[Clinical course, morphology and prognosis of chronic myelomonocytic leukemia]. / Klinik, Morphologie und Prognose chronischer myelomonozytärer Leukämien.

BACKGROUND: The FAB group proposed to distinguish 2 subgroups of chronic myelomonocytic leukemia (CMML): Depending on the total leukocyte count a myelodysplastic type (< 13,000/microliter) was separated from a myeloproliferative type (> 13,000/microliter). Prognostic factors are not well-established until now. PATIENTS AND METHODS: Based on retrospective analyses of patients with CMML diagnosed at our institution, we compared the presenting clinical and hematological features of both disorders and examined the natural course of the disease and prognostic factors. RESULTS: Out of 225 patients with CMML there were 115 patients with myelodysplastic type (MDS-CMML) and 110 patients with myeloproliferative type (MPD-CMML). Median age of patients at diagnosis and sex ratio were not different. Splenomegaly and hepatomegaly were more common in MPD-CMML. With regard to laboratory findings, patients with MPD-CMML presented with significantly higher LDH values. Except for WBC, peripheral blood counts were not different. Median percentage of bone marrow blasts was 8% in both disorders. Signs of bone marrow dysplasia were comparable in both disorders. Cumulative survival rates were similar in both disorders. Five years after diagnosis, actuarial survival for patients with MPD-CMML was 24%, as compared to 15% for patients with MDS-CMML. The probability of transformation to AML was higher in MDS-CMML (29% vs 18% after 5 years). Elevated LDH values, low hemoglobin values and male sex were independent risk factors for the entire group and for the MDS-CMML group. Using the Düsseldorf score, we could define risk groups within MDS-CMML with a median survial of 12 vs 40 months (p = 0.00005). Prognostic factors could not define risk groups within the MPD-CMML group. CONCLUSIONS: In summary, these data suggest that MDS-CMML and MPD-CMML are clinically distinguishing conditions, but the separation provides little prognostic information. The Düsseldorf score can be used to provide risk stratification in CMML.

Multiple basal cell carcinomas associated with hairy cell leukaemia.

We report the case of a caucasian woman who, between the ages of 49 and 51 years, developed multiple (> 20) basal cell carcinomas (BCC). There was no family history of BCC. No abnormalities in the human homologue of the Drosophila segment polarity gene patched (PTCH), glutathione S-transferases T1 and M1, or cytochrome P450 1A1 were detected by polymerase chain reaction (PCR)-based molecular analysis. There was, however, actinic damage of the skin in sun-exposed areas. The patient was diagnosed as having hairy cell leukaemia (HCL) at the age of 51 years, based upon leucocyte morphology as assessed by light and electron microscopy, tartrate-resistant acid leucocyte phosphatase (TRAP) staining, fluorescence activated cell scanning of peripheral blood leucocytes and bone marrow histology. As the leukaemia slowly progressed over a 3-month period, the patient developed four further BCCs. Given that HCL is characterized by a profound defect in T-cell function, it is conceivable that T-cell immune dysregulation can contribute to the pathogenesis of BCC, possibly enhancing the aetiological effect of ultraviolet irradiation.

[Role of aggressive treatment strategies for myelodysplastic syndromes]. / Stellenwert aggressiver Behandlungsstrategien im Therapiekonzept myelodysplastischer Syndrome.

Myelodysplastic syndromes (MDS) constitute a heterogenous group of acquired bone marrow disorders characterized by ineffective hematopoiesis, cellular dysfunction and an increased risk of transformation into acute myeloid leukemia (AML). The percentage of medullary blast cells and the karyotype at diagnosis are the most important predictors of survival. Patients with more than 10% blast cells or an unfavourable karyotype (chromosome 7 abnormalities or complex aberrations) usually survive less than 12 months. This review article focuses on the roles of intensive AML-type chemotherapy, autologous stem cell transplantation and allogeneic bone marrow transplantation in the management of patients with advanced MDS. Recent studies suggest that, with appropriate selection of patients, intensive chemotherapy produces high rates of complete remission. Chances of entering remission are particularly high in patients with a good Karnofsky score, bone marrow blast count < 30% and normal karyotype. When compared with acute myeloid leukemia, results of autologous bone marrow transplantation in MDS are disappointing. A major disadvantage of this approach is the delayed recovery of hematopoiesis. Autologous peripheral blood progenitor cell transplantation overcomes this difficulty and is currently explored as consolidation therapy after successful remission induction with polychemotherapy in an intergroup study of the EORTC and EBMT. Allogeneic bone marrow transplantation remains the treatment of choice for younger MDS patients, offering a good chance of cure if the transplantation is performed at an early stage of disease or if the patient receives the transplant in complete remission after conventional chemotherapy.

