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PubMed2003

Practicability and acute haematological toxicity of 2- and 3-weekly CHOP and CHOEP chemotherapy for aggressive non-Hodgkin's lymphoma: results from the NHL-B trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL).

BACKGROUND: There is evidence that intensified variants of the classical 3-weekly CHOP-21 chemotherapy [cyclophosphamide (C), doxorubicin (H), vincristine (O), prednisone (P)] may improve treatment outcome in aggressive lymphoma. Three variants using either an addition of etoposide (CHOEP-21: 100 mg/m(2) on days 1-3), the shortening to 2-week intervals using recombinant human granulocyte colony-stimulating factor (rhG-CSF; CHOP-14) or both (CHOEP-14) are currently compared with CHOP-21 in the NHL-B trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL). To enable more extensive testing of these schemes we here characterise their practicability regarding schedule adherence, acute haematotoxicity and need for supportive treatment. PATIENTS AND METHODS: The trial included patients with normal lactate dehydrogenase (LDH) aged </=60 years (NHL-B1) and patients aged 61-75 years (NHL-B2). The data are taken from an interim analysis. Data from 959 patients (CHOP-21: 232; CHOP-14: 238; CHOEP-21: 244; CHOEP-14: 245) from 162 institutions with a total of 5331 therapy cycles were evaluated. RESULTS: The dose adherence in the NHL-B1 trial was excellent. The median relative dose (RD; i.e. actually given compared to planned dose) exceeds 98% for the myelosuppressive drugs in all four regimens. Only </=5% of patients received a relative dose <80% (RD <80). The median treatment duration could be shortened as scheduled for both CHOP-14 by 36 days and CHOEP-14 by 35 days. The dose adherence in the NHL-B2 trial was excellent for CHOP-21 and CHOP-14 for the myelosuppressive drugs (median RD >/=98%, RD <80 </=15%). Addition of etoposide, however, was accompanied by more dose erosion (median RD >/=97%, RD <80 </=17% for CHOEP-21 and </=27% for CHOEP-14). The median treatment duration could be shortened by 34 days with CHOP-14 compared with CHOP-21. Less treatment shortening was feasible for CHOEP-14 compared with CHOP-21 (median of 29 days). CHOP-14 and CHOP-21 were similar regarding toxicity profile, rate of infection, use of antibiotics, rate of transfusions and hospitalisation. CHOEP schemes were associated with a higher rate of infections, more transfusion requirements, more antibiotic use and longer hospitalisation than the CHOP schemes, particularly in patients aged >60 years. Haematopoietic recovery was age- and treatment-related. CONCLUSIONS: CHOP-14 with the addition of rhG-CSF is safe and practicable in a large multicentre setting in patients aged 18-75 years. Despite shorter treatment intervals it can be delivered at the same dose as the classical 3-weekly CHOP with a comparable toxicity profile. The addition of etoposide is feasible and safe for patients </=60 years old in both the CHOEP-21 and CHOEP-14 schemes. For patients >60 years of age the addition of etoposide is associated with marked dose erosion due to increased toxicity. In this age group CHOEP should be used with caution.

Acute Disease↗

PubMed2001

Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma.

PURPOSE: To assess the feasibility and efficacy of intensive chemotherapy with hematopoietic stem-cell rescue (IC + HCR) in patients with refractory or recurrent primary CNS lymphoma (PCNSL) or intraocular lymphoma (IOL). PATIENTS AND METHODS: IC consisted of thiotepa 250 mg/m(2)/d days -9 through -7, busulfan 10 mg/kg (total dose) days -6 through -4, and cyclophosphamide 60 mg/kg/d days -3 and -2. Intravenous clonazepam 2 mg/d was given prophylactically from the day before initiation of busulfan therapy to the day after completion of busulfan therapy. Patients with refractory or recurrent PCNSL underwent IC + HCR only if they were chemosensitive to two cycles of salvage treatment with cytarabine (2 g/m(2)/d days 2 through 5 and 50 mg/m(2)/d days 1 through 5 in a 12-hour infusion) and etoposide (VP-16; 200 mg/m(2)/d days 2 through 5) (CYVE). Patients with IOL refractory to high-dose methotrexate (MTX) and cytarabine entered the IC + HCR program directly. RESULTS: Twenty-two patients (10 with relapses, 12 with refractory disease) were enrolled. Twenty patients entered the IC + HCR program: twelve entered after CYVE treatment, seven entered directly, and one had previously been retreated with high-dose MTX. Before IC, eight patients were in complete remission (CR), four were in partial remission (PR), one had stable disease, and seven had refractory disease. After IC + HCR, 16 patients entered CR, two remained in PR, one had stable disease, and one had disease progression. Fourteen patients remained alive (median follow-up time, 41.5 months). The overall probability of survival at 3 years was 63.7%. After IC, that probability was 60% and the 3-year probability of event-free survival was 53%. Seven patients had neurologic adverse events during the entire procedure. CONCLUSION: IC + HCR proved feasible and effective in patients with refractory or recurrent PCNSL or IOL. The entire procedure seemed to be most toxic in patients > or = 60 years. A prospective multicenter study is ongoing.

