Julie M Vose

The Nebraska Medical Center, Omaha, Nebraska, United States

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Publications (360)2909.65 Total impact

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    ABSTRACT: We describe outcomes after allogeneic hematopoietic cell transplantation (HCT) for mycosis fungoides and Sezary syndrome (MF/SS). Outcomes of 129 subjects with MF/SS reported to the Center for the International Blood and Marrow Transplant from 2000-2009. Median time from diagnosis to transplant was 30 (4-206) months and most subjects were with multiply relapsed/ refractory disease. The majority (64%) received non-myeloablative conditioning (NST) or reduced intensity conditioning (RIC). NST/RIC recipients were older in age compared with myeloablative recipients (median age 51 vs 44 years, P=0.005) and transplanted in recent years. Non-relapse mortality (NRM) at 1 and 5 years was 19% (95% confidence interval (CI) 12-27%) and 22% (95% CI 15-31%), respectively. Risk of disease progression was 50% (95% CI 41-60%) at 1 year and 61% (95% CI 50-71%) at 5 years. PFS at 1 and 5 years was 31% (95% CI 22-40%) and 17% (95% CI 9-26%), respectively. OS at 1 and 5 years was 54% (95% CI 45-63%) and 32% (95% CI 22-44%), respectively. Allogeneic HCT in MF/SS results in 5-year survival in approximately one-third of patients and of those, half remain disease-free.Bone Marrow Transplantation advance online publication, 28 July 2014; doi:10.1038/bmt.2014.161.
    Bone marrow transplantation. 07/2014;
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    ABSTRACT: The poor prognosis of diffuse large B-cell lymphoma (DLBCL) patients relapsing within 1-year of initial diagnosis after first-line rituximab-based chemoimmunotherapy has created controversy about the role of autologous transplantation (auto-HCT) in this setting. We compared auto-HCT outcomes of chemosensitive DLBCL patients between 2000 and 2011 in two cohorts based on time to relapse from diagnosis. The early rituximab failure (ERF) cohort consisted of patients with primary refractory disease or those with first relapse within 1-year of initial diagnosis. The ERF cohort was compared with those relapsing >1-year after initial diagnosis (Late Rituximab Failure [LRF] cohort). ERF and LRF cohorts included 300 and 216 patients, respectively. Non-relapse mortality (NRM), progression/relapse, progression-free survival (PFS) and overall survival (OS) of ERF vs. LRF cohorts at 3-years were 9% (95%CI 6-13) vs. 9% (95%CI 5-13), 47% (95%CI 41-52) vs. 39% (95%CI 33-46), 44% (95%CI 38-50) vs. 52% (95%CI 45-59) and 50% (95 CI 44-56) vs. 67% (95%CI 60-74), respectively. On multivariate analysis, ERF was not associated with higher NRM (relative risk (RR) 1.31, p=0.34). ERF cohort had a higher risk of treatment failure (progression/relapse or death) (RR 2.08, p<0.001) and overall mortality (RR 3.75, p<0.001) within the first 9 months post auto-HCT. Beyond this period, PFS and OS were not significantly different between ERF and LRF cohorts. Auto-HCT provides durable disease control to a sizeable subset of DLBCL despite ERF (3-year PFS 44%), and remains the standard-of-care in chemosensitive DLBCL regardless of the timing of disease relapse.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2014; · 3.15 Impact Factor
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    ABSTRACT: Published guidelines recommend baseline cardiac function testing before initiating anthracycline-based chemotherapy. These recommendations are based largely on consensus, and there is little information regarding how often testing leads to alterations in therapy or whether testing is able to predict subsequent cardiac toxicity.
