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Introduction: Manifestation of central nervous system (CNS) disease in patients with aggressive non-Hodgkin’s lymphoma (NHL) during or after first line treatment is often a devastating condition, which is associated with a poor prognosis. There is today no general consensus regarding prophylactic treatment in this patient category, particularly in the elderly. The aim of this study was to define the incidence and risk factors for CNS manifestation in a large cohort of elderly (>60 years) patients with aggressive NHL and no CNS disease at diagnosis. Patients and methods: This Nordic study included a total of 455 previously untreated patients with advanced (stage II–IV) aggressive NHL without CNS involvement at diagnosis (Blood2003;101:3840). The vast majority had diffuse large B cell lymphoma. Patients (median age, 71 years; range, 60–86 years) were randomised to receive CHOP (doxorubicin 50 mg/m 2 ) or CNOP (mitoxantrone 10 mg/m 2 ) with or without G-CSF (5 microg/kg from day 2 until day 10–14 of each cycle every 3 weeks; 8 cycles). Intrathecal methotrexate was given as prophylaxis to patients with lymphoma bone marrow involvement and in patients with testicular, orbital, sinus and epidural sites of presentation. Results: At this time point information is available for 441/455 patients. After a median observation time of 113 months in surviving patients 30/441 (6.8%) developed CNS disease. Advanced stage (p=0.004) and a high age-adjusted International Prognostic Index (IPI; p=0.034) were associated with an increased risk of CNS disease. Age, sex, performance status, bone marrow involvement/extranodal disease, serum lactate dehydrogenase level, or treatment received were not related to the risk of CNS manifestation. All patients with CNS disease were dead at follow-up. Conclusion: A significant proportion of elderly patients with advanced aggressive NHL and no CNS manifestation at diagnosis develop CNS disease despite prophylactic measures in clinically defined high-risk patients. CNS occurrence is related to clinical stage and age-adjusted IPI. The prognosis of elderly aggressive NHL patients with CNS manifestation is poor.

This study was designed to test the hypothesis that administration of granulocyte colony-stimulating factor (G-CSF; filgrastim) during induction chemotherapy with CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone) or CNOP (doxorubicin replaced with mitoxantrone) in elderly patients with aggressive non-Hodgkin lymphoma (NHL) improves time to treatment failure (TTF), complete remission (CR) rate, and overall survival (OS). Furthermore, the efficacy of CHOP versus CNOP chemotherapy was compared. A total of 455 previously untreated patients older than 60 years with stages II to IV aggressive NHL were included in the analysis. Patients (median age, 71 years; range, 60-86 years) were randomized to receive CHOP (doxorubicin 50 mg/m(2)) or CNOP (mitoxantrone 10 mg/m(2)) with or without G-CSF (5 microg/kg from day 2 until day 10-14 of each cycle every 3 weeks; 8 cycles). Forty-seven patients previously hospitalized for class I to II congestive heart failure were randomized to receive CNOP with or without G-CSF (not included in the CHOP versus CNOP analysis). The CR rates in the CHOP/CNOP plus G-CSF and CHOP/CNOP groups were the same, 52%, and in the CHOP with or without G-CSF and CNOP with or without G-CSF groups, 60% and 43% (P <.001), respectively. No benefit of G-CSF in terms of TTF and OS could be shown (P =.96 and P =.22, respectively), whereas CHOP was superior to CNOP (TTF/OS P <.001). The incidences of severe granulocytopenia (World Health Organization grade IV) and granulocytopenic infections were higher in patients not receiving G-CSF. The cumulative proportion of patients receiving 90% or more of allocated chemotherapy was higher (P <.05) in patients receiving G-CSF. Concomitant G-CSF treatment did not improve CR rate, TTF, or OS. Patients receiving CHOP fared better than those given CNOP chemotherapy. The addition of G-CSF reduces the incidence of severe granulocytopenia and infections in elderly patients with aggressive NHL receiving CHOP or CNOP chemotherapy.

