Impacts of ABO-Blood Type Incompatibility on Outcome of Unrelated Bone Marrow Transplantation through the Japan Marrow Donor Program.

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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Peripheral Red Blood Cell Split Chimerism as a Consequence of Intramedullary Selective Apoptosis of Recipient Red Blood Cells in a Case of Sickle Cell Disease

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2014.066 ◽

2014 ◽

Vol 6 (1) ◽

pp. e2014066 ◽

Cited By ~ 1

Author(s):

Marco Marziali ◽

Antonella Isgrò ◽

Pietro Sodani ◽

Javid Gaziev ◽

Daniela Fraboni ◽

...

Keyword(s):

Bone Marrow ◽

Red Blood Cells ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Blood Cells ◽

Marrow Transplant ◽

Mixed Chimerism ◽

Radical Cure ◽

Hematopoietic Stem ◽

Hematopoietic Chimerism

Allogeneic cellular gene therapy through hematopoietic stem cell transplantation is the only radical cure for congenital hemoglobinopathies like thalassemia and sickle cell anemia. Persistent mixed hematopoietic chimerism (PMC) has been described in thalassemia and sickle cell anemia. Here, we describe the clinical course of a 6-year-old girl who had received bone marrow transplant for sickle cell anemia. After the transplant, the patient showed 36% donor hematopoietic stem cells in the bone marrow, whereas in the peripheral blood there was evidence of 80% circulating donor red blood cells (RBC). The analysis of apoptosis at the Bone Marrow level suggests that Fas might contribute to the cell death of host erythroid precursors. The increase in NK cells and the regulatory T cell population observed in this patient suggests that these cells might contribute to the condition of mixed chimerism.

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Presence Of CD55- and/Or CD59-Deficient Erythrocytes In Patients With Rheumatic Diseases: An Immune-Mediated Phenomenon?

Blood ◽

10.1182/blood.v122.21.3429.3429 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3429-3429

Author(s):

John V. Asimakopoulos ◽

Evangelos Terpos ◽

Loula Papageorgiou ◽

Olga Kampouropoulou ◽

Dimitrios Christoulas ◽

...

Keyword(s):