    Clinical lymphoma, myeloma & leukemia. 06/2014;
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    ABSTRACT: PRO131921 is a third-generation, humanized anti-CD20 monoclonal antibody with increased antibody-dependent cytotoxicity and complement-dependent cytotoxicity compared to rituximab. In this phase I study, PRO131921 was administered as a single agent to patients with CD20+, relapsed or refractory, indolent non-Hodgkin's lymphoma (NHL) who had been treated with a prior rituximab-containing regimen. The primary aim of this study was safety and tolerability of PRO131921. The secondary aim of the study, and focus of this report, was to determine the pharmacokinetics (PK) profile of PRO131921 and establish a correlation between drug exposure and clinical efficacy. Patients were treated with PRO131921 by intravenous infusion weekly for 4 weeks and the dose was escalated based on safety in a 3+3 design. Twenty-four patients were treated with PRO131921 at doses from 25 mg/m(2) to 800 mg/m(2). Analysis of PK data demonstrated a correlation between higher normalized drug exposure (normalized AUC) and tumor shrinkage (p=.0035). Also, normalized AUC levels were higher among responders and subjects displaying tumor shrinkage versus subjects progressing or showing no regression (p=0.030). In conclusion, PRO131921 demonstrated clinical activity in rituximab-relapsed and refractory indolent NHL patients. The observation that higher normalized AUC may be associated with improved clinical responses has potential implications in future trials of monoclonal antibody-based therapies, and emphasizes the importance of early PK studies to optimize antibody efficacy.
    Clinical immunology (Orlando, Fla.). 06/2014;
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    ABSTRACT: Idiotypes (Ids), the unique portions of tumor immunoglobulins, can serve as targets for passive and active immunotherapies for lymphoma. We performed a multicenter, randomized trial comparing a specific vaccine (MyVax), comprising Id chemically coupled to keyhole limpet hemocyanin (KLH) plus granulocyte macrophage colony-stimulating factor (GM-CSF) to a control immunotherapy with KLH plus GM-CSF. Patients with previously untreated advanced-stage follicular lymphoma (FL) received eight cycles of chemotherapy with cyclophosphamide, vincristine, and prednisone. Those achieving sustained partial or complete remission (n = 287 [44%]) were randomly assigned at a ratio of 2:1 to receive one injection per month for 7 months of MyVax or control immunotherapy. Anti-Id antibody responses (humoral immune responses [IRs]) were measured before each immunization. The primary end point was progression-free survival (PFS). Secondary end points included IR and time to subsequent antilymphoma therapy. At a median follow-up of 58 months, no significant difference was observed in either PFS or time to next therapy between the two arms. In the MyVax group (n = 195), anti-Id IRs were observed in 41% of patients, with a median PFS of 40 months, significantly exceeding the median PFS observed in patients without such Id-induced IRs and in those receiving control immunotherapy. This trial failed to demonstrate clinical benefit of specific immunotherapy. The subset of vaccinated patients mounting specific anti-Id responses had superior outcomes. Whether this reflects a therapeutic benefit or is a marker for more favorable underlying prognosis requires further study.
    Journal of Clinical Oncology 05/2014; · 18.04 Impact Factor
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    ABSTRACT: Few studies have examined the value of a mandatory second review of outside pathology material for haematological malignancies. Therefore, we compared diagnoses on biopsies referred to an academic medical centre to determine the rate and therapeutic impact of revised diagnoses resulting from a second review. We reviewed 1010 cases referred for lymphoma during 2009–2010. For each case, referral diagnosis and second review diagnosis were compared. Revised diagnoses were grouped into major and minor discrepancies and all major discrepancies were reviewed by a haematologist to determine the effect the diagnostic change would have on therapy. There was no change in diagnosis in 861 (85·2%) cases. In 149 (14·8%) cases, second review resulted in major diagnostic change, of which 131 (12·9%) would have resulted in a therapeutic change. The highest rates of revision were for follicular, high-grade B-cell, and T-cell lymphomas. We found higher rates of major discrepancy in diagnoses from non-academic centres (15·8%) compared to academic centres (8·5%; P = 0·022), and in excisional biopsies (17·9%) compared to smaller biopsies (9·6%; P = 0·0003). Mandatory review of outside pathology material prior to treatment of patients for lymphoma will identify a significant number of misclassified cases with a major change in therapy.
