ALBERT

Description: The antitumor potency of the mTOR inhibitor rapamycin (sirolimus) is the subject of intense investigations. Primary effusion lymphoma (PEL) appears as an AIDS-defining lymphoma and like Kaposi sarcoma has been linked to Kaposi sarcoma–associated herpesvirus (KSHV). We find that (1) rapamycin is efficacious against PEL in culture and in a murine xenograft model; (2) mTOR, its activator Akt, and its target p70S6 kinase are phosphorylated in PEL; (3) rapamycin inhibits mTOR signaling as determined by S6 phosphorylation; (4) KSHV transcription is unaffected; (5) inhibition of IL-10 signaling correlates with drug sensitivity; and (6) addition of exogenous IL-10 or IL-6 can reverse the rapamycin growth arrest. This validates sirolimus as a new treatment option for PEL.

Description: Roux-en-y gastric (RYGB) bypass surgery has become increasingly common as a procedure to control overweight/obesity. Due to the resulting bypass of significant amounts of gastric and duodenal mucosa, patients may develop anemia. We reviewed charts of 28 patients who had undergone RYGB surgery in the past 5 years who were referred to us for evaluation. Eighteen of these patients had no hematologic consequences as a result of the surgery. Five patients were anemic but were excluded because they had other causes for anemia than the bypass surgery: myeloma (1), pregnancy (1), breast cancer (1), and heavy menstruation (2). The remaining 5 patients however revealed hematologic abnormalities an average of approximately 23 months following RYGB surgery. In our retrospective chart review, we found anemia most commonly caused by iron deficiency although 1 patient had B12 deficiency, and we suggest periodic follow up of patients months to years after such surgery to screen for anemia from potential malabsorption of iron or B12 from this surgical alteration of gastrointestinal anatomy. Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Months since RYGB & first heme evaluation 24 months 28 months 39 months 11 months 11 months Pre/Post Menopausal pre pre pre pre pre Hemoglobin 8 12.9 9.8 6.7 9.9 B12 165 501 233 340 660 Ferritin 14 9 7 24.0 16.3 16.4 〉24.0 Creatinine 0.6 0.9 0.9 1.0 0.8 WBC 7.7 8.5 9 6.9 5.6 Platelets 364 300 473 378 462 Reticulocyte Count 1.00% 1.30% 1.20% 1.30% 1.30%