Bone Marrow ◽

Rheumatic Diseases ◽

Blood Cells ◽

Molecular Techniques ◽

Cell Populations ◽

Red Cell ◽

Simple Method ◽

Hematopoietic Stem ◽

Significant Difference ◽

Cd59 Expression

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder characterized by the somatic mutation of X-linked gene PIG-A, required for glycosylphosphatidylinositol (GPI)-anchor biosynthesis. This results in absent or decreased expression of all membrane proteins normally anchored by GPI - including CD55 and CD59 - in all circulating cells, leading to an unusual sensitivity of red blood cells (RBCs) to complement lysis and subsequently intravascular hemolysis and hemoglobinuria. According to the “dual pathogenesis” model, there is an immunoregulatory selection in favor of PNH clones to proliferate preferentially over normal hemopoiesis on a microenvironment of bone marrow failure. The incidence of “PNH-like” defect has been also demonstrated in many hematological diseases and on peripheral blood cells (PBC) of normal individuals. Complement system is recognized as having the potential to provoke severe impairment to host tissues. This is extensively demonstrated in autoimmune disease setting. Multiple regulatory and inhibitory enzymes, such as CD55 and CD59, known as complement regulatory proteins, adjust the progression of complement cascade at all levels, protecting the autologous cells. Complement activation and cytopenias have been associated with diminished CD55 and/or CD59 expression on PBC membranes. The aim of this study was to evaluate the presence of “PNH-like” red-cell populations in patients with rheumatic diseases and investigate possible correlations with clinical or laboratory parameters. CD55 and CD59 expression was evaluated in erythrocytes of 113 patients (94 females, 19 males, median age: 64 years) with rheumatic diseases: 38 with rheumatoid arthritis, 25 with systemic lupus erythematosus, 17 with Sjögren’s syndrome, 7 with systemic sclerosis, 12 with vasculitis, 2 with dermatomyositis, 1 with ankylosing spondylitis and 11 with mixed connective tissue diseas, using the sephacryl-gel microtyping system, a semi-quantitative, inexpensive and simple method useful in screening “PNH-like” red-cell defect, with sensitivity comparable with that of flow cytometry. One hundred and twenty-one (121) healthy blood donors of similar age and gender and 10 patients with PNH were also studied, as control groups. In all samples with CD55- and/or CD59- negative RBCs, Ham and sucrose tests were also performed. Interestingly, the majority of patients (104/113, 92%) demonstrated “PNH-like” erythrocytic populations: 47 (41.6%) with concomitant deficiency of CD55 and CD59, 50 (44.2%) with isolated deficiency of CD55 and 6 (6.2%) with isolated deficiency of CD59. In healthy donors, only 2 (1%) had red cells with concomitant CD55/CD59 negativity and 3 (2%) with isolated CD55 or CD59 deficiency. “PNH-like” erythrocytic clones never surpassed 25% of the total red-cell population, while the most common proportion of deficiency for both antigens was 10%. All PNH patients exhibited simultaneous CD55/CD59 deficiency. Moreover, it should be high-lightened that we found an unprecedented relation between patients' hemoglobin (Hb) and CD55 expression on RBCs (rs= -0.205, p=0.029), while there was a significant difference (δ) when the mean concentration of Hb was compared between patients with normal expression of CD55 and those with deficiency of this protein (δ=-1.4534 g/dl, p=0.0151). There was no clinical or laboratory evidence of hemolysis in our patients. There was no association between the presence of “PNH-like” red-cell populations and cytopenias or specific treatment for the autoimmune disorder. Positive Ham and sucrose tests were found only in PNH patients. In conclusion, this study provides evidence supporting the presence of erythrocytes with CD55- and/or CD59- deficiency in patients with rheumatic diseases. The pre-existence of small PNH clones in the bone marrow of these patients, that acquire a survival advantage to proliferate against normal hemopoietic tissue and become detectable with our methodology, may be the underlying cause for this phenomenon. Moreover, it was demonstrated that CD55- deficiency on RBCs influences the levels of Hb, in these patients. Further studies, using molecular techniques, will be required, to clarify the exact pathophysiologic mechanisms for this deficiency. Disclosures: No relevant conflicts of interest to declare.

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RAP-536 Promotes Terminal Erythroid Differentiation and Reduces Anemia in Myelodysplastic Syndromes

Blood ◽

10.1182/blood.v118.21.610.610 ◽

2011 ◽

Vol 118 (21) ◽

pp. 610-610 ◽

Cited By ~ 2

Author(s):

Rajasekhar NVS Suragani ◽

Aaron Mulivor ◽

R. Scott Pearsall ◽

Ravindra Kumar

Keyword(s):

