P. Knöbl

Treatment of coagulation inhibitors with extracorporeal immunoadsorption (Ig-Therasorb)

Coagulation inhibitors may occur as alloantibodies in patients with congenital factor deficiencies or as autoantibodies in patients with a previously normal coagulation. We treated 10 patients with factor VIII inhibitors (three haemophiliacs and seven patients with acquired factor VIII inhibitors) and one patient with a factor V inhibitor using extracorporeal immunoadsorption to immobilized antibodies against human immunoglobulins (Ig‐Therasorb). The initial inhibitor titre was between 18 BU/ml and 540 BU/ml. Nine patients had signs of bleeding. Eighty‐nine immunoadsorption sessions were performed in the 11 patients (8·1 ± 5·1 per patient), each processing 6980 ± 880 ml of plasma in 3·8 ± 0·5 h. The mean reduction of the inhibitor titre was 71·9 ± 19·4% per session. Serum IgG, IgA and IgM levels decreased by 68·7 ± 10·1%, 55·7 ± 12·7% and 48·6 ± 11·1% respectively. In two haemophiliac patients, an initial titre reduction prior to an immune tolerance protocol was performed. Another haemophiliac patient was treated because of acute cerebral bleeding. In six out of eight patients with acquired inhibitors, a durable elimination was achieved within a median of 18 d. Treatment was safe and well‐tolerated and seems to be a promising method in the treatment of patients with coagulation inhibitors, especially when a fast inhibitor titre reduction is necessary.

Regeneration of erythropoiesis after related- and unrelated-donor BMT or peripheral blood HPC transplantation: a major ABO mismatch means problems.

BACKGROUND: Blood group incompatibility in allogeneic BMT is common but does not appear to affect the outcome in terms of incidence of graft rejection or delayed engraftment. However, major ABO incompatibility may be associated with prolonged erythroid aplasia.

Duration of second complete remission in patients with acute myeloid leukemia treated with chemotherapy: a retrospective single-center study

Abstract A total of 168 patients with de novo AML were retreated with chemotherapy at relapse following first CR; 66 patients (39%) achieved a second complete remission (CR). The probability of achieving a second CR was highly dependent on the duration of the first remission. Patients who received no or conventional postremission chemotherapy after second CR had a median remission duration of 7.5 months, and the probability of remaining in remission at 3 years was 24%. Patients with a first CR of more than 12 months had a median second remission duration of 18 months. The probability of a second CCR was 35% at 3 years and 24% at 5 years, whereas none of the patients with a first CR of less than 12 months was in remission at 3 years. Only a poor correlation (p=0.31) was found when the durations of the first and second CR were compared in patients with a second relapse. Patients with long-lasting remissions and long-term survivors after second CR are characterized by a first CR duration of >12 months and favorable or normal cytogenetics. The type of salvage treatment seems to be less important for achievment of long-term remission, but it is probably important to administer consolidation chemotherapy after second CR. Other so-far ill-defined factors may be responsible for the supression of the leukemic clone in patients with long-lasting remissions following chemotherapy for relapse after second CR.

FLAG (fludarabine, cytosine arabinoside, G-CSF) for refractory and relapsed acute myeloid leukemia.

Abstract Twenty-two patients with refractory or relapsed AML were treated with FLAG [25 mg/m2 fludarabine daily (days 1–5), 2 g/m2 daily Ara-C (days 1–5) and 400 μg/m2 daily G-CSF (day -1 till the absolute neutrophil count was >500/μl)]. Median age was 46 years (range 24–63). Eight patients had leukemia which was primarily refractory to conventional regimens, six were in first, seven were in second, and one was in third relapse.Overall, 11 of 22 (50%) patients achieved complete remission (CR), three had a partial response (PR), and seven did not respond (NR). One patient died of an early cerebral hemorrhage. The median remission duration from achievement of CR after FLAG was 9.9 months and median survival was 13.0 months. One patient is alive in CR at 31.9 months. Hematological toxicity of the regimen was severe. The median time to neutrophil recovery (ANC >500/μl) was 21 days (range 18–33). A median of seven red cell units (range 0–22) and of six platelet concentrate units (range 3–28) had to be given. Median duration of febrile neutropenia was 2 days (range 0–20 days) and patients were on i.v. antibiotics for a median of 16 days (range 0–51). There was no death from infection. Nonhematological toxicity was remarkably low, with almost no neurotoxicity and no major hepatotoxicity. In conclusion, FLAG seems to be an efficient and well tolerated regimen. It may be particularly useful for patients who have a sibling or unrelated donor for subsequent allogeneic bone marrow transplantation.

Specificities of anti‐platelet antibodies in multitransfused patients with haemato‐oncological disorders

The clinical condition and the formation of platelet‐reactive antibodies influence the post‐transfusion platelet increment. We analysed the specificities of platelet‐reactive antibodies in 81 multitransfused patients with haemato‐oncological diseases refractory to platelet transfusions, or prior to a scheduled stem cell transplantation. In 17 additional patients we prospectively determined the development of platelet‐reactive antibodies at the time of chemotherapy in weekly intervals. Sera were tested by the monoclonal antibody‐specific immobilization of platelet antigens (MAIPA)‐technique for antiplatelet antibodies against HLA class I antigens, the human platelet‐specific alloantigens (HPA)‐1, ‐2, ‐3, ‐5, and the platelet membrane glycoproteins (GP) Ia/IIa, Ib/IX, IIb/IIIa (panreactive).

