Inwards, David J.

Abstract Twenty-eight patients with relapsed or refractory CD20+ NHL have been enrolled in an ongoing phase I trial of dose-escalated 90YZ followed by high-dose BEAM and autotransplant in which the 90YZ dose is patient-specific based on dosimetry. 90YZ doses are calculated to deliver cohort-defined radiation doses (100, 300, 500, ... cGy) to critical organs (liver, lung or kidney), with 3–6 patients per group. On D -22, rituximab (R) 250 mg/m2 is infused followed by the imaging dose of 111In Zevalin® (5 mCi). Imaging is performed immediately post-injection and at 4, 24, 72, and 144 hours; dosimetry is performed on D -15. On D -14, R 250 mg/m2 is administered followed immediately by 90YZ at the dose calculated to deliver the cohort-prescribed absorbed radiation dose to the critical organ. On D -6 through -1, patients receive high-dose BEAM. On D0, a minimum of 2.0 X 106 CD34+ cells/kg is infused and G-CSF 5 μg/kg SQ daily begun. The median age was 54 (range: 25–72) years. NHL histologic subtypes were as follows: mantle cell 5, diffuse aggressive 13, low grade 5, and transformed 5. Most had received 3 or more treatment regimens, including R. The toxicity profile was similar to that associated with high-dose BEAM and included a decrease in DLCO for most patients with one patient at the 500 cGy dose level experiencing a transient decline to below 50% of the predicted value corrected for hemoglobin. The most common grade III/IV toxicities were infection, fever, stomatitis, nausea, vomiting, diarrhea, hemorrhage, and edema. One patient experienced transient veno-occlusive disease at the 700 cGy dose level. Engraftment occurred at a median of 10 days (range:8–18) to granulocytes ≥ 500/μL, and 21 days (range:13–40days) to platelets ≥20,000/μL . With a median follow-up of one year, the 3 year overall and progression-free survivals are 60% and 50%, respectively. Figure Figure 90-Y Zevalin Dosing by Cohort (median; range) Cohort (cGy) Total Dose (mCi) mCi/kg 100 (n=3) 5 (2–14) .06(.05–.12) 300 (n=7) 22(14–57) .25(.18–.63) 500 (n=6) 31(16–48) .40(.14–.63) 700 (n=6) 37(26–55) .38(.27–.73) 900 (n=3) 28(27–37) .32(.27–.44) 1100 (n=3) 48(29–65) .57(.50–.75) The liver was the critical organ in nearly all cases. Patient-specific doses calculated to deliver a cohort-prescribed absorbed radiation dose to the critical organ were highly variable suggesting that dosing based on weight and not dosimetry is likely to result in a wide range of absorbed dose to critical organs. In the context of this study, 90YZ has been administered to eight patients at doses of .5 mCi/kg or greater. We conclude that with careful dosimetry, 90YZ doses higher than the conventional .4 mCi/kg may be safely combined with BEAM and autotransplant. Accrual continues at the 1300 cGy dose level.

Abstract The infused autograft absolute lymphocyte count (A-ALC) is an independent prognostic factor for survival after autologous hematopoietic stem cell transplant (AHSCT) in non-Hodgkin’s lymphoma (NHL). Previous studies have shown that A-ALC directly correlates with the peripheral blood absolute lymphocyte count (PC-ALC) at the time of apheresis collection. However, factors affecting the PC-ALC at apheresis remain undefined. We hypothesized that one possible factor impacting PC-ALC may be the time interval from last chemotherapy to stem cell collection (TILC). Data from 160 patients who underwent AHSCT for treatment of relapsed NHL at Mayo Clinic between 1993 and 2001 were collected and analyzed. The primary end point of this study was correlation between TILC and PC-ALC, and our analysis revealed a strong correlation (r = 0.67, p < 0.0001). Further analysis revealed higher PC-ALC numbers in patients with TILC ≥ 60 days versus TILC < 60 days (median of 7.44 x 109/L in the ≥ 60 day group versus 3.87 x 109/L in the < 60 day group, p < 0.0001). Both the median overall survival (figure below) and the progression-free survival were longer in the TILC ≥ 60 days group versus the TILC < 60 days group (76 versus 21 months, p < 0.0037; 76 versus 11 months, p < 0.018, respectively). These findings were independent of other prognostic indicators for relapsed NHL patients undergoing APHSCT. The data supports our hypothesis that TILC affects PC-ALC and survival post-AHSCT in NHL. Figure Figure

