Minichromosome maintenance protein 6, a proliferation marker superior to Ki-67 and independent predictor of survival in patients with mantle cell lymphoma.

Minichromosome maintenance protein 6 (MCM6) is one of six proteins of the MCM family which are involved in the initiation of DNA replication and thus represent a marker of proliferating cells. Since the level of cell proliferation is the most valuable predictor of survival in mantle cell lymphoma (MCL), we investigated lymph node biopsy specimens from 70 patients immunohistochemically with a monoclonal antibody against MCM6. The percentage of MCM6 expressing lymphoma cells ranged from 12.0 to 95.6%, with a mean of 61.0%, and was significantly higher than the percentage of Ki-67-positive cells (P<0.0001). Surprisingly, the ratio of MCM6-positive cells to Ki-67-positive cells was higher than in normal stimulated peripheral blood mononuclear cells, indicating a cell early G1-phase arrest in MCL. A high MCM6 expression level of more than 75% positive cells was associated with a significantly shorter overall survival time (16 months) compared to MCL with a low MCM6 expression level of less than 25% (no median reached, P<0.0001). Multivariate analysis revealed MCM6 to be an independent predictor of survival that is superior to the international prognostic factor and the Ki-67 index. Therefore, aside from gene expression profiling, immunohistochemical detection of MCM6 seems to be the most promising marker for predicting the outcome in MCL.

Topoisomerase IIalpha expression in mantle cell lymphoma: a marker of cell proliferation and a prognostic factor for clinical outcome.

Mantle cell lymphoma (MCL) is a malignant lymphoma associated with a relatively aggressive clinical course and a median overall survival time of 3-4 years. Treatment usually consists of combination chemotherapy, often including topoisomerase (topo) inhibitors such as doxorubicin, etoposide and mitoxantrone. Topo IIalpha is an enzyme that is needed whenever uncoiling of DNA is necessary during the cell cycle. The enzyme is a marker of cell proliferation. We analyzed the expression of topo IIalpha in relation to Ki-67 and the clinical outcome in patients with MCL. Biopsy specimens from 95 untreated patients enrolled in two multicenter trials (1975-1985) were investigated immunohistochemically with monoclonal antibodies against topo IIalpha (Ki-S4) and Ki-67 (Ki-S5). Patients with low (0-10%) topo IIalpha expression had a median overall survival time of 49.0 months, compared to 17.0 months for patients with high (more than 10%) topo IIalpha expression. The Kaplan-Meier analysis showed a significant difference in the overall survival time related to the percentage of topo IIalpha (P<0.001) and Ki-67 (P<0.001) positive tumor cells. Multivariate Cox regression analysis revealed the expression of topo IIalpha as the most important prognostic factor (P<0.001) in MCL superior to the international prognostic index (IPI), the Ki-67 index and other clinical characteristics.

[Brachytherapy after coronary interventions: current state and future perspectives]. / Brachytherapie nach koronaren Interventionen: aktueller Stand und Zukunftsperspektiven.

Intracoronary brachytherapy is a novel, meanwhile established therapy. It is currently the only interventional procedure which has proven to effectively reduce the restenosis rates after intervention of long and diffuse in-stent restenosis. For this indication, brachytherapy can be regarded as the current treatment of choice. Randomized studies yield promising results for bypass interventions or interventions in small vessels or diabetic patients. These findings may encourage the decision to perform a percutaneous, transluminal intervention in such high-risk patients. In clinical practice, implantation of new stents in combination with brachytherapy procedures should be avoided as far as possible. In any case, the combined antiaggregatory therapy should be conducted sufficiently long to minimize the danger of late stent thrombosis. Under this treatment, the expected thrombosis rates ar within the range of placebo-treated patients. The length of the radiation source should be sufficient to cover the entire interventional injury length to avoid recurrent edge stenosis. De novo lesions are currently not a routine indication for intracoronary brachytherapy. Although intracoronary brachytherapy may effectively reduce restenosis rates in sufficiently irradiated de novo lesion segments, de novo lesions should be treated only within the set-up of controlled studies. The current available data with a follow-up period of up to 5 years show that intracoronary brachytherapy is also in the mid-term a safe and effective therapy for the reduction of restenosis after coronary interventions.

Long-term survival after induction therapy with idarubicin and cytosine arabinoside for de novo acute myeloid leukemia.

