A. D. Ho

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) Hodgkins 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 Hodgkins 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 Hodgkins 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.)

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 Hodgkins 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 Hodgkins 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 Hodgkins lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting. FUNDING Deutsche Krebshilfe and the Swiss Federal Government.

Autologous blood stem-cell transplantation in patients with advanced Hodgkin's disease and prior radiation to the pelvic site.

Patients with relapsed Hodgkins disease who respond to salvage therapy are successfully treated with cyclophosphamide, carmustine (BCNU), and etoposide (VP-16) (CBV) followed by autologus bone marrow transplantation (ABMT). Because of heavy pretreatment including radiation to the pelvic site, marrow harvest was not feasible in those patients. We therefore used blood-derived hemopoietic precursor cells as an alternative stem-cell source to rescue them after superdose chemotherapy. Hemopoietic precursor cells were mobilized into the peripheral blood either by chemotherapeutic induction of transient myelosuppression followed by an overshooting of blood stem-cell concentration, or by continuous intravenous (IV) granulocyte-macrophage colony-stimulating factor (GM-CSF) administration. The median time to reach 1,000 WBC per microliter, 500 polymorphonuclear cells (PMN) per microliter, or 20,000 platelets per microliter was 10, 20.5, and 38 days, respectively, for 50% of all patients. The platelet counts of two patients never dropped below 20,000/microL following autologous blood stem-cell transplantation (ABSCT), whereas two other patients had to be supported with platelets for 75 and 86 days posttransplant until a stable peripheral platelet count of 20,000/microL was attained. Among the 11 assessable patients, seven are in unmaintained complete remission (CR) at a median follow-up of 318 days. This is a first report on a series of ABSCTs in patients with advanced Hodgkins disease proving that, despite prior damage to the marrow site, the circulating stem-cell pool is still a sufficient source of hemopoietic precursor cells for stem-cell rescue.

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.

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

BackgroundCentral 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 methodsA 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 resultsCatheters 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.ConclusionOur 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.

Mobilization of peripheral blood stem cells for autologous transplant in non-Hodgkin's lymphoma and multiple myeloma patients by plerixafor and G-CSF and detection of tumor cell mobilization by PCR in multiple myeloma patients

This report describes the first investigational use of plerixafor in Europe and the determination of tumor cell mobilization by polymerase chain-reaction after plerixafor treatment in a subset of patients with multiple myeloma (MM). Thirty-five patients (31 MM and 4 NHL) received granulocyte colony-stimulating factor (G-CSF) (10 μg/kg) each morning for 4 days. Starting the evening of Day 4, patients recieved plerixafor 0.24 mg/kg. Apheresis was initiated 10–11 h later, in the morning of Day 5. This regimen of G-CSF treatment each morning before apheresis and plerixafor treatment in the evening was repeated for up to 5 consecutive days. Mobilization with plerixafor and G-CSF resulted in a median 2.6-fold increase in peripheral blood (PB) CD34+ cell count compared with before plerixafor treatment. All patients collected ⩾2 × 106 CD34+ cells/kg and 32 of 35 patients collected ⩾5 × 106 CD34+ cells/kg. After plerixafor treatment, 3 of 7 patients had a small increase and 4 of 7 patients had a small decrease in PB tumor cells. No G-CSF was given post transplant. The median number of days to polymorphonuclear leukocyte and platelet engraftment was 14.0 and 11.0, respectively. There were no reports of graft failure. Plerixafor was generally well tolerated. Mobilization of PB CD34+ cells was consistent with previous clinical trials. The addition of plerixafor did not significantly increase the relative number of PB MM tumor cells.

