The effects of monoclonal anti-CD47 on RBCs, compatibility testing, and transfusion requirements in refractory acute myeloid leukemia.

BACKGROUND: CD47 is a novel therapeutic target in the treatment of solid-organ and hematologic malignancies. CD47 is also expressed on RBCs. Here, we report our experience of the RBC effects and the impact on blood bank testing and transfusion management in a Phase 1 trial of the humanized anti-CD47 monoclonal antibody Hu5F9-G4 in relapsed or primary refractory acute myeloid leukemia (AML) (NCT02678338). STUDY DESIGN AND METHODS: Nineteen patients with relapsed or primary refractory AML treated across five UK centers were included for analysis. Patients received escalating doses of Hu5F9-G4. Serial laboratory data were collected to evaluate impact on hemoglobin (Hb), markers of hemolysis (bilirubin, lactate dehydrogenase, reticulocyte count), transfusion requirements, and blood compatibility testing. RESULTS: A decline in Hb was observed with drug administration (median Hb change, -1.0 g/dL; range, 0.4-1.6) with associated increase in transfusion requirements. Patients responded to transfusion with a median Hb increment per unit of 1.0 g/dL. RBC agglutination was seen in all cases without associated change in Hb, lactate dehydrogenase, bilirubin, or reticulocyte count. Nine of 19 (47%) patients developed a newly positive antibody screen with a pan-agglutinin identified in plasma. Invalid ABO blood grouping occurred in 4 of 12 (33%) non-group O patients due to anomalous reactivity in the reverse ABO-type results. CONCLUSIONS: Treatment with Hu5F9-G4 in patients with AML resulted in an Hb decline and increased transfusion requirements. Problems with ABO blood typing and compatibility testing were widely observed and should be expected by centers treating recipients of Hu5F9-G4.

The scientific basis for patient blood management.

Patient blood management is an increasingly used term to describe an evidence-based, multidisciplinary approach to optimising the care of patients who might need transfusion. It encompasses measures to avoid transfusion such as anaemia management without transfusion, cell salvage and the use of anti-fibrinolytic drugs to reduce bleeding as well as restrictive transfusion. It ensures that patients receive the optimal treatment, and that avoidable, inappropriate use of blood and blood components is reduced. This paper provides an overview of the scientific basis for patient blood management with a focus on the increasing evidence for restrictive rather than liberal transfusion practice and the use of electronic blood ordering and decision support to facilitate its implementation.

Cryoprecipitate therapy.

Cryoprecipitate, originally developed as a therapy for patients with antihaemophilic factor deficiency, or haemophilia A, has been in use for almost 50 yr. However, cryoprecipitate is no longer administered according to its original purpose, and is now most commonly used to replenish fibrinogen levels in patients with acquired coagulopathy, such as in clinical settings with haemorrhage including cardiac surgery, trauma, liver transplantation (LT), or obstetric haemorrhage. Cryoprecipitate is a pooled product that does not undergo pathogen inactivation, and its administration has been associated with a number of adverse events, particularly transmission of blood-borne pathogens and transfusion-related acute lung injury. As a result of these safety concerns, along with emerging availability of alternative fibrinogen preparations, cryoprecipitate has been withdrawn from use in a number of European countries. Compared with the plasma from which it is prepared, cryoprecipitate contains a high concentration of coagulation factor VIII, coagulation factor XIII, and fibrinogen. Cryoprecipitate is usually licensed by regulatory authorities for the treatment of hypofibrinogenaemia, and recommended for supplementation when plasma fibrinogen levels decrease below 1 g litre(-1); however, this threshold is empiric and is not based on solid clinical evidence. Consequently, there is uncertainty over the appropriate dosing and optimal administration of cryoprecipitate, with some guidelines from professional societies to guide clinical practice. Randomized, controlled trials are needed to determine the clinical efficacy of cryoprecipitate, compared with the efficacy of alternative preparations. These trials will allow the development of evidence-based guidelines in order to inform physicians and guide clinical practice.