We treated 153 patients with de novo acute myeloid leukemia (AML) with two induction courses of conventional-dose cytosine arabinoside (ara-C) and idarubicin (AIDA) followed by either a third course of AIDA, high-dose ara-C or bone-marrow transplantation. The complete remission (CR) rate for all patients was 63.4%, with a higher CR rate for patients with a normal (versus unfavorable) karyotype (73.2% vs 52.5%; P=0.038). The probability of overall survival (OS) was 30.7% after 5 years (26.3% after 7 years). Improved OS at 5 years could be observed for patients up to 50 years old versus patients older than 50 years of age (37.6% vs 19.9%; P=0.001) and patients with a normal (versus unfavorable) karyotype (42.9% vs 14.1%; P=0.0016). Disease-free survival (DFS) after 5 years was 33.2% for all 97 CR patients and was significantly better for patients with a normal (versus unfavorable) karyotype (44.3% vs 12.3%; P= 0.003). Multivariate analysis revealed that the age for OS (P < 0.02) and the karyotype for both OS (P<0.03) and DFS (P< 0.05) were independent prognostic factors. In conclusion, AIDA is an effective and well-tolerated induction regimen (even in elderly patients) with a 5-year survival of more than 30% when combined with ara-C-containing postremission therapy. The karyotype is the most powerful prognostic factor for predicting the outcome of patients treated with this protocol.

In acute myeloid leukemia, coexpression of at least two proteins, including P-glycoprotein, the multidrug resistance-related protein, bcl-2, mutant p53, and heat-shock protein 27, is predictive of the response to induction chemotherapy.

To identify prognostic factors alternative or additional to P-glycoprotein (Pgp), we studied the impact of the multidrug resistance-related protein (MRP), bcl-2 (flow cytometry), mutant p53 (single-strand conformation polymorphism), and heat-shock protein 27 (HSP27, Western blotting) in myeloid blasts obtained at the time of diagnosis in patients with de novo acute myeloid leukemia (AML). We collected bone marrow samples from untreated AML patients, prepared the cells as well as the cellular protein, and froze all the material. We then analyzed 20 patients who responded with complete remission (CR) and 20 patients who had blast persistence (BP). The purpose of the study was to determine whether leukemic blasts from patients with BP were more resistant to chemotherapy than those from patients with CR. There was no significant correlation between the expression of any of these proteins alone and treatment outcome in both groups studied. In contrast, there was a significant correlation between the coexpression of at least two of these proteins and response (p = 0.0298), which turned out to be a significant independent prognostic factor for treatment failure (p = 0.0329, relative risk = 1.5) according to multivariate analysis. We conclude that drug resistance in AML is multifactorial. Thus, coexpression of different resistance mechanisms may be responsible for the primary drug resistance in de novo AML.

[R.E.A.L. classification of non-Hodgkin lymphoma from the clinico-oncologic viewpoint]. / R.E.A.L.-Klassifikation der Non-Hodgkin-Lymphome aus klinisch-onkologischer Sicht.

In 1994 the International Lymphoma Study Group (ILSG) published the "Revised European-American Classification of Lymphoid Neoplasms" (R.E.A.L. Classification). Lymphomas were classified according to their presumed normal counterparts, to the extent possible. Within both T- and B-cell categories differentiation between lymphomas and/or leukemias of "precursor" or "peripheral" neoplasms are defined arising from antigen independend or antigen reactive cell proliferation. Lymphomas undoubtedly characterized by currently available morphologic, immunologic, and genetic technics represent "real" disease entities. Provisional categories include lymphomas that have been described in some detail, but without consensus within the ILSG. Proposed names are based predominantly on established usage. With respect to similar treatment approaches and difficulties of the ILSG members in subclassifying large cell lymphomas, centroblastic, immunoblastic and large cell anaplastic lymphomas of B-cell type were "lumped" together as large B-cell lymphomas. Within a prospective treatment trial overall survival was significantly better in centroblastic as compared to B-cell immunoblastic lymphoma diagnosed by optimal histomorphology according the criteria of the Kiel Classification. Thus the R.E.A.L. Classification fails to identify patients who may require other than standard treatment. Future studies will demonstrate whether subclassifying the proposed "peripheral" T-cell lymphomas, unspecified into T-zone lymphoma, lymphoepitheloid (Lennert's) lymphoma and pleomorphic, small, medium, and large cell lymphomas according the Kiel Classification is of clinicopathologic relevance. On the contrary the subtypes of chronic lymphocytic leukemia of T-cell type form two distinct entities within the R.E.A.L. Classification separating T-CLL/prolymphocytic leukemia from large granular lymphocyte leukemia of T- and NK-cell type. Within the R.E.A.L. Classification the lymphoplasmacytoid immunocytoma of the Kiel Classification will be subsumed together with the prognostically significantly better B-cell chronic lymphocytic leukemia. Opposite to the original intention of the ILSG two proposals are developed on clinical grouping of entities. Clinical indolent lymphoid neoplasms usually have "low grade" histologic appearances, with a predominance of small cells subsuming with the exception of the mantle cell lymphoma all of the low grade lymphomas of the Kiel classification. Aggressive lymphomas (intermediate risk) are defined as tumors whose survival if untreated is measured in months, highly or very aggressive lymphomas and/or leukemias will kill untreated patients within weeks. Unlike the Kiel Classification proposed categories subsume lymphomas irrespective of cytomorphology, thus grouping together potentially curable and uncurable diseases. Undoubtedly the R.E.A.L. Classification forms at present the best compilation of existing knowledge upon neoplasms of the immune system, enabling cooperation between clinicians and scientists all over the world. According to the ILSG this proposal should be considered a starting point for future periodic reevaluations.