Abstract Purpose: Mantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1, a member of the phosphatidylinosital 3 kinase (PI3K) pathway. This study tested whether CCI-779, which inhibits the PI3K pathway at the level of the mammalian target of rapamycin (mTOR) could produce tumor responses in patients (pts) with MCL. Patients and Methods: Eligible pts had biopsy-proven, cyclin D1 positive MCL and had relapsed or were refractory to therapy. Pts received CCI-779 250 mg IV every week as a single agent. Pts were re-staged after 1 cycle (4 doses) and every 3 cycles thereafter. Pts with a tumor response after 6 cycles were eligible to continue drug for a total of 12 cycles or 2 cycles after complete remission (CR) and then were observed. Results: Thirty-five pts were enrolled and evaluable for toxicity; 1 patient had MCL by histology but was cyclin D1 negative and ineligible for efficacy evaluation. The median age was 70 years (range, 38–89), 91% were stage 4, and 69% had ≥ 2 extranodal sites. Pts had received a median of 3 prior therapies (range, 1–11) and 54% were refractory to their last treatment. The overall response rate was 38% (13/34) with 1 CR (3%) and 12 PRs (35%), surpassing the pre-defined criteria for a promising agent. Responses tended to occur rapidly with median time to response of 1 month (range, 1–8). To date, 26 patients have progressed, with a median time-to-progression of 6.8 months (95% CI: 3.8 – 9.7). Median duration of response for the 13 responders was 5.7 months (95% CI: 5.2 – 13.2). Overall, 32 out of 35 patients who received treatment had grade 3 or 4 toxicity. The most common toxicities were hematologic with grade 3 (n=24) or grade 4 (n=4). Thrombocytopenia was the most frequent grade 3/4 toxicity (n=25) and the largest cause of dose-reductions, although counts typically recovered within one week. Only 4 patients could tolerate sustained 250 mg per week throughout their treatment (including one who went on to alternate treatment after 1 cycle) and the median dose/month was 175 mg. Conclusions: Single-agent CCI-779 has substantial anti-tumor activity in relapsed MCL. This study demonstrates that agents, which selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. The high response rate warrants further studies of this agent in MCL, but the high incidence of hematologic toxicity suggests that a lower dose should be explored. CCI-779 at 25mg is currently being evaluated in MCL through an NCCTG trial

7559 Background: Waldenström macroglobulinemia (WM) is a rare indolent lymphoma commonly treated with rituximab (R)-based therapy. The use of rituximab maintenance (mR) in WM is controversial. We present a case-control study of patients (pts) with WM treated with mR. Methods: Pts evaluated at Mayo Clinic, Rochester with active WM that received mR between 1/2000 & 6/2018 were included. Cases comprised pts who received mR following R-based induction as primary therapy. Cases were matched based on the time of diagnosis in 1:2 ratio with a control group treated with R-based primary induction therapy without mR. Time to event analyses were performed from initiation of R-based induction. Results: Of 776 pts with active WM, 42 (5%) cases received mR and 84 pts were selected as controls. The median follow-up and the proportion of high risk pts were comparable between the two cohorts (Table). Pts in the mR cohort show a trend toward longer time to next therapy (TTNT) and a significantly longer overall survival (OS) compared to the control group (Table). The R-based induction therapies were comparable in the two cohorts (p = 0.6). Median duration of mR was 1.9 yrs (95% CI 1.6-2) and mR was used most frequently every (q) 2 (range 1-6) months. Of the 42 mR pts, 25 (60%) received an R-based combination for induction and 17 (40%) received R monotherapy as induction. Five (12%) pts discontinued mR due to toxicity, infections were reported in 13 pts (31%) during mR therapy and 3 pts (7%) received IVIg infusions for recurrent infections. Conclusions: R-based induction followed by mR demonstrates a longer OS in WM compared to R-treated control population not receiving mR, albeit at a high rate of infections. Despite limitations of a retrospective study, with a heterogeneously treated cohort, these data add to the body of literature supporting Rituximab maintenance. Results from an ongoing randomized controlled trial are awaited. [Table: see text]

