Astrid Franke

Rituximab Added to First-Line Mitoxantrone, Chlorambucil, and Prednisolone Chemotherapy Followed by Interferon Maintenance Prolongs Survival in Patients With Advanced Follicular Lymphoma: An East German Study Group Hematology and Oncology Study

PURPOSE Rituximab has been shown to be active in follicular lymphoma (FL), both as monotherapy and in combination with chemotherapy. We conducted a randomized trial comparing mitoxantrone, chlorambucil, and prednisolone (MCP) chemotherapy plus rituximab with MCP alone. PATIENTS AND METHODS Previously untreated patients with stage III or IV CD20+ indolent or mantle cell lymphoma were randomly assigned to either eight 28-day cycles of MCP plus rituximab (R-MCP; n = 181) or eight cycles of MCP alone (n = 177). All patients who achieved a complete or partial remission were treated with interferon maintenance until relapse. Herein, we report the results from the primary analysis population of patients with FL, who constituted the majority of patients (56%) recruited to the trial (n = 201; R-MCP, n = 105; MCP, n = 96). RESULTS Rates of overall and complete response were significantly higher in the R-MCP arm than the MCP arm (overall response, 92% v 75%, respectively; P = .0009; complete response, 50% v 25%, respectively; P = .004). With a median follow-up time of 47 months, median event-free survival (EFS) and progression-free survival (PFS) times were significantly prolonged with R-MCP compared with MCP (EFS, not reached v 26 months, respectively; P < .0001; PFS, not reached v 28.8 months, respectively; P < .0001), and overall survival (OS) was significantly improved with R-MCP compared with MCP (4-year OS rate, 87% v 74%, respectively; P = .0096). CONCLUSION The R-MCP regimen significantly improves complete and overall response rates, EFS, PFS, and OS in patients with previously untreated advanced FL, without a clinically significant increase in toxicity.

Fludarabine plus cyclophosphamide is an efficient treatment for advanced chronic lymphocytic leukaemia (CLL): results of a phase II study of the German CLL Study Group.

The efficacy and toxicity of a combination of fludarabine and cyclophosphamide (FC) was evaluated in patients with B‐cell chronic lymphocytic leukaemia (CLL). Between April 1997 and July 1998, 36 patients with CLL (median age 59 years) received a regimen that consisted of fludarabine 30 mg/m2 in a 30‐min IV infusion, d 1–3, and cyclophosphamide 250 mg/m2 in a 30‐min IV infusion on d 1–3. Cycles were repeated every 28 d. Twenty‐one patients had received between one and three different treatment regimens prior to the study, while 15 patients had received no prior therapy. The median Eastern Cooperative Oncology Group performance score was 1. One patient was at Binet stage A, 18 were stage B and 17 patients were stage C. Objective responses, assessed according to the revised guidelines of the National Cancer Institute‐sponsored Working Group, were recorded in 29 out of 32 assessable patients (90·6%). Twenty‐four partial remissions and five complete remissions were observed. Two patients showed no change and one patient showed disease progression. At February 2000, three of the responders had relapsed. Severe neutropenia, anaemia and thrombocytopenia (Common Toxicity Criteria grade 3 and 4) were observed in 25, six and six patients (69·4%, 16·7% and 16·7%) respectively. Other side‐effects were uncommon. No treatment‐related deaths and no grade 3 or 4 infections occurred. We conclude that the combination of fludarabine and cyclophosphamide showed significant activity in patients with CLL. Myelosuppression was the major side‐effect. These results warrant further study on the FC combination in randomized trials.

Randomized phase III study for the treatment of advanced indolent non-Hodgkin's lymphomas (NHL) and mantle cell lymphoma: chemotherapy versus chemotherapy plus rituximab

Clinical study phase III B, prospective randomized trial. This phase III trial is a prospective randomized comparison of a combined immunochemotherapy [mitoxantrone, chlorambucil, and prednisolone (MCP) plus rituximab] versus chemotherapy (MCP) alone for previously untreated, advanced, treatment-demanding CD20positive indolent non-Hodgkin’s lymphoma (NHL) and mantle cell lymphoma (MCL). Open-label, two-arm study. Central randomization by a clinical research organization (CRO) via fax. Inclusion criteria

Fludarabine and Bendamustine in Refractory and Relapsed Indolent Lymphoma—a Multicenter Phase I/II Trial of the East German Society of Hematology and Oncology (OSHO)