Adult↗

PubMed1985

Large cell lymphoma of the orbit with microvillous projections ('porcupine lymphoma').

A 57-year-old man had a diffuse mass in the lacrimal gland area associated with extensive bony destruction. A malignant epithelial tumor of the lacrimal gland was suspected clinically, and a biopsy specimen disclosed an undifferentiated malignant neoplasm of uncertain origin. Ultrastructural studies, however, revealed features of a lymphoid tumor with myriad cytoplasmic microvillous projections. The patient has had no evidence of systemic lymphoma after more than three years of follow-up. To our knowledge, this is the first report of orbital involvement of a large cell lymphoma with microvillous projections ("porcupine lymphoma"). The role of electron microscopy in the differential diagnosis of this orbital tumor was important, since epithelial tumors of the lacrimal gland are best managed by surgical excision, whereas lymphoid tumors usually respond satisfactorily to radiotherapy.

Biopsy↗

PubMed1999

Quiescent nasal T/NK cell lymphoma manifested as primary central nervous system lymphoma.

A 57-year-old man was diagnosed as primary T/NK-cell central nervous system lymphoma (CNSL) with intraocular involvement. However, review of a surgical specimen taken three years before for chronic paranasal sinusitis revealed an overlooked nasal T/NK cell lymphoma (TNKL), which showed similar histomorphology and immunophenotype with the CNS disease. Another patient, a 43-year-old woman, was initially diagnosed as a rare primary leptomeningeal T-cell lymphoma with ocular manifestation. Three years later, an isolated nasal TNKL emerged. Immunohistochemical and cytogenetic studies confirmed the same nature of the CNSL and the nasal TNKL. The nasal TNKLs of both patients had a strong expression of CD3, CD56, and Epstein-Barr virus antigens, but features of angiodestruction and mucosal ulceration were absent. We propose that: 1. a locally silent "quiescent" form of nasal TNKL may exist; and 2. a thorough examination and even blind biopsy of the nasal cavity is indicated when primary T/NK-cell CNSL is diagnosed.

Adult↗

PubMed2000

Mantle cell lymphoma. A clinicopathologic study of 68 cases from the Nebraska Lymphoma Study Group.

Although mantle cell lymphoma (MCL) is considered a distinctive disease entity within non-Hodgkin's lymphoma (NHL), the cytology and growth pattern of MCL can be quite variable and the clinical significance of these features is unclear. Also, the role of anthracyclines in the management of MCL is unclear. Therefore, we examined our experience with MCL in an effort to clarify these important issues. We identified 68 patients with MCL who were evaluated clinically and treated by the Nebraska Lymphoma Study Group. Treatment consisted of combination chemotherapy containing an anthracycline in 76% of the patients. The cases were grouped by blastic or lymphocytic cytology, and the latter were divided by growth pattern into nodular (or mantle-zone) and diffuse types. The clinical and pathological variables were then evaluated for their prognostic value. The median overall survival (OS) and failure-free survival (FFS) for the entire group were 38 months and 12 months, respectively, and there was no survival advantage for those who received an anthracycline. The cases were grouped as follows: blastic type, 26%; nodular lymphocytic type, 44%; and diffuse lymphocytic type, 30%. Both the cytology and pattern of growth were predictive of OS and FFS. The median OS was as follows: blastic type, 55 months; nodular lymphocytic type, 50 months; and diffuse lymphocytic type, 16 months (P = 0.0038). The clinical features that predicted for a shorter survival included bone marrow involvement, advanced stage disease, B symptoms, a poor performance score, and the International Prognostic Index. We conclude that new therapeutic approaches, with the patients stratified by histologic type and clinical prognostic factors, are clearly needed for MCL.

