Selective ABO immunoadsorption in hematopoietic stem cell transplantation with major ABO incompatibility.

OBJECTIVE: ABO mismatch between donor and recipient occurs in 40% of allogeneic hematopoietic stem cell transplantations (HCT). Different strategies have been described to reduce isohemagglutinins (IHA) before HCT. We describe the effect of selective ABO immunoadsorption (ABO IA) on erythrocyte transfusion rate and the development of post-transplant pure red cell aplasia (ptPRCA). METHODS: 63 patients with major ABO incompatibility were retrospectively analyzed. Nine patients with major ABO incompatibility and high-IHA titer were treated by ABO IA before HCT. We analyzed the need for transfusion and the occurrence of ptPRCA. We compared the outcome with patients treated by other methods to reduce IHA. RESULTS: In all nine patients treated by ABO IA, IHA decreased in a median four times. PtPRCA occurred in one patient. The median number of transfusions was 8 (range: 0-36) between d0 and d100. In 25 patients with high-IHA titer without treatment or treated by other methods to reduce IHA, the need for transfusions was comparable. No difference in the incidence of ptPRCA was observed. CONCLUSIONS: Selective ABO IA is a feasible, safe, and effective method to reduce IHA before HCT in major ABO incompatibility. No effect on transfusion rate or ptPRCA compared to other strategies could be observed.

Treatment for pure red cell aplasia after major ABO-incompatible allogeneic stem cell transplantation: a multicentre study.

Pure red cell aplasia (PRCA) following allogeneic haematopoietic stem cell transplantation (aHSCT) with major ABO incompatibility is responsible for transfusion dependent anaemia, impaired quality of life and iron overload. We conducted a retrospective study, over a 10-year period, which included all consecutive patients who received a major ABO mismatched aHSCT, to assess the impact of specific treatment on PRCA. We did not observe any PRCA in the 57 aHSCT issued from cord blood. Among the remaining 631 patients, cumulative incidence of PRCA was 10·5% [range 8·2-13.0]. The median duration of resolved PRCA was 171 days [IQR 116; 261]. Pre-transplant high isohaemagglutinins titre was associated with an increased risk of PRCA (P < 10-4 ). PRCA did not affect overall survival (P = 0·95). Twenty-two patients (33·3%) received at least one specific treatment. The most commonly used treatments were rituximab (17 patients) and donor lymphocyte infusion (DLI; seven patients). Regarding PRCA resolution, we did not observe a significant difference between treated or untreated subjects (HR = 0·93, 95% confidence interval (CI) 0·48- 1·80; P = 0·82). Similar results were observed with erythropoietin treatment (22 patients, HR = 0·86 95% CI: [0·47-1·57] P = 0·62). Our data do not support the use of erythropoietin, rituximab or DLI for the treatment of PRCA.

Impact of Day 14 Peripheral Blood Chimerism after Allogeneic Hematopoietic Stem Cell Bone Transplantation on the Treatment Outcome of Non-Malignant Disease.

BACKGROUND: The impact of early peripheral blood chimerism on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unclear. We aimed to determine whether day 14 peripheral blood chimerism after allo-HSCT predicts outcomes in patients with non-malignant diseases. METHODS: Data from 56 patients who received allo-HSCT between April 2007 and March 2016 were retrospectively analyzed. Chimerism was evaluated using short-tandem repeat polymerase chain reaction, with mixed chimerism (MC) defined as greater than 1% recipient cells which was further categorized into low-level MC (> 1% and < 15% of recipient-derived cells) and high-level MC (≥ 15% of the recipient-derived cells). RESULTS: Thirty-six patients showed complete donor chimerism (CC), 14 low-level MC, and 6 high-level MC at day 14 post-transplant. The estimated 5-year event-free survival (EFS) was higher in the CC or low-level MC groups than in the high-level MC group (86.1% vs. 71.4% vs. 33.3%; P = 0.001). In BM or peripheral blood stem cell (BM/PBSC) transplants, the 5-year EFS was higher in the CC or low-level MC group than in the high-level MC group (93.1% vs. 66.7% vs. 0%; P < 0.001). However, in cord blood transplants, the 5-year OS and EFS according to the day 14 peripheral blood chimerism did not reach statistical significance. CONCLUSION: Although CC is not always necessary after allo-HSCT for non-malignant diseases, our data suggest that day 14 peripheral blood chimerism may predict outcomes in patients with non-malignant diseases who underwent BM/PBSC transplants.

Pure Red Cell Aplasia in Major ABO-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation Is Associated with Severe Pancytopenia.

