Nowakowski, Grzegorz S.

Key Points The mTOR pathway is constitutively activated in the TCL cells and is responsible for TCL proliferation. This is first trial to demonstrate that mTORC1 inhibitors (everolimus) have substantial antitumor activity (44% overall response rate) in patients with relapsed TCL.

Key Points BCL2 mutations in FL correlate with activation-induced cytidine deaminase expression and frequently alter the amino acid sequence of the protein. Mutations in the BCL2 coding sequence at diagnosis are associated with shortened time to transformation and earlier death due to lymphoma.

AbstractImmune and nonimmune microenvironmental factors play a critical role in the progression, transformation, and resistance to therapy in follicular lymphoma (FL). A recent increase in our understanding of the role of microenvironment in FL biology has led to the development of novel therapeutic strategies targeting the nonimmune and immune microenvironment. These include immunomodulatory drugs, immune checkpoint inhibitors, immnunoconjugates, and small-molecule inhibitors with an impact on the microenvironment in addition to direct antitumor activity. These agents are now at different stages of clinical development, ranging from early clinical trials in relapsed disease to phase 3 studies in the upfront setting, including combinations with other agents such as monoclonal antibodies and chemotherapy. It is important to recognize that, although the current upfront therapy of FL is associated with favorable outcomes in the majority of patients, a significant proportion experience early disease progression and develop treatment resistance and transformation to aggressive lymphoma. Although the development of “chemo-free” combinations using drugs targeting the microenvironment offers a promising approach to minimize toxicity, the identification of patients at risk of relapse and the use of biomarkers allowing the personalization of therapy will likely play a major role in the development of maintenance strategies. Against this landscape of currently available therapy options, this chapter discusses the clinical status of therapies targeting the microenvironment in FL.

Purpose We examined the utility of post-therapy surveillance imaging in a large, prospectively enrolled cohort of patients with diffuse large B-cell lymphoma (DLBCL) from the United States and confirmed our results in an independent cohort of patients from France. Methods Patients with newly diagnosed DLBCL and treated with anthracycline-based immunochemotherapy were identified from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence and the Léon Bérard Cancer Center, Lyon, France. In those with relapse, details at relapse and outcomes were abstracted from records. Results 680 individuals with DLBCL were identified from the MER, 552 (81%) of whom achieved remission after induction. 112 of the 552 patients (20%) suffered a relapse. The majority (64%) of relapses were identified before a scheduled follow-up visit. Surveillance imaging detected DLBCL relapse before clinical manifestations in nine out of 552 patients (1.6%) observed after therapy. In the Lyon cohort, imaging identified asymptomatic DLBCL relapse in four out of 222 patients (1.8%). There was no difference in survival after DLBCL relapse in patients detected at scheduled follow-up versus before scheduled follow-up in both the MER (P = .56) and Lyon cohorts (P = .25). Conclusion The majority of DLBCL relapses are detected outside of planned follow-up, with no difference in outcome in patients with DLBCL detected at a scheduled visit compared with patients with relapse detected outside of planned follow-up. These data do not support the use of routine surveillance imaging for follow-up of DLBCL.

The serum immunoglobulin free light chain (FLC) assay quantitates free kappa (κ) and lambda (λ) light chains. FLC elevations in patients with diffuse large B‐cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and chronic lymphocytic leukemia (CLL) are associated with an inferior survival. These increases in FLC can be monoclonal (as in myeloma) or polyclonal. The goal was to estimate the frequency of these elevations within distinct types of B‐cell and T‐cell non‐Hodgkin lymphoma (NHL) and whether the FLC measurements are associated with event‐free survival (EFS). We studied serum for FLC abnormalities using normal laboratory reference ranges to define an elevated κ or λ FLC. Elevations were further classified as polyclonal or monoclonal. Four hundred ninety‐two patients were studied: 453 B‐cell and 34 T‐cell NHL patients. Twenty‐nine % (142/453) of patients had an elevated FLC of which 10% were monoclonal elevations. Within B‐cell NHL, FLC abnormalities were most common in lymphoplasmacytic (79%), mantle cell (68%), and lymphomas of mucosa associated lymphoid tissue (31%); they were least common in follicular (15%). The hazard ratio (HR) for EFS in all patients was 1.41 (95% CI; 1.11–1.81); in all B‐cell NHL the HR was 1.44 (95% CI 1.11–1.96); in all T‐cell NHL the HR was 1.17 (95% CI 0.55–2.49). FLC abnormalities predicted an inferior OS (HR = 2.75, 95% CI: 1.93–3.90, P < 0.0001). The serum FLC assay is useful for prognosis in both B‐cell and T‐cell types of NHL. In B‐cell NHL further discrimination between a monoclonal and polyclonal elevation may be helpful and should be analyzed in prospective clinical trials. Am. J. Hematol. 89:1116–1120, 2014. © 2014 Wiley Periodicals, Inc.

