Radioimmunotherapy of acquired immunodeficiency syndrome (AIDS) associated lymphoma

Standard therapy for AIDS associated NHL (AANHL) is toxic and often ineffective. Radioimmunotherapy (RIT) is an appealing alternative to chemotherapy because of the radiosensitivity of NHL and the ability of the Lym-1 monoclonal antibody to target therapeutic irradiation to NHL while relatively sparing normal tissue. A Phase I/II study of 90Y-2IT-BAD-Lym-1 was designed specifically for RIT of AANHL. The first patient has been treated with 15 mCi (7.5 mCi/m2) of 90Y-2IT-BAD-Lym-1, after an imaging dose of 111In-2IT-BAD-Lym-1. Before RIT, AANHL in the maxillary sinus extended into the oral cavity and axillary adenopathy was present. Imaging showed excellent accumulation of 111In-2IT-BAD-Lym-1 in the tumors. Substantial shrinkage of the oral lymphoma was observed 18 hours after the therapy dose of 90Y-2IT-BAD-Lym-1 and axillary adenopathy had disappeared by one week after RIT. Transient Grade IV myelosuppression was the only notable toxicity. Further RIT cycles were precluded by development of an antibody response (HAMA) against Lym-1. This novel preliminary study has shown that Lym-1 can target AANHL and produce significant tumor regression thereby providing encouragement to proceed with additional patients.     

Recent advances in acquired immunodeficiency syndrome (AIDS)-related lymphoma

Human immunodeficiency virus-infected patients are at an increased risk for developing both Hodgkin and non-Hodgkin lymphoma when compared with the general population. With the remarkable decrease in the incidence of opportunistic infections since the availability of highly active antiretroviral therapy (HAART), acquired immune deficiency syndrome-related lymphoma (ARL) is now the second most common cancer associated with human immunodeficiency virus after Kaposi sarcoma. Over the last few years, advances in our understanding of the molecular biology of this heterogeneous group of lymphomas have led to the adoption of new classification systems. The prognosis of patients with ARL has improved dramatically with the availability of HAART, and the survival of many of these patients is now comparable to patients in the general population. Apart from the contribution of HAART, this improvement in prognosis can also be attributed to new initiatives in treatment of these patients, such as the use of effective infusional regimens, the feasibility of high-dose therapy with peripheral stem cell rescue for relapsed or refractory disease, and better supportive care. Nonetheless, several controversial issues persist, including the optimal timing of HAART with combination chemotherapy, the role of rituximab when incorporated into treatment regimens, and the optimal therapy for patients with acquired immunodeficiency syndrome-related Burkitt lymphoma. This article reviews the changes in the epidemiology of ARL in the era of HAART, advances in the biology of ARL, new developments in the management of patients with ARL, and several of the controversial issues that oncologists may encounter in the care of these patients.     

Cytomegalovirus (CMV) titers among acquired immunodeficiency syndrome (AIDS) patients with and without a history of Kaposi's sarcoma (KS)

The relationship between a history of Kaposi's sarcoma (KS) and serum titers to cytomegalovirus (CMV) among homosexual patients with acquired immunodeficiency syndrome (AIDS) was studied. Individuals with a history of AIDS and biopsy-proven or clinically confirmed KS were identified and compared with AIDS patients who did not have a history of KS. By demographic parameters and level of immunosuppression, the two groups were similar. Titers to CMV among the 53 AIDS patients (using an indirect fluorescent antibody [IFA] system) demonstrated a median titer for the first group of 1:512 and 1:2048 for the second. The two groups, however, did not differ in a matched study using a McNemar's test for correlated proportions. Wilcoxon ranked sum test performed on the data also demonstrated that the two groups did not differ with respect to the distribution of CMV titers. Serologic data failed to demonstrate a role for CMV infection in the pathogenesis of KS.     