[POEMS syndrome. A rare variant of osteosclerotic multiple myeloma with polyneuropathy, organomegaly, endocrinopathy, M-gradient and skin lesions]. / POEMS-Syndrom. Seltene Variante des osteosklerotischen multiplen Myeloms mit Polyneuropathie, Organomegalie, Endokrinopathie, M-Gradient und Hautläsionen.

BACKGROUND: A rare multi-organ involvement in plasma-cell dyscrasias has been named POEMS-syndrome: it is a synopsis of monoclonal gammopathy (M-gradient), osteosclerotic bone lesions, peripheral polyneuropathy, organomegaly, endocrinopathy and skin lesions. CASE REPORT: A patient is presented who had a classical manifestation of this disease known mainly in Japan. A monoclonal IgA-lambda-gammopathy was determined as cause of a gradually progressive polyneuropathy. The patient had a hypergonadotropic hypogonadism, hyperprolactinaemia, and sclerotic bone lesions. In addition, he showed a changing organomegaly, and hyperpigmentation of the skin. CONCLUSION: As yet, aetiology and pathophysiology are not fully understood. Irradiation or surgical resection of one or several osteosclerotic bone lesions may improve the polyneuropathy or may even lead to a complete remission of all symptoms. Thus, monoclonal immunoglobulins should be searched for in any unclear polyneuropathy, as should be for other symptoms of the POEMS-syndrome.

Mantle cell lymphoma: diagnostic criteria, clinical aspects and therapeutic problems.

In 1992, after a history of more than two decades a subgroup within the diffuse low-grade B cell lymphomas designated centrocytic lymphoma, lymphocytic lymphoma of intermediate differentiation or mantle zone lymphoma gained general acceptance, now referred to as mantle cell lymphoma. Similarities between these entities were emphasized by identification of rearrangement and overexpression of CCND1 (bcl1/PRAD1) gene in the majority of cases. Unlike in all other non-Hodgkin's lymphomas sex distribution demonstrates a striking preponderance of males over females with a ratio of 3:1. Initial parameters in all published series are advanced disease with generalized lymphadenopathy in 90%, bone marrow infiltration in 60-75%, splenomegaly in 55%, hepatomegaly in 35%, gastrointestinal involvement in about 25% and peripheral blood lymphocytosis in 20-30% of patients. In generalized disease, clinical course is characterized by continuous progression with a median survival probability of 3-4 years within most series. Overall response rates of 56-88% with complete remissions in the range of 9-58% are attainable but relapse occurs predominantly within 20 months. At present there is no evidence that any conventional regimen is curative. Prospective multicenter studies are mandatory to overcome this therapeutic dilemma. Patients suitable for some form of maintenance or consolidation therapy should initially be treated intensively by anthracycline-containing regimens. Whether maintenance with interferon or intermittent chemotherapy including new agents, like purine analogues or (un)conjugated monoclonal antibodies are able to influence overall survival is a matter of (ongoing) investigations. Further experimental approaches arise from antisense oligonucleotides or ribozymes blocking the overexpression of bcl-1 especially in this lymphoma entity. At present high-dose myeloablative consolidation radiochemotherapy followed by stem cell rescue in first remission seems to be the most attractive option in younger patients.

