Hubert Köppler

First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial.

BACKGROUND Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab is the standard therapy for physically fit patients with advanced chronic lymphocytic leukaemia. This international phase 3 study compared the efficacy and tolerance of the standard therapy with a potentially less toxic combination consisting of bendamustine and rituximab. METHODS Treatment-naive fit patients with chronic lymphocytic leukaemia (aged 33-81 years) without del(17p) were enrolled after undergoing a central screening process. Patients were randomly assigned (1:1) with a computer-generated randomisation list using randomly permuted blocks with a block size of eight and were stratified according to participating country and Binet stage. Patients were allocated to receive six cycles of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days or to intravenous bendamustine (90 mg/m(2) per day) for the first 2 days of each cycle. Rituximab 375 mg/m(2) was given intravenously in both groups on day 0 of cycle 1 and subsequently was given at 500 mg/m(2) during the next five cycles on day 1. The primary endpoint was progression-free survival with the objective to assess non-inferiority of bendamustine and rituximab to the standard therapy. We aimed to show that the 2-year progression-free survival with bendamustine and rituximab was not 67·5% or less with a corresponding non-inferiority margin of 1·388 for the hazard ratio (HR) based on the 90·4% CI. The final analysis was done by intention to treat. The study is registered with ClinicalTrials.gov, number NCT%2000769522. FINDINGS 688 patients were recruited between Oct 2, 2008, and July 11, 2011, of which 564 patients who met inclusion criteria were randomly assigned. 561 patients were included in the intention-to-treat population: 282 patients in the fludarabine, cyclophosphamide, and rituximab group and 279 in the bendamustine and rituximab group. After a median observation time of 37·1 months (IQR 31·0-45·5) median progression-free survival was 41·7 months (95% CI 34·9-45·3) with bendamustine and rituximab and 55·2 months (95% CI not evaluable) with fludarabine, cyclophosphamide, and rituximab (HR 1·643, 90·4% CI 1·308-2·064). As the upper limit of the 90·4% CI was greater than 1·388 the null hypothesis for the corresponding non-inferiority hypothesis was not rejected. Severe neutropenia and infections were more frequently observed with fludarabine, cyclophosphamide, and rituximab (235 [84%] of 279 vs 164 [59%] of 278, and 109 [39%] vs 69 [25%], respectively) during the study. The increased frequency of infectious complications with fludarabine, cyclophosphamide, and rituximab was more pronounced in patients older than 65 years. INTERPRETATION The combination of fludarabine, cyclophosphamide, and rituximab remains the standard front-line therapy in fit patients with chronic lymphocytic leukaemia, but bendamustine and rituximab is associated with less toxic effects. FUNDING Roche Pharma AG, Mundipharma, German Federal Ministry of Education and Research.

High anti-lymphoma activity of bendamustine/mitoxantrone/rituximab in rituximab pretreated relapsed or refractory indolent lymphomas and mantle cell lymphomas. A multicenter phase II study of the German Low Grade Lymphoma Study Group (GLSG)

On the basis of a preceding phase I study, the current trial explored bendamustine in combination with mitoxantrone and rituximab (BMR) in patients with stage III/IV relapsed or refractory indolent lymphomas and mantle cell lymphoma (MCL) with or without prior rituximab containing chemo-immunotherapy (R-chemo) treatment. Therapy consisted of bendamustine 90 mg/m2 days 1 + 2, mitoxantrone 10 mg/m2 day 1, rituximab 375 mg/m2 day 8. Treatment was repeated on day 29 for a total of four cycles. Between 3 April and 04 July, 57 patients were recruited from 24 participating institutions, 39% of whom had received prior R-chemo therapy. Median age was 66 years (40 – 83). Lymphoma subtypes were 29 follicular (FL), 18 MCL, and 10 other indolent lymphomas. The overall response rate (ORR) was 89% with 35% CR and 54% PR. ORR in R-chemo pretreated patients was 76% (38% CR, 38% PR). After a median observation time of 27 months (1 – 43), the estimated median progression free survival is 19 months. The 2 year overall survival is 60% for patients with FL and MCL. Treatment related toxicities of grade 3/4 comprised a reversible myelosuppression (10% anemia, 78% leukocytopenia, 46% granulocytopenia, 16% thrombocytopenia). However, unexpected hospitalisations were necessary after 4% of BMR-application only. BMR is a very effective new outpatient immuno-chemotherapy with low toxicity for patients with relapsed/refractory FL, MCL and other indolent lymphomas.

