Fibrin-Associated Large B-Cell Lymphoma (FA-LBCL) Involving Solid Organs as Necrotic Cystic Lesions-A Rare Entity with Potential Diagnostic Pitfalls: A Two-Case Series and Review of the Literature.

Fibrin-associated large B-cell lymphoma (FA-LBCL) is a rare subtype of Epstein-Barr virus (EBV)-associated lymphoma, recognized as an independent entity per the 5th edition of the WHO classification of hematolymphoid neoplasms. It is usually associated with longstanding chronic inflammation and arises within fibrinous material in confined anatomic spaces. We report the clinicopathologic manifestations of two patients of FA-LBCL involving the adrenal gland and kidney. Both tumors were diagnosed after presenting as cystic masses on imaging studies. These lymphomas were non-invasive, with microscopic aggregates of large B-lymphoma cells along/within cystic wall and admixed with fibrinous material and without prominent inflammation. By immunohistochemistry and in-situ hybridization, lymphoma cells were positive for CD45, PAX5, CD79a, MUM1, BCL2, PD-L1, and EBV/EBER (Epstein-Barr virus encoded small RNA) with a high proliferation index. Both patients remain in remission after management with complete surgical resection and additional chemo-immunotherapy in one patient. Considering its rarity, scant tumor cells, and varied clinical presentations, FA-LBCL may pose diagnostic challenges, especially when presenting as extensively necrotic cystic lesions, needing multidisciplinary collaboration in formulating management.

Current and potential roles of immuno-PET/-SPECT in CAR T-cell therapy.

Chimeric antigen receptor (CAR) T-cell therapies have evolved as breakthrough treatment options for the management of hematological malignancies and are also being developed as therapeutics for solid tumors. However, despite the impressive patient responses from CD19-directed CAR T-cell therapies, ~ 40%-60% of these patients' cancers eventually relapse, with variable prognosis. Such relapses may occur due to a combination of molecular resistance mechanisms, including antigen loss or mutations, T-cell exhaustion, and progression of the immunosuppressive tumor microenvironment. This class of therapeutics is also associated with certain unique toxicities, such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and other "on-target, off-tumor" toxicities, as well as anaphylactic effects. Furthermore, manufacturing limitations and challenges associated with solid tumor infiltration have delayed extensive applications. The molecular imaging modalities of immunological positron emission tomography and single-photon emission computed tomography (immuno-PET/-SPECT) offer a target-specific and highly sensitive, quantitative, non-invasive platform for longitudinal detection of dynamic variations in target antigen expression in the body. Leveraging these imaging strategies as guidance tools for use with CAR T-cell therapies may enable the timely identification of resistance mechanisms and/or toxic events when they occur, permitting effective therapeutic interventions. In addition, the utilization of these approaches in tracking the CAR T-cell pharmacokinetics during product development and optimization may help to assess their efficacy and accordingly to predict treatment outcomes. In this review, we focus on current challenges and potential opportunities in the application of immuno-PET/-SPECT imaging strategies to address the challenges encountered with CAR T-cell therapies.

Primary central nervous system lymphoma: a real-world comparison of therapy access and outcomes by hospital setting.

Background: This study analyzes sociodemographic barriers for primary CNS lymphoma (PCNSL) treatment and outcomes at a public safety-net hospital versus a private tertiary academic institution. We hypothesized that these barriers would lead to access disparities and poorer outcomes in the safety-net population. Methods: We reviewed records of PCNSL patients from 2007-2020 (n = 95) at a public safety-net hospital (n = 33) and a private academic center (n = 62) staffed by the same university. Demographics, treatment patterns, and outcomes were analyzed. Results: Patients at the safety-net hospital were significantly younger, more commonly Black or Hispanic, and had a higher prevalence of HIV/AIDS. They were significantly less likely to receive induction chemotherapy (67% vs 86%, P = .003) or consolidation autologous stem cell transplantation (0% vs. 47%, P = .001), but received more whole-brain radiation therapy (35% vs 16%, P = .001). Younger age and receiving any consolidation therapy were associated with improved progression-free (PFS, P = .001) and overall survival (OS, P = .001). Hospital location had no statistical impact on PFS (P = .725) or OS (P = .226) on an age-adjusted analysis. Conclusions: Our study shows significant differences in treatment patterns for PCNSL between a public safety-net hospital and an academic cancer center. A significant survival difference was not demonstrated, which is likely multifactorial, but likely was positively impacted by the shared multidisciplinary care delivery between the institutions. As personalized therapies for PCNSL are being developed, equitable access including clinical trials should be advocated for resource-limited settings.