Synchronous Hodgkin's disease and non-Hodgkin's lymphoma in an adult with acquired immunodeficiency syndrome (AIDS)

A 26-year-old male seropositive for human immunodeficiency virus (HIV) infection presented with atypical Hodgkin's disease. Subsequently, synchronous, aggressive non-Hodgkin's lymphoma was identified in this patient. Atypical Hodgkin's disease appears to be an opportunistic neoplasm in patients seropositive for HIV infections and should be considered as an indicator disease for the definition of acquired immunodeficiency syndrome (AIDS).     

Octreotide treatment in secretory and cyrptosporidial diarrhea in patients with acquired immunodeficiency syndrome (AIDS): clinical evaluation.

Our objective was to evaluate the efficacy of octreotide in the treatment of AIDS patients with persistent diarrhea refractory to conventional therapy. We have treated 11 patients with AIDS related diarrhea (M/F-5/2, mean age 28 +/- 3 yr). The stool volume was in all pts > or = 21/24h. In 4 pts the diarrhea was secondary to cryptosporidium infection (Group A); in 7 pts the reason for the diarrhea could not be identified (Group B). Octreotide was administered in subcutaneous escalation doses, from 50 micrograms q8h to a maximum dose of 500 micrograms q8h. The minimal dose controlling symptoms was maintained for 21 days. In all patients stool volume and frequency decreased significantly. Group A pts were "partial responders" (stool 50% of initial daily volume); group B patients were "complete responders" (stools < 250-300 ml/day). Drug suspension resulted in a prompt return of diarrhea, especially in group A and in these patients, the cryptosporidium was continuously eliminated in the stool. With octreotide therapy there was a reduction in stool volume and frequency; whether this treatment is effective as long-term therapy for this AIDS manifestation is unknown.     

Presentation and outcomes of systemic non-Hodgkin's lymphoma: a comparison between patients with acquired immunodeficiency syndrome (AIDS) treated with highly active antiretroviral therapy and patients without AIDS

We used the San Diego/Orange County cancer registry to identify 64 cases of systemic non-Hodgkin's lymphoma (NHL) with AIDS who received highly active antiretroviral therapy (HAART) at the time of NHL diagnosis or thereafter and 64 NHL controls without AIDS, matched on age, sex, race, time of NHL diagnosis (1994-1995 and 1996-1999), and hospital type (academic, large community, and small community). We compared cases and controls by chi-squared tests and Kaplan-Meier methods. Thirty-three percent of cases had high grade histology versus 11% of controls (p < 0.01); 69% had baseline hemoglobin <13 g/dL versus 35% controls (p < 0.001) and 21% had baseline neutrophils <2,000/mcl versus 4% of controls (p < 0.001). Overall median survival was 16 months for cases versus 99 months for controls (p < 0.01). Among 40 matched pairs of cases and controls who received chemotherapy, 32% of cases received reduced-dose chemotherapy versus 5% of controls (p < 0.01) and median survival was 33 months for cases and 99 months for controls (p < 0.44). Patients with AIDS-related NHL who received HAART had high grade histology and baseline cytopenia and received reduced-dose chemotherapy more often than patients without AIDS. However, AIDS patients who received HAART and chemotherapy had survival similar to NHL patients without AIDS, an improvement from the pre-HAART era. Appropriate hematologic support, through growth factors, transfusions, and avoidance of drugs with hematologic toxicity, might allow full dosing of chemotherapy, and perhaps would further improve outcomes among patients with AIDS and NHL.     

Hierarchical regulation of interleukin production: Induction of interleukin 6 (IL-6) production from bone marrow cells and marrow stromal cells by interleukin 3 (IL-3)

IL-3 stimulated the production of IL-6 from a bone marrow-adherent cell population, macrophages and from hemopoietic supportive stromal cell lines. It also induced IL-6 production from a stem cell-enriched population of bone marrow cells which did not produce IL-6 without stimulation. In contrast, stimulation with IL-6 of all the cell populations studied in the present experiments did not induce IL-3 production. These results indicate a hierarchical network in the regulation of interleukin production, and existence of a positive feedback mechanism; IL-3 induces IL-6 production which in turn stimulates stem cells into cycle and induces stem cells to respond to IL-3.     

