ALBERT

Description: INTRODUCTION: An adequate dose of CD34+ cells is necessary for autologous or allogeneic transplants of peripheral blood stem cells (PBSC), to ensure early and sustained hematopoietic engraftment and favorable clinical outcome. CD34+ cell dose was predictive of survival, posttransplant morbidity and rate of hematologic recovery following allogeneic T-cell-depleted BMT [Mavroudis et al. Blood, 1996]. High TNC doses have been found to influence the outcome of autologous and allogeneic BMT favorably. A low CD34+ cell dose results in higher mortality and poorer survival after blood and marrow stem cell transplantation from an HLA-identical sibling, and 2 x 106 CD34+ cells/kg has been suggested as minimum cell dose [S Singhal et al, BMT 2000]. There are no comparative data on the relationship of TNC dose and CD34+cell dose of unmanipulated marrow on transplant outcome. METHODS: Fifty-four patients received BMT from HLA-identical sibling donors between January 1999 and June 2004. Twenty-nine (51%) patients had Chronic Myeloid Leukemia, thirteen (24%) Acute Myeloid leukemia, five (9%) Non-Hodgkin’s Lymphoma (NHL), four (7%) Myelodysplastic syndrome, three (5%) Acute Lymphocytic Leukemia, one (2%) Chronic Lymphocytic Leukemia, one (2%) Myelofibrosis, one (2%) Multiple Myeloma (MM), one (2%) Hodgkin’s disease (HD) and one (2%) Aplastic Anemia. Nine patients received autologous, G-CSF mobilized marrow, after failing PBSC collection (7 NHL, 1 HD and 1 MM). These reflect the two populations of BMT patients now commonly seen. TNC and CD34+ cell doses of each graft were analyzed. RESULT: There was no correlation (r = 0.361) between the TNC and the CD34+ cell content of the grafts in either allogeneic (allo) (figure 1 below) or autologous (auto) BMT. The median TNC and CD34+ cell doses were 3.16x 108/kg and 3.67 x 106/kg respectively for allo patients and 3.62 x 108/kg and 1.61 x 106/kg for auto patients. In allo patients, TNC dose above 3.16x 108/kg correlated with better neutrophil (p=0.0130) and platelet engraftment (p=0.0002), while CD34+ cell dose above 3.67 x 106/kg correlated with better platelet engraftment (p= 0.0221), but not neutrophil engraftment (p=0.6106). Both TNC and CD34+ cell doses were not predictive of overall survival (p=0.1265, p=0.3216 respectively) in allo patients. Both TNC and CD34+ cell doses in auto patients did not correlate with neutrophil (p= 0.481 and 0.1122 respectively) engraftment, but CD34+ cell dose correlated with platelet engraftment (p= p= 0.0448). Average neutrophil recovery time was 20 days in both auto and allo patients, while platelet recovery time was 29 days for allo and 48 days for auto. Figure Figure bold]CONCLUSION: For patients undergoing allogeneic BMT, CD34+ count in the allograft may not add valuable information, while in patients who failed autologous PBSC mobilization and undergoing BMT, CD34+ counts may add useful information, particularly for platelet engraftment.

