Jia Ruan

Bortezomib Plus CHOP-Rituximab for Previously Untreated Diffuse Large B-Cell Lymphoma and Mantle Cell Lymphoma

PURPOSE The proteasome inhibitor bortezomib may enhance activity of chemoimmunotherapy in lymphoma. We evaluated dose-escalated bortezomib plus standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab (R) in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). PATIENTS AND METHODS Seventy-six subjects with untreated DLBCL (n = 40) and MCL (n = 36) received standard CHOP every 21 days (CHOP-21) with R plus bortezomib at 0.7 mg/m(2) (n = 4), 1.0 mg/m(2) (n = 9), or 1.3 mg/m(2) (n = 63) on days 1 and 4 for six cycles. RESULTS Median age was 63 years (range, 20 to 87), and International Prognostic Index (IPI) scores were generally unfavorable (39% with IPI of 2, and 49% with IPI of 3 to 5), as were Mantle Cell Lymphoma International Prognostic Index scores in patients with MCL (28% intermediate risk and 39% high risk). Toxicity was manageable, including neuropathy in 49 subjects (8% grade 2 and 4% grade 3) and grade 3/4 anemia (13%), neutropenia (41%), and thrombocytopenia (25%). For DLBCL, the evaluable overall response rate (ORR) was 100% with 86% complete response (CR)/CR unconfirmed (CRu; n = 35). Intent-to-treat (ITT, n = 40) ORR was 88% with 75% CR/CRu, 2-year progression-free survival (PFS) of 64% (95% CI, 47% to 77%) and 2-year overall survival (OS) of 70% (95% CI, 53% to 82%). For MCL, the evaluable ORR was 91% with 72% CR/CRu (n = 32). The ITT (n = 36) ORR was 81% with 64% CR/CRu, 2-year PFS 44% (95% CI, 27% to 60%) and 2-year OS 86% (95% CI, 70% to 94%). IPI and MIPI correlated with survival in DLBCL and MCL, respectively. Unlike in DLBCL treated with R-CHOP alone, nongerminal center B cell (non-GCB) and GCB subtypes had similar outcomes. CONCLUSION Bortezomib with R-CHOP-21 can be safely administered and may enhance outcomes, particularly in non-GCB DLBCL, justifying randomized studies.

Surveillance CT scans are a source of anxiety and fear of recurrence in long-term lymphoma survivors

BACKGROUND We aimed to assess anxiety and the psychological impact of routine surveillance scans in long-term survivors of adult aggressive lymphoma. PATIENTS AND METHODS In this cross-sectional observational study of 70 survivors of curable adult aggressive lymphoma, we measured anxiety and the doctor-patient relationship and performed a qualitative interview (n = 30) focused on patient perception of routine follow-up imaging studies. RESULTS Participants were diagnosed with aggressive lymphoma a median of 4.9 years (2.4-38.0 years) before enrollment. Thirty-seven percent of patients were found to meet criteria for clinically significant anxiety, which was not associated with years since diagnosis. In multivariate analysis, history of relapse and a worse doctor-patient relationship were independently associated with higher anxiety levels. Despite representing a largely cured population, in qualitative interviews patients reported fear of recurrence as a major concern and considerable anxiety around the time of a follow-up imaging scan. CONCLUSIONS Routine surveillance scans exacerbate underlying anxiety symptoms and fear of recurrence in survivors of aggressive lymphoma. Strategies to minimize follow-up imaging and to improve doctor-patient communication should be prospectively evaluated to address these clinically significant issues.

