CBF

iii. Immune Cytopenias

  1. Post Transplant Autoimmune Hemolytic Anemia and Other Cytopenias Are Increased in Very Young Babies after Unrelated Donor Umbilical Cord Blood Transplantation. Kristin M. Page, Adam Mendizabal, Paul Szabolcs, Susan Wood, Vinod Prasad, Joanne Kurtzberg Blood 2007;110:319a [Abstract #1054 at the ASH Meeting, December 8-11, 2007]

Over the past 9 years, the authors treated 18 neonates ( 3 months of age at transplant) with Krabbe disease (n=11) metachromatic leukodystrophy (n=1), Tay Sachs disease (n=1), Hurler syndrome (n=2), Hunter syndrome (n=2), and Beta-Thalassemia Major (n=1) with UCBT after myeloablative conditioning therapy with Busulfan, Cyclophosphamide and ATG. All babies received cyclosporine + methylprednisolone (n=16) or cyclosporine + cellcept (n=2) for 9 months post transplant for prophylaxis against GVHD. Engraftment, acute and chronic GVHD, survival, treatment related mortality, and deaths were scored.

Seventeen of the 18 babies were evaluable for engraftment, GVHD, and survival. One baby died before engraftment of pulmonary hypertension day 15 post transplant. The cumulative incidence of overall survival was 94.4% (95% CI 83.9%–100.0%), 88.9 (95% CI 74.4%–100.0%) and 77.8% (95% CI 53.8%–100.0%) at 1, 2, and 5 years, respectively. In these infants receiving very high cell doses from their UCB graft (median total nucleated cell dose of 18.71x107/kg), neutrophil engraftment with an ANC >500/uL occurred at a median of 19 days with a cumulative incidence of engraftment of 94.1% (95%CI 77.9%–100.0%) by 42 days. Platelet engraftment (platelet count of 50K/uL untransfused) occurred in a median of 56 days with a cumulative incidence of engraftment of 94.1% (95%CI 77.8%–100.0%) at 6 months post transplant. Grade I-II acute GVHD occurred in 15/18 infants while one infant developed grade III acute GVHD of skin and gut. The cumulative incidence of grade II-III acute GVHD by day +100 was 29.4% (95%CI 6.9%–51.9%).

Nine of seventeen evaluable patients developed cGVHD manifesting as autoimmune cytopenias with a cumulative incidence of 41.2% (95%CI 16.9%–65.5%) and 52.9% (95%CI 28.0–77.8%) at 1 and 2 years, respectively. In six patients, cGVHD presented as autoimmune cytopenia de novo. No graft factors were identified as being significant to development of cGVHD. All patients responded to treatment with methylprednisolone, azithroprine +/– rituximab. One patient required splenectomy. In contrast, the incidence of cGVHD in a group of otherwise similar older patients was 14.7%.

In conclusion, there was an unexpected and high incidence of cGVHD manifesting primarily as autoimmune hemolytic anemia with other cytopenias, post-UCBT in a population of very young babies. The authors hypothesize that post-transplant immunosuppression interferes with the normal development of the immune system in the first year of life creating immune dysregulation and graft directed cell destruction. After lytic agents to stabilize disease, removal of chronic immunosuppressive therapy appears to facilitate recovery. Alternative strategies to prevent GVHD should be considered for this unique patient population.

  1. Immune hemolysis associated with transplantation. Petz LD. Semin Hematol. 2005;42:145-55.

This article provides a detailed differential diagnosis of hemolysis following hematopoietic cell transplantation. Among causes to be considered are the passenger lymphocyte syndrome following minor ABO incompatible transplants, post-transplant hemolysis after major ABO-incompatible transplants, hemolysis caused by RBC alloantibodies produced by engrafted donor cells or by residual cells of the patient, autoimmune hemolytic anemia, passive transfer of antibody, drug-induced hemolytic anemia, and miscellaneous causes.

Although some of these causes of hemolysis have not yet been reported following cord blood transplantation, case reports of autoimmune hemolytic anemia (AIHA) have appeared (See: citations #4, 5 and 6 below). The mortality of AIHA following HSCT has been high.

This review also discusses the recognition of RBC alloantibodies produced by engrafted cells of the donor's immune system and those produced by residual cells of the patient. These antibodies provide a potential cause of hemolysis, but the incidence of RBC alloantibody formation following HSCT is low.

Although significant adverse effects have frequently been reported after ABO incompatible BM/PBSC transplants, there are no publications devoted to such complications after cord blood transplants. (See Interactive Forums for Medical Professionals from the navigation bar in left column of Home Page). In particular, although the passenger lymphocyte syndrome is a well recognized and important syndrome following BMT/PBSCT, it has not yet been reported following cord blood transplantation. This may be due to the fact that the incidence and severity of the syndrome is related to the lymphoid content of the graft. The higher lymphoid content of PBSCs compared to conventional marrow harvests may be the explanation for the higher incidence and greater severity of the passenger lymphocyte syndrome after PBSC transplantation than after BMT.

