Tandem high-dose therapy (HDT) for multiple myeloma: recombinant human erythropoietin therapy given between first and second HDT allows second peripheral blood stem cell transplantation without red blood cell transfusion

We evaluated the ability of recombinant human erythropoietin (rHuEpo) therapy, given before high-dose therapy (HDT), to allow autologous peripheral blood stem cell transplantation (PBSCT) without red blood cell (RBC) transfusions. Eleven multiple myeloma patients underwent tandem HDT and autologous PBSC, receiving 500 U/kg/week rHuEpo from d 30 after initial transplant. Haemoglobin levels were 9.5 +/- 1.1 g/dl and 12.5 +/- 0.9 g/dl at the first and second transplant respectively (P < 0.001). RBC transfusions were required for 10/11 patients for the first transplant versus 1/11 for the second (P < 0.001). To conclude, a short course of rHuEpo therapy before HDT facilitates the performance of an autologous transplant without RBC transfusions.     

Effect of recombinant human erythropoietin in preterm infants.

Twenty-five premature infants (mean gestational age+/-SD, 31.4+/-1.9 weeks) were administered subcutaneously recombinant human erythropoietin (rHuEpo) at a dose of 300 u/kg of body weight three times a week beginning on the third day of life and continuing for 6 weeks. The controls (n=23) were premature infants with a mean gestational age of 32.2+/-2.3 weeks who did not receive rHuEpo. Haematological indices, haemoglobin and serum phosphate (Pi), and red blood cell (RBC) phosphate metabolites (ATP, 2,3-DPG, RBCPi) were tested monthly until the 6th month and thereafter at the 9th and 12th months of life. The level of serum soluble transferrin receptors (sTfR) correlated significantly with rHuEpo (p<0.05). The ratio of sTfR to log (ferritin) was significantly higher (p<0.001) in the infants treated with rHuEpo than the controls. Intracellular organic and inorganic Pi changes were not affected by the Epo administration. The RBC 2,3-DPG seemed adequate in infants receiving rHuEpo.     

Impact of ABO incompatibility on outcome after allogeneic peripheral blood stem cell transplantation

Few studies have addressed the incidence of graft-versus-host disease (GVHD) or survival after ABO-incompatible allogeneic peripheral blood stem cell transplantation (PBSCT). We analyzed the clinical outcome of ABO incompatibility after allogeneic PBSCT. A total of 89 consecutive adult patients with hematological diseases including 49 ABO-identical, 20 major, 15 minor, and five bidirectional ABO-incompatible transplants were enrolled from four medical centers in Korea. No significant difference in engraftment times, graft failure, or transfusion requirements between groups was noted. A clinical diagnosis of severe immune hemolysis or pure red cell aplasia was not made for any patient after transplantation. The incidence of acute or chronic GVHD did not statistically differ between groups. With a median follow-up duration of 13 months (range, 0.5-61 months), the 3-year overall survival estimates for the ABO-identical, major/bidirectional, and minor group were 44.6.0+/-9.0, 43.1+/-11.6, and 43.8+/-13.5%, respectively (P=0.8652), while the 3-year disease-free survival estimates were 33.8+/-7.6, 39.9+/-11.4, and 45.7+/-13.1%, respectively (P=0.8546). We observed that time to neutrophil, platelet, and red blood cell engraftment, transfusion requirements, incidence of acute or chronic GVHD, relapse, and survival were not influenced by ABO incompatibility after allogeneic PBSCT from HLA-matched sibling donors.     