Postpartum hemorrhage treated with a massive transfusion protocol at a tertiary obstetric center: a retrospective study.

BACKGROUND: A massive transfusion protocol may offer major advantages for management of postpartum hemorrhage. The etiology of postpartum hemorrhage, transfusion outcomes and laboratory indices in obstetric cases requiring the massive transfusion protocol were retrospectively evaluated in a tertiary obstetric center. METHODS: We reviewed medical records of obstetric patients requiring the massive transfusion protocol over a 31-month period. Demographic, obstetric, transfusion, laboratory data and adverse maternal outcomes were abstracted. RESULTS: Massive transfusion protocol activation occurred in 31 patients (0.26% of deliveries): 19 patients (61%) had cesarean delivery, 10 patients (32%) had vaginal delivery, and 2 patients (7%) had dilation and evacuation. Twenty-six patients (84%) were transfused with blood products from the massive transfusion protocol. The protocol was activated within 2h of delivery for 17 patients (58%). Median [IQR] total estimated blood loss value was 2842 [800-8000]mL. Median [IQR] number of units of red blood cells, plasma and platelets from the massive transfusion protocol were: 3 [1.75-7], 3 [1.5-5.5], and 1 [0-2.5] units, respectively. Mean (SD) post-resuscitation hematologic indices were: hemoglobin 10.3 (2.4)g/dL, platelet count 126 (44)×10(9)/L, and fibrinogen 325 (125)mg/dL. The incidence of intensive care admission and peripartum hysterectomy was 61% and 19%, respectively. CONCLUSIONS: Our massive transfusion protocol provides early access to red blood cells, plasma and platelets for patients experiencing unanticipated or severe postpartum hemorrhage. Favorable hematologic indices were observed post resuscitation. Future outcomes-based studies are needed to compare massive transfusion protocol and non-protocol based transfusion strategies for the management of hemorrhage.

Detection, evaluation, and management of preoperative anaemia in the elective orthopaedic surgical patient: NATA guidelines.

Previously undiagnosed anaemia is common in elective orthopaedic surgical patients and is associated with increased likelihood of blood transfusion and increased perioperative morbidity and mortality. A standardized approach for the detection, evaluation, and management of anaemia in this setting has been identified as an unmet medical need. A multidisciplinary panel of physicians was convened by the Network for Advancement of Transfusion Alternatives (NATA) with the aim of developing practice guidelines for the detection, evaluation, and management of preoperative anaemia in elective orthopaedic surgery. A systematic literature review and critical evaluation of the evidence was performed, and recommendations were formulated according to the method proposed by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) Working Group. We recommend that elective orthopaedic surgical patients have a haemoglobin (Hb) level determination 28 days before the scheduled surgical procedure if possible (Grade 1C). We suggest that the patient's target Hb before elective surgery be within the normal range, according to the World Health Organization criteria (Grade 2C). We recommend further laboratory testing to evaluate anaemia for nutritional deficiencies, chronic renal insufficiency, and/or chronic inflammatory disease (Grade 1C). We recommend that nutritional deficiencies be treated (Grade 1C). We suggest that erythropoiesis-stimulating agents be used for anaemic patients in whom nutritional deficiencies have been ruled out, corrected, or both (Grade 2A). Anaemia should be viewed as a serious and treatable medical condition, rather than simply an abnormal laboratory value. Implementation of anaemia management in the elective orthopaedic surgery setting will improve patient outcomes.

Iron overload and toxicity: the hidden risk of multiple blood transfusions.