[Choroid infiltration in myelodysplastic syndrome]. / Choroidales Infiltrat auf dem Boden eines Myelodysplastischen Syndroms.

BACKGROUND: Myelodysplastic syndrome is a clonal disease of the hematopoetic system characterized by insufficiency of affected bone marrow cell lines. After long-term course of myelodysplastic syndrome an acceleration towards acute myeloic leukemia is a frequent finding. Involvement of the eye is a well known phenomenon in acute leukemia or in blast crisis with chronic leukemias. Eye involvement in myelodysplastic syndrome showing its transition into acute myeloic leukemia however has been published in only few cases. CASE REPORT: We present a 70-year-old male patient suffering from myelodysplastic syndrome, complaining of an acute visual decrease to 0.05 in the left eye. Clinical findings, ultrasound and fluoresceine angiography were in accordance with choroidal infiltration. From the hematologic findings, the myelodysplastic syndrome had been in partial remission after chemotherapy without any sign of relapse or exacerbation. Only because of the ophthalmologic diagnosis, bone marrow aspiration was performed and revealed progression of myelodysplastic syndrome to acute myeloic leukemia. Prompt administration of chemotherapy and external radiation of the posterior pol of the eye led to complete resolution of the fundus lesion within 10 days and visual acuity recovered to 0.8. CONCLUSION: To the best of our knowledge this is the first patient with a choroidal infiltration as the initial sign of progression of myelodysplastic syndrome to acute myeloic leukemia. Realizing this possibility helps for an early diagnosis and rapid therapy which is so crucial in prolonging life.

Dyshematopoiesis in de novo acute myeloid leukemia: cell biological features and prognostic significance.

Dyshematopoiesis was found in 44 (42.3%) of 104 cases of de novo acute myeloid leukemia (AML). Dyshematopoietic AML (dys-AML) and AML without hematopoietic dysplasia (non-dys-AML) were compared with regard to biological, hematological, immunophenotypic, and cytogenetic parameters as well as prognostic criteria. Median age of patients was 55 years in both groups. In dys-AML, the median leukocyte count (p = 0.04), peripheral blast (p = 0.02) and medullary blast cell count (p < 0.001) were significantly decreased, whereas the median platelet count (p - 0.04) was increased. Immunophenotyping demonstrated that leukemic blast cells in dys-AML more frequently expressed the adhesion molcules CD54 (p = 0.05) and CD58 (p = 0.08) than leukemic cells in non-dys-AML. Cytogenetically, we distinguished two karyotypic patterns, one group with a normal karyotype or prognostically favorable single chromosome aberrations ("P(0)-karyotype"), and another one with unfavorable single aberrations or complex aberrations ("P(1)-karyotype"). The incidence of these groups was not significantly different between dys-AML and non-dys-AML. Complete remission rate (CRR) after induction chemotherapy (p = 0.03) and overall survival time (OS; p = 0.03) were significantly lower in dys-AML. In addition, median disease free survival (DFS; p = n.s.) was inferior compared to non-dys-AML. In the dys-AML as well as in the non-dys-AML patient group, CRR, DFS, and OS were decreased in the P(1)-compared to the P(0)-subgroup. We conclude that dyshematopoietic AML is characterized by specific cell biological features and that hematopoietic and cytogenetic status represent complementary prognostic factors in de novo AML.

Plasma levels of D-dimer and circulating endothelial adhesion molecules in veno-occlusive disease of the liver following allogeneic bone marrow transplantation.