Angiogenesis and antiangiogenic therapy in non-Hodgkin's lymphoma

Angiogenesis, the growth of new blood vessels, requires dynamic expansion, assembly and stabilization of vascular endothelial cells in response to proangiogenic stimuli. Antiangiogenic strategies have become an important therapeutic modality for solid tumors. While many aspects of postnatal pathological angiogenesis have been extensively studied in the context of nonhematopoietic neoplasms, the precise role of these processes in lymphoma pathogenesis is under active investigation. Lymphoma growth and progression is potentiated by at least two distinct angiogenic mechanisms: autocrine stimulation of tumor cells via expression of vascular endothelial growth factor (VEGF) and VEGF receptors by lymphoma cells, as well as paracrine influences of proangiogenic tumor microenvironment on both local neovascular transformation and recruitment of circulating bone marrow-derived progenitors. Lymphoma-associated infiltrating host cells including hematopoietic monocytes, T cells and mesenchymal pericytes have increasingly been associated with the pathogenesis and prognosis of lymphoma, in part providing perivascular guidance and support to neoangiogenesis. Collectively, these distinct angiogenic mechanisms appear to be important therapeutic targets in selected non-Hodgkins lymphoma (NHL) subtypes. Understanding these pathways has led to the introduction of antiangiogenic treatment strategies into the clinic where they are currently under assessment in several ongoing studies of NHL patients.

Magnitude of Stromal Hemangiogenesis Correlates with Histologic Subtype of Non–Hodgkin's Lymphoma

Purpose: Tumor stromal microenvironment promotes neoplastic growth and angiogenesis. We have previously shown that recruitment of marrow-derived vascular endothelial growth factor receptor-1+ (VEGFR-1+) proangiogenic hematopoietic progenitors contributes instructively and structurally to neoangiogenesis in mouse models. Here, we investigated whether stromal incorporation of CD68+ hemangiogenic cells and α-smooth muscle actin+ (α-SMA+) stromal cells correlates with neoangiogenesis and progression in human non–Hodgkins lymphoma subtypes. Experimental Design: Spatial localizations of vascular and stromal cells expressing CD34, VEGFR-1, α-SMA, and CD68 were examined by immunohistochemistry in 42 cases of non–Hodgkins lymphoma, including diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and compared with benign follicular hyperplasia. Results: Compared with indolent lymphomas, there was a profound increase in recruitment of CD68+ cells and VEGFR-1+ neovessels in aggressive subtypes (including those transformed from indolent subtypes), where CD68+ cells were localized to the perivascular region of neovessels as well as the stromal compartment. The perivascular CD68+ cells expressed VEGFR-1 and VEGF-A. In contrast, there was a diffuse increase in α-SMA incorporation throughout the stromal compartment of indolent subtype of CLL/SLL compared with the scant perivascular pattern in aggressive subtypes. Overall, there was no correlation between CD34+ microvessel density and lymphoma histologic subtype. Conclusions: Heightened stromal hemangiogenesis as marked by infiltration of proangiogenic VEGFR-1+CD68+VEGF-A+ cells and their paracrine cross-talk with neovasculature appears to be a distinct feature of aggressive lymphoma, providing novel targets for antiangiogenic therapy, whereas α-SMA+ stromal vascular network may be differentially targeted in CLL/SLL.

Intensive treatment strategies may not provide superior outcomes in mantle cell lymphoma: overall survival exceeding 7 years with standard therapies

BACKGROUND Reported median overall survival (OS) in patients with mantle cell lymphoma (MCL) has been reported to be just 3-4 years. As a consequence, first-line treatment has become more aggressive. Single-center studies with R-Hyper-CVAD and/or autologous stem-cell transplant (ASCT) have produced 3-year OS rates >80%, prompting many to adopt their use. We evaluated outcomes from a single-center cohort managed in a more traditional fashion. METHODS We identified patients with MCL evaluated at Weill Cornell Medical Center since 1997, and included those with known date of diagnosis. An online social security database was used to verify survival. RESULTS We identified 181 patients with MCL, and date of diagnosis could be determined in 111. Three-year OS from diagnosis was 86% [95% confidence interval (CI) 78% to 92%]. Median OS was 7.1 years (95% CI 63-98 months). Adequate information on therapy was available for 75 patients. Only five were treated upfront with (R)-Hyper-CVAD or ASCT while an additional four patients received one of these regimens subsequently. Treatment type had no significant effect on OS. CONCLUSION Outcomes with standard approaches can yield similar survival to that achieved with more intensive approaches. Biases may account for the perceived superiority of aggressive strategies.

