Mark Bower

Viable Malignant Cells After Primary Chemotherapy for Disseminated Nonseminomatous Germ Cell Tumors: Prognostic Factors and Role of Postsurgery Chemotherapy—Results From an International Study Group

PURPOSE To assess the value of postsurgery chemotherapy in patients with disseminated nonseminomatous germ-cell tumors (NSGCTs) and viable residual disease after first-line cisplatin-based chemotherapy. PATIENTS AND METHODS The outcome of 238 patients was reviewed. Tumor markers had normalized in all patients before resection. A multivariate analysis of survival was performed on 146 patients. RESULTS The 5-year progression-free survival (PFS) rate was 64% and the 5-year overall survival (OS) rate was 73%. Three factors were independently associated with both PFS and OS: complete resection (P <.001), < 10% of viable malignant cells (P =.001), and a good International Germ Cell Consensus Classification (IGCCC) group (P =.01). Patients were assigned to one of three risk groups: those with no risk factors (favorable group), those with one risk factor (intermediate group), and those with two or three risk factors (poor-risk group). The 5-year OS rate was 100%, 83%, and 51%, respectively (P <.001). The 5-year PFS rate was 69% (95% confidence interval [CI], 62% to 76%) and 52% (95% CI, 40% to 64%) in postoperative chemotherapy recipients and nonrecipients, respectively (P <.001). No significant difference was detected in 5-year OS rates. After adjustment on the three prognostic factors, postoperative chemotherapy was associated with a significantly better PFS (P <.001) but not with better OS. Patients in the favorable risk group had a 100% 5-year OS, with or without postoperative chemotherapy. Postoperative chemotherapy appeared beneficial in both PFS (P <.001) and OS (P =.02) in the intermediate-risk group but was not statistically beneficial in the poor-risk group. CONCLUSION A complete resection may be more critical than recourse to postoperative chemotherapy in the setting of postchemotherapy viable malignant NSGCT. Immediate postoperative chemotherapy or surveillance alone with chemotherapy at relapse may be reasonable options depending on the completeness of resection, IGCCC group, and percent of viable cells. Validation is necessary.

