALL cells were effectively killed by allogeneic NK cells from adult peripheral blood (PB) in a perforin-dependent manner when KIR (killer cell Ig-like receptor) ligand incompatibility exists between ALL cells and NK cells. This KIR ligand incompatibility has been reported to possibly reduce the relapse rate of acute myeloid leukemia post SCT. To pursue the clinical implication in KIR ligand incompatible cord blood transplantation (CBT) for the treatment of MLL-rearranged ALL, we examined the KIRs expression on allogeneic NK cells from umbilical cord blood (CB) by flow cytometry and their in vitro cytotoxic activities against MLL-rearranged ALL cell lines by a standard Cr-release assay at an effector-to-target ratio of 20 to 40. The results were compared between NK cells from adult PB and CB, and between KIR ligand compatible and incompatible NK cells. NK cells from CB were enriched by negative selection and classified into 2 groups based on HLA-C alleles; C1/C1 type (n=5) both alleles belonging to group I (Cw1, Cw3 et. al.) and C1/C2 type (n=4) each of alleles belonging to group I and group II (Cw2, Cw4, et. al.). NK cells from adult PB were similarly classified into C1/C1 type (n=4) and C1/C2 type (n=5). All of the MLL-rearranged ALL cell lines established in our laboratory (n=10) were C1/C1 type, and two cell lines with MLL-ENL (KOPN1, KOCL50) were used as targets. K562 lacking HLA class I expression was used as a positive control target. Although there was no significant difference in the HLA-C group II receptor (KIR2DL1, CD158a) expression between CB- and adult PB-NK cells (17.8±6.3% vs. 26.5±15.2%), the HLA-C group I receptor (KIR2DL2/L3, CD158b) expression on CB-NK cells was significantly lower than on adult PB-NK cells (24.3±10.2% vs. 47.4±19.2%, p=0.009). The CD158b expression showed no difference between C1/C1 and C1/C2 types of CB-NK cells, but it expressed higher on C1/C1 type of adult PB-NK cells than on C1/C2 type (58.9±17.4% vs. 35.9±14.0%. p=0.047), suggesting that the CD158b expression on NK cells increases as getting older particularly in C1/C1 type individuals. In the cytotoxic assay, CB-NK cells irrespective of C1/C1 and C1/C2 types exhibited a lower cytotoxicity against K562 compared with adult PB-NK cells (42.0±19.2% vs. 63.6±9.5%, p=0.009). Of importance, although both C1/C1 and C1/C2 CB-NK cells showed a similar cytotoxicity against K562, C1/C2 CB-NK cells exhibited a significantly higher cytotoxicity against C1/C1 MLL-rearranged ALL cell lines than did C1/C1 CB-NK cells when assessed by a relative cytotoxicity to K562 (KOPN1, 0.84±0.19 vs. 0.47±0.13, p=0.028; KOCL-50, 0.87±0.27 vs. 0.40±0.14, p=0.028), suggesting that a loss of inhibitory signal to CD158a on NK cells from leukemia cells can specifically enhance their alloreactivity. Taken together, MLL-rearranged ALL cells are sensitive to killing by KIR ligand incompatible allogeneic CB-NK cells, and therefore the maximal GVL effect against this leukemia could be expected if the specific CB whose NK cells can exert their alloreactivity is selected for CBT.
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Xing, Dongxia, William Decker, Sufang Li, Simon Robinson, Nina Shah, Hong Yang, Richard E. Champlin, et al. "Targeting Chronic Lymphocytic Leukemia with Cord Blood NK Cells In NSG Model." Blood 116, no. 21 (November 19, 2010): 2453. http://dx.doi.org/10.1182/blood.v116.21.2453.2453.
Full textAbstract:
Abstract Abstract 2453 The incompatibility between donor killer cell immunoglobulin-like receptors (KIRs) and their corresponding ligands has been reported to reduce the risk of relapse after haploidentical and human leukocyte antigen (HLA) mismatched hematopoietic stem cell transplantation in patients with acute myeloid leukemia. We tested this KIR-ligand mismatch hypothesis in the context of allogeneic cord blood NK cells as an adoptive transfer of lymphocytes treating residual chronic lymphocytic leukemia (CLL). As a model for targeting malignant B cells in CLL, we examined allogeneic cord blood NK cell function in NOD scid gamma (NSG) mice, which carry the null interleukin-2 receptor gamma chain mutation, as the mice developed leukemia. Positively selected CD56+ cord blood NK cells were expanded ex vivo with interleukin-2 for 14 days. CLL cells were established in the NSG model by infusion of CLL cells obtained from patients. The leukemia that develops in NSG mice resembles human CLL, with a proliferating CD19+CD23+CD5+ B-cell population detected in the bone marrow, spleen, lymph nodes, and peripheral blood. Subsequently, expanded cord blood NK cells (5 × 106 per mouse) were intravenously infused into NSG-CLL mice. The NK cells that were infused into the CLL mice were typed for HLA and KIR (four main KIRs: KIR2DL2, KIR2DL3, KIR3DL1, and KIR2DL1). The CLL patients' samples that had been used in the NSG models were genotyped for KIR ligands (HLA-C group or HLA-Bw4 group and HLA-A3). In the six pairs of cord blood NK and CLL cells typed, all were HLA mismatched. Five pairs were KIR-ligand mismatched; these mice showed robust NK cell–mediated killing of CLL cells 7 days after NK cell infusion. Of interest, although no KIR-ligand mismatch was seen between the cord blood NK cells and CLL cells in one pair, we still observed NK cell–mediated killing of CLL cells in the mice. In this instance, NK cell–mediated cell killing could have been attributed to possible lower expression of HLA ligands by leukemic cells. Overall survival was significantly improved in CLL-NSG mice that had received cord blood NK cell treatment compared with overall survival in untreated mice (Kaplan-Meier analysis, p < 0.03). These results showed that adoptive transfer of allogeneic cord blood NK cells can be effective in killing CLL, and will be explored in the clinic. Disclosures: Gribben: Roche: Consultancy; Celgene: Consultancy; GSK: Honoraria; Napp: Honoraria.