Subclassification of diffuse large B-cell lymphomas according to the Kiel classification: distinction of centroblastic and immunoblastic lymphomas is a significant prognostic risk factor.

Among high-grade malignant non-Hodgkin's lymphomas the updated Kiel classification identifies three major B-cell entities: centroblastic (CB), B-immunoblastic (B-IB), and B-large cell anaplastic (Ki-1+) (now termed anaplastic large cell [CD30+], [B-ALC]). The clinical prognostic relevance of this distinction was evaluated in a randomized prospective treatment trial (COP-BLAM/IMVP-16 regimen randomly combined +/- radiotherapy in complete responders) conducted in adult (age 15 to 75) patients with Ann Arbor stage II-IV disease (n = 219) diagnosed by optimal histomorphology (Giemsa staining) and by immunohistochemistry. Overall survival was significantly better in CB lymphoma as compared to B-IB (P = .0002) or B-ALC (P = .046). Relapse-free survival was worse for B-IB (P = .0003) as compared to CB lymphomas. The prognostic differences between CB and B-IB were confirmed by multivariate analyses including the risk factors of the International Index. Overall survival was significantly determined by performance status (P = .0003), serum-LDH (P = .036), and B-IB histology subtype (P = .036). Relapse-free survival was influenced by age (P = .007) and histological subtype (P = .007). Thus, the diagnosis of the CB and B-IB lymphomas by the histological criteria of the Kiel classification was identified as an independent prognostic factor in diffuse large B-cell lymphomas.

Myeloablative therapy with blood stem cell transplantation is effective in mantle cell lymphoma.

Long-term disease-free survival following conventional cytotoxic therapy is extremely rare in patients with advanced-stage mantle cell lymphoma (MCL). High-dose conditioning therapy consisting of hyperfractionated total body irradiation (TBI, 14.4 Gy) and cyclophosphamide (200 mg/kg) was therefore offered to 13 patients (four females/nine males) with advanced-stage MCL. The patients were relatively young with a median age of 49 years (range 30-60). High-dose cytarabine and mitoxantrone with granulocyte colony-stimulating factor (G-CSF) support were given for second-line therapy and mobilization of peripheral blood stem cells (PBSC). During cytokine-stimulated marrow recovery, a median of two leukaphereses (range 1-4) were performed. Using direct immunofluorescence analysis including two-color staining, the proportion of CD19+ B cells and CD34+/CD19+ B lymphoid progenitor cells was found to be extremely low with quantities below detection limit in approximately 50% of the autografts. At the time of autografting, nine patients (pts) were in first partial (five pts) or complete (four pts) remission, while four patients had achieved a second complete remission. Following myeloablative therapy a median number of 7.5 x 10(6) CD34+ cells/kg were autografted. The median time for neutrophil (> or = 0.5 x 10(9)/l) and platelet recovery (> or = 20 x 10(9)/l) was 13 and 10 days, respectively. Hematological recovery was delayed in a patient who received 5.8 x 10(6) positively selected CD34+ cells/kg. There was one toxic death 17 days post-transplantation because of overwhelming interstitial pneumonia. Two patients with a history of previous treatment failure relapsed 10 and 11 months post-transplantation, respectively, at sites of previous disease. Ten patients are disease-free with a median follow-up time of 18 months (range 10-47). The results presented here suggest that PBSC-supported high-dose therapy including TBI may provide long-term disease-free survival for patients with advanced-stage mantle cell lymphoma.

Infection by Alcaligenes xylosoxidans subsp. xylosoxidans in neutropenic patients.

Alcaligenes xylosoxidans subsp. xylosoxidans (A. x. xylosoxidans) is a nonfermenting gram-negative peritrichous rod and opportunistic pathogen. The organism is frequently found in an aqueous environment. In the past few years, nosocomial infections caused by A. x. xylosoxidans have become more evident. The literature suggests that systemic infections are severe and often lethal and an optimal antibiotic therapy is not well established. This report describes nosocomial infections in 11 patients of a hematology ward over a 2-month period. Primary infection occurred during the neutropenic phase after cytotoxic chemotherapy. Reinfection spread from central venous catheters that had been implanted before the first infection. The bacteremia was successfully treated by imipenem. None of the 11 patients died from the bacteremia, but 3 died of their underlying diseases. Despite an intensive search for the source, the route of infection remained uncertain. Nosocomial infections by A. x. xylosoxidans are of growing importance in high-risk patients. Although the source of infection often remains unknown, infection seems to originate from contaminated solutions. Treatment with imipenem and the removal of central venous catheter systems successfully eliminated A. x. xylosoxidans, which adheres to plastic material.