Alemtuzumab (Campath-1H) is a humanized CD52 monoclonal antibody that targets normal as well as malignant B- and T-lymphocytes. Alemtuzumab has significant antitumor activity in chronic lymphocytic leukemia (B-CLL) but also induces immunosuppression. We describe a case of fatal adenovirus infection in a heavily pretreated patient with fludarabine-refractory B-CLL receiving alemtuzumab therapy, drawing attention to the fact that also viruses other than cytomegalovirus (CMV) and herpes simplex (HSV) need to be considered in B-CLL patients with fever of unknown origin while on alemtuzumab treatment.

In general, elderly patients with aggressive non-Hodgkin's lymphoma (NHL) have a less favourable prognosis than younger patients. Established predictors of prognosis in NHL are less discriminatory in the elderly, which is why there is a need for additional markers giving guidance on treatment decisions and prediction of outcome. The expected length of life of an individual in the general population is intimately associated with that of his/her parents. The aim of this study was to test the hypothesis that parental longevity is associated with improved outcome also among elderly patients with aggressive NHL and thus serves as an easily accessible non-disease associated prognostic factor. A total of 220 patients (> 60 years) with aggressive NHL with a median age of 71 years (range 60-86) were included. Patients were randomized to receive CHOP or CNOP ( doxorubicin replaced with mitoxantrone) chemotherapy with or without the addition of granulocyte colony-stimulating factor. The median follow-up time was 56 (19-89) months. Parental data regarding age at death were available through parish offices for 425 (97%) parents. Relative risk (RR) of death (disease-specific and all-cause) associated with parental lifespan was assessed using Cox proportional hazards regression analyses, with adjustment for sex, age, prognostic index, symptoms, and calendar period of diagnosis. Maternal lifespan below (versus above) median was associated with a borderline significant reduced disease-specific (adjusted RR of death from NHL=1.5; 95% confidence interval 1.0-2.1) and overall survival. The effect of maternal lifespan was somewhat more pronounced in patients receiving CHOP than CNOP treatment. Paternal lifespan below the median was associated with a borderline significant increased disease-specific ( adjusted RR of death from NHL=0.8 [0.5-1.0]) and overall survival. Combined, maternal, and paternal lifespan had little impact on survival. These effects were true also when CHOP and CNOP treated patients were analysed separately. Maternal and paternal lifespan may predict survival in NHL, but with opposing effects. At present parental age appears not to be a clinically useful predictor of prognosis in the elderly with aggressive NHL.

Rhabdomyolysis is a rare complication in haematological malignancies, and a diverse range of factors has been implicated in the etiology of the syndrome. In the present study we analysed muscle morphology and antibody reactivities to skeletal muscle proteins in a patient diagnosed with lambda (lambda) light chain-secreting multiple myeloma (MM) and amyloidosis, who developed a progressive rhabdomyolysis. The muscle tissue analysis showed focal amyloid depositions and a low degree of atrophy and inflammation. Antibody reactivities against muscle proteins of approximately 42, 51 and 66 kD, respectively, were present in the patient's serum. The antibody specificities were revealed by lambda light chain- or IgM-specific antibodies. The results indicate a possible etiologic link between antibody reactivities towards muscle proteins and muscle tissue disorder in a patient with the unique combination of rhabdomyolysis, amyloidosis and MM of the light chain type.