In major ABO-mismatched allogeneic hematopoietic stem cell transplantation (HSCT) persistence of antidonor isohemagglutinins leads to pure red cell aplasia (PRCA). To investigate severe pancytopenia noted in a previous study of PRCA, we analyzed all major ABO-mismatched HSCT between January 2003 and December 2012. Of 83 PRCA patients, 13 (16%) had severe pancytopenia. Severe pancytopenia was defined as an absolute neutrophil count (ANC) < 1.5 K/µL or requiring granulocyte colony-stimulating factor, platelets < 50 K/µL or transfusion dependent, and PRCA with RBC transfusion dependence at post-transplant day 90. In 6 patients (46%) severe pancytopenia resolved after PRCA resolution. Two patients (15%) received a second transplant because of persistent pancytopenia/secondary graft failure, 1 (8%) died from secondary graft failure despite a stem cell boost, 1 (8%) did not recover his platelet counts despite RBC/ANC recovery, and 3 patients (23%) died from disease relapse. We found that severe pancytopenia is frequently associated with PRCA in 16% of major ABO-incompatible HSCT with a higher incidence in males and pancytopenia resolved with resolution of PRCA in 46% of patients.

Long-term outcome of patients with acquired chronic pure red cell aplasia (PRCA) following immunosuppressive therapy: a final report of the nationwide cohort study in 2004/2006 by the Japan PRCA collaborative study group.

Immunosuppressive therapy has been employed as the initial treatment for acquired chronic pure red cell aplasia (PRCA), such as idiopathic, thymoma-associated, or large granular lymphocyte (LGL) leukaemia-associated PRCA, which is thought to be immune-mediated. To explore the overall long-term outcome following immunosuppression and to identify the risk factors for death in these disorders, we conducted nationwide surveys in Japan 2004 and 2006, and identified a total of 185 patients with acquired chronic PRCA, including 72 idiopathic, 41 thymoma-associated and 14 LGL leukaemia-associated cases of PRCA for whom data was available. The present study evaluated 127 patients with these three subsets of PRCA. The median overall survival has not yet been reached in idiopathic PRCA. The estimated median overall survival times in patients with thymoma-associated and LGL leukaemia-associated PRCA were 142·1 and 147·8 months, respectively. Twenty-two deaths were reported, and the response to induction therapy and relapse of anaemia were found to be associated with death. The major causes of death were infection in seven patients and organ failure in another seven patients. The results suggest that maintenance therapy and the management of infectious complications are crucial for improving the prognosis of chronic PRCA.

Efficacy and long-term outcome of treatment for pure red cell aplasia after allogeneic stem cell transplantation from major ABO-incompatible donors.

No standard of care for pure red cell aplasia (PRCA) after major ABO-incompatible hematopoietic stem cell transplantation (HSCT) has been established. We conducted a retrospective cohort study to learn the efficacy and outcome of treatment for PRCA. One hundred forty-five recipients who showed delayed recovery of erythropoiesis and survived >100 days after transplantation without early disease progression were selected from 2846 records of major ABO-incompatible transplantation in the registry database in Japan, and detailed data of 46 recipients were collected. Treatment of PRCA, such as rapid tapering of calcineurin inhibitors, corticosteroids, or additional immunosuppressants, was given to 22 patients but not to the other 24 patients. The overall response rate of the treatment group was 54.5%. The number of days from diagnosis of PRCA to recovery of reticulocytes >1% and the cumulative number of red blood cell transfusions were not significantly different between the 2 groups. Infections accounted for the death of 7 of 11 patients in the treatment group. Univariate analysis identified 5 variables influencing survival, including graft-versus-host disease, disease progression, and treatment of PRCA; disease progression remained as the only factor negatively affecting survival by multivariate analysis. The present study could not provide supportive evidence for the beneficial effects of treatment for PRCA after major ABO-mismatched HSCT.

Rituximab-cyclophosphamide-dexamethasone combination in the management of autoimmune cytopenias associated with chronic lymphocytic leukemia.

