EBV-positive PCNSL in older patients: incidence, characteristics, tumor pathology, and outcomes across a large multicenter cohort.

The objective of this multicenter retrospective study was to examine the incidence, patient characteristics, pathology, and outcomes associated with Epstein-Barr virus (EBV)-related CNS lymphoma (CNSL) in older patients. Among 309 CNSL patients aged ≥60, 11.7% had EBV + tumors of which 72.2% were solid organ transplant (SOT)-related post-transplant lymphoproliferative disorders (PTLD). Younger age, SOT or autoimmune disease, and immunosuppressive treatment correlated highly with EBV-positivity. EBV + tumors were associated with absent C-MYC and BCL6 expression. EBV + PTLD was more likely to be associated with the absence of CD5 expression. EBV + non-PTLD had better median OS (not reached) compared to EBV + PTLD (10.8 months) and EBV-negative patients (43 months). Multivariable Cox regression analysis showed that age, performance status, and PTLD were negative predictors of OS. EBV status and immunosuppressive treatment were not correlated with OS. Our findings merit further investigation of EBV + PCNSL tumors and EBV-directed therapies.

Older patients with primary central nervous system lymphoma: Survival and prognostication across 20 U.S. cancer centers.

There is a paucity of large-scale data delineating outcomes and prognostication of older patients with primary central nervous system lymphoma (PCNSL). We retrospectively analyzed 539 newly-diagnosed PCNSL patients ages ≥60 years across 20 U.S. academic centers. The median age was 70 years (range 60-88); at least one geriatric syndrome was present in 46%; the median Cumulative Index Ratings Scale-Geriatrics (CIRS-G) score was 6 (range, 0-27); and 36% had impairment in activities of daily living (ADL). The most common induction regimens were high-dose methotrexate (HD-MTX) ± rituximab; methotrexate, temozolomide, rituximab (MTR); and rituximab, methotrexate, procarbazine, vincristine (R-MPV). Overall, 70% of patients achieved remission, with 14% undergoing consolidative autologous stem cell transplant (ASCT) and 24% receiving maintenance. With 58-month median follow-up, median progression-free survival (PFS) and overall survival (OS) were 17 months (95% CI 13-22 months) and 43 months (95% CI 31-56 months), respectively. Three-year PFS and OS were highest with MTR (55% and 74%, respectively). With single-agent methotrexate ± rituximab, 3-year PFS and OS were 30% (p = .0002) and 47% (p = .0072). On multivariate analysis, increasing age at diagnosis and Cooperative Oncology Group (ECOG) performance status (PS) was associated with inferior PFS; age, hypoalbuminemia, higher CIRS-G score, and ECOG PS adversely affected OS. Among patients receiving maintenance, 3-year PFS was 65% versus 45% without maintenance (p = 0.02), with 3-year OS of 84% versus 61%, respectively (p = .0003). Altogether, outcomes in older PCNSL patients appeared optimized with HD-MTX combination induction regimens and maintenance therapy. Furthermore, several prognostic factors, including geriatric measures, were associated with inferior outcomes.

HIV-associated Burkitt lymphoma: outcomes from a US-UK collaborative analysis.

Data addressing prognostication in patients with HIV related Burkitt lymphoma (HIV-BL) currently treated remain scarce. We present an international analysis of 249 (United States: 140; United Kingdom: 109) patients with HIV-BL treated from 2008 to 2019 aiming to identify prognostic factors and outcomes. With a median follow up of 4.5 years, the 3-year progression-free survival (PFS) and overall survival (OS) were 61% (95% confidence interval [CI] 55% to 67%) and 66% (95%CI 59% to 71%), respectively, with similar results in both countries. Patients with baseline central nervous system (CNS) involvement had shorter 3-year PFS (36%) compared to patients without CNS involvement (69%; P < .001) independent of frontline treatment. The incidence of CNS recurrence at 3 years across all treatments was 11% with a higher incidence observed after dose-adjusted infusional etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide (DA-EPOCH) (subdistribution hazard ratio: 2.52; P = .03 vs other regimens) without difference by CD4 count 100/mm3. In multivariate models, factors independently associated with inferior PFS were Eastern Cooperative Oncology Group (ECOG) performance status 2-4 (hazard ratio [HR] 1.87; P = .007), baseline CNS involvement (HR 1.70; P = .023), lactate dehydrogenase >5 upper limit of normal (HR 2.09; P < .001); and >1 extranodal sites (HR 1.58; P = .043). The same variables were significant in multivariate models for OS. Adjusting for these prognostic factors, treatment with cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) was associated with longer PFS (adjusted HR [aHR] 0.45; P = .005) and OS (aHR 0.44; P = .007). Remarkably, HIV features no longer influence prognosis in contemporaneously treated HIV-BL.

Outcomes of Burkitt lymphoma with central nervous system involvement: evidence from a large multicenter cohort study.