Which patients are more likely to benefit from postoperative shed blood salvage after unilateral total knee replacement? An analysis of 581 consecutive procedures

INTRODUCTION: Requirements for allogeneic blood transfusion (ABT) after total knee replacement (TKR) are still high (30-50%), and salvage of unwashed filtered postoperative shed blood (USB) may represent an alternative to ABT. We evaluated that patients are more likely to benefit of USB reinfusion after TKR. PATIENTS AND METHODS: Data from 581 consecutive primary TKR, managed with (reinfusion group, n = 382) or without (control group, n= 199) reinfusion of USB, were retrospectively reviewed. RESULTS: Patients from reinfusion group received 119 +/- 88 ml of red blood cells from USB, without clinically relevant incidents, and showed a lower ABT rate (30.6% vs. 8.4%, for control and reinfusion groups, respectively; P = 0.001) (transfusion trigger, haemoglobin [Hb] < 9 g/dl). Differences in ABT rate between groups were significant for all preoperative Hb levels, except for Hb < or = 12 g/dl. A lower transfusion threshold (Hb < 8 g/dl) might have further decreased ABT rate (14.6% vs. 5.2%, respectively; P < 0.001), with differences being significant for preoperative Hb between 12 and 15 g/dl. There were no differences with respect to postoperative infection rate, but patients from reinfusion group had a shorter length of hospital stay (11 +/- 4 vs. 13 +/- 4 days, respectively; P= 0.001). CONCLUSIONS: Return of USB after TKR seems to reduce the need for ABT, especially in patients with preoperative Hb between 12 and 15 g/dl. There is little benefit of USB reinfusion for patients with preoperative Hb > 15 g/dl, whereas patients with preoperative Hb < 12 g/dl would probably benefit from the combination of USB with some other blood-saving method.     

Plasma apolipoproteins in patients with multi-infarct dementia

We examined 27 elderly patients with multi-infarct dementia developed on the basis of cerebral arteriosclerosis. The levels of plasma cholesterol and triglyceride in the patients were 177 +/- 48 and 91 +/- 27 mg/dl (mean +/- SD), respectively. Despite normal plasma lipid levels, the patients had significantly higher plasma apo B (102 +/- 30 vs. 82 +/- 21 mg/dl for controls, P less than 0.01) and lower plasma apo A-I levels (104 +/- 25 vs. 130 +/- 22 mg/dl for controls, P less than 0.01) than the controls. Isoelectric focusing of apo E showed a 2-fold higher relative frequency for the epsilon 4 allele in patients than in Japanese controls (20.8 vs. 8.6-11.7% of total, P less than 0.05). The patients with phenotypes of E4/4 (n = 1) and E4/3 (n = 8) had higher plasma cholesterol levels than those with E3/3 (n = 15) (196 +/- 45 vs. 169 +/- 43 mg/dl). The results indicate that the patients had abnormalities in plasma lipoprotein metabolism and this may contribute to the development of cerebral arteriosclerosis.     

Administration of erythopoietin and granulocyte colony-stimulating factor in donor/recipient pairs to collect peripheral blood progenitor cells (PBPC) and red blood cell units for use in the recipient after allogeneic PBPC transplantation.

BACKGROUND AND OBJECTIVES: It may be useful to reduce the exposure of transplant recipients to homologous blood. This may be achieved by procuring donor-derived red blood cell (RBC) units, collecting more peripheral blood progenitor cells (PBPC) with a combination of granulocyte colony-stimulating factor (G-CSF) + recombinant human erythropoietin (rHuEpo) and by administering rHuEpo post-transplantation. DESIGN AND METHODS: Eight ABO-compatible donors were treated with rHuEpo and intravenous iron to collect 12 RBC units for use in their recipients. PBPC were collected after mobilization with rHuEpo and G-CSF in the same donors. The recipients received G-CSF and rHuEpo post-transplantation. A control group of 10 donor/recipient pairs received G-CSF alone for PBPC mobilization and after the transplantation. RESULTS: Eighty-six out of 91 planned RBC units were collected in the donors without significant decrease in hematocrit because of a 4-fold increase in RBC production despite functional iron deficiency. After 2 leukaphereses, the cumulative yields of NC and CFU-GM were lower in the study group while those of BFU-E, CFU-Mix and CD34+ cells were similar. However, erythroid recovery was significantly accelerated in the study group. INTERPRETATION AND CONCLUSIONS: Collection of 12 RBC units within 6 weeks is feasible with rHuEpo and intravenous iron; this strategy allows a dramatic reduction in recipient exposure to homologous blood; rHuEpo has no synergistic effect with G-CSF for mobilization of PBPC in normal donors and may even be deleterious; and rHuEpo in the recipient may enhance erythroid engraftment.     