BACKGROUND: The quantity of iron in body is carefully regulated, primarily by control of iron absorption, and excess total body iron can be extremely toxic. Since humans have no mechanism for elimination of excess iron, multiple transfusions of red blood cells, which are required for the management of a number of disorders, inevitably result in iron overload. Cumulative iron overload, in turn, leads to iron toxicity with organ dysfunction and damage. MATERIALS: This review examines the relationship between iron metabolism and hematologic disorders treated with multiple transfusions, with emphasis on the diagnosis and current methods of management of iron overload and toxicity in transfusion-dependent patients. Primarily using key words, we identified and reviewed more than 100 pertinent articles in English and other languages in the Medline database plus an additional number of abstracts of presentations at recent meetings of relevant scientific associations. RESULTS: Transfusion-dependent disorders include those characterized by decreased red blood cell production, increased red blood cell destruction, or chronic blood loss. Patients receiving chronic transfusion therapy should be screened and monitored for iron overload, yet in our opinion, this is not always done routinely. Once iron overload has been identified, it should be treated to reduce the risk of morbidity and mortality from iron toxicity, which particularly affects the liver and heart. CONCLUSION: Increased awareness of the risks of iron overload from chronic transfusion therapy should result in greater use of interventions such as iron chelation to reduce total body iron and the risk of long-term sequelae.

Retrospective analysis of transfusion outcomes in pregnant patients at a tertiary obstetric center.

BACKGROUND: The decision to use red blood cell transfusion and/or blood products (fresh frozen plasma, platelets, cryoprecipitate) to manage obstetric hemorrhage or treat postpartum anemia is often made empirically by physicians. We performed a retrospective study to review transfusion outcomes in pregnant and postpartum patients at a large obstetric center. METHODS: A retrospective, observational study was performed of obstetric in-patients who received red blood cell transfusion and/or blood products over a one-year period. Data abstracted included transfusion data, pre-transfusion hemoglobin (Hb) and lowest recorded (nadir) Hb, and maternal and neonatal outcomes. RESULTS: During the study period, 74 patients received transfusion therapy (1.4%). Pre-transfusion and nadir Hb values were 7.6 g/dL and 7.0 g/dL respectively. Median [IQR] total red blood cells transfused were 2 units [2-3], with 41 (55%) patients receiving 1-2 units. Based on chart review, no specific indications for transfusion were identified in 25 patients (34%), and 13 patients (18%) had undetected postpartum anemia (Hb values <8.2 g/dL) at least 24h after delivery. CONCLUSION: More formal assessment and documentation of the etiologic factors associated with transfusion management in pregnant patients is advised. In addition, the identification and management of undetected postpartum anemia is underappreciated.

Reduced risk of acute GVHD following mobilization of HLA-identical sibling donors with GM-CSF alone.

We retrospectively reviewed the results of transplanting peripheral blood progenitor cell (PBPC) allografts from HLA-matched sibling donors mobilized using various hematopoietic cytokines. Patients had received allografts mobilized with Granulocyte colony-stimulating factor (G-CSF) (G, N = 65) alone, G plus Granulocyte-macrophage colony stimulating factor (GM-CSF) (G/GM, N = 70), or GM-CSF alone at 10 or 15 microg/kg/day (GM, N = 10 at 10 microg/kg/day and 21 at 15 microg/kg/day). The CD34+ and CD3+ cell content of grafts were significantly lower following GM alone compared to G alone (P < 0.001 and 0.04, respectively). Nonhematopoietic toxicity observed in donors precluded dose escalation of GM-CSF beyond 10 microg/kg/day. Hematopoietic recovery was similar among all three groups. Grades II-IV acute graft-versus-host disease (GVHD) was observed in only 13% of patients in the GM alone group compared to 49 and 69% in the G alone or G/GM groups, respectively (P < 0.001). In a multivariate analysis, receipt of PBPC mobilized with GM alone was associated with a lower risk of grades II-IV acute GVHD (hazard ratio 0.21; 95% CI 0.073, 0.58) compared to G alone or G/GM. There were no differences in relapse risk or overall survival among the groups. Donor PBPC grafts mobilized with GM-CSF alone result in prompt hematopoietic engraftment despite lower CD34+ cell doses and may reduce the risk of grades II-IV acute GVHD following HLA-matched PBPC transplantation.

Supraventricular tachyarrhythmias after hematopoietic stem cell transplantation: incidence, risk factors and outcomes.

