1. Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study. Bhatia S, Francisco L, Carter A, Sun CL, Baker KS, Gurney JG, McGlave PB, Nademanee A, O'Donnell M, Ramsay NK, Robison LL, Snyder D, Stein A, Forman SJ, Weisdorf DJ. Blood. 2007;110:3784-3792. 
The authors assessed late mortality in 1479 individuals who had survived 2 or more years after allogeneic hematopoietic cell transplantation (HCT). Median age at HCT was 25.9 years and median length of follow-up was 9.5 years. The conditional survival probability at 15 years from HCT was 80.2% (SE = 1.9%) for those who were disease-free at entry into the cohort, and the relative mortality was 9.9 (95% confidence interval, 8.7-11.2). Relative mortality decreased with time from HCT, but remained significantly elevated at 15 years after HCT (standardized mortality ratio = 2.2). Relapse of primary disease (29%) and chronic graft-versus-host disease (cGVHD: 22%) were the leading causes of premature death. Nonrelapse-related mortality was increased among patients older than 18 years at HCT (18-45 years: relative risk [RR] = 1.7; 46+ years: RR = 3.7) and among those with cGVHD (RR = 2.7), and was lower among patients who received methotrexate for GVHD prophylaxis (RR = 0.5). HCT survivors were more likely to report difficulty in holding jobs (odds ratio [OR] = 13.9), and in obtaining health (OR = 7.1) or life (OR = 9.9) insurance compared with siblings. This study demonstrates that mortality rates remain twice as high as that of the general population among 15-year survivors of HCT, and that the survivors face challenges affecting their health and well-being.
2. Impact of ABO incompatibility on engraftment and transfusion requirement after unrelated cord blood transplantation: a single institute experience in Japan. Tomonari A, Takahashi S, Ooi J, Tsukada N, Konuma T, Kobayashi T, Sato A, Iseki T, Yamaguchi T, Tojo A, Asano S. Bone Marrow Transplant. 2007;40:523-528.
ABO incompatibility is defined as “major” when the recipient plasma has isohemagglutinins against donor RBC antigens, and “minor” when the donor has isohemaggluginins against recipient RBC antigens. When combined features of major and minor incompatibility coexist, the incompatibility is defined as “bidirectional.”
Many reports have described the occurrence of pure red-cell aplasia (PRCA) or delayed erythroid engraftment and increased requirement for RBC transfusion in patients after major/bidirectional ABO-incompatible allogeneic BMT or PBSC transplants. Some investigators have shown that recipients of bidirectional ABO-incompatible HSCT had a lower survival rate. In this study, 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.
Although ABH antigens are expressed on platelets as well as RBCs, most previous studies did not show an association between major/bidirectional ABO incompatibility and delayed platelet engraftment or increased platelet transfusion after HSCT.
These results indicate that ABO incompatibility affected platelet engraftment and transfusion requirement of RBCs and platelets in CBT recipients.
3. Hepatic injury following reduced intensity unrelated cord blood transplantation for adult patients with hematological diseases. Kusumi E, Kami M, Kanda Y, Murashige N, Seki K, Fujiwara M, Koyama R, Komatsu T, Hori A, Tanaka , Yuji K, Matsumura T, Masuoka K, Wake A, Miyakoshi S, Taniguchi S. Biol Blood Marrow Transplant. 2006;12:1302-9.
Liver injury is a common complication in allogeneic hematopoietic stem cell transplantation. Its major causes comprise graft-versus-host disease (GVHD), infection, and toxicities of preparative regimens and immunosuppressants; however, few data are available regarding liver injuries after reduced-intensity cord blood transplantation (RICBT).
The authors reviewed medical records of 104 recipients who underwent RICBT between March 2002 and May 2004. Preparative regimen and GVHD prophylaxis comprised fludarabine/melphalan/total body irradiation and cyclosporine or tacrolimus. The authors assessed the etiology of liver injuries based on the clinical presentation, laboratory results, comorbid events, and imaging studies in 85 patients who achieved primary engraftment. The severity of liver dysfunction was assessed according to the National Cancer Institute Common Toxicity Criteria version 2.0. Hyperbilirubinemia was graded according to a report by Hogan et al (Blood. 2004;103:78-84).