    British Journal of Haematology 04/2014; · 4.94 Impact Factor
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    ABSTRACT: BACKGROUND The objective of this study was to compare the outcomes of patients with classical Hodgkin lymphoma (cHL) who achieved complete remission with frontline therapy and then underwent either clinical surveillance or routine surveillance imaging.METHODS In total, 241 patients who were newly diagnosed with cHL between January 2000 and December 2010 at 3 participating tertiary care centers and achieved complete remission after first-line therapy were retrospectively analyzed. Of these, there were 174 patients in the routine surveillance imaging group and 67 patients in the clinical surveillance group, based on the intended mode of surveillance. In the routine surveillance imaging group, the intended plan of surveillance included computed tomography and/or positron emission tomography scans; whereas, in the clinical surveillance group, the intended plan of surveillance was clinical examination and laboratory studies, and scans were obtained only to evaluate concerning signs or symptoms. Baseline patient characteristics, prognostic features, treatment records, and outcomes were collected. The primary objective was to compare overall survival for patients in both groups. For secondary objectives, we compared the success of second-line therapy and estimated the costs of imaging for each group.RESULTSAfter 5 years of follow-up, the overall survival rate was 97% (95% confidence interval, 92%-99%) in the routine surveillance imaging group and 96% (95% confidence interval, 87%-99%) in the clinical surveillance group (P = .41). There were few relapses in each group, and all patients who relapsed in both groups achieved complete remission with second-line therapy. The charges associated with routine surveillance imaging were significantly higher than those for the clinical surveillance strategy, with no apparent clinical benefit.CONCLUSIONS Clinical surveillance was not inferior to routine surveillance imaging in patients with cHL who achieved complete remission with frontline therapy. Routine surveillance imaging was associated with significantly increased estimated imaging charges. Cancer 2014. © 2014 American Cancer Society.
    Cancer 04/2014; · 5.20 Impact Factor
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    ABSTRACT: There are limited data on the outcomes of autologous or allogeneic hematopoietic cell transplantation in diffuse large B-cell lymphoma transformed from follicular lymphoma. We analyzed transplant outcomes in 141 subjects with biopsy-proven diffuse large B-cell lymphoma transformed from follicular lymphoma reported to the Center for International Blood and Marrow Transplant Research from 1990-2009. Two groups were identified: autotransplant (N=108) and allotransplant (N=33). Fewer autotransplants were done for transformed follicular lymphoma in 2003-2009, with a shift favoring allotransplants. Autotransplant had 1 year non-relapse mortality of 8% (95% confidence intervals [CI] 4-14), 5 year progression free survival of 35% (95% CI 26-45), and 5 year overall survival of 50% (95% CI 40-59). Allotransplant had 1 year non-relapse mortality of 41% (95% CI 23-58), 5 year progression free survival of 18% (95% CI 6-35), and 5 year overall survival of 22% (95% CI 8-41). Autotransplant for transformed follicular lymphoma achieves sustained remission in a high proportion of subjects. The high non-relapse mortality of allotransplant obscured any benefit that might be associated with this transplant modality.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2014; · 3.15 Impact Factor
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    ABSTRACT: Peripheral T-cell lymphoma (PTCL) encompasses a heterogeneous group of neoplasms with generally poor clinical-outcome. Currently 50% of PTCLs are not-classifiable (PTCL-NOS).Gene-expression profiles on 372 PTCLs were analyzed and findings were validated by immunohistochemistry and mutation analysis. Robust molecular classifiers and oncogenic pathways that reflect the pathobiology of tumor cells and their microenvironment were identified for major PTCL-entities, including angioimmunoblastic T-cell lymphoma (AITL; n=114), anaplastic lymphoma kinase (ALK)-positive (n=31) and ALK-negative anaplastic large cell lymphoma (n=48), adult T-cell leukemia/lymphoma (n=14) and extranodal NK/T-cell lymphoma (ENKTL). ENKTL were further separated into NK-cell (n=23) and γδT-cell lymphomas (n=21). We re-classified 37% of morphologically-diagnosed PTCL-NOS cases into other specific subtypes by molecular signatures. Pathologic re-examination, immunohistochemistry and IDH2 mutation analysis supported the validity of re-classification. The remaining PTCL-NOS cases (n=121) were classified into two major molecular subgroups, characterized by high expression of either GATA3 (33%;40/121) or TBX21 (49%;59/121) and corresponding target genes. GATA3-subgroup was significantly associated with poor overall-survival (p=0.01), and also revealed distinct enriched oncogenic pathways. However, high expression of cytotoxic gene-signature within TBX21-subgroup showed poor clinical-outcome (p=0.05). In AITL, high expression of pan B-cell signatures correlated with favorable-outcome (p=0.01), whereas high monocytic-signature was associated with inferior-survival (p=0.017). Combined prognostic score was predictive of AITL survival in independent cohort (p=0.004), suggesting role of tumor microenvironment.
