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Background: Extracorporeal photopheresis (ECP) is an immunomodulatory cellular therapy which has been shown to induce a tolerogenic state in patients with acute and chronic graft-vs-host disease. ECOG-ACRIN explored the activity of ECP as a part of a reduced intensity conditioning regimen in two multicenter trials in patients with MDS (E1902) and lymphomas (E1402). While both studies closed before completing accrual, we report results in 23 patients (17 MDS and 6 lymphoma)., Study Design and Methods: Patients received 2 days of ECP followed by pentostatin 4 mg/m2 /day for two consecutive days, followed by 600 cGy of total body irradiation prior to stem cell infusion. Immunosuppression for aGVHD was infusional cyclosporine A or tacrolimus and methotrexate on day +1, +3, with mycophenolate mofetil starting on day 100 for chronic GVHD prophylaxis., Results: All patients engrafted, with median time to neutrophil and platelet engraftment of 15-18 days and 10-18 days respectively. Grade 3 or 4 aGVHD occurred in 13% and chronic extensive GVHD in 30%., Conclusions: These studies demonstrate that ECP/pentostatin/TBI is well tolerated and associated with adequate engraftment of neutrophils and platelets in patients with lymphomas and MDS., (© 2020 AABB.)

Purpose: To determine if maintenance rituximab (MR) after standard chemotherapy improves progression-free survival (PFS) in advanced-stage indolent lymphoma., Patients and Methods: Patients with stage III-IV indolent lymphoma with responding or stable disease after cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy were stratified by initial tumor burden, residual disease after CVP (minimal or gross), and histology, and randomly assigned to observation (OBS) or MR 375 mg/m(2) once per week for 4 weeks every 6 months for 2 years. PFS was the primary end point., Results: Three hundred eleven (282 with follicular lymphoma) evaluable patients who received CVP were randomly assigned to OBS (n = 158) or MR (n = 153). Best response improved in 22% MR versus 7% OBS patients (P = .00006). Toxicity was minimal in both study arms. Three-year PFS after random assignment was 68% MR versus 33% OBS (hazard ratio [HR] = 0.4; P = 4.4 x 10(-10) [all patients]) and 64% MR v 33% OBS (HR = 0.4; P = 9.2 x 10(-8) [patients with follicular lymphoma]). There was an advantage for MR regardless of Follicular Lymphoma International Prognostic Index score, tumor burden, residual disease, or histology. In multivariate analysis of MR patients, minimal disease after CVP was a favorable prognostic factor. OS at 3 years was 92% MR versus 86% OBS (HR = 0.6; log-rank one-sided P = .05) and, among patients with follicular lymphoma, OS was 91% MR versus 86% (HR = 0.6; log-rank one-sided P = .08). A trend favoring MR was observed among patients with high tumor burden (log-rank one-sided P = .03)., Conclusion: The E1496 study provides the first phase III data in untreated indolent lymphoma that MR after chemotherapy significantly prolongs PFS.

The validity of self-reported information about familial Hodgkin lymphoma (HL), important for epidemiologic research and clinical practice, is undetermined. We attempted to validate 55 familial lymphomas previously reported by 48 subjects in a population-based case-control study of HL in women. Of 44 diagnoses (80%) reported by 40 (83%) recontacted subjects, we obtained medical documentation for 36 (82%). Twenty-nine (81%) were validated as lymphoma, with accuracy better for first-degree relatives and subjects with larger nuclear families and other family illness. Fourteen reports of familial HL were validated as lymphoma for 13 (93%) and as HL for nine (64%). Fifteen reports of familial NHL were validated as lymphoma for 10 (67%) and as NHL for 10 (67%). Thus, familial HL reported by HL patients and controls is highly likely to be lymphoma even in extended family members but less likely to be HL per se. Validity may vary with the subject's family size and medical history.

