Parkash S. Gill

Non-Hodgkin's lymphoma in 90 homosexual men: relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome

We describe the histologic and clinical features of non-Hodgkins lymphoma diagnosed between January 1980 and December 1983 in 90 homosexual men from San Francisco, Los Angeles, Houston, and New York. The median age was 37 years, with an age distribution identical to that for cases of AIDS reported to the Centers for Disease Control. Sixty-two per cent of the patients had high-grade (aggressive) subtypes of lymphoma, 29 per cent had subtypes of intermediate grade, and 7 per cent had low-grade subtypes. Histologic subtypes and malignant cell phenotypes were consistent with a B-cell origin. All but two men had extranodal lymphoma: central-nervous-system, bone-marrow, bowel, and mucocutaneous sites were most commonly involved. Thirty-five of 66 evaluable men (53 per cent) had complete responses to combination chemotherapy or radiotherapy or both, and thus far, 19 (54 per cent) of them have had a relapse. Mortality and morbidity were closely related to prodromal manifestations; death or illness have occurred in 19 (91 per cent) of the 21 men who presented with AIDS, in 26 (79 per cent) of the 33 who presented with generalized lymphadenopathy, and in 5 (42 per cent) of the 12 who had no prodromal manifestations. Mortality rates analyzed according to histologic grade were higher than currently reported rates in other patient populations. Kaposis sarcoma or severe opportunistic infections characteristic of AIDS developed in 14 of 33 men (42 per cent) who presented with generalized lymphadenopathy and in 3 of 12 (33 per cent) without prodromal manifestations. We conclude that non-Hodgkins lymphoma in members of an AIDS risk group is a serious manifestation of AIDS and the AIDS-related complex.

Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma.

PURPOSE To compare the safety and efficacy of liposomal daunorubicin (DaunoXome; NeXstar Pharmaceuticals, Inc, Boulder, CO) with a reference regimen of doxorubicin, bleomycin, and vincristine (ABV) in advanced AIDS-related Kaposis sarcoma (KS). PATIENTS AND METHODS In a prospective randomized phase III trial, 232 patients were randomized to receive DaunoXome 40 mg/m2 or a combination regimen of doxorubicin 10 mg/m2, bleomycin 15 U, and vincristine 1 mg, administered intravenously every 2 weeks. Treatment was continued until complete response (CR), disease progression, or unacceptable toxicity. RESULTS Of 232 patients randomized, 227 were treated: 116 with DaunoXome and 111 with ABV. The overall response rate (CR or partial response [PR]) was 25% (three CRs and 26 PRs) for DaunoXome and 28% (one CR and 30 PRs) for ABV. The difference in response rates was not statistically significant. The median survival time was 369 days for DaunoXome patients and 342 days for ABV patients (P = .19). The median time to treatment failure was 115 days for DaunoXome and 99 days for ABV (P = .13). ABV patients experienced significantly more alopecia and neuropathy (P < .0001). DaunoXome patients experienced more grade 4 neutropenia (P = .021). Cardiac function remained stable, with no instances of congestive heart failure on either treatment arm. CONCLUSION In this large phase III trial, the efficacy of DaunoXome was comparable to that of ABV. Response rates, time to treatment failure, and overall survival were similar on both treatment arms. DaunoXome is a safe and effective primary therapy for advanced AIDS-related KS.

Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine

BACKGROUND Infection with the human T-cell lymphotropic virus type I, a retrovirus, can cause a distinctive cancer, adult T-cell leukemia-lymphoma. The median survival of patients with the acute and lymphomatous forms of the disease is short, despite the use of cytotoxic chemotherapy. METHODS We treated 19 patients with acute or lymphomatous forms of adult T-cell leukemia-lymphoma with oral zidovudine (200 mg five times daily) and interferon alfa (Intron A, 5 to 10 million units subcutaneously each day). Seven of these patients had either relapsed after multiagent cytotoxic chemotherapy or failed to respond to that treatment. RESULTS Major responses were achieved in 58 percent of the patients (11 of 19), including complete remission in 26 percent (5 of 19). Four patients in whom prior cytotoxic therapy had failed had major responses, two of which were complete remissions. Six patients have survived for more than 12 months, with the longest remission since the discontinuation of treatment lasting more than 59 months. CONCLUSIONS The combination of zidovudine and interferon alfa has activity against adult T-cell leukemia-lymphoma, even in patients in whom prior cytotoxic therapy has failed. This regimen should be evaluated further for its role in the treatment of adult T-cell leukemia-lymphoma.