Recent studies suggest that cancer patients may be at increased risk for supraventricular tachyarrhythmias (SVTA). We have observed clinically significant SVTA in patients undergoing hematopoietic stem cell transplantation occurring at a median of 6 days post transplant, manifesting as atrial fibrillation/flutter or regular narrow-complex tachycardia and persisting for a median of 3 days (range, 0-8). All patients received aggressive medical therapy and/or electrical cardioversion to restore sinus rhythm and to re-establish hemodynamic stability. Non-Hodgkin's lymphoma (NHL) was the most common diagnosis (53%), and a case control analysis in those patients demonstrated that SVTA occurred in 12% of patients and was associated with older age and pre-existing cardiac conditions. In conclusion, patients undergoing HSCT are at moderate risk for developing SVTA, particularly older patients with a diagnosis of NHL. These arrhythmias are clinically significant, and are a marker for increased mortality and prolonged hospital stay. Additional studies are needed to identify high-risk patients who may benefit from prophylactic anti-arrhythmic therapy.

Outcomes of adults with acute myelogenous leukemia in remission given 550 cGy of single-exposure total body irradiation, cyclophosphamide, and unrelated donor bone marrow transplants.

On the basis of observations from dog models and human studies, we hypothesized that a low-dose (550 cGy), single-exposure total body irradiation (TBI)-based regimen would result in improved survival when given to adult patients with acute myelogenous leukemia (AML) who were undergoing unrelated donor bone marrow transplantation in complete remission (CR). The regimen consisted of single exposure (550 cGy) of TBI given at a high dose rate (30 cGy/min) and cyclophosphamide. Graft-versus-host disease prophylaxis consisted of cyclosporine, methotrexate, and corticosteroids. Thirty-two consecutive adult patients (median age, 47 years) with AML in CR (15 in CR 1 and 17 in CR > or =2) were treated. Sixteen patients (50%) were alive and in remission at last follow-up (median, 2.2 years; range, 0.6-4.0 years). Kaplan-Meier estimates of overall and leukemia-free survival at 3 years were 55% +/- 14% (mean +/- SE) and 57% +/- 14% in CR 1 patients and were both 39% +/- 12% in CR > or =2 patients. Transplant-related mortality was 13% for patients in CR 1 and 41% for those in CR > or =2. Only 1 patient (3%) experienced fatal regimen-related organ toxicity, and only 1 had grade III or IV acute graft-versus-host disease. Graft failure was not observed. Relapse occurred in 22% of patients. This low-dose (550 cGy), single-exposure TBI-based regimen resulted in good survival and a low risk of fatal regimen-related organ toxicity in adult patients with AML who underwent unrelated donor bone marrow transplantation in CR.

Hydroxychloroquine for the prevention of acute graft-versus-host disease after unrelated donor transplantation.

Hydroxychloroquine (HCQ) is an immunosuppressive agent that interferes with antigen presentation and with activity against graft-versus-host disease (GVHD). In a phase II trial assessing the GVHD prophylactic effects of HCQ, 51 consecutive unrelated donor transplant recipients received HCQ in addition to cyclosporin A, methylprednisolone, and methotrexate. HCQ was initiated on pretransplantation day -21 at 800 mg/d and continued until day +100 after transplantation. HCQ was extremely well tolerated and was not associated with side effects. Pharmacokinetic analyses demonstrated large inter- and intrapatient variability. The addition of HCQ did not affect posttransplantation immune recovery. Grade II to IV acute GVHD was observed in 56% of patients, and grade III and IV GVHD was observed in 17%. Day +100 mortality was 22%. When compared with a matched cohort of patients reported to the International Bone Marrow Transplant Registry, patients receiving HCQ had comparable cumulative incidences of grade II to IV acute GVHD. However, lower incidences of grades III and IV GVHD and better GVHD-free survival were observed in HCQ-treated patients (P =.01). We conclude that prophylactic HCQ is well tolerated and associated with a low incidence of severe acute GVHD. An ongoing placebo-controlled randomized trial will further determine what role HCQ plays in preventing GVHD after allografting.

Low-dose short-course intravenous ganciclovir as pre-emptive therapy for CMV viremia post allo-PBSC transplantation.