A Combined Biomarker of Bright CD38 and MYC ≥55% Is Highly Predictive of Double-/Triple-Hit High-Grade B-Cell Lymphoma.

OBJECTIVES: Diagnosis of high-grade B-cell lymphoma with MYC and BCL2 or BCL6 rearrangements (double-/triple-hit lymphoma [DTHL]) appears to mandate fluorescence in situ hybridization (FISH) testing for all large B-cell lymphoma (LBCL). Given the low incidence of DTHL, we aimed to identify flow cytometry (FC) and immunohistochemistry (IHC) features of DTHL that could be used to develop an optimal screening strategy. This combined FC-IHC approach has not yet been studied. METHODS: We compared features of 40 cases of DTHL and 39 cases of diffuse LBCL (DLBCL) without MYC rearrangement. RESULTS: Bright CD38 expression (CD38bright) by FC, high MYC expression (≥55%), and double-expressor phenotype by IHC were significantly associated with DTHL. The biomarker combining FC and IHC, CD38bright and/or MYC ≥55%, was superior to FC and IHC markers alone in predicting DTHL. Restricting FISH testing to approximately 25% of LBCL based on CD38brightand/or MYC ≥55% would detect approximately 95% of DTHL-BCL2 and approximately 75% of DHL-BCL6. CONCLUSIONS: Our study demonstrated that the novel biomarker of CD38bright and/or MYC ≥55% is highly predictive of DTHL. Awareness of the advantages and limitations of this screening strategy would facilitate development of a rational diagnostic workflow to provide high-quality patient care.

Lymphomatoid granulomatosis of the central nervous system (CNS-LYG) posing a management challenge.

Isolated central nervous system lymphomatoid granulomatosis (CNS-LYG) can mimic aggressive glioblastomas. We describe a complex presentation of CNS-LYG coexisting with immune thrombocytopenia successfully managed with rituximab and ultra-low-dose radiation therapy.

Outcomes Associated With Thiotepa-Based Conditioning in Patients With Primary Central Nervous System Lymphoma After Autologous Hematopoietic Cell Transplant.

IMPORTANCE: Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens. OBJECTIVE: To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM). DESIGN, SETTING, AND PARTICIPANTS: This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021. INTERVENTIONS: Patients received 1 of 3 conditioning regimens: TBC (n = 263), TT-BCNU (n = 275), and BEAM (n = 65). MAIN OUTCOMES AND MEASURES: The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival. RESULTS: Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P = .03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P < .001). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79; 95% CI, 1.07-2.98; P = .03), lower risk of nonrelapse mortality (NRM) (HR, 0.50; 95% CI, 0.29-0.87; P = .01), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54; 95% CI, 0.93-2.55; P = .10). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC. CONCLUSIONS AND RELEVANCE: In this cohort study, thiotepa-based conditioning regimen was associated with higher rates of survival compared with BEAM, despite higher rates of early toxic effects and NRM; these findings may assist clinicians in choosing between TBC or TT-BCNU based on patient and disease characteristics.

Combined immune checkpoint blockade and radiotherapy induces durable remission in relapsed natural killer/T-cell lymphoma: a case report and review of the literature.

BACKGROUND: Extranodal natural killer/T-cell lymphoma is a rare, aggressive non-Hodgkin lymphoma that is treated upfront mostly with L-asparaginase containing regimens. Relapsed extranodal natural killer/T-cell lymphoma is associated with a poor prognosis, and there is no established standard of care. CASE PRESENTATION: We report the case of a 72 year-old white male with a distant extranasal relapse of extranodal natural killer/T-cell lymphoma that has been managed successfully with a combination of radiation and immune checkpoint blockade with pembrolizumab. Pseudoprogression with new skin and bone lesions on positron emission tomography imaging was encountered during this Caucasian patient's immunotherapy and was successfully managed with supportive care and continuation of immune checkpoint blockade. CONCLUSIONS: The patient has been in complete clinical, radiologic, and molecular remission for close to 3 years and has not had any immune-related adverse effects. Pseudoprogression is a clinical challenge that can be encountered while patients are treated with immunotherapy, and astute clinical acumen is needed for accurate management. We believe this is the longest duration of response to immune checkpoint blockade in relapsed extranodal natural killer/T-cell lymphoma reported to date in literature. There is a strong biologic rationale in combining radiation with immunotherapy. The optimal timing, dose, and duration of radiation combined with immunotherapy in extranodal natural killer/T-cell lymphoma need to be prospectively evaluated.