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Pascal, Laurent B., Luciana Tucunduva, Annalisa Ruggeri, Didier Blaise, Mohamad Mohty, Patrice Ceballos, Patrice Chevallier, et al. "Impact Of Rabbit Anti-Thymocyte Globulin-Containing Reduced-Intensity Conditioning Regimens On Outcomes Of Adults Undergoing Unrelated Cord Blood Transplantation For Hematological Malignancies." Blood 122, no. 21 (November 15, 2013): 412. http://dx.doi.org/10.1182/blood.v122.21.412.412.
Full textAbstract:
Abstract To assess the impact of antithymocyte globulins (ATG), on patients' outcome after unrelated cord blood transplantation (UCBT) following a reduced-intensity regimen (RIC), we conducted a retrospective registry-based analysis on 661 adults with hematological malignancies who underwent unrelated single (s) or double (d) UCBT following RIC with the TBI/cyclophosphamide/fludarabine regimen (TCF) between 2004 and 2011 in EBMT centers. Participating centers were asked to provide additional information on type, timing and total dose of ATG used. Diagnosis was AML/ALL in 51%, MDS/CML in 19% and lymphoid malignancies in 30%; 28% of patients were transplanted in early disease status, 28% in intermediate and 44% in advanced disease. Thirty percent of patients had a previous autologous transplantation. Single UCBT was used in 226 (34%) patients, while 435 (66%) were transplanted with dUCBT. HLA matching was defined as low resolution for HLA-A and HLA-B, and high resolution for HLA-DRB1, and for dUCBT, the highest degree of HLA incompatibility was considered. Therefore, most of the HLA incompatibilities were 4/6 (n=435, 72%). Median number of collected total nucleated and CD34+ cells were 4.4x107/kg and 1.6x105/kg, respectively. All patients received TCF, with TBI 2Gy (86%), TBI 4Gy (12%) and TBI 6Gy (2%). Rabitt ATG (rATG) was used as part of RIC in 82 patients (12.4%) with a median total dose of rATG (Fresenius®) of 20mg/kg (5-60) and rATG (Genzyme®) of 8mg/kg (5-15). GVHD prophylaxis consisted of cyclosporine A (CsA)+ mycophenolate mofetil (MMF) in 91%, Csa alone±other in 9%. The median follow-up was 36.3 months. When compared to patients not receiving rATG-TCF, patients given rATG-TCF had more MDS/CML (30% vs 20%, p<0.01), were transplanted more recently (p=0.02) and there was a trend of being transplanted with more advanced disease (53% vs 43%, p=0.06). Table below shows overall outcomes for 661 patients and univariate analysis for outcomes by the use of rATG-TCF. Type and dose of rATG were not associated with any outcomes. Multivariate (MV) models for outcomes were built adjusting for the differences between 2 groups of rATG-TCF (yes and no) and other risk factors that impact outcomes (patients's age>51 years, positive CMV serology, MDS/CML, advanced disease status, year of transplant, HLA 4/6 and ABO incompatibility). In the final MV models, use of rATG was associated with decreased incidence of aGVHD (HR=0.31, 95%, CI=0.17-0.55, p<0.0001), higher incidence of NRM (HR=1.68, 95% CI=1.16-2.43, p=0.0009) and decreased OS (HR=1.69, 95% CI=1.19-2.415, p=0.003), however it was not associated with engraftment, chronic GVHD and relapse. In rATG-RIC-group, the main cause of death was transplantation related in 51% of cases. Death related to infections was 72% in the rATG-RIC group compared to 39% in the non rATG group. In conclusion, in this retrospective and multicentre analysis, use of rATG as part of TCF regimen, was associated with decreased incidence of acute GVHD, however with increased NRM and decreased OS, probably related to the higher incidence of infections. Despite the retrospective design of our study, we suggest that in UCBT for adults with hematological malignancies given a TCF regimen, systematic use of rATG might be a matter of concern. In addition, timing and dose of rATG are still open questions and only randomized studies may address this issue. Disclosures: Yakoub-Agha: Genzyme: Honoraria, Research Funding.
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Farag, Sherif, Andrea Bacigalupo, Bo Dupont, Michael Caligiuri, Gene Nelson, Jeffrey Miller, and Stella Davies. "The Effect of Killer Immunoglobulin-Like Receptor (KIR) Ligand Incompatibility on Outcome of Unrelated Donor Bone Marrow Transplantation (UDT)." Blood 104, no. 11 (November 16, 2004): 434. http://dx.doi.org/10.1182/blood.v104.11.434.434.
