AIDS-related Primary Central Nervous System Lymphoma Research Articles

EBV-associated primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity

Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV− HIV− PCNSL and 2 EBV− HIV+ PCNSL; and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV− PCNSL. As with prior studies, EBV− HIV− PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV− PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV− HIV− PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment.

Aids Related Primary Central Nervous System Lymphoma Is Still a Challenge in the Cart Era: A Single Centre Experience

Abstract Introduction. Aids Related Primary Central Nervous System Lymphoma (AR-PCNSL) is an aggressive entity, with a markedly inferior prognosis to PCNSL in immunocompetent. The introduction of combination antiretroviral therapy (cART) has substantially reduced the incidence of AR-PCNSL, but sporadic cases of AR-PCNSL continue to represent a therapeutic challenge and there is little information to guide clinical management for these patients (pts). To evaluate the chance of cure of AR-PCNSL in the cART era, we retrospectively analyzed outcomes of all AR-PCNSL diagnosed and treated at our center, a public hospital with history of dedicated care for Aids Related-lymphoma (AR-ly). Patients and Methods. Since 1985, all pts with AR-ly diagnosed at our center are prospectively recorded in a database. Data concerning AR-PCNSL were extracted and electronic medical records and physical charts were also revised. Inclusion criteria required diagnosis of SNC non Hodgkin lymphoma (NHL) in the absence of preceding or concomitant systemic lymphoma. Demographic, HIV-and lymphoma-related characteristics were analysed, as well as treatment and outcome. Results. Among 231 HIV positive pts with aggressive NHL diagnosed between 1985-2016, 26 pts with AR-PCNSL were identified and included in this analysis. Diagnosis was histologically or cytologically confirmed in 25. Fourteen pts were diagnosed between 1987-1996 (pre-cART era) and 12 between 1997-2016 (post-cART era). The proportion of pts with AR-PCNSL decreased from 14.4% to 9% after the advent of cART. During the pre-cART era, the median time from HIV and AR-PCNSL diagnosis was 27.5 mo (6-126) and median CD4 count 24.5/mcl (1-136). Eleven pts had prior opportunistic infections. Due to early deaths and poor PS, only 3 pts could receive specific treatment for NHL (2 whole brain radiotherapy, WBRT, and 1 unspecified chemotherapy); the pt treated with chemotherapy died after few months due to liver and heart failure. The 2 pts who received WBRT died early (ischemic heart failure and unknown cause) without evidence of response. The median overall survival (OS) of AR-PCNSL in the pre-cART era was only 2 mo (1-5). During the post-caART era HIV and AR-PCNSL diagnoses were consensual in 4/12 pts (33%). Among the others, 4/8 pts were on cART at AR-PCNSL onset and 6/8 pts had already experienced one or more opportunistic complications. The median time from HIV and AR-PCNSL diagnosis was 46 mo (0-272) and median CD4 count was 39/mcl (12-1044). Of 12 pts diagnosed in the post-cART era, 3 died before receipt of any intervention and 5 received only cART because of advanced disease, poor PS and comorbidity. Four pts received CNS NHL directed therapy, in combination with cART. One pt received WBRT and 3 received HD-MTX-based chemotherapy (dose 3-3.5 gr/sm, for 1-2 cycles). Overall, a CR was documented in 2 pts (1 after WBRT and 1 after cART alone) and a partial remission (PR) in 2 (1 after HD-MTX-based therapy and 1 after cART alone). All other pts progressed and died early from NHL (1 pt failed both HD-MTX therapy and WBRT). As a result, the OS remained extremely poor even in the cART era in the whole group of pts (median OS 2.5 mo, 1-118), and was 5 mo (2-10) in the 4 pts who received CNS NHL directed therapy. The only 2 pts alive at the time of this analysis are those obtaining a CR (at mo +118 and +10). Notably, the long survivor pt received only cART for CNS NHL; however, 16 mo later he developed a systemic plasmablastic lymphoma which was successfully treated. Of the 3 pts receiving HD-MTX-based therapy, 2 (1 with plasmablastic histology) progressed during treatment and 1 with CD4 1044/mcl, receiving HD-MTX/ARA-C + Thiotepa + Rituximab, achieved PR after 2 cycles, but lymphoma progressed after treatment suspension due to neurologic and infectious toxicity. Conclusions: Treating patients with AR-PCNSL remains a challenge even in the cART-era, especially for delayed diagnosis, poor clinical conditions and severe immunodeficiency. A prompt diagnosis and effective cART are highly desirable. We can not recommend a specific therapeutic strategy from our experience. However, due to the favourable results observed in the HIV negative setting, the role of HD-MTX integrated with cART deserves prospective evaluation in order to identify clinical benefit and potential toxicity. Similarly, innovative approaches, including lenalidomide and ibrutinib, might also be considered for their favourable safety profile. Disclosures Rossi: Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

Long-term survival in AIDS-related primary central nervous system lymphoma.