Moderate to very severe liver injuries were observed in 36 patients. Their causes included cholestatic liver disease (CLD) related to GVHD or sepsis (n = 15), GVHD (n = 7), cholangitis lenta (n = 5), and others (n = 9). Median onsets of CLD, GVHD, and cholangitis lenta were days 37, 40, and 22, respectively. Frequencies of grade 3-4 alanine aminotransferase elevation were comparable across the 3 types of hepatic injuries. Serum gamma-glutamil transpeptidase was not elevated in any patients with cholangitis lenta, whereas 27% and 40% of patients with CLD and GVHD, respectively, developed grade 3-4 gamma-glutamil transpeptidase elevation.
Multivariate analysis identified 2 risk factors for hyperbilirubinemia; grade II-IV acute GVHD (relative risk, 2.23; 95% confidence interval, 1.11-4.47; P = .024) and blood stream infection (relative risk, 3.77; 95% confidence interval, 1.91-7.44; P = .00013).
The authors conclude that their study indicates that hepatic injuries are significant problems after RICBT, and that GVHD and blood stream infection contribute to their pathogenesis.
4. Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group. Ruutu T, Barosi G, Benjamin RJ, Clark RE, George JN, Gratwohl A, Holler E, Iacobelli M, Kentouche K, Lammle B, Moake JL, Richardson P, Socie G, Zeigler Z, Niederwieser D, Barbui T; European Group for Blood and Marrow Transplantation; European LeukemiaNet. Haematologica. 2007; 92:95-100. 
There are no widely accepted criteria for the definition of hematopoietic stem cell transplant -associated microangiopathy (TAM). An International Working Group was formed to develop a consensus formulation of criteria for diagnosing clinically significant TAM. The participants proposed a list of candidate criteria, selected those considered necessary, and ranked those considered optional to identify a core set of criteria.
Three obligatory criteria and four optional criteria that ranked highest formed a core set. In an appropriateness panel process, the participants scored the diagnosis of 16 patient profiles as appropriate or not appropriate for TAM. Using the experts' ratings on the patient profiles as a gold standard, the sensitivity and specificity of 24 candidate definitions of the disorder developed from the core set of criteria were evaluated. A nominal group technique was used to facilitate consensus formation. The definition of TAM with the highest score formed the final proposal.
The Working Group proposes that the diagnosis of TAM requires fulfilment of all of the following criteria: (i) >4% schistocytes in blood; (ii) de novo, prolonged or progressive thrombocytopenia (platelet count <50 x 109/L or 50% or greater reduction from previous counts); (iii) sudden and persistent increase in lactate dehydrogenase concentration; (iv) decrease in hemoglobin concentration or increased transfusion requirement; and (v) decrease in serum haptoglobin. The sensitivity and specificity of this definition exceed 80%.
5. Systemic thrombotic thrombocytopenic purpura (TTP) following unrelated cord blood transplantation. Ferra C, Sancho JM, Xicoy B, Batlle M, Grifols JR, Pujol M, Feliu E, Ribera JM. Leuk Lymphoma. 2006; 47:1173-1175.
TTP is a rare complication which may develop after hematopoietic stem cell transplantation. The authors report what they believe to be the first two cases of TTP after an ablative cord blood transplant.
Patient 1 was a 35-year-old male with Ph+ ALL. The cord blood unit had two serological mismatches in class I antigens, with the remaining A, B and DR antigens being identical at molecular level. Neutrophil and platelet engraftment were achieved on days +13 and +38, respectively. The patient developed grade III aGVHD and prednisone was increased to 2 mg/kg/d. The patient was admitted to the hospital due to persisting diarrhea and abdominal pain, and MMF was added to the treatment. He suddenly presented drowsiness and a CT scan was negative. There was sudden drop in platelet count (9 x 109/L) and hemoglobin (60 g/L). At that time 8% schistocytes were observed on blood smear, serum bilirubin was 27 µmol/L, LDH 927 U/L (N:170-260), haptoglobin 0.23 mg/L (N:0.7-2.7), reticulocyte count 69.2 x 109/L and the direct antiglobulin test was negative. A diagnosis of TTP was made, cyclosporine was discontinued plasmapheresis initiated and defibrotide (10 mg/kg/6hr for 3 days) was given. However, neurological symptoms and laboratory data worsened and the patient died 3 days after the diagnosis of TTP was established.