Human immunodeficiency virus‐related lymphoma. Prognostic factors predictive of survival

In an attempt to determine factors predictive of survival in patients seropositive for human immunodeficiency virus (HIV) with acquired immune deficiency syndrome (AIDS)‐related lymphoma, the authors studied 60 such patients, all of whom were treated with curative intent. Eleven patients presented with lymphoma primary to the brain (P‐CNS); the remaining 49 had systemic AIDS‐related lymphoma. Patients with P‐CNS lymphoma had more severe underlying HIV‐related disease than did patients with systemic lymphoma as evidenced by a higher incidence of AIDS before the diagnosis of lymphoma (73% versus 37%; P = 0.04), and lower median number of CD‐4–positive lymphocytes in peripheral blood at diagnosis of lymphoma (30/dl versus 189/dl; P = 0.005). Median survival of such patients was 2.5 months versus 6.0 months for patients with systemic lymphoma (P = 0.04). Forty patients with systemic AIDS‐related lymphoma have died; three factors were strongly associated with shorter survival: (1) Karnofsky performance status (KPS) of less than 70% (multivariate relative survival risk [RSR] = 3.1); (2) history of AIDS before the diagnosis of lymphoma (multivariate RSR = 3.0 for opportunistic infection plus Kaposis sarcoma); and (3) bone marrow involvement (RSR = 3.1)). All three factors (KPS of less than 70%, prior AIDS diagnosis, and marrow involvement) were associated with early demise attributed to AIDS, whereas death attributed to lymphoma per se was associated with only two factors (KPS of less than 70% and marrow involvement). In the absence of all three risk factors, a “good prognosis” group of 17 patients was defined, with a median survival of 11.3 months; the median survival of the remaining patients (“poor prognosis”) was 4.0 months (P = 0.0002). Attainment of complete response to therapy (CR) was strongly related to prolonged survival in the patients in the good prognosis group (17.8 months in patients with CR versus 5.0 months in those with less than CR); however, such meaningful prolongation of survival was not seen in patients with poor prognosis who attained CR (6.3 months versus 3.4 months). The patients with poor prognosis may be unable to tolerate the insult of multiagent chemotherapy, experiencing low CR rates (25%) and death caused by lymphoma and AIDS. However, patients in either prognostic category who attained CR remained at risk for dying of AIDS while the lymphoma was in remission. Thus, it is apparent that meaningful prolongation of survival in the patient with AIDS‐related lymphoma will require not only effective antineoplastic intervention, but also control of the underlying HIV infection. In addition, future therapeutic trials should stratify patients based upon the prognostic factors defined here in an attempt to clarify the results obtained. 68:2466‐2472, 1991.

Phase I/II Clinical and Pharmacokinetic Evaluation of Liposomal Daunorubicin

PURPOSE Since liposomal encapsulation of anticancer drugs may enhance antitumor activity while reducing toxicity in vitro, we evaluated liposomally encapsulated daunorubucin (DaunoXome; Vestar, Inc, San Dimas, CA) for safety, pharmacokinetics, and potential efficacy in patients with AIDS-related Kaposis sarcoma (AIDS-KS). PATIENTS AND METHODS Forty patients with advanced AIDS-KS were accrued. Successive cohorts received DaunoXome at doses of 10, 20, 30, and 40 mg/m2 given once every 3 weeks, and 40, 50, and 60 mg/m2 given once every 2 weeks. Selected KS and solid-tumor patients underwent pharmacokinetic evaluation. RESULTS The area under the plasma concentration curve (AUC) ranged from 16.9 micrograms.h/mL to 375.3 micrograms./mL and the alpha half-life ranged from 7.8 to 8.3 hours at 10 mg/m2 to 60 mg/m2, respectively. Both pharmacokinetic profiles were significantly better compared with free daunorubicin. DaunoXome was well tolerated with no significant alopecia, mucositis, or vomiting. Neutropenia (< 1,000/microL occurred in 17% of cycles and was severe (< 500/microL) in only 2%. Anemia and thrombocytopenia were uncommon. Other adverse events included mild to moderate fatigue, nausea, and diarrhea. Even after cumulative doses greater than 1,000 mg/m2, no significant declines in cardiac function were observed. Twenty-two patients who received 50 and 60 mg/m2 were assessable for tumor response; 12 (55%) had a partial response (PR) or clinical complete response (CR). The median survival duration in all patients was 9 months. Prognostic factors for short survival were low CD4 lymphocyte counts (P = .004) and prior anthracycline therapy (P = .02). CONCLUSION DaunoXome has an improved pharmacokinetic profile compared with free daunorubicin, and is well tolerated. DaunoXome can be given safely at doses up to 60 mg/m2 every 2 weeks and has significant antitumor activity in patients with AIDS-KS.