Full textAbstract:
Abstract KIR ligand incompatibility in the graft-versus-host (GvH) direction has been associated with a significant reduction in relapse, graft rejection and graft-versus-host disease (GvHD) in patients with high-risk acute myeloid leukemia (AML)undergoing full haplotype-mismatched, T-cell depleted transplants. The effect in UDT has been less consistent. This study investigates the effect of KIR ligand mismatching on the outcome of UDT in a large combined data set from the National Marrow Donor Program and the European Group for Blood and Marrow Transplantation, comparing the outcome of 1,816 KIR ligand matched and mismatched transplants for AML (n=501), chronic myelogenous leukemia (n=1024), and myelodysplasia (n=291). All cases had high-resolution HLA typing, and were matched for HLA-A, and -DRB1 alleles. Based on HLA typing for -B and -C alleles, cases were divided into one of 4 groups for comparison of outcome: KIR ligand incompatible in GvH direction (n=156), KIR ligand incompatible in host-versus-graft (HvG) direction (n=185), HLA mismatched for -B and/or -C, KIR ligand compatible (n=301), and fully HLA matched (n=1174). All received myeloablative preparative regimens, and ex-vivo T-cell depletion of the graft was performed in 18%, 22%, 16% and 15% of patients in the 4 groups, respectively. Overall, a beneficial effect of KIR ligand incompatibility in the GvH direction could not be demonstrated. KIR ligand incompatibility was associated with increased risk of grade III/IV acute GvHD and worse overall survival (OS). However, the effect varied according to whether or not ex-vivo T-cell depletion of the graft was performed (see Table). Our results suggest a detrimental effect of KIR ligand incompatibility in unmanipulated UDT, whereas this negative effect is lost with ex-vivo T-cell depletion. With ex-vivo T-cell depletion, KIR ligand incompatibility in the GvH direction may be associated with a reduced risk of severe acute GvHD and improved OS compared to HLA mismatched, KIR ligand matched transplants, with the outcome approaching that of fully HLA matched transplants. Therefore, full MHC class I matching remains the best option in UDT. KIR ligand mismatching in the GvH direction may be considered if only HLA-B and or -C incompatible donors are available and ex-vivo T-cell depletion is performed. This requires validation in prospective studies. GvH KIR ligand mismatch HvG KIR ligand mismatch No KIR ligand mismatch, HLA mismatch HLA matched P-value T-cell depleted UDT Treatment mortality 51% ± 17% 64% ± 14% 61% ± 13% 47% ± 7% 0.12 Grade III/IV acute GvHD 14% ± 13% 25% ± 13% 37% ± 13% 17% ± 6% 0.04 Chronic GvHD at 3 years 50% ± 21% 39% ± 17% 32% ± 15% 53% ± 8% 0.09 Relapse 18% ± 14% 12% ± 9% 22% ± 11% 20% ± 6% 0.49 OS 31% ± 17% 27% ± 14% 18% ± 11% 38% ± 7% 0.06 T cell replete UDT Treatment mortality 63% ± 8% 63% ± 8% 54% ± 6% 44% ± 3% <0.0001 Grade III/IV acute GvHD 47% ± 9% 45% ± 8% 31% ± 6% 28% ± 3% <0.0001 Chronic GvHD at 3 years 45% ± 10% 67% ± 9% 61% ± 7% 63% ± 3% 0.005 Relapse 22% ± 7% 12% ± 5% 15% ± 4% 17% ± 2% 0.09 OS 19% ± 7% 28% ± 8% 33% ± 6% 43% ± 3% <0.0001
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Crawford, Regina D., David Krugh, William Blum, and Steven Devine. "Transplantation without Hemolysis in a Kell Antigen Positive Patient Undergoing Peripheral Hematopoietic Stem Cell Transplant from a Donor with Anti-Kell Antibodies." Blood 108, no. 11 (November 16, 2006): 4137. http://dx.doi.org/10.1182/blood.v108.11.4137.4137.
Full textAbstract:
Abstract Red blood cell (RBC) antibody formation, with or without hemolysis, is a well known post-transplant complication of ABO and non-ABO mismatched patients and is seen in both solid organ and hematopoietic stem cell transplants (HSCT). Hemolysis secondary to donor lymphocytes transfused during transplant, which produce antibodies directed toward the patient’s remaining red blood cells, is most commonly reported among HSCT donor-recipients with minor ABO blood group mismatching. Passenger Lymphocyte Syndrome (PLS) has been noted to occur in non-ABO group mismatched HSCTs involving the following blood group systems: Rh, Kidd, Lewis, MNS and Duffy. We present a case of a patient with acute myeloid leukemia (AML) in first complete remission who was Kell antigen positive and underwent a non-myeloablative peripheral blood HSCT from a 10/10 HLA matched, related donor who had anti-Kell antibodies. The patient was a 69-year-old male with AML in first remission who consented for transplant with non-myeloablative conditioning on CALGB 100103. At the time of transplantation, the patient was ABO type A positive, had a negative antibody screen, and was positive for the Kell (K1) antigen. The patient had not been transfused RBC or platelets for 4 months prior to HSCT. The related donor was found to be A positive and had anti-Kell that was reactive 1+ at antihuman globulin phase (GEL) prior to filgrastim mobilized peripheral blood HSC collection. The patient received a conditioning regimen of fludarabine 30mg/m2 daily (days -7 to -3) and bulsulfan 0.8mg/kg IV every 6 hours for 8 doses (days -4 to -3). GVHD prophylaxis consisted of methotrexate (5mg/m2) on day +1, +3, and +6 and tacrolimus starting on day -2. After HSCT, no RBC or platelet transfusions were required throughout the patient’s course. Neutrophil and platelet engraftment occurred by day +20. Chimerism studies on peripheral blood[c1] at day +30 revealed 61% donor CD3 T cells, 99% CD14 and CD15, myeloid cells, 90% CD19, B cells, and 96% donor whole blood. Weekly direct antiglobulin tests were performed (day +7 through day +21) with monitoring of hemoglobin, hematocrit, LDH, total and direct bilirbuin, BUN, and creatinine to evaluate for hemolysis. No evidence of hemolysis was seen in the immediate post-transplant period, and the patient’s antibody screen has remained negative to date through day +100. In conclusion, this case demonstrates that peripheral blood HSCT may be done safely in the setting of non-ABO incompatibility due to Kell in the donor-recipient direction. Given the increasing use of non-myeloablative conditioning regimens and peripheral blood HSCT, both of which increase the risk of PLS, the case highlights that the risks of hemolysis for HSCT are evolving and demonstrates the successful implementation of one strategy for monitoring at risk patients.
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Michallet, Mauricette, Karine Goldet, Stephane Morisset, Mohamad Sobh, Youcef Chelghoum, Xavier Thomas, Helene Labussiere, et al. "Erythropoietin Use In Patients with AML or Undergoing Allogeneic HSCT Significantly Improves Quality of Life and Reduces Red Blood Cells and Platelets Transfusions without Any Survival Effect." Blood 116, no. 21 (November 19, 2010): 3810. http://dx.doi.org/10.1182/blood.v116.21.3810.3810.
