G. Meckenstock

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

Abstract 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-Hodgkins 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-Hodgkins 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.

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

SummaryConventional-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 (M1n=3, M2n=10, M4n=6, M5n=2, M6n=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.

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

Abstract: 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 μg/1 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.

Abstract 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.

LightCycler®-based quantitative real-time PCR monitoring of patients with follicular lymphoma receiving rituximab in combination with conventional or high-dose cytotoxic chemotherapy

Abstract:  Objectives: Quantitative real‐time polymerase chain reaction (qPCR) is a suitable method to measure residual disease in hematological malignancies. Our objective was to assess a LightCycler®‐based qPCR for t(14;18)(q32;q21)(IgH/bcl‐2)‐positive cells quantification in the context of clinical and morphopathological characteristics of patients with follicular lymphoma treated with rituximab (R) in combination with conventional or high‐dose chemotherapy. Methods: A total of 270 bone marrow (BM) and peripheral blood (PB) samples collected from 52 patients with follicular lymphoma at diagnosis or at relapse before or sequentially during therapy were examined by qPCR and nested‐PCR. Results: A greater amount of t(14;18)‐positive cells was observed in BM in comparison with PB in 76% of paired samples. The presence and number of t(14;18)‐positive cells in BM and PB correlated with lymphoma activity. Significantly higher numbers of lymphoma cells were found in patients under non‐remission compared with patients in clinical remission. During non‐remission, 10‐fold higher numbers were measured at relapse than at diagnosis. During remission, significantly higher levels were found in partial compared with complete remission. During first‐line therapy, R/cyclophosphamide/adriamycin/vincristine/prednisone (CHOP) had higher in vivo purging ability than R/fludarabine/mitoxantrone (FM). After R/high‐dose cytosine‐arabinoside and mitoxantrone (HAM) or R/carmustine/etoposide/cytarabine/melphalan (BEAM), the level of t(14;18)‐positive cells dropped below the detection limit in 80% of patients. Conclusions: LightCycler® qPCR is a reliable method for quantitative molecular monitoring of t(14;18)‐positive cells in BM and PB of patients with follicular lymphoma. It reflects the clinical characteristics of patients and allows assessment of response to different treatment regimens on a molecular level.

T-cell receptor γ/δ expressing acute leukemia emerging from sideroblastic anemia: Morphological, immunological, and cytogenetic features

Abstract Striking numerical and structural chromosome abnormalities (-Y, +8, i(7q), del(10)(q24), and del(11)(q21)) were detected by cytogenetic analysis in a patients 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 γ/δ-T-cell receptor antigen and coexpressing CD11b and CD16. Exhibiting an identical phenotype as the leukemic cells, a prominent γ/δ-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 γ/δ-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 + γ/δ-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 γ/δ-TCR + lymphocyte population.