Description: Introduction: Patients (pts) infected with HIV have a 6-8 fold increased risk of classic Hodgkin lymphoma (cHL). Incidence may have increased with the implementation of combined anti-retroviral therapy (cART) in the mid 1990s. Frontline therapy for HIV-associated cHL (HIV-cHL) using, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in the pre-cART era showed a 2 year overall survival (OS) of 48%, but outcomes are currently similar to the non-HIV population. Pts with advanced disease have a 30% chance of relapse with ABVD. Brentuximab vedotin (BV), an anti-CD30 an antibody drug conjugate that selectively induces apoptosis of CD30+ cells with a complete response of 34% in patients with relapsed/refractory cHL. An international trial of BV with doxorubicin, vinblastine, and dacarbazine (AVD) vs. ABVD is ongoing. Here we present the phase I portion of the first trial using BV with AVD in the upfront treatment of HIV-cHL. The Phase II portion is actively accruing in both the United States and France as part of an AIDS Malignancy Consortium (AMC)/Lymphoma Study Association (LYSA) collaboration. Methods: The Phase I was a 3+3 dose de-escalation design evaluating 3 dose levels of BV (1.2 mg/kg, 0.9 mg/kg, and 0.6 mg/kg) every 2 weeks combined with standard, fixed doses of doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2 (AVD) in a 28 day cycle. Eligibility: HIV+ pts diagnosed with untreated cHL stage II-IV with CD4 counts ≥50 cells/mm3 were required to take cART regimens for at least 1 week before treatment. Ritonavir, zidovidine, and cobisistat were excluded. Baseline, cycle 2, and post treatment PET/CT scans were required. Dose limiting toxicities (DLTs) were defined during cycle 1. Results: Sixpts (5 men and 1 woman) were treated in the phase I portion from 3/2013-5/2015. Staging: II (n=1), III (n=1) IV (n=4). Pathology: mixed cellularity (n=2), nodular sclerosis (n=3), and lymphocyte depleted/mixed cellularity (n=1) HIV-cHL. The median CD4 T cell count at lymphoma diagnosis was 499 cells/mm3 (range 86-784) and the median viral load was 44 copies/ml (range 20-77). No cycle 1 DLTs were identified in the first 6 eligible patients and only 3 grade 3 adverse events in later cycles were noted, pneumonia, n=1, and neuropathy n=2, and neutropenia, n=1. In 2 pts, toxicity required delays in therapy of over 3 weeks (after c5d1 and after c6d1) resulting in subject removal from further protocol therapy. One pt had a decrease in the diffusion lung capacity for carbon monoxide (DLCO) to 65% after cycle 2, and BV was withheld while AVD continued as per protocol. Two pts were later deemed ineligible, and excluded from any analysis, due to the concomitant use of ritonavir-based cART at enrollment. Both developed febrile neutropenia and one developed a grade 3 pancreatitis during cycle 1, emphasizing the importance of not treating patients with BV + AVD with concurrent CYP3A4 inhibitors. Five of the 6 pts achieved cycle 2 PET/CT negativity as defined by a Deauville score 1-3. The PET/CT positive patient ultimately had a negative post-therapy scan. The 5 pts who completed therapy achieved CR post-therapy, and one patient has yet to complete treatment. Phase II is enrolling at BV 1.2 mg/kg in combination with AVD. Conclusions: AVD-BV in stage II-IV HIV-cHL was well-tolerated therapy as no DLT were identified. Five of the 6 patients achieved a negative C2 PET/CT and 5/5 of the patients who completed therapy thus far achieved a CR. The recommended Phase II dose is 1.2 mg/kg +AVD every other week. The phase II portion (51 subjects) is actively accruing in both the USA and France, in an AMC/LYSA collaboration, clinicaltrials.gov NCT01771107. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 891 Background: Chronic Immune thrombocytopenia (ITP) is characterized by low platelet counts and increased risk of bleeding. Rescue medications used to treat or prevent bleeding produce transient increases in platelet counts but may be associated with additional toxicities and costs. Romiplostim, approved for the treatment of adult chronic ITP, is a TPO mimetic peptibody protein that increases platelet production. Previously published data from phase 3 romiplostim trials showed that despite the increased use of rescue medication in the placebo arm, patient (pt) incidence of bleeding was reduced in the romiplostim arm vs placebo arm: 15% vs 34% (p = 0.02) for bleeding of grade ≥2 severity and 7% vs 12% (p=0.36) for grade ≥3 severity. Objective: To evaluate the effects of romiplostim treatment on bleeding outcomes in the phase 3 placebo controlled studies in chronic ITP pts with and without previous splenectomy. Bleeding events were captured as adverse events making it difficult to identify a single event reported multiple times versus persistent or recurrent bleeding. Further, we have developed a composite endpoint, termed bleeding-related episodes (BREs), which combines bleeding events and rescue medication administration to account for use of rescue medications to prevent bleeding. Methods: Adults with chronic ITP and a mean baseline platelet count