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Abstract Abstract 3810 Introduction: Despite frequent anemia and multiple transfusions during AML chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT), recommendations and marketing authorization for erythropoietin (EPO) use are still missing. In the current prospective study, as primary objective, we evaluated the effect of EPO on patient's quality of life (QOL). Secondary objective was hemoglobin (Hb) recovery. In addition, a paired matched analysis using similar population was conducted to compare platelets (Pt) and red blood cells (RBC) transfusion number. Materials and methods: We included adult patients with Hb level ≤11g/dl induced by 1, 2 or 3 consolidation chemotherapy for AML in complete remission (CR) (group 1); or by allo-HSCT for any hematological disease (group 2). EPO was administered Sc. once per week during a maximum period of 6 months: for group 1, ARANESP® 150μg; for group 2, NEORECORMON® 30000IU; Hb level was monitored every week. Injections were stopped once the Hb level reached 12g/dl without any transfusion. If after 4 injections, no improvement was observed, doses were doubled, and if after 8 injections, no improvement was observed, patient was taken off-study for EPO inefficiency. The QOL was measured at baseline, at 1, 2, 3 and 6 months by the Functional Assessment of Cancer Therapy–Anemia (FACT–An). EPO responders patients were defined as having Hb level ≥12g/dl (EPO CR) or a ≥ 2g/dl increase [EPO partial response (EPO PR)] compared with baseline value without any transfusion requirement. The matching analysis took into account: sex, age, disease status, for the two groups, associated to cytogenetics, type of chemotherapy, sequential chemotherapy number for group 1, and diagnosis, conditioning, HSC source, number of previous transplants and GVHD for group 2. Results: Between April 2006 and December 2009, among 261 screened patients, 55 were included in group1 and 61 in group 2, patient characteristics for each group are summarized in Table1. Main exclusion criteria were EPO contra-indication and patient refusal. The median number of EPO injections/patient was 13 (3 – 24) in group1 and 8 (2 - 28) in group 2. For the global population (111 evaluable patients [52 group1 and 59 in group 2]), we have noticed a significant improvement of QOL during the 6 months follow-up according to FACT-An anemia (p=0.01). Despite a non-significant improvement for FACT-G, we observed a significant improvement in physical well-being (p<0.0001). There were 85 EPO CR (83% in group1 and 71% in group 2) and 3 (6%) EPO PR (only in group1). Among patients who reached the 6 months follow-up, 81% had a normal Hb level. Fourteen patients (13%) were withdrawn (6 in group1 and 8 in group 2) due to EPO inefficacy and 9 in group 2 for relapse or EPO related/unrelated serious adverse events (AEs). In group1: the median time to achieve an EPO CR was 34 days (17-67) after first consolidation and 41 days (12-67) after second consolidation (p=0.35). In group 2: the median time to achieve EPO CR was 39 days (14 - 180). After the pair-matched analysis, 44 patients in each group were matched with at least one case-control patient. When comparing RBC and Pt transfusions, there were 712 units and 751 units in the matched population versus 504 and 669 in the EPO population respectively [208 spared RBC (80 in group1, p=0.008 and 128 in group 2, p=0.004) and 100 spared Pt units (all in group1, p=0.001)]. The multivariate analysis studying different confounding factors on the cumulative incidence of EPO CR showed a significant positive impact of younger age (p=0.001) and intensive chemotherapy (p=0.03) in group1; and for group 2, the positive impact of Pt levels at baseline, the negative impact of female recipient and major ABO incompatibility. We did not find any significant difference in terms of overall (OS) and event free survival (EFS) between EPO and control groups. Conclusion: This prospective study showed a real benefit of EPO administration on QOL, an achievement of a normal Hb level and a significant spare of RBC and Pt transfusions. Young AML patients, male allo-HSCT recipient, ABO compatible pairs seem to be the best candidates to benefit from EPO administration, with low AEs and no impact on OS or EFS. A cost-effectiveness study is ongoing and results will be communicated. Disclosures: No relevant conflicts of interest to declare.
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Lindner, Sarah, Tobias Berg, Christian Seidel, Franziska Kalensee, Michael A. Rieger, Hubert Serve, Gesine Bug, Joachim Schwaeble, and Evelyn Ullrich. "Impact of KIR/HLA Incompatibilities after Posttransplant Cyclophosphamide Based T Cell-Replete Haploidentical Hematopoietic Stem Cell Transplantation." Blood 134, Supplement_1 (November 13, 2019): 3340. http://dx.doi.org/10.1182/blood-2019-125243.
Full textAbstract:
Introduction: Posttransplantation cyclophosphamide (PTCy) based T cell-replete haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) is a valid option for patients with indication for allogeneic HSCT without a human leucocyte antigen (HLA) matched donor. However, selection criteria to determine the optimal among several available haplo donors are still a matter of debate. Especially, the impact of killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen (HLA) incompatibilities (inc) in the setting of PTCy T cell-replete haplo HSCT is unclear. PTCy has been reported to eliminate most mature donor NK cells infused with the graft, including single KIR+ NK cells, thereby blunting NK cell alloreactivity in this setting (Russo et al., Blood 2018). Willem et al. (J Immunol 2019) reported (i) a significant loss of KIR2DL2/3+ NK cells at day +30 in patients with inhibitory KIR/HLA incompatibility (inc.) suggesting that PTCy might target responsive KIR NK cells and (ii) a correlation of genetic KIR2DL/HLA inc. with less relapse, but more graft-versus-host-disease (GvHD). Similarly, NK alloreactivity defined as KIR receptor-ligand mismatch or group B KIR haplotype with the presence of KIR2DS2 has been correlated with improved survival (Salomon et al., BBMT 2018). Aims of our study were to evaluate the impact of (i) HLA/KIR inc, (ii) donor KIR genotype and (iii) HLA-DP mismatch status on survival and incidence of relapse, acute and chronic GvHD in our homogeneously treated, independent patient cohort. Patients and methods: We retrospectively analyzed the outcome of 51 consecutively transplanted patients (AML/MDS (n=28/5), ALL (n=9), HD (n=2), NHL (n=5), CML (n=1), PMF (n=1)) receiving a PTCy based T cell-replete haplo HSCT between 01/2011-12/2018. All patients received a myeloablative conditioning regimen (fludarabine/total body irradiation (FTBI) or thiotepa/busulfan/fludarabine (TBF)) with unmanipulated