Background: This trial studied the feasibility and efficacy of a new preparatory regimen for autologous bone marrow transplantation for patients with advanced lymphoid malignancies., Methods: Twenty-one patients with Hodgkin's disease (n = 12) and non-Hodgkin's lymphoma (n = 9) were treated in this study. Lomustine was substituted for carmustine) in a dose-escalation study with an initial dose of 6 mg/kg and increasing by 3 mg/kg in groups of four patients. The preparatory regimen consisted of lomustine (6-15 mg/kg) orally on Day -6, etoposide (60 mg/kg) intravenously (i.v.) on Day -4, and cyclophosphamide (100 mg/kg) i.v. on Day -2. Peripheral blood progenitor cells and/or bone marrow were infused on Day 0., Results: Lomustine was well tolerated in all patients with no significant toxicity specific to this drug. Engraftment was prompt: the time to achieving greater than or equal to 500 granulocytes/microliters was 12 days (range, 9-16 days) and the time to achieving greater than or equal to 25,000 platelets/microliters without transfusion support was 16 days (range, 9-22 days). Five patients experienced interstitial pneumonitis, three of whom had active or recent interstitial pneumonitis before bone marrow transplantation, and one who just completed mantle irradiation. Three patients died from this preparatory regimen, one of progressive interstitial pneumonitis, one of Legionella pneumonia, and one of multiorgan failure. Three patients with non-Hodgkin's lymphoma relapsed. Fourteen patients are currently alive and disease free to date. The actuarial are currently alive and disease free to date. The actuarial disease free survival was 57%, with a median follow-up of 23 months (range, 1-48 months)., Conclusion: The preparatory regimen consisting of lomustine/etoposide/cyclophosphamide is active in treating patients with lymphomas. Further trials with high doses of lomustine are warranted.

Objective: To determine the hemopoietic effects of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients having autologous hemopoietic stem cell transplantation for Hodgkin or non-Hodgkin lymphoma., Design: Placebo or GM-CSF was administered after bone marrow or peripheral blood stem cell transplantation or both in a randomized, double-blind phase III trial by daily intravenous infusion (10 micrograms/kg body weight) until absolute neutrophil counts reached greater than or equal to 1000/mm3 on 3 consecutive days., Setting: Bone marrow transplantation unit in a university hospital., Patients: Sixty-nine consecutive patients with Hodgkin or non-Hodgkin lymphoma received GM-CSF (36 patients) or placebo (33 patients)., Measurements and Main Results: Patients who received GM-CSF achieved absolute neutrophil counts greater than or equal to 500/mm3 (median, 12 compared with 16 days, P = 0.02) and absolute neutrophil counts greater than or equal to 1000/mm3 (median, 15 compared with 24 days, P less than 0.001) more quickly than patients who received placebo. Multivariate analysis indicated that use of GM-CSF, peripheral blood stem cells, and unpurged bone marrow were the strongest predictors for early neutrophil recovery greater than 500/mm3. Bacterial infections were significantly reduced in the GM-CSF group (P = 0.04). Delayed engraftment (neutrophils less than 500/mm3 at day 30) occurred in 26% and 17% of the placebo and GM-CSF groups, respectively, and correlated with the absence of detectable myeloid progenitor cells (colony-forming units-granulocyte macrophage, CFU-GM) (P less than 0.001) in marrow aspirate specimens obtained on day 15. Time to platelet independence, duration of hospital stay, severe adverse reactions, relapse, and disease-free survival rates did not differ significantly between the two groups., Conclusions: Administration of GM-CSF after autologous hemopoietic stem cell transplantation in patients with lymphoma resulted in accelerated myeloid recovery, particularly in patients who received peripheral blood stem cells and nonpurged bone marrow, and was associated with a decreased incidence of bacterial infections.

Ten cases of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) and AILD-like lymphoma were studied by immunophenotypic and immunogenotypic analysis. All specimens were found to have a predominance of T cells by immunophenotypic analysis. DNA hybridization analyses showed three of five specimens of AILD and five of six specimens of AILD-like lymphoma to contain clonal rearrangements of the beta T-cell receptor gene. No rearrangements of the heavy or light chain immunoglobulin genes were seen in any case. A single case showed a progression of AILD with a germ-line pattern of beta T-cell receptor DNA to AILD-like lymphoma with detectable clonal rearrangements for beta T-cell receptor DNA. These results suggest that many, but not all, cases diagnosed histologically as AILD or AILD-like lymphoma contain a clonal proliferation of T-lymphocytes.

