A Randomized Comparison of Doxorubicin and Doxorubicin-DNA in the Treatment of Acute NonLymphoblastic Leukemia.

In the light of previous findings that treatment of leukemia patients with DNA-linked doxorubicin gave higher doxorubicin concentrations in leukemic cells than treatment with doxorubicin alone, the Leukemia Group of Middle Sweden performed a randomized clinical trial to compare the effects of doxorubicin and doxorubicin-DNA in patients with acute non-lymphoblastic leukemia. One hundred and twenty consecutive patients within the age range 15 to 60 years were randomized to one of three treatment groups. In two of these, remission induction treatment was performed with prednisolone, vincristine, ara-C and thioguanine combined with either doxorubicin or doxorubicin-DNA. Patients entering a complete remission received intensive consolidation during 16 months with 4 courses each of doxorubicin (+/ - DNA)/ara-C, doxorubicin (+/ - DNA)/azacytidine, ara-C and amsacrine. The third treatment group followed a protocol from a previous study with daunorubicin and ara-C for induction therapy and a less intensive maintenance therapy. No further patients were assigned to this "control" group after 3 years or to the two other groups after 6 years. This report is based on a follow-up 31 months thereafter. The overall rate of complete remission was 67% and the mean time to complete remission was 71 days, with no differences between the treatment groups. Patients treated with the doxorubicin-DNA conjugate had a significantly longer survival [median for all patients 27.2 months (p < 0.01) and for patients in CR 47.0 months (p < 0.025)] and longer duration of first remission (median 23.6 months, p < 0.025) than the other groups. There were significantly fewer reports of cardiotoxicity (p < 0.05) and severe intestinal toxicity (p < 0.02) in patients treated with the doxorubicin-DNA conjugate and there was a tendency towards less hepatic (p < 0.08) and renal toxicity (p < 0.08). The frequency of myelosuppression, fever and infectious complications was similar in all three groups. Complex binding to DNA appears to increase the therapeutic effects and reduce some toxic effects of doxorubicin in patients with ANLL.

A population-based cohort study on early-stage Hodgkin lymphoma treated with radiotherapy alone: with special reference to older patients.

BACKGROUND: Combined modality treatment has reduced the risk of relapse among younger early-stage Hodgkin lymphoma (HL) patients. Older HL patients may not tolerate chemotherapy and their prognosis is less favorable. We conducted a population-based study to evaluate long-term follow-up outcome in older early-stage HL patients initially treated with radiotherapy (RT) alone. PATIENTS AND METHODS: We included 308 consecutive patients (22% were >or=60 years) diagnosed 1972-1999 (median follow-up 20 years; range 1-28). Using Cox regression models we defined risk of relapse and survival in relation to clinical factors. RESULTS: 272/308 (88%) patients obtained complete remission following first-line RT alone. Among these, 42% relapsed within a median of 21 months. The relapse rate was independent of gender and age at diagnosis (median age 32 years, range 14-85); however, lymphocyte-predominant HL was associated with borderline (P=0.049) 56% decreased risk of relapse. Among patients<60 years and >or=60 years, we observed 29 (median latency 10 years, range 2-25) and 11 (median latency 3 years, range 1-10) second tumors, respectively. CONCLUSIONS: Older age (>or=60 years) was not associated with an increased risk of relapse following RT alone. Given the risks of iatrogenic morbidity/mortality of chemotherapy in older patients, RT alone could be an alternative first-line therapy in early-stage older HL patients.

Clinical and laboratory findings in untreated patients with Hodgkin's disease with special reference to age.

