Ifosfamide, etoposide, cytarabine, and dexamethasone as salvage treatment followed by high-dose cyclophosphamide, melphalan, and etoposide with autologous peripheral blood stem cell transplantation for relapsed or refractory lymphomas.

High-dose chemotherapy (HD-CT) with autologous stem cell transplantation is considered to be the treatment of choice for relapsed high-grade non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) patients, but the optimal treatment has not yet been defined. We evaluated a salvage treatment regimen consisting of conventional cycles with ifosfamide, etoposide, cytarabine, and dexamethasone (IVAD) followed by two cycles of HD-CT consisting of cyclophosphamide, melphalan, and etoposide (CMV) with autologous stem cell support in patients with relapsed or refractory NHL (n = 59) and HL (n = 16). Response to IVAD was complete remission (CR) in 16 patients (21%), partial remission (PR) in 39 patients (52%), stable disease (SD) in 18 patients (24%), and progressive disease (PD) in two patients (2.7%). Of 70 patients treated with HD-CT, 41 patients (59%) showed a CR, 20 patients a PR (29%), eight patients a SD (11%), and one patient a PD (1.4%). The 5-yr overall survival for the entire group of patients was 29%, and for patients with NHL and HL 25%, and 38%, respectively. The respective event-free survival probabilities at 5 yr were 22%, 16%, and 31%. Seven treatment-related deaths due to septicemia (three), cardiac arrhythmia (one), pneumonia (one), pneumonitis (one), and toxic epidermal necrolysis (one) were observed. In multivariate analysis, an International Prognostic Index of > or = 2 and resistant disease to first-line chemotherapy were poor independent prognostic factors for the subgroup of patients with NHL. In conclusion, these results indicate that IVAD/CMV is feasible as a salvage therapy for lymphoma patients. This treatment is currently evaluated with the addition of rituximab.

Epoetin beta (NeoRecormon) therapy in patients with solid tumours receiving platinum and non-platinum chemotherapy: a meta-analysis.

BACKGROUND: Anaemia is a common complication of chemotherapy (CT), including both non-platinum (Pt)-based as well as Pt-based CT. PATIENTS AND METHODS: Patients from three controlled trials with solid tumours receiving either Pt- or non-Pt-based CT, who had been randomised to epoetin beta treatment or standard care, were included in this meta-analysis (n=255, n=199, respectively), to see if epoetin beta was equally effective in both CT types. The primary endpoint was haemoglobin (Hb) change. Secondary end-points included transfusion requirement, adverse events (AEs), survival, time to tumour progression and thromboembolic events (TEEs). RESULTS: All patients responded rapidly to epoetin beta treatment, showing a median Hb increase of > or = 1 g/dl from baseline at week 4. A median Hb of 12.2, 12.5 and 11.8 g/dl was achieved in all patients, those receiving Pt-based CT and those receiving non-Pt-based CT, respectively, after 16 weeks of treatment. Transfusion risk reductions associated with epoetin beta treatment of 53% (p<0.0001), 61% (p<0.0001) and 26% (non significant) were observed for all patients, Pt- and non-Pt-based CT patients, respectively. Overall, for all three populations, there were no risks identified for tumour progression or overall survival. There was a statistically non-significant incidence of TEEs (5.9% versus 4.5%) and no marked differences were observed between groups for frequency or type of AEs reported. CONCLUSION: The type of CT has no impact on the ability of epoetin beta to rapidly increase Hb in patients with solid tumours and CT-induced anaemia.

Hemolytic uremic syndrome following prolonged gemcitabine therapy: report of four cases from a single institution.

Hemolytic uremic syndrome (HUS) has been described following the administration of multiple antineoplastic agents, most notably mitomycin C. More recently, several cases of gemcitabine-induced HUS have been observed with the overall incidence of gemcitabine-induced HUS estimated at 0.015-0.25%. We here report on four patients who developed HUS following gemcitabine therapy at our institution within the last year (incidence 1.4%). All these patients had advanced-stage disease, were heavily pretreated, and received prolonged gemcitabine application, suggesting that in this subgroup of patients HUS may be more frequently encountered than documented so far.

