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A randomized study comparing melphalan/prednisone (M/P) therapy with MP + natural alpha-IFN in untreated patients with multiple myeloma stages II and III started April 1, 1986. By March 1989, 78 patients were evaluable in the MP group and 80 in the MP/IFN group. 48% of the MP patients achieved a response and 66% in the MP/IFN group (p = 0.04). Stage II patients responded better to MP/IFN (76%) than MP alone (47%) (p = 0.02), while no statistically significant difference was noted for stage III patients. 90% of the IgA myelomas responded to MP/IFN and 52% to MP (p = 0.02). Both for IgG and BJ myelomas the response rates of MP/IFN were higher than of MP, although the differences were not statistically significant. The observation period is still short. There was no difference in total survival between the two treatment groups. However, in patients less than or equal to 65 years a tendency to a longer survival was seen for those receiving the IFN combination (p = 0.12).

Background: Treatment with granulocyte colony-stimulating factor (G-CSF) is given in order to mitigate chemotherapy-induced granulocytopenia and the risk of infectious complications, which constitute a major threat to elderly patients, in particular, with malignant disorders. The aim of this study was to evaluate whether G-CSF therapy would improve granulocyte defence mechanisms against infectious agents in this elderly, high-risk patient population. Methods: Fourteen elderly (>60 years) patients with aggressive non-Hodgkin’s lymphoma were enrolled in the study. Using flow cytometry we studied the expression of CD11b, before and after stimulation with fMLP, and CD16, as well as granulocyte metabolic activation measured as intracellular accumulation of dichlorofluorescein during induction chemotherapy. Eight patients were randomised to receive G-CSF treatment (5 μg/kg) on days 2–15. Granulocyte studies were done regularly during one 3-week cycle of chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or CNOP (doxorubicin substituted by mitoxantrone). Results: Patients receiving G-CSF showed a faster restitution of granulocyte counts. Granulocyte CD11b expression following fMLP stimulation in vitro decreased during G-CSF therapy (P

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 (λ) 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 λ 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.

Estimation of complete response (CR) and partial response (PR) in patients with non-Hodgkin's lymphoma (NHL) is associated with a number of potential sources of error. The aim of this study was to define the reproducibility of response evaluation performed by an independent review committee (RC). In a phase III study of patients60 yr with aggressive NHL, 60 patients who were already evaluated by the independent review committee (RC 1) for response were randomized to three groups and re-evaluated (RC 2). The assessment was classified into one of seven mutually exclusive categories, where the important borderlines with regard to one of the major end-points of the study, the CR rate, were between CR, "CR uncertain" (CR(U)), and PR. A discrepancy between RC 1 and 2 was found in 8/60 patients (13.3%), influencing the CR/CR(U) status in four of these patients. Two CR and two PR patients were reclassified as CR(U). Thus, CR/CR(U) was changed in 4/60 (6.7%). The reports of the local investigators were compared with that of RC 1 in 254 patients. The CR/CR(U) status was affected in 41 of these patients (16.1%). It is concluded that an independent RC is a major prerequisite for a uniform response evaluation in phase III clinical trials. However, the good RC reproducibility does not motivate a second assessment. Moreover, in the phase III setting end-points other than the CR rate, such as time to treatment failure, cause specific and overall survival are preferred.

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.

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 allogeneic 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-γ 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 l00 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-γ 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.

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.

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 11 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-CSIF (5 mug/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 11 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. (C) 2003 by The American Society of Hematology.

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.

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.

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 mono-clonal 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-gamma 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.

Fifty-six patients with refractory multiple myeloma were treated with intermittent courses of etoposide, doxorubicin, cyclophosphamide and high-dose betamethasone (EACB) every 4th week. The overall response rate was 30%. Durable remissions exceeding 1 year were obtained in 12 of the 17 responding patients. A significant prolongation of the survival time was found for responding patients (median 13 months) compared to those patients who did not respond (median 9 months) to EACB therapy (p = 0.01). A low frequency of neutropenic fever episodes was noted compared to other salvage treatment regimens. The EACB regimen was usually well tolerated and could be administered safely on an out-patient basis. This regimen might be an alternative especially for elderly patients unresponsive to initial therapy.

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.