During a 6-yr period 258 adult patients (greater than or equal to 15 yr) with biopsy verified Hodgkin's disease (HD) were reported to the Stockholm-Gotland Oncologic Center. In 57 elderly patients (mean age 74 yr) the diagnosis was established shortly before death or at autopsy. One hundred and eighty-two of remaining 201 patients (118 men and 64 women, mean age 47 yr) were investigated. They were evenly distributed in stages I-IV and 43% had B symptoms. NS, 38% and MC, 38% were the most common histological subtypes in contrast to LP, 14% and LD, 10%. Stage II disease and NS histopathology dominated among patients below 50 yr. Patients with hilar/mediastinal lymphomas were often young and had NS histopathology with B symptoms. The diagnosis was established within 3 months after the first symptoms in 52% while 15% had symptoms for more than one year. Eleven patients reported a previous malignancy which is similar to the expected number of 13.8. The results support the concept that in unselected patient series HD seems to be at least as common among elderly as in young people. In the investigated series advanced disease and MC and LD histopathology did not dominate among patients above 50 yr which has been reported previously.

Familial longevity and prognosis in Hodgkin's disease.

The authors studied the influence of familial longevity on the prognosis in 98 patients with Hodgkin's disease (HD) followed for a long period of time. The survival of parents and grandparents to patients older than 50 years of age who died from progressive HD was significantly shorter than that of ancestors to survivors in the same age group. The excess death rate among relatives to the deceased patients was mainly caused by tuberculosis, which suggests a T-cell defect. The prognostic information achieved by analyzing duration of life of ancestors was superior to that given by the clinical stage. No association between familial longevity and prognosis was observed in young patients (less than or equal to 50 years of age). These findings are consistent with the hypothesis that HD in the elderly may be a separate clinical entity, and may also have important implications as to the understanding and treatment of HD in the elderly.

Blood lymphocyte functions in relation to splenic weight and tumor involvement in untreated Hodgkin's disease.

Spontaneous and mitogen induced blood lymphocyte DNA synthesis was studied in relation to weight and tumor involvement of the spleen in 33 untreated patients with Hodgkin's Disease. Splenic tumor involvement was found in 14 patients. In this group there was a strong inverse correlation between spleen weight and lymphocyte DNA synthesis induced by PWM, ConA and PPD. In patients with uninvolved spleens the spontaneous blood lymphocyte DNA synthesis increased with spleen weight. No correlation with the mitogen response was observed in this group.

Clinical findings and prognostic factors in chronic myeloid leukemias.

Ninety-one previously untreated patients with chronic myeloid leukemia admitted to three Stockholm hospitals 1973-1978 were studied. There were 49 men and 42 women with a mean age of 56 years (range 15-93). Sixty-five patients were Philadelphia chromosome (Ph1) positive and 17 were Ph1 negative (mean age 51 and 70 years, respectively). After a mean observation time of 5.2 years, 64 patients had deceased, 45 of them in blast transformation. A low hemoglobin value and a high total blast cell count at diagnosis were associated with a poor prognosis in the Ph1 positive group. Other routine clinical and laboratory variables were of subordinate prognostic importance. Early splenectomy in 15 Ph1 positive patients did not improve survival. Median survival from diagnosis was 38 months for Ph1 positive patients as compared to 12 months for the Ph1 negative group.

Immune status of untreated patients with Hodgkin's disease and prognosis.

In this study of 127 previously untreated adult patients with Hodgkin's disease and 167 age- and sex-matched controls, highly purified blood lymphocytes were studied for E+ receptors; their spontaneous DNA synthesis and that induced by concanavalin A, pokeweed mitogen, or purified protein derivative of tuberculin were measured as incorporation of 14C-thymidine. T-cell counts and the response to mitogens and antigen were significantly decreased in the patients, while the spontaneous lymphocyte activity was increased. Forty-nine patients had died after a mean observation time of 6 years. In these patients, there had been an increase in spontaneous DNA synthesis and a decrease in that induced by mitogens and antigen. These differences also remained significant when patients who died were compared with surviving patients in stages I-II. The 5-year survival rate of "bad immunology" patients was 30% as compared to 80% for the remainder. We suggest that these lymphocyte tests should be considered in an "immunologic staging system," which may give guidance in the future management of patients with Hodgkin's disease.

Lymphocytotoxic serum factors and lymphocyte functions in untreated Hodgkin's disease.