Deep venous thrombosis and pulmonary artery embolism in high-grade non Hodgkin's lymphoma: incidence, causes and prognostic relevance.

To analyse incidence, risk factors, causes and prognostic significance of venous thromboembolism (VTE) in high-grade non-Hodgkin's lymphoma (HG-NHL) a prospective clinical trial (N = 593), also undertaken to analyse other aspects of HG-NHL, a study of haemostasis (N = 25) and a post-mortem analysis (N = 70) were performed. Clinical analysis documented a 6.6% incidence of VTE, and 77% of all cases occurred before or within the first 3 months of chemotherapy. Ann Arbor stage IV and B-mediastinal clear cell histology were risk factors for VTE, while rapid changes in tumour load or application of consolidation chemotherapy were not. Vessel compression by HG-NHL was the leading cause of VTE, whereas a significant (paraneoplastic or chemotherapy-induced) thrombophilic state was not disclosed by haemostatic tests. While VTE-related fatality was found to be low in the clinical trial (1.7%) and at necropsy (8.5%), the occurrence of VTE was associated with an unsatisfactory response of HG-NHL to chemotherapy and a high incidence of treatment-related mortality due to diffuse alveolitis. Thus, fatal VTE in HG-NHL is rare, but VTE is associated with an unfavourable clinical course of HG-NHL.

Recovery by splenectomy in patients with relapsed thrombotic thrombocytopenic purpura and treatment failure to plasma exchange.

Thrombotic thrombocytopenic purpura is a serious, potentially fatal disease, and conventional plasma exchange appears to be the best initial therapy. Following this approach, survival in 90% of patients is available. In patients with relapse and treatment failure to plasma exchange, splenectomy is recommended. The rationale for splenectomy and the relevant pathomechanisms involved are obscure. In the present paper two patients with TTP are reported who first responded to conventional treatment strategies but later relapsed. Resumption of previous therapy was not able to continuously maintain normal platelet levels. Thus, splenectomy was considered to be indicated. In contrast to former reports, repeated cycles of conventional plasma exchanges were performed until a transient steady state (12 hrs) of the platelet counts occurred. Then splenectomy was performed immediately and, in contrast to former reports, no reinstitution of treatment was necessary after splenectomy. In addition no postoperative complications (bleeding, neurologic impairment) have been observed. This favorable outcome might be due to the strategy of repeated conventional plasma exchange procedures. The follow-up shows now event free disease for 2 years.

Randomized, double-blind, placebo-controlled, phase III study of recombinant human granulocyte-macrophage colony-stimulating factor as adjunct to induction treatment of high-grade malignant non-Hodgkin's lymphomas.

We evaluated recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; Sandoz Pharma [Basel, Switzerland]/Schering-Plough [Kenilworth, NJ]) as an adjunct to a modified (mainly cyclophosphamide and doxorubicin increased 1.5-fold) COP-BLAM regimen in the primary treatment of high-grade malignant non-Hodgkin's lymphomas (NHL). Patients (n = 182; stage II-IV; age, 15 to 73 years) were randomized to rhGM-CSF (400 micrograms) or placebo for 7 days subcutaneously after chemotherapy. Efficacy was analyzed for patients receiving at least 70% of study medication (n = 125). The frequency of clinically relevant infection was reduced by rhGM-CSF (28 v 69 infections, 16 v 30 patients, P = .02) with a cumulative probability of remaining infection free in 70% versus 48% (P = .05 log rank test at 190 days). Periods of neutropenia (P = .01 in 5 of 6 courses), days with fever (2.1 v 4.0, P = .04) and days of hospitalization for infection (3.5 v 8.0 days, P = .01) were significantly reduced. Complete response (CR) rates, assessed by prognostic risk, were 15 of 19 (79%) in treated versus 20 of 21 (95%) in controls in the low-risk group (P = .12). In the high-risk group, 31 of 45 (69%) treated patients achieved CR versus 25 of 52 (48%) of controls (P = .04). No difference in survival has been seen after 1 year. Only injection site reactions (45% treated v 7% controls) and rash (26% v 2%) occurred more frequently in treated patients (n = 176). These data show that rhGM-CSF is well tolerated in most patients with NHL, significantly reduces infection, and improves response.

