Barta, Stefan K

Abstract Introduction The International Prognostic Index (IPI) and the age-adjusted IPI (aaIPI) are the most commonly used tools to predict outcomes in patients with Non-Hodgkin Lymphoma (NHL). The IPI does not take into account sex or race. In the pre-rituximab era, sex was found to be a strong predictor of poor prognosis in low-grade lymphomas. While there is emerging evidence that female sex is associated with better survival in patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP, much less is known about the prognostic impact of race. We retrospectively assessed the impact of sex and race on overall survival in patients with indolent and aggressive NHL treated at any stage with rituximab at our institution. Methods We retrospectively identified all patients >/=18 years who were diagnosed with B-cell NHL (except SLL/CLL and Burkitt lymphoma) between 1/1/2000 and 12/31/2010 and received rituximab at any stage as part of their therapy at the Montefiore Medical Center. We collected data on histology, age (<60 vs. >/=60), date of diagnosis, date and status at last follow-up, and stage from the MECCC Cancer registry, and we obtained data on the Charlson Comorbidity Index (CCI) from Clinical Looking Glass® (CLG), an interactive software application developed at Montefiore Medical Center which integrates clinical and administrative datasets. The histological subtypes DLBCL and grade 3 follicular lymphoma (FL) were classified as “high-grade lymphoma” (HGL), while other types of lymphoma were termed “low-grade lymphoma” (LGL; these included marginal zone lymphoma, mantle cell lymphoma, grade 1 & 2 FL, and malignant lymphoma NOS). Self-reported race was classified as White, Black, Hispanic or “Other”. Only <2% of the patients were of “Other” racial background and therefore excluded from this analysis. The primary outcome was overall survival (OS) calculated as time from diagnosis to time of death. We used the Kaplan-Meier (KM) method to describe OS for race and sex and the log-rank test to test for significance (p<0.05). We used a Cox proportional hazard (CPH) model to assess the association of variables with OS. Except for age, race and sex, variables that were not significantly associated with OS (i.e. p-value>0.10 in the multivariate model) were excluded from the final model (backward elimination). Results 353 patients were included in the analysis. Median follow-up for all patients was 37.3 months (range 0.03-202.40). Baseline characteristics between male and females were similar with the exception of age at diagnosis and histology (see Table 1). On univariate analysis there was no OS difference between male and female patients (p=0.13), while race was associated with significant differences in OS (p=0.04; see Fig. 1). In the multivariate model, only stage >/=3 was associated with worse survival (Hazard Ratio [HR] 2.78, 95% CI 1.62-4.77; p<0.0001), but there was no significant association with OS for type of lymphoma (HGL vs. LGL) or the CCI (low vs. high score) and these 2 variables were therefore eliminated from the final multivariate model. In the final multivariate model, female sex was associated with a 37% reduction in the risk of death (HR 0.63; 95%CI 0.40-0.98; p=0.04), while race was no longer associated with OS (Hispanic vs. White: HR 0.76, 95%CI 0.41-1.40, p=0.38; Black vs. White: HR 0.66, 95%CI 0.40-1.10; p=0.11; Black vs. Hispanic: HR 1.15; 95% CI 0.63-2.08, p=0.65). Conclusions Female patients treated at any stage with rituximab for high-grade and low-grade B-cell NHL at our institution experienced longer OS. However, we observed no racial disparity in survival in our analysis. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas associated with poor prognosis and repeated recurrence for most subtypes. Currently, anthracycline-based therapies such as cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like therapies are recommended as the first-line treatment for PTCL, but the prognosis remains poor with most patients relapsing within 5 years. Thus, improved treatment strategies are still needed. Belinostat is a potent, pan-histone deacetylase inhibitor that was recently approved in the United States for the treatment of patients with relapsed or refractory PTCL (R/R PTCL). Approval was based on results from the pivotal Phase 2 BELIEF study (O'Connor et al, JCO, 2015) of belinostat in R/R PTCL, which demonstrated durable clinical benefit (objective response rate [ORR] 25.8%) and tolerability. Since belinostat (Bel) and each of the components of the CHOP regimen target different aspects of the cell cycle with different mechanisms of action, there is potential for a synergistic effect of a Bel-CHOP combination treatment regimen for patients with PTCL. Methods: Patients with PTCL received CHOP in association with 1000 mg/m2 of belinostat on various schedules, repeated every 21-days for up to 6 cycles. The cohort schema followed a traditional "3+3" dose escalation design. The objective of Part A of the study was to determine the Maximum Tolerated Dose (MTD) of the Bel-CHOP combination. Once the MTD was determined, at least 10 more patients were to be treated in the Expansion Phase (Part B). Belinostat was to be administered as a 1000 mg/m2 IV infusion once daily for up to 5 days, depending on the assigned cohort (Fig 1). The starting cohort was Cohort 3 (CHOP + 1000 mg/m2 of daily belinostat on Days 1-3). Patients received primary prophylaxis with growth factor (G-CSF) support. Dose-limiting toxicities (DLT) were considered during the 1st cycle and included: non-hematological toxicity Grades 3-4, platelet count &lt; 25 X 109/L at any time or ANC &lt; 0.5 X 109/L lasting more than 7 days despite G-CSF administration. The primary endpoint of the study was the determination of the MTD of the Bel-CHOP combination. Secondary endpoints included safety, tolerability and ORR (complete response [CR] + partial response [PR]) and pharmacokinetics. Results: A total of 23 patients were enrolled in the study, 11 of which were treated in Part A. One patient in Part A was deemed inevaluable because the patient died due to disease progression before completing Cycle 1. The