Central Nervous System non-Hodgkin Lymphoma Research Articles

CFT7455, a Novel IKZF1/3 Degrader, Demonstrates Potent Anti-Tumor Activity in Models of Non-Hodgkin's Lymphoma As a Single Agent or in Combination with Clinically Approved Agents

Immunomodulatory drugs, such as pomalidomide and lenalidomide are approved for the treatment of multiple subtypes of non-Hodgkin's lymphoma (NHL). These drugs induce an interaction between Ikaros family zinc finger proteins 1 and 3 (IKZF1/3) and cereblon (CRBN), an E3 ligase, resulting in IKZF1/3 degradation. IKZF1/3 are master transcription factors that play a key role in B and T-cell differentiation and maintain levels of interferon regulatory factor 4 (IRF4), a critical regulator in NHL. Clinically, immunomodulatory drugs have shown activity as single agents and when used in combination with several classes of targeted therapies, such as rituximab, in both first line and relapsed/refractory NHL subtypes. We previously described the preclinical characterization of CFT7455 as a novel IKZF1/3 degrader with 800-1600-fold increased potency over pomalidomide in CRBN binding and cellular IKZF1 degradation assays. We demonstrated that this increased activity translated into dramatically greater efficacy compared to pomalidomide in cellular and in vivo preclinical models of multiple myeloma and NHL. Here we show that the increased catalytic activity and improved potency of CFT7455 also translates into potent anti-tumor activity as single agent or in combination with clinically approved agents in central nervous system (CNS) and subcutaneous models of NHL. In both the Raji and OCI-Ly10 CNS xenograft models, CFT7455 (100 µg/kg/day) led to a significant increase in survival in comparison to pomalidomide (P=0.002, P=0.0002). The combination of immunomodulatory drugs with CD20, BTK, or HDAC targeting agents shows promising clinical activity in the treatment of NHL. Combination studies were conducted, dosing CFT7455 in combination with rituximab, ibrutinib, or the HDAC inhibitor romidepsin in several models of NHL. In the mantle cell lymphoma (MCL) model, Mino, the combination of CFT7455 with rituximab demonstrated synergistic activity and complete tumor regression. In the diffuse large B-cell lymphoma (DLBCL) model, TMD8, the combination of ibrutinib and CFT7455 was synergistic and resulted in a significant increase in survival probability. In the CNS NHL model, OCI-Ly10, the combination of CFT7455 with rituximab or ibrutinib also led to a significant increase in survival probability highlighting the therapeutic potential of this combination. Synergistic activity was also observed with the combination of CFT7455 and romidepsin in two models of anaplastic large cell lymphoma (ALCL). In conclusion, CFT7455 is a potent, selective catalytic degrader of IKZF1/3, with single agent and combination antitumor activity in DLBCL, ALCL, and MCL models, supporting clinical investigation of CFT7455 for NHL.

First-line high-dose therapy and autologous blood stem cell transplantation in patients with primary central nervous system non-Hodgkin lymphomas\u2014a single-centre experience in 61 patients

Primary central nervous system non-Hodgkin lymphomas (PCNS-NHLs) are extranodal B-cell lymphomas with poor prognosis. The role of high-dose therapy (HDT) followed by autologous blood stem cell transplantation (ASCT) as first-line therapy is still not clear. We retrospectively collected long-term follow up data of 61 consecutive patients with PCNS-NHL at the University Hospital Düsseldorf from January 2004 to December 2016. Thirty-six patients were treated with conventional chemoimmunotherapy (cCIT) only (CT-group). Seventeen patients received an induction cCIT followed by HDT and ASCT. In the CT-group, the overall response rate (ORR) was 61% (CR 47%, PR 14%), and there were 8% treatment-related deaths (TRD). Progression-free survival (PFS) was 31.8 months, and overall survival (OS) was 57.3 months. In the HDT-group, the ORR was 88% (59% CR, 29% PR), and there were 6% TRD. Median PFS and OS were not reached at 5 years. The 5-year PFS and OS were 64.7%. After a median follow up of 71 months, 10 patients (59%) were still alive in CR/PR following HDT and ASCT, one patient was treated for progressive disease (PD), and 7 had died (41%, 6 PD, 1 TRD). All patients achieving CR prior to HDT achieved durable CR. In the CT-group, 8 patients (22%) were alive in CR/PR after a median follow-up of 100 months. Twenty-eight patients died (78%, 24 PD, 2 TRD, 2 deaths in remission). In the univariate analysis, the HDT-group patients had significantly better PFS (not reached vs 31.8 months, p = 0.004) and OS (not reached vs 57.3 months, p = 0.021). The multivariate analysis showed HDT was not predictive for survival. Treatment with HDT + ASCT is feasible and offers the chance for long-term survival with low treatment-related mortality in younger patients. In this analysis, ORR, PFS and OS were better with HDT than with conventional cCIT alone. This result was not confirmed in the multivariate analysis, and further studies need to be done to examine the role of HDT in PCNSL.

