Cellular distribution of a B-cell specific surface antigen (gp54) detected by a monoclonal antibody (anti-BL4)

A monoclonal antibody (anti-BL4) recognizing a previously characterized Mr 54,000 glycoprotein (gp54) was developed by immunizing BALB/c mice with cells from a precursor B-cell line (Josh-7). In normal individuals, this antigenic molecule was present on tonsillar B-cells (60-80%) and on a fraction of peripheral blood B-cells (5-25%). BL4 (gp54) expression was investigated in 186 patients with a variety of hematological malignancies using indirect immunofluorescence and flow cytometric analysis. Twenty-six of 37 cases of B-cell chronic lymphocytic leukemia (CLL) and 18 of 33 cases of B-cell non-Hodgkin's lymphoma were BL4 positive. Surface expression of BL4 on reactive cases of CLL and non-Hodgkin's lymphoma was brighter than those of B1, B2, and B4, BL4 positive CLL cases expressed a higher proportion of mouse rosette forming cells and Leu-1 positive cells than the BL4 negative subgroup and were not associated with elevated serum immunoglobulin levels. Four of 7 BL4 negative CLL cases were associated with increased serum levels of immunoglobulin M. Lymphoblasts from 14 of 14 cases of non-T acute lymphoblastic leukemia and 3 of 3 pre-B lymphoid blast crisis of chronic myeloid leukemia were BL4 negative. Neoplastic cells from 2 of 3 cases of Waldenstrom's macroglobulinemia and 4 of 7 cases of hairy cell leukemia were BL4 reactive. None of 7 cases of multiple myeloma and plasma cell leukemia were BL4 positive. All 11 T acute lymphoblastic leukemia cases, 6 other T-cell malignancies, 5 cases of Hodgkin's disease, 51 cases of acute nonlymphocytic leukemia, and 9 cases of chronic myeloid leukemia in chronic phase thus far studied were BL4 negative. An in vitro induction experiment using phorbol ester on a case of B-CLL demonstrated disappearance of BL4 accompanied with further B-cell differentiation. Our study further substantiates the previous finding that gp54 is a differentiation antigen restricted to the B-cell lineage and expressed during the intermediate stage of B-cell ontogeny.     

Growth and Development of Children Born to Patients after Cancer Therapy

Eighteen children born to parents who had previously received chemotherapy or radiotherapy were examined for physical health, growth, and development. The immunologic and the hematologic status of these children was also evaluated. Their ages ranged from birth to 15 years. The children had a careful history and physical examination to detect any abnormal symptoms or signs, and the parent's previous treatment was carefully documented. Four sets of parents had children while one of the parents was on active treatment (2 male and 2 female). Of the male patients, one patient's wife had a baby that was “small for gestational age” at birth and had transient failure to thrive; the other child was normal. Of the female patients, one offspring was small for gestational age at birth and the other was normal, but both continued to have failure to thrive for up to 17 months and 26 months, respectively. Ten parents procreated after being treated with chemotherapy and/or radiotherapy, to whom 14 children were born. One child was a stillbirth with multiple congenital abnormalities, and another child had trisomy 13-15 and died 6 months later. The other 12 children were normal at birth, but one child is under the 5th percentile for growth at twelve months of age. In all children studied, immune function test, complete blood count, and viral tilers were considered normal for age. In our study, we found that three out of four children born to parents who were on chemotherapy had failure to thrive. Of the 14 children born to parents who conceived after being off chemotherapy, 11 were found to be normal in growth and development. These results imply that there is a high risk of complications in children born to parents who procreated while receiving chemotherapy. Further studies are needed to develop better guidelines for counseling cancer patients who want to have children.     

T-cell growth factor (Interleukin 2) and terminal transferase activity in human leukemias and lymphoblastic cell lines

Summary Mononuclear blood cells from patients with different types of leukemia, and from controls as well as cells from established lymphoblastic cell lines were analyzed with respect to terminal transferase (TdT) activity and T-cell growth factor (TCGF; Interleukin 2, IL-2), to determine the significance of TCGF production and response as functional markers for human leukemias.The data obtained so far suggest that the aberrant proliferation and lack of maturation observed in these leukemias may be associated with or be the result of a break-down in cellular-mediated control of proliferation.Supported in part by grants CA-20194, CA-08748, awarded by the National Cancer Institute, DHEW, grant 1-724 from the National Foundation, a grant from the National Leukemia Association, Inc., and by the Gar Reichman Foundation. S. G. is a special Fellow of the Leukemia Society of America     

Improved biochemical assay for terminal deoxynucleotidyl transferase in human blood cells: Results in 89 adult patients with lymphoid leukemias and malignant lymphomas in leukemic phase

Ion filtration chromatography of crude cell homogenates on DEAE-Sephadex allows determination of terminal deoxynucleotidyl transferase (TdT) activity in 10⁶ blast cells from acute lymphoblastic leukemia (ALL) and in 2 × 10⁷ normal bone marrow (BM) cells. Ninety-seven determinations of TdT in 40 patients with ALL during various stages of their disease revealed high levels of activity in BM and peripheral blood samples from all patients studied at diagnosis and in relapse. In $\text{10}\text{34}$ BM samples from patients with ALL in remission, levels of TdT activity were found to be significantly elevated as compared to normal controls. The remaining cases exhibited TdT activities within the normal range. In 20 patients with non-Hodgkin's lymphomas of null and T cell type in leukemic phase, TdT activities were within the same range as observed in active ALL. Eighteen of these had a histological diagnosis of diffuse poorly differentiated lymphoma of lymphoblastic type, one of giant follicular lymphoma and one of diffuse histiocytic lymphoma. In two patients with unclassifiable lymphoproliferative diseases of T cell type, no TdT activity was found, possibly indicating a disease of mature T cells. All 27 patients with lymphoid neoplasias of B cell type were found to exhibit no TdT activity in involved tissues. Determination of TdT activity appears to be a sensitive assay for detection of subclinical bone marrow involvement in TdT positive lymphoproliferative diseases. The clinical and theoretical significance of these observations is discussed.     