Systemic treatment of AIDS-related kaposi's sarcoma: Results of a randomized trial

PURPOSE Patients with acquired immunodeficiency syndrome (AIDS)-related epidemic Kaposis sarcoma generally respond well to cytotoxic chemotherapy. However, due to the associated myelosuppression, these patients are at risk for developing complicating infections that may affect survival. We therefore conducted a multi-center randomized clinical trial comparing single-agent against combination chemotherapy in advanced AIDS-related Kaposis sarcoma. Low-dose chemotherapy was employed to evaluate its role in combination therapy for this disease and the toxicities associated with the lower intensity. PATIENTS AND METHODS Sixty-one patients with extensive mucocutaneous Kaposis sarcoma or visceral involvement were randomized for treatment with low-dose Adriamycin (doxorubicin, 20 mg/m2) alone (31 cases) or in combination with bleomycin and vincristine (ABV) (30 cases). Patients were randomized within strata based on prognostic features associated with shorter survival in prior studies. Both treatment arms were evenly matched at study entry. RESULTS Complete and partial tumor remissions were significantly higher with ABV (88%) than with Adriamycin alone (48%) (p = 0.004). The median survival was 9 months in both groups. Study entry criteria significantly associated with shorter survival included CD4 lymphocyte counts less than 100/mm3, hemoglobin level less than 10 g/dL, a history of constitutional symptoms, and a prior history of opportunistic infection(s). Toxicities were similar in both arms, and the regimens were well tolerated. Neutropenia (granulocyte count less than 1,000/mm3) occurred in 34% of patients receiving Adriamycin alone and in 52% of patients receiving ABV and was progressive in successive courses of chemotherapy in both treatment arms. The development of AIDS-defined opportunistic infections was relatively infrequent during therapy (14%). CONCLUSIONS Low-dose ABV is an effective chemotherapy regimen for the treatment of extensive Kaposis sarcoma. ABV chemotherapy is associated with significantly higher responses than Adriamycin alone and with acceptable toxicity.

AIDS-related malignant lymphoma: results of prospective treatment trials.

Twenty-two consecutive patients with high-grade, B-cell lymphomas related to the acquired immunodeficiency syndrome (AIDS) were accrued onto two sequential phase II studies, consisting of a standard regimen (M-BACOD, group no. 1, N = 13), or a novel, intensive regimen (group no. 2, N = 9), which included high-dose cytosine arabinoside (HD-Ara-C), and high-dose methotrexate (HD-MTX), in an attempt to prevent CNS relapse and improve response rates. Stage IV disease was present in 82%. Complete remission (CR) was achieved in seven of 13 patients (54%) in group no. 1, and in three of nine (33%) group no. 2 (P = NS). By multivariate analysis, the most significant factor in predicting response was a Karnofsky performance score (KPS) greater than 60 (P = .04). Three of the ten patients who achieved CR on either regimen have relapsed; in all, five of 13 patients (31%) in group no. 1 have achieved disease-free survival for more than 1 year, compared with one of nine (11%) in group no. 2. CNS progression occurred in six patients in group no. 2, and in two patients in group no. 1. Hematologic toxicity was significantly greater in group no. 2, and these patients had an increased risk of opportunistic infection (one in group no. 1 v seven in group no. 2; P less than .01). Survival was similar, with a median of 11 months in group no. 1 and 6 months in group no. 2. We conclude that the intensive regimen of combination chemotherapy described here is associated with significant risk of early death due to opportunistic infection in patients with AIDS-related lymphoma, and that progression in the CNS remains a major problem. Trials of combination chemotherapy of a less intensive nature, perhaps in combination with immunomodulators or antiretroviral agents should be explored.