Low grade b-cell non-Hodgkin lymphomas (NHL) involving the central nervous system (CNS): An analysis from the National Cancer Database (NCDB).

e13083 Background: CNS involvement from low grade B-cell NHL is rare and has only been reported as case series. The distribution, demographics and outcomes of patients with low grade B-cell CNS NHLs have not been well characterized. Methods: The NCDB represents ~70% of cancer cases in the United States. Using the 2004-2013 NCDB extranodal NHL database, we identified all CNS B-cell NHLs based on ICD-O-3 site and histology codes. Primary or secondary CNS involvement could not be determined. Results: Out of 9435 CNS NHL cases, 475 [5.03%] had low grade histologies. In this group, the median age at diagnosis was 58 years [range 19-89]. Majority of the cases were female [56%], White, non-Hispanic [72%], privately insured [53%], with no comorbidities [74%] and treated in academic/research programs [38%]. Site of CNS disease was not specified in 22%. HIV status was known in 318 cases (6.3% positive). The brain [44%] was the most common site of involvement followed by spinal cord [19%] and meninges [15%]. Follicular lymphoma (FL) [48%] was the most common histology overall followed by marginal zone (MZL) [37%], small lymphocytic (SLL) [8%] and lymphoplasmacytic lymphomas (LPL) [7%]. MZL was the most common histology in the brain [44%] and meninges [61%] while FL was most common in the spinal cord [77%] and nervous system, NOS [69%]. Cranial nerves and eye (retina/optic nerve) involvement was very rare [2 and 1 case each- both MZL]. The overall survival (OS) of CNS B-cell NHL was significantly better if histology was low grade vs other [5-year OS 74% vs 32%, P < 0.0001]. Among CNS low grade B-cell NHLs, 5-year OS varied by histology [MZL 83%, FL 75%, LPL 56% and SLL 50%, P = 0.0003] and site of disease [spinal cord 89%, meninges 78% and brain 63%, P = 0.03] in addition to age at diagnosis and co-morbidities on both uni- and multivariate analysis. Survival was not influenced by sex, race, insurance, year of diagnosis, facility type or location. Conclusions: CNS involvement with low grade B-cell NHL is rare but has a relatively good outcome with most patients surviving beyond 5 years. FL and MZL are the more common low grade histologies. Both histology and disease site are important factors affecting survival.

Primary Central Nervous System Lymphoma in Immunocompetent Patient

We report a case of primary central nervous system non-Hodgkin lymphoma (PCNSL) located in the right temporoparietal lobe with destruction of ethmoid and sphenoid bones in healthy immunocompetent adult. PCNSL accounts for <5% of all cases of primary intracranial neoplasms. The tumor is limited to the central neuroaxis with the absence of systemic lymphoma. For intraoperative neurosurgical consultation, the tissue is usually analyzed by touch imprint cytology and frozen section analysis. The imprint cytology is a rapid and less expensive method with better cellular morphology and fewer artifacts. The clinicopathologic findings of PCNSL in an immunocompetent woman are described herein.