Humans↗

PubMed1977

Establishment of an Epstein-Barr virus-negative B-cell lymphoma line from a Japanese Burkitt's lymphoma and its serial passage in hamsters.

An Epstein-Barr virus (EBV)-negative lymphoma line (JBL) was established in vitro from pleural effusion of an EBV-seropositive 29-year-old Japanese female with Burkitt's lymphoma. JBL cells as well as her original lymphoma cells bore monoclonal surface IgM with lambda light chains. The JBL line grew in single cell suspension with a doubling time of 30 hours. Attempts were made to serially transplant JBL cells in antilymphocyte serum-treated newborn hamsters; intraperitoneal implantation of 1-3 X 10(7) cells gave rise to invasive tumors in all recipients with death after 10 to 14 days. The hamster-passage line, now in the 9th passage, has been converted to an ascitic form with progression to leukemia in some animals. A "starry sky" pattern closely resembling the human tumor material was preserved in every tumor through serial animal passage.

Animals↗

PubMed1981

In vitro growth of lymphoma colonies from children with non-Hodgkin's lymphoma.

Growth in vitro of malignant lymphoid cells has been previously reported, but those studies involved direct establishment of cell lines from the patients' cells. In the present study, an in vitro system for both primary growth and passage of malignant lymphoblastic colony-forming cells (ML-CFC) was established, and for the first time, colony-forming cells from non-Hodgkin's lymphoma patients were cultured, and cell lines were established from individual colonies. Malignant lymphoid colonies grew from 9 of 16 (56%) bone marrow aspirates, which were histologically involved with lymphoma and from 5 of 29 (17%) morphologically normal bone marrow samples. ML-CFCs grew concomitantly with myeloid and monocytic CFCs and were distinguishable by their morphologic characteristics on agar, cytochemical staining characteristics, and cell surface markers. Successful passage of ML-CFCs was accomplished in five patients, and ten distinct cell lines (six null cell, three B cell, and one T cell) were established. This agar assay system provides an opportunity to study malignant lymphoma cell growth both as a primary colony and a cell line established from a primary colony.

Adolescent↗

PubMed1988

Spontaneous regression of a small non-cleaved cell malignant lymphoma (non-Burkitt's lymphoblastic lymphoma). Morphologic, immunohistological, and immunoglobulin gene analysis.

Complete spontaneous regression of high-grade malignant non-Hodgkin's lymphoma is extremely unusual. In this report the authors describe a complete spontaneous remission after surgical excisional biopsy of a small noncleaved cell malignant lymphoma (non-Burkitt's lymphoblastic lymphoma) of the tonsil in a 12-year-old boy. The diagnosis was confirmed by immunohistologic and immunoglobulin gene analysis. Similar studies were performed on the cervical lymph node excised 2 weeks later when spontaneous remission had occurred. The patient has remained in good health for over 3 years.

Adolescent↗

PubMed2004

Differential Emu enhancer activity and expression of BOB.1/OBF.1, Oct2, PU.1, and immunoglobulin in reactive B-cell populations, B-cell non-Hodgkin lymphomas, and Hodgkin lymphomas.