The impact of donor type and ABO incompatibility on transfusion requirements after nonmyeloablative haematopoietic cell transplantation

We retrospectively analyzed transfusion requirements within the first 100 d among allogeneic haematopoietic cell transplantation (HCT) recipients with haematological malignancies given either myeloablative (n = 1353) or nonmyeloablative conditioning (n = 503). We confirmed that myeloablative recipients required more platelet and red blood cell (RBC) transfusions than nonmyeloablative recipients (P < 0·0001 for both). Myeloablative patients given peripheral blood stem cells required less platelet transfusions (P < 0·0001) than those given marrow while RBC transfusion requirements did not differ significantly. Subsequent analyses were restricted to nonmyeloablative recipients. Platelet and RBC transfusions were less frequent among related compared to unrelated recipients (P < 0·0001 for both), with comparable median numbers of transfused units. Major/bidirectionally ABO‐mismatched recipients required more RBC transfusions than ABO‐matched recipients (P = 0·006). Rates of graft rejection/failure, grades II–IV acute and chronic graft‐versus‐host‐disease (GVHD), 2‐year relapse, 3‐year survivals and non‐relapse mortality were comparable among ABO‐matched, minor‐mismatched, and major/bidirectionally mismatched recipients (P = 0·93, 0·72, 0·57, 0·36, 0·17 and 0·79, respectively). Times to disappearance of anti‐donor IgG and IgM isohemagglutinins among major/bidirectionally ABO‐mismatched recipients were affected by magnitude of pre‐HCT titres (P < 0·001 for both) but not GVHD (P = 0·71 and 0·78, respectively). In conclusion, nonmyeloablative recipients required fewer platelet and RBC transfusions and among them, both unrelated and major/bidirectionally ABO‐mismatched recipients required more RBC transfusions. ABO incompatibility did not affect nonmyeloablative HCT outcomes.     

Decreased transfusion requirements for patients receiving nonmyeloablative compared with conventional peripheral blood stem cell transplants from HLA-identical siblings.

Red blood cell (RBC) and platelet transfusion requirements in patients given nonmyeloablative versus conventional peripheral blood stem cell (PBSC) transplants from HLA-matched siblings were compared. Between December 1997 and March 2000, 40 patients, aged 21 to 67 years (median 51), with hematologic malignancies underwent nonmyeloablative allografts after either 2 Gy total body irradiation alone (n = 30) or 2 Gy total body irradiation preceded by fludarabine 30 mg/m(2)/d on days -4, -3, and -2 (n = 10). All received postgrafting mycophenolate mofetil and cyclosporine. Controls included 67 concurrent patients, aged 23 to 66 years (median, 46 years), given conventional PBSC transplants following high-dose conditioning and postgrafting methotrexate and cyclosporine. Among patients given nonmyeloablative transplants, 23% required platelet transfusions compared with 100% among patients given conventional grafts (P <.0001). Further, the number of platelet units given to nonmyeloablative recipients was reduced, with a median of 0 (range, 0 to 214) compared with a median of 24 (range, 4 to 358) after conventional transplantation (P <.0001). Sixty-three percent of nonmyeloablative recipients required RBC transfusions compared with 96% of those with conventional grafts (P =.0001). The number of RBC units transfused was also reduced, with a median of 2 (range, 0 to 50) compared with 6 (range, 0 to 34) after conventional transplantation (P =.0001). High transfusion requirements before transplantation and donor-recipient ABO incompatibility increased transfusion requirements in both patient groups, though neither significantly influenced the outcome of the analysis. Neither patient age, splenomegaly at transplantation, development of graft-versus-host disease, nor posttransplantation cytomegalovirus antigenemia or cytomegalovirus disease had statistically significant influences on posttransplantation transfusions.     