    Blood 03/2014; · 9.78 Impact Factor
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    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease and "double-hit" DLBCL, with both MYC and BCL2 translocations has a poor prognosis. In this study, we investigated whether MYC and BCL2 protein expression in tissue would predict survival in DLBCL. The study included 106 cases of de novo DLBCL treated with rituximab and cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or CHOP-like regimens. The results were validated on an independent cohort of 205 DLBCL patients. Patients with low expression of BCL2 (≤30%) and MYC (≤50%) had the best prognosis, whereas those with high BCL2 (>30%) and MYC (>50%) had the worst outcome. In multivariate analysis, the combination of the BCL2 and MYC was an independent predictor of overall survival (OS) and event-free survival (EFS) (P = 0·015 and P = 0·005, respectively). The risk of death was nine times greater for patients with high BCL2 and MYC compared to those with low expression. High BCL2 and MYC was a strong predictor of poor OS (P < 0·001) and EFS (P = 0·0017) in patients with the germinal centre B-cell (GCB) type, but not in the non-GCB type. In DLBCL, high co-expression of MYC and BCL2 was an independent predictor of poor survival, and could be used to stratify patients for risk-adapted therapies.
    British Journal of Haematology 02/2014; · 4.94 Impact Factor
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    ABSTRACT: Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare subtype of non-Hodgkin lymphoma (NHL) with limited data on pathology and outcome. A multicentre retrospective study was undertaken to determine prognostic factors and the incidence of central nervous system (CNS) relapses. Data was retrospectively collected on patients from 8 US academic centres. Only patients with stage I/II disease (involvement of breast and localized lymph nodes) were included. Histologies apart from primary DLBCL were excluded. Between 1992 and 2012, 76 patients met the eligibility criteria. Most patients (86%) received chemotherapy, and 69% received immunochemotherapy with rituximab; 65% received radiation therapy and 9% received prophylactic CNS chemotherapy. After a median follow-up of 4·5 years (range 0·6-20·6 years), the Kaplan-Meier estimated median progression-free survival was 10·4 years (95% confidence interval [CI] 5·8-14·9 years), and the median overall survival was 14·6 years (95% CI 10·2-19 years). Twelve patients (16%) had CNS relapse. A low stage-modified International Prognostic Index (IPI) was associated with longer overall survival. Rituximab use was not associated with a survival advantage. Primary breast DLBCL has a high rate of CNS relapse. The stage-modified IPI score is associated with survival.