Thalidomide in combination with vincristine, epirubicin and dexamethasone (VED) for previously untreated patients with multiple myeloma.

The present study aimed to evaluate the side-effects and efficacy of thalidomide in combination with an anthracycline-containing chemotherapy regimen in previously untreated myeloma patients. Thalidomide (400 mg/d) was combined with bolus injections of vincristine and epirubicin and oral dexamethasone (VED). Chemotherapy cycles were repeated every 3 wk until no further reduction in myeloma protein was observed, whereas the treatment with thalidomide was continued until disease progression. Thirty-one patients were enrolled, 12 patients were exclusively treated with thalidomide in combination with VED and 19 patients additionally received high-dose melphalan, for consolidation. Adverse events and response to therapy were assessed prior to treatment with high-dose chemotherapy. Response to thalidomide combined with VED was complete remission in six patients (19%), partial remission in 19 patients (61%), stable disease in five patients (16%), and progressive disease in one patient (3.2%). Grade 3 and 4 adverse events consisted of leukocytopenia in 10 patients (32%), and thrombocytopenia and anemia in one patient each (3.2%). Neutropenic infections grade 3 and 4 occurred in seven (23%) and three patients (9.7%), respectively, including two patients (6.5%) who died from septic shock. Deep vein thrombosis occurred in eight patients (26%), constipation in 20 patients (65%), and polyneuropathy in 20 patients (65%). The probability of event-free survival and overall survival in the whole group of patients at 36 months were 26 and 62%, respectively. In conclusion, the combination of thalidomide with VED appears to be highly effective in previously untreated patients with multiple myeloma, but it is associated with a high rate of thrombotic events, polyneuropathy, and neutropenic infections.

FDG-PET/CT in re-staging of patients with lymphoma.

The aim of this study was to evaluate the clinical significance of combined fluorine-18 fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT) in patients with lymphoma, and to compare the FDG-PET/CT staging results with those of FDG-PET and CT alone. Twenty-seven patients were studied. Each patient had clinical follow-up for >12 months and entered complete follow-up evaluation. Patient-based evaluation showed a sensitivity of 78% for CT alone, 86% for FDG-PET alone, 93% for CT and FDG-PET read side by side, and 93% for combined FDG-PET/CT imaging. Region-based evaluation showed a sensitivity for regional lymph node involvement of 61%, 78%, 91% and 96% respectively. FDG-PET/CT imaging is superior to CT alone ( P=0.02) and has additional benefit over FDG-PET alone due to exact anatomical localisation. We conclude that FDG-PET/CT imaging is accurate in re-staging lymphoma and offers advantages over separate FDG-PET and CT imaging.

Antimicrobial therapy of unexplained fever in neutropenic patients--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO), Study Group Interventional Therapy of Unexplained Fever, Arbeitsgemeinschaft Supportivmassnahmen in der Onkologie (ASO) of the Deutsche Krebsgesellschaft (DKG-German Cancer Society).