Tumor responses after daily oral administration of low-dose etoposide have been demonstrated in both hematological and solid tumors. The aim of the present phase II trial was to determine tumor response, and toxicity and to delineate the pharmacokinetics of oral low-dose etoposide in patients with hematological malignancies in a palliative treatment setting. Thirty-two patients with non-Hodgkin’s lymphoma (NHL), acute myeloblastic (AML) and lymphoblastic leukemia, multiple myeloma, and myelodysplastic syndrome (MDS) were included. Patients were given oral etoposide, 100 mg once daily for 14 d in a 21-d cycle. Serum etoposide concentrations were determined on d 1, 7, and 14 of every cycle before etoposide administration and, in addition, 1, 2, 3, 4, and 24 h after drug intake on d 1. The median age of patients was 68 yr (range: 50–89 yr). The median time from diagnosis to inclusion in the study was 21 mo (range: 0.5–144 mo) and most patients had advanced disease and were heavily pretreated. Eleven patients completed three or more cycles. Eight of 11 patients with acute leukemia and 1 of 2 with MDS received only 1 course because of toxicity (n=5) or progression (n=4). One patient with AML, a Jehovah’s Witness, was treated up-front and achieved a complete remission and two patients with low-grade NHL gained a complete and a partial remission, respectively. Twenty-one of 32 patients were evaluable for toxicity during the first cycle. In 67%, the white blood cell count nadir was <2.0 × 109/L and in 38%<1.0 × 109/L. Platelet count nadir was less than 25 × 109/L in 24% of evaluable patients. During all cycles (n=79), eight patients developed febrile neutropenia, four of whom with a fatal outcome. The correlation between the area under the curve (AUC) of the free fraction of etoposide and leukopenia was statistically significant at a log analysis (n=12; p<0.05). There was also a statistically significant correlation between the AUC and the 24-h concentration (n=15; p<0.005) and between the concentrations at 24 h and d 7 (n=11; p<0.005) of the free fractions of etoposide. In conclusion, etoposide had a moderate clinical effect in this group of heavily pretreated patients. Moreover, toxicity was substantial, in particular leukopenia, which correlated to the free-etoposide AUC.

Tumor responses after daily oral administration of low-dose etoposide have been demonstrated in both hematological and solid tumors. The aim of the present phase II trial was to determine tumor response, and toxicity and to delineate the pharmacokinetics of oral low-dose etoposide in patients with hematological malignancies in a palliative treatment setting. Thirty-two patients with non-Hodgkin's lymphoma (NHL), acute myeloblastic (AML) and lymphoblastic leukemia, multiple myeloma, and myelodysplastic syndrome (MDS) were included. Patients were given oral etoposide, 100 mg once daily for 14 d in a 21-d cycle. Serum etoposide concentrations were determined on d 1, 7, and 14 of every cycle before etoposide administration and, in addition, 1, 2, 3, 4, and 24 h after drug intake on d 1. The median age of patients was 68 yr (range: 50-89 yr). The median time from diagnosis to inclusion in the study was 21 mo (range: 0.5-144 mo) and most patients had advanced disease and were heavily pretreated. Eleven patients completed three or more cycles. Eight of 11 patients with acute leukemia and 1 of 2 with MDS received only 1 course because of toxicity (n = 5) or progression (n = 4). One patient with AML, a Jehovah's Witness, was treated up-front and achieved a complete remission and two patients with low-grade NHL gained a complete and a partial remission, respectively. Twenty-one of 32 patients were evaluable for toxicity during the first cycle. In 67%, the white blood cell count nadir was < 2.0 x 109/L and in 38% < 1.0 x 10(9)/L. Platelet count nadir was less than 25 x 10(9)/L in 24% of evaluable patients. During all cycles (n = 79), eight patients developed febrile neutropenia, four of whom with a fatal outcome. The correlation between the area under the curve (AUC) of the free fraction of etoposide and leukopenia was statistically significant at a log analysis (n = 12; p < 0.05). There was also a statistically significant correlation between the AUC and the 24-h concentration (n = 15; p < 0.005) and between the concentrations at 24 h and d 7 (n = 11; p < 0.005) of the free fractions of etoposide. In conclusion, etoposide had a moderate clinical effect in this group of heavily pretreated patients. Moreover, toxicity was substantial, in particular leukopenia, which correlated to the free-etoposide AUC.

INTRODUCTION:Plasma cell leukaemia is a rare disorder that usually carries an aggressive course with a rapidly fatal outcome. A variety of chromosomal abnormalities have been reported in plasma cell leukaemia but the clinical significance of an abnormal karyotype is still unclear. MATERIALS AND METHODS:We have applied the molecular cytogenetic techniques multicolour spectral karyotyping and microdissection in combination with fluorescence in situ hybridization on metaphases from a patient with primary plasma cell leukaemia and a fatal outcome. RESULTS AND CONCLUSION:The chromosome analysis showed severe hypodiploidy and 12 marker chromosomes. Identification of the structural rearrangements was not possible using routine cytogenetic methods. Utilizing the methods above, all marker chromosomes could be identified in detail and the karyotype was shown to be very complex. Forty-three breakpoints were found, and 25 could be identified at the band level, among others 14q32 where the immunoglobulin heavy chain locus is situated. Thus, these techniques provide the opportunity to resolve very complex chromosomal changes in a way that has not been previously possible and will consequently be of great importance in the search for hot spots that may harbour new cancer genes.