Brief Communication: Rituximab in HIV-Associated Multicentric Castleman Disease

Context Castleman disease is a rare lymphoproliferative condition. Risk for the condition is elevated in people with HIV infection. Case reports and series suggest that rituximab shows some therapeutic promise in patients previously treated with chemotherapy, but data on initial therapy with rituximab are lacking. Contribution This uncontrolled case series suggests that initial treatment with rituximab can achieve better overall and disease-free survival than that anticipated in untreated patients. Laboratory measures improved with therapy. Caution The absence of a control group precludes definitive assessment of the efficacy or safety of rituximab in treating HIV-associated Castleman disease. The Editors Multicentric Castleman disease is a rare lymphoproliferative disorder that is increasingly occurring in people with HIV infection. It is associated with Kaposi sarcoma, sharing an etiologic agent, Kaposi sarcomaassociated herpesvirus (KSHV), also known as human herpesvirus-8 (1, 2). The gold-standard therapy for HIV-associated multicentric Castleman disease is yet to be established. The use of an anti-CD20 monoclonal antibody, rituximab, to target KSHV-infected plasmablasts in multicentric Castleman disease is a novel and potentially beneficial approach. It has been the subject of case reports and clinical series, in which patients were often pretreated with chemotherapy and follow-up was brief (310). We investigated the efficacy and safety of rituximab as initial monotherapy and correlate clinical findings with immune subset, plasma cytokine, and HIV and KSHV virologic variables. Methods Between 2003 and 2006, 21 patients (18 men) with multicentric Castleman disease were treated prospectively in a nonrandomized, open-label, phase II study with 4 infusions of rituximab at a standard dose of 375 mg per m2 of body surface area at weekly intervals. All biopsy specimens were reviewed and confirmed to be plasmablastic variants of multicentric Castleman disease with no microlymphoma, as defined by previous studies (11, 12). The plasmablasts showed immunoglobulin light chain restriction, were KSHV latent nuclear antigenpositive, and expressed CD20 on immunohistochemistry. Patients were recruited from 3 HIV and cancer centers, where local ethics review committees approved the study and patients gave informed consent. Toxicity was recorded at each visit and was graded by using the Common Terminology Criteria for Adverse Events, version 3.0 (13). We measured plasma KSHV DNA viral load at diagnosis and at 1 and 3 months after rituximab therapy by using Lightcycler quantitative polymerase chain reaction (Roche, Lewis, United Kingdom) on DNA extracted from whole blood using primers specific to KSHV ORF-7 gene, as described elsewhere (14). We assessed progression-free and overall survival by using the KaplanMeier method (15) and used the Wilcoxon rank-sum test to assess the statistical significance of changes in hematologic, biochemical, and immunologic variables. Summaries of data that were not normally distributed are presented as medians with interquartile ranges. All P values are 2-sided (Statview, version 4.57, Abacus Concepts, Berkeley, California). Role of the Funding Source Support for the cytokine assays was provided by St. Stephens AIDS Trust, a national charity supporting clinical research in HIV/AIDS, which had no role in the design, conduct, or reporting of this review or in the decision to publish the manuscript. Results We enrolled 21 patients with a histologically confirmed plasmablastic variant of multicentric Castleman disease without microlymphoma. Their median age was 37 years (range, 31 to 69 years), 9 (43%) patients had a previous AIDS-defining diagnosis, and 13 (62%) patients were receiving highly active antiretroviral therapy (HAART) at diagnosis of multicentric Castleman disease. The median CD4 cell count at diagnosis was 0.30109 cells/L (range, 0.08 to 0.73109 cells/L). Four patients had a plasma HIV-1 viral load less than 50 copies/mL, and 5 other patients had a viral load less than 400 copies/mL (Table 1). Table 1. Hematologic, Biochemical, and Immunologic Variables at Presentation and Change from Baseline 1 Month after Completion of Rituximab Therapy* At diagnosis, the median duration of symptoms was 4 months (range, 0.5 to 24 months), all patients had significant lymphadenopathy, 20 (95%) patients had fever of unknown origin, 18 of 20 (90%) patients had splenomegaly (1 had had splenectomy), and 11 (52%) patients had cutaneous Kaposi sarcoma. Ninety-five percent of the patients had an increased erythrocyte sedimentation rate (ESR) (>20 mm/h), 82% had an increased C-reactive protein (CRP) level (>10 mg/L), 67% were anemic (hemoglobin level <100 g/L), 67% were hypoalbuminemic (serum albumin level <30 g/L), and 14% were thrombocytopenic (platelet count <100109 cells/L). All patients had polyclonal hypergammaglobulinemia, and 2 patients had a serum IgG monoclonal paraprotein band (Table 1). One patient who was receiving intensive care at diagnosis died of progressive disease before completing the rituximab course. All 20 remaining patients achieved resolution of symptoms and fever by the end of rituximab treatment. Of the 21 patients, 14 (67%) had a partial response and 6 (29%) had stable disease according to the radiologic Response Evaluation Criteria in Solid Tumors. The median follow-up was 12 months (range, 1 to 49 months). The 2-year overall survival rate was 95% (95% CI, 86% to 100%), and the relapse-free survival rate was 92% (CI, 75% to 100%) at 1 year and 79% (CI, 52% to 100%) at 2 years. One month after completion of rituximab therapy, 0 of 20 patients were anemic, 0 of 20 were thrombocytopenic, 11 of 17 had an increased ESR, 2 of 16 had an increased CRP level, and 1 of 20 had hypoalbuminemia. Hemoglobin level, platelet count, and serum albumin level increased, whereas ESR and CRP level decreased, 1 month after rituximab treatment (Table 1). Quantitative polymerase chain reaction for KSHV was available for 11 patients at diagnosis and was detectable in 9 patients (median, 700 copies/mL; range, 0 to 400000 copies/mL). One month after treatment, only 2 of 10 (20%) patients had detectable KSHV (Table 1). In both cases, the titer was only 100 copies/mL. Three months after rituximab therapy, only 1 of 10 (10%) patients had detectable KSHV DNA, and once again the titer was only 100 copies/mL (P= 0.018). Serum IgG and IgM levels decreased 1 month after rituximab therapy, but IgA levels did not change (Table 1). Similarly, the CD19 cell count decreased, which persisted at 3 months (median decrease from baseline, 104 cells/mL; interquartile range, 14 to 350 cells/mL; P= 0.002), but the CD19 cell count had recovered to prerituximab levels by 12 months. We performed immune subset analysis on the 13 patients who were already receiving HAART at the time of rituximab therapy. The CD4, CD8, CD56 (natural killer) cell subsets, or HIV viral load did not change during this period. No Common Terminology Criteria for Adverse Events grade 3 or 4 toxicities were recorded with rituximab therapy; however, Kaposi sarcoma progressed during rituximab therapy in 4 of 11 (36%) patients who had cutaneous Kaposi sarcoma at diagnosis. We also measured 15 plasma cytokines: interleukin (IL)1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 p40/p70, IL-13, IL-15, IL-17, interferon-, interferon-, tumor necrosis factor-, and granulocyte macrophage colony-stimulating factor, before and after rituximab therapy and again 3 months after the completion of rituximab therapy. Most patients had elevated plasma cytokine levels at presentation, and the proportion with increased levels declined on completion of therapy (Table 2). Table 2. Proportion of Patients with Elevated Plasma Cytokine Levels at Diagnosis and Changes during Treatment* Discussion Rituximab therapy seems to be a promising first-line treatment for HIV-associated multicentric Castleman disease: Patients completing 4 weekly infusions achieved a clinical and biochemical remission within 1 month, and the radiologic response rate was 67%. Plasma KSHV viral load significantly decreased in individuals with this measurement (P= 0.018). The 2-year overall survival rate was 95% (CI, 86% to 100%), and the relapse-free survival rate was 79% (CI, 52% to 100%). This compares favorably with the median survival of 14 months recorded for 20 patients from the pre-HAART era (16). The clinical response to rituximab occurred within 1 month of completing therapy, and normalization of acute-phase inflammatory markers, such as ESR, CRP, and albumin, occurred by this point. Plasma KSHV DNA viral load was measured before, during, and after treatment and decreased dramatically with treatment and increased at relapse. The high plasma titers of KSHV reflect lytic replication, which is not a feature of Kaposi sarcoma but correlates with disease activity in multicentric Castleman disease. Indeed, KSHV-infected B-lymphocytes from lymph nodes in patients with multicentric Castleman disease are known to express KSHV lytic gene products (17, 18). Rituximab produced a decrease in CD19-positive B-lymphocytes, as would be expected, but was well tolerated in patients with HIV-related multicentric Castleman disease, with no grade 3 or 4 toxicities. In addition, rituximab did not seem to cause exacerbation of HIV infection, with no adverse effect on the immune T-cell subsets, including CD4 cell count or HIV viral load. However, Kaposi sarcoma progressed in 36% of patients with this disease, a phenomenon that has been recorded previously (4). The reason for this is unclear, but the rapid decrease in B-lymphocytes observed with rituximab therapy may play a role in the progression of Kaposi sarcoma (19). Because rituximab has also been associated with an increased risk for death from infection in AIDS-related non-Hodgkin lymphoma (20), the data we present should provide reassurance to clinicians. A recent trial i