We report our experience on rituximab-cyclophosphamide-dexamethasone (RCD) combination therapy for the treatment of autoimmune disorders (AIDs) in 48 chronic lymphocytic leukemia (CLL) patients. Overall, 81% of patients were relapsing for AID after previous treatment with corticosteroids, splenectomy, rituximab or alemtuzumab. Diagnosis of AID was autoimmune hemolytic anemia (AIHA) in 26 (54%), autoimmune thrombocytopenia (AITP) in 9 (18.8%), Evan's syndrome in 8 (16.7%) and pure red cell aplasia (PRCA) in 5 patients (10.5%). Median time of autoimmune disorder (AID) onset from CLL diagnosis was 60 months (range: 0-240), and CLL was considered progressive in 40% of subjects upon AID diagnosis (complex AID). Median hemoglobin pre-treatment was 7.7 g/100 ml, and median platelet count 36.5 × 10(9)/l, returning to a median of 12.5 /100ml and 37.5 × 10(9)/l, respectively. Overall, an 89.5% response rate was obtained with this combination, irrespective of the AID type. Relapse occurred in 19 patients (39.6%). Median duration of response for autoimmunity (DR-AI) was 24 months, but DR-AI was higher for patients presenting: (1) AID early during CLL course (<3 years), or (2) both PRCA and AIHA. Median time to CLL progression in 48 patients was 16 months, but this time was statistically shorter for Evan's syndrome and AITP patients as compared with AIHA and PRCA patients. This study emphasizes the relevance of CLL-directed immune chemotherapy in the management of CLL-associated AID.

Diagnosis and management of autoimmune complications of chronic lymphocytic leukemia/ small lymphocytic lymphoma.

Autoimmune cytopenia is an important but poorly understood clinical complication of chronic lymphocytic leukemia/ small lymphocytic lymphoma. We review the pathogenesis, clinical presentation, and management of autoimmune hemolytic anemia, immune thrombocytopenia, and pure red blood cell aplasia in patients with chronic lymphocytic leukemia/ small lymphocytic lymphoma.

Long-term outcome of patients with acquired primary idiopathic pure red cell aplasia receiving cyclosporine A. A nationwide cohort study in Japan for the PRCA Collaborative Study Group.

BACKGROUND AND OBJECTIVES: Cyclosporine A (CsA) has become one of the leading agents for the treatment of pure red cell aplasia (PRCA). However, further studies are necessary to determine the relapse-free survival (RFS) and overall survival (OS) of patients treated with this drug, the minimum duration of therapy for induction of remission, and whether or not there is need for maintenance treatment. DESIGN AND METHODS: We conducted a nationwide survey in Japan. From a total of 185 patients (with 73 primary idiopathic PRCA and 112 with secondary PRCA), we evaluated 62 patients with primary idiopathic PRCA for this report. RESULTS: The remission induction therapy for these patients included CsA (n=31), corticosteroids (CS) (n=20) or other drugs (n=11). CsA and CS produced remissions in 23 (74%) and 12 (60%) patients, respectively. The salvage treatment produced remissions in 58 patients (94%). Forty-one and 15 patients were maintained on CsA+/-CS (CsA-containing group) or CS alone (CS group), respectively. The median RFS in the CsA-containing group was 103 months, longer than that seen in the CS group (33 months) (p<0.01). Of 14 patients whose CsA was discontinued, 12 patients (86%) relapsed after a median of 3 months (range 1.5 to 40 months), while only 3 of 27 patients (11%) relapsed during CsA-containing maintenance therapy. Thus, the discontinuance of maintenance therapy was strongly correlated with relapse (p<0.001). Four patients in the CsA-containing group died; however, the OS of this group was not significantly different from that of the CS-groups (p=0.104). INTERPRETATION AND CONCLUSIONS: CsA-containing regimens sustain prolonged RFS more effectively than CS in primary idiopathic PRCA and seem to be important to prevent relapse.

Pure red-cell aplasia following major and bi-directional ABO-incompatible allogeneic stem-cell transplantation: recovery of donor-derived erythropoiesis after long-term treatment using different therapeutic strategies.

Blood group incompatibility between donor and recipient of allogeneic stem cell transplants may be associated with post-transplant erythroid aplasia. A total of 548 patients (pts) received allogeneic transplant for malignant and non-malignant hematologic disorders. In a retrospective analysis, the prevalence and outcome of pure red-cell aplasia (PRCA) in 44 pts with major and bi-directional ABO-mismatch were investigated. Bone marrow grafts were major ABO incompatible in 30 pts; there was bi-directional mismatch in the remaining 14 pts. The median number of transplanted mononuclear cells (NC) was 4.74 x 10(8)/kg (range 0.1-26.4) including CD34+ cells, 3.02 x 10(6)/kg (range 0.9-21.7). Granulocyte engraftment >0.5 x 10e9/l occurred after a median of 21 days (7-32), and platelet exceeded >50 x 10e9/l after a median of 23.5 days (12-109). Acute and chronic graft vs host disease (GVHD) developed in 23 (52%) and 26 (59%) of the patients, respectively. Six (13%) patients transplanted with major and bi-directional ABO-incompatibility developed PRCA. The treatment of PRCA consisted of plasmapheresis (PEX), rapid cyclosporine (CsA) discontinuation, donor lymphocyte infusions (DLI), erythropoietin (EPO), azathioprine, and rituximab. The therapy resulted in erythroid recovery in five out of six patients after a median of 13 months (range 3-16). The median number of transfused red blood cells (RBCs) was 36 U (range 8-57). With a median follow-up of 37 months, the 5-year probability of overall survival (OS) for the PRCA group was 66%. Major ABO mismatch may lead to delayed donor erythroid engraftment. It results in long-term transfusion dependence and, therefore, the risk of iron overload. The therapy is long lasting, but usually effective in majority of patients.