Bendamustine/Mitoxantrone/Rituximab (BMR): a very effective, well tolerated outpatient chemoimmunotherapy for relapsed and refractory CD20-positive indolent malignancies. Final results of a pilot study.

We have developed a new chemoimmunotherapy for patients with relapsed or refractory CD20-positive indolent lymphomas and CLL by combining the chemotherapeutic agents Bendamustine (B) and Mitoxantrone (M) with the monoclonal antibody Rituximab. Treatment consisted of (B): 90 mg/m2 (80 mg/m2 in CLL) day 1 + 2, (M): 10 mg/m2 day 1 and (R): 375 mg/m2 day 8,15,22 and 29. BM was repeated 3 times starting on day 36, thereafter every 4 weeks. The maximal therapy consisted of 1 × BMR followed by 5 × BM. We have treated 54 patients with BMR. Median age was 68 years (36 - 82). Disease distribution was as follows: 21 B-CLL, 1 B-PLL, 8 lymphoplasmacytic, 14 follicular, 2 mantle cell, 2 marginal zone, 6 secondary high grade. Median number of previous treatments was 2 (1 - 7). ORR was 96% with 41% CR and 55% PR. Median time to progression is 17 months in CLL and has not been reached in indolent lymphomas with a median observation time of 27 months (3 - 60 + ). The time to next antilymphoma treatment is prolonged significantly by BMR. No therapy associated death or hospitalization occurred within the study period. BMR is a well tolerated very effective outpatient treatment for relapsed and refractory CD20-positive indolent lymphomas and CLL.

Bendamustine Plus Mitoxantrone—A New Effective Treatment for Advanced Chronic Lymphocytic Leukaemia: Results of a Phase I/II Study

The toxicity arid efficacy of the combination bendamustine plus mitoxantrone (BM) was evaluated in 22 patients with advanced chronic lymphocytic leukaemia (CLL). Twenty out of twenty-two patients had received at least one prior regimen. Median age was 71 years (range 53-86). Six out of twenty-two patients were Binet stage B and 16/22 Binet stage C. Bendamustine was given in escalating doses from 80 up to 240 mg/m2 divided in two to three doses per course, mitoxantrone was given as short infusion with 8 up to 10 mg/m2 per course. The number of courses was limited to six and chemotherapy stopped when a complete remission (CR) or partial remission (PR) according to NCI-Criteria was achieved. Haematotoxicity and infection were dose limiting with 4/6 patients suffering from grade 3 infectious complication in the bendamustine level with 240 mg/m2. Six out of twenty-two patients achieved a CR and 13/22 patients a PR resulting in an overall response rate of 86% (19/22 patients). Median time to progression was 10 months (range 4-22) and median survival 39 months (range 6-50). For further studies we recommend a bendamustine dose of 150 mg/m2 combined with 10 mg/m2 mitoxantrone.

The polyneuropathy associated with Waldenström's macroglobulinaemia can be treated effectively with chemotherapy and the anti-CD20 monoclonal antibody rituximab

A 50‐year‐old male developed headache, impaired balance, visual defects and severe deafness. Ten months later he presented with markedly reduced power and tremor of his right arm. Waldenströms macroglobulinaemia (WM) with accompanying polyneuropathy was diagnosed. The patient received chemotherapy, which resulted in a partial improvement of the arm tremor. Subsequently, he was treated with rituximab (4 × 375 mg/m2), leading to complete resolution of the tremor and the paresis of his arm. Additionally, his headache and imbalance disappeared. Fifteen months after rituximab therapy he remained free of any neurological symptoms. This is the first report showing that WM‐associated polyneuropathy can be treated effectively with a combination of chemotherapy and the anti‐CD20 monoclonal antibody rituximab.

