Two cycles of risk-adapted consolidation therapy in patients with acute promyelocytic leukemia. Results from the SAL-AIDA2000 trial.

The combination of all-trans retinoic acid (ATRA) and idarubicin (AIDA) for induction therapy followed by three cycles of risk-adapted consolidation cycles is considered standard of care for patients with acute promyelocytic leukemia (APL). We report the outcome of 141 patients (median age 51 years; range, 19-82, 31 % ≥60 years) enrolled into the prospective Study Alliance Leukemia (SAL)-AIDA2000 trial, which comprised AIDA-based induction followed by only two courses of risk-adapted consolidation (daunorubicin or mitoxantrone ± cytarabine) followed by 2-year maintenance treatment. The early death rate was 7 % (median age 66 years), and additional 9 % stopped further treatment after induction. The estimated 6-year disease-free survival (DFS) was 80 % in all patients, 84 % in patients ≤60 and 72 % in patients >60 years (p = 0.140). No significant survival differences were observed between the high-risk and the non-high-risk patients (6-year OS 78 vs. 81 %, p = 0.625). Our results confirm the efficacy of a risk-adapted approach in APL patients. Furthermore, long-term outcomes are comparable to the results obtained with three cycles of consolidation. A modification of the number and intensity of conventional consolidation treatment may be a less toxic but equally effective approach and should be considered for further evaluation in randomized clinical trials in APL.

Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial.

BACKGROUND: The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkin's lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy. METHODS: In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkin's lymphoma aged 18-60 years were randomly assigned to receive either eight cycles of BEACOPP(escalated) (8×B(esc) group), six cycles of BEACOPP(escalated) (6×B(esc) group), or eight cycles of BEACOPP(14) (8×B(14) group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041. FINDINGS: Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8×B(esc) group, 711 in the 6×B(esc) group, and 710 in the 8×B(14) group. Freedom from treatment failure was sequentially non-inferior for the 6×B(esc) and 8×B(14) groups as compared with 8×B(esc). 5-year freedom from treatment failure rates were 84·4% (97·5% CI 81·0-87·7) for the 8×B(esc) group, 89·3% (86·5-92·1) for 6×B(esc) group, and 85·4% (82·1-88·7) for the 8×B(14) group (97·5% CI for difference between 6×B(esc) and 8×B(esc) was 0·5-9·3). Overall survival in the three groups was 91·9%, 95·3%, and 94·5% respectively, and was significantly better with 6×B(esc) than with 8×B(esc) (97·5% CI 0·2-6·5). The 8×B(esc) group showed a higher mortality (7·5%) than the 6×B(esc) (4·6%) and 8×B(14) (5·2%) groups, mainly due to differences in treatment-related events (2·1%, 0·8%, and 0·8%, respectively) and secondary malignancies (1·8%, 0·7%, and 1·1%, respectively). The negative predictive value for PET at 12 months was 94·1% (95% CI 92·1-96·1); and 225 (11%) of 2126 patients received additional radiotherapy. INTERPRETATION: Treatment with six cycles of BEACOPP(escalated) followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPP(escalated) should be the treatment of choice for advanced stage Hodgkin's lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting. FUNDING: Deutsche Krebshilfe and the Swiss Federal Government.

Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma.

