R. Gregory Bociek

Addition of Rituximab to Standard Chemotherapy Improves the Survival of Both the Germinal Center B-Cell–Like and Non–Germinal Center B-Cell–Like Subtypes of Diffuse Large B-Cell Lymphoma

PURPOSE Diffuse large B-cell lymphoma (DLBCL) includes at least two prognostically important subtypes (ie, germinal center B-cell-like [GCB] and activated B-cell-like [ABC] DLBCL), which initially were characterized by gene expression profiling and subsequently were confirmed by immunostaining. However, with the addition of rituximab to standard chemotherapy, the prognostic significance of this subclassification of DLBCL is unclear. PATIENTS AND METHODS We studied 243 patient cases of de novo DLBCL, which included 131 patient cases treated with rituximab plus standard chemotherapy (rituximab group) and 112 patient cases treated with only standard chemotherapy (control group). The cases were assigned to GCB or non-GCB subgroups (the latter of which included both ABC DLBCL and unclassifiable DLBCL) on the basis of immunophenotype by using the Hans method. Clinical characteristics and survival outcomes of the two patient groups were compared. RESULTS The clinical characteristics of the patients in the rituximab and the control groups were similar. Compared with the control group, addition of rituximab improved the 3-year overall survival (OS; 42% v 77%; P < .001) of patients with DLBCL. Rituximab-treated patients in either the GCB or the non-GCB subgroups also had a significantly improved 3-year OS compared with their respective subgroups in the control group (P < .001). In the rituximab group, the GCB subgroup had a significantly better 3-year OS than the non-GCB subgroup (85% v 69%; P = .032). Multivariate analyses confirmed that rituximab treatment was predictive for survival in both the GCB and the non-GCB subgroups. CONCLUSION In this retrospective study, we have shown that the subclassification of DLBCL on the basis of the cell of origin continues to have prognostic importance in the rituximab era.

ATM, CTLA4, MNDA, and HEM1 in High versus Low CD38–Expressing B-Cell Chronic Lymphocytic Leukemia

Purpose: In B-cell chronic lymphocytic leukemia (CLL), high CD38 expression has been associated with unfavorable clinical course, advanced disease, resistance to therapy, shorter time to first treatment, and shorter survival. However, the genes associated with CLL patient subgroups with high and low CD38 expression and their potential role in disease progression is not known. Experimental Design: To identify the genes associated with the clinical disparity in CLL patients with high versus low CD38 expression, transcriptional profiles were obtained from CLL cells from 39 different patients using oligonucleotide microarray. Gene expression was also compared between CLL cells and B cells from healthy individuals. Results: Gene expression analysis identified 76 differentially expressed genes in CD38 high versus low groups. Out of these genes, HEM1, CTLA4, and MNDA were selected for further studies and their differential expression was confirmed by real-time PCR. HEM1 overexpression was associated with poor outcome, whereas the overexpression of CTLA4 and MNDA was associated with good outcome. Down-regulation of HEM1 expression in patient CLL cells resulted in a significant increase in their susceptibility to fludarabine-mediated killing. In addition, when gene expression patterns in CD38 high and low CLL cells were compared with normal B-cell profiles, ATM expression was found to be significantly lower in CD38 high compared with CD38 low CLL as confirmed by real-time reverse transcription-PCR. Conclusions: These results identify the possible genes that may be involved in cell proliferation and survival and, thus, determining the clinical behavior of CLL patients expressing high or low CD38.

Outcomes After Hematopoietic Stem-Cell Transplantation for Hematologic Malignancies in Patients With or Without Advance Care Planning

PURPOSE Engagement in advance care planning (ACP) is viewed as a way to prepare for possible death. In patients undergoing hematopoietic stem-cell transplantation (HSCT), an aggressive but possibly curative procedure for cancer, encouraging engagement in ACP is difficult. We conducted this analysis to determine if engagement in ACP among patients who undergo HSCT is associated with adverse outcomes. PATIENTS AND METHODS Adult patients who were undergoing their first HSCT for hematologic malignancies between 2001 and 2003 were included. ACP was defined as having a living will, a power of attorney for health care, or life-support instructions. Outcomes assessed included the length of hospital stay, in-hospital mortality, and overall survival. RESULTS Of the 343 patients, 172 did not have ACP, whereas 171 did have ACP, and 127 of those were reviewable. Of those with reviewable ACP, 28 patients (22%) completed ACP before cancer diagnosis, 87 (68%) completed ACP after the cancer diagnosis but before HSCT, and 12 (10%) engaged in ACP after HSCT. Patients without ACP before HSCT had a significantly greater risk of death compared with patients with ACP (hazard ratio, 2.11; 95% CI, 1.34 to 3.33; P = .001) while adjusting for statistically significant factors. CONCLUSION Our study demonstrated that lack of engagement in ACP is associated with adverse outcomes after HSCT. Thus, the patients least likely to have planned for poor outcomes are the ones most likely to face them. Additional studies should evaluate the nature of this association and should seek modifiable explanatory factors that could be the target of interventions.