Central nervous system (CNS) involvement in Burkitt lymphoma (BL) poses a major therapeutic challenge, and the relative ability of contemporary regimens to treat CNS involvement remains uncertain. We described prognostic significance of CNS involvement and incidence of CNS recurrence/progression after contemporary immunochemotherapy using real-world clinicopathologic data on adults with BL diagnosed between 2009 and 2018 across 30 US institutions. We examined associations between baseline CNS involvement, patient characteristics, complete response (CR) rates, and survival. We also examined risk factors for CNS recurrence. Nineteen percent (120/641) of patients (age 18-88 years) had CNS involvement. It was independently associated with HIV infection, poor performance status, involvement of ≥2 extranodal sites, or bone marrow involvement. First-line regimen selection was unaffected by CNS involvement (P=0.93). Patients with CNS disease had significantly lower rates of CR (59% versus 77% without; P<0.001), worse 3-year progression-free survival (adjusted hazard ratio [aHR], 1.53, 95% confidence interval [CI], 1.14-2.06, P=0.004) and overall survival (aHR, 1.62, 95%CI, 1.18-2.22, P=0.003). The 3-year cumulative incidence of CNS recurrence was 6% (95%CI, 4-8%). It was significantly lower among patients receiving other regimens (CODOX-M/IVAC, 4%, or hyperCVAD/MA, 3%) compared with DA-EPOCH-R (13%; adjusted sub-HR, 4.38, 95%CI, 2.16-8.87, P<0.001). Baseline CNS involvement in BL is relatively common and portends inferior prognosis independent of first-line regimen selection. In real-world practice, regimens with highly CNS-penetrant intravenous systemic agents were associated with a lower risk of CNS recurrence. This finding may be influenced by observed suboptimal adherence to the strict CNS staging and intrathecal therapy procedures incorporated in DA-EPOCH-R.

Burkitt lymphoma in the modern era: real-world outcomes and prognostication across 30 US cancer centers.

We examined adults with untreated Burkitt lymphoma (BL) from 2009 to 2018 across 30 US cancer centers. Factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate Cox models. Among 641 BL patients, baseline features included the following: median age, 47 years; HIV+, 22%; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to 4, 23%; >1 extranodal site, 43%; advanced stage, 78%; and central nervous system (CNS) involvement, 19%. Treatment-related mortality was 10%, with most common causes being sepsis, gastrointestinal bleed/perforation, and respiratory failure. With 45-month median follow-up, 3-year PFS and OS rates were 64% and 70%, respectively, without differences by HIV status. Survival was better for patients who received rituximab vs not (3-year PFS, 67% vs 38%; OS, 72% vs 44%; P < .001) and without difference based on setting of administration (ie, inpatient vs outpatient). Outcomes were also improved at an academic vs community cancer center (3-year PFS, 67% vs 46%, P = .006; OS, 72% vs 53%, P = .01). In multivariate models, age ≥ 40 years (PFS, hazard ratio [HR] = 1.70, P = .001; OS, HR = 2.09, P < .001), ECOG PS 2 to 4 (PFS, HR = 1.60, P < .001; OS, HR = 1.74, P = .003), lactate dehydrogenase > 3× normal (PFS, HR = 1.83, P < .001; OS, HR = 1.63, P = .009), and CNS involvement (PFS, HR = 1.52, P = .017; OS, HR = 1.67, P = .014) predicted inferior survival. Furthermore, survival varied based on number of factors present (0, 1, 2 to 4 factors) yielding 3-year PFS rates of 91%, 73%, and 50%, respectively; and 3-year OS rates of 95%, 77%, and 56%, respectively. Collectively, outcomes for adult BL in this real-world analysis appeared more modest compared with results of clinical trials and smaller series. In addition, clinical prognostic factors at diagnosis identified patients with divergent survival rates.

Activated Ras alters lens and corneal development through induction of distinct downstream targets.

BACKGROUND: Mammalian Ras genes regulate diverse cellular processes including proliferation and differentiation and are frequently mutated in human cancers. Tumor development in response to Ras activation varies between different tissues and the molecular basis for these variations are poorly understood. The murine lens and cornea have a common embryonic origin and arise from adjacent regions of the surface ectoderm. Activation of the fibroblast growth factor (FGF) signaling pathway induces the corneal epithelial cells to proliferate and the lens epithelial cells to exit the cell cycle. The molecular mechanisms that regulate the differential responses of these two related tissues have not been defined. We have generated transgenic mice that express a constitutively active version of human H-Ras in their lenses and corneas. RESULTS: Ras transgenic lenses and corneal epithelial cells showed increased proliferation with concomitant increases in cyclin D1 and D2 expression. This initial increase in proliferation is sustained in the cornea but not in the lens epithelial cells. Coincidentally, cdk inhibitors p27Kip1 and p57Kip2 were upregulated in the Ras transgenic lenses but not in the corneas. Phospho-Erk1 and Erk2 levels were elevated in the lens but not in the cornea and Spry 1 and Spry 2, negative regulators of Ras-Raf-Erk signaling, were upregulated more in the corneal than in the lens epithelial cells. Both lens and corneal differentiation programs were sensitive to Ras activation. Ras transgenic embryos showed a distinctive alteration in the architecture of the lens pit. Ras activation, though sufficient for upregulation of Prox1, a transcription factor critical for cell cycle exit and initiation of fiber differentiation, is not sufficient for induction of terminal fiber differentiation. Expression of Keratin 12, a marker of corneal epithelial differentiation, was reduced in the Ras transgenic corneas. CONCLUSIONS: Collectively, these results suggest that Ras activation a) induces distinct sets of downstream targets in the lens and cornea resulting in distinct cellular responses and b) is sufficient for initiation but not completion of lens fiber differentiation.