Regulation of the T cell receptor-alpha mRNA expression in the human lymphoblastic T cell line CEM.

We analyzed the transcriptional events involved in the T cell receptor (TcR)-alpha mRNA expression in a human lymphoblastic T-cell line CEM. CD3-negative and CD3-positive CEM subclones that either lack mature TcR-alpha mRNA or express TcR-alpha mRNA were used. Exposure of the TcR-alpha mRNA negative subclones to phorbol 12-myristate 13-acetate (PMA) was followed by 2- to 3-fold increase of transcription, indicating that PMA acts on a transcriptional level. No increase of transcription was observed after blocking protein synthesis with cycloheximide (CHX) or after sequential stimulation with CHX followed by PMA. On the posttranscriptional level, CHX as well as PMA induced a progressive stabilization of TcR-alpha mRNA in the nuclear compartment, which was independent of ongoing transcription. The half-life of the TcR-alpha mRNA upon stimulation was about 6 hours. The accumulation of mature TcR-alpha mRNA seemed to be controlled by nuclear events on a transcriptional as well as posttranscriptional level. The data imply that alterations of TcR-alpha gene transcription are dependent on protein synthesis. DNA-binding proteins enhance transcription and labile nuclear proteins target TcR-alpha mRNA for rapid turnover.

Molecular analysis of an ataxia telangiectasia T-cell clone with a chromosomal translocation t(14;18)--evidence for a breakpoint in the T-cell receptor delta-chain gene.

We established a clonal T-cell line with a reciprocal chromosomal translocation t(14;18)(q11;q23) from a patient with ataxia telangiectasia (AT) and T-cell chronic lymphocytic leukemia (T-CLL). The tumor cells and the derived T-cell line were compared with respect to phenotype, karyotype, and rearrangement pattern. Restriction fragment analyses of the T-cell receptor (TCR)-delta gene, which is located within the TCR-alpha gene on chromosome 14q11, indicated that the breakpoint is located within the TCR-delta locus, splitting the TCR-delta gene between the variable and joining segments. This specific chromosomal translocation was only detected in the derived T-cell line and may be involved in the genesis of T-cell malignancies in AT.

Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. The German Aplastic Anemia Study Group.

BACKGROUND AND METHODS: Immunosuppression is the most effective treatment for patients with aplastic anemia, except for bone marrow transplantation. The best results are achieved with antilymphocyte globulin or cyclosporine. Patients have been treated successfully with a combination of both agents, but there has been no controlled evaluation of its efficacy. We conducted a randomized, multicenter trial in 84 patients not eligible for bone marrow transplantation, comparing treatment with antilymphocyte globulin and methylprednisolone (41 patients--the control group) with antilymphocyte globulin, methylprednisolone, and cyclosporine (43 patients--the cyclosporine group). RESULTS: At three months significantly more patients in the cyclosporine group had a complete or partial remission in response to treatment than did patients in the control group (65 percent vs. 39 percent, P less than 0.03); this difference was confirmed at six months (70 percent vs. 46 percent, P less than 0.05). The superior results of the regimen including cyclosporine were most evident in the patients with severe or very severe aplastic anemia, whose response rate at six months was 65 percent, as compared with 31 percent of such patients in the control group (P less than 0.02). Granulocyte and hemoglobin levels became normal in most patients who responded, but platelet counts continued to be subnormal in 61 percent of the patients. Ten of 52 patients with responses (3 in the cyclosporine group and 7 in the control group) relapsed 4 to 37 months after treatment. The actuarial survival of all patients at 41 months is 64 percent in the cyclosporine group and 58 percent in the control group (P = 0.16); among the patients with severe or very severe disease, survival is 80 percent and 44 percent, respectively (P = 0.077). Cyclosporine had substantial but reversible side effects. CONCLUSIONS: Immunosuppressive treatment of aplastic anemia with antilymphocyte globulin, methylprednisolone, and cyclosporine appears to be more effective than a regimen of antilymphocyte globulin and methylprednisolone without cyclosporine and may thus represent a treatment of choice for patients who are not eligible for bone marrow transplantation.