Survival Disparities in Patients With Lymphoma According to Place of Residence and Treatment Provider: A Population-Based Study

PURPOSE Health disparities exist according to an individuals place of residence. We evaluated the association between primary area of residence (urban v rural) according to treatment provider (university based v community based) and overall survival in patients with lymphoma and determined whether there are patient groups that could benefit from better coordination of care. PATIENTS AND METHODS Population-based, retrospective cohort study of 2,330 patients with centrally confirmed lymphoma from Nebraska and surrounding states and treated by university-based or community-based oncologists from 1982 to 2006. RESULTS Among urban residents, 321 (14%) were treated by university-based providers (UUB) and 816 (35%) were treated by community-based providers (UCB). Among rural residents, 332 (14%) were treated by university-based providers (RUB), and 861 (37%) were treated by community-based providers (RCB). The relative risk (RR) of death among UUB, UCB, and RUB were not statistically different. However, RCB had a higher risk of death (RR, 1.37; 95% CI, 1.14 to 1.65; P = .01; and RR, 1.26; 95% CI, 1.06 to 1.49; P = .01) when compared with UUB and RUB, respectively. This association was true in both low- and intermediate-risk patients. Among high-risk patients, UCB, RUB, and RCB were all at higher risk of death when compared with UUB. CONCLUSION Survival outcomes of patients with lymphoma may be associated with place of residence and treatment provider. High-risk patients from rural areas may benefit from better coordination of care.

Cell of origin fails to predict survival in patients with diffuse large B-cell lymphoma treated with autologous hematopoietic stem cell transplantation

Diffuse large B‐cell lymphoma (DLBCL) includes two prognostically important subtypes, the germinal center B‐cell (GCB) and the non‐GCB types. The aim of this study was to evaluate immunohistochemical approaches for predicting the survival of patients with DLBCL following autologous hematopoietic stem cell transplantation (AHSCT). We identified 62 patients with DLBCL who either had an initial complete remission (17 patients) or received salvage chemotherapy for relapsed or refractory disease (45 patients), followed by AHSCT. Tissue microarrays were immunostained with monoclonal antibodies against GCET1, CD10, BCL6, MUM1, FOXP1 and LMO2. Using the Hans algorithm, we classified 50% of the cases as GCB type, whereas the Choi algorithm classified 58% as GCB type and LMO2 was positive in 69%. However, no significant differences were found in the 5‐year overall or event‐free survivals using any of these approaches. In conclusion, cell of origin fails to predict survival of DLBCL patients treated with AHSCT. Copyright

Lymphodepleting effects and safety of pentostatin for nonmyeloablative allogeneic stem-cell transplantation

Nonmyeloablative allogeneic stem-cell transplantation (alloNST) is the focus of investigations searching for less-toxic transplantation regimens. We report studies on the kinetics of lymphodepletion and safety of pentostatin (PT) conditioning in alloNST. Patients with hematologic malignancy received mobilized blood from human leukocyte antigen-matched related (n=4) or unrelated (n=8) donors. PT 4 mg/m2 was administered on days -21, -20, and -19 and 200 cGy of total-body irradiation was administered on day -1, followed by cyclosporine A and mycophenolate mofetil. Mononuclear cell adenosine deaminase after PT was inhibited 84%. The absolute CD3+ cells decreased significantly by day -7 (49%) and CD19+ cells declined 92% by day -1. CD4+ cells were depressed more than CD8+ cells. Neutrophils and monocytes were minimally affected by PT. Median posttransplant peripheral blood chimerism on day 70 showed 95% donor leukocytes and 82.5% donor CD3 lymphocytes. PT demonstrated lymphodepleting effects and promising safety, supporting alloNST as early as 7 days after initiation of PT.

Mortality Patterns Among Recipients of Autologous Hematopoietic Stem Cell Transplantation for Lymphoma and Myeloma in the Past Three Decades