Vitreoretinal Lymphoma: Changing Trends in Diagnosis and Local Treatment Modalities

To report changing trends in treatment (external beam radiation therapy (EBRT) and intravitreal chemotherapy) from a single institution and report clinical and ocular imaging findings of patients (pts) with vitreoretinal lymphoma (VRL). A retrospective chart review of pts with non-responsive uveitis and vitritis was performed. Only pts with vitreous biopsy proven lymphoma were included. Data recorded included demographics, systemic lymphoma status and treatment, ocular symptoms and clinical findings, optical coherence tomography (OCT), fluorescein angiography (FA) and immunocytological findings, treatment methods intravitreal methotrexate 300 micrograms/0.05 ml, 1000 mcg of rituximab in 0.1 cc and EBRT) and response to treatment. Ocular and systemic lymphoma outcomes at last follow-up visit were also included. Twelve eyes of 8 pts were included in the study. All 8 pts were whites. The mean age of pts was 64.5 years (range 50-83). Central nervous system non-Hodgkin lymphoma (CNS-NHL) was present in 7 of 8 pts (87.5%). Four pts had bilateral disease at presentation (50%). Most common ocular symptoms were diminution of vision in 4 and floaters in 3 pts. Prior to presentation to our center, 50% pts were treated with topical steroids and other 50% did not receive any treatment. Iritis and uveitis were seen in 6 eyes (50%) and vitritis in 11 eyes (91.7%). Retinal infiltrates were present in 8 eyes (66.7%). Two eyes had choroidal lesions (16.7%), of which one was associated with exudative retinal detachment another with papillitis. On OCT, mean central foveal thickness was 270 (range 215-371) μ with presence of cystoid macular edema was present in 2 eyes, subretinal fluid in 1 and pigment epithelial irregularities in 3 eyes. Most common FA findings were macular edema in 6 eyes (60%), perivascular leakage in 2 (20%) and no leakage in 2 eyes (20%). Vitreous biopsy revealed B cell lymphoma in all patients (100%). Immunocytologic analysis in 2 pts showed elevated levels of IL-6 (26.7 pg/ml), IL-10 (12783.5 pg/ml) and IgH gene rearrangement suggestive of lymphoma. Three pts were treated with EBRT (36-45 Gy), of which one had primary VRL. Six eyes were treated with intravitreal methotrexate (range 2-15, mean 9.7). Two pts developed marked keratitis secondary to methotrexate toxicity (33.3%), one of which received intravitreal rituximab injections for persistent vitritis. None developed rituximab related side effects. The mean duration of follow-up was 37.8 months (range 4-96). VRL had resolved in 7 eyes (58.3%) and persistent in 5 eyes (41.7%). Systemic lymphoma was in remission in 5 pts (62.5%). One pt died due to advanced CNS NHL. Intravitreal chemotherapy provided good control rates for VRL pts in our limited series. OCT and FA are superior ocular imaging helpful tools in work-up. Pts with associated CNS NHL had poorer outcomes.

Vitreoretinal Lymphoma: Changing Trends in Diagnosis and Local Treatment Modalities at a Single Institution

In this retrospective study on vitreoretinal lymphoma, there was significant change in diagnosis and treatment trends over 17 years at a single institution. Fine needle aspiration biopsy had replaced vitrectomy to collect vitreous sample and external beam radiotherapy in combination with systemic chemotherapy was replaced by intravitreal methotrexate and rituximab, which regressed vitreoretinal lymphoma (VRL) with no relapses or major ocular complications. The purpose of this study was to report the changing trends in treatment (external beam radiotherapy [EBRT] and intravitreal chemotherapy) of VRL and treatment outcomes at a single institution. A retrospective chart review of vitreous biopsy proven patients was performed. The data analysis included demographics, systemic lymphoma status, ocular symptoms, clinical and immunocytological findings, treatment methods, and response (intravitreal methotrexate 300 μg/0.05 mL, 1000 μg/0.1 mL of rituximab and EBRT 36-45 Gy) and ocular and systemic lymphoma outcomes at last follow-up. Twelve eyes of 8 patients had intraocular B-cell lymphoma (median age, 61 years; range, 50-83). Central nervous system non-Hodgkin's lymphoma (CNS-NHL) was present in 7 of 8 patients. Most common ocular symptoms were diminution of vision in 4 and floaters in 3 patients. Iritis and uveitis were found in 6 eyes and vitritis in 11 eyes. Retinal infiltrates were present in 8 eyes. Immunocytology revealed elevated levels of interleukin (IL)-10 (12,783.5 pg/mL), IL-6 (26.7 pg/mL), and IgH gene rearrangement. Three patients were treated with EBRT, 6 eyes with intravitreal methotrexate (median, 9.5; range, 2-15), and 2 eyes with intravitreal rituximab injections (median, 4; range, 2-6). Two patients developed marked keratitis because of methotrexate toxicity. At median follow-up of 33.5 months (range, 4-96), VRL had resolved in 7 eyes and persistent in 5 eyes. One patient died because of advanced CNS-NHL. Intravitreal chemotherapy provided good control rates for VRL patients in our limited series. Patients with associated CNS-NHL had poorer outcomes.