Forty-nine patients with non-Hodgkin's lymphoma or Hodgkin's disease were entered into a multi-institutional phase II trial to evaluate the antitumor activity of human interferon alpha, prepared from buffy coats. Interferon alpha was administered intramuscularly in doses of 1 X 10(6) u, 3 X 10(6) u or 9 X 10(6) u daily for 30 days. Objective partial responses were seen in 3 of 18 patients with nodular lymphoma, all at the 9 X 10(6) u dose. Interferon alpha was not observed to be of therapeutic benefit in the other subtypes of non-Hodgkin's lymphoma or Hodgkin's disease. The major toxicities consisted of fatigue, fever, myalgias and weight loss. Serum interferon levels obtained 3 to 4 hours after injection varied widely, even among patients treated at the same dose level. Despite the relatively low doses of interferon used and the brief period of administration, this study extends the earlier observations of the antitumor effect of interferon in nodular lymphoma. These results are discussed in relation to the cumulative experience in human lymphoma using alpha interferons induced in human leukocytes and those produced in bacteria by recombinant DNA techniques.

We have studied 14 hematopoietic malignancies with histologic features of histiocytic differentiation, using frozen section immunologic stains, plastic section enzyme histochemistry, and paraffin section immunocytochemistry. There was morphologic, immunologic, and enzymatic heterogeneity, including findings in seven cases that suggested differentiation toward specialized subsets of histiocytes. Four cases expressed a mature monocyte/macrophage phenotype by frozen section monoclonal antibody staining and three of these had histologic patterns diagnostic of malignant histiocytosis; two other cases had ATPase and S100 protein reactivity and morphologic features consistent with interdigitating (reticulum) cell proliferations; and one case was alkaline phosphatase positive, suggestive of differentiation toward fibroblastic reticulum cells. Four cases had histologic findings consistent with malignant histiocytosis, but weak or unreactive staining patterns and were considered poorly differentiated histiocytic or primitive hematopoietic malignancies. Three other cases, also morphologically consistent with malignant histiocytosis, were identified as probably T-cell lymphomas. The morphologic and phenotypic characteristics of non-neoplastic histiocytes and dendritic cell types and their related neoplasms are discussed. Histiocytic malignancies comprise a diverse group that can be identified and subclassified by immunologic and enzymatic techniques.

Malignant lymphoma is frequently diagnosed when immunohistochemical techniques are applied to otherwise unclassified neoplasms. In this analysis of 35 patients with a histologically unclassified neoplasm that expressed leukocyte-common antigen(s) (LCA), actuarial survival was 63%, and 45% of patients were free from disease progression at 30 months following treatment as for lymphoma. The clinical features at diagnosis and the results of combination chemotherapy were found to be similar to a group of patients with a diagnosis of diffuse large-cell lymphoma (DLCL) concurrently treated at this institution. This study further emphasizes the importance of improved diagnostic techniques in the management of histologically unclassified tumors.

Forty-one cases of T cell lymphoma were identified on the basis of morphology and the expression of two or more T cell antigens with an absence of B cell markers. Mycosis fungoides and lymphoblastic lymphoma were excluded. Marked clinical, morphological, and immunologic diversity was observed. Cutaneous lymphoma was found in approximately 50% of the patient group, and 27% had a prior history of dermatologic or immunologic disease. No correlations among immunologic and morphologic phenotypes and clinical course were apparent. Survival data was comparable to that of a concurrent group of non-T cell lymphoma patients studied at this institution, suggesting that, contrary to previous reports, T cell lymphoma may not necessarily confer a more unfavorable prognosis. Prospective studies using uniform treatments are necessary to address the clinical significance of the T cell phenotype definitively, independent of established histologic and clinical features.