Cytostatic chemotherapy of hematological malignancies is often complicated by neutropenia, which increases the risk of infections, especially if the neutrophil count is below 500/microl. Frequently, fever is the first, and in most patients the only, sign of an infection. Unexplained fever is defined as follows: temperature of >/=38.3 degrees C or >/=38.0 degrees C for at least 1 h, or measured twice within 12 h, if the neutrophil count is <500/microl or <1000/microl with predicted decline to 500/microl. Different risk categories can be identified according to the duration of neutropenia: low risk /=10 days. An empirical mono- or duotherapy with antipseudomonal and antistreptococcal agents should be initiated immediately. In the low risk patient group, oral therapy with cipro-, levo-, or ofloxacin combined with amoxicillin/clavulanic acid is permissible. For standard and high risk patients, monotherapy can be carried out with either ceftazidime, cefepime, piperacillin with tazobactam or a carbapenem. In duotherapy, a single dose of an aminoglycoside is combined with acylaminopenicillin or a cephalosporin of the third or fourth generation. The addition of glycopeptides in empirical therapy should only be considered in the presence of severe mucositis, or if a catheter-associated infection is suspected. If fever persists after 72-96 h of first-line therapy with antibiotics, the regimen should be modified (with the exception of e.g. coagulase-negative staphylococci infections, because these infections take longer to respond). Intermediate risk patients should additionally receive an aminoglycoside after monotherapy (penicillin or a cephalosporin). If a carbapenem was administered for monotherapy, this can be followed by a quinolone and/or a glycopeptide. In the high risk group, the same modifications should be made as in the intermediate risk group but with additional systemic antifungal treatment. In the presence of unexplained fever, fluconazole can be administered at first, but if this fails, amphotericin B (conventional or liposomal), itraconazole, voriconazole or caspofungin should be started. After defervescence to <38 degrees C, treatment should be continued for 7 days if the neutrophil count is <1000/microl, and for 2 days if the neutrophil count is >1000/microl.

Impact of chemotherapy regimen and hematopoietic growth factor on mobilization and collection of peripheral blood stem cells in cancer patients.

Various chemotherapy regimens, combined with recombinant human granulocyte colony-stimulating factor(rhG-CSF) or recombinant granulocyte-macrophage CSF (rhGM-CSF) are used in cancer patients to mobilize and collect peripheral blood stem cells (PBSC). In this retrospective study, we evaluated and compared the efficacy of such regimens in 262 patients with different types of malignant diseases. The following chemotherapy regimens were applied: ifosfamide-etoposide-cisplatin or bleomycin (n = 96; mainly patients with testicular cancer); ifosfamide-etoposide plus or minus cytosine arabinoside (Ara-C) or vincristine (VCR)(n = 52; mainly patients with lymphoma); cyclophosphamide-anthracycline (n = 53; mainly patients with breast cancer); intermediate to high dose (ID-HD) cyclophosphamide (n = 37; mainly patients with breast or ovarian cancer. or multiple myeloma; and others (n = 24). rhG-CSF or rhGM-CSF, each at an average daily dose of 5 microg/kg body weight, were used in 166 and 96 patients, respectively. The study evaluated and compared the efficacy of these two cytokines. In patients receiving rhG-CSF, CD34+ cells could be collected earlier (median: day 14 versus day 16) and there was a significantly higher white blood cell count (WBC)(median 11,350 versus 5550/microl) and CD34+ cell count (median 88 versus 43/microl) at the start of apheresis, and a significantly higher CD34+ cell yield (median 7.4 x 10(6) versus 4.6 x 10(6)/kg) than in patients who receivedrhGM-CSF. Among the various chemotherapeutic regimens used, each combined with rhG-CSF, ifosfamide-etoposide plus or minus Ara-C or VCR mobilized a significantly higher number of CD34+ cells (median 119/microl) and produced a significantly higher harvest of these cells (median 13 x 10(6)/kg) than cyclophosphamide-anthracycline (median 87/microl and 7 x 10(6)/kg, respectively) or ID-HD cyclophosphamide (median 59/microl and 5 x I 0(6)/kg, respectively). Ifosfamide-etoposide plus or minus Ara-C or VCR was also superior to ifosfamide-etoposide-cisplatin or bleomycin (median 78/microl and 9 x 10(6)/kg, respectively), but at borderline significance. The outcome of PBSC mobilization and collection appeared to be negatively influenced by the number of relapses before the current salvage treatment. These data indicate that mobilization and collection of PBSCstrongly depend on the type of hematopoietic growth factor and chemotherapeutic regimen used. The data further show rhG-CSF is a more effective growth factor than rhGM-CSF and ifosfamide-etoposide-based regimens, particularly ifosfamide-etoposide plus or minus Ara-C or VCR, are highly effective regimens in mobilizing and collecting CD34+ cells.