Description: Background: DLBCLpatients (pts) with an elevated international prognostic index (IPI) score are at an increased risk of disease relapse rate in the first year after completion of standard therapy with rituximab (R) -CHOP. Lenalidomide (len), an immunomodulatory drug, has activity in relapsed DLBCL. Len enhances the natural killer cell mediated antibody-dependent cellular cytotoxicity of rituximab in lymphoma cell lines and inhibits angiogenesis as well as alters cytokine production. Given the activity of len in DLBCL, we explored this combination as a consolidative approach for one year following R-CHOP therapy. Methods: Intermediate-high/high risk IPI patients with DLBCL were randomized to len (arm A) alone or len and rituximab (arm B). The primary endpoint of the study was to assess the one year disease-free survival (DFS). We expected that a 25% difference of relapse from an expected 40% relapse based on historical controls would have clinical significance when compared with current standard therapy. Patients in arm A received len at a dose of 25 mg daily for 21 days of 28 days. Patients on arm B received len at a dose of 20 mg daily for 21 days of 28 days along with rituximab on day 8 of even cycles. Aspirin was administered to all patients. Treatment on both arms was continued for one year. Treatment was discontinued for disease progression. Len dose adjustments were incorporated in the protocol. Results: Forty-four pts, 22 arm A/ 22 arm B, 21 female/23 male, with a median age of 59.6 yrs (range 19-85 yrs) were enrolled. The median IPI was 4 for patients over the age of 60 and the median aa-IPI was 3. Three patients received radiation to areas of bulky disease. At a median follow-up of 3.64 years, the two-year DFS and overall survival (OS) was 86% (72%-94%) and 91% (77%-96%), respectively. For patients in arm A and arm B the two-year DFS was 86% (63% - 95%)% vs. 86% ( 62% - 95%)% (figure 1) and the two-year OS was 86% (62% - 95%)% vs. 95% ( 72% - 99%)% (figure 2), respectively (P=NS). Two pts discontinued treatment due to adverse events. The most common grade 3-4 toxicities include neutropenia (57%), fatigue (9%), diarrhea (8%), rash (1%). Related grade 1-2 toxicities include endocrine abnormalities [hypo/hyperthyroidism] (29.5%) and rash (65%). Conclusions: Len alone as maintenance therapy demonstrates significant clinical activity following standard chemotherapy and improves DFS and OS in DLBCL patients with high-risk prognostic features as compared with historical controls. This trial is registered with NCI- #NCT00765245 Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Reddy: ImmunoGen: Consultancy; PCYC: Consultancy; Gilead: Other: Speaker; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding. Off Label Use: Lenalidomide following R-CHOP. Park:TEVA: Research Funding; Seattle Genetics: Research Funding; Jannsenn: Other: Travel.

Description: Background: DLBCL is the most common subtype (30-40%) of non-Hodgkin lymphoma and 50-60% of patients (pts) are cured with standard R-CHOP therapy. Among pts who fail R-CHOP, only 10-20% experience prolonged disease-free intervals with high-dose chemotherapy and autologous stem cell transplant (SCT). In particular, pts relapsing within 12 months (mo) of diagnosis and/or refractory pts have a very poor outcome (Crump, ASCO 2016). In addition, many pts are SCT-ineligible due to advanced age and/or comorbidities (Friedberg, ASH Educ Program 2011). Therefore, R/R DLBCL represents a clear unmet medical need. Ibrutinib (ibr), a first-in-class, oral, once-daily inhibitor of Bruton's tyrosine kinase, has shown activity as a single agent in R/R DLBCL, particularly in the non-germinal center B-cell-like (non-GCB) subtype (Wilson, Nat Med 2015). Lenalidomide (LEN) is an immunomodulatory agent that has shown activity in combination with rituximab (RTX) in phase 2 studies of R/R DLBCL (Wang, Leukemia 2013). This multicenter, open-label, phase 1b/2 study is designed to evaluate the safety and efficacy of ibr in combination with LEN and RTX in pts with R/R DLBCL. Here, we report preliminary results of the phase 1b portion of the study. Methods: The primary objective of the phase 1b portion is to determine the maximum tolerated dose and/or recommended phase 2 dose of ibr in combination with LEN and RTX in R/R DLBCL using a modified 3+3+3 design; the secondary objective is overall response rate (ORR) (Cheson, J Clin Oncol 2007). In phase 2, efficacy of the combination will be evaluated in R/R non-GCB DLBCL. SCT-ineligible pts, aged ≥18 years with histologically confirmed R/R DLBCL after ≥1 prior therapy, ECOG PS 10%) grade 3/4 AEs were neutropenia (32%), thrombocytopenia (14%) and maculopapular rash (11%). Any-grade serious AEs (SAEs) occurred in 15 (41%) pts (Table 1). Dose-limiting toxicities (DLTs) were observed in 5 (13%) pts (rash [2], neutropenia [2], sepsis [1]; Table 1). Due to 3 DLTs in Cohort 1, a cohort at Dose Level −1 was opened. As 1 DLT was observed at this dose level, re-escalation to higher levels (starting at 15 mg LEN) occurred. Twenty-four (65%) pts discontinued treatment due to disease progression (14/24), AE (8/24), and withdrawal of consent (2/24); 14 (38%) died, primarily due to progressive disease (n=9). Deaths due to AEs (n=4) included E. coli sepsis, cardiac arrest (after progression