It has previously been demonstrated that in cultured and in situ tumour cells of classical Hodgkin lymphoma (cHL), the immunoglobulin (Ig) promoter is inactive and its transcription factors Oct2 and/or BOB.1/OBF.1 are down-regulated. In this study, the analysis of these transcription factors has been extended to a broad spectrum of B-cell malignancies and the findings have been related to the situation in normal B-cells of various differentiation stages and to the expression of Ig. Furthermore, an additional Ig transcription factor, PU.1, recently described to be absent from cHL, and a further regulatory element of the Ig gene, the intronic Emu enhancer, have been studied. BOB.1/OBF.1 and Oct2 were present in all B-cells expressing Ig, whereas PU.1 proved to be absent from late B-cell differentiation stages and from a subset of germinal centre B-cells. Interestingly, there were several normal (eg germinal centre centroblasts and monocytoid B-cells) and malignant B-cell populations (eg a proportion of diffuse large B-cell lymphomas, DLBCLs) that were Ig-negative, despite their BOB.1/OBF.1 and Oct2 expression. This study further shows that absence of PU.1 alone, as well as inactivation of the intronic Emu enhancer, is not sufficient to down-regulate Ig transcription. Taken together, the simultaneous absence of PU.1, Oct2, and/or BOB.1/OBF.1 is unique to Hodgkin and Reed-Sternberg (HRS) cells and cannot be detected in normal B-cell subsets or B-cell non-Hodgkin lymphomas (B-NHLs). This supports the concept that the down-regulation of Ig in cHL does not reflect a physiological situation, but a defect probably closely linked to the pathogenesis of cHL.

B-Lymphocytes↗

PubMed1993

Perspective on the usefulness of the mouse lymphoma assay as an indicator of a genotoxic carcinogen: ten compounds which are positive in the mouse lymphoma assay but are not genotoxic carcinogens.

The mouse lymphoma assay is commonly included in batteries of tests for the mutagenic and carcinogenic potential of chemicals. Unlike other bacterial and mammalian cell tests, it has an unacceptably high incidence of false positive results. This paper reviews data on ten chemicals, all of which are positive in the mouse lymphoma assay but negative in all other genotoxicity tests. Three are non-genotoxic rodent carcinogens acting through a variety of secondary mechanisms, while seven are not carcinogenic. It is concluded that a positive mouse lymphoma assay alone cannot be a barrier to the human use of drugs and other chemicals.

Allylbenzene Derivatives↗

PubMed1993

Monoclonal antibodies to lymphocyte function-associated antigen-1 inhibit invasion of human lymphoma and metastasis of murine lymphoma.

The leukocyte integrins are cell adhesion molecules which play pivotal roles in the development of a variety of immune responses including T-cell-mediated cytotoxicity, lymphocyte proliferation, macrophage presentation of antigen, and adhesion of leukocytes to vascular endothelium. The relevance of lymphocyte function-associated antigen-1 (LFA-1) to leukocyte malignancies is currently under examination in a number of laboratories. Here, we present evidence demonstrating that LFA-1 plays a role during the in vitro invasion of human endothelium by JY lymphoma cells and during in vivo metastasis of two distinct models of murine leukemia: P815 mastocytoma and EL4 lymphoma. When assayed in vitro, a murine anti-human LFA-1 (alpha subunit) monoclonal antibody (mAb) inhibits up to 80% of JY lymphoma cell invasion. When assayed in vivo, a rat anti-LFA-1 (alpha subunit) mAb significantly inhibited the development of experimental metastases, when administered concomitantly with either P815 or EL4 tumor cells. The leukocyte integrins, particularly LFA-1, may represent useful targets for the therapeutic modulation of metastasis.

Animals↗

PubMed1992

Expression of LFA-1/ICAM-1 in CNS lymphomas: possible mechanism for lymphoma homing into the brain.

We examined a possible role for the adhesion molecules LFA-1 and ICAM-1 in localizing central nervous system non-Hodgkin's lymphomas (CNS-NHLs) to the brain. Fresh frozen sections from 12 monoclonal CNS NHLs (11 primary, one secondary) were stained with monoclonal antibodies to LFA-1 alpha chain (CD11a), beta chain (CD18) and, ICAM-1 (CD54). Additional staining made use of rat monoclonal antibodies to the human and mouse high endothelial venule antigens HECA 452 and MECA 79 and mouse ICAM-1. The expression of these same molecules was also studied in mice with severe combined immunodeficiency (SCID) mice, bearing intracranial human lymphoblastoid cells. Eleven of the CNS-NHL tumors expressed LFA-1 alpha (one strongly, one intermediate, nine weakly). Nine of the tumors weakly expressed LFA-1 beta.. Nine of twelve tumors weakly expressed ICAM-1. In six of seven tumors definite blood vessels stained for ICAM-1. Non-tumor brain from two patients and non-tumor cerebral blood vessels showed no staining with CD11a, CD18 or CD54 antibodies. Strong expression of LFA-alpha and LFA-beta as well as ICAM-1 was noted in human lymphoblastoid cells (LCLs)/SCID mouse CNS lymphomas. Tumor blood vessels in these mice stained for mouse ICAM-1. Normal SCID mouse brains showed no staining with CD11a, CD18, CD54 or mouse ICAM-1 antibodies. Human, human/mouse CNS lymphomas, normal human, and mouse brains showed no staining with either HECA 452 or MECA 79.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1983