    British Journal of Haematology 01/2014; · 4.94 Impact Factor
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    ABSTRACT: A phase I/II trial was designed to evaluate the safety and activity of adding bortezomib to standard BEAM (BCNU, etoposide, cytarabine, melphalan) and ASCT. Eligible patients (pts) had relapsed/refractory indolent or transformed NHL or MCL that was relapsed/refractory or in first partial (PR1) or complete remission (CR1). Pts received bortezomib on D-11, -8, -5, and -2 before ASCT. Phase I had 4 dose cohorts (0.8, 1, 1.3, and 1.5 mg/m2) and 3 pts were accrued to each. Any non-hematological ASCT-related toxicity > 2 on the Bearman scale occurring between D-11 and engraftment defined the maximum tolerated dose (MTD). Once the MTD has been reached, another 20 pts were enrolled at this dose to determine a preliminary overall response rate (ORR). Pts who were in CR or PR at D+100 were considered responders. The study enrolled 42 pts through 8/14/2009. The median age was 58 (34-73) years; with 33 males and 9 females. The commonest diagnoses were MCL (23 pts) and FL (7 pts). The median number of prior therapies was 1 (0-6). The median follow-up was 4.88 (1.07 to 6.98) years. 13 pts were treated in phase I and 29 pts in phase II. The MTD was initially determined to be 1.5 mg/m2 but it was later decreased to 1 mg/m2 because of excessive GI toxicity and peripheral neuropathy. ORR was 95% at 100 days and 87% at 1 year (y). For all 38 evaluable pts at 1y, responses were CR 84%, PR 1%, and progressive disease 13%. Progression-free survival (PFS) was 83% (95% CI of 68-92%) at 1y, and 32% (15-51%) at 5y. Overall survival (OS) was 91% (95% CI 79-96%) at 1y and 67% (50-79%) at 5y. The commonest NCI grade 3 toxicities were neutropenic fever (59%), anorexia (21%), peripheral neuropathy (19%), orthostatic hypotension/vasovagal syncope (16%) and 1 pt had failed to engraft. Compared to 26 MCL in CR1 historic controls treated with BEAM and ASCT, PFS was 85 and 43% for the BEAM group vs. 87 and 57% for V-BEAM at 1 and 5 years respectively (log-rank p=0.37). OS was 88 and 50% for the BEAM group vs. 96 and 72% for V-BEAM at 1 and 5 years respectively (log-rank p=0.78). In conclusion, the addition of bortezomib to standard BEAM (V-BEAM) and ASCT is feasible. The toxicities were manageable and we didn't observe any treatment-related mortalities however we did observe an excess of autonomic dysfunction and ileus which is concerning for overlapping toxicity with BEAM conditioning. Determining relative efficacy of V-BEAM compared to BEAM would require a randomized trial.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2014; · 3.15 Impact Factor
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    ABSTRACT: We observed a disproportional 18 F-fluorothymidine (F-FLT) uptake in follicular lymphoma (FL) relative to its low cell proliferation. We tested the hypothesis that the 'excess' uptake of 18 F-FLT in FL is related to error-prone DNA repair and investigated whether this also contributes to 18 F-FLT uptake in diffuse large B cell lymphoma (DLBCL). We performed immunohistochemical stainings to assess the pure DNA replication marker MIB-1 as well as markers of both DNA replication and repair like PCNA, TK-1 and RPA1 on lymph node biopsies of 27 FLs and 35 DLBCLs. In 7 FL and 15 DLBCL patients, 18 F-FLT-PET had been performed. 18 F-FLT uptake was lower in FL than in DLBCL (median SUVmax 5.7 vs. 8.9, p = 0,004), but the ratio of 18 F-FLT-SUVmax to percentage of MIB-1 positive cells was significantly higher in FL compared with DLBCL (p = 0.001). The median percentage of MIB-1 positive cells was 10% (range, 10% to 20%) in FL and 70% (40% to 80%) in DLBCL. In contrast, the median percentages of PCNA, TK-1 and RPA1 positive cells were 90% (range, 80 to 100), 90% (80 to 100) and 100% (80 to 100) in FL versus 90% (60 to 100), 90% (60 to 100) and 100% (80 to 100) in DLBCL, respectively. This is the first demonstration of a striking discordance between 18 F-FLT uptake in FL and tumour cell proliferation. High expression of DNA replication and repair markers compared with the pure proliferation marker MIB-1 in FL suggests that this discordance might be due to error-prone DNA repair. While DNA repair-related 18 F-FLT uptake considerably contributes to 18 F-FLT uptake in FL, its contribution to 18 F-FLT uptake in highly proliferative DLBCL is small. This apparently high contribution of DNA repair to the 18 F-FLT signal in FL may hamper studies where 18 F-FLT is used to assess response to cytostatic therapy or to distinguish between FL and transformed lymphoma.