BACKGROUND:Second- and third-generation chemotherapy protocols for the treatment of aggressive non-Hodgkin's lymphomas (NHL) have considerable, and age-related, toxic effects. In addition, they do not seem to prolong overall survival in comparison to standard CHOP chemotherapy. In this phase II study we investigated the feasibility and efficacy of the addition of etoposide to the conventional CHOP regimen.PATIENTS AND METHODS:Toxicity and clinical efficacy were determined in 132 patients with previously untreated high-grade NHL. There were 51 patients in clinical stage I and II and 81 patients in stage III and IV, with a median age of 54 years (range 17-85). Patients received standard-dose CHOP plus etoposide 100 mg/m2 i.v. on day 1 and 200 mg/m2 p.o. on days 2-3.RESULTS:The overall response rate was 84%, with 70% complete and 14% partial responses. The predicted three- and five-year survivals for the group as a whole were 60% and 53%, respectively, and the corresponding disease-free survivals for patients achieving complete remissions were 65% and 56%, respectively. Outcome was not different from that of CHOP-treated patients in a recently completed Nordic study performed during the same time period. Myelosuppression (WHO grade 3-4), observed in 87% of patients and infectious complications (WHO grade 3-4) in 33%, dominated the toxicity profile of this regimen. Fifty-seven of 92 complete responders (62%) received 6-8 CHOP-E cycles with no reductions in planned dose intensity. LDH level higher than normal, extranodal sites = 2, stage III-IV at diagnosis were all indicators of a poor survival.CONCLUSIONS:We conclude that CHOP-E treatment is effective in high-grade NHL. However, mainly due to severe myelosuppression frequent schedule modifications were required and the results are not obviously superior to those of conventional CHOP.

Multiple myeloma is characterized by a proliferation of clonal B lymphocytes and plasma cells. The idiotypic structure of clonal immunoglobulin (Ig) expressed on the tumour B‐cell surface can be regarded as a tumour‐specific antigen and, as such, a potential target for anti‐idiotypic T and B cells in an immune regulation of the tumour‐cell clone. Active immunization using the autologous monoclonal Ig as a ‘vaccine’ was shown to induce tumour‐specific immunity in murine B‐cell tumours and in human B‐cell lymphoma. With the aim to induce or amplify an anti‐idiotypic response in multiple myeloma, five stage I–III patients were repeatedly immunized with the autologous monoclonal IgG. Induction of idiotype‐specific cellular immunity was analysed in vitro by an enzyme‐linked immunospot assay (interferon‐γ and interleukin‐4 secreting cells). B cells secreting anti‐idiotypic IgM antibodies were also analysed. An anti‐idiotypic T‐cell response was amplified 1.9–5‐fold in three of the five patients during immunization. The number of B cells secreting anti‐idiotypic antibodies also increased in these three patients. In two of the patients induction of idiotype‐specific immunity was associated with a gradual decrease of blood CD19+ B cells. The induced T‐cell response was eliminated during repeated immunization. Further studies are warranted to optimize the immunization schedule in order to achieve a long‐lasting T‐cell immunity against idiotypic determinants on the tumour clone. A role for immunity in controlling the tumour clone remains to be established.