In contrast to allogeneic bone marrow transplantation (allo-BMT), there is a paucity of data on cytomegalovirus (CMV) infection and preemptive therapy (PT) strategies following allogeneic peripheral blood stem cell (allo-PBSC) transplantation. We report here on the patterns of CMV infection in a cohort of 225 patients following sibling donor allo-PBSC transplantation. In an attempt to reduce neutropenia, we used intravenous low-dose short-course (LDSC) ganciclovir (GCV) 5 mg/kg once daily for 21 days as preemptive therapy. A total of 165 recipient-donor pairs were CMV seropositive. An initial episode of viremia (detected by shell vial/tube culture) occurred in 75/165 (45%) at a median of day +35 (17-445) post allo-PBSC. In all, 58 patients received PT with LDSC GCV. Among 58, 55 (94%) completed the 21-day course of PT. A second episode of viremia occurred in 19/58 (33%) at day+80 (50-174) and a third episode in 5/58 (9%) at day+134 (103-218). Among patients receiving LDSC GCV, 5/58(9%) developed disease (four pneumonia, one colitis) at day+211 (63-487). No patient on LDSC GCV exhibited a decline in their ANC below 500/microl and none required growth factors. LDSC GCV is extremely well tolerated and cost-effective as PT for CMV viremia following allo-PBSC transplantation.

[Autologous blood procurement--acute normovolemic hemodilution vs. preoperative autologous blood donation]. / Autologe Blutgewinnung--akute normovolämische Hämodilution vs. präoperative Eigenblutspende.

Autologous blood procurement remains in evolution. Interest in preoperative autologous blood donation (PAD) increased substantially in the 1980's due to the recognition that HIV was transmissible by blood. Concomitant with increased blood safety, however, PAD activity has declined approximately 40% since 1992. Reasons for this decline are unclear; patients may feel more comfortable with issues regarding blood safety, but associated costs and discard rates of up to 50% of blood units are other important factors. An alternate strategy is acute normovolemic hemodilution (ANH), which has the advantages of lower costs along with no wastage of blood units. A further advantage is that since ANH units never leave the patient's bedside, there is no possibility of an administrative error that could lead to ABO-related hemolysis (as could occur with PAD units stored in the blood bank). Concerns regarding the adequacy of national blood inventories may restimulate interest in autologous blood procurement, independent of issues regarding blood risks or costs.

Low-dose (550 cGy), single-exposure total body irradiation and cyclophosphamide: consistent, durable engraftment of related-donor peripheral blood stem cells with low treatment-related mortality and fatal organ toxicity.

On the basis of observations of dog models and from earlier studies with humans, we hypothesized that a low-dose (550 cGy) TBI-based conditioning regimen would result in sustained engraftment of HLA-matched sibling peripheral blood stem cells (PBSC) with low treatment-related mortality (TRM) and low serious organ toxicity if the TBI was given as a single dose and at a high dose rate. The regimen included 550 cGy TBI administered as a single dose at 30 cGy/min and cyclophosphamide. Cyclosporine was given as GVHD prophylaxis. Twenty-seven good-risk (acute leukemia in first remission and chronic-phase chronic myelogenous leukemia) and 53 poor-risk (other) patients were accrued. Complete donor engraftment occurred in 93% to 100% of evaluable patients at each scheduled assessment and was durable through 4 years. Mixed chimerism (50% to 98% donor) was observed in 9 patients (11%). Without further intervention, all patients had complete donor engraftment on subsequent assessments. Graft failure did not occur. TRM through at least 2 years was 7% in the good-risk and 19% in the poor-risk diagnostic groups. Grade 4 (fatal) organ toxicity occurred in only 2 patients (2.5%). Other causes of TRM included infection and GVHD. Median follow-up for the surviving patients was 1234 days (range, 780-1632 days). Current status includes 39 patients (49%) alive and in complete remission, 2 alive in relapse, and 39 dead. Relapse occurred in 15% of the good-risk group and 45% of the poor-risk group. The Kaplan-Meier estimates of 3-year disease-free and overall survival of the good-risk group were 77% and 85%, respectively, and of the poor-risk group were 34% and 36%, respectively. Low-dose (550 cGy), single-exposure TBI given at a high dose rate with cyclophosphamide resulted in consistent durable engraftment of HLA-matched sibling PBSC with a low risk of fatal organ toxicity and TRM.