    EJNMMI research. 01/2014; 4(1):3.
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    ABSTRACT: Angioimmunoblastic T-cell lymphoma (AITL) is a frequent subtype of peripheral T-cell lymphoma (PTCL) that is clinically characterized by generalized lymphadenopathy, extranodal involvement, advanced stage at presentation, hypergammaglobulinemia, and significant immune dysregulation resulting in infections as the most common cause of death. Recent advances in pathobiology of AITL have improved our understanding of it as a clonal T-cell disorder and of its effect on B cells in the tumor microenvironment. Reponses to first-line therapies have largely been dismal. In this review, we discuss the clinical features, pathobiology, prognostic models, standard therapy, and newer therapeutic agents used and their implications for the future.
    Seminars in Hematology 01/2014; 51(1):52-8. · 3.36 Impact Factor
  • Julie M Vose
    Clinical advances in hematology & oncology: H&O 01/2014; 12 Suppl 2(1):12-3.
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    ABSTRACT: We previously reported that constitutive STAT3 activation is a prominent feature of the activated B-cell subtype of diffuse large B-cell lymphomas (ABC-DLBCL). In this study, we investigated whether STAT3 activation can risk stratify patients with DLBCL. By an immunohistochemical method, we investigated phosphotyrosine STAT3 (PY-STAT3) expression from 185 patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Cell line-based siRNA experiments were also performed to generate an 11-gene, PY-STAT3 activation signature, which was used to study a previously published cohort of 222 patients with DLBCL. The STAT3 activation status determined by these two methods and by STAT3 mRNA levels were then correlated with survival. PY-STAT3 was detected in 37% of DLBCL and enriched in ABC-DLBCL cases (P = .03). PY-STAT3 positivity significantly correlated with poor overall survival (OS; P = .01) and event-free survival (EFS; P = .006). Similar observations were made for high levels of STAT3 mRNA. In multivariable analysis, PY-STAT3 status (P = .02), International Prognostic Index (P = .02), and BCL2 expression (P = .046) were independent prognosticators of OS in this cohort. Among the cell-of-origin subgroups, PY-STAT3 was associated with poor EFS among non-germinal center B-cell DLBCL cases only (P = .027). Similarly, the 11-gene STAT3 activation signature correlated with poor survival in the entire DLBCL cohort (OS, P < .001; EFS, P < .001) as well as the ABC-DLBCL subgroup (OS, P = .029; EFS, P = .025). STAT3 activation correlated with poor survival in patients with DLBCL treated with R-CHOP, especially those with tumors of the ABC-DLBCL subtype.
    Journal of Clinical Oncology 11/2013; · 18.04 Impact Factor
  • Julie M Vose
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    ABSTRACT: Although Diffuse Large B-Cell lymphoma (DLBCL) represents 30% of all non-Hodgkin lymphomas, there are many different subtypes of DLBCL with various prognostic implications. We are now recognizing that the molecular subtype of the DLBCL may be associated with specific clinical characteristics as well as outcome of the treatment. With this additional information, we may be able to better select a treatment for the patient which will improve the expected response. Only large scale clinical testing will help us with understanding these molecular subtypes and designing therapies for patients with DLBCL.