Between January 1978 and December 1986, 94 patients with Stage I-II large cell lymphoma were evaluated at Stanford University Medical Center and treated with a combination of chemotherapy (CTX) and irradiation (XRT). The predominant histology was diffuse large cell (78), followed by immunoblastic (7), follicular large cell (6), and diffuse mixed small and large cell lymphoma (3). Twenty-three patients had Stage I and 71 had Stage II disease. Fifty-one had extranodal involvement (13 IE, 38 IIE), and 11 had B symptoms (2 IB, 9 IIB). Lymphoma was supradiaphragmatic in 58 patients, infradiaphragmatic in 21, and only in extranodal sites in 15. Patients received either involved (81) or extended (13) field XRT with a median dose of 40 Gy and combination CTX with 2 to 9 cycles (median 6) of either CHOP (68), M-BACOD (8), C-MOPP (8), MACOP-B (4), or other (6). Seventy-two patients remain with no evidence of disease, 21 are dead with disease, and one suffered an intercurrent death. Among the 19 patients who relapsed, there were six failures within the XRT field only, two within and outside the XRT field, and 11 outside of the XRT fields only. Actuarial survival and freedom from relapse (FFR) for the entire population were 74% and 72% at 5-years, respectively (33 month median follow-up). Stage I patients achieved 81% survival and 78% FFR, and Stage II patients had 72% survival and 70% FFR. In univariate and multivariate analyses, a favorable outcome was associated with the CTX-XRT-CTX sequence of therapy (p = 0.001), low LDH (p = 0.01), and small tumor bulk (p = 0.04). There were no relapses or deaths among the 21 patients receiving the "sandwich" sequence (CTX-XRT-CTX) of therapy. This series may serve as a comparison with single modality treatment programs for localized large cell lymphoma using either XRT or CTX alone.

To learn more about the natural history of low-grade non-Hodgkin's lymphoma, we have studied 83 patients in whom the advanced disease was initially managed without therapy. Actuarial survival was 82 per cent at 5 years and 73 per cent at 10 years. The median time until therapy was required was three years. Spontaneous regressions occurred in 19 untreated patients (23 per cent), including 30 per cent of patients with nodular, poorly differentiated lymphocytic lymphoma. Histologic transformation to an intermediate-grade or high-grade lymphoma occurred both before and after primary therapy. The actuarial risk of transformation among the initially untreated patients was similar to that in a group of patients treated at this institution immediately after diagnosis. Neither the time to histologic transformation nor the incidence of transformation was influenced by when therapy was started.

The clinical records and initial biopsy materials from 76 patients with mixed small-cleaved and large-cell lymphoma containing both a follicular and diffuse architectural pattern were reviewed. The characteristics of this group, treated at Stanford University Medical Center (SUMC) between 1963 and 1983, are described. The 5-year actuarial survival and freedom from progression are 70% and 27.5%, respectively. Classification according to the degree of follicularity indicated that patients with focally follicular areas (ie, less than 25% of the histologic section) have a significantly worse freedom from progression and overall survival at 5 years compared with those patients with a predominantly follicular architecture (ie, greater than 50% follicular areas). Based on our analysis, we feel that the degree of follicularity is an important prognostic factor and that mixed lymphoma patients with only focally follicular areas behave more like an intermediate-grade lymphoma and should be treated aggressively.

Despite substantial progress in curative therapy of malignant lymphomas, some patients fail current treatment and die of refractory disease. Although Although high-dose chemotherapy and supralethal total body irradiation followed by bone marrow transplantation may salvage and cure a proportion of these refractory patients, treatment of such end-stage patients with marrow grafting often fails because of resistant disease or transplant-related complications. Using the analogy of transplantation in the early phases of acute and chronic leukemias, results of marrow transplant in Hodgkin's disease and non-Hodgkin's lymphoma might be improved if performed earlier in the course of the malignancy. The following collaborative report by the Seattle and Stanford groups examines current results of conventional lymphoma therapy to define subgroups of patients with "high-risk" lymphoma for whom early marrow transplant might be offered to control otherwise incurable disease.

The "host cell infiltrates" in five patients with low-grade follicular lymphoma who had spontaneous regression without therapy were studied with the use of immunohistochemical methods applied to frozen sections. These infiltrates were compared with the "host cell infiltrates" in six patients with follicular lymphoma with progressive disease. The group with progressive disease was selected to be similar to the group with spontaneous regression in age, sex, histologic characteristics, and stage of disease. The patients with spontaneous regression had significantly more T-helper cells in the host cell infiltrate than the control patients. There were no statistically significant differences between the two groups in numbers of cytotoxic/suppressor T-cells, macrophages, Tac-positive cells, Leu-7-positive cells, or proliferating cells.