Malignant lymphoma with a high content of epithelioid histiocytes (so-called Lennert's lymphoma). Immunocytochemical and ultrastructural observations.

The clinicopathological findings of four cases of an uncommon form of non-Hodgkin's lymphoma called malignant lymphoma with a high content of epithelioid histiocytes (MLHH) are described. In each case the peroxidase antiperoxidase technique was used for detecting cytoplasmic immunoglobulins (CIg) in the diagnostic lymphoid tissue. In one case (patient 1), IgG and IgM heavy chains and kappa light chain were detected in 30 to 40 percent of the atypical lymphoid cells. This result suggests that the proliferating B lymphocytes in this patient with MLHH are neoplastic rather than reactive in nature. We were unable to identify CIg in the proliferating lymphoid cells of the other three patients. Our case when coupled with others reported in the literature suggest that the morphologic features of MLHH (so-called Lennert's lymphoma) can be associated with a neoplastic proliferation of either T or B lymphocytes. The ultrastructural findings of one case are presented.

Aged↗

PubMed1993

Phase II study of NK313 in malignant lymphomas: an NK313 Malignant Lymphoma Study Group trial.

Liblomycin (NK313) is a bleomycin analog that has proved to be associated with less pulmonary toxicity and with more potent antitumor activity than bleomycin in animal tumors. In a phase I study, pulmonary toxicity was not observed, whereas myelosuppression was the dose-limiting factor. The maximum tolerated dose was 140 mg/m2 given once a week for 4 weeks. In the present phase II study, patients with malignant lymphomas received liblomycin at 80 or 100 mg/m2 by intravenous infusion over 15 min once a week for 4 weeks. A total of 39 patients were entered, and 31 [4 with Hodgkin's disease (HD) and 27 with non-Hodgkin's lymphoma (NHL)] were evaluable. The median age of the patients was 52 years (range, 22-74 years), and their performance status ranged from 0 to 3. In all, 28 of the patients had a history of intensive anticancer chemotherapy. Responses were evaluated according to WHO criteria. We obtained 1 complete remission and 9 partial remissions (PRs), for an overall response rate of 37%, in the 27 patients with NHL, whereas 1 PR was achieved in the 4 patients with HD. In all, 9 PRs (32.1%) were obtained in patients who had been exposed to prior chemotherapy, including 4 PRs (33.3%) in 12 patients who had previously been treated with bleomycin. Myelosuppression and nausea and vomiting were the major toxicities, which occurred in about 50% of the patients, and myelosuppression was severe in two patients treated at a dose of 100 mg/m2. We concluded that liblomycin demonstrated significant antitumor activity against malignant lymphomas.

Adult↗

PubMed1985

Follicular malignant non-Hodgkin's lymphoma with pronounced plasmacytic differentiation: a plasmacytoma-like lymphoma.

A case of follicular centroblastic-centrocytic lymphoma with an unusually pronounced plasmacytic component occurring in the gingiva and cervical lymph nodes of a 74-year-old male patient is described. Immunohistological analysis revealed a monotypic intracytoplasmic immunoglobulin pattern (IgM/lambda). The relation between follicular malignant non-Hodgkin's lymphomas and extramedullary plasmacytome is discussed. In the present case the tumour may represent the development of an autonomous plasma cell clone within a follicular centroblastic-centrocytic lymphoma.