The optimal therapeutic approach for patients with AIDS-related primary central nervous system lymphoma (AR-PCNSL) remains undefined. While its incidence declined substantially with combination antiretroviral therapy (cART), AR-PCNSL remains a highly aggressive neoplasm for which whole brain radiotherapy (WBRT) is considered a standard first-line intervention. To identify therapy-related factors associated with favorable survival, we first retrospectively analyzed outcomes of AR-PCNSL patients treated at San Francisco General Hospital, a public hospital with a long history of dedicated care for patients with HIV and AIDS-related malignancies. Results were validated in a retrospective, multicenter analysis that evaluated all newly diagnosed patients with AR-PCNSL treated with cART plus high-dose methotrexate (HD-MTX). We provide evidence that CD4+ reconstitution with cART administered during HD-MTX correlates with long-term survival among patients with CD4 <100. This was confirmed in a multicenter analysis which demonstrated that integration of cART regimens with HD-MTX was generally well tolerated and resulted in longer progression-free survival than other treatments. No profound differences in immunophenotype were identified in an analysis of AR-PCNSL tumors that arose in the pre- versus post-cART eras. However, we detected evidence for a demographic shift, as the proportion of minority patients with AR-PCNSL increased since advent of cART. Long-term disease-free survival can be achieved in AR-PCNSL, even among those with histories of opportunistic infections, limited access to health care, and medical non-adherence. Given this, as well as the long-term toxicities of WBRT, we recommend that integration of cART plus first-line HD-MTX be considered for all patients with AR-PCNSL.

Primary central nervous system lymphomas.

Primary central nervous system lymphoma (PCNSL) is an aggressive B cell lymphoma that occurs in immunocompetent and immunosuppressed patients. Primary ocular lymphoma represents an important variant of this disease. The outcome for patients with PCNSL is rapidly improving with new treatment strategies. This review focuses on recent advances, investigations, and controversies in the management of these increasingly important malignancies. The incidence of PCNSL is rising in immunocompetent patients over the age of 60 years for unexplained reasons. However, the incidence of AIDS-related PCNSL, which is related to Epstein-Barr virus infections, has fallen with the institution of highly active antiretroviral therapy. During the past decade, standard therapy has evolved from cranial irradiation to high dose methotrexate-based regimens. This shift in therapy has been associated with an increase in the median survival of patients from 1 year to longer than 3 years, and with an equally striking reduction in neurotoxicity if whole brain radiation is avoided. Optimal therapeutic results require careful attention to opportunistic infections, thromboembolic disease, and renal toxicities associated with high dose methotrexate. Overall, PCNSLs are increasing in frequency and the results of therapy for this disease have dramatically improved during the past decade. Many important therapeutic questions remain unanswered. These include the optimal dose, frequency, and duration of methotrexate, as well as the roles of additional systemic chemotherapy drugs, intrathecal therapy, and cranial irradiation. Further progress in this uncommon disease will depend on entering patients into carefully designed multicenter clinical trials to build upon the significant advances that have been made.

LINFOMA PRIMARIO DEL SISTEMA NERVIOSO CENTRAL COMO PRIMERA MANIFESTACIÓN DE SIDA. PRESENTACIÓN DE UN CASO Y REVISIÓN DE LA LITERATURA

El linfoma primario del sistema nervioso central (LPSNC) es una neoplasia infrecuente que comprende solo el 5% del total de los linfomas de localización extranodal. El LPSNC se define como un linfoma de tipo No Hodgkin (LNH) que solo infiltra el eje cerebro espinal sin compromiso sistémico. Esta neoplasia es más frecuente en sujetos con inmunodeficiencias congénitas y adquiridas. En los pacientes con SIDA, el LPSNC ocurre con igual incidencia en todos los grupos de riesgo y edades pero con una mayor prevalencia en aquellos con recuentos de linfocitos T CD4 + de &lt; de 50 células/µL. Se trata de un linfoma de células grandes, de alto grado de malignidad, y fuertemente asociado en su patogenia al virus de Epstein Barr (VEB) cuyo genoma se detecta en las células linfoides atípicas. La presencia del genoma del VEB se detecta en el 100% de los casos de LPSNC asociado al SIDA pero esto no ocurre en otras clases de pacientes con esta misma neoplasia. En pacientes con SIDA y lesiones de masa cerebral ocupante, la detección del genoma del VEB en el líquido cefalorraquídeo (LCR) a través de la reacción en cadena de la polimerasa (PCR) tiene una sensibilidad del 83% a 100% y una especificidad &gt; del 90% para el diagnóstico. El uso difundido de la terapia antirretroviral de gran actividad (TARGA) se asoció con una declinación en la incidencia de LPSNC. El pronóstico de esta neoplasia en pacientes con SIDA es pobre y se asocia con una mediana de supervivencia de 2 a 3 meses en la era previa a la TARGA con una discreta prolongación en la supervivencia con la TARGA. Se presenta un paciente que desarrolló un LPSNC como primera manifestación de SIDA y se efectúa una actualización de la literatura sobre el tema.