The therapy of patients with relapsed or refractory indolent lymphoma relies on the development of new drug combinations. The drugs bendamustine and fludarabine have cytotoxic activity as monotherapy in indolent lymphoma and show synergism in vitro. In this study, we combined both drugs in a multicenter clinical phase I/II trial to evaluate their toxicity and efficacy. Bendamustine was given at 30 or 40 mg/m2/d (dose levels 1 and 2), fludarabine at 30 mg/m2/d, each drug on days 1 to 3. Six cycles were to be given every 4 weeks. A total of 29 patients with relapsed or refractory indolent lymphoma were included in the study. During phase I, 9 patients were treated at dose level 1 and 7 patients at dose level 2. Thirteen patients were added to the study during phase II. Fourteen patients had follicular lymphoma, 11 patients mantle cell lymphoma, 2 patients lymphoplasmocytic and 2 patients nodal marginal zone lymphoma. Median age was 62 years (range 39-74). All patients were in stages III or IV of their disease and had received prior chemotherapy with or without additional radio- or immunotherapy. The dose limiting toxicity was hematotoxicity in all cases and occurred in 3 of 7 evaluable patients at dose level I and in 3 of 7 patients at dose level 2. One patient at dose level 2 died of sepsis in neutropenia with persistent thrombocytopenia. The study was continued at dose level 1 (phase II). Analysis of 19 evaluable patients treated at dose level 1 reveiled hematotoxicity CTC grade III in 47% and grade IV in 26%. Neutropenic fever occurred in 4 patients (21%). On an intent-to-treat basis, 45% or 32% of all patients at dose level 1 reached CR or PR, respectively. Nine of 9 patients with mantle cell lymphoma responded to therapy. The overall response rate was 77%. Eight of 15 responders relapsed after a median follow-up time of 14 months (range 2-43). The major complication of fludarabine in combination with bendamustine is hematotoxicity. Dose level 1 with 30 mg/m2/d of both drugs on days 1 to 3 was defined as the recommended dose. Despite unfavorable prognostic features (histologic subtype, stage of disease, pretreatment) response rates were good with this regimen.

Effect of Atrial Fibrillation on Hematopoietic Progenitor Cells. A Novel Pathophysiological Role of the Atrial Natriuretic Peptide

Background—Injury to the heart causes hematopoietic progenitor cells (HPCs) to migrate to the site of damage and to undergo cell differentiation. Studies suggest that myocardial progenitor cells invade atrial tissue. So far it is unclear, however, whether an atrial disease per se affects circulating HPCs. Methods and Results—Seventeen patients with persistent atrial fibrillation (persistAF), 12 with paroxysmal AF (paroxAF), and 17 matched patients with sinus rhythm (SR) were studied. HPCs (CD34+ and CD34+/CD117+) were quantified with the use of a fluorescence-activated cell sorter; stromal cell–derived factor-1&agr; (SDF-1&agr;), vascular endothelium growth factor (VEGF), and atrial natriuretic peptide (ANP) were determined by immunoassays. In patients with persistAF, blood samples were obtained before as well as 10 minutes, 24 hours, and 48 hours after electrical cardioversion. CD34+HPCs (AF, 7.0±2.3×103/mL versus SR, 5.0±1.6×103/mL; P <0.01) were increased during persistAF only. Highest SDF-1&agr; levels were also observed during persistAF. Successful and unsuccessful cardioversion decreased CD34+HPCs temporarily (7.0±2.3×103/mL versus 24 hours: 5.0±1.5×103/mL; P <0.05). Forty-eight hours after successful cardioversion, SDF-1&agr; and CD34+HPC levels started to decline, reaching control levels after 59±19 days. CD34+/CD117+ and VEGF levels, however, were increased by DC energy but not by AF. ANP levels correlated with CD34+HPC (r =0.76; P <0.01) and SDF-1&agr; (r =0.56; P <0.01). HPCs from patients with AF had a greater tendency to differentiate into cells expressing (cardio)myocyte markers ANP and myocyte enhancer factor-2. Conclusions—PersistAF appears to increase the potential of HPCs for (cardio)myogenesis. Restitution of CD34+HPC levels, mediated by SDF-1&agr; and possibly ANP, occurs within several weeks after successful cardioversion.

The role of diagnosis in patients failing peripheral blood progenitor cell mobilization.

BACKGROUND: Failure to mobilize PBPCs for auto‐logous transplantation has mostly been attributed to previous therapy and poses therapeutic problems.