Autologous Stem Cell Transplantation with Thiotepa, Busulfan, and Cyclophosphamide (TBC) Conditioning in Patients with CNS Involvement by Non-Hodgkin Lymphoma

Primary central nervous system non-Hodgkin lymphoma (PCNSL) carries a poor prognosis and, although it responds to chemotherapy, fewer than 20% of patients are long-term disease-free survivors. Secondary CNS non-Hodgkin lymphoma (SCNSL) has an even worse prognosis with a median survival of only months and very few reported long-term survivors. For both of these groups of patients, there has been interest in using high-dose chemotherapy with autologous stem cell transplantation (ASCT) following conditioning with thiotepa, busulfan, and cyclophosphamide (TBC). We performed a retrospective review (from 2006-2010) of 32 patients from the Dana-Farber Cancer Institute and Massachusetts General Hospital with PCNSL or SCNSL who underwent ASCT with TBC conditioning. Of the 32 patients, 56% received TBC/ASCT after achieving brain magnetic resonance imaging (MRI) and/or cerebrospinal fluid complete response in brain, and 44% of patients were treated with TBC/ASCT in the setting of measurable CNS disease. The 100-day transplant-related mortality rate was only 3%. The most common nonhematologic grade 3 or 4 toxicity was mucositis, which occurred in 73% of patients. Notably, there was only 1 patient with prolonged significant neurologic toxicity that manifested as ataxia and dysphagia. The 1-year OS estimate is 93% (95% confidence interval [CI]: 75%-98%), and the 1-year progression-free survival (PFS) estimate is 90% (95% CI: 72%-96%) from the date of transplantation. Although these outcomes are encouraging, longer follow-up is required and comparison with other traditional ASCT regimens used for patients with non-Hodgkin lymphoma (NHL) is warranted.

Use of F-18 FDG PET/CT in Non-Hodgkin Lymphoma With Central Nervous System Involvement

Central nervous system (CNS) is a rare site of involvement by non-Hodgkin lymphoma (NHL). Therapeutic approach for primary and secondary CNS NHL is different and remains challenging. Therefore imaging data are essential at staging to discriminate these 2 clinical entities and during follow-up to assess therapy response. The adjunct role of positron emission tomography using F-18 fluorodeoxyglucose to morphologic imaging is still undefined. We report 2 didactic cases of primary and secondary CNS NHL assessed by F-18 fluorodeoxyglucose positron emission tomography. Metabolic imaging seems to be complementary to conventional imaging techniques for the extent-of-disease evaluation and therapy monitoring of CNS lesions.

The effect of HAART and calendar period on Kaposi's sarcoma and non-Hodgkin lymphoma: results of a match between an AIDS and cancer registry

To assess the impact of HAART use on AIDS-defining Kaposi's sarcoma and non-Hodgkin lymphoma (NHL) among adults with AIDS. Registry linkage study. Adults diagnosed with AIDS from 1990 to 2000 in the San Francisco AIDS case registry were matched with cancer cases diagnosed from 1985 to 2002 in the California Cancer Registry. Multivariate Cox proportional hazard models were used to evaluate the risk and survival of AIDS-related Kaposi's sarcoma, systemic NHL, and primary central nervous system (CNS) lymphoma. Of the 14 183 adults with AIDS, 3028 were diagnosed with Kaposi's sarcoma, 776 with systemic NHL, and 254 with CNS NHL. After adjustment for potential confounders, more recent calendar period and use of HAART were significantly associated with a decreased risk of Kaposi's sarcoma, whereas HAART use but not calendar period was significantly associated with systemic and CNS NHL. In adjusted analysis of Kaposi's sarcoma survival time, there was strong evidence of a reduced risk of death associated with HAART use and more recent calendar period. In contrast, in adjusted analyses of systemic NHL survival time, HAART use was not associated with improved survival time; however, calendar period was associated with longer survival. In adjusted analysis of CNS NHL survival time, only cancer treatment was associated with a longer survival time. After controlling for calendar period and other confounders, use of HAART decreased the risk of Kaposi's sarcoma, systemic NHL, and CNS NHL. Use of HAART also increased Kaposi's sarcoma survival time but not NHL survival time.