The role of immune suppression and HHV-8 in the increasing incidence of HIV-associated multicentric Castleman's disease

BACKGROUND In HIV cohorts with access to highly active antiretroviral therapy (HAART), the incidence of Kaposis sarcoma (KS) is falling; however, the incidence of multicentric Castlemans disease (MCD) in HIV has not previously been described. METHODS The incidence of HIV-associated MCD was calculated from a prospective HIV database with 56 202 patient-years of follow-up and compared with KS. Univariate and multivariate analyses were carried out to identify factors associated with MCD. Plasma human herpesvirus (HHV)-8 DNA levels were measured in HIV-seropositive individuals with newly diagnosed MCD (n = 24), KS (n = 72), HIV-associated lymphoma (n = 74) and HIV-positive controls (n = 53). RESULTS From 24 cases of HIV-associated MCD, the incidence measured 4.3/10,000 patient-years [95% confidence interval (CI) 2.7-6.4]. The incidence in the pre-HAART (1983-1996), early-HAART (1997-2001) and later HAART (2002-2007) eras were 2.3 (95% CI 0.02-4.2), 2.8 (95% CI 0.9-6.5) and 8.3 (95% CI 4.6-12.6), respectively, representing a statistically significant increase over time (P < 0.05). In contrast, from 1180 cases of KS, the incidence in this cohort decreased with time. Multivariate analysis demonstrated that a nadir CD4 count >200/mm(3), increased age, no previous HAART exposure and non-Caucasian ethnicity were all associated with an increased risk of MCD. Plasma HHV-8 DNA levels were higher in patients with newly diagnosed MCD than with KS, lymphomas or HIV-positive controls (Mann-Whitney U-test, P < 0.0001). CONCLUSIONS The incidence of HIV-associated MCD is increasing. It appears to occur more frequently in older HIV-positive individuals with well-preserved immune function.