Angiogenesis in hematologic malignancies

Abstract. Angiogenesis defined as the blood vessel generation from preexisting blood vessels was found to play an important role in the progression of solid tumors. In addition, bone marrow-derived endothelial precursor cells may contribute to tumor angiogenesis. Recently angiogenesis induction was described in several hematologic neoplasms as leukemia, lymphoma, myelodysplastic syndrome and multiple myeloma (MM). Clinical angiogenesis research also termed as angiodiagnosis has established the prognostic relevance of markers of angiogenesis e.g., microvessel density and circulating levels of angiogenic peptides. Development of antiangiogenic treatment for hematologic neoplasms has recently been sparked by the success of Thalidomide (Thal) which has antiangiogenic properties in MM. Antiangiogenic treatment strategies are now being tested in clinical trials on several types of hematologic neoplasms.

Occurrence of sarcoidosis subsequent to chemotherapy for non-Hodgkin's lymphoma: report of two cases

Abstract. Sarcoidosis-lymphoma syndrome is a well-established syndrome where sarcoidosis is followed by the development of a lymphoproliferative disease such as non-Hodgkins lymphoma (NHL). Here we report two patients with NHL who developed sarcoidosis subsequent to the diagnosis of lymphoproliferative disease. In both cases, chemotherapeutic treatment had already been initiated or was completed when sarcoidosis occurred. In these patients, sarcoidosis may have been triggered by immunologic aberrations induced by antineoplastic therapy or as a consequence of an underlying immunologic disturbance associated with the lymphoma. When a suspected relapse of lymphoma presents with signs and symptoms compatible with sarcoidosis, this rare immunologic disorder has to be ruled out by careful clinical and histopathologic analysis to prevent mistreatment.

Prognostic factors for the clinical outcome of patients with follicular lymphoma following high-dose therapy and peripheral blood stem cell transplantation (PBSCT).

This is a report on 111 patients with advanced stage follicular lymphoma who where autografted using PBSC. Seventy patients were enrolled in first remission, whereas 41 were treated in second or higher remission. High-dose therapy consisted of total body irradiation plus cyclophosphamide in 103 patients, while eight patients received BEAM (carmustine, etoposide, cytosine-arabinoside, melphalan). Autografts contained 8.1 ± 0.6 × 106 CD34+ cells/kg body weight. At a median follow-up of 44.2 months from PBSCT (range 4.9–77.4 months), 93 patients are alive, with a probability of overall and relapse-free survival (RFS) of 83% and 64%, respectively. A significantly higher probability of relapse was associated with male gender, involvement of more than eight lymph node areas, extra-nodal manifestations other than bone marrow and PBSCT performed in second or higher remission. In the latter group of patients, previous radiotherapy was associated with poor prognosis. The relevance of chemosensitivity as a prognostic factor was reflected by a better RFS in patients who had achieved complete remission at the time of PBSC mobilization. In a multivariate analysis, involvement of eight or more lymph nodes and high-dose therapy performed in second or higher remission were independent prognostic factors. Bone Marrow Transplantation (2000) 25, 957–964.

Plerixafor (Mozobil) for stem cell mobilization in patients with multiple myeloma previously treated with lenalidomide

Lenalidomide and other new agents have considerable activity in multiple myeloma (MM) and have changed the landscape of treatment. Data suggest that lenalidomide therapy before autologous hematopoietic stem cell transplantation has a detrimental effect on stem cell mobilization. This retrospective study examined the efficacy of plerixafor in combination with G-CSF among patients with MM previously treated with lenalidomide (median, 4 cycles; range, 1–20 cycles). Data were analyzed for 60 patients who received plerixafor plus G-CSF for frontline mobilization in a phase 3 clinical trial or an expanded access program (n=20) or for remobilization in a compassionate use program (n=40). The overall median number of CD34+ cells collected was 5.6 × 106 per kg (range, 0.45 × 106–37.2 × 106). The minimum number of CD34+ cells (⩾2 × 106 per kg) was collected from 86.7% of patients in a median of 1 day. This minimum was collected from 100% of patients who underwent frontline mobilization and 80% of patients who underwent remobilization. These data suggest that CD34+ hematopoietic stem cells can be successfully and predictably collected with combination plerixafor plus G-CSF for primary or secondary mobilization in the majority of patients with MM who have been previously treated with lenalidomide.