Successful treatment of clozapine induced agranulocytosis with granulocyte-colony stimulating factor (G-CSF)

alpha1 -antitrypsin by immunoperoxidase staining. These findings are compatible with Ki-1 lymphoma. Tumour cells of the pleural effusion were positive for the following antibodies: Ki-1, EMA, alpha-I-antitrypsin, OKT9. HLA-DR. IL-2R. CDwl2 and were negative for CD1. CD2. CD4, CD5, CD7. CDl0. CDIl , CDwl3. CDIS. CD19. CD20, CD24. 0KTlO.TdT. IgG. IgM, IgA. kappa and lamda. Assay of G-CSF production by lymphoma cells. A portion of the bioposied lymph node was minced and the tumour cells ( 5 x 1 05/ml) were suspended in RPMI 1640 medium with 10% fetal bovine serum. The suspension was incubated at 37°C in humidified air with 5% C02. After day 7 of culture, G CSF in the lymphoma cell-conditioned medium (LC-CM) was assayed by two methods, by in vitro colony formation and by enzyme iummunoassay (EM) (Watari et al. 1989). The method of colony formation has been described elsewhere (Nishihara et al, 1977). Non-adherent bone marrow mononuclear cells from a normal volunteer were used for colony formation. Cultures were performed in the presence of the LCCM at a concentration of 10% or in the presence of purified natural type G-CSF 100 units (Chugai. Japan). The G-CSF level of the patients serum at the time of neutrophilia was also assayed by H A . Neutrophil colony forming activity ofthe LC-CM was 3 times higher than that of G-CSF 100 units. GCSF activity assayed by EIA showed 64 1 6 pg/ml in the LC-CM and 3007 pg/ml in the patients serum (normal serum level less than 50 pg/ml). This may be the first case of Ki-1 lymphoma producing GCSF. Although we cannot completely exclude the possibility of G-CSF produced by nonmalignant cells, the cause of neutrophilia in this case is likely to have been excessive production of G-CSF by the lymphoma cells, because the degree of neutrophilia correlated clinically with the tumour burden, absence of other causes of neutrophilia. most of the colonies formed by the LC-CM consisted of neutrophils, and the G-CSF level of the LC-CM and the patients serum were extremely high. Ki-1 lymphoma is very heterogenous in its clinical symptoms, histology, tumour cell biology and prognosis. An excessive production of G-CSF may be a unique finding of Ki1 lymphoma.

Bendamustine Mitoxantrone and Rituximab (BMR): A New Effective Regimen for Refractory or Relapsed Indolent Lymphomas

Bendamustine (B) and mitoxantrone (M) have been shown to be potent cytotoxic drugs for the treatment of relapsed or refractory indolent lymphomas. The anti-CD20 monoclonal antibody rituximab (R) has produced an overall response rate (ORR) of 50% as a single agent in relapsed or refractory indolent lymphomas. We posed the question whether a combination of the above agents (BMR) could improve these results. This study was an open label, single center pilot study for patients with relapsed or refractory, CD20-positive (indolent) lymphoma or chronic lymphocytic leukaemia. The therapy consisted of bendamustine (80 mg/m 2, day 1-3), mitoxantrone (10 mg/m 2, day 1), rituximab (375 mg/m 2, week 2-5). BM was repeated on day 36 or when the haematological parameters had recovered. The maximum therapy consisted of one BMR-cycle, followed by five BM courses. Treatment was stopped when the disease responded with PR/CR. During March 1999 and December 2000, 20 patients received the BMR-regimen (four secondary high grade lymphoma, 12 indolent lymphoma, four B-CLL). The median age of the patients was 67 years (range 36-82) and their performance status ranged from 0 to 3. Median number of previous treatment regimens was two (1-6). Of the lymphoma patients, 14 had stage IV disease, 1 stage III and 1 stage II. B-CLL patients were all Rai stage IV (Binet C). Overall response rate was 95% (19/20) with seven patients achieving a CR(35%) and 12 patients achieving a PR (60%). Median time to progression is 7 months (1-21) with a median observation time of 7 months (1-21). Response is still durable in 15/20 patients (75%) (1+ to 21+ months after therapy). Symptomatic, reversible grade three or four haematotoxicity occurred in 4/20 patients (20%). Non-symptomatic grade three or four haematotoxicity was seen in 9/20 patients (45%). No major non-haematological toxicity was observed. In conclusion, BMR is a well tolerated, very effective outpatient regimen of treatment for relapsed and refractory indolent lymphoid malignancies.