Interleukin-2 correction of defectivein vitro T-cell mitogenesis in patients with common varied immunodeficiency

We studied the ability of phytohemagglutinin (PHA) and two anti-T-cell monoclonal antibodies, OKT3 and Pan T2, to induce interleukin-2 (IL2) production and proliferation in peripheral blood lymphocytes (PBL) from 14 patients with combined varied immunodeficiency (CVI). The median values of endogenous IL2 produced by mitogen-stimulated PBL was significantly lower in patients than controls irrespective of the mitogen used. The patients, taken as a group, had a significantly decreasedin vitro PBL response to mitogen stimulation when compared to controls. With the addition of a highly purified human IL2 preparation, the proliferative response in the majority of patients was significantly improved with all mitogens. Three patient groups could be distinguished: Group A (3/14) had full restoration of proliferative response with the addition of IL2, Group B (5/14) had partial restoration, and Group C (6/14) had no significant response. The monoclonal antibody, Pan T2, recognized a T-cell proliferative defect in 5 of 14 patients which neither PHA nor OKT3 recognized. This was not significantly corrected by the addition of IL2. This T-cell proliferative defect correlated with the lack of B-cell proliferation and immunoglobulin production in response to B-cell mitogens in three-fourths of the patients assayed. These data show that CVI patients are a heterogeneous group but have in common a decreasedin vitro production of IL2 resulting in a proliferative defect which is correctable at least in part,in vitro, in the majority by the addition of purified IL2.     

Combination chemotherapy of advanced chronic lymphocytic leukemia: the M-2 protocol (vincristine, BCNU, cyclophosphamide, melphalan, and prednisone)

The M-2 protocol (vincristine, cyclophosphamide, BCNU, melphalan, and prednisone) was administered monthly to 63 evaluable patients with advanced chronic lymphocytic leukemia. Complete remission (absence of all clinical and bone marrow evidence of leukemia) and partial response (greater than 50% decrease in organ enlargement and reduction of WBC count to below 15,000 x 10(6)/liter) were achieved in 17% and 44%, respectively, for a total response rate of 61%. The median survivals from therapy of patients achieving a CR, RR, or no response were 73+, 40, and 14 mo respectively. The median survival time from onset of treatment for stages II, III, and IV disease were 47, 20 and 19 mo, respectively, which was not statistically different from historical controls. However, when untreated patients are compared to this latter group, a significant survival advantage from diagnosis was found (p = 0.01), stressing the importance of prior therapy as the only unfavorable prognostic factor. Although complete remissions in CLL, as reflected in apparently normal bone marrow B-lymphocyte markers, can be induced wih acceptable morbidity, the majority of patients relapse after cessation of therapy. An alternative approach to the M-2 protocol will be needed to eradicate the disease.     

Treatment of advanced Hodgkin's disease with chemotherapy and irradiation. Controlled trial of two versus three alternating, potentially non-cross-resistant drug combinations

From January 1979 to June 1983, 71 evaluable, previously untreated patients with advanced Hodgkin's disease completed a randomized trial of two or three potentially non-cross-resistant drug combinations and low-dose radiotherapy to initially involved nodal regions (2,000 to 3,000 rads). All patients received nine cycles of alternating chemotherapy regimens and radiotherapy between cycles 6 and 7. Thirty-four patients received three combinations: lomustine, melphalan, vindesine (CAD), MOPP, and doxorubicin, bleomycin, vinblastine (ABV). The complete remission rate was 82 percent, partial remission rate 12 percent, and progression rate 6 percent. There were two relapses from complete remission and three deaths. Thirty-seven patients received MOPP and ABV plus dacarbazine (D). The complete remission rate was 78 percent, partial remission rate 16 percent, and progression rate 6 percent, with three relapses from complete remission and five deaths. Myelosuppression was more frequent with CAD/MOPP/ABV/radiotherapy, and nausea and vomiting with MOPP/ABVD/radiotherapy. The results for both are among the best reported, and CAD/MOPP/ABV/radiotherapy was more acceptable to patients.     

Massive lymphadenopathy mimicking lymphoma in leukemic reticuloendotheliosis.

Leukemic reticuloendotheliosis is increasingly noted to have a spectrum of laboratory findings suggestive of both lymphocytes and monocytes. However, previous reports have not noted a clinical presentation which may be confused with lymphoma. This report documents a case of leukemic reticuloendotheliosis in a 29 year old man with clinical findings of diffuse lymphadenopathy, organomegaly and cutaneous involvement. As cytotoxic agents may be dysfunctional in leukemic reticuloendotheliosis, the ability to distinguish between the disorder and a lymphomatous process may be critical to the patient's management. Both morphologic examination of the "hairy-cell" and cytochemistry may not give an unequivocal differentiation between these two diseases. However, functional studies of the neoplastic cell, such as cell-marker analysis, phagocytic function and ultrastructural morphology, can define by noninvasive methods the correct diagnosis in the atypical presentation of leukemic reticuloendotheliosis.