Purpose Lenalidomide has significant single-agent activity in relapsed diffuse large B-cell lymphoma (DLBCL). We demonstrated that lenalidomide can be safely combined with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone); this new combination is known as R2CHOP. The goal of this phase II study was to evaluate the efficacy of this combination in newly diagnosed DLBCL. Patients and Methods Eligible patients were adults with newly diagnosed untreated stages II to IV CD20 + DLBCL. Patients received lenalidomide 25 mg orally per day on days 1 through 10 with standard-dose R-CHOP every 21 days for six cycles. All patients received pegfilgrastim on day 2 of each cycle and aspirin prophylaxis throughout. DLBCL molecular subtype was determined by tumor immunohistochemistry and classified as germinal center B-cell (GCB) versus non-GCB in the R2CHOP patients and 87 control patients with DLBCL from the Lymphoma Database who were treated with conventional R-CHOP. Results In all, 64 patients with DLBCL were enrolled, and 60 were evaluable for response. The overall response rate was 98% (59 of 60) with 80% (48 of 60) achieving complete response. Event-free survival and overall survival (OS) rates at 24 months were 59% (95% CI, 48% to 74%) and 78% (95% CI, 68% to 90%), respectively. In R-CHOP patients, 24-month progression-free survival (PFS) and OS were 28% versus 64% (P < .001) and 46% versus 78% (P < .001) in non-GCB DLBCL versus GCB DLBCL, respectively. In contrast, there was no difference in 24-month PFS or OS for R2CHOP patients on the basis of non-GCB and GCB subtype (60% v 59% [P = .83] and 83% v 75% [P = .61] at 2 years, respectively). Conclusion R2CHOP shows promising efficacy in DLBCL. The addition of lenalidomide appears to mitigate a negative impact of non-GCB phenotype on patient outcome.

Patients with diffuse large B‐cell lymphoma (DLBCL) and pre‐treatment bone marrow (BM) involvement require a restaging BM biopsy to document complete remission (CR). We investigated whether BM assessment by restaging PET‐CT could obviate the need for a repeat BM biopsy. Patients with DLBCL and a positive BM biopsy at diagnosis were identified from the Mayo Clinic Lymphoma Data Base. The concordance of BM status on restaging histopathology and PET‐CT reports and the positive (PPV) and negative predictive value (NPV) of PET‐CT were determined. One thousand eighty patients with DLBCL were evaluated and 69 patients (6%) had DLBCL involving the BM at diagnosis. Of 46 patients who completed frontline chemoimmunotherapy, 34 had a restaging PET‐CT and BM biopsy and were included in the analysis. Thirty‐three patients had a negative BM by both PET‐CT and BM biopsy; one patient had persistent BM involvement by biopsy and PET‐CT. Thus, restaging PET‐CT had 100% PPV and 100% NPV for assessing residual BM disease. The findings were validated in a prospective cohort of 68 DLBCL patients treated on a phase II clinical trial where four patients (6%) had DLBCL involving the BM at diagnosis. All had a negative BM by both restaging BM biopsy and PET‐CT. Compared with the gold standard of BM biopsy, PET‐CT had a 100% NPV to exclude residual BM disease after frontline therapy. If further validated, DLBCL practice guidelines and response criteria could be modified so that BM biopsy is no longer required to document CR if the restaging PET‐CT is negative. Am. J. Hematol. 89:865–867, 2014. © 2014 Wiley Periodicals, Inc.

Abstract Purpose: Transformation of follicular lymphoma is a critical event associated with a poor prognosis. The role of the tumor microenvironment in previous transformation studies has yielded conflicting results. Experimental Design: To define cell subtypes associated with transformation, we examined tissue specimens at diagnosis from patients with follicular lymphoma that later transformed and, using immunohistochemistry (IHC), stained for CD68, CD11c, CD21, CXCL13, FOXP3, PD1, and CD14. Cell content and the pattern of expression were evaluated. Those identified as significantly associated with time to transformation (TTT) and overall survival (OS) were further characterized by flow cytometry and multicolor IHC. Results: Of note, 58 patients were analyzed with median TTT of 4.7 years. The pattern of PD1+ and CD14+ cells rather than the quantity of cells was predictive of clinical outcomes. On multivariate analysis, including the follicular lymphoma international prognostic index score, CD14+ cells localized in the follicle were associated with a shorter TTT (HR, 3.0; P = 0.004). PD1+ cells with diffuse staining were associated with a shorter TTT (HR, 1.9; P = 0.045) and inferior OS (HR, 2.5; P = 0.012). Multicolor IHC and flow cytometry identified CD14+ cells as follicular dendritic cells (FDC), whereas PD1+ cells represented two separate populations, TFH and exhausted T cells. Conclusion: These results identify the presence of PD1+ T cells and CD14+ FDC as independent predictors of transformation in follicular lymphoma. Clin Cancer Res; 20(11); 2862–72. ©2014 AACR.