Veno-occlusive disease (VOD) of the liver is a frequent and life-threatening complication of BMT. Recently, successful treatment by t-PA has been reported but has been compromised by fatal bleeding events. Therefore, t-PA application should be restricted to patients with severe VOD. However, moderate and severe forms of VOD are difficult to distinguish in early stages. We analyzed plasma levels of cross-linked fibrin degradation products (D-dimer) and soluble endothelial adhesion molecules such as sE-selectin, sVCAM-1 and sICAM-1 in 10 consecutive patients undergoing allogeneic BMT to evaluate their use in identifying severe forms of VOD. During the observation period, 4 episodes of VOD occurred, 2 of which were fatal due to early onset of multiorgan failure. Concentrations of D-dimer generally increased after transplantation. However, there was an additional significant increase in D-dimer levels during severe VOD. Thus, D-dimer levels above 1000 microg/l were only found in 2 cases with severe VOD and fatal outcome. When compared with bilirubin concentrations substantial increases of D-dimers appeared earlier during the course of severe VOD. In contrast, VOD episodes were not accompanied by significant increases in sE-selectin, sVCAM-1 and sICAM-1 levels. It is concluded that measurement of D-dimer concentrations may aid accuracy to the early diagnosis of severe VOD.

Pseudomonas aeruginosa blepharoconjunctivitis during cytoreductive chemotherapy in a woman with acute lymphocytic leukemia.

Patients undergoing chemotherapy regimens for hematologic malignancies are prone to develop unusual and potentially life-threatening infections during periods of leukopenia- induced immunosuppression. We report the case of a woman who received consolidation chemotherapy for acute lymphocytic leukemia and acquired necrotizing Pseudomonas aeruginosa blepharoconjunctivitis of the right eye during a period of mild leukopenia. The infection led to severe orbital and periorbital inflammation, spreading down to the neck. High-dose antibiotic treatment with ceftazidime and tobramycin combined with granulocyte cell-stimulating factor cleared the infection after several days, but plastic surgery was needed to restore normal eye closure.

Lymphoid myelofibrosis associated with high grade B cell lymphoma of the liver: morphological, cytogenetic, and clinical features.

Severe pancytopenia associated with moderate hepatosplenomegaly, increased serum lactic dehydrogenase (LDH) levels, and hypogammaglobulinemia were found in a young male patient. Bone marrow histology showed extensive fibrosis, hypoplasia of erythro- and granulocytopoiesis, and hyperplasia of megakaryocytopoiesis associated with histiocytic fat cell phagocytosis and infiltration of abnormal lymphocytes, compatible with lymphoid myelofibrosis. Striking chromosomal aberrations indicating karyotype evolution were also demonstrated by cytogenetic analyses (47, XY, +3 / 47, XY, +3, 1p+ / 46, XO, +3, 1p+, -Y). The clinical course was characterized by cyclic febrile episodes accompanied by excessive increase of serum LDH levels and leukocyte counts, and decrease of platelet counts, followed by spontaneous regression. Further diagnostic procedures, including two liver biopsies and computed tomography, did not detect any manifestation of lymphoma. Eventually, the patient developed rapidly progressive, lethal pulmonary aspergillosis. At autopsy, high grade B cell lymphoma of the liver was found. In this case, the lymphoid myelofibrosis seen on bone marrow biopsy may be considered as a manifestation of "discordant" bone marrow histology related to high grade lymphoma. With respect to the cyclic clinical course, a possible role of apoptotic mechanisms in the physiopathology of this disorder is reviewed.

Pathologic rupture of the spleen in hematologic malignancies: two additional cases.