MTD was determined to be 1000 mg/m2 on Days 1-5 (Cohort 5); 12 more patients were then treated at this dose level (Part B). The only DLT experienced in the study was in Cohort 3 (Grade 3 Nausea and Vomiting). At the time of this abstract, 18/23 patients (78%) have completed all 6 cycles of Bel-CHOP, with 87% completing at least 4 cycles. Ten patients (43%) had at least one serious adverse event (SAE) and 18 (78%) had at least one Grade 3 or 4 adverse event (AE). The most frequent Grade 3/4 AEs were hematological in nature: neutrophil count decreased (26%), anemia (22%), neutropenia (17%) and white blood cell count decreased (17%). The ORR for the18 patients that have completed an End of Study Visit is 89% (16/18), with the vast majority achieving a CR [72% (n=13)], and 17% (n=3) a PR. Progressive disease was reported in 2 patients. Conclusions: These results demonstrate that the combination of belinostat with CHOP (Bel-CHOP) is well tolerated, with all components of CHOP and belinostat being given at their standard therapeutic doses. The rates of AEs were consistent with those typically reported with CHOP alone, and clinical activity was demonstrated with a response rate of 89% based on 18 evaluable patients. Thus, Bel-CHOP is a promising new regimen in PTCL that will be further tested in a Phase 3 randomized trial. Table. Table. Figure 1. Summary of Demographic and Baseline Characteristics AITL= angioimmunoblastic T-cell lymphoma; ALCL =anaplastic large-cell lymphoma; ALK = anaplastic lymphoma kinase; NOS = not otherwise specified Figure 1. Summary of Demographic and Baseline Characteristics. / AITL= angioimmunoblastic T-cell lymphoma; ALCL =anaplastic large-cell lymphoma; ALK = anaplastic lymphoma kinase; NOS = not otherwise specified Disclosures Barta: Seattle Genetics: Research Funding. Bhat:Spectrum Pharmaceuticals, Inc: Employment. Song:Spectrum Pharmaceutical, Inc: Employment. Choi:Apectrum Pharmaceuticals, Inc: Employment. Allen:Spectrum Pharmaceuticals, Inc: Employment. Foss:Spectrum Pharmaceuticals; Celgene: Seattle Genetics: Infinity; Millenium: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Abstract Background: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature T-cell and natural-killer-cell aggressive non-Hodgkin lymphomas associated with poor prognosis with current therapies. Numerous studies have reported poor survival for PTCL patients with a median Overall Survival (OS) shorter than 2 years and 5-year survival rates of <30%. Traditionally, patients with PTCL have been treated with a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like first-line chemotherapeutic regimen. Unfortunately, the prognosis remains poor with most patients relapsing within 2 years. Thus, improved front line treatment strategies are needed. Pralatrexate (Folotyn) is a folate analogue metabolic inhibitor that was the first drug approved in the US for the treatment of patients with relapsed or refractory PTCL (R/R PTCL). Approval was based on results from the pivotal Phase 2 PROPEL study (O'Connor et al, JCO, 2011) of pralatrexate in R/R PTCL, in which pralatrexate monotherapy demonstrated a durable clinical benefit (objective response rate of 29%). Pralatrexate is administered intravenously (IV) at a dose of 30 mg/m2 weekly for 6 weeks of a 7-week treatment cycle. Since pralatrexate and each of the components of the CHOP regimen target different aspects of tumor cell growth and proliferation, there is a potential for synergistic anti-tumor effect, and limited additive toxicities. Objectives: The primary endpoint of the study is the determination of the MTD of pralatrexate in combination with CHOP (Fol-CHOP) in previously untreated PTCL patients. Secondary endpoints included safety, tolerability and ORR (complete response [CR] + partial response [PR]) and pharmacokinetics. Methods: In this study, patients with PTCL received CHOP in combination with pralatrexate, repeated every 3-weeks for up to 6 cycles. Part 1 of the study was to determine the Maximum Tolerated Dose (MTD) of the Fol-CHOP combination. Once the MTD was determined, an additional 10 patients were treated in the Expansion Phase (Part 2). The cohort schema followed a traditional "3+3" design. Pralatrexate was to be administered as 10, 15, 20, 25, or 30 mg/m2 IV push over 3 to 5 minutes on Days 1 and 8 of each cycle. The starting cohort was CHOP + 10 mg/m2 of pralatrexate. Patients received prophylaxis with acyclovir and sulfamethoxazole/trimethoprim during the study and primary prophylaxis with growth factor (filgrastim or pegfilgrastim) support. Dose-limiting toxicities (DLT) were considered during the 1st cycle and included: Severe infections, study treatment-related non-hematological toxicity Grade 3-4, platelet count < 25 X 109/L at any time or ANC < 0.5 X 109/L lasting more than 7 days despite G-CSF administration. Results: A total of 12 patients have been enrolled in Part 1 of the study at the time of abstract submission. Nine patients have completed Cycle 1 and no DLT was reported. Among these nine patients, three patients each were treated at CHOP + 10 mg/m2, 15 mg/m2 and 20 mg/m2 of pralatrexate. One patient (11%) treated with CHOP + 10 mg/m2 had one serious adverse event (SAE) of febrile neutropenia that was deemed unrelated to any study drug. Only four Grade 3 AEs (anemia, constipation, mucosal inflammation, and nausea) were reported, in one patient (11%). The enrollment into the study continues. Conclusions: These interim results demonstrate that the combination of pralatrexate with CHOP (Fol-CHOP) is well tolerated, with all components of CHOP as well as pralatrexate being given at close to or at standard doses. The rates of AEs are comparable to those typically reported with CHOP alone. The study is ongoing to confirm the MTD and to assess preliminary efficacy of the Fol-CHOP combination. Updated results will be presented at the meeting. Disclosures Oki: Novartis: Research Funding. Barta:Celgene, Merck, Seattle Genetics: Research Funding; Janssen: Honoraria, Speakers Bureau. Sharma:Spectrum Pharmaceuticals: Employment. Song:Spectrum Pharmaceuticals: Employment. Mourya:Spectrum Pharmaceuticals: Employment.