7526 Background: Stem cell transplant (SCT) was considered to be beneficial in CLL patients with Richter transformation (RT). We report a single center experience of SCT for RT. Methods: CLL patients with biopsy-confirmed RT to DLBCL who underwent SCT were identified from Mayo Clinic CLL database, and clinical information was abstracted by chart review. Survival analysis was done with the Kaplan-Meier method. Results: Twenty-four of 204 RT patients underwent SCT, 20 autologous and 4 allogeneic. The median lines of prior CLL therapy was 1 (range 0-4). Only 4 patients were exposed to ibrutinib prior to RT. The median age at RT diagnosis was 62 (range 41-73). Five of 17 (29%) patients had bulky disease (≥ 5 cm), 12 of 20 (60%) had elevated LDH, and 6 of 15 (40%) had TP53 disruption (del(17p) or TP53 mutation). The median lines of RT therapy prior to SCT was 2 (range 1-4); treatments included R-CHOP-like alone (n = 7), platinum-based alone (n = 1), both R-CHOP-like and platinum-based (n = 11), novel agents (n = 2), and high dose MTX-based (n = 3). Response prior to SCT was CR in 12 (50%) and PR in 12 (50%) patients. The median time from RT diagnosis to SCT was 6.8 months (range 3.3-42.3). After a median follow-up of 52.7 months after SCT, there were 10 RT relapses, 4 CLL progression, and 11 deaths (7 RT, 1 CLL and 3 unrelated). The median progression-free survival (PFS) was 28.5 months (95% CI 8.3-NA; 1-year PFS 61.8%, 2-year PFS 50.5%). The median post-SCT survival was 56.3 months (95% CI 30.6-76.6; 2-year survival 82.0%, 4-year survival 65.6%). Elevated LDH was associated with worse PFS (median 8.9 months vs NA, P= 0.014) and a trend of worse post-SCT survival (53.7 vs 67.4 months, P= 0.153). Other factors including age, prior CLL treatment (untreated vs treated), bulky disease, response prior to SCT, and TP53 disruption were not associated with PFS or post-SCT survival. Among the 4 allogeneic SCT patients, 1 had RT relapse 10.5 months after SCT and was treated with venetoclax, ibrutinib and obinutuzumab and remained alive at last follow-up (12.9 months after SCT). All 3 other patients remained in remission and alive at last follow up (15.6, 16.1 and 108.5 months after SCT, respectively). Conclusions: SCT may benefit select RT patients. The role of SCT in the novel agent era needs further study.

7509 Background: Waldenstrom macroglobulinemia (WM) is a rare lymphoma for which scant comparative data exist to guide frontline therapy. Herein, we compare 3 commonly used regimens in WM: R-Benda, DRC, and BDR in frontline setting. Methods: Patients (Pts) with active WM seen at Mayo Clinic between 2000 & 2018 who received R-Benda, DRC or BDR as primary therapy were included in this retrospective study. Response rates were assessed by Consensus Criteria. All time to event analyses were performed from the frontline therapy, using Kaplan-Meier method. Results: The study included 172 pts with active WM (R-Benda, n=67, DRC, n=75, BDR, n=30).The median follow-up for the entire cohort was 3.7 years (y) (95% CI 3.7-3.0). Baseline characteristics, including IPSS, and time to frontline therapy from WM diagnosis were similar across the 3 cohorts. Clinically relevant endpoints are shown in the Table. Hematologic and non-hematologic toxicities were similar across the 3 groups. Grade 3 neuropathy requiring treatment discontinuation was encountered in 13% pts treated with BDR. 56 pts received subsequent salvage therapy [(10% in R-Benda arm, 44% in DRC arm, & 53% in BDR arm]; 29% pts in the R-Benda arm and 30% pts in DRC arm received a PI-based regimen while 69% pts in the BDR arm received alkylator-rituximab based therapy. Conclusions: Outcomes (MRR, TTNT and EFS) with frontline R-Benda are superior in comparison to frontline DRC or BDR in patients with WM. Clinically relevant endpoints are not significantly different with DRC vs. BDR. The toxicity profile across the 3 groups was comparable. [Table: see text]