and subsequent antineoplastic therapy), pneumonia, and worsening DLBCL. Cause of death was unknown in 1 pt. In the response-evaluable population (Table 2), on 10 mg LEN (n=7), there were no responses. On 15 mg LEN (n=18, including 2 pts with DLTs who received ≤15 days of study drug), the ORR was 44%; there were 3 complete responses (CRs) and 5 partial responses (PRs, among them, 3 pts with refractory disease); 6/9 (67%) with non-GCB/ABC DLBCL responded (including all 3 CRs). On 20 mg LEN, 2 response-evaluable pts did not respond, other response evaluations are pending. Conclusions: Based on safety data from the phase 1b portion of the study and the DLRC recommendation, the phase 2 portion of the study is being initiated at the 20 mg LEN dose level in combination with RTX and ibr. Preliminary efficacy results demonstrate responses at 15 mg LEN and suggest that a dose level above 10 mg LEN might be needed to induce a response in R/R DLBCL. In summary, despite small pt numbers, the results seen in this high-risk refractory DLBCL population are encouraging. Disclosures Goy: Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Writing support, Speakers Bureau; Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ghosh:Gilead: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; SGN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Research Funding. Dang:Eisai: Research Funding; Seattle Genetics: Research Funding; Novartis: Honoraria; Pharmacyclics LLC, an AbbVie Company: Research Funding; Valor: Research Funding; Oncomed Pharmaceuticals Inc: Research Funding. Knapp:Insys Therapeutics, Inc.: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Kingsley:Pharmacyclics LLC, an AbbVie Company: Equity Ownership; Gilead: Equity Ownership. Tran:Pharmacyclics LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses; AbbVie: Equity Ownership. Ping:Exelixics, Inc.: Employment, Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Beaupre:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Other: Leadership; Travel, Accommodations, Expenses, Patents & Royalties, Research Funding. Neuenburg:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. Ruan:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics, LLC, an AbbVie Company: Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Janssen: Research Funding.

Description: Abstract 4954 Background: Standard chemotherapy with R-CHOP has a cure rate of approximately 60% for diffuse large B-cell lymphoma (DLBCL). Salvage therapy followed by autologous stem cell transplantation can cure 40–50% of patients. For patients who relapse following high dose therapy, salvage regimens are incurable. Combination therapy with rituximab, gemcitabine, vinorelbine, and liposomal doxorubicin (R-GND) has been shown to be efficacious in the setting of Hodgkin Lymphoma. We present the results of R-GND therapy among pts with relapsed refractory DLBCL. Methods: Patients treated with R-GND at Vanderbilt University Medical Center for DLBCL from January 2004 through December 2010 with R-GND regimen are presented. Clinical outcomes studied included response to therapy, overall mortality, and drug toxicities, in particular grade 3/4, including neutropenia, anemia, and opportunistic infection. Wilcoxon rank sum, chi square analysis, and Kaplan-Meier analysis were performed using SPSS-19 software. Results: Twenty one pts with relapsed large cell lymphoma following immuno-chemotherapy were treated with R-GND therapy. The median age of pts was 60.5 (range 24–81). Eleven pts were male. The cell of origin of DLBCL based on pathology was available on 13 patients. Ten were germinal center histogenic origin and 3 patients had DLBCL of non-germinal center origin. The median number of prior therapies was 2. Seven pts underwent prior autologous stem cell transplantation. Eight pts received prior radiation therapy. Six pts were stage II at initial diagnosis, 2 were stage III and 13 were stage IV. Rituximab 375mg/m2, gemcitabine 1000 mg/m2, vinorelbine at 100 mg/m2 and liposomal doxorubicin 30mg/m2 were administered on day 1 and day 8 of every 21 day cycle. Dose reductions were based on patient tolerability. Colony stimulating factors was used on day 9 of each cycle. Radiological studies were performed after 2 cycles or earlier if there was clinical suspicion for progression. The total number of cycles for all patients was 42 cycles. The major grade 3/4 toxicities were anemia in 42%, thrombocytopenia in 38%, neutropenia in 33%, infection in 14% and respiratory failure in 4% of patients. Objective responses were noted in 9 patients (42%). Three patients attained a complete response to therapy and 6 pts had a partial response or stable disease. The median progression free survival was 1.3 months. The median overall survival of all patients was 3.9 months. The three patients attaining a complete response had DLBCL of non-germinal center cell origin. Conclusions: R-GND is an alternative regimen with an overall response rate of 42% among patients with relapsed diffuse large B cell lymphoma. The interesting observation of the 3 patients who attained a complete response were of non-germinal center origin of DLBCL warrants further exploration of the role of gemcitabine based combination treatment in large cell lymphoma. Disclosures: No relevant conflicts of interest to declare.