As treatment of HIV has improved, people living with HIV (PLWH) have experienced a decreased risk of AIDS and AIDS-defining cancers (non-Hodgkin’s lymphoma, Kaposi sarcoma, and cervical cancer), but the risk of Kaposi sarcoma in PLWH is still elevated about 500-fold compared with the general population in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AIDS-Related Kaposi Sarcoma provide diagnosis, treatment, and surveillance recommendations for PLWH who develop limited cutaneous Kaposi sarcoma and for those with advanced cutaneous, oral, visceral, or nodal disease.

PURPOSE Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger. PATIENTS AND METHODS We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score–weighted (PSW) analysis were performed. RESULTS Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2). CONCLUSION In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.

BACKGROUNDIn an ECOG‐ACRIN Cancer Research Group study (E1496), maintenance rituximab (MR) was reported to prolong progression‐free survival (PFS) in comparison with observation (OBS) alone in patients with indolent lymphoma after induction chemotherapy. Here the long‐term follow‐up of the same patient cohort is presented.METHODSPatients with indolent lymphoma received induction chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP). Patients with stable disease or a better response were then randomized to weekly rituximab (375 mg/m2 × 4 doses) every 6 months for 2 years (MR) or to OBS. The primary endpoint was PFS; the secondary endpoints were overall survival (OS), response rate, and toxicities.RESULTSOf the 387 patients who initially received CVP induction, 158 were randomized to MR, and 153 were randomized to OBS. After a median follow‐up of 11.5 years, patients on MR had longer median PFS (4.8 years) than patients on OBS (1.3 years; hazard ratio [HR], 0.49; P < .0001). However, there was no difference in OS between MR and OBS (10‐year OS, 67% vs 59%; median OS, 13.5 years vs not reached; HR, 0.91; P = .69). Other than MR, only minimal residual disease after induction therapy was significantly associated with PFS on multivariate analysis (HR, 0.71; P = .02). A low initial tumor burden, minimal residual disease, follicular histology, a low Follicular Lymphoma International Prognostic Index score, and female sex were associated with longer OS. There was no increase in the rate of second primary malignancies with MR vs OBS.CONCLUSIONSWith long‐term follow‐up, MR did not influence OS. The PFS benefit was maintained. MR should be considered optional for patients with indolent B‐cell lymphoma. Cancer 2016;122:2996‐3004. © 2016 American Cancer Society.

AbstractCentral nervous system (CNS) involvement with diffuse large B‐cell lymphoma (DLBCL) is a relatively uncommon manifestation; with most cases of CNS involvement occuring during relapse after primary therapy. CNS dissemination typically occurs early in the disease course and is most likely present subclinically at the time of diagnosis in many patients who later relapse in the CNS. CNS relapse in these patients is associated with poor outcomes. Based on a CNS relapse rate of 5% in DLBCL and weighing the benefits against the toxicities, universal application of CNS prophylaxis is not justified. The introduction of rituximab has significantly reduced the incidence of CNS relapse in DLBCL. Different studies have employed other agents for CNS prophylaxis, such as intrathecal chemotherapy and high‐dose systemic agents with sufficient CNS penetration. If CNS prophylaxis is to be given, it should be preferably administered during primary chemotherapy. However, there is no strong evidence that supports any single approach for CNS prophylaxis. In this review, we outline different strategies of administering CNS prophylaxis in DLBCL patients reported in literature and discuss their advantages and drawbacks.