Description: INTRODUCTION: Cancer-related anemia can contribute to fatigue among cancer patients (pts). Few large scale surveys of cancer pts have been conducted to characterize fatigue from the patient’s perspective. This study was conducted to assess the prevalence of fatigue in cancer pts and examine relationships between fatigue, anxiety, depression, and somatization (physical symptoms). METHODS: A cross-sectional survey was conducted from April to May 2006 using a random sample of pts from a chronic illness panel of 550,233 pts. Inclusion criteria were being at least 18 years of age, diagnosed with cancer, and receiving chemotherapy and/or radiotherapy either currently or during the 12 months prior to participating in the study. An 8-item brief fatigue questionnaire developed from four validated instruments (scores ranging from 0–100, higher being better status) and the 13-item Functional Assessment of Cancer Therapy - Fatigue (FACT-F; scores ranging from 0–52, higher being better status) were used to assess fatigue. The 18-item Brief Symptom Inventory (BSI; scores ranging from 0–100, higher being worse status) was used to measure anxiety, depression, somatization and to obtain a global severity index. Single items with numerical rating scales ranging from 0 to 10 were used to assess degree of debilitation related to fatigue and importance of fatigue reduction. Pearson correlation coefficients were used to assess relationships between continuous variables. RESULTS: A total of 1,569 cancer pts were surveyed. Online interviews were conducted with 1,302 pts and phone interviews with 267 pts. No significant differences were found between phone and online respondents. Most patients were white (84%) and 50% were males. Most females were diagnosed with breast cancer (56%) and most males with prostate cancer (40%). Approximately 79% of pts rated fatigue as the most common symptom of cancer treatment. One in three patients considered a reduction in fatigue to be very important. Approximately 54% of patients rated their fatigue to be debilitating (six or higher on a ten point scale). Worse levels of fatigue measured by the FACT-F were significantly associated with higher levels of anxiety (r = −0.56, p 〈 0.0001), depression (r = −0.63, p 〈 0.0001), somatization (r = −0.75, p 〈 0.001), and the global severity index (−0.71, p 〈 0.001). Scores from the brief fatigue questionnaire confirmed results obtained with the FACT-F. CONCLUSIONS: Fatigue was the most common symptom reported in this study and was significantly associated with anxiety and depression. More research is needed to examine the relationship between physical and psychological symptoms in cancer patients. Table 1. Correlations between Fatigue and Scores from the Brief Symptom Inventory among All Cancer Patients Brief Fatigue Questionnaire (n=1569) FACT-F (n=1569) Variable Pearson’s R Lower CI (95%) Upper CI (95%) Pearson’s R Lower CI (95%) Upper CI (95%) * p 〈 0.0001 Global Severity Index −0.71* −0.69 −0.73 −0.73 −0.71 −0.75 Anxiety −0.54* −0.5 −0.57 −0.56* −0.53 −0.59 Depression −0.61* −0.58 −0.64 −0.63* −0.6 −0.66 Somatization (physical symptoms) −0.75* −0.73 −0.77 −0.75* −0.73 −0.77

Description: A set of commonly accepted hematologic endpoints is used to assess ESAs by regulatory bodies like the FDA, clinical guideline committees like NCCN, and independent health care assessment bodies like AHRQ. These include percentage of pts who received transfusions (TFNs) from week (wk) 1 to end of treatment period (EOTP), reached target Hb ≥11g/dL, and achieved a ≥3-point change in FACT-F score from baseline (BL). Other exploratory, unvalidated endpoints have been suggested (1 g/dL rise in Hb in 4 wks or change in area-under-the-Hb-concentration curve [ΔHbAUC]), but the AHRQ report (2006) characterized these as being insensitive to discriminate between ESAs. We examined the commonly accepted and the exploratory hematologic endpoints described above using pooled data from 10,328 pts with CIA enrolled in 20 clinical trials: 8079 darbepoetin alfa (DA) pts, 1677 epoetin alfa (EA) pts, and 572 placebo (PBO) pts. DA dosing frequencies were every 1 (QW), 2 (Q2W), or 3 (Q3W) wks; EA dosing frequencies (3 times a week and QW) were pooled. A mixed logit model was used to analyze the percentage of pts with TFNs and who achieved the target Hb, a ≥3-point change in FACT-F score, and a 1-g/dL Hb rise in 4 wks; a linear mixed model was used to analyze ΔHbAUC. Values were adjusted for BL Hb (