Bone Marrow ◽

Mouse Model ◽

Supportive Care ◽

Red Blood Cells ◽

Blood Cells ◽

Significant Proportion ◽

Erythroid Differentiation ◽

Wild Type ◽

Erythroid Progenitor ◽

Hematopoietic Stem

Abstract Abstract 610 Myelodysplatic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell disorders characterized by ineffective hematopoiesis. Patients develop peripheral blood cytopenias; however, the bone marrow shows increased proliferation and apoptosis. In addition to bone marrow apoptosis, a failure of differentiation contributes to reduced terminally differentiated blood cells. A significant proportion of patients with MDS will develop anemia that are refractory to treatment with recombinant human erythropoietin (EPO) and must rely on transfusions as supportive care. The use of blood transfusions as supportive care is associated with iron overload and significant morbidity. Therefore, alternative therapies to treat anemia in MDS patients are needed. Members of the TGFβ super family of signaling molecules have been implicated in erythropoiesis and represent alternative, EPO-independent targets for the treatment of anemia. ACE-536 is a soluble receptor fusion protein consisting of a modified Activin Receptor Type IIB extracellular domain linked to a human Fc domain. ACE-536 acts as a ligand trap to modulate the activity of TGFβ ligands and promote erythroid differentiation in an EPO independent manner. Subcutaneous administration of ACE-536 to C57BL/6 mice resulted in significant increases in hematocrit, hemoglobin and red blood cells compared to vehicle treated controls within four days. These effects were observed with concurrent treatment of an EPO neutralizing antibody, indicating that EPO is not directly responsible for the initial RBC response of ACE-536. BFU-E or CFU-E colony formation assays from bone marrow or spleen of mice 48 hours after ACE-536 were normal, indicating no effect on the erythroid progenitor population. Differentiation profiling of bone marrow and splenic erythroblasts by FACS analysis following 72 hours after RAP-536 (murine version of ACE-536) treatment revealed a decrease in basophilic erythroblasts and an increase in late stage poly-, ortho-chromatophilic and reticulocytes in bone marrow and spleen compared to vehicle treated mice. The data demonstrate that while EPO treatment increases proliferation of erythroid progenitors, ACE-536 promotes maturation of terminally differentiating erythroblasts. The efficacy of ACE-536 has been demonstrated in various animal models of acute and chronic anemia. In this study we investigated the effect of ACE-536 on anemia in mouse model of MDS. The NUP98-HOXD13 (NHD13) transgenic mouse carries a common translocation found in MDS patients. NHD13 mice develop anemia, neutropenia and lymphopenia at 4–7 months of age, with normal or hypercellular bone marrow. Starting at 4 months of age, mice were treated with RAP-536 (murine homolog of ACE-536) at 10 mg/kg or vehicle control twice per week for 8 months. Wild-type littermate controls were also dosed on the same schedule. As expected, at study baseline (mice 4 months of age), NHD13 mice had reduced RBC, Hb and HCT compared to wild-type littermates. The progression of anemia over the study period was reduced by treatment with RAP-536 compared to vehicle (HCT: −8.3% v. −22%, RBC: −13% v. −30%). Based on blood smear analyses, there was no indication of increased leukemic cells with ACE-536 treatment. Our data demonstrate that RAP-536 can increase hematology parameters through enhancing maturation of terminally differentiated red blood cells and can serve as a therapeutic molecule for the treatment of anemia. As anemia contributes significantly to the morbidity of patients with MDS, a mouse model was used to test the therapeutic efficacy of ACE-536 in this disease. We have shown that systemic administration of RAP-536 to MDS mice promotes increases in red blood cell mass without enhanced progression to AML. Therefore ACE-536 may represent a novel treatment for anemia associated with MDS, particularly in patients that are refractory to EPO therapy. Disclosures: Suragani: Acceleron Pharma Inc: Employment. Mulivor:Acceleron Pharma Inc: Employment. Pearsall:Acceleron Pharma Inc: Employment. Kumar:Acceleron Pharma Inc: Employment.

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Peri-Engraftment Syndrome in Pediatric Allogenetic Hematopoietic Stem Cell Transplantationand the Effect of Methylprednisolone on Improving the Process of Peri-ES

Blood ◽

10.1182/blood.v124.21.3878.3878 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3878-3878

Author(s):