Cell Surface Relocalization of the Endoplasmic Reticulum Chaperone and Unfolded Protein Response Regulator GRP78/BiP

The recent discovery that GRP78/BiP, a typical endoplasmic reticulum (ER) lumenal chaperone, can be expressed on the cell surface, interacting with an increasing repertoire of surface proteins and acting as receptor in signaling pathways, represents a paradigm shift in its biological function. However, the mechanism of GRP78 trafficking from the ER to the cell surface is not well understood. Using a combination of cellular, biochemical, and mutational approaches, we tested multiple hypotheses. Here we report that ER stress actively promotes GRP78 localization on the cell surface, whereas ectopic expression of GRP78 is also able to cause cell surface relocation in the absence of ER stress. Moreover, deletion of the C-terminal ER retention motif in GRP78 alters its cell surface presentation in a dose-dependent manner; however, mutation of the putative O-linked glycosylation site Thr648 of human GRP78 is without effect. We also identified the exposure of multiple domains of GRP78 on the cell surface and determined that binding of extracellular GRP78 to the cell surface is unlikely. A new topology model for cell surface GRP78 is presented.

Pulmonary Kaposi's Sarcoma: Clinical Findings and Results of Therapy

PURPOSE Kaposis sarcoma occurs commonly in patients with the acquired immunodeficiency syndrome (AIDS). Kaposis sarcoma may remain localized or disseminate to involve visceral organs such as the lungs. Disseminated pulmonary involvement, when it occurs, is often fatal. Effective therapy may improve survival in such patients. We herein report on 20 patients with disseminated pulmonary Kaposis sarcoma treated with cytotoxic chemotherapy. PATIENTS AND METHODS Twenty previously untreated patients with pulmonary Kaposis sarcoma were identified. All were treated with cytotoxic chemotherapy consisting of either Adriamycin alone, a combination of Adriamycin, bleomycin, and vincristine (ABV), or bleomycin and vincristine (BV). The response to therapy and factors affecting prognosis were analyzed retrospectively. RESULTS Twelve (60%) patients showed a favorable response to therapy. The median survival from the initiation of chemotherapy for the 12 responders was 10 months (range: three to 31 + months) versus six months (range: one to 17+ months) for the non-responders. Eleven of the patients showing a response received ABV or BV combination chemotherapy (p = 0.004). Survival was shortened by the presence of either pleural effusion (p = 0.002), T4 lymphopenia of less than 100/mm3 (p = 0.03), or both at study entry. CONCLUSIONS In patients with pulmonary Kaposis sarcoma, combination chemotherapy consisting of ABV or BV is associated with dramatic clinical and functional improvement. The median survival of 10 months demonstrates the value of combination chemotherapy in this group of patients.

Primary central nervous system lymphoma in homosexual men. Clinical, immunologic, and pathologic features☆

Primary central nervous system lymphoma constitutes one of the criteria for the acquired immune deficiency syndrome (AIDS), yet a paucity of information is currently available regarding the clinical, immunologic, or pathologic features of these patients. Six homosexual men presenting with primary central nervous system lymphoma were evaluated. Five of these patients presented with altered mental status. All lymphomas were intracranial. B cell immunoblastic sarcoma was found in five. Immune phenotyping studies performed in five patients revealed monoclonal lambda light chain in three, whereas one expressed only IgG heavy chain, and one demonstrated another B cell (LN-1) surface antigen. Hypodense, contrast-enhancing lesions were apparent on computed axial tomographic scanning of the brain, in sharp contrast to isodense or hyperdense lesions reported in primary central nervous system lymphomas without underlying immunodeficiency. Immunologic abnormalities in these patients were similar to those in AIDS presenting as Kaposis sarcoma or with opportunistic infections. In spite of therapeutic interventions, survival was short, and only one patient is currently alive.