Replacement therapy for a homozygous protein C deficiency-state using a concentrate of human protein C and S

A severe congenital deficiency of protein C was diagnosed in a 10‐month‐old girl who had been suffering from skin necrosis since the age of 7 months. The patient was treated initially with fresh frozen plasma, 10 ml per kg body weight, every 24 h. Following treatment, the mean plasma level of protein C was 0.1 U/ml after 30 min and less than 0.02 U/ml after 24 h. The child was then treated with a concentrate of human protein C and S, 100 U protein C per kg body weight, given every 48 h for a period of 9 months. The mean plasma level of protein C was 0.93 U/ml 30 min after administration of the concentrate and 0.13 and 0.08 U/ml after 24 and 48 h, respectively. The mean post‐transfusional in vivo recovery of protein C was 44% and the half life was 8.3 h. The mean plasma level of ‘free’protein S increased from 1.1 to 2.2 U/ml after administration of the concentrate. There was no increase in ‘bound’protein S. The in vivo recovery of ‘free’protein S was 49% and the half life was about 17 h. Since the start of this replacement therapy using a human protein C and S concentrate, the patient has not developed any thromboembolic complications. These results indicate the therapeutic value of human protein C and S concentrate in the treatment of severe protein C deficiency.

Factors affecting long-term outcome after allogeneic haematopoietic stem cell transplantation for acute myelogenous leukaemia: a retrospective study of 172 adult patients reported to the Austrian Stem Cell Transplantation Registry.

Summary. Between 1982 and 2000, 172 patients with acute myelogenous leukaemia (AML) received haematopoietic stem cell transplants (SCT) from related (n = 132) or unrelated (n = 40) donors at four Austrian transplant centres and their results were reported to the Austrian Stem Cell Transplantation Registry. Conditioning for SCT consisted of cyclophosphamide and total body irradiation in 156 (91%) patients. Graft‐versus‐host disease (GVHD) prophylaxis was with standard cyclosporine and methotrexate in 95 (55%) patients. Median post‐transplant follow‐up was 5·6 years (range, 0·2‐‐16·7). Multivariate analysis of transplant‐related mortality (TRM) identified four variables associated with a lower risk: disease status of first complete remission (CR) at SCT, patient age of 45 years and younger, transplant performed during or after 1995, and lack of acute GVHD. Variables associated with significantly improved leukaemia‐free survival were: bone marrow as the stem cell source, disease status of first CR at SCT, and occurrence of chronic GVHD. In multivariate analysis, transplantation performed during or after 1995, first CR at SCT, occurrence of limited chronic GVHD and lack of acute GVHD grades III to IV were associated with increased overall survival. Based on these analyses, options for the improvement of results obtained with allogeneic SCT in patients with AML could be defined.

Spontaneous remission of acute myeloid leukemia after infection and blood transfusion associated with hypergammaglobulinaemia

Abstract Spontaneous remissions of acute myeloid leukemia (AML) have been documented in association with infection as well as blood transfusions. Activation of the immune system including an increased number of NK cells and cytokine release have been implicated in the mechanism of this phenomenon. We have observed spontaneous remissions in two patients with AML (one with a t(8;21)-positive M2, one with M5b), both occurring after infection and blood transfusions. The bone marrow showed a reduction of blast cells from 65% to 2% or 40% to 1%, respectively. Remission was accompanied by a marked polyclonal hypergammaglobulinemia in both cases (IgG values of 6420 and 2160 mg/dl, IgA of 802 and 811 mg/dl, respectively). A concomitant increase in bone marrow plasma cells was observed in both patients. Reduction of AML1/ETO PCR positivity from one-step to two-step PCR (approximately 100-fold) was documented in the patient with a t(8;21), while a regression of lymph node and skin leukemic infiltrations occurred in the patient with M5b. One patient relapsed after 4 months, at a time when his serum immunoglobulin levels had markedly decreased. The other patient is in continuous remission after 14 months. These cases suggest a potential role for a humoral immune response in the mechanism of spontaneous remission.

Platelet-reactive HLA antibodies associated with low posttransfusion platelet increments:a comparison between the monoclonal antibody-specific immobilization of platelet antigens assay and the lymphocytotoxicity test

BACKGROUND: Platelet‐reactive HLA antibodies are a major reason for low posttransfusion platelet increments. The clinical importance and value of the test systems for their in vitro determination is still controversial.

Extracorporeal Immunoadsorption for the Treatment of Haemophilic Patients with Inhibitors to Factor VIII or IX

Background and Objectives:This article reviews the relevance of immunoadsorption in the treatment of haemophilic patients with inhibitors. Materials and Methods: Immunosorba (sepharose–bound staphylococcal protein A) and Ig–Therasorb (sepharose–bound polyclonal sheep antibodies to human immunoglobulin) columns are suitable for the clinical use of immunoadsorption. They allow the processing of large plasma volumes (>7,000 ml) without relevant side–effects. Results: A haemophilic patient was treated with the Malmö protocol, another was admitted with intracerebral bleeding. Immunoadsorption reduced the inhibitor titer by 70–90%. Conclusions: Immunoadsorption can be used in cases of acute bleeding, before surgery, acquired factor VIII (FVIII) antibodies, and before the start of immune tolerance therapy. We suggest the inclusion of this method in immune tolerance protocols in order to improve levels, recovery, and half–life of FVIII and to save concentrates.