7041 Background: Prognostic factors for diffuse large B-cell lymphoma (DLBCL) at day 100 post-autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT) have not been evaluated. We previously reported that absolute monocyte (AMC)/lymphocyte count (ALC) prognostic score (AMLCPS) at diagnosis of DLBCL patients is a prognostic factor of survival, stratifying patients into three risk groups: low- (AMC<630/μL and ALC>1000/μL), intermediate- (AMC ≥ 630/μL or ALC ≤ 1000/μL) and high-risk (AMC ≥ 630/μL and ALC ≤ 1000/μL) (Leukemia 25: 1502-9, 2011). Therefore, we evaluated day 100 AMLCPS as a prognostic factor of survival by landmark analysis from day 100 post-APBHSCT in DLBCL patients. Methods: DLBCL patients that achieved complete response by day 100 post-APBHSCT qualified for the study. From 2000 to 2007, 134 consecutive DLBCL patients were evaluated. Overall survival (OS) and progression free survival (PFS) were calculated using Kaplan-Meier analysis. Results: The median follow up from day 100 for the cohort was 5.5 years (range: 0.17-12.17 years) and for living patients (N=93) was 6.9 years (range: 2.5-12.17 years). Day 100 AMLCPS was able to stratify patients into three risk groups low-, intermediate-, and high-risk for OS [low: median OS = not reached, 5-year survival rate = 94% (95%CI 83.3%-98.1%); intermediate: median OS = not reached, 5-year survival rate = 70% (95%CI 58.0%-79.8%); high: median OS = 2.2 years, 5-year survival rate = 13% (95%CI 3.4%-40.5%); p<0.0001] and PFS [low: median PFS = not reached, 5-year progression free rate = 87% (95%CI 74.5%-94.3%); intermediate: median PFS = 10.9 years, 5-year progression free rate = 67% (95%CI 55.4%-77.5%); high: median PFS = 1 year, 5-year progression free rate = 13% (95%CI 3.4%-40.5%); p<0.0001]. The day 100 AMLCPS was balanced in relation to the International Prognostic Index (IPI; p=0.22), infused CD34+ stem cells (p=0.92), and disease status pre-APBHSCT (complete remission versus partial response; p=0.11). Conclusions: The day 100 AMLCPS is a simple biomarker that can help identify DLBCL patients post-APBHSCT with poor clinical outcomes.

9057 Background: The incidence of CAM use among patients with cancer is higher when compared to the general population. However, there are few studies examining CAM use in NHL survivors, and limited data are available regarding beliefs in CAM. This study was conducted to examine the prevalence of CAM use in NHL, define CAM beliefs among NHL survivors, and explore differences between patients with indolent and aggressive lymphoma. Methods: Newly diagnosed lymphoma patients were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource from 2002-2008. NHL patients who completed the 3-year post diagnosis questionnaire, which includes questions regarding CAM use and beliefs, were included in this study. Chi-squared tests and Wilcoxon rank-sum tests were used to assess the association of CAM use with prognostic and demographic factors. Results: 719 patients were included with a median age of 63 years (range 22-92). 53% were male. Overall, 636 (89%) reported ever using CAM. 78% of patients used vitamins and 54% alternative therapies (chiropractic (36%) and massage therapy (24%)). Among CAM users, 141 (22%) believe CAM can assist the body to heal, 123 (19%) believe CAM can relieve cancer symptoms, 115 (18%) believe CAM use gives a feeling of control, 106 (17%) believe CAM can boost immunity, 24 (4%) believe CAM can cure cancer, and 35 (6%) believe CAM can prevent the spread of cancer. Female gender was associated with increased overall CAM use (p<0.0001) as well as use of vitamins (p<0.0001), herbal supplements (p=0.006) and alternative therapy (p=0.0002) specifically for cancer. Older age was also associated with increased vitamin use (p=0.005) and decreased herbal supplements use (p=0.008). There was no significant difference in overall CAM use between those with follicular lymphoma grades I-II (n=195, 91%) and non-relapsed diffuse large B-cell lymphoma (n=151, 87%), although massage therapy was utilized more often by FL survivors (29% versus 18%, p=0.005). Conclusions: CAM modalities are used by the majority of NHL survivors (89%). The assessment of CAM use and education regarding potential harms is imperative for the NHL survivor.