De-fei Zheng ◽

Lin Wan ◽

Jun LU ◽

Peifang Xiao ◽

Xin-ni Bian ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Stem Cell ◽

Cord Blood ◽

Hematopoietic Stem Cell ◽

Peripheral Blood ◽

Blood Type ◽

Hematopoietic Stem ◽

Host Disease ◽

Engraftment Syndrome

Abstract Objective and Purpose: Despite improvements in medical management, both engraftment syndrome (ES) and pre-engraftment syndrome (pre-ES) which were named as peri-engraftment (peri-ES)remain associated with severe morbidity and decreased the survival following hematopoietic stem cell transplantation (HSCT). Though many studies on peri-EShave been published in recent years, there is no report on the incidence of peri-ES and related factors in pediatric HSCT, Meanwhile, the intervention with MP on peri-ES remains controvertial. Methods and patients: We retrospectively analyzed the data of 34 cases of pediatric allo-HSCT patients and the effect of methylprednisolone (MP) on the outcome of children with peri-ES transplanted between Nov 2010 and Dec 2013. The stem cell sources came from bone marrow alone [n=7], combining with peripheral blood [n=10], and cord blood alone [n=10], combining with bone marrow anf peripheral blood (n=7). Clinical characteristics and HSCT type were illustrated in Table 1 and 2. The incidence rate of peri-ES in cord blood transplantation (CBT), haploid transplants and sibling matched donor were 88.24%, 87.570% and 11.11%, respectively. All patients, who received either CBT or Hapolidentical SCT in conjunction of cord blood as the third part donor,developed peri-ES. We also identified that the peri-ES was highly associated with HLA disparity and mismatched ABO and aGvHD (Table 3 and 4).The median time of onset of peri-ES was 9 days after allo-HSCT. The most common symptoms of the peri-ES was eruthrodermous rash, followed by fever (Table 5). Twenty three children with peri-HSCT received intravenous MP at three doses of 0.5mg/kg, 1mg/kg, and 2mg/kg, respectively, based on the organs involved and the severity of peri-ES (Table 6). An excellent outcome was observed with relieving peri-ES in every patientand without influencingthe outcome of acute graft versus host disease (aGvHD), chronicgraft versus host disease (cGvHD), cytomegalovirus (CMV) infection, relapse, and overall survival (OS) with median follow up of xx months. (Table 4 and Figure 1 and 2). Conclusion: Peri-ES is closely associated with the stem cell source with the sequence of CB, PB and BM. Meanwhile, disparity of HLA type and blood type mismatch also contributed to peri-ES. peri-ES caneasily proceeded into aGvHD. MP efficiently relieved the process of peri-ES without any significant adverse event or affecting theoutcome of HSCT and can be recommended to control peri-ES in this patient population.Table 1.The clinical and laboratory characteristics of HSCT patientsViable NumberAge (year)Median, range9(1-16)SexMale/female20/14Primary diseaseAcute myeloid leukemia17Acute lymphoblastic leukemia4Chronic myelogenous leukemia2Aplastic anemia8Myelodysplastic syndrome (monosome 7)1Juvenile myelomonocytic leukemia2Number of infused nuclear cellsCB Median (range), 107/kg4.8(1.2-9.6)Haplo Median (range), 108/kg10.65(7.2-14.39)Sibling Median (range), 108/kg9.6(6.48-18.66)Number of infused CD34+ cellsCB Median (range), 106/kg0.32(0.047-0.52)Haplo Median (range), 106/kg4.6(1.92-8.36)Sibling Median (range), 106/kg4.4(2.5-8.37)HLA matching(low resolution) of A, B, DR6/6(sibling or CBT)175/6(Haplo or CBT)74/6(Haplo or CBT)63/6(Haplo or CBT)4Table 2.Risk factors for peri-ESRisk factorsperi-ES group(n=23 )Non peri-ES group (n= 11)Totalperi-ES /Total(%) SourceBM0440BM+PB15616.67BM+PB+CB707100CB1521788.24 Transplantation typesibling18911.11unrelated1521788.24Haploid71887.50 sexMale1282060.00Female1131478.57 ABO compatibilitymatched991850.00mismatched1421687.50 HLA disparitymatched891747.06mismatched1521788.24Neutrophilengraftmentmedian+14+13.5STR(2W)median96.8%95.7%Table 3.The Effect of MP on HSCT complicationsOutcome 0.5mg/kg1mg/kg2mg/kgNon peri-ESP 1P 2Neutrophil engraftment(median day)+16+15+13.513.50.5320.478aGVHD4/85/76/82/110.5290.010cGVHD1/82/72/82/110.7251.000CMV infection4/85/76/87/110.5291.000Relapse1/80/70/82/110.4980.239 BM, bone marrow; CB, cord blood; PB, peripheral blood; HLA, human leukocyte antigen; STR on second week. Note: P1: the comparison among three different doses of MP; P2: A comparison between peri-ES group and non-peri-ES group. Figure 1 Overall survival of pediatric allo-HSCT with and without peri-ES Figure 1. Overall survival of pediatric allo-HSCT with and without peri-ES Disclosures No relevant conflicts of interest to declare.

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Patients with Therapy-Related Myelodysplastic Syndromes (t-MDS) Have Shorter Median Overall Survival Than De Novo MDS: Mayo Clinic Experience

Blood ◽

10.1182/blood.v126.23.5234.5234 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5234-5234 ◽

Cited By ~ 2

Author(s):

Muhanad Hreh ◽

Darci Zblewski ◽

Mrinal M Patnaik ◽

Firas Baidoun ◽

Naseema Gangat ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Multivariate Analysis ◽

Peripheral Blood ◽

Mayo Clinic ◽

Median Overall Survival ◽

De Novo ◽

Wilcoxon Test ◽

World Health ◽

Significant Difference

Abstract Background: MDS is a clonal bone marrow disorder characterized by ineffective hematopoiesis with peripheral blood cytopenias and an increased risk for transformation to acute leukemia. Patients with MDS who have a history of prior exposure to chemotherapy and/or radiotherapy are called therapy-related MDS (t-MDS). We hereby describe our experience with this entity and compare it to our experience with de novo MDS patients. Aim: To study the differences of clinical outcome between t-MDS and de novo MDS patients. Method: A retrospective single institution study chart review of cases with MDS at Mayo Clinic Rochester between 1993- 2011 was performed. De novo MDS, t-MDS and leukemic transformation (LT) were defined according to the World Health Organization (WHO) classification (Swerdlow et al 2008). Prior exposures to chemotherapy, radiotherapy and/ or both were defined as t-MDS; while lack of any as de novo MDS. Appropriate IRB approval was obtained in accordance with the Helsinki declaration. Comparison between group medians was done using Wilcoxon test, comparison between values was done using contingency and One-way analyses (Means/Anova/Pooled t), while survival estimates were calculated using Kaplan-Meier curves JMP V10 Results: Out of 827 patients with MDS, 153 (19%) patients were t-MDS (group (Gr) 1) versus 674 (81%) (rest of patients, Gr 2). Out of the t-MDS, 79 (52%) pts had CTX, and 42 (27%) had XRT, and 32 (21%) pts had both CTX/XRT). Upon comparison between Gr 1 vs 2, statistical significant difference was seen in median age 69 vs 72 (p=0.01), Platelets 68 vs 114 x109(<p0.0001), and WBC 3.2 vs 3.6 x109(0.02), respectively. No significant statistical difference was found in median Hg 9.6 vs 9.7 gm/dL (p 0.6), peripheral blood (PB) blasts 0% in both groups, and bone marrow (BM) blasts 2% in both groups. IPSS was low, int-1, int-2, high in 16%, 40%, 34%, 9%in Gr 1 and 32%, 46%, 18%, 4% in Gr 2. IPSS-R was very low, low, int, high, very high in 9%, 24%, 18%, 20%, 28% in Gr 1 vs 18%, 36%, 20%, 16%, 10% in Gr 2. AML transformation (LT) was identical in both groups at 12%. Upon comparison between Gr 1 and 2, median time to AML transformation was 7.9 vs 13 months (p=0.08). Median overall survival (mOS) was shorter in Gr 1 vs 2 at 16 vs 34 months (P<0.0001). When analysis was limited to diploid cytogenetics, median OS was 63 vs 50 months, respectively (p=0.9). Both IPSS and IPSS-R were prognostic of mOS in t-MDS (p<0.0001). On multivariate analysis; age (<0.0001), IPSS-R (p<0.0001) and previous CTX and/ or XRT (P=0.02) were the only variables that affected mOS. Conclusion: T-MDS comprises a small portion of all MDS cases (19%). Median overall survival in the de novo MDS group was longer than t-MDS group; however this difference was not maintained in patients with diploid cytogenetics. Similarly, time to AML was longer in de novo MDS compared to t-MDS (although similar rates of incidence). All of age, IPSS-R and t-MDS did affect median OS on multivariate analysis. Disclosures Al-Kali: Celgene: Research Funding.

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Successful Treatment of Pure Red Cell Aplasia after Major ABO-Incompatible Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia with Repeated Doses of the Single-Agent Rituximab: A Case Report.

Blood ◽

10.1182/blood.v110.11.4934.4934 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4934-4934

Author(s):