Factors associated with survival among patients with AIDS-related primary central nervous system lymphoma

AIDS-related primary central nervous system lymphoma (AR-PCNSL) has a poor prognosis. Improved understanding of specific patient, infectious, diagnostic, and treatment-related factors that affect overall survival (OS) is required to improve outcomes. Population-based registry linkage study. Adult cases from the San Francisco AIDS registry (1990-2000) were matched with the California Cancer Registry (1985-2002) to ascertain AR-PCNSL data. Survival time was assessed through 31 December 2007. Risk factors and temporal trends for death were measured using two-sided Kaplan-Meier and Cox analyses. Two hundred and seven AR-PCNSL patients were identified: 68% were white, 20% Hispanic, 10% African-American, and 2% Asian. Nineteen percent of patients had central nervous system (CNS) opportunistic infections diagnosed prior to AR-PCNSL. Fifty-seven percent of patients received radiation and/or chemotherapy and 12% used HAART prior to or within 30 days of AR-PCNSL diagnosis. One hundred and ninety-nine patients died (34 deaths/100 person-years). In adjusted analysis, prior CNS opportunistic infection diagnosis increased risk of death (hazard ratio 1.9, P = 0.0006) whereas radiation and/or chemotherapy decreased risk (hazard ratio 0.6, P < 0.0001). AR-PCNSL diagnosis 1999-2002 had a lower mortality risk (hazard ratio = 0.4, P = 0.02) compared to 1990-1995. African-Americans had an increased risk of death compared to whites or Asians (hazard ratio = 2.0, P = 0.007). OS among AR-PCNSL patients improved over time but remains poor, especially among African-Americans. Prospective evaluation of curative therapy in AR-PCNSL is urgently needed. Accurate diagnosis of CNS mass lesions in patients with AIDS is required and for those with AR-PCNSL, antiretroviral therapy with concomitant AR-PCNSL therapy, and antimicrobial supportive care may improve OS.

High-Dose Methotrexate Is Effective, Safe, and Leads To Durable Responses In Patients With AIDS-Related Primary Central Nervous System Lymphoma Treated During The Era Of Combined Anti-Retroviral Therapy

▪ IntroductionThe use of high-dose methotrexate (HD MTX) as first-line treatment for patients with primary central nervous system lymphoma (PCNSL) has resulted in dramatic improvements in survival and functional status for immunocompetent individuals. However, there is minimal data describing either its efficacy or safety in patients with AIDS-related (AR) PCNSL, a uniformly fatal disease in the era preceding combined anti-retroviral therapy (cART). Furthermore, it is unclear whether HD MTX and cART may be safely co-administered. Here we report our experience in treating patients with AR PCNSL in the pre-cART, cART, and HD MTX eras at San Francisco General Hospital (SFGH). MethodsThe medical records of 93 patients with biopsy-proven, AR PCNSL diagnosed between April 1988 and August 2012 were culled via electronic tumor registry, electronic medical record, and physical chart review. All patients required documentation of biopsy-proven disease for inclusion in this analysis, and all but one patient record originated from SFGH, the exception being an HIV+ individual who received treatment at our university hospital. Patients receiving a diagnosis prior to 1997 were grouped into the pre-cART era as this was the year in which combined anti-retroviral therapy was widely available and incorporated into treatment regimens at SFGH. The HD MTX era began in 2002 at SFGH with its routine use as first-line treatment for PCNSL. ResultsMedian age at diagnosis for the entire cohort (N = 93) was 36 years, and 95% of the patients were male. The majority of diagnoses were made in the pre-cART era (N = 75, or 81%). With regard to histology, all patients were diagnosed with either diffuse large B-cell lymphoma (DLBCL) or large cell lymphoma NOS, and there were no T-cell nor indolent B-cell histologic subtypes recorded. Median CD4 count at diagnosis was 11 (range 0 to 386) for the 37 patients with this data recorded. The median Karnofsky Performance Status (KPS) score at diagnosis was 30 for the entire cohort with no differences between pre-cART or cART eras. A total of 56 patients (60%) suffered from opportunistic infections (OIs) prior to PCNSL diagnoses, and the proportion was higher among the cART era patients (15 of 18, or 83%). Only 14 patients (15%) were on anti-retroviral (ARV) therapy of any kind prior to diagnosis, and while the majority (10/14) of these patients were diagnosed in the cART era, none were compliant or otherwise receiving treatment on a consistent basis.Regarding treatment, of the 57 patients with documented whole-brain XRT (WBXRT) doses, 55 were treated in the pre-HD MTX era (N = 81) and received a median dose of 3100 cGy with a median of 26 days from diagnosis to completion of therapy. Among the 12 patients diagnosed in the era of HD MTX + cART, 10 patients had clinical data available to calculate a median IELSG score of 4. Ten patients in the HD MTX era received a median 7 cycles of HD MTX with a median dose of 8 gm/m2 per cycle; two patients expired prior to receiving any therapy. No patient in this era received WBXRT as part of first line therapy. One patient experienced grade 4 thrombocytopenia, otherwise there were no noted grade 3/4 toxicities. There were 6 complete remissions (CRs) and 2 partial remissions (PRs) for an overall response rate (ORR) of 80% among patients treated with HD MTX. The median post-treatment KPS among patients treated with HD MTX was 80.Finally, the median OS for the entire cohort (N = 93) was 2.2 months. Among patients diagnosed in the pre-cART era (N = 75), median OS was 2 months. Patients diagnosed in the cART era (N = 18) and patients treated with HD MTX in the cART era (N = 10) had median OS of 8.1 and 29.7 months, respectively. Notably, among survivors (N = 6) of patients treated with HD MTX in the cART era, the median OS was 75 months. ConclusionsAR PCNSL was a uniformly and rapidly fatal disease at SFGH between the years 1988 and 1997 with the use of WBXRT as first-line treatment. In contrast, for patients diagnosed with AR PCNSL in the cART era, HD MTX has been safely and effectively administered with concomitant anti-retroviral therapy at similar doses used for immunocompetent patients. Furthermore, such treatment can lead to durable remissions even in patients with a history of non-compliance or sustained periods off cART therapy. Supported by Leukemia and Lymphoma Society and NIH R01CA139-83-01A1.▪ Disclosures:Rubenstein:Genentech: Research Funding; Celgene: Research Funding.