Bacterial and fungal infections in patients with the acquired immunodeficiency syndrome

Over a 14-month period, 136 episodes of bacterial and 26 episodes of fungal infection were identified from the microbiology records of 444 patients with acquired immunodeficiency syndrome (AIDS). The respective rates for infection were 31 of 100 admissions (bacterial) and 5 of 100 admissions (fungal). Contributory factors appeared to be therapy with antineoplastic agents, ganciclovir and zidovudine, resulting in neutropenia, corticosteroid therapy, and increased use of central venous catheters. Bacteria isolated most often were Staphylococcus spp., the Enterobacteriaceae, and Pseudomonas aeruginosa. Aspergillus spp. and Candida spp. were the common fungal pathogens. However, several unusual fungal organisms seem to be emerging as important pathogens and can cause disseminated infection. Appropriate and prompt antimicrobial therapy resulted in the resolution of most bacterial infections. Disseminated fungal infections were difficult to treat and responded less often.     

Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome

BACKGROUND: Human papillomavirus (HPV)-associated anogenital malignancies occur frequently in patients with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). The purpose of our study was to determine if the high frequency of these cancers is due to lifestyle factors associated with both HPV and HIV infections or to immunosuppression following HIV infection. METHODS: We studied invasive and in situ HPV-associated cancers among 309 365 U.S. patients with HIV infection/AIDS (257 605 males and 51 760 females) from 5 years before the date of AIDS onset to 5 years after this date. Sex-, race-, and age-standardized ratios of observed-to-expected cancers served as measures of relative risk (RR). Trend tests were used to evaluate changes in the RRs during the 10 years spanning AIDS onset. All statistical tests were two-sided. RESULTS: All HPV-associated cancers in AIDS patients occurred in statistically significant excess compared with the expected numbers of cancers. For in situ cancers, overall risks were significantly increased for cervical (RR = 4.6; 95% confidence interval [CI] = 4.3-5.0), vulvar/vaginal (RR = 3.9; 95% CI = 2.0-7. 0), anal (in females, RR = 7.8 [95% CI = 0.2-43.6]; in males, RR = 60.1 [95% CI = 49.2-72.7]), and penile (RR = 6.9; 95% CI = 4.2-10.6) cancers, and RRs increased during the 10 years spanning AIDS onset for carcinomas in situ of the cervix (P: for trend <.001), vulva/vagina (P: for trend =.04), and penis (P: for trend =.04). For invasive cancers, overall risks were significantly increased for cervical (RR = 5.4; 95% CI = 3.9-7.2), vulvar/vaginal (RR = 5.8; 95% CI = 3.0-10.2), and anal (RR = 6.8; 95% CI = 2.7-14.0) cancers in females and for anal (RR = 37.9; 95% CI = 33.0-43.4), penile (RR = 3. 7; 95% CI = 2.0-6.2), tonsillar (RR = 2.6; 95% CI = 1.8-3.8), and conjunctival (RR = 14.6; 95% CI = 5.8-30.0) cancers in males. However, RRs for invasive cancers changed little during the 10 years spanning AIDS onset. CONCLUSIONS: HPV-associated malignancies occur at increased rates in persons with HIV/AIDS. Increasing RRs for in situ cancers to and beyond the time of AIDS onset may reflect the gradual loss of control over HPV-infected keratinocytes with advancing immunosuppression. However, the lack of a similar increase for invasive HPV-associated cancers suggests that late-stage cancer invasion is not greatly influenced by immune status.     