Karla O. Mota ◽

Maria Cristina Macedo ◽

Roberto Silva

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Red Blood Cells ◽

Cell Transplantation ◽

Blood Cells ◽

Myeloid Leukemia ◽

Pure Red Cell Aplasia ◽

Hematopoietic Stem ◽

Allogeneic Hsct

Abstract Background: ABO incompatibility occurs in up to 20–40% of HLA matched allogeneic hematopoietic stem cell transplantation (HSCT). Pure red cell aplasia (PRCA) following ABO-incompatible allogeneic HSCT is a rare complication associated with interaction of recipient anti-A or anti-B isoagglutinins, produced by residual B cells, with donor erythrocytes precursors expressing A and/or B antigens. The best treatment approach for PRCA is not established. Plasma exchange and immunoadsorption are regarded as a first-line treatment strategies. Other therapeutic approaches include: erythropoietn (EPO), donor-derived leukocyte infusion (DLI), steroids or induction of graft versus host disease (GVHD) by immunosuppression withdraw. Moreover, recovery or erythropoiesis is often incomplete and may induce futher complications. Recent reports describe successful treatment of PRCA and others cytopenias after HSCT using Rituximab (Mabthera®; Roche; Switzerland). This drug is a chimeric IgG1 monoclonal antibody directed against the CD20 surface antigen expressed by most human B lymphocytes. Its exact mechanism of action is not known. Case Report: We treat a 47-year-old woman with PRCA after a major ABO-mismatched (Donor A Rh-; Recipient O Rh-) allogeneic HSCT after a second remission of a acute myeloid leukemia. Allogeneic HSCT was performed in November 2005, from a HLA-matched older sister, using bone marrow graft (Mn cell dose 1,72x108/kg) following a myeloablative conditioning with busulfan (16mg/kg) and melfalan (140mg/m2). GVHD prophylaxis included cyclosporine A and methotrexate. Baseline anti-A isoagglutinin IgM titers of the paient before transplantation was 1:128 and after immunoadsorption with plasma A for 48 hours decreased to 1:32. One plasmapheresis session was performed to remove ABO antibodies from the patient and her anti-A IgM titer dropped to 1:4 before bone marrow infusion. We also removed red blood cells from the donor’s marrow product to prevent risk of hemolysis. After bone marrow transplantation, the patient developed a severe anemia that required weekly red blood cells transfusion over six months. Reticulocyte counts were extremely low during this period, bone marrow aspirate was normal, except for decreased erythrocyte precursors (only 1% of total cells). In August 2006, the diagnosis of PRCA was set after exclusion of red blood cells alloantibodies, hemolysis and viral or bacterial infection. Donor chimerism (STR) was totally completed and the recipient anti-A IgM titer was 1:16 and the patient showed no evidence of GVHD. In October 2006, she was treated with rituximab 375mg/m2 administered once weekly for four weeks. In the next two months, after the treatment with rituximab, her hemoglobin (Hb) increased from 5.5g/dl to 12g/dl. Up to her last medical avaluation (July 2006), she was in PRCA remission, her Hb was 12g/dl and she had no detectable anti-A titer. Conclusion: Rituximab can be a very effective treatment to PRCA secondary to major ABO-incompatible allogeneic stem cell transplantation. The best dose schedule and long term effects must be establish.

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Overall Survival in Hematopoietic Stem Cell Transplantation Is Not Correlated with Age of Red Cells Transfused Pre- and Post-Transplantation

Blood ◽

10.1182/blood.v124.21.1213.1213 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1213-1213

Author(s):