High reliability and sensitivity of the BCR/ABL1 D-FISH test for the detection of BCR/ABL rearrangements

Abstract. The BCR/ABL1 fusion gene is mainly caused by the t(9; 22)(q34; q11.2) translocation, which results in the Philadelphia (Ph) chromosome. The Ph chromosome is the typical hallmark in chronic myeloid leukemia (CML), but can also be present in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The BCR/ABL1 rearrangement is an important tumor classification marker and a useful prognostic factor allowing an adequate therapy management. Ph chromosome detection by conventional cytogenetics (CC) can be hampered by low quantity and quality of metaphases from tumor cells. Furthermore, BCR/ABL1 rearrangements may be hidden due to cryptic rearrangements or complex aberrations. Therefore, molecular cytogenetic methods turned out to be useful tools for the detection of BCR/ABL1 rearrangements. We performed fluorescent in situ hybridization (FISH) with the recently developed BCR/ABL1 D-FISH probe (QBIOgene, Illkirch, F) on cultured bone marrow and peripheral blood cells of 71 patients with CML, ALL, AML, and myeloproliferative disorder (MPD). FISH results and the results of banding methods were directly compared. Based on the analyses of >200 nuclei per patient, D-FISH correlated closely with CC and allowed an accurate quantification of BCR/ABL1 rearrangements even in a low percentage of aberrant cells. No false-positive or false-negative results were obtained. Furthermore, the D-FISH probe detected three cryptic and one complex BCR/ABL1 rearrangement, which were not visible by CC. We conclude that D-FISH reliably detects standard Ph chromosomes as well as its variant translocations and accurately quantifies BCR/ABL1 rearrangements prior and during cancer treatment as well as in the phase of remission, in daily routine tumor cytogenetic diagnostics.

Prognostic significance of dysplastic features of hematopoiesis in patients with de novo acute myelogenous leukemia

Abstract The detection of dysplastic features of hematopoiesis in de novo acute myeloid leukemia (AML) by light microscopy is defined as AML with trilineage myelodysplasia (AML/TLMD). The prognostic relevance of these dysplastic features for patients with de novo AML remains unclear. In order to evaluate the role of dysplasia in de novo AML, bone marrow aspirates from 69 patients were analyzed prospectively and investigated separately for erythropoiesis, granulopoiesis and megakaryopoiesis by three independent investigators.The overall complete remission (CR) rate was 48.8% and partial remission (PR) or nonresponders consituted 52.2% of the patients investigated. The median overall survival time was 5 months with a disease-free interval of 3.5 months for all patients. Dysgranulopoiesis (DysG) was observed in 30.4%, dysmegakaryopoiesis (DysM) in 50.7%, and dyserythropoiesis (DysE) in 43.5%. Of all patients, 26.0% showed trilineage dysplastic features and were thus classified as AML/TLMD.A significantly worse prognosis (Kaplan-Meyer plot, Students t–test) was calculated for those patients with detection of only DysG (p=0.002), DysM (p=0.02), DysE (p=0.04) as compared with patients without any dysplastic signs. An unfavorable karyotype was correlated with patients showing DysG (P=0.02) and DysM (P=0.04). For these patients with an unfavorable karyotype, the occurrence of any dysplastic features had no additional prognostic impact.Dysplastic features (DysG, DysM, DysE) seem to be an important prognostic factor in de novo AML correlating with short overall survival. DysG and DysM correlated well with the appearance of unfavorable chromosomal abnormalities. It may be reasonable to assume that patients with dysplastic features should be considered for more aggressive treatment schedules at the time of diagnosis.

Thymic hyperplasia following successful treatment for nodular-sclerosing Hodgkin's Disease

Abstract A young female patient showed up with mediastinal bulky disease and lymph node swelling in her left supraclavicular region. Clinical and histological investigations proved nodular-sclerosing Hodgki ns lymphoma. The patient received combined modality treatment according to the protocols of the German Hodgki ns Disease Study Group and achieved complete remission. Six months later the chest X-ray and thoracic CT-scan showed mediastinal tumor masses suggesting relapsed Hodgki ns disease. Surprisingly, the histological investigation showed thymic hyperplasia as well as the absence of any signs of Hodgkin lymphoma. Thymic hyperplasia is well known as a potential differential diagnosis of mediastinal space-occupying lesions and also as a long-term complication in patients cured of Hodgki ns disease. A detailed case report and a complete review of literature are provided.

Pulmonary low-grade MALT-lymphoma associated with localized pulmonary amyloidosis. A case report

Summary We report on a female patient, who, at the age of 63 years, was found to suffer from low-grade MALT-lymphoma localized at her right upper eyelid. At the time of initial diagnosis, clinical staging showed no further organ involvement. Within the following two months, nodular infiltrates occurred in both lungs. Histopathological investigation of the pulmonary lesions showed pulmonary involvement by the low-grade MALT-lymphoma associated with large globular amyloid deposits of γ-light chain origin. Since the tumor cells of the MALT-lymphoma showed restriction to γ-light chain the amyloid deposits in this case were interpreted as being related to the MALT-lymphoma.