Eighty-one previously untreated patients with multiple myeloma stage II entered a randomized trial comparing oral melphalan (0.25 mg/kg/day; n = 40) with intravenous melphalan (0.125 mg/kg/day; n = 41) in combination with oral prednisone (2 mg/kg/day). The courses were given for 4 days and repeated every sixth week. The treatment groups were well comparable with regard to major prognostic factors. There was no statistically significant difference in the response rates, the response duration times and the survival times. No significant difference in non-hematological and hematological toxicity was noted. Since intravenous administration of melphalan did not result in a substantial increase in response rate or survival, this study supports the use of oral melphalan/prednisone as first-line therapy for patients with multiple myeloma.

Introduction: Mitoxantrone (M), an anthracenedion, was introduced in the early/mid 1980s as a more tolerable alternative to anthracyclines. This agent has a broad anti-tumour activity including lymphoma with potentially less cardiotoxicity than doxorubicin (D), which may be of particular importance in the elderly patient population. However, an important issue is whether M is as efficacious as D in the treatment of NHL patients. Methods: Through search of several relevant databases and direct contacts with lymphoma investigators worldwide, we identified seven randomized studies of previously untreated patients comparing CHOP and CNOP chemotherapy in aggressive NHL. In this analysis we included five trials where (D;50mg/m2) was compared with (M;10–12mg/m2; table) and the interval between chemotherapy courses was 3–4 weeks. Patients reported in the Pavlovsky article were included in the Bezwoda report, why analyses were performed separately with either but not both of these reports. Odds ratios of complete remission (CR) and overall survival (OS) were pooled using a fixed effects model. Results: CHOP was significantly superior to CNOP with regard to both CR rate and OS (figure a–b). No formal testing of side effects could be made. However, myelosuppression was similar with both regimens as was the incidence of infections and neutropenic fever episodes. In addition, clinical evidence of symptomatic congestive heart failure was not more frequent among patients treated with CHOP. In contrast, the incidence of gastrointestinal toxicity and alopecia was significantly higher in this patient group. Conclusion: CHOP chemotherapy is more efficacious than CNOP at equitoxic (myelosuppression) doses leading to higher CR rates and improved survival. This regimen is, however, also associated with more alopecia and gastrointestinal toxicity. Table Randomized trials comparing doxorubicin (CHOP) with mitoxantrone (CNOP) in untreated patients with aggressive NHL Figure Figure

In a questionnaire study 140 subjects answered 4200 questions in 1980 and 1986. They consisted of patients with myeloma, acute leukemia, lung carcinoma, and non-malignant disease and their relatives. In 22 additional cases the questionnaire was not answered. The results show that myeloma patients are less content with the general care than leukemia patients (P less than 0.05). Similarly, relatives of decreased myeloma patients are less satisfied with the information given to them than relatives of deceased leukemia patients (P less than 0.001). The information has improved with time, however, since the patients were more satisfied in 1986 than in 1980 (P less than 0.001) and relatives of myeloma patients still alive were more satisfied than relatives of patients who had died earlier (P less than 0.001). The opinions of patients were similar to those of their relatives. However, the relatives of leukemia patients were even more satisfied with the contact with the medical staff than the patients themselves (P less than 0.05). As many as 10-30% of the relatives never gave up hope for their relative's survival. Only two out of 27 deaths were considered not dignified. The lung carcinoma patients reported a less good quality of life (P less than 0.001), and less satisfaction with the information given (P less than 0.01), than the hematological patients from the same year. Similarly, their attitude to the medical care improved less (P less than 0.01), and they were less content with the general care than the leukemia group (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The sera of 49 subjects with IgG, IgA or IgM benign monoclonal gammopathy-components were examined by agarose gel isoelectric focusing followed by Coomassie Brilliant Blue R-250 staining as well as avidin-biotin amplified double-antibody peroxidase labelling after nitrocellulose blotting. IgG-components gave 2–10 distinct bands within the isoelectric point (pI)-range of pH 6.5–9.5, IgA-components were focused into 10–15 bands with pI-values of pH 4.5–6.5 and the IgM-components gave 1–2 fractions within the pI-range of pH 4.5–6.5. The avidin-biotin peroxidase complex (ABC) technique exhibited some tendency to non-specific labeling related to the avidin-biotin component and depending on the relative amounts of the individual proteins. However, the method has a definite potential for the visualization of submicrogram quantities of immunoglobulins blotted to nitrocellulose membranes after isoelectric focusing.