Moreira, Jonathan

Abstract Introduction: T-PLL is a rare, aggressive leukemia with poor prognosis and limited therapies. Previous studies on T-PLL patients receiving an allogeneic stem cell transplant (alloSCT) are limited by small numbers with limited data on disease and transplant characteristics. Further, recent data from our large national cohort of patients demonstrated significant survival difference between TCL1A+ and TCL1A- T-PLL, and CD8+ T-PLL vs CD8- T-PLL. In this large multi-center series, utilizing comprehensive disease subtype and alloSCT clinical data, we evaluated prognostic and survival therapeutic outcomes in T-PLL patients that had an alloSCT with a particular focus on T-PLL disease subtypes. Methods: We retrospectively evaluated 572 diagnosed with T-PLL at 21 academic cancer centers throughout the USA between 2000-2023, of which we performed a further evaluation on the169 that proceeded with alloSCT. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier methods and Cox proportional hazard models. Results: Among n=169 alloSCT recipients with T-PLL, the median follow-up time was 20.9 months post-alloSCT (range: 0.2-182.9), the median age at transplant was 59 years (range: 35-77) and 52% were male. In evaluated patients (n=109), TCL1A was positive by cytogenetics or FISH in 69%. As our recent analysis demonstrated significant differences in survival among specific subtypes of T-PLL, we evaluated outcomes in patients with CD4+CD8- T-PLL (n=90, 53%), CD4-CD8+ (n=17, 10%) T-PLL, and CD4+CD8+ T-PLL (n=52, 31%). 53% (87/164) had known nodal involvement at diagnosis identified by PET or CT scan and 45% (43/96) of known patients had minimal residual disease (MRD) at the time of transplant [defined as <5% T-PLL in marrow by flow, or +cytogenetics (e.g. TCL1A)] prior to alloSCT. At the time of alloSCT, 136 (80%) patients were in CR and 23 (14%) patients were in PR. Forty-nine (30%) had a myeloablative (MAC)conditioning regimen and 114 (70%) had a reduced intensity chemotherapy (RIC) conditioning regimen. Eighty (49%) patients had TBI as part of their regimen. The most common regimens were fludarabine (flu)/melphalan based regimens (n=44; 26.0%), flu/cyclophosphamide (cy) based regimens (n=33; 19.5%), flu/busulfan based regimens (n=22; 13.0%), flu/total body irradiation (TBI) (n=8; 4.7%), and cy/TBI (n=4; 2.4%). Across the whole cohort, the median OS and PFS post-alloSCT was 32.6 months (95% CI: 21.0-41.9) and 20.8 months (95% CI: 14.4-30.5) months while the 1-year cumulative incidences (CI) of NRM and relapse were 17% and 20%, respectively. The incidences of grade II-IV acute GVHD and cGVHD were 19% and 23%. There was no difference between patients with myeloablative conditioning (MAC) (n=49, 29%) when compared to patients that received reduced intensity conditioning (RIC) (n=114, 67%) in OS (33.1 vs 29.2; p=0.68) and PFS (20.2 vs 20.8; p=0.97). Patients that were MRD+ (n=31) had worse OS (22.2 vs 48.6; p=0.1) and PFS (14.1 vs 32.5; p=0.04) and higher rates of relapse (1-year relapse 20% vs 8%; p=0.08) than patients that were MRD- (n=50). PFS was improved in those who received alloSCT though only trended towards significance due to low numbers (HR 0.76, p=0.09). In subtype analysis, TCL1A+ T-PLL had significantly worse outcomes compared to TCL1A negative T-PLL. TCL1A+ disease had significantly worse OS (21.6 vs 63.1; p=0.01) and PFS (12.4 vs 50.7; p=0.01) compared to TCL1A-. Additionally, in TCL1A+ disease CI of NRM (24% vs 3%; p=0.02) and relapse (25% vs 12%; p=0.86) was higher vs TCL1A- PLL. CD4+CD8-, CD4-CD8+, and CD4+CD8+ disease had no difference in survival via either OS (28.0 vs 34.4 vs 21.0; p=0.17) or PFS (29.4 vs 23.5 vs 13.6; p=0.09) as well as no difference 1-year CI of NRM ( 11.6 vs 23.5 vs 26.2; p=0.35) and relapse (18.5 vs 23.5 vs 20.0; p=0.67).Conclusions: AlloSCT significantly improved outcomes for patients with T-PLL compared to those who did not proceed to alloSCT and remains he only curative therapy for those with T-PLL. OS, PFS, and CI relapse were significantly worse for patients with TCL1A+ subtype of T-PLL, or those with MRD positivity or PR prior to alloSCT. Novel strategies to decrease relapse such as post-alloSCT maintenance therapy to improve outcomes are urgently needed in these patients.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hematopoietic Cell Transplantation (HCT) provide expert, multidisciplinary recommendations for autologous and allogeneic HCT based on current evidence. The NCCN Guidelines focus on pretransplant recipient evaluation, hematopoietic cell mobilization, conditioning, and the diagnosis and management of graft-versus-host disease (GVHD), a common complication of allogeneic HCT that is associated with significant morbidity. This selection from the NCCN Guidelines for HCT focuses on the diagnosis, workup, and management of acute and chronic GVHD, as well as important supportive care considerations.