Erythropoietin therapy versus red cell transfusion.

Erythropoietin therapy was approved for use as a blood conservation intervention beginning in 1989 for patients with medical anemia and in 1997 for surgical patients. The adoption of this strategy has been rapid in some settings (such as renal failure patients), progressive in others ( eg, cancer patients), and slow in others (surgery patients, for instance). At the same time, the risks of blood transfusion have declined substantially whereas the costs of blood transfusion have increased significantly. The evolution of new techniques such as acute normovolemic hemodilution (ANH) and the novel erythropoiesis-stimulating protein (NESP) bring new options to allogeneic blood transfusion. Erythropoietin therapy, with or without autologous blood procurement, is undergoing new scrutiny as an alternative to blood transfusion. This is not only because of traditional concerns regarding blood risks but because of new blood inventory and cost considerations.

Immune hemolysis involving non-ABO/RhD alloantibodies following hematopoietic stem cell transplantation.

We report two cases of severe alloimmune hemolysis after hematopoietic stem cell (HSC) transplant resulting from an anti-Jk(a). The time course of hemolysis and Jk phenotypes of the donor and recipient in the cases reported suggest that the antibody was produced by donor-derived passenger lymphocytes. Retrospective analysis of the blood bank records of all allogeneic HSC transplant patients at Barnes-Jewish Hospital from 1994 to 1999 suggests that the incidence of alloimmune hemolysis due to incompatibilities involving non-ABO or RhD red cell antigens is very low, approximately 1%. In one patient, the duration of hemolysis was shortened significantly by performing red cell exchange at the first sign of intravascular hemolysis.

Prestorage universal WBC reduction of RBC units does not affect the incidence of transfusion reactions.

BACKGROUND: Febrile nonhemolytic transfusion reaction (FNHTR) has been identified as a pivotal reason for prestorage universal WBC reduction. A regional blood center implemented universal prestorage WBC reduction for RBCs on January 1, 2000. Whether prestorage universal WBC reduction of RBC units will affect FNHTR is not known. STUDY DESIGN AND METHODS: All reports of RBC transfusion reactions at Barnes-Jewish Hospital submitted for evaluation to the blood bank, before and after the implementation of WBC reduction of RBCs, were retrospectively evaluated. RESULTS: For the 36,303 allogeneic RBC transfusions administered in 1999, 85 reactions (0.23%) were reported. These reactions were classified as FNHTR in 43 cases, allergic in 13, delayed hemolytic in 19, and miscellaneous in 10. For the 31,543 non-WBC-reduced RBC transfusions performed in 1999, 78 reactions (0.25%) were reported. These reactions were classified as FNHTR in 39 cases, allergic in 13, delayed hemolytic in 19, and miscellaneous in 7. In the first half of 2000, 32 reactions (0.20%) were reported for 16,093 prestorage WBC-reduced RBC transfusions (p = 0.41). There were 13 FNHTRs and 10 allergic, 7 delayed hemolytic, and 2 miscellaneous reactions. The use of prestorage WBC-reduced RBCs did not significantly affect the rate of reactions classified as allergic (0.04% in 1999; 0.06% in 2000; p = 0.43) or as FNHTR (0.12% in 1999; 0.08% in 2000; p = 0.33). For all patients, universal WBC reduction in 2000 did not reduce the rate of FNHTR from the rate seen with selective bedside WBC reduction, the practice used in 1999 (0.12% in 1999; 0.08% in 2000; p = 0.36). CONCLUSION: No significant difference was found in the incidence of transfusion reactions in patients receiving prestorage WBC-reduced RBCs and non-WBC-reduced RBCs. In addition, no difference was found in transfusion reaction rates when periods of prestorage universal WBC reduction were compared to those of selective WBC reduction.