One complication that would be expected to occur regardless of the source of stem cells is delayed hematopoiesis, particularly delayed erythropoiesis following major ABO incompatibility (e.g., donor, group A; recipient, group O). This is true because the cause of the delayed onset of hematopoiesis is the reaction of the ABO-antibody in the patient's serum versus newly engrafting hematopoietic cells. One would expect the antibody to react with the engrafting cells regardless of their source. Nevertheless this complication has not been reported following cord blood transplantation.

(Comment: For further information on Immune Hemolysis Associated with Transplantation see Annotated Bibliography XXII. BOOKS, citation #7, Chapter 12. For reviews of this book, click HERE.)
  1. Cold agglutinin disease associated with adenovirus infection after allogeneic bone marrow transplantation. Mori T, Yamada Y, Aisa Y, Uemura T, Ishida A, Ikeda Y, Okamoto S. Bone Marrow Transplant. 2005;36:263-4.

The authors describe a patient with cold agglutinin disease (CAD) that occurred in a 39 year old female who underwent allogeneic BMT from her one human leukocyte antigen (HLA) mismatched, ABO-matched sister. On day 240 she developed macroscopic hematuria accompanied by urinary urgency and adenovirus (type 11) was detected in her urine, leading to the diagnosis of adenovirus hemorrhagic cystitis. At this time her blood tests showed a rapidly progressing anemia (hemoglobin level decreased from 10.1 to 5.2 g/dL over 6 days) with marked reticulocytosis (13.1%), serum LDH of 651 IU/l. The direct antiglobulin test was strongly positive due to C3d sensitization of her cells. The cold antibody reacted up to 30°C and had the characteristics of an anti-Pr antibody. She was treated with a transfusion and corticosteroids in addition to avoiding cold exposure. Corticosteroid was tapered after a 2-week administration, and cold agglutinin was no longer detected in the patient's serum 3 months after the onset of hemolysis. The authors suggest that the cold agglutinin disease may have been caused by the adenovirus infection, since CAD is know to be associated with other infectious disorders, notably mycoplasma pneumonia and infectious mononucleosis. The only two previous case reports of CAD associated with anti-Pr antibody occurred in association with infectious events, pericarditis and cytomegalovirus infection, respectively.

(Comment: Although this case occurred after BMT and not cord blood transplantation, it is of significance since the benign course in this case contrasts with other cases of post-transplant AIHA. This lends some credence to the authors' suggestion that the case was caused by the infection rather than because of a deranged immune system following transplantation.)
  1. Unrelated umbilical cord blood transplantation in infancy for mucopolysaccharidosis type IIB (Hunter syndrome) complicated by autoimmune hemolytic anemia. Mullen CA, Thompson JN, Richard LA, Chan KW. Bone Marrow Transplant. 2000;25:1093-7.Abstract

Nine months after an unrelated umbilical cord blood transplantation for mucopolysaccharidosis IIB (Hunter syndrome), the patient developed severe autoimmune hemolytic anemia and required 14 months of corticosteroid treatment to prevent clinically significant anemia. Two years after transplant approximately 55% normal plasma enzyme activity has been restored and abnormal urinary excretion of glycosaminoglycans has nearly completely resolved. The boy has exhibited normal growth and development after transplant.

In addition to reporting this patient, the authors review hematopoietic cell transplantation for Hunter syndrome and post-transplant hemolytic anemia.

  1. Autoimmune haemolytic anaemia complicating haematopoietic cell transplantation in paediatric patients: high incidence and significant mortality in unrelated donor transplants for non-malignant diseases. O'Brien TA, Eastlund T, Peters C, Neglia JP, Defor T, Ramsay NK, Scott Baker K. Br J Haematol. 2004;127:67-75.

Data from adult hematopoietic cell transplant patients suggests that post-transplant autoimmune hemolytic anemia (AIHA) occurs in approximately 3-5% of patients, which far exceeds the expected incidence of AIHA in the non-transplant setting, which is one or two cases per 100,000 population. Between January 1995 and July 2001, 439 consecutive allogeneic HCT were performed in pediatric patients at the University of Minnesota, 31% (n = 136) from related donors (RD) and 69% (n = 303) from unrelated donors (URD). Nineteen cases of AIHA were identified with documented significant hemolysis and a positive direct antiglobulin test. All cases of AIHA occurred in URD transplants, yielding a cumulative incidence of post-transplant AIHA in this population of 6% at 1 year. Patients transplanted for non-malignant disease, particularly metabolic diseases, had a higher incidence of AIHA post-HCT when compared with patients transplanted for malignancies (RR 4.2, 95% CI 1.2-15.4, P = 0.01). Nine of the 16 patients who developed AIHA had received a cord blood transplant (Umbilical cord blood transplants are commonly performed at the University of Minnesota with over 100 URD transplants in this series being from umbilical cord blood). However, stem cell source (BM vs cord blood), donor/recipient blood group matching, recipient CMV serostatus, T-cell depletion, development of aGVHD and conditioning regimen were not identified as risk factors for the development of AIHA.