Storage of noncryopreserved periphered blood stem cells for transplantation

Mobilized peripheral blood stem cells (PBSC) were collected in autologous plasma and acid-citrate-dextrose formula A (ACD-A) by leukaphereses using the CS3000 cell separator (Baxter) and stored at 4°C in a refrigerator for 8 days. We have looked at the viability of the nucleated cells with the trypan blue test and the proliferation and differentiation capacity using a standardized progenitor cell cloning assay. The changes in viability, granulocyte-macrophage colonyforming units (CFU-GM), erythroid burst-forming units (BFU-E), and mixed-lineage colony-forming units (CFU-GEMM) were determined daily during the storage period. Viability was 90.8% (SD 8%) at day 0 and declined to a mean of 69.5% (SD 15.5%) at day 8. CFU-GM decreased to 47% (SD 28.7%), CFU-GEMM to 48% (SD 42.2%), and BFU-E to 40.1% (SD 18.4%) after 6 days. After 5 days of storage the mean viability was 79.7% (SD 17.8%), whereas the mean CFU-GM were 65.3% (SD 28.4%) the mean CFU-GEMM were 61.8% (SD 30.4%) and the mean BFU-E were 55.1% (SD 18.2%). At day 4 viability was still 82.5% (SD 17.0%), recovery of CFU-GM was 78.5% (SD 28.8%), recovery of CFU-GEMM was 70.7% (SD 40.4%) and recovery of BFU-E was 65.0% (SD 17.5%). These data show, that PBSC can be stored safely over at least 5 days at 4°C while the patient receives high-dose chemotherapy.

Evaluation of psychosocial distress in patients treated in a community-based oncology group practice in Germany

Background: Systematic evaluation of psychosocial distress in oncology outpatients is an important issue. We assessed feasibility and benefit of standardized routine screening using the Distress Thermometer (DT) and Problem List (PL) in all patients of our community-based hematooncology group practice. Patients and methods: One thousand four hundred forty-six patients were screened between July 2008 and September 2008. Five hundred randomly selected patients were sent a feedback form. Results: The average distress level was 4.7, with 37% indicating a distress level >5. Patients with nonmalignant diseases (81% autoimmune diseases or hereditary hemochromatosis) showed the highest distress level of 5.2. Most distressed were patients who just learned about relapse or metastases (6.4), patients receiving best supportive care (5.4) and patients receiving adjuvant antihormonal therapy (5.4). Ninety-seven percent of patients appreciated to speak to their doctor about their distress. Fifty-six percent felt better than usual after this consultation. Conclusion: DT and PL are feasible instruments to measure distress in hematooncology outpatients receiving routine care. DT and PL are able to improve doctor–patient communication and thus should be implemented in routine patient care. The study shows that distress is distributed differently between individuals, disease groups and treatment phases.

Induction of Complete Haematological Remission After Monotherapy with AntLCD20 Monoclonal Antibody (RITUXIMAB) in a Patient with Alkylating Agent Resistant Waldenstrom's Macroglobulinaemia

Response of Waldenströms macroglobulinaemia to chemotherapy with alkylating agents is usually only transient. We report a case with marked bone marrow involvement and resistance to chemotherapy with alkylating agents. The patient was red cell and platelet transfusion dependent. Three weeks after rituximab-monotherapy, he achieved a complete haematological remission which is continuing 6 months after the end of therapy. Our case demonstrates that treatment with the unconjugated anti-CD20-monoclonal antibody (rituximab) may be a new powerful tool for a better treatment of Waldenströms macroglobulinaemia.