The use of intravenous catheterisation with a rest period is useful for determination of plasma cortisol levels but not plasma prolactin levels

OBJECTIVE: The use of an intravenous catheter with a rest period has been recommended to avoid false-positive results for hyperprolactinaemia and false-negative results for hypocortisolaemia. We tested the relevance of this recommendation. DESIGN: Plasma cortisol and prolactin levels were determined before (T-15) and after a 15-min rest period (T0) in 119 patients, 38 males (M) and 81 females (F). 52 of the 119 patients were known (K; 30 females and 22 males) and 67 unknown (UK; 49 females and 18 males) to the unit. RESULTS: Prolactin was lower after rest in women (12.3+/-22.7 ng/l vs 11.7+/-22.5 ng/ml, P=0.03), but not in men (6.2+/-4.5 ng/ml at T-15 vs 5.8+/-3.2 ng/ml at T0, P=0.09), in the UK subgroup (10.6+/-20.7 ng/ml at T-15 vs 10.1+/-20.9 ng/ml at T0, P=0.06) and in the K subgroup (10.1+/-16.7 ng/ml at T-15 vs 9.7+/-15.8 ng/ml at T0, P=0.08). None of the patients with prolactin levels higher than 20 ng/ml at T-15 diminished its prolactin value below this cut-off value. Plasma cortisol levels were lower after rest in women (17.9+/-5.9 microg/dl at T-15 vs 16.5+/-6.1 microg/dl at T0, P<0.0001), in the UK subgroup (18+/-6.1 microg/dl at T-15 vs 16.6+/-6.4 microg/dl at T0, P=0.0003) but not in men (18+/-4.4 microg/dl at T-15 vs 17.5+/-5.8 microg/dl at T0, P=0.47) and in the K subgroup (17.8+/-4.6 microg/dl at T-15 vs 17+/-5.4 microg/dl at T0, P=0.13). At T0, 3.3% and 15% of patients presented values below the cut-off value of 10 microg/dl (276 nmol/l) and 17 microg/dl (470 nmol/l), respectively. CONCLUSION: These results don't justify intravenous catheterisation with a rest period for plasma prolactin determination in contrast with plasma cortisol determination.     

Comparative effects of red blood cell transfusion and increasing blood flow on tissue oxygenation in oxygen supply-dependent conditions

Red blood cell (RBC) transfusion is usually administered to improve oxygen delivery (DO(2)) in order to sustain tissue oxygen demand. However, this practice is not supported by firm clinical or experimental data. Using a randomized two-period crossover design, this study compared the efficacy of "fresh" RBC transfusion and increased blood flow to restore tissue oxygenation in oxygen supply-dependent conditions. In 12 ketamine-anesthetized mongrel dogs submitted to nonpulsatile normothermic cardiopulmonary bypass, DO(2) was reduced by a progressive decrease in pump flow. DO(2) dependency was defined as an O(2) uptake (V O(2)) decrease by more than 15% from baseline value. Then, intervention consisted of a 40% increase in DO(2) obtained either by transfusion of "fresh" dog's RBC (stored < 3 d) or by increase in pump flow. Animals received both interventions sequentially in a random order, while O(2) saturation was maintained constant. In O(2) supply-dependent conditions, rising pump flow from 1.6 +/- 0.4 to 2.7 +/- 0.7 L/ min increased DO(2) from 5.4 +/- 1.1 to 9.0 +/- 1.3 ml/kg/min (p < 0.01) and V O(2) from 3.5 +/- 0.4 to 4.1 +/- 0.5 ml/kg/min (p = 0.02). "Fresh" RBC transfusion, which increased the hemoglobin concentration from 6.4 +/- 0.9 to 11.1 +/- 1.3 g/dl, increased DO(2) from 5.4 +/- 1.2 to 9.0 +/- 1.4 ml/kg/min (p < 0.01) and V O(2) from 3.6 +/- 0.4 to 4.1 +/- 0.5 ml/kg/min (p = 0.02). There was no difference in V O(2) resulting from both interventions. In oxygen supply-dependent conditions, "fresh" RBC transfusion and increased blood flow are equally effective in restoring tissue oxygenation.     