The NCCN Guidelines for Hematopoietic Cell Transplantation (HCT) provide an evidence- and consensus-based approach for the use of autologous and allogeneic HCT in the management of malignant diseases in adult patients. HCT is a potentially curative treatment option for patients with certain types of malignancies; however, recurrent malignancy and transplant-related complications often limit the long-term survival of HCT recipients. The purpose of these guidelines is to provide guidance regarding aspects of HCT, including pretransplant recipient evaluation, hematopoietic cell mobilization, and treatment of graft-versus-host disease—a major complication of allogeneic HCT—to enable the patient and clinician to assess management options in the context of an individual patient’s condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for HCT, including the incorporation of a newly developed section on the Principles of Conditioning for HCT.

Hematopoietic cell transplantation (HCT) involves the infusion of hematopoietic progenitor cells into patients with hematologic disorders with the goal of re-establishing normal hematopoietic and immune function. HCT is classified as autologous or allogeneic based on the origin of hematopoietic cells. Autologous HCT uses the patient’s own cells while allogeneic HCT uses hematopoietic cells from a human leukocyte antigen-compatible donor. Allogeneic HCT is a potentially curative treatment option for patients with certain types of hematologic malignancies, and autologous HCT is primarily used to support patients undergoing high-dose chemotherapy. Advances in HCT methods and supportive care in recent decades have led to improved survival after HCT; however, disease relapse and posttransplant complications still commonly occur in both autologous and allogeneic HCT recipients. Allogeneic HCT recipients may also develop acute and/or chronic graft-versus-host disease (GVHD), which results in immune-mediated cellular injury of several organs. The NCCN Guidelines for Hematopoietic Cell Transplantation focus on recommendations for pretransplant recipient evaluation and the management of GVHD in adult patients with malignant disease.