Relation between S-phase fraction of myeloma cells and anemia in patients with multiple myeloma.

In an attempt to define the relation among anemia, tumor mass, and proliferative activity of tumor cells in vivo, we measured the proportion and cell cycle distribution of erythropoietic cells and myeloma cells in the bone marrow of patients with multiple myeloma using four-parameter flow cytometry. Forty-three bone marrow samples from 33 patients with stage II or III disease and normal renal function at diagnosis (n = 9), in partial remission (n = 9), and in progression or relapse after chemotherapy (n = 25) were evaluated. Early and late erythropoietic cells were discriminated based on published light scatter properties in combination with CD71 expression. Myeloma cells were detected by exploiting their strong CD38 positivity and light scatter characteristics. Cell cycle distribution of the three cell populations was determined by propidium iodine staining. In the whole group of patients, hemoglobin (Hb) concentration was inversely correlated with beta2-microglob-ulin (p = 0.03), percentage of marrow CD38++ cells (p = 0.008), and percentage of CD38(++) cells in S phase (S-CD38++; p < 0.001). Partial correlation analysis revealed S-CD38++ to be the only independent predictor of Hb concentration (p < 0.001). No correlation was found between Hb concentration and the S-phase fraction of erythropoietic cells. In the subgroup of patients with moderate to severe anemia, defined as Hb concentration <11 g/dL, Hb level correlated negatively only with S-CD38++ (p < 0.001) but not with beta2-microglobulin and percentage of marrow CD38++ cells. In addition, Hb and the S-phase proportion of early erythropoietic cells correlated positively (p = 0.029). The strong inverse correlation between Hb concentration and percentage of myeloma cells in S phase suggests that in multiple myeloma, tumor proliferative activity may have a more important impact on the development of anemia than tumor mass. The S-phase fraction of tumor cells appears to be the most important pathogenic factor, especially in anemic patients. In these patients, the positive relation between Hb concentration and the S-phase fraction of erythropoietic progenitors indicates that development of anemia is associated with inhibition of erythropoiesis.

Gemcitabine as a single agent in the treatment of relapsed or refractory aggressive non-Hodgkin's lymphoma.

PURPOSE: A multicenter phase II trial was conducted to evaluate the efficacy and toxicity of gemcitabine in patients with relapsed or refractory aggressive non-Hodgkin's lymphomas (NHL). PATIENTS AND METHODS: Thirty-one patients with B-cell intermediate or high-grade NHL (Working Formulation) were enrolled onto the study. The median age was 61 years, with a Karnofsky performance status of

Recombinant human erythropoietin in the treatment of cancer-related or chemotherapy-induced anaemia in patients with solid tumours.

Patients with cancer frequently develop anaemia, due either to the malignant disease itself or to its treatment. Various factors, including the type of malignancy and the type and intensity of chemotherapy, influence the prevalence of anaemia and the need for transfusions. Among patients with solid tumours, those with lung cancer and ovarian cancer are reported to have the highest frequency of anaemia (52% and 51%, respectively) and the highest rate of transfusion requirements (28% and 25%, respectively). Patients with a low level of haemoglobin (Hb) (10-12 g/dl) at the start of chemotherapy are particularly at risk of developing anaemia and requiring transfusions. Similarly, patients treated with platinum-based regimens more often develop anaemia and need transfusions. The frequency of transfusion requirements in these patients can amount to 47%-100%, depending on the cumulative dose of platinum and other risk factors, such as advanced age, loss of body weight before treatment, advanced disease stage, and particularly a low primary level of Hb (11 g/dl) and a decrease in Hb level (1-2 g/dl) after the first cycle of treatment. The causative mechanism of platinum-induced anaemia is reported to be, beside myelosuppression, a deficient production of erythropoietin (EPO) resulting from drug-induced renal tubular damage. In a number of randomised and nonrandomised studies, recombinant human (rh) EPO has been shown to be effective in the treatment of cancer-related anaemia (CRA) and in the prevention and treatment of chemotherapy-induced anaemia. An appropriate dose of rhEPO for the start of treatment is 150 U/kg given subcutaneously three times per week (t.i.w.). The response rate of anaemia ranges from 40% to 85%. rhEPO is well tolerated, but the cost of treatment requires patient selection and parameters predicting response as early as possible after the start of treatment. Appropriate groups of patients for treatment with rhEPO are those with an Hb level of < 10 g/dl and those with a higher Hb level, but symptomatic anaemia. Other groups are patients who are going to receive chemotherapy and have a low primary level of Hb (10-12 g/dl) and patients who receive platinum-based chemotherapy and have experienced a marked decrease in their Hb level (1-2 g/dl) from baseline to the second cycle of treatment. These patients have a high risk of becoming anaemic and requiring transfusions during chemotherapy. In anaemic cancer patients treated with rhEPO, an early indicator of response is an increase in Hb level of at least 0.5 g/dl in patients not receiving chemotherapy and 1 g/dl in those receiving chemotherapy, combined with an increase in reticulocyte count of at least 40,000 cells/microliter after 2 weeks of treatment in the first group of patients and after 4 weeks in the second.