Postibrutinib outcomes in patients with mantle cell lymphoma

Despite unprecedented clinical activity in mantle cell lymphoma (MCL), primary and acquired resistance to ibrutinib is common. The outcomes and ideal management of patients who experience ibrutinib failure are unclear. We performed a retrospective cohort study of all patients with MCL who experienced disease progression while receiving ibrutinib across 15 international sites. Medical records were evaluated for clinical characteristics, pathological and radiological data, and therapies used pre- and postibrutinib. A total of 114 subjects met eligibility criteria. The median number of prior therapies was 3 (range, 0-10). The Mantle Cell Lymphoma International Prognostic Index (MIPI) scores at the start of ibrutinib were low, intermediate, and high in 46%, 31%, and 23% of patients, respectively. Of patients with available data prior to ibrutinib and postibrutinib, 34 of 47 and 11 of 12 had a Ki67 >30%. The median time on ibrutinib was 4.7 months (range 0.7-43.6). The median overall survival (OS) following cessation of ibrutinib was 2.9 months (95% confidence interval [CI], 1.6-4.9). Of the 104 patients with data available, 73 underwent subsequent treatment an average of 0.3 months after stopping ibrutinib with a median OS of 5.8 months (95% CI, 3.7-10.4). Multivariate Cox regression analysis of MIPI before postibrutinib treatment, and subsequent treatment with bendamustine, cytarabine, or lenalidomide failed to reveal any association with OS. Poor clinical outcomes were noted in the majority of patients with primary or secondary ibrutinib resistance. We could not identify treatments that clearly improved outcomes. Future trials should focus on understanding the mechanisms of ibrutinib resistance and on treatment after ibrutinib.

Imatinib disrupts lymphoma angiogenesis by targeting vascular pericytes

Pericytes and vascular smooth muscle cells (VSMCs), which are recruited to developing blood vessels by platelet-derived growth factor BB, support endothelial cell survival and vascular stability. Here, we report that imatinib, a tyrosine kinase inhibitor of platelet-derived growth factor receptor β (PDGFRβ), impaired growth of lymphoma in both human xenograft and murine allograft models. Lymphoma cells themselves neither expressed PDGFRβ nor were growth inhibited by imatinib. Tumor growth inhibition was associated with decreased microvascular density and increased vascular leakage. In vivo, imatinib induced apoptosis of tumor-associated PDGFRβ(+) pericytes and loss of perivascular integrity. In vitro, imatinib inhibited PDGFRβ(+) VSMC proliferation and PDGF-BB signaling, whereas small interfering RNA knockdown of PDGFRβ in pericytes protected them against imatinib-mediated growth inhibition. Fluorescence-activated cell sorter analysis of tumor tissue revealed depletion of pericytes, endothelial cells, and their progenitors following imatinib treatment. Compared with imatinib, treatment with an anti-PDGFRβ monoclonal antibody partially inhibited lymphoma growth. Last, microarray analysis (Gene Expression Omnibus database accession number GSE30752) of PDGFRβ(+) VSMCs following imatinib treatment showed down-regulation of genes implicated in vascular cell proliferation, survival, and assembly, including those representing multiple pathways downstream of PDGFRβ. Taken together, these data indicate that PDGFRβ(+) pericytes may represent a novel, nonendothelial, antiangiogenic target for lymphoma therapy.

Durable responses with the metronomic rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma.

Targeting the tumor microenvironment and angiogenesis is a novel lymphoma therapeutic strategy. The authors report safety, activity, and angiogenic profiling results with the rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide (RT‐PEPC) regimen in patients with recurrent mantle cell lymphoma (MCL).

Phase 1 trial of bortezomib plus R-CHOP in previously untreated patients with aggressive non-Hodgkin lymphoma

Bortezomib has preclinical and clinical in B‐cell lymphomas, both alone and in combination with other agents. A phase 1 evaluation was conducted of bortezomib with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) in patients with untreated diffuse large B‐cell lymphoma (DLBCL) or mantle cell lymphoma (MCL).

Prednisone, etoposide, procarbazine, and cyclophosphamide (PEP‐C) oral combination chemotherapy regimen for recurring/refractory lymphoma: Low‐dose metronomic, multidrug therapy

Many patients with recurrent lymphoma are unable to tolerate intensive therapies, or have disease that is refractory. Metronomic chemotherapy offers a novel, potentially less toxic yet effective treatment strategy.