Abstract Abstract 3903 INTRODUCTION: Monoclonal B-Cell Lymphocytosis is an asymptomatic hematologic condition characterized by the presence of small populations of clonal B-cells in the blood or bone marrow occurring in 3–5% of the general population over age 40. Although MBL is considered the precursor state to CLL and other sub-types of indolent non-Hodgkin Lymphoma, most individuals with MBL will not develop a B-cell malignancy. It is unknown, however, whether individuals with MBL may be at risk for other adverse outcomes associated with CLL, such as increased risk of infection. To explore this aspect, we evaluated the risk of hospitalization for infection among patients with clinically recognized MBL and compared this to a cohort of general medicine patients and a cohort of CLL patients. METHODS: The Mayo Clinic Rochester (MCR), a tertiary referral center in rural southeastern Minnesota, is also the primary hematology center for southeastern Minnesota, northern Iowa, and western Wisconsin. There are no metropolitan areas or hematology specialty centers within a 50 mile radius. To explore the natural history of infection in a local, community dwelling cohort of individuals with clinically identified, CLL-phenotype MBL, we used the Mayo Clinic CLL database to identify all patients with newly diagnosed MBL seen in the MCR Hematology Division between January 1999 and December 2009. Analysis was limited to MBL cases who resided within 50 miles of MCR. The comparison cohort consisted of 689 adult patients also resided within 50 miles of MCR who were seen for a general medical examination between September 2002 and December 2009 and who were enrolled as controls in a case-control study of non-Hodgkin lymphoma. Rates of infection among individuals with MBL were also compared to a cohort of 174 patients with newly diagnosed CLL diagnosed in the same time interval and who resided within 50 miles of MCR. All hospitalizations in these 3 groups were audited to document hospitalization with infection including cross-referenced with the electronic Mayo Clinic infection database, which contains all culture results obtained from hospitalized patients at MCR. Serologies and viral assays (e.g. CMV viral load) were also reviewed. Patients whose cultures were negative but who were given a clinical diagnosis of infection (e.g. pneumonia) and who were treated with a full course of antibiotics were considered to have a culture negative infection. Among the cases, only hospitalizations after CLL or MBL diagnosis were considered. RESULTS: In May 2010, there were 524 individuals in the Mayo Clinic MBL/CLL Database with the diagnosis of CLL-phenotype MBL made between January 1999 – December 2009. Of these, 154 (29%) patients resided within a 50 mile radius of Mayo Clinic and were considered a local, community-based cohort of MBL patients. Median age at MBL diagnosis for these 154 patients was 70 years (range 45–94). After median follow-up of 4.2 years (range 0.3–10.6 years), 25 (16%) individuals with MBL were hospitalized with infection as compared to 20/689 (3%) individuals in the control population (odds ratio MBL relative to control=6.5; p<0.001) and 32/174 (18%) in the cohort of patients with newly diagnosed CLL (OR MBL relative to CLL=0.9; p=0.61) (Figure 1). The 25 MBL patients hospitalized for infection were hospitalized a total of 39 times (median 1 hospitalization for infection per individual). A specific infectious organism was identified by cultures or serologies in 8/39 (21%) hospitalizations among individuals with MBL, 10/27 (37%) hospitalizations for infection among controls, and 60 (63%) of the 89 hospitalizations for infection in CLL cases. Finally we performed a pooled multivariable analysis of all patients (n=1017) adjusting for age, sex, presence of MBL, diagnosis of CLL, and whether patients with CLL or MBL received treatment for CLL during follow-up. All factors were independently associated with risk of hospitalization for infection [Age (per year, OR=1.02, p=0.02), sex (male, OR=2.6, p=0.001), presence of MBL (OR=3.3, p<0.001), diagnosis of CLL (OR=3.0, p=0.002), and treatment for CLL (OR=3.3, p<0.001)]. CONCLUSIONS: In this cohort study, patients with newly diagnosed clinical-MBL had a 6.5 fold risk of hospitalization for infection relative to the control cohort. MBL was an independent risk factor for hospitalization for infection after controlling for age, sex, and treatment. Disclosures: Zent: GlaxoSmithKline: Research Funding; Genentech: Research Funding; Genzyme: Research Funding. Kay:Biothera: Research Funding; Clegene: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Glaxo Smith Kline: Research Funding; Hospira: Research Funding; Novartis: Research Funding; Supergen: Research Funding; Calistoga: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Emergent Biosolutions (Formerly Trubion): Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 4610 Introduction: Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). Up to 50% of patients with CLL will develop infectious complications during the course of their disease, and 30–50% of all deaths from CLL are attributed to infections and infectious complications. The risk of infection in CLL is related to immune deficiencies associated with the primary disease process, as well as immunosuppression secondary to treatment. Available research on infectious complications of CLL has focused on patients in clinical trials receiving chemotherapy. Little is known about the natural history of infection in community dwelling patients with newly diagnosed CLL. Method: To explore the natural history of infection in a local, community dwelling cohort of patients diagnosed with CLL, we used the Mayo Clinic CLL database to identify all patients with newly diagnosed CLL seen in the Mayo Clinic Division of Hematology after January 1, 1999 and who resided within 50 mi of Mayo Clinic (Rochester, MN). All patient hospitalizations were reviewed to document infection including cross-referencing with the electronic Mayo Clinic infection database which includes all culture and serology results obtained from hospitalized Mayo Clinic patients. Patients who had positive blood, sputum, cerebrospinal fluid, pleural fluid, or paracentesis fluid culture results were identified. Patients whose cultures were negative were considered to have culture negative infection. Serologies and viral assays (e.g. CMV viral load) were also reviewed to identify infections. Results: In May 2010, there were 2022 patients in the Mayo Clinic CLL Database with the diagnosis of CLL/SLL made between Jan 1999 – Dec 2009. Of these, 336 (17%) patients resided within a 50 mi radius of Mayo Clinic and were considered non-referred, community-based CLL patients. Median age at diagnosis for these 336 patients was 69 yrs (range 27–97) and most had early stage CLL (57% stage 0; 34% stage I-II). With respect to prognostic markers, 206 (70%) patients were CD38 negative, 125 (64%) ZAP-70 negative, 85 (53%) IgVH mutated, and 101 (63%) had either no abnormality or 13q14- as a sole abnormality on FISH analysis. Consistent with being a community dwelling cohort, ~90% (152/165) of patients had co-morbid health problems and ~50% (86/165) had a major comorbidity (e.g. coronary artery disease, cerebral vascular disease, CHF, diabetes, COPD, other malignancy). Although ~17% (43/249) of patients had gamma-globulin levels below the reference range at diagnosis, only 2% (6/249) had an IgG level <500 mg/dL. Median follow-up for all patients was 49 months (range 0–121) and 104 (31%) patients progressed to require treatment for CLL. Although 222 (66%) patients required hospitalization during follow-up, only 38 (11.3%) were hospitalized with infection. Collectively, these 38 patients were hospitalized for infection 139 times (median 2 hospitalizations for infection per patient). Among these 38 patients, 13 had no organism identified on cultures (culture negative infection) while the remaining 25 (66%) had an organism identified during at least hospitalization for infection. Of the 38 patients hospitalized with infection, 18/38 (47%) had a gram positive organism (8 strep pneumonia, 11 staphylococcus Aureus, 2 nocardia), 11/38 (29%) had a gram negative organism (3 E.Coli, 4 Pseudomonas, 4 Hemophilus influenzae), 5/38 (13%) a mycobacterial infection (4 MAC, 1 M. gordonae), 15/38 (40%) a cytomegalovirus infection, 19/38 (50%), cryptococcus and/or cryptosporidium (18 cryptococcus AG, 4 cryptosporidium), and 12/38 (32%) a filamentous fungi infections (12 aspergillous). In aggregate, hospitalization for an opportunistic infection (e.g. cytomegalovirus, cryptococcus, filamentous fungi, myocobacteria, pneumocystis) occurred in 26/336 (8%) CLL patients during follow-up. Being male (OR 2.7; p=0.02), ZAP-70+ (OR 3.9; p=0.004), IGHV unmutated (OR 5.5; p=0.002), and receiving treatment (OR 4.7, p<0.001; Figure) were associated with increased risk of hospitalization for infection. Conclusions: Approximately 8% of newly diagnosed, community dwelling CLL patients will require hospitalization for opportunistic infection at some point during the course of their disease. Gender, disease factors (e.g. ZAP-70, IGHV status), and treatment characteristics are associated with infection risk. Disclosures: Zent: Genzyme: Research Funding; Genentech: Research Funding; Novartis: Research Funding; G.S.K.: Research Funding. Shanafelt:Celgene: Research Funding; Hospira: Research Funding; Genentech: Research Funding.