Recombinant human erythropoietin in the treatment of chemotherapy-induced anemia and prevention of transfusion requirement associated with solid tumors: a randomized, controlled study.

BACKGROUND: Anemia is a common side effect of anticancer chemotherapy. Blood transfusion, previously the only available treatment for chemotherapy-induced anemia, may result in some clinical or subclinical adverse effects in the recipients. Recombinant human erythropoietin (rhEPO) provides a new treatment modality for chemotherapy-induced anemia. PATIENTS AND METHODS: To evaluate the effect of rhEPO on the need for blood transfusions and on hemoglobin (Hb) concentrations, 227 patients with solid tumors and chemotherapy-induced anemia were enrolled in a randomized, controlled, clinical trial. Of 189 patients evaluable for efficacy, 101 received 5000 IU rhEPO daily s.c., while 88 patients received no treatment during the 12-week controlled phase of the study. RESULTS: The results demonstrate a statistically significant reduction in the need for blood transfusions (28% vs. 42%, P = 0.028) and in the mean volume of packed red blood cells transfused (152 ml vs. 190 ml, P = 0.044) in patients treated with rhEPO compared to untreated controls. This effect was even more pronounced in patients receiving platinum-based chemotherapy (26% vs. 45%, P = 0.038). During the controlled treatment phase, the median Hb values increased in the rhEPO patients while remaining unchanged in the control group. The response was seen in all tumor types. CONCLUSIONS: RhEPO administration at a dose of 5000 IU daily s.c. increases hemoglobin levels and reduces transfusion requirements in chemotherapy-induced anemia, especially during platinum-based chemotherapy.

Bolus vincristine and epirubicin with cyclophosphamide and dexamethasone (VECD) as induction and salvage treatment in multiple myeloma.

The VAD regimen (infusional vincristine, doxorubicin and intermittent high-dose dexamethasone) is widely considered the standard salvage chemotherapy for multiple myeloma resistant to alkylating agents and is increasingly used for induction in previously untreated patients prior to high-dose chemotherapy. We investigated the VECD protocol, a VAD-based regimen using bolus injections of vincristine 1.5 mg day 1 and epirubicin 20 mg/m2 days 2 and 3 with 1 h infusions of cyclophosphamide 200 mg/m2 days 1-3 and oral dexamethasone 20 mg/m2 days 1-5 as induction and salvage treatment in multiple myeloma. Fifteen previously untreated and 25 patients with relapsed or refractory myeloma were included. Cycles were repeated every 3 weeks. In the group of previously untreated patients the response rate was 53% and the median survival has not been reached at 59 months. For relapsed and refractory patients the response rate was 44% and the median survival 13 months. In the group of patients with truly refractory disease on prior chemotherapy a response rate of 47% was achieved, which appears superior to the results observed for VAD alone. The main toxicities were leukocytopenia WHO grade IV and infections grade III/IV with both toxicities being significantly more pronounced in pretreated patients. VECD appears to be an effective regimen for induction and salvage therapy in multiple myeloma. Based on the limited number of patients treated the results are comparable to those reported for VAD, with the advantage that the infusional application of vincristine and the anthracycline is omitted.