Underestimation of Relative Risks by Standardized Incidence Ratios for AIDS-Related Cancers

Registry-based studies provide valuable data regarding cancer risk among people with HIV/AIDS (PWHA). Such studies utilize the standardized incidence ratio (SIR) to estimate the relative risk (RR), an etiologically relevant measure. However, SIR may underestimate RR when HIV/AIDS prevalence in the general population or RR is high. We quantified the extent of this underestimation for 3 AIDS-related cancers: Kaposi sarcoma (KS), central nervous system non-Hodgkin lymphoma (CNS NHL) and cervical cancer. We used data on cancer risk among PWHA from the U.S. HIV/AIDS Cancer Match Study. SIRs were compared with RRs estimated using two methods: (1) SIRs calculated using pre-AIDS era (1973-1979) cancer incidence rates (SIRpre-AIDS) and (2) SIRs calculated after subtraction of cancers known to be among PWHA from general population rates (SIRexclusion). For KS and CNS NHL, SIRs (117.8 and 133.9, respectively) calculated using overall general population rates substantially underestimated both SIRpre-AIDS (19,778 and 3,612, respectively) and SIRexclusion (657.7 and 536.4, respectively). In contrast, the extent of underestimation was negligible for cervical cancer (SIR = 4.9 vs. SIRexclusion = 5.1). For KS and CNS NHL, SIRs were higher in females than in males. However, SIRpre-AIDS and SIRexclusion estimates were more similar, indicating that SIR differences artifactually reflect differences in HIV/AIDS prevalence between males and females. For KS and CNS NHL, trends across calendar time were weaker in SIRs than in SIRpre-AIDS and SIRexclusion. For KS and CNS NHL, SIRs substantially underestimate RRs. This underestimation arises from the exceptionally high relative risk of KS and CNS NHL among PWHA. SIRs must be interpreted cautiously when HIV/AIDS prevalence is high or varies across groups of interest.

AIDS-Related Cancer and Severity of Immunosuppression in Persons With AIDS

The incidence of Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer has been declining among persons with AIDS. We investigated the association between cancer risk and CD4 cell count among such persons. Data from US AIDS registries were linked to local cancer registry data. Cancer incidence per 100,000 person-years was determined for the 4-27 months from the onset of AIDS from January 1, 1990, through December 31, 1995--before highly active antiretroviral therapy (HAART) became available--and from January 1, 1996, through December 31, 2002. The relationships between CD4 count at AIDS onset and cancer incidence were assessed by proportional hazards models. Among 325,516 adults with AIDS, the incidence of Kaposi sarcoma was lower in 1996-2002 (334.6 cases per 100,000 person-years) than in 1990-1995 (1838.9 cases per 100,000 person-years), and the incidence of non-Hodgkin lymphoma followed a similar pattern (i.e., 390.1 cases per 100,000 person-years in 1996-2002 and 1066.2 cases per 100,000 person-years in 1990-1995). In 1996-2002, for each decline in CD4 cell count of 50 cells per microliter of blood, increased risks were found for Kaposi sarcoma (hazard ratio [HR] = 1.40, 95% confidence interval [CI] = 1.33 to 1.50), for central nervous system non-Hodgkin lymphoma subtypes (HR = 1.85, 95% CI = 1.58 to 2.16), and for non-central nervous system diffuse large B-cell lymphoma (HR = 1.12, 95% CI = 1.04 to 1.20) but not for non-central nervous system Burkitt lymphoma (HR = 0.93, 95% CI = 0.81 to 1.06). Cervical cancer incidence was higher in 1996-2002 (86.5 per 100,000 person-years) than in 1990-1995 (64.2 per 100,000 person-years), although not statistically significantly so (relative risk [RR] = 1.41, 95% CI = 0.81 to 2.46). After adjustment for age, race, and sex or mode of HIV exposure, the risks for Kaposi sarcoma (RR = 0.22, 95% CI = 0.20 to 0.24) and for non-Hodgkin lymphoma (RR = 0.40, 95% CI = 0.36 to 0.44) were lower in the period of 1996-2002 than in 1990-1995. Similar relationships of these cancers to CD4 count were observed for 1990-1995. Both before and after HAART was available, CD4 count was strongly associated with risks for Kaposi sarcoma and non-Hodgkin lymphoma but not for cervical cancer and Burkitt lymphoma. The decreasing incidences of most AIDS-associated cancers in persons with AIDS during the 1990s are consistent with improving CD4 counts after HAART introduction in 1996.