Diagnosis and Treatment of AIDS-Related Primary Central Nervous Lymphoma

Primary central nervous system lymphoma (PCNSL) is an intracranial tumorous lesion that develops in acquired immunodeficiency syndrome (AIDS) patients. PCNSL is very rare, but its prevalence has increased with the expansion of human immunodeficiency virus (HIV) infections. It is diagnosed by imaging or biopsy. Serum and cerebrospinal fluid (CSF) have been analyzed for the presence of diagnostic biomarkers for PCNSL. The presence of Epstein-Barr virus in the CSF is a widely used biomarker, but it has a low positive predictive value. B-cell activation-related cytokines, tumor-specific DNA methylation, and microRNAs have been reported as new candidate biomarkers. Previously, the prognosis of AIDS-related PCNSL was very poor. However, highly active antiretroviral therapy emerged in the late 1990s, which continuously inhibits viral replication and facilitates the recovery of immunity in HIV-infected persons, improving the prognosis of PCNSL patients in combination with whole-brain irradiation. In this review, we focus on the diagnosis of and biomarkers for AIDS-related PCNSL and advancements in its treatment.

Whole brain radiation alone produces favourable outcomes for AIDS‐related primary central nervous system lymphoma in the HAART era

Primary central nervous system lymphoma (PCNSL) related to acquired immunodeficiency syndrome (AIDS) is a lethal disorder, but the recent application of highly active antiretroviral therapy (HAART) has significantly improved prognosis. This retrospective cohort study of AIDS-related PCNSL examined the actual clinical outcomes and prognostic variables affecting overall survival (OS) in the HAART era. Twenty-three newly diagnosed AIDS-related PCNSL at 12 regional centre hospitals for HIV/AIDS in Japan between 2002 and 2008 were consecutively enrolled. The estimated 3-yr OS rate of the entire cohort was 64% (95%CI, 41.0-80.3%). Whole brain radiation therapy (WBRT) had an independent positive impact on survival (WBRT >or=30 Gy vs. others, P = 0.02). Nine of 10 patients with a good performance status (PS) (0-2) remained alive with complete response, whereas 10 (77%) of 13 of those with a poor PS (3-4) died mostly after a short period. The estimated 3-yr OS rate of the groups with a good and poor PS was 100% and 38% (95%CI, 14-63%), respectively (P = 0.01). Leukoencephalopathy (grade >or= 2) developed in 21% of those that survived more than 12 months after radiation. The patients receiving a curative intent radiation dose (>or=30 Gy) of WBRT achieved prolonged survival while maintaining a good quality of life in the HAART era, especially among patients with a favourable PS.

Whole Brain Radiation Alone Brings the Favorable Outcomes for AIDS Related Primary Central Nervous System Lymphoma (PCNSL) Especially with Good Performance Status in the HAART Era.