Recurrence of Hodgkin's disease after 10 or more years: late relapse or de-novo malignancy due to HLA-DPB1*0301-linked susceptibility?

Recurrences of Hodgkin's disease (HD) ten or more years after initial therapy are rare and heterogeneous concerning pathological, biological and clinical features. Though usually regarded as relapses of initial disease at least part of these late recurrences may represent de-novo HD due to an increased constitutional risk. Following recent reports genetic risk for HD may be linked to the HLA-DPB1*0301 allele. Therefore, we investigated DPB1 and other HLA class I and II gene loci in three patients with very late recurrences of HD presenting at our institution within the last two years. All patients carry the HD susceptibility allele HLA-DPB1*0301. The expected probability of three patients with HD displaying the HLA-DPB1*0301 phenotype by chance is only p = 0.022. As serologic investigations also revealed Epstein-Barr virus (EBV) activity in all three cases our results support a role of genetic susceptibility possibly leading to impaired immune responses to EBV in very late recurring HD. Additionally, HLA-DPB1*0301 may be valuable for identifying patients with HD who might be candidates for a long term follow-up.

Recombinant human erythropoietin in the treatment of cancer-related anaemia.

The efficacy and safety of recombinant human erythropoietin (rhEPO) were tested when given subcutaneously (s.c.) in an escalating dose of 2000-10,000 units (U) daily in 60 patients with cancer-related anaemia (CRA). A positive response, defined as an increase in haemoglobin more than 2 g/dl and independence of blood transfusions was observed in 23 of 48 evaluable patients (48%) within a median of 8 wk. In detail, rhEPO corrected anaemia in 11 of 14 patients (79%) with malignant lymphoma, in 8 of 15 patients (53%) with multiple myeloma and in 4 of 10 patients (40%) with a solid tumour. The median dose of rhEPO in successful cases was 5000 U daily. Four patients with agnogenic myeloid metaplasia and 5 with myelodysplastic disorder failed to respond to rhEPO. No patient had any severe side effects. Pretreatment serum erythropoietin levels appeared to be a weak predictor for response to rhEPO treatment. In conclusion, rhEPO seems to be safe and effective in correcting CRA in certain groups of patients.

BCR rearrangement without juxtaposition of ABL in pre-T acute lymphoblastic leukaemia.

The incidence and clinical relevance of the Philadelphia (Ph) translocation t(9:22) (q34:q11) in T-lineage acute lymphoblastic leukaemia (ALL) are unknown. We describe a patient with pre-T-ALL and a clonal 22q-aberration detected by conventional cytogenetics, suggestive of a Ph translocation. However, fluorescence in situ hybridization (FISH) using BCR and ABL probes revealed a translocation with one breakpoint within the BCR gene on chromosome 22 without juxtaposition of ABL on chromosome 9. We discuss the diagnostic and possible pathogenetic implications of this Ph-like chromosomal aberration.

Analysis of the novel cyclin-dependent kinase 4 and 6 inhibitor gene p18 in lymphoma and leukemia cell lines.

The genes for the CDK4/6-inhibitors p16INK4A/MTS1 and p15INK4B/MTS2 are frequently deleted in hematological malignancies. A new member of this family of CDK4/6 inhibitors is p18. In order to assess p18 growth-suppressor gene alterations in hematological neoplasms, we investigated 31 lymphoma and leukemia cell lines by PCR for both exons of this gene. No homozygous deletions were observed. Investigation of a new intragenic restriction fragment length polymorphism revealed no differences in allele distribution between the tumor cell lines and healthy volunteers. Our results suggest that homozygous deletion of the p18 gene does not play a major role in leukemogenesis or lymphomagenesis.