    Transfusion and Apheresis Science 09/2013; · 1.23 Impact Factor
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    ABSTRACT: Lymphoma is the fourth most frequent cancer in pregnancy; however, current clinical practice is based largely on small series and case reports. In a multicenter retrospective analysis, we examined treatment, complications, and outcomes for Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) occurring during pregnancy. Among 90 patients (NHL, n = 50; HL, n = 40), median age was 30 years (range, 18 to 44 years) and median diagnosis occurred at 24 weeks gestation. Of patients with NHL, 52% had advanced-stage versus 25% of patients with HL (P = .01). Pregnancy was terminated in six patients. Among the other 84 patients, 28 (33%) had therapy deferred to postpartum; these patients were diagnosed at a median 30 weeks gestation. This compared with 56 patients (67%) who received antenatal therapy with median lymphoma diagnosis at 21 weeks (P < .001); 89% of these patients received combination chemotherapy. The most common preterm complication was induction of labor (33%). Gestation went to full term in 56% of patients with delivery occurring at a median of 37 weeks. There were no differences in maternal complications, perinatal events, or median infant birth weight based on deferred versus antenatal therapy. At 41 months, 3-year progression-free survival (PFS) and overall survival (OS) for NHL were 53% and 82%, respectively, and 85% and 97%, respectively, for HL. On univariate analysis for NHL, radiotherapy predicted inferior PFS, and increased lactate dehydrogenase and poor Eastern Cooperative Oncology Group performance status (ECOG PS) portended worse OS. For HL patients, nulliparous status and "B" symptoms predicted inferior PFS. Standard (non-antimetabolite) combination chemotherapy administered past the first trimester, as early as 13 weeks gestation, was associated with few complications and expected maternal survival with lymphoma occurring during pregnancy.
    Journal of Clinical Oncology 09/2013; · 18.04 Impact Factor
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    ABSTRACT: Mantle cell lymphoma (MCL) is an uncommon type of non-Hodgkin lymphoma with poor overall prognosis, requiring the development of new therapies. Lenalidomide is an immunomodulatory agent demonstrating antitumor and antiproliferative effects in MCL. We report results from a long-term subset analysis of 57 patients with relapsed/refractory MCL from the NHL-003 phase II multicenter study of single-agent lenalidomide in patients with aggressive lymphoma DESIGN: Lenalidomide was administered orally 25 mg daily on days 1-21 every 28 days until progressive disease (PD) or intolerability. The primary end point was overall response rate (ORR). Fifty-seven patients with relapsed/refractory, advanced-stage MCL had a median of three prior therapies. The ORR was 35% [complete response (CR)/CR unconfirmed (CRu) 12%], with a median duration of response (DOR) of 16.3 months (not yet reached in patients with CR/CRu) by blinded independent central review. The median time to first response was 1.9 months. Median progression-free survival was 8.8 months, and overall survival had not yet been reached. The most common grade 3/4 adverse events (AEs) were neutropenia (46%), thrombocytopenia (30%), and anemia (13%). These results show the activity of lenalidomide in heavily pretreated, relapsed/refractory MCL. Responders had a durable response with manageable side-effects. Clinical trial number posted on www.clinicaltrials.gov NCT00413036.
    Annals of Oncology 09/2013; · 7.38 Impact Factor
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    ABSTRACT: Mantle cell lymphoma (MCL) is one of the most aggressive B cell non-Hodgkin lymphomas with a median survival of about five years. Currently, there is no curative therapy available for refractory MCL because of relapse from therapy-resistant tumor cells. The NF-κB and mTOR pathways are constitutively active in refractory MCL leading to increased proliferation and survival. Targeting these pathways is an ideal strategy to improve therapy for refractory MCL. Therefore, we investigated the in vitro and in vivo antilymphoma activity and associated molecular mechanism of action of a novel compound 13-197, a quinoxaline analog that specifically perturbs IκB kinase (IKK) β, a key regulator of the NF-κB pathway. 13-197 decreased the proliferation and induced apoptosis in MCL cells including therapy-resistant cells compared to control cells. Furthermore, we observed down-regulation of IκBα phosphorylation and inhibition of NF-κB nuclear translocation by 13-197 in MCL cells. In addition, NF-κB regulated genes such as cyclin D1, Bcl-XL and Mcl-1 were down-regulated in 13-197-treated cells. 13-197 also inhibited the phosphorylation of S6K and 4E-BP1, the downstream molecules of mTOR pathway that are also activated in refractory MCL. Further, 13-197 reduced the tumor burden in vivo in the kidney, liver, and lungs of therapy-resistant MCL bearing NOD-SCID mice compared to vehicle treated mice; indeed, 13-197 significantly increased the survival of MCL transplanted mice. Together, results suggest that 13-197 as a single agent disrupts the NF-κB and mTOR pathways leading suppression of proliferation and increased apoptosis in malignant MCL cells including reduction in tumor burden in mice.