The prevalence of complement dependent, cold-reactive lymphocytotoxic serum factors (LT) was studied in 80 untreated patients with Hodgkin's disease by a microcytotoxicity assay. Sera from 24 patients (30%) contained LT as judged from at least 50% lysis of lymphocytes from 16 to 23 randomly selected normal donors. The spontaneous incorporation of 14C-thymidine into blood lymphocytes from patients with LT was significantly higher than that of lymphocytes from LT-negative patients and from healthy controls. Total lymphocyte and T-cell counts, Concanavalin A, and pokeweed mitogen-induced lymphocyte DNA synthesis were lower in patients with LT. Lymphocytotoxic sera were more frequently encountered in patients with B symptoms, advanced disease, or nodular sclerosis/lymphocyte predominance histopathologic characteristics. LT were often found in patients with large and tumor-involved spleens. The ability of patient's serum to inhibit control lymphocyte response to Concanavalin A stimulation did not differ between LT-positive and LT-negative patients. We conclude that the presence of LT is associated with a quantitative and qualitative impairment of blood T-lymphocytes in untreated patients with Hodgkin's disease.

Blood T-lymphocyte functions in healthy adults in relation to age.

Blood T-lymphocyte functions were studied in 167 healthy adults (age range 19-91 years). Lymphocyte DNA synthesis induced by concanavalin A, pokeweed mitogen and PPD antigen declined with age while the spontaneous DNA synthesis remained essentially unchanged. Relative and total T-cell counts but not total lymphocyte counts were moderately decreased in elderly persons. The lymphocyte response to mitogens correlated with the PPD-induced activation in vitro. Lymphocyte and T-cell counts did not show any association with the response to mitogens and antigen. A few subjects were tested on several occasions during 2-7 years confirming a good reproducibility of the techniques employed. Thus ageing is associated with diminished number of T-cells and impairment of lymphocyte activation by T-cell mitogens and PPD antigen. The clinical importance of this general age-related T-cell deficiency remains largely unresolved.

Longitudinal studies of blood lymphocyte capacity in Hodgkin's disease.

Blood lymphocyte functional capacity and serum immunoglobulins were studied in 40 patients with Hodgkin's disease (HD) admitted to Radiumhemmet, Stockholm, before treatment and in complete remission 2-56 months following termination of radiotherapy (total nodal irradiation [TNI]; n = 29) or chemotherapy (MOPP; n = 11). Lymphocyte studies included determination of total lymphocyte and T-cell counts and evaluation of spontaneous DNA synthesis during the first day of culture and mitogen-(concanavalin A, pokeweed mitogen) and antigen (purified protein derivative, PPD)-induced activation on the third day. Blood lymphocyte and T-cell counts decreased dramatically following TNI. A slow restitution was seen, but pretreatment levels were not reached even four years following therapy. The responses to ConA and PPD but not PWM were significantly reduced shortly after TNI. The mitogen response did not increase with time as did the PPD response. Lymphocyte counts and lymphocyte stimulation, which were severely depressed before treatment of patients in the chemotherapy group, remained unchanged 2-36 months after termination of therapy. A significant reduction of IgM levels was observed regardless of the mode of treatment. Splenectomy prevented the profound reduction of blood lymphocyte and T-cell counts following therapy but did not influence the other immunologic variables under study.

Lymphocyte function in untreated Hodgkin's disease: an important predictor of prognosis.

One hundred and twenty seven consecutive and previously untreated patients with Hodgkin's disease (HD) (mean age 47 years) from the Stockholm area admitted to Radiumhemmet, Karolinska Hospital, were studied. The age-matched control group consisted of 167 healthy adults. Incorporation of [14C]-dT was measured on Day 1 in unstimulated monocyte-depleted lymphocyte cultures, and on Day 3 in cultures activated by PWM, ConA and PPD, T and B cells were enumerated by surface markers. The patients had significantly decreased relative and total T-cell counts, and the lymphocyte DNA synthesis induced by mitogens and PPD was severely impaired, whilst the spontaneous DNA synthesis was significantly greater than in controls. At follow-up (mean 4 years) 40 patients have died. Deceased patients showed greater spontaneous lymphocyte activation and less response to mitogen and antigen stimulation than the survivors. The 5-year survival of patients with severe lymphocyte impairment was 20%, compared to 80% for the remainder. The lymphocyte tests added prognostic information to that from clinical staging. Disregarding the lack of knowledge of the mechanisms underlying the lymphocyte impairment, we suggest that these relatively simple immunological tests should be included in the clinical evaluation of HD patients and would guide the choice of therapy.