Outcomes of rituximab-BEAM versus BEAM conditioning regimen in patients with diffuse large B cell lymphoma undergoing autologous transplantation.

BACKGROUND: Although rituximab-based high-dose therapy is frequently used in diffuse large B cell lymphoma (DLBCL) patients undergoing autologous hematopoietic cell transplantation (auto-HCT), data supporting the benefits are not available. Herein, we report the impact of rituximab-based conditioning on auto-HCT outcomes in patients who have DLBCL. METHODS: Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, 862 adult DLBCL patients undergoing auto-HCT between 2003 and 2017 using BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning regimen were included. All patients received frontline rituximab-containing chemoimmunotherapy and had chemosensitive disease pre-HCT. Early chemoimmunotherapy failure was defined as not achieving complete remission (CR) after frontline chemoimmunotherapy or relapse within 1 year of initial diagnosis. The primary outcome was overall survival (OS). RESULTS: The study cohort was divided into 2 groups: BEAM (n = 667) and R-BEAM (n = 195). On multivariate analysis, no significant difference was seen in OS (P = .83) or progression-free survival (PFS) (P = .61) across the 2 cohorts. No significant association between the use of rituximab and risk of relapse (P = .15) or nonrelapse mortality (P = .12) was observed. Variables independently associated with lower OS included older age at auto-HCT (P < .001), absence of CR at auto-HCT (P < .001) and early chemoimmunotherapy failure (P < .001). Older age (P < .0002) and non-CR pre-HCT (P < .0001) were also associated with inferior PFS. There was no significant difference in early infectious complications between the 2 cohorts. CONCLUSION: In this large registry analysis of DLBCL patients undergoing auto-HCT, the addition of rituximab to the BEAM conditioning regimen had no impact on transplantation outcomes. Older age, absence of CR pre auto-HCT, and early chemoimmunotherapy failure were associated with inferior survival.

Autologous transplantation versus allogeneic transplantation in patients with follicular lymphoma experiencing early treatment failure.

BACKGROUND: Early treatment failure (ETF) in follicular lymphoma (FL), defined as relapse or progression within 2 years of frontline chemoimmunotherapy, is a newly recognized marker of poor survival and identifies a high-risk group of patients with an expected 5-year overall survival (OS) rate of approximately 50%. Transplantation is an established option for relapsed FL, but its efficacy in this specific ETF FL population has not been previously evaluated. METHODS: This study compared autologous hematopoietic stem cell transplantation (auto-HCT) with either matched sibling donor (MSD) or matched unrelated donor (MUD) allogeneic hematopoietic cell transplantation (allo-HCT) as the first transplantation approach for patients with ETF FL (age ≥ 18 years) undergoing auto-HCT or allo-HCT between 2002 and 2014. The primary endpoint was OS. The secondary endpoints were progression-free survival, relapse, and nonrelapse mortality (NRM). RESULTS: Four hundred forty FL patients had ETF (auto-HCT, 240; MSD hematopoietic stem cell transplantation [HCT], 105; and MUD HCT, 95). With a median follow-up of 69 to 73 months, the adjusted probability of 5-year OS was significantly higher after auto-HCT (70%) or MSD HCT (73%) versus MUD HCT (49%; P = .0008). The 5-year adjusted probability of NRM was significantly lower for auto-HCT (5%) versus MSD (17%) or MUD HCT (33%; P < .0001). The 5-year adjusted probability of disease relapse was lower with MSD (31%) or MUD HCT (23%) versus auto-HCT (58%; P < .0001). CONCLUSIONS: Patients with high-risk FL, as defined by ETF, undergoing auto-HCT for FL have low NRM and a promising 5-year OS rate (70%). MSD HCT has lower relapse rates than auto-HCT but similar OS. Cancer 2018;124:2541-51. © 2018 American Cancer Society.

PARP Inhibitors in Prostate Cancer.