7623 Background: Survival for patient with primary CNS lymphoma (PCNSL), in general, is poor with patients requiring frequent chemotherapy treatments or receiving whole-brain radiation therapy, which can potentially result in significant neurologic decline and dementia. Because of the improved survival of high risk patients with aggressive lymphoma undergoing autologous stem cell transplant (ASCT), we began ASCT for patients with PCNSL in first or later remission with chemotherapy sensitive disease. We now report on outcomes of patients who have had at least 1 year follow up post ASCT. Methods: Between June, 2000 and September, 2004, 11 patients underwent ASCT for PCNSL. The medical records of consenting patients were abstracted for the following information. Median age at transplant was 47 years old (range 30–67). Median number of prior treatments 1 (range 1–3). Median time from diagnosis to transplant was 7.5 months (range 2.9 to 75.8). Median International Extranodal Working Study Group Prognostic Score: 2 (range 0–3). Disease status at transplant: First CR 5 patients, later CR or PR 6 patients. Results: Eleven patients underwent ASCT for PCNSL and have a minimum of 1 year follow-up. All patients received BEAM conditioning. Median follow up was 28.3 months. Four patients have relapsed at a median of 200 days (range 40–523). Of the patients who relapsed, one has died of disease progression and the remaining three are alive after additional therapy. Median overall survival and progression free survival from transplant have not been reached. Two year overall and event free survival are 89% and 61%, respectively. Conclusions: Although limited by patient selection and retrospective biases, this review suggests that ASCT for PCNSL demonstrates improved overall survival when compared to historical controls with similar PCNSL Prognostic Scores (2 year survival for patients from diagnosis with PS 2–3 was 48% in a prior published study). ASCT in first remission in patients with PCNSL appears promising and may limit the need for additional therapy which can be myelosuppressive or result in neurologic decline. No significant financial relationships to disclose.

7586 Background: The immunologic mechanisms of action of rituximab have been described as complement mediated lysis, vaccine like effect, antibody-dependent cellular cytotoxicity (ADCC) and the cellular microenvironment. We hypothesized that in the treatment of follicular grade 1 lymphoma (FL), the presence of a stronger host immune status prior to rituximab therapy would result in a prolonged time to progression (TTP). As a surrogate marker for immune status, we evaluated the absolute lymphocyte count (ALC) prior to rituximab treatment. Methods: Between 1996 and 2002, 1,104 consecutive FL patients were evaluated at Mayo Clinic Rochester. Of these patients, we retrospectively analyzed a group of all FL patients who received rituximab (375 mg/m2 once a week for four weeks) alone at any time during their lymphoma treatment at the Mayo Clinic (n=79). The primary end-point was to assess the impact of ALC just prior to rituximab therapy on TTP for FL. Results: The median age of the cohort was 56.6 years (range: 25–98 years). The median follow-up was 12.5 months (range: 1–76 months). An ALC count of ≥ 890 cells/μL prior to rituximab therapy predicted a longer TTP compared with an ALC < 890 cells/μl (25 months versus 8 months, respectively, p < 0.0124). A higher complete response rate was observed in the ALC ≥ 890 cells/μL group compared with the ALC < 890 cells/μL group [15/40 (38%) vs 5/39 (13%), p < 0.035]. The groups were balanced regarding the Follicular Lymphoma International Prognostic Index (FLIPI) (p = 0.794). Multivariate analysis demonstrated ALC ≥ 890 cells/μL prior to rituximab therapy as an independent prognostic factor for TTP when compared to hemoglobin, LDH, and Ann Arbor stage. The ALC was independent of the FLIPI in multivariate analysis. Conclusions: This data supports the hypothesis that a higher lymphocyte count, as a marker of the immune status of the patient, predicts for a longer TTP following rituximab therapy. No significant financial relationships to disclose.