Aged↗

PubMed2002

Analysis of SH2D1A mutations in patients with severe Epstein-Barr virus infections, Burkitt's lymphoma, and Hodgkin's lymphoma.

Mutations or deletions in the SH2D1A (src homology 2 domain protein 1A) gene result in a severe immunodeficiency called X-linked lymphoproliferative (XLP) disease. XLP is primarily characterized by a defective immune response against the Epstein-Barr virus (EBV), resulting in an unusually severe and often fatal clinical course following EBV infection. The second major cause of death is the development of B cell lymphomas, both in EBV-infected and EBV-negative patients. To study whether the clinical manifestation of XLP gene defects and/or polymorphisms extends beyond the classically recognized phenotype, we analyzed patients for the presence of SH2D1A gene alterations who presented with fatal or nonfatal, yet unusually severe or chronic EBV infections, and other possibly EBV-associated diseases, such as Hodgkin's lymphomas or nonendemic Burkitt's lymphomas and Burkitt-type leukemias. We identified mutations of the SH2D1A gene only in the majority of patients presenting with fatal mononucleosis or an XLP family history, but not in any of the other patients studied. The only alteration determined was a polymorphism in the 5' region of the SH2D1A gene both in patient groups as well as in controls.

Burkitt Lymphoma↗

PubMed2005

An additional segment at 1p36 derived from der(18)t(14;18) in patients with diffuse large B-cell lymphomas transformed from follicular lymphoma.

The particular translocation in follicular lymphomas (FLs) is a t(14;18)(q32;q21), recombining the immunoglobulin heavy chain (IgH) gene on chromosome 14 with the B-cell leukemia/lymphoma 2 (BCL2) gene on chromosome 18. Some low-grade FLs are aggressively transformed into diffuse large B-cell lymphomas, presumably by acquisition of secondary chromosomal changes, including chromosomal band 1p36. A common example is add(1)(p36). Because it is difficult to identify the origin of add(1)(p36) even on high-resolution G-banding analysis, we used spectral karyotyping (SKY) and double-color fluorescence in situ hybridization (DC-FISH) to define the t(14;18) and the extra band at 1p36 in two cases of diffuse large B-cell lymphoma (DLBCL). SKY revealed that the extra chromosomal segment on 1p36 was derived from chromosome 18. DC-FISH defined BCL2/IgH fusion signals at 1p36 in addition to t(14;18), suggesting that BCL2/IgH fusion at 1p36 was an evolutionary alteration following the primary BCL2/IgH translocation on der(18) in both cases. Our results indicate that IgH alleles, implicated in chromosomal rearrangement, may themselves frequently be targets for secondary translocations, suggesting that multiple IgH translocations and insertions are associated with the progression of FL.

Chromosome Banding↗

PubMed2006

Nodal marginal zone B-cell lymphoma: Analysis of 36 cases. Clinical presentation and treatment outcomes of nodal marginal zone B-cell lymphoma.

Nodal marginal zone B-cell lymphoma (NMZL) is a relatively uncommon type of lymphoma. Because of the rarity, the natural history and the optimal treatment modality have not been well defined. Therefore, we performed a retrospective analysis of the clinical features and treatment outcomes of NMZL. Thirty-six patients who were histologically diagnosed as NMZL were included in the analysis. Fifty-three percent of the patients had localized disease (stages I and II), and 21.2% (7/33) had bone marrow involvement at presentation. B symptom was present in only three patients (8.3%). Most patients were categorized as low or low-intermediate risk group by international prognostic index (IPI) (77.1%). Majority (94.4%) of the patients with localized disease achieved complete remission (CR) after the initial treatment. Of the seven patients with disseminated disease, who were treated with anthracycline-based chemotherapy, four patients achieved CR. Of the seven patients who received nonanthracycline-based chemotherapy, no patient achieved CR. After the median follow-up duration of 36 months, the median progression-free survival (PFS) was 3.9 (95% CI; 2.9-5.6) years, and the estimated 5-year PFS and overall survival rates were 47.2 and 82.7%, respectively. The significant predictive factors for PFS were performance status, advanced stage, and follicular lymphoma IPI (FLIPI) in this study. This clinical feature is similar to FL rather than to MZL-MALT type.

Adolescent↗