Abstract 4751 BackgroundPrimary central nervous system lymphoma (PCNSL) is one of an acquired immunodeficiency syndrome (AIDS)-defining illness and is the second common cerebral mass lesion after toxoplasmosis in HIV infected population. The introduction of highly active antiretroviral therapy (HAART) significantly improved the survival of AIDS related PCNSL. But, the standard procedure to manage these patients still remains to be established. We performed the nationwide retrospective survey to elucidate the actual status and the significant prognostic variables of AIDS-related PCNSL in the HAART era. MethodsAll AIDS related PCNSL newly diagnosed at 12 regional center hospitals for HIV/AIDS in Japan during the period 2002-2008 were registered. The data about diagnostic modalities, CD4 counts, performance status (PS), HAART regimens, treatment modalities, and clinical outcomes were collected. A multivariate and univariate Cox regression analysis was performed to assess the effects of treatment and the clinical variables on OS. ResultsTwenty four AIDS related PCNSLs were registered. Median age was 41 (21-60) year old, and male gender was 96%. Ten patients were diagnosed as PCNSL based on imaging features and positive EBV DNA PCR of cerebrospinal fluid without brain biopsy. HAART was administrated in 88%. Twenty two patients were treated by radiotherapy alone, and only one cases were received the combined modality treatment. Multivariate analysis revealed that the significant predictor of improved survival was completion of whole brain radiotherapy (WBRT) with a total dosage more than 30 Gy (P=0.017). Furthermore, 9 of 10 patients with good PS (0-2) group were alive with CR (all were received WBRT), nevertheless 64% of poor PS (3 or 4) group (9/14) died sometimes with short clinical course. The estimated 3yrs overall survival rate of each group was 100% and 38% respectively (p=0.0198). The incidence and grade of radiation related leukoencephalopathy was limited in good PS group. ConclusionRadiotherapy alone with HAART is shown to be the most common treatment for the AIDS-related PCNSLs, but the role of systemic chemotherapy should be elucidated. Some AIDS-related PCNSLs, especially with good PS, achieved the durable remission by WBRT with the curative intent dose, in the HAART era. Disclosures:No relevant conflicts of interest to declare.

AIDS-related primary central nervous system lymphoma: a Norwegian national survey 1989–2003

BackgroundPrimary central nervous system lymphoma (PCNSL) is a frequent complication in acquired immunodeficiency syndrome (AIDS). The objective of this survey was to investigate incidence, clinical features, radiological findings, histologic diagnosis, treatment and outcome for all patients with histologically verified AIDS-related PCNSL diagnosed in Norway in 1989–2003.MethodsWe identified the patients by chart review of all cases recorded as PCNSL in The Norwegian Cancer Registry (by law recording all cases of cancer in Norway) and all cases recorded as AIDS-related PCNSL in the autopsy registry at a hospital having 67% autopsy rate and treating 59% of AIDS patients in Norway, from 1989 to 2003. Histologic material and radiological images were reviewed. We used person-time techniques to calculate incidence rates of PCNSL among AIDS patients based on recordings on AIDS at the Norwegian Surveillance System for Communicable Diseases (by law recording all cases of AIDS in Norway).ResultsTwenty-nine patients had histologically confirmed, newly diagnosed AIDS-related PCNSL in Norway from 1989–2003. Only 2 patients had this diagnosis established while alive. AIDS patients had 5.5% lifetime risk of PCNSL. Their absolute incidence rate of PCNSL per 100 person-years was 1.7 (95%CI: 1.1–2.4) and decreased during the consecutive 5-year periods from 3.6, to 2.5, and to 0.4 (p < 0.001). Median survival from initial symptom of PCNSL was 2.3 months, but one patient was still alive 4 years after completed radiotherapy.ConclusionThis is the first national survey to confirm decreasing incidence of AIDS-related PCNSL. Despite dismal survival in most patients, the possibility of long term survival should prompt more aggressive diagnostics in suspected PCNSL.

Antiviral and Immunomodulatory Treatment for AIDS-Related Primary Central Nervous System Lymphoma: AIDS Malignancies Consortium Pilot Study 019

PurposeA consistent association with Epstein-Barr Virus (EBV) distinguishes acquired immunodeficiency syndrome (AIDS)–related primary central nervous system lymphoma (PCNSL) from that which occurs in the general population. Recent descriptions of long-term remissions in patients with posttransplantation EBV-associated PCNSL who received EBV-specific therapy suggest some antitumor effect is anti-EBV mediated. Patients and MethodsWe enrolled 4 patients with AIDS-related PCNSL into a novel antiviral and immunomodulatory protocol. An additional patient was treated in a similar fashion off protocol. Treatment consisted of intravenously administered zidovudine (1.5 g twice daily), ganciclovir (5 mg/kg twice daily), and interleukin-2 (2,000,000 U twice daily). After 2 weeks of therapy, patients were switched to oral ganciclovir (1 g 3 times daily), patient-specific, highly active, antiretroviral therapy, and subcutaneous interleukin-2 (2,000,000 U 3 times weekly). A final patient was treated with intravenous zidovudine and hydroxyurea. All 6 patients had advanced-stage AIDS as reflected by a CD4+ T-lymphocyte cell count of < 50/μL and a detectable human immunodeficiency virus (HIV).1 viral RNA load (median copies, 135,000/mL; range, 2170-360,000/mL). One of 4 protocol-enrolled patients remains in complete remission with > 4 years' follow-up. ResultsThree patients died from complications of progressive PCNSL. Two patients treated off protocol exhibited favorable responses and remain in complete remission at 28 months and 52 months, respectively. Grade 3/4 myelosuppression was uniformly noted, but there were no clinically significant hemorrhagic or infectious complications. ConclusionWe conclude that for patients with AIDS and PCNSL, treatments with dual efficacy against HIV and EBV merit further investigation. Our experience provides a platform for future studies.

