Marjorie Bernstein-Singer

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.

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.

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.

Clinical Effect of Glucocorticoids on Kaposi Sarcoma Related to the Acquired Immunodeficiency Syndrome (AIDS)

Excerpt Kaposi sarcoma occurs in over 20% of patients with the acquired immunodeficiency syndrome (AIDS), predominantly among homosexual or bisexual men (1). The human immunodeficiency virus (HIV) ...

Treatment of advanced Kaposi's sarcoma using a combination of bleomycin and vincristine.

Eighteen patients with disseminated AIDS-related Kaposis sarcoma (KS) and compromised bone marrow function were treated with a relatively nonmyelosuppressive regimen of bleomycin and vincristine (BV). At study entry, the patients presented with the following median laboratory values: hemoglobin of 9.5 g/dl, granulocyte counts of 1,173/mm3, platelet counts of 218,000/mm3, and CD4 lymphocyte counts of 58/mm3. All patients had extensive Kaposis sarcoma. Nine patients had visceral involvement: four with pulmonary involvement, two with gastrointestinal involvement, and three with both. Following a median number of seven cycles of biweekly chemotherapy, complete or partial tumor responses were achieved in 13 patients (72%). Two patients experienced bleomycin-induced skin toxicities, whereas 10 others (55%) experienced peripheral sensory neuropathy requiring vincristine dose reductions. Opportunistic infections had occurred in 11 patients prior to initiation of chemotherapy and in 16 after initiation of chemotherapy. Despite the frequent development of opportunistic infections, BV chemotherapy was relatively well tolerated and resulted in a high response rate in this patient population that presented with suboptimal marrow function and extremely low CD4 lymphocyte counts.

Acute hepatic injury after the withdrawal of immunosuppressive chemotherapy in patients with hepatitis B

Five patients with lymphoproliferative malignancies and chronic hepatitis B suffered severe acute hepatic injury after the withdrawal of multiagent chemotherapy that included high‐dose corticosteroid. Four patients died of hepatic failure, three of whom received corticosteroid as treatment for the hepatic injury. We believe that the cause of this entity is massive immune‐associated cytolysis of hepatitis B virus infected hepatocytes occurring after a period of immunosuppression and increased viral replication. The literature regarding this complication of chemotherapy and its pathophysiology is reviewed.

Advanced acquired immune deficiency syndrome‐related Kaposi's sarcoma. Results of pilot studies using combination chemotherapy

Pilot studies were conducted to evaluate the toxicity and efficacy of two relatively marrow‐sparing chemotherapy regimens in the treatment of advanced or progressive epidemic Kaposis sarcoma. Chemotherapy regimens consisted of bleomycin (10 mg/m2), vincristine (1.4 mg/m2, 2 mg maximum) and Adriamycin (doxorubicin) at either 10 mg/m2 (Group I) or 20 mg/m2 (Group II). The therapy was given intravenously, every 2 weeks, until intolerable toxicity or maximum antitumor response. Thirty‐three patients were treated. Although the patient populations were similar regarding pretreatment prognostic factors, the patients were not assigned randomly to these two treatment regimens. Major responses (complete or partial remission) were attained in 79% of the cases. The treatment‐related toxicities consisted of mild to moderate nausea, hair loss, and peripheral sensory neuropathy. Bone marrow suppression consisted primarily of neutropenia (< 1000/mm3) which occurred in a third of the patients. Variables significantly associated with shorter survival included hemoglobin (< 10 g/dl), low Karnofsky performance status (< 70%), and weight loss. Opportunistic infections occurred in the majority of cases during administration of chemotherapy, and were most likely related to severe cell‐mediated immune dysfunction and low CD4‐positive lymphocyte counts.

Adriamycin, bleomycin and vincristine chemotherapy with recombinant granulocyte-macrophage colony-stimulating factor in the treatment of AIDS-related Kaposi's sarcoma.

ObjectiveTo determine the maximum tolerated dose of granulocyte-macrophage colony-stimulating factor (CM-CSF) that would reduce the severity and duration of neutropenia from combination cytotoxic chemotherapy in the treatment of AIDS-related Kaposis sarcoma (KS). DesignPhase I, dose escalation. SettingOutpatient clinic of a university hospital. PatientsHIV-seropositive patients with advanced KS. InterventionsCombination chemotherapy consisting of adriamycin, bleomycin, and vincristine (ABV), with escalating doses of recombinant human GM-CSF (rhGM-CSF). Patients were treated for a median of six cycles (range, between two and seven cycles) of biweekly chemotherapy with GM-CSF administered in divided daily subcutaneous doses on days 2–12. Serum cytokine levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α were measured before, during, and after therapy to correlate with response to therapy. ResultsA GM-CSF dose of 250 μg/m2 was well tolerated, whereas the next dose escalation, of 500μg/m2, was associated with dose-limiting toxicities, including grade 3 fever, fatigue, and diarrhea. GM-CSF produced predictable cyclic increases in granulocytes, allowing for delivery of full-dose chemotherapy on schedule. All patients were HIV-p24-antigen-negative at study entry; no activation of p24 antigenemia was observed after repeat testing. Consistent changes in cytokine levels were not observed. Responses included one complete and three partial responses, and two patients with stable disease parameters. ConclusionsWe conclude that GM-CSF can be administered safely to patients with AIDS-related KS receiving myelosuppressive chemotherapy, resulting in granulocytic response, without up-regulation of HIV p24 antigen levels in serum.