Clinical Features and Outcome in HIV-Associated Multicentric Castleman's Disease

PURPOSE To describe clinical features, treatment outcomes and relapse rates in HIV-associated multicentric Castlemans disease (MCD) in a sizeable mature cohort. METHODS From a prospective database, we identified 61 HIV-seropositive patients with histologically confirmed MCD (median follow-up, 4.2 years). Since 2003, 49 patients with newly diagnosed MCD have been treated with rituximab with (n = 14) or without (n = 35) etoposide. RESULTS At MCD diagnosis, 55 (90%) of 61 patients met proposed clinical criteria defining an attack. Four patients (7%) had histologic evidence of coexisting lymphoma, and one developed lymphoma 2 years after treatment. The incidence of lymphoma is 28 per 1,000 patient years. With rituximab-based treatment, the overall survival was 94% (95% CI, 87% to 100%) at 2 years and was 90% (95% CI, 81% to 100%) at 5 years compared with 42% (95% CI, 14% to 70%) and 33% (95% CI, 6% to 60%) in 12 patients treated before introduction of rituximab (log-rank P < .001). Four of 49 rituximab-treated patients have died; three died as a result of MCD within 10 days of diagnosis, and one died as a result of lymphoma in remission of MCD. Eight of 46 patients who achieved clinical remission suffered symptomatic, histologically confirmed MCD relapse. The median time to relapse was 2 years, and all have been successfully re-treated and are alive in remission. The 2- and 5-year progression-free survival rates for all 49 patients treated with rituximab-based therapy were 85% (95% CI, 74% to 95%) and 61% (95% CI, 40% to 82%), respectively. CONCLUSION HIV-associated MCD is a remitting-relapsing disease. The outlook has improved dramatically in recent years with the introduction of rituximab-based therapy and yields high overall survival rates.

How I treat HIV-associated multicentric Castleman disease

HIV-associated plasmablastic multicentric Castleman disease is an increasingly frequent diagnosis. Kaposi sarcoma herpesvirus is found in the monotypic polyclonal plasmablasts that characterize this disease. Unlike Kaposi sarcoma, the incidence does not correlate with CD4 cell count or use of highly active antiretroviral therapy. It is a relapsing and remitting illness, and diagnostic criteria are emerging that define disease activity based on the presence of a fever and raised C-reactive protein coupled with a list of clinical features. Treatment protocols increasingly stratify therapy according to performance status and organ involvement. I advocate rituximab monotherapy for good performance status patients without organ involvement and rituximab with chemotherapy for more aggressive disease. The success of antiherpesvirus agents in controlling active disease is limited, but valganciclovir may have a role as maintenance therapy in the future.

HIV-associated multicentric Castleman's disease

Multicentric Castlemans disease (MCD), a relatively rare lymphoproliferative disorder that presents with heterogenous symptoms including fevers, anemia, and multifocal lymphadenopathy, is today most commonly observed in individuals infected with human immunodeficiency virus type‐1 (HIV). In such individuals, a lymph node biopsy typically identifies cells that stain for Kaposis sarcoma‐associated herpesvirus proteins, and most HIV‐associated MCD features can be attributed to the presence of this γ‐herpesvirus. Surgery and antiviral therapies including highly active antiretroviral therapy, interferon‐α, foscarnet, ganciclovir, and antibodies to interleukin‐6 have proved largely ineffective, and chemotherapy in HIV positive individuals is complicated by limited efficacy and pronounced toxicity. While no randomized trials have been performed, more recently the use of the anti‐CD20 monoclonal antibody rituximab in large single center cohorts has been associated with prolonged remissions, radiologic responses, as well as hematologic and serum chemistry normalization of the inflammatory picture observed, at the expense of B cell depletion and flare of Kaposis sarcoma. MCD represents a model of disease at the interplay between tumor biology, infection, and immunology. Am. J. Hematol., 2008.

Plasma HHV8 DNA predicts relapse in individuals with HIV-associated multicentric Castleman disease.