Pathologic rupture of the spleen in hematologic malignancies is rare. We present two cases of splenic rupture which occurred in a man with a secondary high-grade non-Hodgkin's lymphoma and a woman with chronic lymphocytic leukemia (CLL). In a review of the literature, we have been able to identify 136 cases of pathologic splenic rupture since 1861; 34% have occurred in acute leukemias, 34% in non-Hodgkin's lymphomas, and 18% in chronic myelogenous leukemia (CML). We find a male-to-female ratio of 3:1, with considerable differences for the specific diseases encountered. Pathologic rupture of the spleen has happened almost exclusively in adults and the ruptured spleens are generally moderately to severely enlarged. It seems that, apart from splenic infiltration by a hematologic disease, splenic infarcts and coagulation disorders (which have previously been advanced as the most important pathophysiologic factors leading to rupture), male sex, adulthood, severe splenomegaly, and cytoreductive chemotherapy may increase the risk for pathologic splenic rupture. We briefly discuss symptoms preceding the event, diagnostic possibilities, and the outcome with operative and conservative approaches.

[Indications, technique and risks in bone marrow transplantation in adulthood]. / Indikationen, Durchführung und Risiken der Knochenmarktransplantation Im Erwachsenenalter.

The option of bone marrow transplantation (BMT) significantly improved prognosis of adult patients with hematologic malignancies aged less than 50 years. Allogeneic BMT using the marrow of an HLA-identical family member still provides the most effective method of BMT. Conventional indications for this form of BMT are chronic myeloid leukemia (CML), acute leukemias presenting with adverse risk factors, myelodysplastic syndromes and severe aplastic anemia. If performed early in the disease course (e.g. during the chronic phase of CML or first remission of acute leukemia and MDS) allogeneic BMT cures 50 to 60% of patients. About 20% die of therapy related complications, e.g. graft versus host disease (GvHD), fatal infections or venoocclusive disease of the liver (VOD) and about 20% of patients succumb to relapse of their hematologic disorder. 80% presenting with severe aplastic anemia can be cured, if allogeneic BMT is performed soon after diagnosis without previous immunosuppressive therapy and blood transfusions. BMT with the marrow of a matched unrelated donor or autologous BMT are increasingly used as alternative procedures. A rate of lethal complications as high as 50% hinders rapid extension of BMT with unrelated donors. Therefore, this form of BMT should be restricted to young patients with leukemias, who cannot achieve long-term remission with conventional chemotherapy (in case of acute leukemias) or alpha-interferon (in case of CML). Reconstitution of hematopoiesis is more rapid after peripheral blood stem cell transplantation (PBSCT) compared with autologous BMT. Therefore, PBSCT will replace autologous BMT in most cases. Most favourable results of PBSCT have been reported in patients with malignant lymphomas after relapse or inferior response to primary induction therapy. Due to the higher relapse rate autologous BMT is inferior to allogeneic BMT in leukemia patients. Trials are required to clarify the potential role of myeloablative therapy with stem cell support in the treatment of patients with solid tumors. Many of the preliminary results already published are unsatisfactory and data of larger trials are still lacking. Therefore, BMT or PBSCT cannot be recommended generally for the therapy of patients with solid tumors.

Acute leukemia coexpressing myeloid, B- and T-lineage associated markers: multiparameter analysis of criteria defining lineage commitment and maturational stage in a case of undifferentiated leukemia.

Coexpression of myeloid, B-, and T-lineage associated markers was found in a patient with morphologically and cytochemically undifferentiated acute leukemia. Surface marker analysis using two-color immunofluorescence staining characterized blast cells to express CD34, CD38, CD117, and class II antigens, coexpressing TdT, CD4, CD7, CD13, CD19, and CD33. Cytoplasmic expression of myeloperoxidase, CD3, and CD22 could not be demonstrated. Monosomy for chromosome 7 was found by cytogenetic analysis. The absence of clonal rearrangements of immunoglobulin or T-cell receptor genes was shown by Southern blot analysis. Using a 3H-thymidine incorporation assay, DNA synthesis of leukemic blasts could be stimulated by IL-3, IL-6 and G-CSF in vitro. The present case did not offer specific criteria of lineage commitment. Corresponding to an equivalent counterpart in normal hematopoiesis, the involved cell population may reflect an early, most immature developmental stage within a multipotent progenitor cell compartment.

Hematological parameters influencing the Thrombostat 4000.