Mortality was high with 10 of 19 patients (53%) dying following the onset of AIHA, three as a direct consequence of hemolysis. By Cox regression analysis, patients developing AIHA were twice as likely to die when compared with patients who did not develop AIHA. The majority of patients received multi-agent therapy for AIHA. Fifty per cent of deaths occurred from infection while on immunosuppressive therapy to treat hemolysis. One of three patients treated with rituximab therapy showed response.

The authors concluded that AIHA is a transplant complication that can be refractory to many standard therapies and carries a high mortality rate.

(Comment: For further information on Immune Hemolysis Associated with Transplantation see Annotated Bibliography XXII. BOOKS, citation #6, Chapter 12. For reviews of this book, click HERE.
  1. Acute autoimmune hemolytic anemia following unrelated cord blood transplantation as an early manifestation of chronic graft-versus-host disease. Sevilla J, Gonzalez-Vicent M, Madero L, Diaz MA. Bone Marrow Transplant. 2001;28:89-92. Abstract

A 16-month-old girl diagnosed with osteopetrosis underwent an unrelated, partially matched cord blood stem cell transplant. Twelve months later she developed severe acute autoimmune hemolytic anemia (AIHA). Immunophenotype analysis of lymphocyte subsets 8 months post transplant showed a low number of T lymphocytes, with normal subsets, and with NK cells and B lymphocytes within normal ranges. When the hemolytic anemia developed, the lymphocytes subsets changed and analysis showed higher numbers of B lymphocytes than previously, lower CD3+ T lymphocytes with inversion of the CD4/CD8 ratio and an abnormal proportion of T lymphocyte subsets. She was treated with cyclosporine, steroids and immunoglobulins and initially the AIHA improved, but repeated infectious episodes led the authors to tail off the immunosuppressive treatment. The AIHA relapsed and cyclosporine was restarted. Currently, she is on cyclosporine and low-dose steroid treatment with no hemolytic features. During the 3 months when the AIHA was being treated, she developed extensive skin cGVHD and recurrent pneumothoraces.

  1. Autoimmune hemolytic anemia following allogeneic hematopoietic stem cell transplantation in adult patients. Sanz J, Arriaga F, Montesinos P, Ortí G, Lorenzo I, Cantero S, Puig N, Moscardó F, de la Rubia J, Sanz G, Sanz MA. Bone Marrow Transplant. 2007;39:555-561.

Autoimmune hemolytic anemia (AIHA) after allogeneic hematopoietic stem cell transplantation (HSCT) is still not well characterized. The aim of this study was to analyze the incidence and risk factors for the development of AIHA, as well as its prognosis and response to treatment in a series of patients undergoing allogeneic HSCT at a single institution.

Between 1996 and 2004, 272 adult patients with a variety of malignant hematopoietic disorders underwent allogeneic HSCT. Direct antiglobulin testing was performed in routine pretransfusion compatibility testing or after clinical suspicion of AIHA.

Twelve patients developed AIHA after HSCT at a median time of 147 days (range, 41-170). The 3-year cumulative incidence of AIHA was 4.44%. Eight cold antibodies and four warm antibodies were detected. Multivariate analysis shows that HSCT from unrelated donors (P=0.02) and the development of chronic extensive graft-versus-host disease (GVHD) (P=0.0004) were the only independent factors associated with AIHA. Two patients are still alive. AIHA was never the primary cause of death but added morbidity in patients with other concomitant complications.

  1. Rituximab is effective in the management of refractory autoimmune cytopenias occurring after allogeneic stem cell transplantation. Raj K, Narayanan S, Augustson B, Ho A, Mehta P, Duncan N, Tauro S, Mahendra P, Craddock C, Mufti G. Bone Marrow Transplant. 2005;35:299-301.

Management of autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP) and autoimmune neutropenia (AIN) occurring after allogeneic hematopoietic cell transplantation is unsatisfactory since they frequently prove refractory to conventional therapies including splenectomy. Accordingly, they are associated with substantial morbidity and mortality. Previous reports have described these complications only after myeloablative conditioning regimens.

The authors report four patients who developed AIHA or ITP after allogeneic transplantation -- three of which occurred after a reduced-intensity conditioning regimen. All patients demonstrated a complete response to Rituximab, having failed to respond to conventional treatment including high-dose prednisolone and intravenous immunoglobulin. The authors indicate that Rituximab can be a valuable agent in the management of autoimmune cytopenias occurring after allogeneic hematopoietic cell transplantation, and that autoimmune cytopenias may be a hitherto unrecognized complication of reduced intensity conditioning regimens.