Etoposide is bound to plasma albumin (94%). Previous studies have revealed altered protein binding of etoposide in cancer patients. This has clinical implications since only the free fraction is considered pharmacologically active. We have studied the etoposide protein binding in 11 children (eight acute lymphocytic leukemia, two malignant histiocytosis, and one oligodendroglioma; age 1-17 years) and 46 adult patients (28 acute myelocytic leukemia, eight lymphoma, one multiple myeloma, and nine small cell lung cancer; age 38-81 years). All patients were treated with etoposide 50-200 mg/m2 i.v. or orally. Plasma from ten healthy volunteers, 26-50 years of age, was spiked with etoposide, 10 micrograms/ml, and the protein binding was compared with that in patient samples. The free etoposide concentration was determined by high performance liquid chromatography (HPLC) after ultrafiltration at room temperature. The free etoposide fraction was lower, 2.5 +/- 0.6% (mean +/- SD), in the children compared with 5.0 +/- 3.6% in adult cancer patients. In plasma from healthy adults it was 3.2 +/- 0.3%. It is concluded that children have significantly lower levels of free etoposide compared with adult patients (P = 0.03) as well as with healthy subjects (P = 0.001), which is likely to affect metabolism and renal clearance as well as cellular uptake of the drug.

The prevalence of peripheral blood B cells secreting antibodies reacting with the F(ab')2 fragment of monoclonal IgG was studied in five patients with multiple myeloma (MM), nine patients with monoclonal gammopathy of undetermined significance (MGUS) and six healthy controls. An enzyme‐linked immunospot assay allowed direct visualization of antibody producing B cells. All patients had B cells producing antibodies to autologous or ailogeneic monoclonal IgG. Autoreactive cells were found more frequently than alloreactive cells in seven out of nine patients with MGUS and three out of four patients with MM. The same frequency of alloreactive cells in the patient groups was detected in healthy individuals. These findings show the existence of B cells producing anti‐idiotypic antibodies which could be a part of an idiotypic network in monoclonal gammopathies

The stimulation of peripheral blood mononuclear cells by purified autologous and/or allogeneic monoclonal IgG was studied in five patients with multiple myeloma (MM), nine patients with monoclonal gammopathy of undetermined significance (MGUS) and six healthy individuals.Single cells secreting IFN-gamma or IL-2 were identified using an enzyme-linked immunospot assay. Patients' cells were preferentially stimulated by autologous monoclonal IgG at low concentrations (1-100 pg/ml), while 100 ng/ml or higher stimulated T cells both from patients and, to a lesser degree, healthy individuals. This biphasic dose-response of T-cell stimulation by autologous monoclonal IgG was reproduced in all patients. The numbers of cells secreting IFN-gamma and IL-2 in response to allogeneic IgG were significantly lower than the numbers obtained using autologous IgG in patients with MM and MGUS. Cells from healthy individuals were stimulated by allogeneic monoclonal IgG, but to a lesser extent.The results of this study support the presence of idiotype-reactive T cells in patients with-MM and MGUS and also may suggest a general but less pronounced T-cell reactivity to monoclonal IgG among these patients.

The treatment of relapsing or refractory high-grade malignant non-Hodgkin lymphoma (NHL) following CHOP chemotherapy remains a challenge for the clinician. In this study, 29 patients with relapsing or refractory high- or refractory low-grade malignant NHL received a combination of mitoxantrone 12 mg/m2 i.v. on days 1-2, cytarabine 100 mg/m2 i.v., b.d. d 1-2, etoposide 100 mg/m2 i.v. d 1-3 and prednisone 100 mg/m2 orally d 1-3 (ENAP). An overall response rate of 55% encouraged us to use ENAP alternated with conventional CHOP chemotherapy in 45 previously untreated NHL patients (35 with high-grade and 10 with "aggressive" low-grade malignant NHL). All patients responded with a complete remission rate (CR) of (27%) and a partial remission rate (PR) of 73% after only one course of ENAP. After a median number of 3.5 ENAP/CHOP courses, the CR and PR rate was 69 and 22%, respectively. Myelosuppression was pronounced and fever of unidentified origin and documented infections followed 59% of all cases given ENAP courses. In the last 19 previously untreated patients mitoxantrone was given at a dose of 10 mg/m2 on d 1 and cytarabine 100 mg i.v., b.d. during d 1-2. Nonhematologic toxicity was mild. We conclude that this novel chemotherapy program is effective both as first-line and salvage treatment in patients with high-grade malignant NHL. Furthermore, ENAP appears clinically to be partly non-cross resistant with CHOP chemotherapy. The dose-limiting toxicity is myelosuppression. The combination should be explored as primary therapy in combination with other chemotherapy or radiotherapy programs.