Impact of ABO incompatibility on engraftment and transfusion requirement after unrelated cord blood transplantation: a single institute experience in Japan

The impact of ABO incompatibility between donor and recipient on engraftment and transfusion requirement was studied in 95 adults who underwent unrelated cord blood transplantation (CBT). The patients included 27 ABO-identical, 29 minor, 21 major and 18 bidirectional ABO-incompatible recipients. Neutrophil engraftment did not differ between ABO-identical/minor ABO-incompatible and major/bidirectional ABO-incompatible recipients (hazard ratio (HR) 1.17, P=0.48). Cumulative incidence of platelet engraftment in ABO-identical/minor ABO-incompatible recipients was higher than in major/bidirectional ABO-incompatible recipients (HR 1.88, P=0.013). In addition, fewer platelet transfusions were required during the first 60 days after CBT in ABO-identical/minor ABO-incompatible recipients (HR 0.80, P=0.040). RBC engraftment did not differ between the two groups (HR 1.25, P=0.33). However, fewer RBC transfusions were required in ABO-identical/minor ABO-incompatible recipients than in major/bidirectional ABO-incompatible recipients (HR 0.74, P<0.005). No patients developed pure red-cell aplasia after CBT. These results indicate that ABO incompatibility affected platelet engraftment and transfusion requirement of RBC and platelet in CBT recipients. Further studies including larger patient numbers are required to elucidate the impact of ABO incompatibility on the clinical outcome of CBT.     

Recombinant human erythropoietin therapy in a transfusion-dependent beta-thalassemia major patient

We report on a 28-year-old patient with transfusion-dependent beta-thalassemia major, who was treated effectively with recombinant human erythropoietin (rHuEpo). rHuEpo promotes the differentiation and proliferation of erythroid cells, induces the production of fetal hemoglobin (HbF), and could be useful in the treatment of some selected transfusion-dependent thalassemia patients. Prior to rHuEpo treatment, the patient was on a regular blood transfusion regimen. Splenectomy did not decrease the transfusion requirements. Additionally, red cell alloimmunization had developed; therefore, we decided to start rHuEpo treatment (Eprex, Jansen Cilag, Greece) in an attempt to improve his anemia and the quality of life. Our patient responded well to rHuEpo treatment and was able to extend the intervals between transfusions from 10-14 to 55-65 days and to sustain a pretransfusion hemoglobin level above 7 g/dl. HbF levels were slightly increased from 55% to 60-65%. Indicators of vascular endothelial activation [serum endothelin-3, intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin] were decreased during treatment. rHuEpo was well tolerated without complications. rHuEpo treatment seemed to have had a beneficial effect and to have improved the quality of life in beta-thalassemia major, although it did have a slight effect on HbF levels, suggesting other possible mechanisms of rHuEpo action.     

Aplastic anemia successfully treated with erythropoietin and rhG-CSF]

A 32 year-old female admitted to our hospital with pancytopenia. The hematological data on admission were: RBC: 247 x 10(4)/microliters, Hb: 8.8 g/dl, Plts: 13,000/microliters, WBC: 2,500/microliters. Bone marrow aspirate and biopsied specimen showed marked hypocellularity without infiltration of abnormal cells. A diagnosis of aplastic anemia was made. Neither high-dose methyl-prednisolone pulse therapy nor anti-lymphocyte globulin were effective. With combination of oxymetholone (30 mg/day), recombinant erythropoietin (rHuEpo; 12,000 U/day, three times a week) and recombinant granulocyte-colony simulating factor (rHuG-CSF; 33 micrograms/day) for 3 months, remarkable improvements of hematological data were obtained. Her hemoglobin level reached 11.4 g/dl, and platelets count 49,000/microliters. However, 4 weeks after the withdrawal of erythropoietin and G-CSF administrations, her platelet count fell to 12,000/microliters. It was suggested that combination therapy with erythropoietin and G-CSF were effective for aplastic anemia.     