BACKGROUND: Whether it is possible to reduce the intensity of treatment in early (stage I or II) Hodgkin's lymphoma with a favorable prognosis remains unclear. We therefore conducted a multicenter, randomized trial comparing four treatment groups consisting of a combination chemotherapy regimen of two different intensities followed by involved-field radiation therapy at two different dose levels. METHODS: We randomly assigned 1370 patients with newly diagnosed early-stage Hodgkin's lymphoma with a favorable prognosis to one of four treatment groups: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of radiation therapy (group 1), four cycles of ABVD followed by 20 Gy of radiation therapy (group 2), two cycles of ABVD followed by 30 Gy of radiation therapy (group 3), or two cycles of ABVD followed by 20 Gy of radiation therapy (group 4). The primary end point was freedom from treatment failure; secondary end points included efficacy and toxicity of treatment. RESULTS: The two chemotherapy regimens did not differ significantly with respect to freedom from treatment failure (P=0.39) or overall survival (P=0.61). At 5 years, the rates of freedom from treatment failure were 93.0% (95% confidence interval [CI], 90.5 to 94.8) with the four-cycle ABVD regimen and 91.1% (95% CI, 88.3 to 93.2) with the two-cycle regimen. When the effects of 20-Gy and 30-Gy doses of radiation therapy were compared, there were also no significant differences in freedom from treatment failure (P=1.00) or overall survival (P=0.61). Adverse events and acute toxic effects of treatment were most common in the patients who received four cycles of ABVD and 30 Gy of radiation therapy (group 1). CONCLUSIONS: In patients with early-stage Hodgkin's lymphoma and a favorable prognosis, treatment with two cycles of ABVD followed by 20 Gy of involved-field radiation therapy is as effective as, and less toxic than, four cycles of ABVD followed by 30 Gy of involved-field radiation therapy. Long-term effects of these treatments have not yet been fully assessed. (Funded by the Deutsche Krebshilfe and the Swiss Federal Government; ClinicalTrials.gov number, NCT00265018.)

Treatment with intravenous melphalan and dexamethasone is not able to overcome the poor prognosis of patients with newly diagnosed systemic light chain amyloidosis and severe cardiac involvement.

Treatment with oral melphalan and dexamethasone (M-Dex) was reported to be effective and feasible in patients with systemic light chain amyloidosis (AL) not eligible for high-dose melphalan. We report on 61 patients with advanced AL who were treated with intravenous M-Dex as first-line therapy. Estimated median overall survival (OS) was 17.5 months. Seventeen patients (28%) died within 3 months, mostly of disease-related complications. In addition, nonhematologic toxicity of Common Terminology Criteria grade 3 or 4 was observed in 20 patients, whereas hematologic toxicity was low. Twenty-seven patients (44%) had hematologic response, including complete in 7 patients (11%) and partial remission in 20 patients (33%). Organ response was observed in 15 patients (25%). The amount of the involved free light chains in serum and Karnofsky Index at diagnosis significantly influenced OS. Plasma levels of the cardiac biomarkers before start of treatment and their increase after the third M-Dex cycle also were strong negative predictors of OS. These parameters might help to identify patients who will not benefit from M-Dex chemotherapy.

Replacement of conventional doxorubicin by pegylated liposomal doxorubicin is a safe and effective alternative in the treatment of non-Hodgkin's lymphoma patients with cardiac risk factors.

Anthracyclines are a major component in the therapy of non-Hodgkin's lymphoma. However, due to their cardiac toxicity potential, curative and palliative treatment is often limited in patients with preexisting cardiac dysfunction. Liposomal doxorubicin formulations have been described to be less cardiotoxic than conventional doxorubicin. In the current study, we analyzed the efficacy and toxicity of pegylated liposomal doxorubicin (PLD) as constituent of the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen replacing conventional doxorubicin in 21 patients with impaired cardiac left ventricular ejection fraction or preexisting cardiac risk factors and established diagnosis of diffuse large B cell lymphoma (n = 15), mantle cell lymphoma (n = 3), follicular lymphoma (n = 1), and T cell lymphoma (n = 2). Overall and complete response rate were 85% and 40%, respectively. Event-free survival and overall survival after 2 years were 58%. One lethal event of acute cardiac death occurred during the first cycle in a patient with transposition of the big arteries, atrial flutter, and mitral valve regurgitation. In the remaining 20 patients, no deterioration of myocardial function was observed in echocardiography performed before and after treatment. Seven cases of grade III-IV hematological toxicity were observed as well as four episodes of neutropenic fever leading to hospitalization. No infection-related death occurred. However, 25% of patients developed a hand-foot syndrome (HFS) leading to discontinuation of treatment. Importantly, the incidence of HFS increased considerably when PLD doses of 15 mg/m(2)/week were exceeded. We conclude that replacing conventional doxorubicin with PLD in polychemotherapy regimens such as CHOP is an efficient alternative in the treatment of patients with preexisting cardiac dysfunction. However, we recommend that PLD dose should not exceed 15 mg/m(2)/week. The rationale for the use of non-pegylated liposomal doxorubicin formulations should be evaluated in further studies.