    Molecular Cancer Therapeutics 08/2013; · 5.60 Impact Factor

Publication Stats

16k Citations
2,909.65 Total Impact Points

Institutions

  • 2000–2014
    • The Nebraska Medical Center
      Omaha, Nebraska, United States
  • 1988–2014
    • University of Nebraska at Omaha
      • • Department of Internal Medicine
      • • Department of Genetics, Cell Biology and Anatomy
      • • Department of Pathology and Microbiology
      • • Division of Oncology and Hematology
      Omaha, Nebraska, United States
  • 2013
    • Oregon Health and Science University
      Portland, Oregon, United States
    • University of Manitoba
      • Department of Pathology
      Winnipeg, Manitoba, Canada
  • 2012–2013
    • University of Zagreb
      Zagrabia, Grad Zagreb, Croatia
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
  • 2010–2012
    • Alpert Medical School - Brown University
      Providence, Rhode Island, United States
    • NYU Langone Medical Center
      New York City, New York, United States
    • Emory University
      • Department of Hematology and Medical Oncology
      Atlanta, Georgia, United States
  • 1989–2012
    • University of Nebraska Medical Center
      • • Department of Internal Medicine
      • • Department of Pathology and Microbiology
      Omaha, Nebraska, United States
  • 2011
    • University of Texas Health Science Center at San Antonio
      San Antonio, Texas, United States
    • Weill Cornell Medical College
      • Center for Lymphoma
      New York City, New York, United States
    • Oslo University Hospital
      Kristiania (historical), Oslo County, Norway
    • University of Nebraska at Lincoln
      Lincoln, Nebraska, United States
    • Mayo Foundation for Medical Education and Research
      • Division of Hematology
      Scottsdale, AZ, United States
  • 2010–2011
    • Ente Ospedaliero Cantonale
      Bellinzona, Ticino, Switzerland
  • 2006–2011
    • University of Rochester
      • James P. Wilmot Cancer Center
      Rochester, NY, United States
  • 2008–2010
    • University of Texas MD Anderson Cancer Center
      • Department of Lymphoma and Myeloma
      Houston, Texas, United States
    • BC Cancer Agency
      Vancouver, British Columbia, Canada
    • Creighton University
      Omaha, Nebraska, United States
    • Brownell-Talbot College Preparatory School
      Omaha, Nebraska, United States
  • 2001–2010
    • Case Western Reserve University
      • Department of Medicine (University Hospitals Case Medical Center)
      Cleveland, OH, United States
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • Ankara University
      • Department of Internal Medicine
      Ankara, Ankara, Turkey
  • 2009
    • The University of Chicago Medical Center
      Chicago, Illinois, United States
    • Indiana University-Purdue University Indianapolis
      Indianapolis, Indiana, United States
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 1996–2009
    • Medical College of Wisconsin
      • • Department of Surgery
      • • Center for International Blood & Marrow Transplant Research
      Milwaukee, WI, United States
  • 2002–2007
    • National Institutes of Health
      • • Center for Cancer Research
      • • Branch of Metabolism
      Bethesda, MD, United States
  • 2004
    • National Cancer Institute (USA)
      Maryland, United States
  • 1999
    • University of British Columbia - Vancouver
      • Division of Medical Oncology
      Vancouver, British Columbia, Canada
  • 1991
    • Centre Hospitalier Lyon Sud
      Lyons, Rhône-Alpes, France