bone marrow (98%) as the preferred graft (median CD34+ cells: 3.02 x 106/kg (range, 1.50-6.90) and median CD3+ T cells: 3.54 x 107/kg (range 1.52-43.74)). GvHD prophylaxis with ciclosporin A started on day 0, mycophenolate-mofetil on day +1, PTCy was applied on day +3 and +5. Results: Patient, donor and transplant characteristics as detailed in table 1 were well balanced between the inh. KIR/HLA inc. group (n=29) vs. no inh. KIR/HLA inc. group (n=22) with the exception of the median donor age (41.7 (range, 23.4-73.7) vs. 33.6 years (range, 19.0-56.2), resp. All patients engrafted. At day +28 (range, 20-29; n=26) CD3+ cells were 88.5/nL (range, 3-665), CD3+CD4+ cells 22.5/nL (range, 0-277.0), CD3+CD8+ cells 117.0/nL (range, 7-478), CD19+ cells 1.0/nL (range, 0-12), CD56bright cells 74.4/nL (range11.1-93.4), CD56dim cells 25.5/nL (range, 6.4-88.9) measured by flow cytometry and without differences between the inh. KIR/HLA inc. group vs. no inh. KIR/HLA inc. group. Cytomegalovirus (CMV) reactivation occurred in 73.3% of patients at risk and median time of occurrence was 32 days (range, 12-97) without difference between groups. Median follow-up for surviving patients was 26.1 months (range, 2.8-92.8) and we found no significant differences in 2-year overall survival (OS; 65.3±10.3 vs. 89.6±7.0, p=0.311), 2-year relapse-free survival (RFS; 66.0±9.4 vs 77.8±10.2, p=0.235), GvHD- and relapse-free survival (GRFS; 48.4±9.8 vs 60.5±12.0, p=0.182) as well as cumulative incidence (CI) of relapse (23.3% vs 16.2%, p= 0.283), acute GvHD grade 2-4 (27.6% vs 31.8, p=0.563), moderate-severe chronic GvHD (22.2% vs. 9.9%, p=0.227) and NRM (16.3% vs 5.3%, p=0.283) between the inh. KIR/HLA inc. group vs. no inh. KIR/HLA inc. group. This was also the case for donor KIR genotype AA vs AB (n=46; 2-y OS: 74.9±13.0% vs. 73.0±9.9%, p=0.844; 2-y RFS: 60.0±14.8% vs 74.5±8.4%, p=0.645) and HLA-DP-identical/permissive mismatch (MM) vs non permissive MM (n=45; 2-y OS: 70.7±10.0% vs 72.7±13.4%, p=0.945; 2-y RFS: 73.2±8.2% vs 63.6.0±14.5%, p=0.798) Conclusion: Our outcome data support the hypothesis of PTCy eliminating mature donor NK cells infused with the graft and thereby reducing the impact of alloreactivity in this setting. However, our patient number is quite small and the findings need to be validated in larger cohorts and preferably prospective studies. Disclosures Lindner: Celegene, Sanofi, Neovii: Honoraria, Research Funding. Berg:Riemser Pharma GmbH: Consultancy, Honoraria; Incyte, Abbvie, Astellas, Alexion and Celgene: Other: travel support. Bug:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Neovii: Other: travel grant; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Hexal: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Sanofi: Other: travel grants. Schwaeble:Uniqure BV: Research Funding. Ullrich:CellGenix: Honoraria, Research Funding; Novartis: Research Funding.
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Kamiya, Izumi, Takuya Yamashita, Kyoko Haraguchi, Taku Kikuchi, Ryo Hanajiri, Shihoko Wakabayashi, Kenichi Taoka, et al. "Early Detection of Isohemagglutinin From Donor Lymphocytes Has Impact On Acute Graft-Versus-Host Disease After Minor ABO-Incompatible Hematopoietic Stem Cell Transplantation." Blood 114, no. 22 (November 20, 2009): 1150. http://dx.doi.org/10.1182/blood.v114.22.1150.1150.
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Abstract Abstract 1150 Poster Board I-172 Introduction ABO-incompatibility is not generally considered to be a risk factor of hematopoietic stem cell transplantation (HSCT). However, in our single-institute study of 568 patients, the incidence of acute GVHD was higher in minor-ABO incompatible HSCT than others (45.3% vs 35.2%, p=0.019). We made a hypothesis that there is a potential association between donor-derived isohemagglutinin (IH) and the outcomes of minor-ABO incompatible HSCT. Patients and method There were 1052 patients undergone HSCT between 1988 and 2009 at Komagome hospital. We analyzed 130 of 1052 patients (12.4%), who had received minor- ABO incompatible HSCT. Blood type and anti-A/B antibody titers were evaluated at least weekly in first one month after HSCT, and were repeated monthly until blood type had completely changed to the donor type. Our analysis was especially focused on the impact of IH on the outcome of minor-ABO incompatible HSCT. Result Minor ABO-incompatible HSCT were 130 cases that included AML (n=40), ALL (n=28), CML (n=27), MDS (n=15), SAA (n=9), NHL (n=7), MM (n=2) and ATL (n=2). Median age was 37 (range: 16-67) years old. Seventy-seven patients were male, 53 were female. Stem cell sources were bone marrow (n=96), peripheral blood (n=16) and umbilical cord blood (n=18). Eleven cases were HLA-matched and 9 were HLA-mismatched transplants. Anti-host IgG and IgM IH had been detected in 20 of 130 transplants undergoing minor ABO-incompatible HSCT (15.4%). Median time to IH detection was 13 days after HSCT (12-39days). There was a higher incidence of IH production in the HLA-mismatched group than in the HLA-matched group (p=0.007).There was also a higher incidence of IH production in the unrelated transplants group than in the related transplants group. (p=0.021). None of 18 patients receiving umbilical cord blood transplantation showed evidence of IH production. The incidence of grade II-IV acute GVHD was significantly higher (90% vs 60%, p <0.001) and the severity of target organs was higher in the group with IH (IH group). Onset of acute GVHD was significantly earlier (median: 9 days vs 20 days, p<0.001) in IH group compared to non-IH group. The incidence of chronic GVHD was higher in IH group (69% vs 55%, p=0.036). No statistically significant differences were observed between IH group and non-IH group in time to engraftment, transplantation related mortality (63% vs 65%, p=0.666), disease-free survival (49.5% vs 37.6%,p=0.277) and overall survival (44.9% vs 37.6%,p=0.348). Immune hemolysis called passenger lymphocyte syndrome occurred in 2 cases of IH group. Their onset of acute GVHD was on Day 7 and 8 after HSCT, and IH was detected on Day 11 and 12 that were almost at the same time as hemolysis. Their WBC engraftment occurred on Day14 and 15. In both of 2 cases, hemolysis was resolved without specific treatment. Discussion and Conclusion Our study showed that IH production had association with HLA-mismatched and unrelated transplants in minor-ABO incompatible HSCT. We also showed that early detection of IH was related with the onset of grade II-IV acute GVHD. These findings indicate that strong allo-immunity induces not only severe acute GVHD caused by T lymphocytes but also antibody-production by B lymphocytes. In conclusion, we suggest that early detection of IH has impact on severity of acute GVHD. Disclosures No relevant conflicts of interest to declare.