Routine laboratory tests in relation to spleen size and tumour involvement in untreated Hodgkin's disease.

A number of routine laboratory tests were studied in 39 untreated patients with Hodgkin's disease with respect to size and tumour involvement of the spleen. Eighteen patients with tumour-engaged spleens had lower total lymphocyte counts and IgG and IgM levels than patients with non-involved spleens. However, no significant differences in these respects were found between patients with tumour-involved spleens weighing less than 500 g and patients without splenic tumour involvement. Hemoglobin values were inversely and reticulocyte counts positively correlated with the weight of involved spleens. Remaining laboratory variables under study, e.g. total granulocyte counts, platelet counts, ESR and liver enzymes, were not associated with the size or tumour involvement of the spleen. It may be concluded that routine laboratory tests yield no specific information as to splenic tumour involvement or size.

Prognostic factors in Hodgkin's disease with special reference to age.

A series of 182 patients with Hodgkin's disease, diagnosed between January 1973 and December 1978 was used to identify prognostic factors with special reference to age. There were 118 men and 64 women (mean age, 47 years; r = 15-92). During the same period 57 elderly patients who were never referred, were reported to the Local Cancer Registry. The diagnosis had been established shortly before death or at autopsy. The 182 patients under study were evenly distributed in Stages I-IV. Nodular sclerosis (38%) and mixed cellularity (38%) were the most common histologic subtypes. The 5-year survival probability estimate was 28% in patients above 50 years as compared to 74% in the remainder. Survival was significantly better in patients with Stage I-II disease and lymphocyte predominance/nodular sclerosis histopathology. Age was the main prognostic factor in the whole series as well as in patients older than 50 years. However, in young patients advanced clinical stage and B-symptoms were related to a poor prognosis. Biologic indicators such as ESR, hemoglobin and albumin were intimately linked to the extent of disease and did not add prognostic information besides that given by the clinical stage. It is concluded that the prognosis in elderly remains poor and appears to be partly unrelated to those factors which determine the prognosis in the young, assumingly reflecting a depressed host-response and/or a decreased tolerance to intensive treatment.

Lymphocyte abnormalities predicting a poor prognosis in Hodgkin's disease. A long-term follow-up.

Two hundred sixty-two adult patients with Hodgkin's disease (HD) were studied. Incorporation of carbon-14-thymidine was measured in unstimulated monocyte-depleted lymphocyte cultures, and in cultures activated by concanavalin A (Con-A) before institution of therapy in all patients. Total blood lymphocytes and T-cell subsets were enumerated in the last 108 patients. Patients had significantly decreased total (CD3+, CD4+, CD8+) and relative (CD3+, CD4+) T-cell counts compared with healthy controls. Stage IV patients tended to have lower total lymphocyte and subset counts than remaining patients. However, significantly reduced total lymphocyte and CD8+ counts were only observed in comparison to patients in clinical stage II. Thirty-three percent of patients had an increased spontaneous and a decreased Con-A-induced blood lymphocyte DNA synthesis. Functional lymphocyte abnormalities were related to advanced clinical stage, high age, mixed cellularity, and lymphocyte depletion histopathology and presence of B symptoms. The 10-year survival of patients in this group was 36%, compared with 62% for the remainder. In a multivariate analysis of the whole series lymphocyte DNA synthesis was besides age the strongest predictor of prognosis. In univariate analyses of the second patient series total lymphocyte, T-cell and subset counts were related to prognosis. These relatively simple lymphocyte functional tests may help to identify young HD patients for whom intensive cytoreductive therapy with or without autologous stem cell support may be the best therapeutic option.