Flexible bronchoscopy in the diagnosis of pulmonary infiltrates following autologous peripheral stem cell transplantation for advanced breast cancer.

Flexible bronchoscopy is an important tool in the diagnosis of pulmonary complications following bone marrow transplantation. However, the value of this procedure in autologous peripheral stem cell transplant (APSCT) recipients with pulmonary complications is not well defined. We retrospectively evaluated the diagnostic yield of 27 consecutive bronchoscopies done on 23 APSCT recipients following high-dose chemotherapy for breast cancer. FB resulted in a positive diagnosis in 16 cases (59%). Broncheoalveolar lavage (BAL) was performed on all patients, and transbronchial biopsies (TBB) were carried out in 14. TBB were diagnostic in 10 (71%), with pulmonary drug toxicity as the most common finding (n = 8), followed by metastatic breast cancer (n = 2). BAL was diagnostic in six (22%): bacterial pneumonia (n = 3), aspergillosis (n = 2), Pneumocystis carinii pneumonia (n = 1) and Influenza B (n = 1). The procedure was well tolerated with no major complications except a small pneumothorax in one patient that did not require chest tube insertion. In conclusion, flexible bronchoscopy is a useful tool in the evaluation of pulmonary complications following APSCT for breast cancer. TBB can be done safely with relatively high diagnostic yield. Pulmonary drug toxicity is the most common pathological finding.     

A randomized double-blind placebo-controlled study with subcutaneous recombinant human erythropoietin in patients with low-risk myelodysplastic syndromes

To evaluate the effect of recombinant human erythropoietin (rHuEpo) on the haemoglobin level and transfusion requirement in low-risk myelodysplastic syndromes (MDS), 87 patients were enrolled in a randomized double-blind placebo-controlled study. 44 patients were assigned to epoetin α (150 U/kg/d s.c. for 8 weeks) and 43 to placebo arms. MDS types were homogenous in both groups: refractory anaemia (RA) 47.7–48.8%, refractory anaemia with ringed sideroblasts (RAS) 20.5–25.6%, refractory anaemia with excess of blasts (RAEB) (blasts < 10%) 31.8–25.6%. 14/38 evaluable patients responded to epoetin α versus 4/37 to placebo (P = 0.007). 50% of RA responded to epoetin α versus 5.9% to placebo (P = 0.0072), RAS 37.5% v 18.2% (P = 0.6) and RAEB 16.7% v 11.1% (P = 1.00). 60% of non-pretransfused patients responded to epoetin α (Hb 8.35 ± 0.73 to 10.07 ± 1.87 g/dl), whereas a slight decrease was observed in the placebo group (8.4 ± 0.66 to 8.19 ± 0.92 g/dl) (P = 0.0004). Percentage of transfused patients was similar in both arms. Basal erythropoietin (Epo) serum levels > 200 mU/l predicted for a non-response. At week 4 sTfR levels were increased > 50% in responders (P = 0.013), whereas an increase < 18% predicted for non-response (P = 0.006). Leucocyte and platelet counts were not influenced by epoetin α treatment. Adverse events occurred in 31.8% of the rHuEpo-treated versus 42.9% of the placebo-treated patients (P = 0.2), and seven patients did not complete the course. In conclusion, rHuEpo was effective in the treatment of low-risk MDS. RA subtype, no transfusions prior to rHuEpo therapy, and low basal Epo levels were associated with higher probability of response. Soluble transferrin receptor level at the fourth week was an early predictor of response.     

