Treatment of non-Hodgkin's lymphomas in elderly patients

The roles of evolving treatment strategies for non-Hodgkin's lymphomas (NHL) in elderly patients are still not well defined and their effects on the overall epidemiology of the disease are still not clear. Three questions arise when discussing the management of NHL in elderly patients. First, should older patients be treated with the same regimens usually administered to younger patients? Second, are health outcomes of elderly patients similar to those usually observed in young patients, particularly response rate and overall survival? Third, which strategies should be adopted to improve overall health outcomes? Periodic review of the literature and updated data on the management of NHL in elderly patients may provide an answer to all these queries. In essence, older patients must be treated with the same intensive approaches that are usually reserved for younger patients. The results reported in randomized controlled clinical trials are consistent with the capability of older patients to exhibit overall response rate, event-free survival, and overall survival similar to those observed in their younger counterparts. Combining chemotherapy and monoclonal antibodies seems to be the main optional strategy for better outcomes in elderly patients. In contrast, knowledge concerning the management of indolent lymphomas in elderly patients is still lacking, and available clinical data are limited in this setting, especially in patients with poor prognostic factors who may need an immediate therapeutic intervention.     

Lymphocyte markers in non-Hodgkin's lymphomas.

The lymphocyte marker pattern of non-Hodgkin's lymphoma cells was related to current concepts of lymphoma classification. In a series of 28 lymphomas lymphocyte markers indicated that 2 were of histiocytic origin, 2 were unclassifiable, none were derived from T cells and the remainder were B-cell neoplasms. The immunoglobulin heavy chain associated with the B-cell tumours was gamma in one case, alpha in one case but was mu in the majority of cases, reflecting the predominance of this heavy chain, together with delta chains, on normal lymph node lymphocytes in man. delta chains accompanied mu chains on the tumour cells in 6/17 lymphomas in which anti-delta staining was performed. delta chains were not found on any lymphomas other than well differentiated diffuse lymphocytic types. There was evidence of a reduction in surface immunoglobulin, Fcgamma and C3 receptors on undifferentiated lymphoma cells. T lymphocytes of normal morphology were present in all lymphomas except one, and were more numerous in follicular lymphomas than in diffuse tumours.     

Prognostic factors in Hodgkin's and non-Hodgkin's lymphomas.

A review of prognostic factors described recently in Hodgkin's and non-Hodgkin's lymphomas is presented with some comments on their interest and value for treatment choice and comprehension of the disease. The most important parameters are divided into three categories: 1) age; 2) extent of the tumor, ie, number of nodal or extranodal sites, bulkiness, stage, lactate dehydrogenase level or beta 2-microglobulin level; and 3) host-tumor interaction, ie, performance status, serum albumin level, and erythrocyte sedimentation rate. These initial parameters permit the stratification of lymphoma patients into subgroups with different outcomes in which different therapeutic modalities are tested.     

New chemotherapeutic agents for non-Hodgkin's lymphomas.

Combination chemotherapy regimens achieve complete remissions in 60% to 80% of patients with non-Hodgkin's lymphomas; however, the majority of patients will relapse, and resistant disease remains a problem. Attempts to identify new, effective chemotherapy agents have primarily focused on the development of analogues that, unfortunately, have uniformly failed to provide a substantial therapeutic advantage. Drugs with a unique mechanism of action are more likely to be successful; among these are the purine analogues (e.g., fludarabine, 2'-deoxycoformycin, 2-chlorodeoxyadenosine) and agents that can reverse clinical drug resistance. The number of patients who can be cured can be increased only by incorporating new agents into front-line regimens through carefully designed clinical trials.     

The therapy of non-Hodgkin's lymphomas. Introduction and overview

Non-Hodgkin's lymphomas represent a diverse group of diseases that require an extensive knowledge base in order for physicians to utilize state-of-the-art therapies. This introduction outlines the current classification schemes and combination chemotherapy plans utilized for the non-Hodgkin's lymphomas.     

Primary orbital lymphomas

Between 1950 and 1982, seventeen patients with primary orbital lymphoma were treated at the University of Kansas Medical Center. There were 10 males and 7 females with a median age of 61 years. Four patients had bilateral disease, seven patients had disease involving the conjunctiva, and in ten patients, the disease involved paraocular structures. Fourteen patients received radiation with a median dose of 3500 cGy (range 2250 cGy to 4250 cGy) given in about 3 1/2 to 5 weeks. Median follow-up was 10 years (range 5 to 31 years). Local control was 100% and 5-year survival was 76%. Three patients are living with no evidence of lymphoma; three patients died from progression of the disease, and others died from unrelated causes. Radiation treatment for localized primary orbital lymphomas appears to be the primary treatment of choice.     

Epirubicin in non-Hodgkin's lymphomas

Epirubicin (Epi-DX), a new analog of doxorubicin, was administered I.V. once q 3 weeks at the dose of 90 mg/m2 to 20 evaluable patients with non-Hodgkin's lymphomas (NHL). Eighty-two percent of patients with favorable histology and 67% with unfavorable histology achieved complete or partial remissions, with an overall response rate of 75%. Gastrointestinal and hematologic toxicity was generally mild to moderate. Reversible ST-T changes were observed only in two patients. Epi-DX has high activity in patients with NHL, and further studies in combination with other agents are recommended.     

Primary non-Hodgkin's lymphomas of the female breast.

The charts of 35 women with primary malignant non-Hodgkin's lymphomas (NHL) of the breast were retrieved from the files of the Istituto Nazionale Tumori, Milan, over a 30-year period (1957 to 1986). These cases represented 0.1% of the more than 25,000 primary malignant tumors of the breast treated during the same period. The median age of these patients was 57 years (range, 28 to 81 years). In most cases, the clinical diagnosis was carcinoma. The tumors were either Stage IE(48%) or IIE(52%) at presentation, and only two patients had B symptoms. The right breast was involved in 17 patients, the left breast in 14, and both breasts in two. According to the updated Kiel classification and the Working Formulation (WF) for Clinical Usage, three cases were lymphoplasmacytoid (immunocytoma) NHL (WF, A); three, centroblastic-centrocytic, follicular NHL (WF, B); four, centroblastic-centrocytic, diffuse NHL (WF, F); 17 centroblastic NHL (WF, G); three immunoblastic NHL (WF, H); two B-lymphoblastic NHL (WF, I); and one, a Burkitt-like NHL (WF, J). Treatment consisted either of a combination of surgery, radiation therapy, and chemotherapy or radiation therapy and chemotherapy. The follow-up period for 32 patients ranged from 6 to 161 months (mean, 45 months); 17 patients died of their disease. The prognosis appeared to be related to the histologic type and stage of the disease. Median survival periods were 63, 52, 42, and 47 months for centroblastic-centrocytic follicular, centroblastic-centrocytic diffuse, centroblastic, and immunoblastic NHL, respectively. The overall 5-year survival rate was 43%; the 5-year survival rate and the probability of freedom from progression at 5 years were, respectively, 61% and 50% for Stage I and 27% and 26% for Stage II disease.     

Medical history and the risk of non-Hodgkin's lymphomas.

The relationship between selected aspects of medical history and the risk of non-Hodgkin's lymphomas (NHLs) was investigated using data from a hospital-based case-control study conducted in northern Italy on 177 cases of NHL and 561 controls in hospital for acute conditions, other than nonneoplastic or immunological. Among six viral diseases considered, only herpes zoster (shingles) had a relative risk (RR) significantly above unity [RR = 2.7; 95% confidence intervals (CI), 1.5 to 4.7]. The association, however, was restricted to subjects whose diagnosis of herpes zoster dated back to less than 10 years, suggesting that this slow-acting virus could be reactivated by the early development of NHL. Six of eight bacterial diseases considered showed RR above unity, and the estimate was significant for scarlet fever (RR = 1.9; 95% CI, 1.1 to 3.5) and pyelonephritis (RR = 5.3; 95% CI, 1.8 to 16.2). These associations were not restricted to the few years before lymphoma diagnosis. When various classes of infectious or inflammatory diseases were grouped together, no association was evident for viral infections (RR = 0.8; 95% CI, 0.6 to 1.2), acute bacterial diseases (RR = 1.0; 95% CI, 0.7 to 1.5), or allergic conditions (RR = 1.0; 95% CI, 0.6 to 2.1). The risk estimates were nonsignificantly above unity for chronic bacterial diseases (RR = 1.2; 95% CI, 0.7 to 1.2) and autoimmune conditions (RR = 1.4; 95% CI, 0.9 to 2.2), and significantly elevated for chronic inflammatory disease (RR = 1.9; 95% CI, 1.2 to 3.0).(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical course of early extranodal non-Hodgkin's lymphomas.

The subsequent sites of relapse following local X-ray therapy treatment of early stage non-Hodgkin's lymphoma were analyzed. The short interval to recurrence, the involvement of noncontiguous sites, and the rapid progression to death all suggest that seemingly early extranodal non-Hodgkin's lymphoma often is disseminated at diagnosis and that local treatment alone is ineffective. The analysis of sites of first relapse suggests that extended field treatment such as total nodal irradiation would benefit only a minority of these patients but would be superior to a radiation technique covering only the adjacent lymph node regions. While immediate contiguity of lymph node involvement was often seen with extranodal presentations, the more common pattern of relapse in bone marrow, liver, lung, stomach, and extranodal sites, indicates the need for an effective systemic therapy.     

Extranodal primary tumor site indicates poor prognosis in childhood head and neck non-Hodgkin's lymphomas

As a result of the diversity of lymphoid structures in the head and neck, we analyzed clinical characteristics and outcomes of 87 consecutive children with non-Hodgkin's lymphoma (NHL) arising in this region to determine if the nodal versus extranodal primary site influences prognosis. Thirty-one children had primary nodal NHL whereas 56 had extranodal NHL. The two groups were similar in the distribution of age, gender, race, serum lactic dehydrogenase levels, and disease stage. However, extranodal tumors were slightly more likely to have small non-cleaved cell histology (32/56 versus 11/31, p = 0.07) than nodal tumors. In a multivariate analysis, extranodal involvement (p = 0.017), advanced stage disease (p = 0.054) and treatment era (p = 0.056) were each significantly associated with a shorter time of event-free survival. Children with extranodal and extralymphatic NHL had an even worse treatment outcome than did others (p = 0.006). The poor prognosis of extranodal involvement was also evident among children with stage I or II NHL. We conclude that extranodal involvement has an adverse influence on treatment outcome in children with NHL arising in the head and neck region.     

Medical history and risk of Hodgkin's and non-Hodgkin's lymphomas.

The relationship between a history of selected medical conditions and risk of lymphomas was investigated in a hospital-based case-control study conducted in Northern Italy on 429 incident, histologically confirmed cases of non-Hodgkin's lymphoma (NHL), 158 cases of Hodgkin's disease (HD) and 1157 controls admitted to hospitals for acute conditions. The odds ratios (OR) for NHL were above unity in patients with a history of infectious mononucleosis (OR 2.9), herpes zoster (OR 1.8), pyelonephritis (OR 4.9), tuberculosis (OR 1.8), malaria (OR 1.9), any chronic bacterial diseases (OR 1.7), rheumatoid arthritis (OR 1.7) and psoriasis (OR 2.5). With reference to HD, the ORs were 4.0 for infectious mononucleosis, 2.9 for herpes zoster, 3.3 for pyelonephritis, 2.3 for tuberculosis, 1.4 for chronic bacterial diseases, 2.4 for rheumatoid arthritis, 2.7 for psoriasis and 2.1 for diabetes. The association of NHL and HD with herpes zoster was restricted to the first ten years since the onset of the disease. The relationships between NHL and mononucleosis (OR 12.9), malaria (OR 2.8) and psoriasis (OR 14.0) were stronger for cases aged > or = 60 years, and that with tuberculosis (OR 3.5) was stronger for younger cases. For HD, the positive association was stronger for cases aged > or = 40 years for herpes zoster (OR 3.8) and diabetes (OR 2.6). An increased risk of NHL was found in association with poliomyelitis (OR 1.6) (restricted to cases aged > or = 60 years, OR 4.0) and BCG immunizations (OR 1.6), but not with vaccination against smallpox, tetanus and diphtheria; increased risks of HD were found in relation to poliomyelitis and BCG immunization in cases aged > or = 40 years (OR respectively 2.5 and 2.1), or > or = 50 years (OR 4.3 and 2.2). Thus, our results confirm the association between a history of several chronic infectious and inflammatory diseases and the risk of NHL or HD, and are compatible with a role of chronic immunological alterations in the aetiology of lymphomas.     

CDK1 and cyclin A expression is linked to cell proliferation and associated with prognosis in non-Hodgkin's lymphomas.

Cellular proliferation is regulated by several kinasic complexes associating cyclins and their catalytic subunits cyclin-dependent kinases (CDKs). In order to gain insight into the mechanisms underlying proliferation in non-Hodgkin's lymphoma (NHL), we examined the expression of certain cell cycle regulatory proteins normally expressed in lymphoid cells, cyclins A, B, D3 and E and cdk1, 2, 4, and 6. In 70 patients presenting a previously untreated lymphoma, cyclins and CDKs were studied by Western blotting and quantified by densitometry. Flow cytometry study of DNA content was carried out for all patients in order to study cell proliferation and level of ploidy. The results were analysed according to the histological types, the immunological phenotypes of the lymphomas and the outcome of the patients. Cdkl and cyclin A were correlated with the percentage of cells in S and S+G2/M phases, and significantly different according to the grade of malignancy, with the lowest expression in low-, and the highest in high-grade NHL according to the Working Formulation. In B-NHLs, cdk1, cyclin A, as well as cdk2, cyclin D3 and E expression was higher in the aneuploid than in the euploid group. Our results point to some particularities of cell cycle regulation in two lymphoma sub-types: 1) a low expression of cyclin D3 and cdk6 in mantle cell lymphomas and 2) a discrepancy between the high proliferative activity and the level of protein expression in Burkitt's lymphomas. CDK1 and cyclin A showed a significant prognostic value for achievement of complete remission (Cdk 1) and for both disease free (cyclin A) and overall survival (cyclin A and cdk1): low protein level was associated with the best prognosis in B-NHLs. Our results show that differential cell cycle regulating protein expression may be associated with different biological and clinical behaviour of NHLs and confirm the usefulness of the study of cell cycle regulation as a tool for understanding lymphoid malignancies.