Second hematopoietic stem cell transplantation in pediatric patients: overall survival and long-term follow-up.

Despite potent intensive conditioning regimens, hematopoietic stem cell transplantation (HSCT) may fail because of either relapse of the malignancy or the rejection of the graft. We report on 27 pediatric patients who received a second HSCT from an allogeneic donor for relapsed malignancy or graft failure. One-year, 5-year, and 10-year probabilities of survival for all patients were 53%, 36%, and 24%, respectively. Twenty patients received second HSCTs for relapsed malignancy, of whom 6 were alive and disease free at the time of this report. Seven patients received a second HSCT for graft failure, of whom 3 were alive and well as of this report. Twenty-five patients were tested for immune reconstitution following their second HSCT. Sixteen patients developed antigen-specific T-lymphocyte responses; the median time to development of antigen-specific responses was 13 months. There was no significant neurocognitive decline in patients tested 1 to 3 years following their second HSCT. Endocrine evaluations revealed deficiencies in growth hormone (7 patients), gonadal function (3 patients), and thyroid function (2 patients). Three patients developed significant abnormalities of tooth development, including absence of secondary teeth. These results show that a second HSCT offers curative therapy for selected pediatric patients whose first HSCT failed. Although toxicity is considerable following a second transplantation, the major causes of mortality continue to be relapse and infection.

Resolution of organ-specific complications of human immunodeficiency virus infection in children with use of highly active antiretroviral therapy.

Opportunistic infections are a major source of morbidity and mortality in children and adults infected with human immunodeficiency virus (HIV). In addition, organ-specific complications of HIV infection, such as cardiomyopathy, nephropathy, encephalopathy, and others, contribute substantially to the morbidity and mortality associated with HIV infection. Highly active antiretroviral therapy (HAART) has produced a dramatic decline in the incidence of opportunistic infections among patients with HIV infection. Nevertheless, there is very little information concerning the value of HAART for organ-specific complications of HIV infection. In this report, we describe 3 children with HIV infection in whom the dominant clinical manifestations were cardiomyopathy, red cell aplasia, and nephropathy. HAART produced a decrease in the HIV ribonucleic acid level, an increase in the CD4 cell count, and resolution of the organ-specific complications in all patients. These cases add to our knowledge concerning the benefits of HAART for children with HIV infection.

[High-dose immunoglobulin therapy of aplastic syndrome]. / Hochdosis-Immunglobulin-Therapie aplastischer Syndrome.

Idiopathic pure red-cell aplasia was successfully treated by high-dose intravenous immunoglobulin infusions (HDivIg) in 2 patients; 1 of these patients was refractory to other immunosuppressive drugs. We have observed responses to this therapy also in 3 of 5 patients--without pretreatment--with severe aplastic anemia. HDivIg treatment had no significant side effects; patients with aplastic syndromes could be treated as outpatients. Patients responding to HDivIg demonstrated different response patterns to ciclosporin A. Sequential treatment of aplastic syndromes with high-dose prednisone, HDivIg and ciclosporin A was effective in 6 of 7 patients. The results in this pilot study are comparable to those with other immunosuppressive strategies in patients with severe aplastic anemia who lack a bone marrow donor. Optimal dosage, sequence, and duration of this treatment modality remain to be defined.

Thymomas associated with pure red cell aplasia. Histologic and follow-up studies.

Seventeen cases of pure red cell aplasia (PRCA) with thymoma were studied clinically, histologically, and immunologically. Two cases were associated with myasthenia gravis (MG), and three with hypogammaglobulinemia. Coombs test and antinucleus antibody test were positive in five cases. All thymomas were spindle cell types, and the adjacent thymuses had no germinal center, but showed epithelial clusters frequently. All patients, except one whose tumor was unresectable, had thymo-thymomectomy. The operation was effective in six cases (37.5%), and the effects were not different between two operative procedures (simple and extended thymectomy). Myasthenic symptoms in two patients remitted after the operation, but effects on hypogammaglobulinemia were conincident with those on PRCA.