Improved haematopoietic recovery following transplantation with ex vivo-expanded mobilized blood cells

Infusions of ex vivo-expanded (EXE) mobilized blood cells have been explored to enhance haematopoietic recovery following high dose chemotherapy (HDT). However, prior studies have not consistently demonstrated improvements in trilineage haematopoietic recovery. Three cohorts of three patients with breast cancer received three cycles of repetitive HDT supported by either unmanipulated (UM) and/or EXE cells. Efficacy was assessed by an internal comparison of each patient's consecutive HDT cycles, and to 106 historical UM infusions. Twenty-one cycles were supported by EXE cells and six by UM cells alone. Infusions of EXE cells resulted in fewer days with an absolute neutrophil count (ANC) <0.1 x 10(9)/l (median 2 vs. 4 d, P = 0.002) and 3 d faster ANC recovery to >0.1 x 10(9)/l (median 5 vs. 8 d, P = 0.0002). This resulted in a major reduction in the incidence of febrile neutropenia compared with UM cycles (0% vs. 83%; P = 0.008) and in 66% of historical UM cycles (P = 0.01) and a marked reduction in hospital re-admission. There were also fewer platelet transfusions required (43% vs. 100%; P = 0.009). We conclude that EXE cells enhance both neutrophil and platelet recovery and reduce febrile neutropenia, platelet transfusion and hospital re-admission.     

Engraftment of early erythroid progenitors is not delayed after non-myeloablative major ABO-incompatible haematopoietic stem cell transplantation

We hypothesized that patients undergoing major ABO-incompatible non-myeloablative haematopoietic stem cell transplantation (nm-HSCT) might experience prolonged haemolysis after transplant due to the delayed disappearance of host plasma cells producing anti-donor isohaemagglutinins (HAs). To address this question, we analysed data from 107 consecutive patients transplanted with allogeneic peripheral blood stem cells from human leucocyte antigen-matched (related, n = 84; unrelated, n = 23) donors after non-myeloablative conditioning (200 cGy total body irradiation +/- fludarabine). In total, 23 out of the 107 patients received major or major/minor ABO-incompatible transplants. Red blood cell (RBC) transfusion requirements during the first 120 d post transplant were higher in major ABO-mismatched than in ABO-matched recipients (0.12 vs 0.03 median units RBC concentrate/d, P = 0.04). Two patients developed transient pure red cell aplasia, which had resolved spontaneously by 9 months after transplant. Major ABO incompatibility did not influence rates of engraftment. Patients with sustained engraftment experienced gradual declines of anti-donor HAs, and the estimated median time to reaching IgM and IgG titres of < 1:1 was at least 133 d in evaluable patients, approximately twice longer than reported after myeloablative conditioning. There was a strong correlation between degrees of donor chimaerism in erythroid burst-forming units, granulocyte macrophage colony-forming units and granulocytes, indicating that donor erythroid engraftment, defined by early erythroid progenitors, was as prompt as myeloid engraftment. In conclusion, our data suggest that major ABO-incompatibility is not a barrier to successful non-myeloablative HSCT.     

Immunophenotypic parameters and RBC alloimmunization in children with sickle cell disease on chronic transfusion

Alloimmunization against red blood cell (RBC) antigens is a cause of morbidity and mortality in transfused patients with sickle cell disease (SCD). To investigate distinguishing characteristics of patients who develop RBC alloantibodies after transfusion (responders) versus those who do not (non‐responders), a cross‐sectional study of 90 children with SCD on chronic RBC transfusion therapy at a single institution was conducted in which 18 immune parameters (including T and B cell subsets) were tested via flow cytometry, and medical records were reviewed. RBC alloimmunization was present in 26/90 (29%) patients, with anti‐E, K, and C among the most commonly detected alloantibodies despite prophylactic matching for these antigens at the study institution. In addition, RBC autoantibodies had been detected in 18/26 (69%) of alloimmunized versus 7/64 (11%) of non‐alloimmunized patients (P < 0.0001). Alloimmunized patients were significantly older (median 13.0 years vs. 10.7 years, P = 0.010) and had more RBC unit exposures (median 148 U vs. 82 U, P = 0.020) than non‐alloimmunized patients. Sex, age at initiation of chronic transfusion, splenectomy, stroke, and transfusion outside of the study institution were not significantly associated with RBC alloimmunization. Alloimmunized patients had a significantly increased percentage of CD4+ T memory cells compared to non‐alloimmunized patients (57% vs. 49%, P = 0.0047), with no other significant differences in immune cell subsets or laboratory values detected between these groups. Additional research of RBC alloimmunization is needed to optimize transfusion therapy and to develop strategies to prevent alloimmunization. Am. J. Hematol. 90:1135–1141, 2015. © 2015 Wiley Periodicals, Inc.     