THE STATUS OF BCL-6, CD138/SYNDECAN-1, LMP-1 AND BCL-2 IDENTIFIES DISTINCT CATEGORIES OF AIDS-RELATED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: PATHOGENETIC AND HISTOGENETIC IMPLICATIONS.

89 Background: Primary central nervous system lymphoma (PCNSL) is a major cause of morbidity and mortality among HIV-infected individuals. AIDS-related PCNSL (AIDS-PCNSL) derive from B-cells, display an aggressive clinical behavior, and are histologically classified as diffuse large cell lymphoma. The precise histogenetic derivation of AIDS-PCNSL, as well as their molecular pathogenesis, are poorly understood. This study aimed at clarifying the histogenesis and pathogenesis of AIDS-PCNSL by defining the genotypic and/or phenotypic profile of cancer-related genes and of other biologic markers harboring pathogenetic and histogenetic implications for B-cell neoplasia. Methods: Twenty-six AIDS-PCNSL formed the basis of this study. For comparison. 23 AIDS-unrelated PCNSL were also investigated. All PCNSL were monoclonal B-cell expansions. PCNSL were investigated for protein expression of the BCL-6 and BCL-2 proto-oncogenes, the CD138/syndecan-1 antigen, the hMSH2 DNA mismatch repair enzyme, and the EBV-encoded LMP-1 antigen. These markers bear histogenetic relevance throughout the B-cell lineage, since expression of BCL-6 and hMSH2 cluster with germinal center (GC) B-cells, whereas expression of CD138/syndecan-1 associates specifically with late stages of B-cell differentiation. Molecular investigations of PCNSL included infection by EBV, rearrangements of BCL-2, BCL-6, and c-MYC proto-oncogenes, as well as analysis of mutations of BCL-6 5′ noncoding regions, which denote B-cell transition through the GC. Results: Expression of the BCL-6 protein was detected in 56.2 % AIDS-PCNSL. Expression of BCL-6 was mutually exclusive with expression of LMP-1, of CD138/syndecan-1 and, with few exceptions, of BCL-2, BCL-6+/LMP-1−/BCL-2− AIDS-PCNSL generally displayed a large noncleaved cell morphology, whereas cases expressing the BCL-6−/LMP-1+/BCL-2+ phenotype displayed features consistent with large cell immunoblastic plasmacytoid lymphoma. All AIDS-PCNSL expressed the hMSH2 protein. The most frequent proto-oncogene alteration of AIDS-PCNSL was represented by mutations of BCL-6 5′ regions, occurring in 42 % of cases. Conversely, all AIDS-PCNSL tested were devoid of gross rearrangements of BCL-6, BCL-2, or c-MYC. Infection by EBV occurred in all AIDS-PCNSL. Conclusions: The implications of these data are threefold. First, AIDS-PCNSL are heterogeneous and may be distinguished into two major phenotypic categories, i.e. BCL-6+/syndecan-1−/LMP-1−/BCL-2− and BCL-6−/syndecan-1+/LMP-1+/BCL-2+. Second, the combination of positive BCL-6 expression, hMSH2 expression and frequent BCL-6 5′ mutation suggests that a substantial fraction of AIDS-PCNSL derive from GC B-cells. Finally, BCL-6 mutations represent the most frequent proto-oncogene lesion of AIDS-PCNSL and may provide a molecular inarker for disease monitoring.

Palliation of AIDS-related primary lymphoma of the brain: Observations from a multi-institutional database

To catalogue the presenting symptoms of patients with AIDS who are presumed to have primary central nervous system lymphoma (PCNSL). To document the palliative efficacy of cranial irradiation (RT) relative to the endpoints of complete and overall response for the respective symptoms. An analysis of 163 patients with AIDS-related PCNSL who were evaluated at nine urban hospitals was performed. These patients were treated for PCNSL after the establishment of a tissue diagnosis or on a presumptive basis after failing empiric treatment for toxoplasmosis. All patients were treated between 1983 and 1995 with radiotherapy (median dose-fractionation scheme = 3 Gy x 10) and steroids (>90% dexamethasone). Because multiple fractionation schemes were used, prescriptions were converted to biologically effective doses according to the formula, Gy10 = Total Dose x (1 + fractional dose/alpha-beta); using an alpha-beta value of 10. The overall palliative response rate for the entire group was 53%. In univariate analysis, trends were present associating complete response rates with higher performance status (KPS > or = 70 vs. KPS < or = 60 = 17% vs. 5%), female gender (women vs. men = 29% vs. 8%), and the delivery of higher biologically effective doses (BED) of RT (Gy10 > 39 vs. < or = 39 = 20% vs. 5%). In multivariate analysis of factors predicting complete response, both higher KPS and higher BED retained independent significance. A separate univariate analysis identified high performance status (KPS > or = 70 vs. KPS < or = 60 = 71% vs. 47%), and young age (< or = 35 vs. > 35 = 61% vs. 40%) as factors significantly correlating with the endpoint of the overall response. In multivariate analysis, high performance status and the delivery of higher biologically effective doses of irradiation correlated significantly with higher overall response rates. Most AIDS patients who develop symptoms from primary lymphoma of the brain can achieve some palliation from a management program that includes cranial irradiation. Young patients with excellent performance status are most likely to respond to treatment. The delivery of higher biologically effective doses of irradiation also may increase the probability of achieving a palliative response.