Highly Active Antiretroviral Therapy is Associated with Improved Survival among Patients with AIDS-Related Primary Central Nervous System Non-Hodgkins Lymphoma

Highly active retroviral therapy (HAART) has been in widespread use in the United States since 1996. We sought to determine how the use of HAART influenced survival among patients with acquired immunodeficiency syndrome (AIDS) and primary central nervous system (CNS) non-Hodgkin's lymphoma (NHL). We used the population-based San Diego and Orange County cancer registry to identify 94 patients with both AIDS and CNS NHL diagnosed 1994-1999, of whom 31 were diagnosed 1996-1999. We performed Kaplan-Meier analyses to compare survival between patients who received HAART at NHL diagnosis or thereafter versus untreated patients and Cox proportional hazard models for adjusted survival. Among the patients diagnosed with NHL in 1996-1999, seven (23%) were taking HAART at the time of NHL diagnosis. Median survival was eight months for those who received HAART at the time of lymphoma diagnosis or after, versus one month for untreated patients. HAART, radiation therapy, and better performance status were associated with improved survival. We conclude that HAART prolongs survival in AIDS-related CNS NHL.

Primary central nervous system non-Hodgkin lymphoma in childhood presenting as bilateral optic neuritis

Primary central nervous system lymphoma is a very rare condition in pediatric patients. We describe the case of a 10-year old girl who presented with acute bilateral vision impairment. At the time of presentation, the only positive finding was optic disk swelling, and the brain MRI scan was normal. Seventeen months later, she developed a large-cell non-Hodgkin lymphoma in the brain, with no evidence of neoplasia elsewhere. Immunodeficiencies and Epstein-Barr virus infection could not be demonstrated. The patient was successfully treated with a combination of cyclophosphamide, etoposide, vincristine, methotrexate, and cytarabine, plus intrathecal chemotherapy. Craniospinal irradiation was not used. The patient's condition is still in remission 68 months after completing the treatment. This case is the only non-Hodgkin lymphoma with primary central nervous system location treated in our institution in the last 10 years and represents less than 0.5% of our non-Hodgkin lymphoma series. Due to its rare occurrence, not much is known about the clinical features and treatment outcome of primary central nervous system lymphoma in pediatric patients.

Changes in acquired immunodeficiency syndrome‐related non‐Hodgkin lymphoma in the era of highly active antiretroviral therapy

The authors sought to determine whether the availability of highly active antiretroviral therapy (HAART) coincided with changes in the epidemiology of acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). Cancer registry data from 1988-2000 were linked with AIDS registry data from 1981 to July 2003 for San Diego County to identify 537 AIDS-NHL patients. By using the total number of patients with AIDS who were alive as of July 1 annually as the AIDS population denominator, the average annual incidence of NHL was estimated among patients with AIDS for the pre-HAART period (1988-1995) and post-HAART period (1996-2000). The chi-square test was used to compare proportions, and a Cox proportional hazards model was used to compare survival between the pre-HAART and post-HAART periods. The incidence of NHL decreased from 29.6 per 1000 person-years pre-HAART to 6.5 per 1000 person-years post-HAART. The proportion of patients who had NHL of central nervous system (CNS) origin decreased from 28% pre-HAART to 17% post-HAART. Among patients with systemic NHL, 54% received chemotherapy pre-HAART, and 72% received chemotherapy post-HAART. The percentage of intermediate-grade NHL increased from 33% pre-HAART to 49% post-HAART, and the percentage of high-grade NHL decreased from 38% to 19%, respectively. A diagnosis of human immunodeficiency virus infection preceding the NHL diagnosis and Stage IV NHL were associated with worse survival, whereas a diagnosis of NHL in the post-HAART period and chemotherapy were associated with better survival. The median survival was 4 months pre-HAART and 9 months post-HAART. Since the introduction of HAART, there has been a decrease in the incidence of systemic and CNS NHL among patients with AIDS. Among patients with systemic, AIDS-related NHL, there has been decreased high-grade histology, increased use of chemotherapy, and improved survival.