Fleur M. Aung ◽

Roland L Bassett ◽

Benjamin Lichtiger ◽

Emil J. Freireich ◽

Issa F Khouri

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Red Blood Cells ◽

Hematopoietic Stem Cell ◽

Study Design ◽

Blood Cells ◽

Red Cells ◽

Icu Patients ◽

Hematopoietic Stem ◽

Post Transplant

Abstract Red blood cells undergo biochemical and morphologic changes during storage and the time-dependent changes known as “storage lesions” are well documented. These changes have raised concerns that stored older red cells (RBC) could increase the patient’s mortality risk. The primary aim of blood storage has been to extend the storage life of RBCs with the use of additive storage solutions. However, the clinical consequences of transfusion of newer versus older red cells remain unclear for Hematopoietic stem cell transplant (HSCT) patients. Objectives The primary objective of this retrospective study was to analyze the association of aged RBCs and ICU admission, short-term and long-term survival and the association between overall survival with the number of RBCs transfused up to D+100 post-transplant. Methods: Study Design The study design was approved by the MDACC Institutional Review Board. The 2008-2009 Blood Bank records were reviewed for HSCT patients. All transfused RBC data pre-transplant (D-100 to D-1) and post-transplant (D0 to D+100) was included without exclusion of patients who received a mixture of different ages of RBCs. The age of RBCs transfused was categorized into two groups: <14/>14 days and < 28/ > 28 days of age. The patients were categorized into ICU vs. Non-ICU patients. A further categorization of the non-ICU patients was made by number of RBCS received post-transplant: 0-5, 6-10 and >11 RBCS. Definition Age of Red cells A patient was defined as having aged red blood cells (RBC) pre-transplant if he/she received at least one RBC that was >14 days old. A separate definition of aged red blood cells categorized patients as having received at least one unit that was >28 days old. This categorization was repeated for post-transplant RBCs at both 14 and 28 days. Statistical Analysis: Fisher’s exact test was used to compare ICU rates between patients who did and did not receive aged RBCs. The Kaplan-Meier was used to estimate the distribution of overall survival (OS) from the date of transplant, and distributions were compared using the log-rank test. Analyses are performed for all patients, and then repeated for the subset of patients with AML. Results: 397 HSCT patients (229 [58%] males: 168 [42%] females), median 52 years (range 2-74) received median 3 RBCs (range 0-44) pre-transplant and 8 RBCs (range 0-111) post-transplant. 252 (63.5%) patients received peripheral hematopoietic progenitor cells, 262 (66%) patients received an ABO mismatched graft and the majority 297 (75%) was Caucasian. The diagnoses were as follows: AML (47%), ALL (42%), CLL (12%), CML (7%), Lymphoma (19%), Myeloma (2%), Aplastic Anemia (1%), and other non-hematologic disorders (1%). There were 73 (18%) patients (41 [56%] male:32 [44%] female, median 54 years [range 14-74] admitted to the ICU with a median stay 37 days (range 1-64) post-transplant who received 438 (median 3 [range 0-30]) RBCs pre-transplant and 1475 ( median 18 [range 2-73]) RBCs post-transplant. The 324 (72%) non-ICU patients (188[58%] male: 136 [42%} female, median 52 years [range 2-72]) received 1869 RBCs (median 3 [range 0-44]) pre-transplant and 3348 RBCS (median 7 [range 0-112]) post-transplant. When the age of the RBCS transfused to ICU vs. Non-ICU patients pre-and post-transplant was analyzed there was statistical significance noted (p=0.002) between age of RBCs (< 14/>14 days) transfused post-transplant and ICU stay. For the 324 non-ICU patients, as worse survival was noted in those who received more red cell transfusion with strong evidence of a difference between patients who received 0-5 RBCS vs.6-10 RBCS vs. >11 RBCS (p=0.001). The median overall survival is 3.4 years for 136 (42%) patients who received 0-5 RBCs vs. 3.1 years for 72 (22%) patients who received 6-10 RBCs vs. 0.7 years for 116 (36%) patients who received > 11 RBCs post-transplant. Of the 73 ICU patients, 2 (3%) are alive (post-transplant day 1819 and 1981) vs. 134 (41%) non-ICU patients, median 1561 (range 175-2203) post-transplant day. The cause of death for the ICU patients was related to transplant related causes. Conclusion: Our findings reveal that the number of RBCs transfused had a correlation with overall survival rather than the age of the red cells transfused pre- and post-transplant. We were unable to confirm the conclusion reached by Wang et.al that newer blood if used exclusively may save lives based on published clinical experience. Disclosures No relevant conflicts of interest to declare.

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A Restrictive Strategy Reduces the Number of Transfused Packed Red Blood Cells in Allograft Recipients

Blood ◽

10.1182/blood.v124.21.5106.5106 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5106-5106 ◽

Cited By ~ 3

Author(s):

Jean-Baptiste Mear ◽

Sylvain Chantepie ◽

Anne-Claire Gac ◽

Agnes Bazin ◽

Oumedaly Reman

Keyword(s):