Evaluation of cerebrospinal fluid EBV-DNA and IL-10 as markers for in vivo diagnosis of AIDS-related primary central nervous system lymphoma.

Acquired immunodeficiency syndrome (AIDS)-related primary central nervous system lymphoma (PCNSL) is almost always associated with the Epstein-Barr virus (EBV), and EBV-DNA in cerebrospinal fluid (CSF) has been indicated as a useful tumour marker for this HIV-related neoplasm. AIDS lymphomas also show an enhanced production of IL-10 which is generally associated with the presence of EBV in lymphoma cells. We performed a prospective study in 19 HIV seropositive patients with brain mass lesions, and in 21 other AIDS patients with or without other neurological disorders, to assess the in vivo diagnostic value of EBV-DNA and of IL-10 levels in the CSF for primary lymphoma of the central nervous system (CNS). EBV-DNA was detected by a nested polymerase chain reaction (PCR) in the CSF from seven of eight patients with PCNSL, diagnosed by brain biopsy (87.5% sensitivity) and in none of the 11 controls with brain mass lesions (100% specificity) and of the other 21 AIDS patients with or without neurological disorders. The only patient with PCNSL without detectable EBV-DNA in the CSF was also negative for EBV-DNA in the lymphoma tissue, whereas the samples of the other seven brain lymphomas were all positive for EBV-DNA by nested PCR. Therefore 100% of patients with an EBV-positive primary CNS lymphoma had detectable EBV-DNA in the CSF. No patient from the control group without PCNSL with EBV-negative CSF developed a lymphoma after a mean follow-up of 157 +/- 173 d. IL-10 levels in the CSF from the patients with PCNSL were not significantly different from those in the other groups of patients with AIDS. Due to uniformly high levels in the CSF from AIDS patients, IL-10 is not a useful diagnostic marker for AIDS-related brain lymphoma. The detection of EBV-DNA from the CSF by nested PCR is an extremely sensitive and specific diagnostic tool for AIDS-related PCNSL and should be further evaluated as a possible alternative in patients from whom brain biopsy is not advisable.

Gamma Knife Radiosurgery in AIDS-Related Primary Central Nervous System Lymphoma

The frequency of AIDS-associated primary central nervous system (PCNS) lymphoma is rapidly increasing in adults and children. In AIDS-related PCNS lymphoma, different authors have reported an overall poorer response rate to conventional radiation compared with immunocompetent patients. This poorer response consists of a significantly positive, although transient effect on survival following radiotherapy (XRT), with a poor toleration for prolonged whole-brain RT (WBR) and with radiation-induced changes within the normal CNS tissue on autopsy examinations after a course of XRT. These observations led us to consider highly focused single-session radiosurgical treatments as a potentially useful therapeutic modality for AIDS-associated PCNS lymphomas. A multi-institutional diagnostic and therapeutic protocol for the evaluation and treatment of AIDS patients with high-risk intracerebral space-occupying lesions has been developed at the University Hospital of Verona. Therapy is based on tumor biopsy. Tumors < or = 3.5 cm in diameter are subjected to Gamma Knife radiosurgery, whereas tumors < or = 4.5 cm are treated with stereotactic brachytherapy. At the Department of Neurosurgery, Verona, Italy, Gamma Knife treatment was performed in 2 cases of deep-seated histologically verified malignant non-Hodgkin's lymphoma. A short-term cliniconeuroradiological follow-up (2 months later) showed neurologic improvement and virtually complete disappearance of the tumor in both patients. The excellent local control and the well-tolerated single-session treatment and absence of brain toxicity signs on CT scan indicate a putative role for Gamma Knife radiosurgery in the treatment of these patients.