BACKGROUND Understanding the mortality patterns of patients with lymphoma and myeloma, who have undergone autologous hematopoietic stem cell transplantation (ASCT) might identify improvement opportunities. PATIENTS AND METHODS The present retrospective study included patients with lymphoma and myeloma, aged ≥ 18 years, who had undergone ASCT from 1983 to 2010 at the University of Nebraska Medical Center. Of the 2284 patients, 972 had died within first 5 years after ASCT. The patients were divided into 3 cohorts according to the time of transplantation: 1983 to 1990 (cohort I), 1991 to 2000 (cohort II), and 2001 to 2010 (cohort III). Using Cox proportional hazards regression analysis, the risk of cause-specific mortality was compared across the 3 cohorts. RESULTS Of a total of 1215 deaths, 972 (80%) occurred within the first 5 years after ASCT. Disease relapse (73.4%), organ failure (7.8%), infection (4.7%), and secondary malignancy (4.2%) accounted for most of the deaths. The risk of death from infection (P < .0001), but not from relapse (P = .26), organ failure (P = .68), or secondary malignancy (P = .15), had declined in the more recent cohorts. CONCLUSION The 5-year overall survival of patients undergoing ASCT has improved significantly owing to a decline in infectious mortality. Our results highlight that the mortality from relapse remains the most common cause of death, warranting investigation of different strategies to reduce the incidence of relapse and improve the therapy for relapse after ASCT.

Central Nervous System Complications and Outcomes After Allogeneic Hematopoietic Stem Cell Transplantation

BACKGROUND Central nervous system complications (CNSC) can be the cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aimed to determine the incidence of CNSC and its impact on survival. PATIENTS AND METHODS This retrospective cohort study included patients with hematologic disorders who received allo-HSCT between 2002 and 2011 at the University of Nebraska Medical Center. RESULTS Of the 351 patients identified, 45 developed CNSC (12.8%). The 100-day cumulative incidence of CNSC was 8% (95% confidence interval, 8-15). The most common CNSC included posterior reversible encephalopathy syndrome (40%), stroke or transient ischemic attack (24%), seizures (20%), and infection (9%). The 5-year overall survival was significantly lower among patients with versus without CNSC (14% vs. 44%, P = .0004). In multivariate analysis, the risk of mortality for patients with versus without CNSC was significantly higher (hazard ratio, 1.56; 95% confidence interval, 1.03-2.36; P = .04). CONCLUSION The occurrence of CNSC after allo-HSCT was associated with reduced survival. Identifying patients at risk, monitoring, early detection, and management of CNSC after allo-HSCT are needed to improve outcomes.

High-Dose Therapy/Autologous Hematopoietic Stem Cell Transplantation in Relapsed or Refractory Marginal Zone Non-Hodgkin Lymphoma

The optimal therapy for patients who have relapsed or refractory marginal zone lymphoma has not been defined. We analyzed the clinical outcomes of 14 patients who had relapsed or refractory marginal zone lymphomas and underwent high-dose therapy/autologous hematopoietic stem cell transplantation (HDT/AHSCT) at the University of Nebraska from August 1992 to August 2008. The median age of patients was 48 years (range, 29 to 62 years). All patients had relapsed or refractory disease. There were three treatment-related deaths within 100 days of transplantation. With a median follow-up of 138 months, the median duration of failure-free survival is 108 months, and the median duration overall survival is 120 months. Only two patients have relapsed. Secondary malignancies were seen in three patients (myelodysplastic syndrome, n = 2; gastric carcinoma. n = 1). We conclude that HDT/AHSCT is feasible in patients who have relapsed/refractory marginal zone lymphomas. Approximately one- third of patients can achieve long-term disease-free survival.

ENGAGE- 501: phase II study of entinostat (SNDX-275) in relapsed and refractory Hodgkin lymphoma.

Classical Hodgkin lymphoma treatment is evolving rapidly with high response rates from antibody-drug conjugates targeting CD30 and immune checkpoint antibodies. However, most patients do not achieve a complete response, therefore development of novel therapies is warranted to improve patient outcomes. In this phase II study, patients with relapsed or refractory Hodgkin lymphoma were treated with entinostat, an isoform selective histone deacetylase inhibitor. Forty-nine patients were enrolled: 33 patients on Schedule A (10 or 15 mg oral entinostat once every other week); 16 patients on Schedule B (15 mg oral entinostat once weekly in 3 of 4 weeks). Patients received a median of 3 prior treatments (range 1–10), with 80% of the patients receiving a prior stem cell transplant and 8% of patients receiving prior brentuximab vedotin. In the intention-to-treat analysis, the overall response rate was 12% while the disease control rate (complete response, partial response, and stable disease beyond 6 months) was 24%. Seven patients did not complete the first cycle due to progression of disease. Tumor reduction was observed in 24 of 38 (58%) evaluable patients. Median progression-free survival and overall survival was 5.5 and 25.1 months, respectively. The most frequent grade 3 or 4 adverse events were thrombocytopenia (63%), anemia (47%), neutropenia (41%), leukopenia (10%), hypokalemia (8%), and hypophosphatemia (6%). Twenty-five (51%) patients required dose reductions or delays. Pericarditis/pericardial effusion occurred in one patient after 12 cycles of therapy. Future studies are warranted to identify predictive biomarkers for treatment response and to develop mechanism-based combination strategies. (clinicaltrials.gov identifier: 00866333)