HIV-associated multicentric Castleman disease (HIV-MCD) is a rare lymphoproliferative disorder caused by infection with human herpesvirus-8. The disease follows a relapsing and remitting clinical course, with marked systemic symptoms during an active attack, which can prove fatal. Its incidence is rising, and new data indicate the utility of the anti-CD20 monoclonal antibody rituximab at inducing remissions in both first- and second-line settings, although biomarkers associated with relapse have not been previously identified. In 52 individuals with a histologic diagnosis of HIV-MCD, we performed univariate and multivariate analyses to predict factors associated with an HIV-MCD attack. Although a younger age (< 50 years) was associated with an attack, the strongest association was observed with plasma levels of human herpesvirus-8 DNA. Rising levels predicted an attack (hazard ratio = 2.9; 95% confidence interval, 1.3-6.7), and maintenance therapy with rituximab should be considered in these individuals.

Anal intraepithelial neoplasia in HIV positive people

Objective: To review the current literature on HIV associated anal intraepithelial neoplasia (AIN). Methods: A comprehensive Medline/Pubmed search was performed for the years 1980–2001 (January) for articles pertaining to HIV associated anal intraepithelial neoplasia. From the MeSH terms “anal intraepithelial neoplasia” and “anal cancer” the following subheadings were used: HIV, homosexual men, HPV, Epidemiology, Etiology, Mortality, Diagnosis, Screening, Drug Therapy, Surgical Therapy, Radio Therapy, Risk factors, ASIL. The search was limited to “human” for all searches. In the absence of enough “randomised controlled trials” the search was extended to clinical trials, reviews, and case reports. One analysis on cost effectiveness and two abstracts presented at 12th World AIDS Conference and 6th Conference on Retrovirus and Opportunistic Infections were included. The 44 publications referred to originate from the United Kingdom (9), the United States (26), and Denmark (5), with one each from Switzerland, Germany, Australia, and France. The Cochrane Database of systematic reviews yielded 11 complete reviews for “anal cancer” and none for “anal intraepithelial neoplasia.” The textbook of AIDS-related cancers and their treatment was consulted. We also included our personal experience from the treatment of patients at the Chelsea and Westminster Hospital, one of the largest centres for the management of HIV disease in Europe. Conclusion: Routine anal cytological screening followed by appropriate management of AIN is an important issue for HIV infected patients. The natural history of AIN has not been fully established and this prevents clinicians from defining clear management protocols. There is early evidence that the benefits of highly active antiretroviral therapy (HAART) in terms of restoring immune function and reducing opportunistic infections and some neoplasms may not extend to regression of AIN. Under these circumstances it might be predicted that AIN and subsequent progression to invasive anal cancer would rise as HAART prolongs the lives of seropositive people. However, routine anal cytological screening will surely have to await an effective proved intervention for AIN and this would seem to be a pressing clinical goal. Sex Transm Inf (Sex Transm Inf 2001;77:327–331)

Cytokine changes during rituximab therapy in HIV-associated multicentric Castleman disease

Recent data highlight the importance of inflammatory markers during human immunodeficiency virus type 1 (HIV) infection. HIV-associated multicentric Castleman disease (HIV-MCD) presents with systemic symptoms attributed to cytokine disarray, and we have previously shown that the use of the anti-CD20 monoclonal antibody rituximab induces clinical remissions. Before and during successful rituximab therapy, 15 plasma cytokines were measured as were adaptive (CD4, CD8, CD19) and innate (CD16/56) immune cell populations and HIV-1 viral loads. A significant reduction from baseline of the CD19 B-cell count, consistent with rituximabs mechanism of action, was observed. Markedly elevated cytokine levels were observed before rituximab therapy, and a reduction from baseline values with rituximab therapy was observed for interleukin (IL)-5, IL-6, and IL-10. Therapies that reduce the inflammatory cytokine response are likely to be successful in a range of diseases, including HIV-MCD, and in the future may be used to guide therapeutic strategies.

AIDS related systemic non-Hodgkin's lymphoma

Objective: To review the current literature on HIV associated non-Hodgkins lymphoma. Methods: A comprehensive Medline/Pubmed search of articles pertaining to HIV associated non-Hodgkins lymphoma as well as personal experience from the treatment of over 200 patients at the Chelsea and Westminster Hospital, one of the largest centres for the management of HIV disease in Europe. Conclusion: High grade B cell non-Hodgkins lymphoma is the second commonest tumour affecting people with HIV. The incidence of this tumour is not declining following the introduction of highly active antiretroviral therapy. Chemotherapy has been employed with modest success in this group of patients; however, the prognosis remains worse than for immunocompetent patients. Advances in molecular genetics and virology have led to a greater understanding of the biology of these tumours. However, these advances have yet to be translated into improvements in the clinical management of patients with AIDS associated non-Hodgkins lymphoma.