Combined‐modality therapy in the treatment of primary central nervous system lymphoma in AIDS

Conventional therapy--ie, treatment with corticosteroids and cranial radiotherapy (RT)--is inadequate to treat AIDS-related primary central nervous system lymphoma (PCNSL), as it achieves a median survival of only 2 to 5 months. Chemotherapy added to RT in non-AIDS PCNSL improves disease control and prolongs survival. We studied the efficacy of this approach with RT in AIDS-related PCNSL. Ten AIDS patients with PCNSL were treated with chemotherapy--nine at diagnosis and one at recurrence. None had evidence of systemic lymphoma. All patients treated at diagnosis received pre-RT methotrexate--eight also received thiotepa and procarbazine--followed by whole-brain RT. The patient treated at recurrence (who had been previously irradiated) received chemotherapy alone, including methotrexate, thiotepa, and procarbazine. All had enhancing lesions on MRI and five (50%) had a single lesion (seven [70%] had a ring-enhancing mass). No patient had a response to corticosteroids. Four of seven (57%) assessable patients had a partial or complete response to chemotherapy prior to RT. Six of seven (86%) assessable patients had a complete response at the end of treatment. Median survival was 3.5 months for all 10 patients and 7 months for the eight patients who completed therapy. Two patients survived for 1 year or longer. Eight patients died--six from infection (two treatment-related), one from progressive dementia, and one from a gastrointestinal hemorrhage. AIDS-related PCNSL responds to chemotherapy and RT, but only a few patients benefit with prolonged survival.

Detection of Eber-1 RNA in primary brain lymphomas in immunocompetent and immunocompromised patients

Tissue from primary central nervous system lymphoma (PCNSL) which developed in five patients with acquired immuno deficiency syndrome (AIDS), nine patients without immunodeficiency, and two Epstein-Barr virus (EBV)-positive control cell lines (B95-8 and Raji) were examined for the presence of EBER-1 RNA. The tissues were hybridized with digoxigenin-labeled sense or anti-sense EBER-1 riboprobes. In all five AIDS-related PCNSLs, strong hybridization signals were found with the EBER-1 anti-sense probe. Signals could be eliminated by preincubation of the tissues with RNase-A. Hybridization with the EBER-1 sense probe showed no signal. All PCNSLs from immunocompetent patients (five paraffin-embedded, four frozen) showed no hybridization signals with EBER-1 sense or antisense probe but good hybridization signals with probes to immunoglobulin kappa or lambda light chain indicating RNA preservation. The paraffin-embedded B95-8-positive control cell-line showed positive hybridization in most cells with the anti-sense EBER-1 probe, and up to one percent of the cells had a weak signal with the sense probe. Most Raji cells showed a uniform signal with the anti-sense EBER-1 probe only. We conclude that, PCNSLs that arise in AIDS patients are associated with latent EBV infections, whereas PCNSLs from immunocompetent patients are not indicating a probable role for EBV in pathogenesis of these tumors.

Epstein-Barr virus in acquired immune deficiency syndrome (AIDS) and non-AIDS primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) still occurs mainly in patients who are immunosuppressed, but its incidence is rising dramatically among immunocompetent individuals. The Epstein-Barr virus (EBV) has been detected by in situ hybridization in PCNSL tumor tissue from patients who are immunodeficient, but not from patients who are immunocompetent. Using the more sensitive polymerase chain reaction (PCR) technique, the authors analyzed PCNSL tissue from 13 patients with acquired immune deficiency syndrome (AIDS) and 13 patients who were immunocompetent for the presence of EBV genome. DNA was extracted from paraffin-embedded biopsy or autopsy specimens. PCR was run using primers for EBV (from the first internal repeat segment of the EBV genome), and identical samples were run simultaneously with primers against actin or the p53 gene as controls to establish the presence of DNA in the sample. Reaction products were also Southern blotted to confirm EBV specificity. EBV was detected in the tumor tissue of 11 of 13 patients (85%) with AIDS and of 7 of 13 patients (54%) who did not have AIDS. There was a history of illness that might suggest or predispose to immune compromise in 5 of 13 patients without AIDS; however, prior illness did not predict EBV-positive tumors. Although mechanisms remain to be clarified, EBV was present in a high percentage of patients with AIDS-related PCNSL and non-AIDS-related PCNSL:

Primary central nervous system lymphoma in AIDS. Results of radiation therapy.

Primary central nervous system (CNS) lymphoma is one of the clinical presentations of the acquired immune deficiency syndrome (AIDS). Ten patients had biopsy-proven high-grade lymphomas that were confirmed by further staging as limited to the CNS. All ten patients received cranial irradiation (total dose, 2200 to 5000 cGy). Six patients demonstrated complete response (CR) of the intracranial masses at the time of repeat computed tomography (CT) scan, whereas one attained a partial response (PR). Two of the CR patients died of multiple opportunistic infections, two experienced relapse of lymphoma, and died at 7 and 16 months from diagnosis, and two were alive without evidence of disease at 8 and 14 months from diagnosis. The median survival of the whole group was 5.5 months (range, 2 to 16 months). Patients with AIDS-related primary CNS lymphoma may respond to radiation treatment; however, response duration is usually short, and survival is influenced by refractory disease or systemic opportunistic infections.