The effects of platelet counts, hematocrit, and leukocyte counts were studied on the closure times of the Thrombostat 4000 (in-vitro bleeding time, IVBT). Closure times became longer with platelet counts < 50 x 10(9)/L; an inverse linear correlation could be established. Hematocrit was also inversely correlated with the closure time. At constant platelet counts a hematocrit of 55% yielded an immediate closure of the filter, while with a hematocrit < 15% no closure times could be measured. At constant platelet counts and hematocrits, nomonuclear and polymorphonuclear leukocytes also influenced closure times; increased counts resulted in shorter closure times. Leukocytes from a patient with chronic myelocytic leukemia had the same effects.

Possible transmission of sarcoidosis via allogeneic bone marrow transplantation.

Allogeneic bone marrow transplantation (BMT) was performed in a 34-year-old man for non-Hodgkin's lymphoma. Two years before bone marrow harvest, pulmonary sarcoidosis was diagnosed in the donor. After steroid therapy, disease of the donor was in clinical remission with only minor radiological signs at the time of BMT. On day 90 after BMT, active sarcoidosis was diagnosed in the recipient. Besides radiologic signs and increased angiotensin converting enzyme levels, diagnosis was proved by characteristic histologic changes in lung and liver biopsies. Immunosuppressive therapy was changed from high dose cyclosporine to high dose methylprednisolone and symptoms promptly resolved within 10 weeks. This case indicates the possibility of transmission of sarcoidosis by marrow transplantation.

Results of conventional-dose cytosine arabinoside and idarubicin in elderly patients with acute myeloid leukemia.

Conventional-dose Ara-C (200 mg/m2 d 1-5) combined with idarubicin (12 mg/m2 d 1-3) was employed as remission induction and consolidation therapy in 23 elderly AML patients with a median age of 66 years (range, 60-75) with AML according to the FAB criteria (M1 n = 3, M2 n = 10, M4 n = 6, M5 n = 2, M6 n = 2), eligible for the study. In seven patients earlier MDS had been documented by previous bone marrow aspirates. The CR rate after one induction course was 65% (15/23). Toxicity was acceptable, with four patients dying during the chemotherapy-induced hypoplasia (4/23). Although 80% of the CR patients received two additional cycles of Ara-C and idarubicin as consolidation therapy, only two patients are still in continuous complete remission more than 12 months after achieving CR. The median disease-free survival of the CR patients was 11.5 months and the median survival of the entire group was 10 months. We conclude that conventional dose Ara-C/idarubicin is an effective protocol for inducing complete remission in elderly patients with AML, but that consolidation therapy consisting of two courses of the same regimen does not produce a relevant rate of long-term disease-free survival.

[Ex-vivo bleeding time as a control for platelet transfusion]. / Ex-vivo-Blutungszeit zur Kontrolle der Thrombozytentransfusion.

Thrombocytopenia is the most common cause of bleeding tendency and, if due to impaired platelet production, is best treated by platelet transfusion. For patients with acute leukemia prophylactic platelet transfusion should be considered if platelet count is below 20 x 10(9)/l. This will be underlined by a retrospective analysis at our clinic of 231 patients suffering from acute myelocytic leukemia (AML FAB M1-7) and showing an early-death rate of 7.7% by bleeding complications. To estimate the effectiveness of platelet transfusions, not only stopping of bleeding symptoms and corrected count increment (CCI) should be taken into account but also whether the patient has fever, sepsis, hepato-splenomegaly or has taken special drugs. Measuring the in vivo bleeding time is of little use for low reproduction and is stressing for patients. In 1985 Kratzer described a new and sensitive method for the evaluation of platelet function. After modifying this method it is now possible to test platelet function even with platelet counts below 50 x 10(9)/l.

[Embolizing aortic valve endocarditis in the differential diagnosis of thrombotic thrombocytopenic purpura]. / Embolisierende Aortenklappenendokarditis als Differentialdiagnose der thrombotisch-thrombozytopenischen Purpura.