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Wang, Zejing, Mohamed L. Sorror, Wendy Leisenring, Gary Schoch, David G. Malonely, Brenda M. Sandmaier, and Rainer F. Storb. "Transfusion Requirements in Allogeneic Hematopoietic Cell Transplantation (HCT) Recipients Given Either Myeloablative or Nonmyeloablative Conditioning, and Effect of ABO Incompatibility on HCT Outcomes." Blood 112, no. 11 (November 16, 2008): 3268. http://dx.doi.org/10.1182/blood.v112.11.3268.3268.
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Abstract We retrospectively assessed 1) overall platelet (PLT) and red blood cell (RBC) transfusion requirements within the first 100 days after allogeneic among HCT recipients given either nonmyeloablative (n=365) or myeloablative conditioning (n=1430); 2) transfusion requirements among nonmyeloablative recipients given grafts from related (n=187) vs. unrelated donors (n=178), and grafts from ABO matched (n=203) vs. ABO mismatched donors (n=159); and 3) the impact of ABO incompatibility on HCT outcomes among nonmyeloablative recipients. Table 1 summarizes results. We confirmed that myeloablative recipients were more likely to receive both PLT and RBC transfusions than nonmyeloablative recipients (both p<0.0001). Subsequent analyses were restricted to nonmyeloablative recipients. Both PLT and RBC transfusion requirements were increased among recipients of unrelated grafts (both p<0.0001) and those with major or bi-directional ABO mismatched grafts (p = 0.019 and p=0.003, respectively). No statistically significant differences were observed in cumulative incidences of graft rejection/failure, grades II-IV acute GVHD and in 3-year survivals between ABO-matched, minor-mismatched, and major/bidirectional mismatched pts (p=0.89, 0.48, and 0.49, respectively). Times to disappearance of anti-donor IgM and IgG isohemagglutinins were not statistically significantly different among major or bi-directional ABO mismatched related (43 days for both) vs. unrelated recipients (58 and 57 days, p=0.20 and 0.27, respectively). Major/bidirectional ABO-mismatched recipients with grades II-IV vs. 0–I acute GVHD had comparable likelihoods of reaching IgM (p=0.20) and IgG (p=0.63) titer endpoints. In conclusion, nonmyeloablative pts had reduced PLT and RBC transfusion requirements compared to myeloablative pts. Among nonmyeloablative pts, unrelated (vs. related) grafts and ABO-incompatibility (vs. ABO compatibility) between donors and recipients led to increased PLT and RBC transfusion requirements. ABO incompatibility did not increase graft rejection nor GVHD or adversely affect survival after non-myeloablative HCT. The tempo of disappearance of anti-donor isohemagglutinin titers was not influenced by donor type or occurrence of GVHD. Table 1. Percentage of patients requiring at least one PLT or RBC transfusion. % of Patients Requiring Transfusions N PLT p-value† RBC p-value† † p-value from Chi-square test. * Reference group for comparisons. £ Information were missing from 3 patients. Non-myeloablative 365 36% * 76% * Myeloablative 1430 99% <0.0001 96% <0.0001 Non-myeloablative Related grafts 187 25% * 67% * Unrelated grafts 178 47% <0.0001 86% <0.0001 Non-myeloablative£ ABO-matched 203 33% * 70% * ABO minor mismatched 79 33% 0.95 80% 0.11 Major bi-directional ABO-mismatched 80 48% 0.019 88% 0.003 Non-myeloablative ABO-mismatched Related grafts 66 32% * 77% * Unrelated grafts 93 46% 0.068 88% 0.067
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Lieberman, Lani, Andreas Greinacher, Michael F. Murphy, Tamam Bakchoul, Stacy Corke, Susano Tanael, Mette Kjaer, et al. "Fetal-Neonatal Alloimmune Thrombocytopenia (FNAIT): Guidance to Reduce the Risk of Intracranial Bleeding." Blood 132, Supplement 1 (November 29, 2018): 4717. http://dx.doi.org/10.1182/blood-2018-99-109906.