Patterns and outcome of relapse after autologous stem cell transplantation for mantle cell lymphoma.

BACKGROUND: Autologous stem cell transplantation (autoSCT) has improved the outcome of patients with mantle cell lymphoma (MCL) considerably. However, little is known about the patterns and outcome of MCL recurrence after autoSCT. METHODS: The authors conducted a retrospective study of 118 patients with MCL who underwent autoSCT from August 1992 to August 2008 at 3 different referral centers in Germany. RESULTS: Fifty-two relapses occurred for a cumulative incidence of 46% after 5 years. Only 3 patients relapsed after 5 years (at 90 months, 91 months, and 171 months) after undergoing autoSCT. A Cox regression analysis of the incidence of relapse identified not receiving rituximab before autoSCT and undergoing salvage autoSCT as predictive factors for relapse, whereas cytosine arabinoside intensification; a total body irradiation-based, high-dose regimen; patient age; and year of transplantation had no influence. The median overall survival (OS) after relapse was 23 months. Twenty patients (39%) underwent allogeneic stem cell transplantation (alloSCT) for relapse, and 11 of those patients remained in ongoing complete remission at the time of the current report. It is noteworthy that there were 4 long-term survivors who lived for >5 years after relapse even without undergoing alloSCT. A Cox regression analysis of OS after relapse revealed that the response duration after autoSCT was an adverse predictor of OS, whereas alloSCT was associated with a significantly longer OS after relapse. CONCLUSIONS: The current results indicated that autoSCT was capable of inducing long-term remission up to 16 years after treatment, but the outcome of patients with MCL who relapsed after autoSCT was poor, especially if their response duration after autoSCT was short. However, for a subset of patients with relapsed MCL, alloSCT may offer the possibility of durable survival, and individual patients can enjoy long-term survival after relapse even without undergoing alloSCT.

Chlorhexidine and silver-sulfadiazine coated central venous catheters in haematological patients--a double-blind, randomised, prospective, controlled trial.

BACKGROUND: Central venous catheters (CVCs) are essential for the intensive care of patients with haematological illness. Catheter-related infections (CRI) are an important problem in modern medicine, which may lead to life-threatening situations, to prolonged hospitalisation and increased cost. In immunocompromised patients suffering from haemato-oncological diseases, CRI is a significant factor for adverse outcome. Several clinical studies have shown that CVCs coated with antiseptics such as chlorhexidine and silver-sulfadiazine (CHSS) reduce the risk of catheter-related bacteraemia. Most studies, however, were performed on intensive care patients not suffering from chemotherapy-induced immunosuppression. PATIENTS AND METHODS: A prospective double-blind, randomised, controlled trial was performed to investigate the effectiveness of CHSS-coated catheters in haemato-oncological patients. A total number of 184 catheters (median duration of placement, 11 days) were inserted into 184 patients (male 115, female 69), of which 90 were antiseptically coated. After removal, all catheters were investigated for bacterial growth. MAIN RESULTS: Catheters coated with CHSS were effective in reducing the rate of significant bacterial growth on either the tip or subcutaneous segment (26%) compared to control catheters (49%). The incidence of catheter colonisation was also significantly reduced (12% coated vs 33% uncoated). Data obtained show a significant reduction of catheter colonisation in CHSS catheters. There was no significant difference in the incidence of catheter-related bacteraemia (3% coated vs 7% uncoated). However, due to the overall low rate of CRI, we could not observe a significant reduction in the incidence of catheter-related bacteraemia. CONCLUSION: Our data show that the use of CHSS catheters in patients with haematological malignancy reduces the overall risk of catheter colonisation and CRI, although the incidence of catheter-related bacteremia was similar in both groups.