Abstract Abstract 4610 Introduction Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). Up to 50% of CLL patients develop infectious complications, and 30–50% of all deaths in CLL patients are attributed to infections. Despite these data, the available research on infectious complications in CLL is primarily limited to patients participating in clinical trials of chemotherapy, obscuring the distinction between the risk of infection due to the disease’s natural history relative to the risk associated with therapy related immune suppression. METHODS: The Mayo Clinic Rochester (MCR), a tertiary referral center in rural southeastern Minnesota, is also the primary hematology center for southeastern Minnesota, northern Iowa, and western Wisconsin. There are no metropolitan areas or hematology specialty centers within a ∼50 mile radius. To explore the natural history of infection in a community-based cohort of CLL patients, we used the Mayo Clinic CLL database to identify all patients with newly diagnosed CLL who resided within 50 miles of MCR and diagnosed between January, 1999 and December, 2009. The comparison cohort consisted of 689 adult patients who also resided within 50 miles of MCR who were seen for a general medical examination between September, 2002 and December, 2009 and who were enrolled as controls in a case-control study of non-Hodgkin lymphoma. All hospitalizations at MCR among both cohorts were audited to document hospitalization with infection and cross-referenced with the Mayo Clinic infection database, which includes all culture results obtained from hospitalized MCR patients. Serologies and viral assays were also reviewed. Patients whose cultures were negative but who were given a clinical diagnosis of infection (e.g. pneumonia) and who were treated with a full course of antibiotic therapy were considered to have a culture negative infection. RESULTS: In May 2010, there were 2022 CLL patients in the Mayo Clinic CLL Database diagnosed between 1999 and 2009. Of these, 174 (9%) were local CLL patients residing within 50 miles of MCR. Median age at diagnosis for these non-referred CLL patients was 69 years (range 27–97). Most had early stage disease (60% stage 0; 32% stage I-II). On prognostic evaluation, 121 (75%) patients were CD38 negative, 66 (61%) ZAP-70 negative, 47 (50%) IGHV mutated, and 56 (62%) had either no abnormality or 13q14- as a sole abnormality on FISH analysis. 64 (37%) patients progressed to require treatment for CLL during follow-up. After median follow-up of 4.0 years (range 0–11), 32 (18.4%) CLL patients were hospitalized with infection at least once as compared to 20/689 (2.9%) individuals in the control cohort (odds ratio=7.5; p<0.0001) Figure 1A. Even prior to receiving treatment for CLL, the rate of hospitalization for infection remained higher than the control cohort (p=0.002; Figure 1B). The 32 CLL patients hospitalized with infection were admitted with infection a total of 89 times (median 1 hospitalization for infection per patient). A specific infectious organism was identified by cultures or serologies in 60 (63%) of the 89 infections in CLL cases and 10/27 (37%) infections among controls. Hospitalization for an opportunistic infection (e.g. cytomegalovirus, cryptococcus, filamentous fungi, mycobacteria, Pneumocystis) occurred in 5/174 (3%) CLL patients during follow-up compared to 0/689 controls (p<0.001). Finally, we performed a pooled multivariable analysis of all patients (n=863) to identify factors (age, sex, CLL diagnosis, CLL treatment) associated with infection risk. Most factors were independently associated with hospitalization for infection [Age (per year, OR=1.03, p=0.02), sex (male, OR=4.0, p<0.001), diagnosis of CLL (OR=2.1, p=0.09), and treatment for CLL (OR=5.9, p<0.001)]. In univariate analysis of CLL patients [sex (OR=4.2, p=0.01), higher Rai stage (p=0.046), unfavorable (del 17p13; del 11q23) FISH [OR=4.6, p=0.02] and unmutated IGHV [OR=2.8, p=0.07]) were associated with risk of infection. CONCLUSIONS: In this cohort study, patients with newly diagnosed CLL had a 7.5-fold risk of hospitalization for infection relative to the control cohort. After 4 year follow-up, ∼1 in 5 CLL patients required hospitalization for infection. Although CLL treatment was a substantial risk factor for infection, the risk of infection among untreated patients remained higher than controls. Disclosures: Kay: Biothera: Research Funding; Clegene: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Glaxo Smith Kline: Research Funding; Hospira: Research Funding; Novartis: Research Funding; Supergen: Research Funding; Calistoga: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Emergent Biosolutions (Formerly Trubion): Membership on an entity’s Board of Directors or advisory committees. Zent:GlaxoSmithKline: Research Funding; Genentech: Research Funding; Genzyme: Research Funding.