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.Zusammenfassung□ HintergrundDiagnostik und Klassifizierung der chronischen myelomonozytären Leukämien (CMML) sind morphologisch schwierig und werden durch heterogene Klinik und Erkrankungsverlauf kompliziert. Angaben über die Häufigkeit des Leukämieübergangs schwanken erheblich. Die FAB-Gruppe hat die Unterscheidung zweier Subgruppen der CMML vorgeschlagen: Anhand der peripheren Leukozytenzahlen wird eine myelodysplastische Verlaufsform (MDS-CMML, <13 000/μl) von einer myeloproliferativen Verlaufsform (MPD-CMML, >13 000/μl) abgegrenzt. Eindeutige Prognoseparameter konnten bislang nicht etabliert werden.□ Patienten und MethodenAnhand des umfangreichen Datenmaterials des Düsseldorfer MDS-Registers wurden in einer retrospektiven Analyse klinische, hämatologische und morphologische Charakteristika sowie natürlicher Krankheitsverlauf und Prognosefaktoren der CMML und ihrer morphologischen Subgruppen verglichen.□ ErgebnisseVon insgesamt 225 Patienten mit CMML wurden 115 als MDS-CMML und 110 als MPD-CMML klassifiziert. Das mediane Erkrankungsalter betrug 70 bzw. 73 Jahre. In beiden Gruppen war das Geschlechtsverhältnis zugunsten des männlichen Geschlechts verschoben. Splenomegalie (50 vs. 28%) und Hepatomegalie (45 vs. 25%) wurden häufiger in der Gruppe der MPD-CMML beobachtet. In der MDS-Gruppe wurden signifikant höhere LDH-Werte gemessen. Die peripheren Blutzellwerte unterschieden sich, abgesehen von den Leukozytenzahlen, nicht wesentlich. Der mediane medulläre Blastenanteil betrug in beiden Gruppen 8%, Dysplasiezeichen aller drei Zellreihen konnten in beiden Gruppen in ähnlicher Weise nachgewiesen werden. Fünf Jahre nachDiagnosestellung lebten in der MDS-Gruppe noch 24% und in der MPD-Gruppe noch 15% der unbehandelten Patienten. Die Häufigkeit des Übergangs in eine akute myeloische Leukämie war in der MDS-Gruppe höher als in der MPD-Gruppe (29 vs. 18% nach fünf Jahren). Unabhängige ungünstige Prognoseparameter der Gesamtgruppe und der MDS-Gruppe waren erhöhte LDH-Werte, erniedrigte Hämoglobinwerte und männliches Geschlecht. Mit Hilfe des Düsseldorf-Score gelang die Unterscheidung von Risikogruppen innerhalb der MDS-Gruppe mit medianen Überlebenszeiten von zwölf vs. 40 Monaten (p=0,00005). Innerhalb der Gruppe der MPD-CMML konnten keine Prognoseparameter identifiziert werden.□ SchlußfolgerungMDS-CMML und MPD-CMML stellen klinisch unterschiedliche Enritäten dar, die sich allerdings prognostisch nicht wesentlich voneinander unterscheiden. Eine Risikostratifizierung der CMML kann mit Hilfe des Düsseldorf-Score vorgenommen werden.Abstract□ BackgroundThe FAB group proposed to distinguish 2 subgroups of chronic myelomonocytic leukemia (CMML): Depending on the total leukocyte count a myelodysplastic type (<13,000/μl) was separated from a myeloproliferative type (>13,000/μl). Prognostic factors are not well-established until now.□ Patients and MethodsBased 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.□ ResultsOut 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.□ ConclusionsIn 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.

Validation of the IPSS and Other Scoring Systems in Patients with Primary MDS

The International Prognostic Scoring System (IPSS) was proposed to improve risk evaluation in MDS. The IPSS is based on bone marrow blast count, number of peripheral cytopenias and cytogenetic findings. The Dusseldorf score does not include cytogenetics, but uses LDH levels as prognostic parameter. The Spanish-score includes bone marrow blast count, number of peripheral cytopenias and age, the Bournemouthscore includes bone marrow blast count and number of peripheral cytopenias.

Results of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with High-Risk MDS

Myelodysplastic syndromes encompass a heterogenous group of cloncal stem cell disorders which are characterized by abnormal hematopoietic differentiation and blast cell accumulation in the bone marrow and reduced peripheral blood cell counts. Most patients with these disorders succumb to complications of bone marrow failure or transformation to AML within months or years of diagnosis. Life expectancy is particularly poor for patients with an increased medullary blast infiltration (RAEB and RAEB/T), profound pancytopenia and abnormal cytogenetics (particularly complex aberrations and chromosome 7 anomalies). Allogeneic stem cell transplantation offers a potential cure for younger patients with myelodysplastic syndromes. Although increasingly used during recent years, clinical experience with this treatment modality is still limited and most reports include only small patient series. In addition, it is unclear whether BMT should be performed as consolidation treatment after induction chemotherapy or whether patients should be transplanted immediately after diagnosis of MDS. In this paper, we report our own data of 20 patients with advanced primary MDS which were subjected to allogeneic stem cell transplantation over a period of 10 years.