Phase I evaluation of combination therapy with interleukin 2 and gamma-interferon

Recombinant interleukin 2 (IL-2) is a potent inducer of lymphokine-activated killer (LAK) activity directed against autologous and allogeneic tumors; these effects are mediated by CD3-negative, CD56-positive, and CD16-positive lymphocytes. Although IL-2 therapy has been associated with clinical responses, particularly in patients with renal cell carcinoma and melanoma, these responses have occurred with high, toxic doses of this cytokine. Since gamma-interferon (IFN-gamma) potentiates LAK activity in vitro and in animal models, we initiated a dose-escalating Phase I trial of IFN-gamma and IL-2 in patients with advanced cancer. Patients were treated three times weekly (Monday, Wednesday, and Friday) for 6 weeks with bolus injections of IL-2; each dose was preceded 2 h earlier by a s.c. injection of IFN-gamma. Patients were treated with IFN-gamma at 0.01, 0.05, 0.1, or 0.25 mg/m2/dose. At each IFN-gamma dose, cohorts of at least three patients were treated with IL-2 at 1, 2.5, 5.0, or 7.5 x 10(6) Cetus units/m2 dose. Patients with clinical responses continued therapy three times weekly, while those with stable disease at 6 weeks were then treated twice weekly. A total of 41 patients were treated, all with Eastern Cooperative Oncology Group performance status 0 or 1. All patients were evaluable for toxicity. Dose-limiting toxicities were cumulative fatigue and constitutional symptoms. One documented transmural myocardial infarct occurred. The maximally tolerated dose combination, based on analysis of IL-2 dose intensity, was 0.1 mg IFN-gamma/m2 and 7.5 x 10(6) Cetus units IL-2/m2 per dose. Two partial responses and two minor responses were observed. Treatment was not associated with dose-associated changes in peripheral blood lymphocyte phenotype, but there was a trend favoring IFN-gamma dose-associated rises in IL-2 induction of natural killer and LAK activity by treated patients' lymphocytes. Analysis of the cumulative effects of therapy on induction of natural killer and LAK activity by measurement of the median area under the curve of activation showed clear evidence of IFN-gamma and IL-2 dose-associated changes. The IL-2 dose effects on cell lysis were monotone, while the optimal IFN-gamma dose appeared to be 0.1 mg/m2/dose, with a bell-shaped dose-response curve described previously for other effects of this cytokine. Using this novel statistical method of evaluating the biological effects of treatment, the optimal biological dose was identical to the maximally tolerated dose.(ABSTRACT TRUNCATED AT 400 WORDS)     

Phorbol myristate acetate-induced expression of high-affinity interleukin 2 receptors and production of interleukin 2 by human acute lymphoblastic leukemia T cells.

The effect of phorbol myristate acetate (PMA) on the expression of interleukin 2 receptors (IL-2R), production of IL-2 and IL-2-dependent proliferation of acute lymphoblastic leukemia T cells (T-ALL cells) from 10 patients was studied. First, the effect of PMA on the expression of cell surface markers was assessed: a decrease of CD3 and CD4, and an enhanced expression of CD8 molecule were observed on T-ALL cells. Moreover, PMA exhibited an heterogenous effect on various activation-associated molecules such as a decreased expression of transferrin receptor and T10 molecule and an induced expression of 4F2 and CD9 molecules. It is known that functional high-affinity IL-2R are composed of at least two IL2 binding molecules, the alpha (p55) and beta (p70) chains. We found that PMA induced the expression of both IL-2R alpha and IL-2R beta chains, as well as IL-2 production by T-ALL cells. These effects were time- and dose-dependent. Cross-linking experiments with 125I-labelled recombinant IL-2 (125I-rIL-2) revealed both p55 (IL-R alpha) and p70 (IL-2R beta) IL-2-binding polypeptides, whereas binding equilibrium assays on PMA-treated cells demonstrated the presence of a low number (31-413) of high-affinity binding sites/cell in five out of six cases analysed, as well as intermediate affinity IL-2R (1234-3919 sites/cell) in four out of six cases, according to the time of incubation with PMA. In two cases tested high-affinity IL-2R on PMA-treated T-ALL cells could internalize 125I-rIL-2 at 37 degrees C. PMA alone enhanced the spontaneous proliferation of T-ALL cells in three cases, whereas a clear synergy between IL-2 and PMA could be detected in three patients' cells. Moreover, exogenous rIL-2 enhanced cell proliferation of PMA-preincubated T-ALL cells in four cases studied. Taken together, these observations indicate that a short-term incubation of T-ALL cells with PMA can activate the IL-2/IL-2R system on these cells without inducing strong modifications of their differentiation status. These results thus suggest that this system may be involved in the proliferation process of some activated immature T cells.     