Patient 2 was a 31 year-old female with AML who underwent an autologous SCT when in first CR. Subsequently, an unrelated CBT was performed using a unit with a serological mismatch in class I antigens while the remaining A, B, and DR antigens were identical at the molecular level. Neutrophil engraftment occurred on days +24. She developed grade III aGVHD and prednisone was given at a dose of 2 mg/kg/day with only a partial response so sirolimus was added to the regimen. Gancyclovir was administered because of a positive CMV antigen test and she developed CMV intestinal disease. Platelet and RBC transfusion requirements increased at that time and she was diagnosed with TTP (10% schistocytes, bilirubin 55 µmol/L, LDH 927 u/L, haptoglobin 0 g/L, reticulocyte count 189.4 x 109/L, negative antiglobulin test). There was no evidence of renal or neurological damage. Cyclosporine was withdrawn, MMF was administered and plasmapheresis was started. She completed 45 plasmapheresis sessions and was finally discharged with only daily prednisone 0.5 mg/kg/d without any evidence of hemolysis. She became platelet and RBC transfusion independent on day +120 and was alive and well 180 days after transplantation.
Factors that have been suggested as predisposing to TTP are: unrelated transplant, GVHD prophylaxis with cyclosporine, increased age, HLA-mismatched transplant, active GVHD, female sex and extensive prior therapy. The diagnosis is sometimes uncertain because of the presence of multiple HSCT-associated complications and the presence of other causes of a low platelet count or a high LDH level. Further, the presence of fragmented cells is common after an allogeneic HSCT.
Management requires urgent intervention with cyclosporine suppression, optimization of immunosuppressive treatment if there is active GVHD and administration of specific treatment (plasma exchange with or without defibrotide).
6. Fatal Hemorrhage from Androgen-Related Hepatic Adenoma After Hematopoietic Cell Transplantation. Ashish R. Kumar, John E. Wagner, Arleen D. Auerbach, James E. Coad, Charles A. Dietz, Sarah J. Schwarzenberg, and Margaret L. MacMillan J Pediatr Hematol Oncol 2004; 26:16-18
Hematopoietic cell transplantation (HCT) is currently the only treatment option with curative potential for Fanconi Anemia. When a suitable HLA-matched sibling donor is not available, patients are often treated with androgenic steroids before considering HCT. Such androgen treatments can lead to the development of hepatic adenomas, which usually regress upon stopping androgen therapy. The authors describe a patient with Fanconi anemia who underwent an unrelated umbilical cord blood transplant with a history of a hepatic adenoma related to androgen therapy. No adenomas were detected on an ultrasound examination prior to HCT. Soon after HCT, he died due to sudden rupture and hemorrhage of a hepatic adenoma. The authors suggest that extra vigilance in the detection and management of hepatic adenomas in indicated in patients treated with androgens, especially prior to HCT.
7. Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: donor type matters. El-Zimaity M, Saliba R, Chan K, Shahjahan M, Carrasco A, Khorshid O, Caldera H, Couriel D, Giralt S, Khouri I, Ippoliti C, Champlin R, De Lima M. Blood 2004;103:4674-4680.
Hemorrhagic cystitis (HC) remains a common complication of allogeneic blood and marrow transplantation. The authors postulated that HC is more prevalent in matched unrelated donor (MUD) and unrelated cord blood (UCB) transplants than in matched related donor (MRD) transplants. Retrospective study on 105 acute lymphocytic leukemia patients treated with 12 Gy total body irradiation based regimens and allogeneic transplants (MUD n=38; UCB, n=15; mismatched related, n=20 MRD, n=32). HC occurred in 16% of patients receiving MRD transplants, 30% of recipients of mismatched related, and 40% of MUD or UCB transplants (Hazard ratio 2.9, 95%CI 1.0-7.9 for the comparison of MRD versus MUD). The authors concluded that HC is more prevalent in MUD and UCB transplants.