Hospital Stay ◽

Red Blood Cells ◽

Blood Cells ◽

Cell Transplant ◽

Transfusion Strategy ◽

Term Survival ◽

Hematopoietic Stem ◽

Multicentric Study ◽

Packed Red Blood Cells ◽

Significant Difference

Abstract Objectives. The number of transfusion is increasing faster than the rate of new blood donations. Further more, a transfusion excess, causing iron overload may have a deleterious effect on long term survival of patient with a malignant blood disease. We therefore tried to reduce the number of Packed Red Blood Cells (PRBC) by transfusing only one PRBC per transfusion instead of two. Material and methods. We conducted a prospective monocentric study between January and December 2013, with an historic comparative arm (from January 2010 to December 2012). We compared the number of PRBC transfused per hospital stay between two cohorts receiving only one PRBC per transfusion (Experimental arm or 1PRBC arm) or two PRBC per transfusion (Historical or 2PRBC arm). All patients admitted for remission-inducing therapy for acute leukemia or allogenic hematopoietic stem cell transplant (alloHSCT) aged ≥ 18 were eligible. The study was approved by local ethical committee. Transfusion triggers were hemoglobin lower than 80g/l or symptomatic anemia. Data analysis was performed in intention to treat. Results are mean ± standard deviation. Results. Seventy-five patients were included in the 1PRBC arm and 194 in the 2PRBC arm. Population distribution for sex, age, pathology and treatment was comparable between the two arms. There was no significant difference of transfused PRBC per hospital stay between the two groups. (7,92±5,39 vs. 9,27±7,42, 15% decrease. p=0,18). However, the restrictive strategy saved 1PRBC per hospital stay (estimated mean of 75 PRBC/year in our center). In the subgroup analysis, alloHSCT recipients from the 1PRBC arm (N=23) received significantly less PRBC than the 2PRBC ones (N=81) (4,13±4,34 vs. 7,51±8,96, 45% decrease. p=0,0058). Savings in this arm is 3 PRBC by hospital stay (estimated mean of 69 PRBC/year in our center). The number of adverse events and symptomatic anemia did not significantly differ between the two arms. Conclusion. A restrictive transfusion strategy is not inferior to a standard 2PRBC transfusion strategy and saves 1 CGR per hospital stay. This effect is especially patent in alloHSCT recipients. A prospective randomized multicentric study is ongoing to confirm these preliminary results. Disclosures No relevant conflicts of interest to declare.

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The repopulation potential of fetal liver hematopoietic stem cells in mice exceeds that of their liver adult bone marrow counterparts

Blood ◽

10.1182/blood.v87.8.3500.bloodjournal8783500 ◽

1996 ◽

Vol 87 (8) ◽

pp. 3500-3507 ◽

Cited By ~ 161

Author(s):

VI Rebel ◽

CL Miller ◽

CJ Eaves ◽

PM Lansdorp

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Blood Cells ◽

Fetal Liver ◽

Hematopoietic Stem ◽

Adult Bone Marrow ◽

Significant Difference ◽

Adult Bone ◽

Marrow Cells

Varying, limiting numbers of unseparated or purified cells (Ly-5.1), either from 14.5-day-old fetal liver (FL) or from adult bone marrow (BM) were coinjected with 10(5) unseparated BM cells (Ly-5.2) into lethally irradiated adult C57B1/6 recipients (Ly-5.2). The kinetics of donor cell repopulation of the lymphoid and myeloid compartments by Ly- 5.1+ donor hematopoietic stem cells (ie, competitive repopulation units [CRU]) were monitored at various time points after the transplantation by Ly-5 analysis of the peripheral white blood cells (WBC). Recipients that had received on average less than 2 adult BM or FL CRU did not show a significant difference in the level of donor-reconstitution when analyzed 4 weeks after the transplantation, However, at 8 and 16 weeks, the FL recipients showed a significantly higher percentage of donor- derived nucleated peripheral blood cells than did the recipients of adult BM cells. Analysis of individual mice showed that approximately 80% of the recipients of FL CRU showed an increase in mature WBC output between 4 and 8 weeks after transplantation, whereas this occurred in less than 40% in the recipients of adult BM cells. In addition to this effect on mature cell output, the cellularity of the reconstituted BM was significantly higher in recipients of FL CRU than in recipients of adult BM CRU, even at 7 to 9 months after transplantation, which is consistent with an increased clonal expansion of FL CRU. When marrow cells from primary recipients of FL CRU were injected into secondary recipients, a significantly higher percentage of these mice showed donor-reconstitution of their lymphoid and myeloid compartments (P < .01) and to a greater extent (P < .008) as compared with mice that had received marrow cells from primary recipients of similar numbers of adult BM CRU. Taken together, these results show that individual FL CRU exhibit a greater proliferative activity in vivo than similar cells from adult BM that is accompanied by a greater production of daughter CRU.

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