Urinary excretion of modified nucleosides in patients with acquired immune deficiency syndrome (AIDS) and individuals at high risk of AIDS

Patients with certain malignant diseases excrete in their urine elevated levels of modified nucleosides originating from breakdown of transfer RNA (tRNA). A high incidence of acquired immune deficiency syndrome (AIDS), often associated with rapidly progressing Kaposi's sarcoma (KS), is currently being observed in many countries. Male homosexuals are considered to be at highest risk of developing these disorders. We have examined 10 patients with AIDS and 77 male homosexuals without clinical manifestations of AIDS at the time of examination. Elevated levels of modified nucleosides were found in all patients with AIDS. Of further interest was the finding of a high prevalence of abnormal nucleoside levels in the high-risk group, with a trend toward higher levels in those high-risk individuals who had lymphadenomegaly, considered a prodrome of AIDS. These findings indicate that determination of urinary nucleoside levels may help identify individuals at high risk of developing AIDS thereby increasing the possibility for prevention and early therapy.     

Activation of monocyte-mediated tumoricidal activity in patients with acquired immunodeficiency syndrome

The purpose of these studies was to determine whether peripheral blood monocytes from acquired immunodeficiency syndrome (AIDS) patients with Kaposi's sarcoma could be activated to lyse human tumor target cells in vitro. Monocytes were isolated and incubated for 24 hours in vitro with either medium (control), a crude mitogen-induced lymphokine preparation (MAF), or endotoxin before the addition of [125I]IUdR-labeled A375 melanoma target cells. Cytolysis was determined 72 hours later. Twelve (100%) of 12 patients tested had monocyte-mediated cytotoxicity values that were comparable to those of normal individuals. Recombinant human gamma interferon (IFN gamma) activated both normal and AIDS monocyte-mediated tumoricidal function only when combined with lypopolysaccharide (LPS). In addition, mononuclear cells from ten AIDS patients were also tested for their ability to secrete MAF and IFN gamma in response to a mitogenic stimulus. Lymphokines generated from all ten patients contained substantial amounts of IFN gamma (100 to 2,500 U/mL); however, three of these ten lymphokine preparations failed to activate normal monocytes to lyse tumor cells. These results suggest that monocyte-mediated tumoricidal function of AIDS patients is intact and thus suggest new approaches for the therapy of AIDS.     

A comparison of bone marrow findings in patients with acquired immunodeficiency syndrome (aids) and aids related conditions

Bone marrow biopsies and smears were examined from 70 patients with acquired immunodeficiency syndrome (AIDS) or AIDS related conditions: 32 patients with AIDS; 9, at risk, group patients with B-cell lymphoma; 22 patients with AIDS related complex (ARC) and 7, at risk, group patients with idiopathic thrombocytopenic purpura (ITP). The first three groups showed similarity with respect to frequency of nonspecific findings: hypo and hypercellularity, marrow damage, lymphoid aggregates, histiocytosis, plasmacytosis and features of myelodysplasia. AFB and fungal organisms were present in the biopsies of 17 per cent of AIDS and 18 per cent of ARC patients. The organisms were associated with bone marrow granulomas or histiocytosis, peripheral lymphopenia and anemia. Only one out of 9 biopsies in patients with previous diagnoses of lymphoma showed involvement of the marrow. One case each of Hodgkin's disease and non-Hodgkin's lymphoma were discovered incidentally among the 22 biopsies from ARC patients without a previous diagnosis of lymphoma. Except for those presenting with ITP alone, bone marrow changes are similar in patients with AIDS and AIDS related conditions.