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Abstract Introduction FNAIT is associated with severe bleeding, especially intracranial hemorrhage (ICH), in the fetus and/or newborn. More than 75% of ICHs occur in utero and up to 50% before 32 weeks gestation. The consequences of ICH include death (35%) or serious neurological sequelae in survivors (83%). FNAIT requires prompt identification and treatment antepartum, postpartum and in subsequent pregnancies. An international panel was convened by the International Collaboration for Transfusion Medicine Guidelines (ICTMG) to develop evidence based recommendations for diagnosis and management of FNAIT. Methods The international panel consisted of specialists in adult and pediatric hematology, maternal fetal medicine (MFM), neonatology, methodology, transfusion medicine, and a patient representative. Clinical questions were developed for diagnostic testing, antenatal screening and management, and postnatal interventions. A systematic search for articles published between 1946 and June 2017 in MEDLINE, EMBASE and Cochrane was conducted. Recommendations were formulated based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method which incorporates the quality of the evidence, benefits and risks, and resource utilization. Web conferences and electronic correspondence were used to discuss the results of the systematic reviews and formulate recommendations. Considerations for clinical practice such as dosing of intravenous immunoglobulin (IVIG) and corticosteroids were detailed. Electronic surveys were sent to all members to assess agreement with recommendations. The final guidance document was sent to maternal fetal, hematology and pediatric societies for comments. Results Three systematic reviews (antenatal management, postnatal management and use of laboratory investigations to identify pregnancies at risk) were developed. Antenatal recommendations: Women with FNAIT in a previous pregnancy or sisters of women with FNAIT should be referred to MFM centers. Fetal HPA typing (e.g. HPA-1a/1b) should be performed in HPA-immunized pregnant women when the paternity is unknown or the partner is heterozygous or unavailable for testing. Prenatal HPA-1 typing should preferentially be performed by a non-invasive method e.g. cell-free fetal DNA (cffDNA) in maternal plasma if adequately quality assured. Antenatal IVIG administration to the mother commencing at 12-16 weeks gestation should be offered to all women in a subsequent pregnancy with maternal fetal incompatibility who have had a previous fetus or neonate with FNAIT related ICH. For all other pregnancies with a previous neonate with FNAIT (without ICH), administering antenatal IVIG to the mother should be discussed prior to a subsequent pregnancy or when pregnancy with maternal fetal incompatibility is confirmed. If corticosteroids are used with IVIG, dexamethasone should not be used because of the associated risk of oligohydramnios. Postnatal recommendations: HPA-selected platelets should be made available at delivery for potentially affected infants to increase the neonatal platelet count. If HPA-selected platelets are not immediately available, unselected platelets should be used. In the presence of life-threatening neonatal hemorrhage such as intracranial or gastrointestinal bleeding, platelets should be transfused to maintain platelet counts above 50 to 100x109/L for at least 7 days. In the absence of life-threatening bleeding in a neonate such as intracranial or gastrointestinal bleeding, platelets should be transfused to maintain a platelet count above 30x109/L. Conclusions The intent of this guidance document developed from systematic reviews is to promote best practices in the management of FNAIT. The guideline development group developed algorithms for treatment, podcasts for physicians and patients, pamphlets for patients and a slide set to assist with the implementation of recommendations into practice. This expert panel identified key areas for future research. One is the optimal approach to antenatal management of the next affected pregnancy. Developing biomarkers of fetal severity would be critical to this endeavor. In addition, creating comprehensive screening to identify HPA-1b1b women at risk of FNAIT would advance successful prevention of this disease. Disclosures Bakchoul: German Research Society (DFG): Research Funding; Aspen Germany gGmbH, CLS Behring, Stago gGmbH: Honoraria; Robert Bosch gGmbH: Research Funding. Kjaer:Prophylix Pharma: Equity Ownership. Kjeldsen-Kragh:Prophylix Pharma: Equity Ownership. Oepkes:Towards routine HPA screening in pregnancy: Research Funding. Bussel:Uptodate: Honoraria; Rigel: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Protalex: Consultancy; Amgen Inc.: Consultancy, Research Funding; Prophylix: Consultancy, Research Funding; Momenta: Consultancy. Arnold:Bristol Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding; UCB: Consultancy; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; UCB: Consultancy; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Savoia:Neonatal Alloimmune Thrombocytopenia Registry of the Transfusion Outcomes Research Collaborative (TORC) Australia: Membership on an entity's Board of Directors or advisory committees.
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Michallet, Mauricette, Quoc Hung Le, Marie Robin, Nathalie Fegueux, Sabine Furst, Mohamad Mohty, Eric Deconinck, et al. "Double Cord Blood Cell (CBC) Hematopoietic Stem Cell Transplantation after Standard or Reduced Intensity Conditioning: Report of the SFGMTC Registry." Blood 112, no. 11 (November 16, 2008): 1972. http://dx.doi.org/10.1182/blood.v112.11.1972.1972.
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Abstract This analysis concerned 164 allogeneic HSCT after standard (Std) or reduced intensity conditioning (RIC) using double cord blood cells (CBC), reported to the SFGM-TC registry. There were 57 females (F) and 107 males (M) with a median age of 39.5 years (18–66). The diagnosis pretransplant were acute leukaemia: 93 (56 AML and 37 ALL), MDS: 9, MPS: 9 (CML: 4), CLL: 5, NHL: 18, HD: 7, MM: 13, AA: 7, other diseases: 3 (2 inborn errors and 1 solid tumour). The median interval between diagnosis and HSCT was 20.6 months (2.6–385.5). Among 154 evaluated patients (pts), disease status prior conditioning were 92 CR (CR1: 45, CR 2: 34, >CR2: 12 and 1 non classified), 21 PR, 21 stable diseases (SD) (SD: 6, AA: 6, inborn errors: 2, CML in CP: 3, myelofibrosis: 2 and MDS: 2), 22 progressive diseases (PD) (PD: 4, relapses: 10 and refractory diseases: 8), 8 pts were not documented. Among 158 pts documented, 49 (31%) were completely sex matched and 109 (69%) sex mismatched [72 CBC1+2 (F+F or F+M) for a M recipient and 37 CBC1+2 (M+M or M+F) for a F recipient]. Among 158 documented, 42% of recipients, 37% of CBC1 and 38% of CBC2 were CMV+; there was a complete ABO compatibility between the 2 CBC and the recipient in 38 cases, 1 or 2 minor incompatibilities in 40 cases and almost 1 major incompatibility in 80 cases. For HLA matching, we distinguished 3 groups: group1 [n=78 (HLA compatibility at least 4/6 between recipient and CBC1+2) and between CB1 and CB2 including total HLA DRB1 matching)], group 2 [n=55 (HLA compatibility at least 4/6 between recipient and CBC1+2) considering neither HLA compatibility between CBC1-CBC2 nor HLA DRB1 matching)] and