Intermittent injections vs. continuous infusion of factor VIII in haemophilia patients undergoing major surgery

Continuous infusion (CI) of factor VIII (FVIII) has been proved to be a safe alternative to intermittent bolus injections (BI) in haemophilia A. Most reports on CI suggest a considerable saving in FVIII compared with historical controls treated with BI, but some recent reports failed to demonstrate such an effect. The present study prospectively compared safety, efficacy and factor requirements in 43 major surgical procedures performed in severe haemophilia A patients who were treated with either BI (18 operations) or CI (25 operations). The aim was to maintain factor VIII levels above the same minimum levels. Improved safety of CI over BI was observed, despite a bias in favour of the BI group (all underwent unilateral operations, compared with 24% of the CI group who underwent bilateral operations). Higher nadir levels were found in the CI group (0.44 +/- 0.06 vs. 0.31 +/- 0.09 IU/ml; P < 0.01) with a lower incidence of dangerous drops below 0.3 IU/ml (8% vs. 44% of patients respectively; P < 0.01), and a lower drop in haemoglobin (Hb) (1.56 +/- 1.21 vs. 3.01 +/- 2.13 g/dl; P < 0.05) and blood transfusion requirements (12% vs. 39%; P < 0.01). Major bleeding complications developed in three out of 18 patients (17%) in the BI group and none of the CI group (P = 0.06). The FVIII dosage was lower by 36% in the CI group (467 +/- 104 vs. 733 +/- 126 IU/kg; P < 0.01). Had the trough factor levels been maintained at the target levels, a greater difference of 72% would probably have been observed.     

Serum erythropoietin (EPO) levels correlate with survival and independently predict response to EPO treatment in patients with myelodysplastic syndromes

Treatment with recombinant erythropoietin (EPO) can alleviate anaemia in patients with myelodysplastic syndromes (MDS). The present study, based on a long-term follow-up of 68 MDS patients (26RA, 16 RAS, 26 RAEB) treated with EPO alone, pinpoints pre-treatment variables associated with response induction, response duration and overall survival. Response, defined as an increase in haemoglobin >15gL1 or eliminated erythrocyte transfusion requirements, was observed in 22 of 66 (33%) evaluable patients. The median response duration was 15 (range 3-64+) months. Using univariate logistic regression models, responders displayed significantly lower baseline serum EPO levels (S-EPO), more often normal bone marrow blast cell content (RA/RAS vs. RAEB), normal cytogenetics and no need for erythrocyte transfusion. In a multiple logistic regression model, S-EPO (P=0.009), marrow blast content (P=0.031) and erythrocyte transfusion need (P=0.024) remained associated with response induction. The probability of response for a patient with S-EPO >50UL1, RA/RAS and no transfusion need was 0.79 (0.53-0.93, 95% CI). The median overall survival time from start of EPO treatment was 26 months, significantly longer for responders than for non-responders (49 vs. 18 months, P=0.018). Survival was also predicted by baseline S-EPO; patients with S-EPO >50UL1 (n=50) had a median survival of 17 months, as compared to 65 months for those with S-EPO >50UL1 (n=14, P=0.024). The international prognostic scoring system (IPSS) for MDS predicted survival (P=0.003) and progression to acute leukemia (P<0.001) but not response to EPO treatment. Furthermore, in a logistic regression model with S-EPO and IPSS, S-EPO (but not IPSS) was again a significant predictor for response (P=0.007). Our data facilitate the optimal selection of MDS patients suitable for EPO treatment and pinpoint S-EPO as a powerful predictor of response and overall survival in MDS.