Search

Seven hundred and twenty-four CLL-outpatients with a median age of 67 (35-92) were analyzed. Four hundred and twenty-seven (59%) were male, 297 (41%) female. At diagnosis 556 (77%) were in Binet stage A, 91 (13%) stage B and 36 (5%) stage C. Forty-six percent received treatment during the evaluation period. Treatment consisted of purine analogs in 38%, alkylating agents in 96%, chemoimmunotherapy with anti-CD20 monoclonal antibodies in 63%, ibrutinib in 9%, venetoclax in 1% and idelalisib in 3%. 3% received allogeneic hematopoietic stem cell transplantation. Overall survival (OS) according to Binet stage was: A 13.9 years (0.1-37.4), B 9.2 years (1.4-29.3) and C 7.9 years (0.5-19.4) respectively. Median OS from the start of therapy improved over time; 1995-2001: 5.8 years, 2002-2008: 6.1 years and 2009-2017: median not reached. Survival of patients with CLL has improved in routine care and was strongly related to active disease, disease stage, performance status and whether therapy included an anti-CD20 monoclonal antibody.

Bendamustine and bendamustine/rituximab combinations have shown high efficacy in relapsed/refractory chronic lymphocytic leukemia (CLL) and indolent B-cell malignancies (non-Hodgkin lymphoma, NHL). No data exist about bendamustine retreatment after relapse, concerning efficacy and toxicity in this patient population. Eighty-eight outpatients (57 patients with CLL, 31 patients with NHL) who had previously been treated with bendamustine were retreated with a bendamustine regimen. Treatment consisted of bendamustine (B) or bendamustine + mitoxantrone (BM) or bendamustine + rituximab (BR) or bendamustine + mitoxantrone + rituximab (BMR). Median age was 72 years (50-88). A reversible grade 3 or 4 leukocytopenia or thrombocytopenia was observed in 24% and 13%, respectively. The overall response rate (ORR) was 76% (7% complete remission [CR], 69% partial remission [PR]) with 77% (6% CR, 71% PR) in CLL and 71% (8% CR, 63% PR) in NHL. ORR according to regimen was as follows: B: 57% (14% CR, 43% PR), BM: 70% (4% CR, 66% PR), BR: 55% (10% CR, 45% PR), BMR: 84% (7% CR, 78% PR). Bendamustine retreatment is feasible and achieves high response rates and some long lasting remissions.

We have evaluated all outpatients with relapsed or refractory chronic lymphocytic leukemia (CLL) who were treated with bendamustine/mitoxantrone/rituximab (BMR) between May 1999 and December 2008. Treatment consisted of bendamustine 90 mg/m2 on day 1 + 2, Mitoxantrone 6 mg/m2 on day 1, and Rituximab 375 mg/m2 on day 8, 15, 22 + 29. Thirty-nine patients (19 males, 20 females) received BMR with a median age of 69 years (46–81). Nineteen patients (49%) were above 70 years and 13 patients (33%) were 75 years or above. Performance score ranged between 0 and 2. The median number of previous therapies was 2 (1–4). Therapy was tolerated well with two observed therapy-associated hospitalizations. A reversible grade 3 or 4 hematotoxicity was seen in 30 patients (77%). Other reversible grade 3 or 4 toxicities were seen in two patients (5%). The overall response rate was 92% (10% complete remission, 82% partial remission). Median time to next CLL-therapy was 13 months (0–69). We conclude that BMR is a short and effective outpatient chemoimmunotherapy for patients with relapsed or refractory CLL, which can be used safely in elderly patients.

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/m(2) days 1 + 2, mitoxantrone 10 mg/m(2) day 1, rituximab 375 mg/m(2) 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.

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 x BMR followed by 5 x 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.

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.

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/m2, day 1-3), mitoxantrone (10 mg/m2, day 1), rituximab (375 mg/m2, 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.

Response of Waldenström's 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 Waldenström's macroglobulinaemia.

A patient with acute monoblastic leukemia (AML, M5A) was treated successfully in December 1987. In 1993 after 6 years in complete remission, she presented with an intracutaneous nodular mass on her right upper arm which was resected in toto and shown to be undifferentiated monoblastic leukemia. Two further chloroma lesions were excised in July 1994 and March 1995 respectively. Bone marrow cytology and histology always showed a continuing complete remission with no evidence of leukemia relapse. In July 1995 she presented with a disseminated skin infiltrate and a relapse with 80% monoblasts in the bone marrow. After one course of chemotherapy (Idarubicin/Ara-C), a second complete remission was achieved and her leukemic skin infiltrate disappeared completely. This case illustrates that chloromas of the skin can occur as late as 6 years after treatment for AML and also emphasizes that the occurrence of a chloroma does not necessarily mean immediate leukemia relapse. It also stresses that a second complete remission can be achieved with standard AML-induction therapy despite widespread leukemic skin infiltrates in such patients.

The results of different investigators show that lack of p105 expression is relatively common in human myeloid leukemias, especially in monocytic leukemias. This suggests that loss of p105 expression could contribute to the altered growth control of these cells. So far no clear data exist which show that low p105 levels in AML blasts predict a poor therapy outcome. Therefore it is not very likely that p105 expression will become a strong prognostic factor for the different treatment strategies in AML.

A case is described of a 71 year old woman with scirrhous breast cancer and multiple hypoechogenic lesions in the spleen. The patient was treated successfully by mastectomy and splenectomy. Morphologic examination of the spleen showed a primary, centroblastic-centrocytic, low grade non-Hodgkin's lymphoma. Eight months after splenectomy the patient still remains in complete remission.