group3 [n=25 (all others)]. At harvesting, the median number of total nucleated cells (TNC) (x107/kg) was 4.67(1.6–12.2), the CD34+ (x105/kg) 1.8 (0.3–10.8), the CFU-GM (x104/kg) 3.67 (0.94–25), and after thawing 3.24(0.58–12), 1.4(0.2–9.2) and 2(0.27–16.4) respectively. The TNC threshold number was set to 5x107/kg because more than 96% of pts received more than 3x107/kg. Among 135 documented, 26 (19%) received Std conditioning and 109 (81%) RIC. After transplantation, 129 pts (96%) engrafted with 86% (80–92) of neutrophil recovery at day 60 with no significant difference according to TNC (<5x107/kg: 88%, ≥ 5 x107/kg: 90%; p=0.28) and HLA matching (group1: 86.6%, group2: 89.6% and group3: 83.3%; p=0.81). Eighty-four pts developed an AGVHD: gr I: 20 and ≥ gr II: 60 (35 gr II, 16 gr III and 4 grade IV), 4 patients were not classified. At day 90, the cumulative incidence of AGVHD grI was 10.4%(5–16), gr ≥ II: 42%(33–51)[grII: 24%(16.5–32), grIII-IV: 18%(11–25)]. Moreover, we observed for AGVHD gr ≥ II according to HLA typing and TNC: group1: 41%(28–54), group2: 46%(31–60) and group3: 33%(8–58); TNC<5x107/kg: 38%(25–51) and TNC>5.107/kg: 46%(32–60). Twenty-one pts presented a chronic GVHD (9 limited and 12 extensive) and the cumulative incidence at 1 year was 13.7%(4–24) for limited and 20%(9–21) for extensive. With a median follow-up of 7.3 months, the probability of 1-year and 2-year overall survival and disease-free survival were 49.6% (40–61.5) and 38% (27–54), 43% (33.5–54.5) and 36% (25–51) respectively. The probabilities of OS, NRM and RM according to TNC, disease status pre-transplant, HLA matching and sex matching are shown in Figure 1 and Table1.The multivariate analysis showed a significant impact of 2 factors on OS: disease status PD vs CR: HR=6.16 (1.87–20.25) (p=0.002); HLA matching group2 vs group1: HR=0.29 (0.11–0.82) (p=0.01), and 3 significant factors on DFS: sex-matched HR=0.29 (0.09–0.94) (p=0.03), sex-mismatched (F recipient) HR=0.15 (0.04–0.61) (p=0.008) and HLA matching (group 2 vs group1) HR=0.32(0.11–0.88) (p=0.02).A refined chimerism analysis is ongoing and will be presented. In conclusion, this large retrospective analysis showed that the quantitative objective of double cord blood use for allogeneic HSCT is achieved (only 4% had received < 3x107/kg TNC) with no further significant impact of TNC number on OS, NRM and RM. As usual in other types of allogeneic HSCT, we demonstrated the significant impact of disease status before transplantation on transplant outcome. Finally, the most interesting point was the better results observed in group 2 but which needs more precise analysis in the future. Table 1. Probability of OS, NRM, RM according to different variables. Probability of OS Probability of NRM Probability of RM Whole population (cummulative 1 year) 49.6%(40–61.5) 49.7%(39–60) 7.5%(2–17) TNC TNC < 5 × 107/kg 50%(36.6–68.5)) 47%(32–62) 8%(0–16) TNC ≥ 5 × 107/kg 44.5%(29.6–67) 56.5%(38.5–74.5) 9.5%(0–20) Disease status pre-transplant CR 51%(38–68) PR 54%(31–92.5) SD 75%(43–100) PD relapse 35.5%(18–70) HLA compatibility Group 1: 4/6 or more for all(2/2 for DRBI) 34%(21–54) 62%(46–78) 10%(3–20) Group 2: 4/6 or more for R-CB1 and R-CB2 61%(45–81) 39%(21–57) 2%(0–6) Group 3: Others 61.6%(42–90) 42.5%(19–66) 10%(0–24.5) Sex matching M recipient with sexmismatch 35%(22–57) 63%(46–79) 8%(2–14) Sexmatch 61%(45–82) 43%(23.5–63) 4.5%(0–13.5) F recipient with sexmismatch 54%(36.5–80)) 42%(24–62) 9%(0–22) Figure 1: Probability of OS according to different HLA groups Figure 1:. Probability of OS according to different HLA groups
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Migliaccio, Anna Rita F., Carolyn Whitsett, and Giovanni Migliaccio. "Expansion of Red Blood Cells for Transfusion." Blood 116, no. 21 (November 19, 2010): SCI—46—SCI—46. http://dx.doi.org/10.1182/blood.v116.21.sci-46.sci-46.
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Abstract Abstract SCI-46 Blood transfusion, the earliest form of cell replacement therapy, has become indispensable for modern medicine making the safety and adequacy of the blood supply a national priority. The US blood supply is adequate overall because in 2006 the number of blood units collected exceed by 7.8% the number of those transfused. However, issues surrounding blood transfusion, such as sporadic shortages and potential adverse events to recipients (related to changes in red cell physiology during storage and alloimmunization in chronically transfused patients) prompted past and current efforts to develop alternative transfusion products. Recently, the culture conditions to generate erythroid cells have greatly improved making the production of a transfusion product ex-vivo a theoretically possible, although expensive, proposition. This recognition is inspiring several investigators to develop production processes for ex-vivo generation of red cell transfusion products. A proof-of-concept demonstrating that ex-vivo generated red cells protect mice from experimentally induced lethal anemia has been obtained. Alternative sources of stem cells which include human embryonic stem cells (hESC) and induced pluripotency stem cells (iPS), are being explored. Since red cells do not have a nucleus, safety considerations suggest that they may represent the first cell therapy product to be generated from hESC and iPS. In addition, discarded hematopoietic stem cells present in adult and cord blood donations may theoretically generate numbers of red cells ex-vivo sufficient for transfusion. Affordable clinical grade humanized culture media have also been developed. Possible differences in immunological and biological properties of erythroid cells from different sources are under investigation. These differences include size, levels of activity of glycolytic enzymes and carbonic anhydrase, expression of different isozymes, hemoglobin and antigenic profiles (HLA class II antigens). This last aspect is particularly important because ex-vivo expanded red cells pose the same risk for infection and incompatibility as any transfusion product but pose unique antigenic risks. Since expression of blood group antigens is susceptible to post-transcriptional modifications, the ex-vivo expansion process itself may induce antigenic variability. Therefore, even cells generated from completely matched stem cell sources may induce auto-immunity and/or appear incompatible. Regarding the identity of ex-vivo generated red cell transfusion products, a conservative approach would be to define them as “enucleated red cells”. In principle, however, ex-vivo generated erythroblasts may also serve as transfusion product. Since they undergo 4–64 further divisions and reduce iron overload, they may represent a more potent transfusion product for patients that require chronic transfusion. The clinical use of these cells, however, may involve development of specific procedures to facilitate their homing/maturation in the erythroid niches of the recipients. In summary, on the basis of these cost, logistic and safety considerations we hypothesize that the clinical application of ex-vivo expanded erythroblasts will involve in sequence, drug discovery for personalized therapy, systemic drug delivery, genotypically matched transfusion for alloimmunized patients and then transfusion in the general population. Disclosures: No relevant conflicts of interest to declare.