The epidemiology of non-Hodgkin lymphoma

Non-Hodgkin lymphoma (NHL) includes a group of more than 20 different malignant lymphoproliferative diseases that originate from lymphocytes. Rates of NHL have increased dramatically over the past few decades, although the rate of increase has recently slowed. It is now the sixth most common cancer in Australia. Globally, it is somewhat more common in men than in women, and rates are highest in North America and Australia. The causes of the increase in NHL rates are largely unknown. The best described risk factor for NHL is immune deficiency; rates of NHL are greatly increased, with relative risks of 10-100 or more, in people with immune deficiency associated with immune suppressive therapy after transplantation, HIV/AIDS, and congenital conditions. In addition, some NHL subtypes are associated with specific infections. These include immune-deficiency-associated central nervous system NHL (Epstein-Barr virus); gastric mucosa-associated lymphoid tissue NHL (Helicobacter pylori); adult T-cell leukemia/lymphoma (human T-lymphotrophic virus type 1) and body cavity-based lymphoma (human herpesvirus 8). However, these specific infections account for a very small proportion of total NHL incidence. In addition to immune deficiency and infection, other immune-related conditions are increasingly being recognised as related to NHL risk. Specific autoimmune conditions, including rheumatoid arthritis, systemic lupus erythema, Sjogren's syndrome, psoriasis and coeliac disease are associated with moderately increased risk of NHL. On the other hand, allergic and atopic conditions and their correlates such as early birth order, appear to be associated with a decreased risk of NHL.A variety of other exposures are less strongly related to NHL risk. These include occupational exposures, including some pesticides, herbicides, and solvents. Recently, two studies have reported that sun exposure is associated with a decreased risk of NHL. Smoking appears to be weakly positively associated with risk of follicular NHL, and alcohol intake is associated with a decreased risk of NHL. The pooled analysis of several case-control studies of NHL risk that are currently in the field promises to help clarify which of these risk factors are real, and will contribute to the elucidation of the mechanisms of how disorders of the immune system, and other factors, are related to NHL risk.

Clinical features and predictors of survival of AIDS-related non-Hodgkin's lymphoma in a population-based case series in Sydney, Australia.

To analyse clinical features and predictors of survival for AIDS-related non-Hodgkin's lymphoma (NHL) in the era of highly active antiretroviral therapy (HAART), compared to earlier in the HIV epidemic. All AIDS-NHL cases diagnosed at three inner Sydney hospitals caring for people with AIDS during 1985-2001 were identified through medical record searches. Demographic, clinical, immunological and histopathological information was recorded. Year of NHL diagnosis was grouped into three periods, corresponding to whether monotherapy (1985-1991), dual therapy (1992-1995) or HAART (1996-2001) was the main treatment for HIV infection. Statistical comparisons were made between the pre-HAART and post-HAART eras. Three hundred cases of AIDS-NHL were identified. Divergent trends were identified for systemic and primary central nervous system (CNS) NHL. For systemic NHL, the CD4 count at NHL diagnosis increased markedly to 208 cells/microL in the post-HAART era (P=0.014) and there was a trend towards presentation as the first AIDS-defining illness (69%, P=0.053), and as earlier stage NHL disease (42%, P=0.048). Median survival time increased from 4.2 months in 1985-1991 to 19 months in the post-HAART era (P<0.001). In a multivariate model, predictors of poor survival from systemic NHL included: NHL diagnosis after another AIDS-defining illness (P<0.001), stage 4 NHL (P<0.001), presentation at extra lymphatic sites (P=0.001), and nonreceipt of chemotherapy (P=0.002). After adjusting for the factors, those diagnosed in the era of HAART had a significant 56% reduction in rate of death (P<0.001). In contrast, for CNS NHL, clinical features were little changed and survival did not improve in the era of HAART. Systemic NHL is presenting earlier in the course of HIV disease, and at a less advanced NHL stage. There has been a marked improvement in survival in the era of HAART even after adjustment for other prognostic variables. In contrast, primary CNS NHL remains a disease which presents late in the course of HIV infection and is associated with a very poor prognosis.