Abstract Abstract 2893 Introduction: Monoclonal B-Cell Lymphocytosis (MBL) is a common asymptomatic condition characterized by a clonal B-cell population detected in the blood or bone marrow. The prevalence of MBL is approximately 3–5% in adults over age 40 but rises with age. MBL is a precursor state to CLL and other types of indolent non-Hodgkin lymphoma (NHL). Only a small subset of patients with MBL comes to clinical attention, typically during evaluation for low grade lymphocytosis (designated now as clinical MBL). The rate of progression to CLL requiring treatment among individuals with clinical MBL is ∼1%/yr, and the vast majority of patients with MBL will never develop a B-cell malignancy. Recent data indicate that individuals with MBL are at increased risk of infection similar to CLL. It is unknown whether individuals with MBL are at risk for other adverse outcomes associated with CLL, such as increased risk of non-hematologic cancers (NHC). We investigated the incidence of NHC among patients with clinical MBL and compared this to a cohort of general medicine patients and a cohort of CLL patients. Methods: Mayo Clinic Rochester (MCR) is the primary center for hematologic care in a region including southeastern Minnesota, northern Iowa, and western Wisconsin. No other hematology specialty centers are available within a 50 mile radius of MCR. To explore the risk of NHC in a local, community dwelling cohort of individuals with clinically-identified, CLL-phenotype MBL, we used the MCR CLL database to identify all individuals with newly diagnosed MBL seen in the MCR Hematology Division between January 1, 1999 and December 31, 2009. Analysis was limited to 154 MBL cases residing within 50 miles of MCR. The comparison cohort consisted of 596 adult general medicine patients, with no prior cancer, residing within 50 miles of MCR, who were seen for a general medical exam and enrolled as controls in a case-control study for NHL between April 25, 2004 and December 31, 2009. Rates of NHC in the MBL cohort were also compared to a cohort of 174 patients with newly diagnosed CLL seen in the same time interval as the MBL cohort and also living within 50 miles of MCR. NHC were identified using the Mayo Clinic Cancer Tumor Registry as well as review of medical records in all 3 cohorts. Patients with a NHC diagnosis >3 months prior to the diagnosis date of MBL/CLL were excluded from analysis while those with MBL/CLL and a NHC within 3 months of one another were considered to have a concurrent diagnosis. Results: There were 125 patients in the MBL cohort, 153 in the CLL cohort, and 596 in the control cohort after excluding patients with prior cancers. The MBL and CLL patients tended to be older (median age MBL=69, CLL=68, Control=58; p<0.0001) and more likely to be male (% male MBL=61, CLL=67, Control=46; p<0.0001) than the controls. After a median follow-up of 4.2 years (range 0–11), 20 (16%) individuals with MBL developed NHC as compared to 22 (4%) of the controls (Hazard Ratio (HR) MBL relative to control=5.0; 95% confidence interval (CI)=(2.6, 9.4; p<0.0001). Twenty CLL patients (13%) developed NHC, supporting a similar rate to that of MBL patients (HR MBL relative to CLL=1.3; 95% CI=(0.6, 2.5; p=0.49;See Figure). Specifically, the MBL cohort had a higher incidence of cancer of the breast, lung, and nervous system than that of the control cohort. The higher risk of NHC among individuals with CLL and MBL persisted even when patients with “concurrent diagnosis” of CLL/MBL and NHC were excluded (p=0.006) and when patients treated for progressive CLL were censored at the date of treatment (p=0.001) Finally, we performed a pooled multivariable analysis of all patients (n=874) adjusting for age, sex, major co-morbidities, presence of MBL, and diagnosis of CLL. Age (HR each year older=1.03; 95% CI 1.01–1.06; p=0.003), major comorbidities (HR=1.81; 95% CI 1.07–3.00; p=0.02), CLL (HR=2.10; 95% CI 1.01–4.01; p=0.04), and MBL (2.47; 95% CI 1.30–4.69; p=0.02) were independent risk factors for NHC. The results were similar when the effects of age was modeled in a non-linear (e.g. logarithmic) manner. Conclusions: In this cohort study, patients with newly diagnosed clinical MBL had a 2.5-fold increased risk of developing NHC relative to the control cohort. MBL was an independent risk factor for development of NHC after adjusting for age, sex, and other comorbidities. This finding adds to the growing evidence that clinical MBL has a distinct clinical phenotype. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding.