E. S. Henderson

Prognostic Importance of Cytogenetic Abnormalities in Patients with Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia is recognized as having a variable prognosis, but its staging has depended exclusively on anatomical sites of involvement and the presence or absence of anemia and thrombocytopenia. The recent availability of techniques permitting cytogenetic analysis of malignant B lymphocytes led us to examine the karyotypic abnormalities in chronic lymphocytic leukemia and to correlate them with clinical stage, progression of disease, and survival. Of 53 patients with metaphases adequate for study who were followed for a minimum of one year, 21 (40 per cent) had abnormal karyotypes, of which trisomy 12 was the most frequent (25 per cent). Abnormal karyotypes were found to be significant correlates of advanced clinical stage (P less than 0.005) and of shortened survival (P less than 0.05). We conclude that cytogenetic analysis provides useful clinical and prognostic information in patients with chronic lymphocytic leukemia.

Immunoregulatory T cell function in multiple myeloma

Multiple myeloma is a malignancy characterized by uncontrolled monoclonal B cell differentiation and immunoglobulin production. In most instances, there is concomitant reduction in polyclonal differentiation and immunoglobulin synthesis both in vivo and in vitro. In in vitro pokeweed mitogen-induced B cell differentiation assays, proliferation and polyclonal immunoglobulin secretion optimally requires T cell help and can be inhibited both by monocytes and suppressor T cells. Helper function and monocyte-mediated suppression are relatively radio-resistant whereas T suppressor function is sensitive to 2,000 rad x-irradiation. We have examined myeloma T cell subset function in this assay using recombinations of isolated patient and normal B cells, T cells, and T cell subsets. Monocytes were removed by a carbonyl iron ingestion technique, normal and myeloma T cells were fractionated on the basis of Fc receptors for immunoglobulin (Ig) G (Tgamma) or IgM (Tmu or T non-gamma), and proliferation and IgG secretion after co-culture determined by [(3)H]thymidine incorporation and radio-immunoassay, respectively. Myeloma B cells demonstrate quantitatively and qualitatively normal blastogenic responses and are appropriately regulated by either autologous or allogeneic T helper and suppressor subsets. Despite normal proliferation, however, myeloma B cells remain deficient in subsequent differentiation and immunoglobulin secretion even when co-cultured in the absence of monocytes or suppressor T cells and the presence of normal helper cells. Myeloma T cell populations, in contrast, are entirely normal in helper capacity over a range of T:B ratios but are markedly deficient in radiosensitive and concanavalin A-induced suppressor activity. T suppressor cell dysfunction in multiple myeloma is apparently due to a deficit in the T non-gamma suppressor subset, whereas Tgamma cells, although proportionately reduced, are functionally normal. This unique T suppressor deficit reflects the heterogeneity of suppressor mechanisms in this disease and may represent a compensatory response to the monoclonal proliferation or the involvement of regulatory T cells in the pathogenesis of the malignancy.

Establishment and characterization of the tumors of chronic lymphocytic leukemia cell line in nude and scid mice

A new cell line, designated MO1043, was established from the peripheral blood (PB) of a patient with B-cell chronic lymphocytic leukemia (CLL). Both the PB leukemia cells and MO1043 were found to have an abnormal cytogenetic marker of trisomy 12, the most common cytogenetic abnormality in CLL. In addition, both the PB cells and MO1043 expressed a cell surface phenotype of typical B-CLLs. The MO1043 was efficiently transplanted into X-irradiated athymic nude mice by i.p. inoculation after it was subjected to serial passages in new born (1 week old) and irradiated adult nude mice. The tumor of a CLL cell line (termed CLL tumor) was also generated in the nude mice by s.c. inoculation of the cells. The MO1043 was inoculated i.p. into mice with severe combined immunodeficiency (SCID) which had not been subject to any preconditionings. The CLL tumor in the non-conditioned SCID mice was disseminated to various tissues in a manner more analogous to CLL tumors in patients as compared with nude mice, where the CLL tumors were not as widely disseminated. At each of four different tumor doses, i.e. 2 x 10(6), 6 x 10(6), 1.8 x 10(7) and 5.4 +/- 10(7) cells of MO1043, the transplantability was 100%. Titration experiments revealed a reciprocal relationship between survival and the number of tumor cells inoculated. FACS analysis showed that several cell surface markers of the parental MO1043 were maintained in CLL tumors from nude and SCID mice. Fluorescence in situ hybridization with novel DNA probes demonstrated that CLL tumors of both nude and SCID mice maintained trisomy 12. The CLL tumor models developed here, particularly the SCID mouse model, may be very useful for therapeutic studies of CLL.

The influence of histologic type on the incidence and duration of response in non-Hodgkin's lymphoma.

A group of 227 cases of non‐Hodgkins lymphoma included seven favorable and four unfavorable histologic classes with collective median survival times of 83 and 16 months, respectively. The favorable group included three follicular subgroups (cleaved, mixed, and large noncleaved) and four diffuse classes (small lymphocytic, cleaved, Burkitts noncleaved, and convoluted lymphocytic). The unfavorable group consisted of four diffuse subgroups (plasmacytoid lymphocytic, mixed, and small and large noncleaved). There were significant differences in collective median survivals between patients in Stage I‐II and those in Stage III‐IV in both the favorable group (not reached, NR versus 62 months, P < 0.001) and the unfavorable group (57 months versus 12 months, P < 0.01). The incidence of complete response to primary treatment was higher in the favorable than in the unfavorable group (75% versus 56%, P = 0.002) and in those with limited as compared with advanced disease. Complete responders in both prognostic groups had longer survival times than did partial or minimal responders. A significant difference in median complete remission duration was found between responders in Stage I‐II versus Stages III‐IV in the favorable group (not reached versus 40 months, P = 0.001) but not in the unfavorable one (56 months versus 22 months, P > 0.05). The absence of relapses after 41 months among complete responders in the favorable but not in the unfavorable group suggests a potential for cure in a proportion of cases from the former group. The incidence of complete response was lower and median remission duration was shorter after secondary as compared with primary treatment. The results of this study confirm the prognostic value of the Lukes and Collins classification system and the importance of initial staging and of achieving a complete response to primary treatment in both the favorable and unfavorable lymphomas.

The influence of histologic type on survival in non-Hodgkin's lymphoma

Histologic groups in 231 cases of malignant lymphoma were correlated with survival data at 100 months from the time of initiation of the study. Patients in the first two decades of life fared comparably with adults, but those over 60 years of age showed a poorer survival trend. Seven favorable and four unfavorable histopathologic groups were found with collective median survivals of 83 and 16 months, respectively (P < 0.001). The favorable group included three follicular classes (cleaved, mixed, and large noncleaved) and four diffuse classes (small lymphocytic, cleaved, Burkitt non‐cleaved, and convoluted lymphocytic). The unfavorable group consisted of four diffuse classes (plasmacytoid lymphocytic, mixed, and small and large non‐cleaved). The group of 88 patients with follicular lymphoma had significantly longer overall survival than the group of 143 patients with diffuse lymphomas. No significant differences in survival were noted within three grades of follicular involvement. The favorable and unfavorable diffuse lymphomas had collective median survivals of 82 and 16 months, respectively (P = 0.01). Significant survival differences due to pattern of nodal involvement (P = 0.01) were found in patients with mixed and large non‐cleaved cell lymphomas, but not in those with cleaved cell lymphomas. The group with large cleaved cells had significantly longer survival than those with large non‐cleaved cells. Patients with mixed and large non‐cleaved cell lymphomas of the same nodal pattern had similar survival data.