Primary leptomeningeal lymphoma in a patient with concomitant CD4+ lymphocytopenia

Idiopathic CD4+ lymphocytopenia (ICL) is a rare disorder in which patients have mild and/or severe opportunistic infections or maybe without symptoms. The etiology is currently unknown. Diagnosis is made by excluding retroviral infections (human immunodeficiency virus-1 or -2, human T cell lymphotropic virus-1 or -2) or other known causes of immunosuppression. To provide a case report of a patient with possible ICL who presented with a rare form of primary non-Hodgkin lymphoma (NHL) of the central nervous system (CNS). Review of the literature has identified only five other patients with NHL and ICL; however, none of these had a CNS lymphoma. We describe a patient with possible ICL, and address links between lymphopenia and lymphoproliferative disorders. Although not uncommon for patients infected with human immunodeficiency virus to develop CNS NHL, this is the first case of a possible ICL patient with such a lymphoma. This case revisits an important relationship between lymphopenia and lymphoproliferative disorders.

HIV-associated lymphomas.

Intermediate and high-grade non-Hodgkin lymphomas (NHL) with a B-cell phenotype are AIDS-defining illnesses. The incidence of systemic NHL is over 100 times increased, primary central nervous system NHL is over 3000 times increased, and Hodgkin's disease is approximately 10 times increased in the HIV-infected population. Unusual extranodal presentations of NHL and Hodgkin's disease are seen in HIV-infected individuals. High-grade histologies are common for both NHL and Hodgkin's disease in the HIV setting. Treatment approaches may be changing with the advent of highly active antiretroviral therapy, which may allow patients to tolerate more intensive treatment.

Systemic non-Hodgkin's lymphoma presenting as a serpiginous choroidopathy: Report of a case and review of the literature

Intraocular lymphoma is a rare tumour, the two main types being primary central nervous system non-Hodgkin's lymphoma (CNS-NHL) and, less commonly, systemic lymphoma that has spread to involve the eye. We present a case of a systemic NHL resulting in a serpiginous choroidopathy. To our knowledge, this presentation has not previously been reported. The diagnosis of this case was made based on the temporal relationship between the clinical activity of the choroidopathy and its response to chemotherapy. Diagnosis of intraocular lymphoma on vitreous biopsy is notoriously difficult, and this case is presented along with a review of the literature regarding vitreous biopsy and diagnostic techniques.

High-dose therapy with hematopoietic cell transplantation for patients with central nervous system involvement by non-Hodgkin's lymphoma

Central nervous system (CNS) involvement by non-Hodgkin's lymphoma (NHL) carries a poor patient prognosis whether it occurs as a primary site of disease or secondarily in patients with systemic disease. In a group of 481 patients undergoing high-dose therapy with hematopoietic cell transplantation (HCT) for NHL, 15 patients (3.1%) were identified with CNS involvement. Two patients had primary CNS lymphoma, and 13 had secondary disease. All patients received intrathecal chemotherapy, and 13 received CNS radiotherapy before transplantation. Fourteen patients received systemic chemotherapy. At the time of transplantation, both patients with primary CNS lymphoma and 8 patients with secondary disease had achieved a complete response, 3 patients had achieved a partial response, 1 had failed induction therapy, and 1 had progression of CNS disease before high-dose therapy. Fourteen patients received carmustine, etoposide, and cyclophosphamide as the preparative regimen, and 1 patient received fractionated total body irradiation instead of carmustine. The 2 patients with primary CNS lymphoma were alive and free of disease, 1 at 1,085 days after HCT and 1 at 3,704 days after HCT. The actuarial 5-year event-free survival (EFS) was 46% +/- 26%, and overall survival (OS) was 41% +/- 28%. The median EFS and OS were 2.2 and 1.5 years, respectively. Three patients experienced symptomatic memory loss or intellectual decline after therapy, 1 patient developed paraplegia, and 1 patient had a thrombotic stroke 20 months after HCT. Despite treatment-related toxicities, 7 patients responding to quality-of-life questions at approximately 1 year after HCT gave their overall quality of life a median rating of 9 out of a possible 10 (range, 6-10). High-dose therapy with autologous HCT can produce extended EFS in patients with secondary CNS lymphoma and possibly in those with primary CNS NHL. Biol Blood Marrow Transplant 2000;6(3A):352-8.