A 50-year-old man complained of lumbar pains, lack of energy, dysarthria and ataxic gait. Investigation revealed progressive anaemia (haemoglobin initially 10.5 g/dl, later 6.8 g/dl) and thrombocytopenia (initially 67,000/microliters, later 25,000/microliters). In addition he had unexplained pyrexia of up to 39.8 degrees C. Lactate dehydrogenase was 780 U/l and fragmented red cells were noted in the blood film. Because of suspicion of thrombotic thrombocytopenic purpura, treatment with fresh plasma by infusion was immediately initiated. On the third day of treatment he developed left ventricular failure; auscultation revealed a blowing early diastolic murmur over Erb's point together with a spindle-shaped early diastolic murmur over the right second intercostal space. Computed tomography of the skull showed recent haemorrhage into the left half of the cerebellum and an older right posterior infarct. The abdominal ultrasound scan suggested a haemorrhagic spleen infarct. In view of these findings the diagnosis was revised to embolizing aortic endocarditis with aortic reflux (confirmed by colour Doppler echo-cardiography). Aortic valve replacement was performed immediately, and the patient was treated with gentamycin 80 mg/d and teicoplanin 400 mg/d for four weeks. Postoperatively he was given 12 units of platelet concentrate and the platelet count remained stable thereafter (greater than 100,000/microliters). Splenectomy became necessary because the splenic haematoma increased in size during oral anticoagulant therapy. After a 6 week hospital stay the patient was discharged in good condition.

T-cell receptor gamma/delta expressing acute leukemia emerging from sideroblastic anemia: morphological, immunological, and cytogenetic features.

Striking numerical and structural chromosome abnormalities (-Y, +8, i(7q), del (10)(q24), and del (11)(q21)) were detected by cytogenetic analysis in a patient's bone marrow with morphological features of both acute lymphoblastic leukemia and myelodysplastic disorder. Surface marker analysis characterized blast cells to be CD2+ CD7+ CD3+ CD4- CD8- expressing gamma/delta-T-cell receptor antigen and coexpressing CD11b and CD16. Exhibiting an identical phenotype as the leukemic cells, a prominent gamma/delta-TCR+ lymphocyte population was found in the bone marrow as well as in the peripheral blood. Cells of the latter compartment coexpressed CD56 and HLA-DR antigens and exhibited nonspecific cytotoxic activity. In the bone marrow cells NSCA could be induced after stimulation with interleukin 2 in vitro. Morphological, immunological, and cytogenetic findings suggest that gamma/delta-T-ALL emerged from a myelodysplastic disorder after sequential steps of malignant transformation. Leukemic cells with "mixed lineage" character may provide evidence for a common progenitor cell in the bone marrow. Assuming that the leukemic cells represent the malignant counterpart of normal CD3+ gamma/delta-TCR+ cells the results may contribute to our understanding of the origin and differentiation as well as the possible steps of malignant transformation of a gamma/delta-TCR+ lymphocyte population.

[The leukostasis syndrome with a cerebral infarct in rapidly progressing chronic lymphatic leukemia]. / Leukostase-Syndrom mit Hirninfarkt bei rasch progredienter chronischer lymphatischer Leukämie.

An 82-year-old woman developed acute neuropsychiatric signs (confusion, disorders of speech and vision) together with ataxic gait and left hemiparesis mainly affecting the lower limb. For 10 years she had been known to have chronic lymphatic leukaemia (CLL) which had not hitherto needed treatment. The patient had an exceptionally high leucocyte count (1,300,000/microliters), most of the cells being morphologically atypical lymphocytes. The computed tomogram of the skull showed a marginal zone infarct with a hypodense focus in the area of the right middle and posterior cerebral arteries, extending from the cortical to subcortical zones almost as far as the posterior horn. This was interpreted as a leukostasis syndrome with cerebral infarction due to rapid progression of the CLL. Significant reduction of leucocyte count with considerable improvement in clinical signs was achieved after three doses of vincristine and prednisone together with one cycle of COP (cyclophosphamide, vincristine, prednisone) therapy. Although the leucocyte count is not an important criterion in planning the therapy of CLL, in the event of rapidly increasing leucocytosis it is important to begin cytoreductive treatment in good time so as to avert the leukostasis syndrome.