OPINION STATEMENT: The genomic landscape of metastatic prostate cancer (mPCa) reveals that up to 90% of patients harbor actionable mutations and >20% have somatic DNA repair gene defects (DRD). This provides the therapeutic rationale of PARP inhibition (PARPi) to achieve "synthetic lethality" in treating this fatal disease. Clinical trials with PARP inhibitors have shown significant response rates up to 88% for PCa patients having DRD like BRCA1/2 or ATM mutations. The FDA has awarded "breakthrough designation" to develop the PARPi olaparib in treating this subset of metastatic PCa patients. The search for predictive biomarkers has expanded the realm of DNA repair genetic defects and combination genetic platforms are being evaluated as tools to assess potential "BRCAness" of tumors. Ongoing clinical trials seek to determine the optimal timing and sequence of using these agents in current PCa treatment algorithms. Combination strategies of PARPi with chemo-, radiation, and hormonal therapies, targeted agents, and immunotherapy are promising avenues of current research. Multi-center international collaborations in well-designed biomarker-driven clinical trials will be key to harness the potential of PARPi in managing a heterogeneous disease like prostate cancer.

The Association between EGFR and cMET Expression and Phosphorylation and Its Prognostic Implication in Patients with Breast Cancer.

EGFR and cMET cross-talk is involved in breast cancer (BC) progression and resistance to different targeted therapies, however little is known about the co-expression patterns of EGFR and cMET or its prognostic significance in BC. Protein levels of EGFR, cMET and their phosphorylated proteins were measured in 825 BC samples using reverse phase protein array (RPPA). Given unimodal distribution of proteins, the median was selected as a cut-off after sensitivity analyses. Kaplan-Meier survival curves were used to estimate relapse-free (RFS) and overall survival (OS). Cox-proportional hazards models were utilized to determine associations between EGFR and cMET with outcomes. Mean age was 58 years with 457 (55%) hormone receptor (HR) positive, 211 (26%) triple-negative (TN) and 148 (18%) HER2 positive tumors (HER2+). HER2+ was associated with higher EGFR expression and phosphorylation, compared to HR and TN (p<0.05). High EGFR expression was associated with higher phosphorylated-cMET (p-cMET) but not cMET (ANOVA p-cMET p < 0.001; cMET p = 0.34). The same association was found with high phosphorylated-EGFR (p-EGFR) group at Tyr992 and Tyr1068 (both p < 0.001). High expressions in either of two p-EGFRs were linked with higher cMET as well (all p<0.001). For the TN subtype, high expression in EGFR and p-EGFR at Tyr992 but not at Tyr1068 was associated with higher p-cMET (p<0.00, p = 0.012, p = 0.4 respectively). Only high expression in p-EGFR at Tyr992 was linked with higher expression of cMET (p = 0.02). In contrast, among HER2 subtype, high expression in p-EGFR at Tyr1068 but not at Tyr992 was associated with higher cMET and p-cMET (cMET p = 0.023;p-cMET p<0.001). Four subgroups of patients defined by dichotomized EGFR/p-EGFR and cMET/p-cMET level demonstrated no significant differences in survival. In multivariate analyses, neither cMET nor EGFR expression/activation was found to be an independent prognostic factor in survival outcome.

Thrombotic thrombocytopenic purpura and cardiac papillary fibroelastoma: a 'unique coexistence'.

Thrombotic thrombocytopenic purpura (TTP), a complex thrombotic microangiopathy, remains an evolving enigma. A 49-year-old African-American woman presented with acute left hemiplegia, an ischemic cerebrovascular accident involving the right middle cerebral artery. Sequential appearance of thrombocytopenia and evidence of microangiopathic haemolysis led to the diagnosis of acquired idiopathic autoimmune TTP. This was managed with plasma exchange (PEX) and steroids. Early haematologic relapse within a month was managed with the addition of rituximab attaining sustained remission. The patient presented 3 years later with acute confusion and expressive aphasia due to multiple infarcts involving the left parieto-occipital cortex. Transoesophageal echocardiography demonstrated a pedunculated 6 mm mitral valvular mass consistent with a papillary fibroelastoma. Anticoagulation was instituted and the patient was continued on therapeutic oral warfarin. A haematologic relapse of TTP eventually emerged and was managed with PEX, steroids and rituximab. This vignette demonstrates several dilemmas in the clinical presentation, diagnosis and management of TTP in current day practice. Rituximab has adjuvant benefits to PEX and is being investigated as potential first-line therapy. Monitoring ADAMTS13 activity and inhibitor titre, as in our case, prove to have prognostic significance. Cardiac fibroelastomas are rare benign cardiac tumours usually arising from valvular endocardium with thromboembolic potential. One of the proposed mechanisms of origin of these masses is organizing thrombi in the setting of endocardial injury and inflammation questioning a possible link to thrombotic microangiopathy. To the best of our knowledge, this is the first report of this unique coexistence.