Description: Various laboratory parameters are used to guide the treatment of anemic patients; however, their interpretation may be complicated by the etiology of the anemia. We compared anemia-related laboratory values obtained from 261 patients (174 female) screened prior to participation in a clinical trial for cancer and chemotherapy related anemia (ACD), with those from a group of 50 otherwise-healthy women referred for treatment of anemia related to heavy menses (IDA). Pairwise correlations were explored graphically and analyzed using Pearson’s correlation coefficients. Highly skewed data were log transformed. Relationships between Hb and laboratory values associated with anemia were explored using multiple linear regression models; the most parsimonious model was arrived at by stepwise regression. For the ACD group, laboratory values tested in the regression analyses included: ferritin, transferrin saturation (TSAT), reticulocyte Hb content, folate, vitamin B12, transferrin, iron, and albumin. For the IDA group, regression analyses included: ferritin, iron binding capacity (TIBC), iron, albumin, BUN, Creatinine, WBC, C-reactive protein, and endogenous EPO. Complete set of lab values was not available for all patients. In the IDA group, a strong correlation was identified between markers of iron status, serum ferritin and TSAT, but this association was much weaker among the ACD group. In the ACD group, negative correlations were identified between ferritin and TIBC, and between ferritin and albumin, along with a moderately strong positive correlation between albumin and TIBC. These relationships were different in the IDA group. Albumin tended to increase with increasing ferritin, while TIBC tended to decrease. Albumin and TIBC were unrelated. Lab value, mean, 95% CI ACD group IDA group Hgb g/dL 10.1, 10.0–10.3 8.6, 8.01–9.10 ferritin ng/mL 455, 396–513 10, 6.1–13.0 TSAT% 21.3, 19.7–23.0 12.8, 0.01–25.7 TIBC mg/dL 275, 267–282 422,375–469 iron mcg/dL 61, 57–66 49, 2.5–95.7 albumin g/dL 3.6, 3.55–3.65 4.0, 3.86–4.11 Correlations ferritin vs TSAT r=0.208, p=.001 r=0.793, p

Description: Abstract 1388 Poster Board I-410 Introduction: A common problem with chemotherapy treatments is reduced dose-intensities from treatment delays due to chemotherapy induced toxicities. In 2004, Lyman and colleagues assessed the overall incidence of reduced dose-intensities for 4,522 non-Hodgkin's lymphoma (NHL) patients. They determined that 53% of the patients, due to treatment delays of 〉7 days (24%) or reduced doses of 〉15% (40%), received a relative dose intensity (RDI) of 15% and 10 patients (17%) had treatment delays of 〉7 days. The mean RDI was 91% and the median was 95%. There was minimal difference between the average RDIs for the treating regimens (CHOP = 91%, R-CHOP 14 = 91%, R-CHOP 21 = 91% and R-CVP = 88%). Patients over the age of 65 received an average RDI of 85% whereas patients under the age of 65 received an average RDI of 94%. Stage I patients (n=10, 16.7%) received an average RDI of 95%, stage II patients (n=11, 18.3%) received an average RDI of 90%, stage III patients (n=17, 28.5%) received an average RDI of 92%, and stage IV patients (n=22, 36.5%) received an average RDI of 87%. Forty-seven patients (78.3%) had a complete response to chemotherapy (average RDI = 92%), 4 patients (6.7%) exhibited a partial response (average RDI = 90.75%), 5 patients (8.3%) showed signs of stable disease (average RDI = 80.6%), and 4 patients (6.7%) had progressive disease (average RDI = 91%). The overall 2 year survival rate for all patients was 93.3%: the survival rate of patients with RDIs 85% were both 93.3%. Conclusion: Both the mean and median RDI we found were higher than those found in the study by Lyman et al (91% and 95% respectively compared to 81% and 86%), and only 25% of patients received

Description: INTRODUCTION: The time incurred in seeking care for the treatment of side effects of chemotherapy (CT) or radiotherapy (RT) can result in lost productivity and resulting lost wages for cancer patients (pts) and their caregivers. The purpose of this study was to assess the amount of time spent by pts and caregivers to seek treatment for side effects of CT/RT and to examine productivity losses associated with such visits. METHODS: A cross-sectional survey was conducted from April to May 2006 using a random sample of pts from a chronic illness panel of 550,233 pts. Inclusion criteria were being at least 18 years of age, diagnosed with cancer, and receiving CT and/or RT either currently or during the 12 months prior to participating in the study. Percentages and means were used to calculate descriptive statistics. RESULTS: A total of 1,569 cancer pts were surveyed: 1,302 pts online and 267 pts by telephone. No significant differences were found between phone and online respondents. Of the pts currently receiving CT and/or RT (N=814), a total of 249 pts received treatment for side effects of CT/RT. The total time spent per visit to receive treatment for side-effects of CT/RT was approximately 5 hrs/visit including preparation time, travel time, and time spent at the clinic. Approximately one-half (54%) of the 249 patients currently receiving treatment for side effects of CT/RT were employed full-time (44%) or part-time (10%). Among employed patients currently receiving treatment for side effects of CT/RT, the mean number of work days missed as a result of visits for the treatment of CT/RT related side effects was 20 days per year. The primary reason for continuing to work during cancer treatment was financial need, reported by 59% of patients. Approximately 83% of all patients indicated that a caregiver generally accompanied them on their visits to the doctor’s office, clinic, or hospital to receive treatment for side effects of CT/RT. Seven out of ten caregivers (68%) were reported as being employed either full-time (62%) or part-time (6%). CONCLUSIONS: Time related burden for patients receiving treatment for side effects of CT/RT and their caregivers is significant. Reduction in frequency of such visits is important from the standpoint of patients’ economic livelihood and can stand to benefit employers and society. Table 1. Time Spent on Healthcare Provider Visits for Treatment of Side Effects Related to Chemotherapy and/or Radiation (N=249) Activity (per visit) Minutes Spent (mean) Standard Deviation Minutes Spent (median) Preparing to go to the doctor’s office, clinic or hospital 81 127 55 Travel to and from the doctor’s office, clinic, or hospital 102 188 58 Waiting at the doctor’s office, clinic, or hospital to see the doctor or another healthcare professional 64 72 39 Seeing the doctor or another healthcare professional 64 75 43 Total 311 380 210

Description: Introduction: Six cycles of rituximab plus infusional EPOCH is considered a preferred regimen for first-line treatment of HIV-associated diffuse large B-cell lymphoma (DLBCL), HHV8-positive DLBCL, and primary effusion lymphoma, and is among the preferred regimens for HIV-associated Burkitt's lymphoma in the 2019 NCCN guidelines. A phase III trial demonstrated non-inferiority of 4 cycles of R-CHOP (followed by 2 additional doses of rituximab) compared with 6 cycles of R-CHOP in immunocompetent patients with low-risk DLBCL (stage I-II, age 18-60 years, and an age-adjusted International Prognostic Index score of 0), indicating that de-escalation of treatment duration may be safely achieved without compromising curability in an appropriately selected patient population. Here we report the outcomes for patients with HIV-associated DLBCL and high-grade non-Hodgkin lymphoma (NHL) treated with 4-6 cycles of EPOCH plus rituximab based a response-adapted treatment strategy under a completed prospective clinical trial (AMC-034). Methods: One hundred-six patients with HIV-associated DLBCL or high-grade CD20-positive NHL enrolled at multiple centers across the U.S. were randomized to receive rituximab (375 mg/m2) given either concurrently prior to each infusional EPOCH cycle, or sequentially (weekly for 6 weeks) following completion of dose-adjusted EPOCH regimen tailored for HIV+ patients. EPOCH consisted of a 96-hour IV infusion of etoposide, doxorubicin, and vincristine plus oral prednisone followed by IV bolus cyclophosphamide every 21 days for 4 to 6 cycles. Patients received 2 additional cycles of therapy after documentation of a complete response (CR) by computerized tomography after cycles 2 and 4. Results: Sixty-four of 106 patients (60%, 95% CI 50%, 70%) had a CR in both treatment arms; characteristics of entire population and CR proportions stratified by number of EPOCH treatment cycles were similar (Table 1).The 2-year event-free survival (EFS) rates were similar in the 24 patients with CR who received 4 or fewer EPOCH cycles (78%, 95% confidence intervals [55%, 90%]) due to achieving a CR after 2 cycles, compared with those who received 5-6 cycles of EPOCH (85%, 95% CI 70%, 93%) due to failure to achieve a CR after 2 cycles (Table 2 and Figure 1). Time to disease progression and overall survival wer also similar for those treated with 4 or fewer cycles compared with 5-6 cycles (91% vs. 87%, and 78% vs. 90%, respectively) (Table 2 and Figure 1). Conclusion: A response-adapted strategy may permit a shorter treatment duration without compromising therapeutic efficacy in an appropriately selected population of patients with HIV-associated NHL, which merits further evaluation in additional prospective trials. Disclosures Noy: Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding.