ALBERT

Description: Granulocytic sarcoma (GS) is a rare extra medullary manifestation of acute myeloid leukemia (AML). It may also represent blastic transformation of myelodysplastic syndromes or myeloproliferative neoplasms. Although usually seen in the context of advanced and poorly controlled disease, it may also present as the first manifestation of illness, without concurrent bone marrow or blood involvement. In the medical literature chloroma and GS are terms that have been used interchangeably with myeloid sarcoma. GS usually manifest as soft tissue or bony masses in several extra cranial sites such as bone, periosteum and lymph nodes; involvement of the head and neck region is uncommon. Herein, we report a case of a 63 yearr-old woman with insidious onset of progressive nasal congestion and diminished hearing who was diagnosed with an isolated GS of the nasopharynx. With involved field radiotherapy she achieved a complete remission of 12 months duration before being diagnosed with overt AML. Following induction and consolidation chemotherapy she has remained disease free for now greater than 18 months. Through a MEDLINE®/PubMed® search we identified an additional 13 cases of nasopharyngeal GC. The median age was 37 years (range, 1 to 81 years). The cases were equally distributed among the sexes. The most common presenting symptoms were conductive hearing loss and sino-nasal congestion. Isolated GC was identified in 6 cases and the median time from diagnosis of GS to AML was 12 months (range, 3 to 48 months). Treatment varied, but responses were seen in all patients who received chemotherapy with or without radiotherapy.REFERENCE (YEAR)AGE (YEARS), SEXCLINICAL FEATURESASSOCIATED DIAGNOSISCYTOGENETICSOUTCOMEBassichis et al. (2000)1, maleMasseter muscleSynchronous AMLNot reported (NR)Died during chemotherapy.Au WY et al. (2001)37, maleConductive hearing loss, infiltrative nasopharyngeal massSolitary site of GSNormalInvolved field radiotherapy (IFRT) and chemotherapy. Complete remission (CR) at 3 years.Nayak et al.(2001)24, femaleBilateral parotid and nasopharyngeal massSolitary site of GSNRpatient died on 17th day of chemotherapy due to systemic infectionGeisse et al. (2002)60, maleWaldeyer’s ring lymphadenopathySynchronous MDSNRDiagnosis made on autopsyPrades et al.(2002)20, femaleSino-nasal obstruction; right maxillary and sphenoid sinus massGS of the nasal cavity and paranasal sinust(19:1)Allogeneic hematopoietic stem cell transplant (AHSCT) following chemotherapy; CR at 18 monthsOzcelik et al. (2003)37, maleVocal cord paralysis, involvement of 9th, 10th, 12th cranial nervesAML (M0) 6 months earlier - treated with chemotherapy to CRNRTreated with chemotherapy with partial regression of the nasopharyngeal masses; patient died on 17th day of chemotherapy due to pulmonary infectionSugimoto et al.(2004)31, femaleNasopharynx, external acoustic meatusAML (M2) 3 months earlier - treated with chemotherapy to CRt(8;21)(q22;q22)Achieved CR2 with IFRT, re-induction chemotherapy, followed by AHSCT.Imamura et al.(2004)7, femaleWaldeyer’s ring and cervical lymphadenopathySynchronous juvenile myelomonocytic leukemiat(9;12) (p22;q24.1)AHSCT following chemotherapy; CR at 3 yearsFerri et al. (2005)72, femaleRight facial swelling and fever; maxillo-ethmoidal massAML (M0) 1 year earlier – treated with hydroxyurea.NRBest supportive care only; died after 10 days of hospitalization.Teramoto et al.(2006)81, femalenaso-pharyngeal massDeveloped AML (M2) 1 year later.Complex genomic defects on cDNA microarrayRadiation therapy only for GS; chemotherapy for AML; died 6 months after diagnosis of AML.Selvarajan et al. (2008)25, maleDysphagia, hoarseness, facial nerve palsyAML (M2) 4 years earlier – treated with chemotherapy to CR followed by AHSCTt(8:21)Treated with chemotherapy but had systemic relapse 1 year laterCho et al. (2011)18, maleConductive hearing loss, infiltrative nasopharyngeal massSynchronous AMLRUNX1-RUNX1T1Recurrence after 7 months of chemotherapy; achieved CR2 with re-induction chemotherapy, followed by AHSCT.Mei et al. (2013)56, femaleLeft maxillary sinusSolitary site of GSNRSurgical resection followed by chemotherapy; CR at 4 months(Current) case63, femaleConductive hearing loss, infiltrative nasopharyngeal massDeveloped AML one year later.NormalRadiation therapy only for GS; chemotherapy for AML; CR at 18 months Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: EPOCH-based chemotherapy is considered a preferred first-line treatment for HIV-associated diffuse large B-cell lymphoma (DLBCL) and primary effusion lymphoma in the 2019 NCCN guidelines. We previously reported that adding the HDAC inhibitor vorinostat (VOR) to EPOCH had no impact on complete response (CR) rate, the primary trial endpoint, and similar 1-year survival rates (ASCO 2018, abstract 7573). Here, we report updated results from AMC075 and evaluate the impact of a DTI ≥15 days on clinical outcomes. A DTI ≥15 days has been shown to be associated with a better prognosis in an HIV-negative population treated with R-CHOP (Maurer et al. J Clin Oncol 2018; 36:1603-1610). We also look at the impact of allowing 1 cycle of systemic therapy given prior to study enrollment in order to circumvent logistical challenges in recruiting otherwise eligible trial subjects. Methods: Between 2012 and 2017 we conducted a randomized phase II study of EPOCH (with rituximab in CD20+ tumors) ± VOR 300 mg administered on days 1-5 of each cycle with HIV antiretroviral therapy in 90 participants with aggressive HIV-NHLs. Eligible patients had at least one of the following high-risk features or tumor characteristics: Age-adjusted International Prognostic Index (aa-IPI) of 2-3, Ki-67 ≥ 80%; activated B-cell (ABC) diffuse large B-cell lymphoma(DLBCL); or any other aggressive non-germinal center (non-GCB), non-Burkitt B-cell NHL. Patients who received 1 prior cycle of chemotherapy (CHOP-like or EPOCH) +/- rituximab were allowed to register. The primary endpoint was CR rate. Secondary objectives included determining adverse events, survival rates, and the effect of EPOCH +/- VOR on HIV viral reservoirs. We performed a post-hoc analysis evaluating the impact of time from DTI ≥15 days vs. 200 cells/mm3(Table 1). The 3-year overall survival rates for VOR-EPOCH was 70% and for EPOCH 77% (log-rank P=0.39), and 3-year event-free survival rates were 63% vs. 69%, respectively (log-rank P=0.32) [Figure 1]. Thirty-six patients (86% of n=42) with long DTI (≥15 days) had CR, compared to only 25 (57% of n=44) with short (

Description: Background: T cells can be activated and expanded ex vivo using the Xcellerate™ Process, in which peripheral blood mononuclear cells (PBMC) are incubated with anti-CD3 and anti-CD28 antibody-coated magnetic beads (Xcyte™-Dynabeads®). In an ongoing trial of Xcellerated T Cells in subjects with chronic lymphocytic leukemia, marked and sustained reductions in lymphadenopathy and splenomegaly were observed (Wierda et al., ASCO 2004). Increases in neutrophil, platelet and NK cell counts were also documented. This study is designed to determine if similar effects can be observed in subjects with indolent non-Hodgkin’s lymphoma (NHL). Methods: Subjects must have indolent NHL (follicular, small lymphocytic, marginal zone, or mantle cell lymphoma), have relapsed or refractory disease, and have received at least 1 but not more than 4 prior treatment regimens. PBMC are collected by leukapheresis for the Xcellerate Process, and subjects subsequently receive two infusions of 20–60 x 109 Xcellerated T Cells separated by 6–8 weeks. Approximately 40 subjects will be treated. Results: Seven subjects have been enrolled and Xcellerated T Cells have been manufactured in 5 subjects to date. T cells expanded 181.8 ± 88.5 fold and the final product was 〉99.0 ± 0.0% T cells (mean + SD). One subject with small lymphocytic lymphoma has been treated with two infusions of 38.6 x 109 Xcellerated T Cells. There have been no serious adverse events to date. Following the first treatment, the lymphocyte count increased from 1.8 x 109/L to 2.9 x 109/L on Day 28. The neutrophil count also increased from 2.9 x 109/L to 5.5 x 109/L six weeks following infusion. The subject had a significant reduction in cervical lymphadenopathy and a slight decrease in bulky mesenteric lymphadenopathy six weeks following the first infusion. Conclusions: Xcellerated T Cells can be manufactured in subjects with indolent NHL. Treatment leads to significant increases in T cell and neutrophil counts. Preliminary data suggest a reduction in peripheral lymphadenopathy. Data on additional subjects will be presented.

Description: BACKGROUND Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). Recent advances in imaging, use of prognostic indices and molecular profiling has improved our ability to characterize disease and predict outcomes in DLBCL. About one-third of patients with DLBCL have bone marrow involvement at the time of diagnosis, and bone marrow aspirate/biopsy (BMAB) is considered gold standard to detect such involvement. 18 F-fluro-2-deoxy-D-glucose positron emission tomography combined with computed tomography (PET-CT), has become standard pre-treatment imaging in DLBCL and may be a non-invasive alternative to BMAB. Prior studies have suggested that PET-CT scan may obviate the need for BMAB as a component for staging patients with newly-diagnosed DLBCL, but owing to a variety of reasons this is not yet a standard of practice. We investigated whether FDG uptake-based bone marrow assessment can replace BMAB in newly-diagnosed DLBCL. METHODS This study is a single institution retrospective medical records' review. All patients with newly-diagnosed DLBCL at Virginia Mason Medical Center between January 2003 to December 2013 who underwent pre-treatment PET-CT and BMAB were included. FDG-PET/CT images were visually assessed for bone marrow involvement in posterior iliac crest. Patients with primary mediastinal DLBCL, previous history or coexistence of another lymphoma subtype and those with a non-diagnostic BMAB, and in whom the PET-CT did not show marrow signal abnormality were excluded from the analysis. Ann Arbor stage was determined using PET-CT with and without the contribution of BMAB, and the proportion of stage IV cases by each method was measured. RESULTS 105 eligible patients were identified. The median age was 62 years (range, 24-88), 62 (59%) were male, 53 (50%) had elevated LDH and 17 (16%) had an ECOG performance status of 〉2. Thirteen (12%) patients had 〉 1 extra-nodal site of lymphoma involvement. R-IPI score was 0-1 in 39 (37%), 2 in 42 (40%), 3 in 20 (19%), and 4 in 4 (4%) patients. A total of 38 (36%) patients had bone marrow involvement established by either PET-CT (n=24, 19%), BMAB (n=14, 13%), or both (n=12, 11%). 12 of the 24 patients (50%) with positive PET-CT had marrow involvement by DLBCL, while only 2 of the 81 patients (2%) with negative PET/CT showed marrow involvement. BMAB upstaged 1 of the 53 (2%) stage I/II patients to stage IV. The sensitivity of PET-CT scan to detect marrow involvement by DLBCL was 86% while the specificity was 87%. The positive predictive value of PET-CT was only 50% while the negative predictive value was 98%. CONCLUSIONS In patients with newly diagnosed DLBCL, PET-CT is complementary to BMAB in detecting marrow involvement by lymphoma. Although PET-CT has a high negative predictive value for bone marrow involvement, it overestimates the number of cases with marrow involvement by lymphoma. In clinical practice, routine BMAB may no longer be necessary for all patients with DLBCL, who are staged by PET-CT, unless the results would change both staging and therapy. The prognostic implication of marrow involvement identified by PET-CT compared to BMAB remains unknown. Disclosures No relevant conflicts of interest to declare.

Description: Background: Our practice at Virginia Mason Medical Center (VMMC) includes 600 HIV+ patients, 60 of whom died in the last decade. Our intimate doctor-to-patient care allows for increased precision when determining the underlying causes of patient mortality. Large cohort studies such as the ASD project may not allow for such detail because of dependence on medical records or death certificates to determine causes of death. Objective: To determine variances in death between a single provider VMMC patient dataset, and a larger public health cohort during the HAART era. Methods: We contrasted two datasets. The first was the Seattle/King County ASD dataset (n=4721), which recorded 351 patient deaths during 1996–2004. The second was the 1996–2006 VMMC HIV mortality cohort. Abstracted data include patient demographics, causes of death, co-morbidities, treatment adherence, CDC AIDS classification, and relevant laboratory data. We used X2 and Fisher Exact test for our statistical analysis. Results: Of the 60 VMMC patients who died, 57 (95%) were male, 16 (27%) injection drug users (IDU), 50% with significant mental illness, and 44 (73%) with a C2/C3 CDC AIDS classification. Median time between HIV diagnosis to death was 11 years (range, 0–22). There were 33 (55%) patients with poor/moderate adherence. Of the 351 ASD patients who died, 301 (86%) were male, 43 (12%) IDU, 250 (71%) with significant mental illness, and 285 (81%) with a C2/C3 CDC AIDS classification. Median time between HIV diagnosis and death was 6 years (0–18). Of 92 patients for whom adherence data was collected, 69 (75%) had poor/moderate adherence. 39 (65%) VMMC patients died from non-opportunistic illness (OI), 18 (30%) from OI, and 3 (5%) from both (see table). The most common OIs were wasting, non-Hodgkin’s lymphoma, and progressive multi-focal leukoencephalopathy (PML). The most common non-OIs were malignancy, liver failure, and pneumonia. 11 of 60 patients (18%) died despite a non-detectable HIV viral load (NDVL) and median CD4+ count of 216 cells/μL (range, 16–952). 301 of 351 ASD patients had a known cause of death. 135 (45%) died from non-OI, 105 (35%) from OI, and 61 (20%) from both non-OI and OI (see table). The most common OIs were mycobacteria, dementia, and cytomegalovirus. The most common non-OIs were liver failure, pneumonia, and sepsis. 35 of 351 patients (10%) died despite a NDVL and median CD4+ count of 223 cells/μL (5–1616). Conclusions: Males and those with substance abuse, mental illness, poor/moderate adherence, and a C2/C3 AIDS designation were heavily represented in both datasets. The VMMC patients had a longer interval between HIV diagnosis and death than those in the Seattle/King County ASD project. Liver failure and pneumonia were the dominant non-OIs in both datasets. Malignancy as a cause of death was over-represented in VMMC due to the concentration of such patients in a Hem/Onc practice. ASD had a greater proportion of patients without a known cause of death, suggesting greater difficulty designating the underlying cause of death when patients are not intimately known. Table Outcome VMMC (N=60); N (%) ASD (N=301); N (%) p-value Opportunistic Illness (OI) 18 (30) 105 (35) No Significance Non-OI 39 (65) 135 (45) .004 Both OI & non-OI 3 (5) 61 (20) .005

Description: Introduction: In the pre-highly active anti-retroviral therapy (HAART) era, ITP was a relatively common hematologic abnormality, which was seen in as many as 30% of patients infected with HIV. With the advent of HAART, the incidence of HIV-associated ITP has been reduced substantially, with some epidemiological studies showing contemporary rates as low as 1 to 3% (Vannappagari, Platelets 2011). In cases where HAART does not lead to adequate improvement in platelet counts, next lines of therapy have traditionally consisted of corticosteroids, including dexamethasone and prednisone, intravenous immunoglobulin (IVIG), anti-Rho(D) immune globulin, rituximab and, in the current era, more sparingly, splenectomy. When platelet counts remain persistently 200 cells/ µL, viral loads 〈 40 copies/mL, and platelet counts ≤20 x 109/L before starting TRA therapy. Results: Each patient responded to TRA use with a mean pre-treatment platelet count of 15 x 109/L, and this increased to a mean of 110 x 109/L 6 weeks following treatment initiation. 2 of the patients have maintained a sustained response with adequate platelet counts 3 years after discontinuing TRA therapy. 1 patient succumbed to a myocardial infarction while on eltrombopag and 1 patient, while on romiplostim, expired from complications of a presumed pulmonary embolus after undergoing lumbar spine surgery. Abstract 5014. Table: Characteristics of HIV-related ITP patients given TRA Case Nadir CD4+ count (cells/µL) /HIV viral load (copies/mL) HAART Regimen CD4+ count (cells/µL) /HIV viral load (copies/mL) at time of use of TPA Platelet count pre-TRA treatment Lines of ITP treatment before TRA TRA (dose where response was observed and sustained) 6 month f/u platelet count Sustained Response after stopping TRA (duration) Case 1 261/ 5,000 Atripla® 340 /

Description: In 2016, the World Health Organization provisionally classified Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) as a lymphoid neoplasm under the subcategory of mature B-cell neoplasms. Here we describe a 59-year-old Chinese woman with a long history of recurrent sinus and oropharyngeal infections and was diagnosed initially with EBVMCU and later, diffuse large B-cell lymphoma (DLBCL). She had sought medical attention after a particularly long bout of increased facial pressure and nasal obstruction. As a young adult she had undergone a tonsillectomy, adenoidectomy, and received innumerable treatments for bronchiectasis and recurrent sinopulmonary infections. A sinus computerized tomography (CT) scan showed mucosal thickening and swellings of the left frontal posterior sinus. A subsequent 18fludeoxyglucose (18FDG) positron emission tomography (PET)-CT scan showed a large hypermetabolic mass (standardized uptake value [SUV] 30.6) centered in the left half of the nasopharynx and sinus processes and extending across the mid-line. She underwent an endoscopic turbinate reduction with removal of a polypoid soft-tissue mass. Immunohistochemical studies indicated large atypical lymphoid cells that stained positively for CD20, CD30, EBER-1, MUM-1, OCT-2, and PAX-5 and variably for BCL-6, CD15, CD45, and CD79a. The Ki-67 proliferation index was 100% in the atypical cells. Tissue blocks were reviewed locally and at the National Institute of Health and were felt to be most consistent with EBVMCU. She received 4000 cGy involved-field external-beam radiation therapy over 20 fractions. At completion of treatment, no residual abnormalities were identified and no additional adjuvant therapy was pursued. Three years later she presented to medical attention with shortness of breath and a non-productive cough. A PET-CT scan showed whiteout of the left lung and intense 18FDG uptake in a left perihilar nodule (SUV of 18). Bronchoscopy revealed many reactive polypoid bronchial wall masses and a complete collapse of the lower left lobe due to an obstructing mass. The left lower lobe intraluminal mass biopsies however showed EBV-positive DLBCL of non-germinal center phenotype. She received six cycles of conventional R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone) and 36 months later she remains cancer free but with persistent bronchial inflammatory nodules and recurrent infections. Using the key words "EBV mucocutaneous ulcers," "EBV-associated lymphoproliferative disorders," and "lymphoproliferative disorders," we identified 100 cases of EBVMCU in the literature. EBVMCU is manifested as a well-circumscribed ulcer typically unifocal (90%) and of the oropharynx (58%), gastrointestinal (GI) tract (20%), and skin (20%). Immunohistochemical studies of the ulcers reveal monoclonal B-immunoblasts staining positively for CD20, CD30, EBER-1, MUM-1, OCT-2, and PAX-5 and staining variably for BCL-6, CD15, CD45, and CD79a. EBVMCU is most commonly associated with medication-induced (iatrogenic) immunosuppression (65%), advanced age-associated immunosenescence (27%), and primary (3%) and acquired (3%) immunodeficiencies. The median age for all EBVMCU cases is 68.5 (range, 16 -101) years. Of the 65 cases where medication-induced immunosuppression contributed to EBVMCU, 45 (69%) were in patients greater than 60 years-old. EBVMCU is a predominantly indolent disease reminiscent of post-transplant lymphoproliferative disorders in which conservative strategies are primarily employed with potential escalation to B-cell targeted therapy with or without cytotoxic chemotherapy, resection, and/or radiotherapy. Surveillance for EBVMCU should follow B-cell directed therapies and should be considered in the differential diagnosis in cases of suspected lymphoma relapse. Additionally, other LPDs, including lymphomas, should be monitored after resolution of EBVMCU. Due to overlap of the immunohistochemical profiles and risk factors associated with EBVMCU and other ulcerative LPDs of the oral and sinus cavities, nasopharynx, or GI tract, EBVMCU should be considered in the differential diagnosis to prevent under- or over-diagnosis and their associated potential repercussions. Disclosures No relevant conflicts of interest to declare.

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.

Description: Most commonly, histologic transformation (HT) from follicular lymphoma (FL) manifests as a diffuse large B cell lymphoma, not otherwise specified (DLBCL, NOS). Less frequently, HT may result in a high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 gene rearrangements, also known as "double-hit" or "triple-hit" lymphomas. In the 2016 revision of the WHO classification of lymphoid neoplasms, the category B-cell lymphoma, unclassifiable was eliminated due to its vague criteria and limiting diagnostic benefit. Instead, the WHO introduced the high-grade B-cell lymphoma (HGBL) category, characterized by MYC and BCL2 and/or BCL6 rearrangements. Cases that present as an intermediate phenotype of DLBCL and Burkitt lymphoma (BL) will fall within this HGBL category. Very rarely, HT results in both the intermediate DLBCL and BL phenotype, and exhibits lymphoblastic features, in which case the WHO recommends that this morphological appearance should be noted. In comparison to de-novo patients with DLBCL, NOS, those with MYC and BCL2 and/or BCL6 gene rearrangements have a worse prognosis. A 63-year-old female presented with left neck adenopathy. Lab assessment including complete blood count (CBC), complete metabolic panel (CMR), serum lactate dehydrogenase (LDH) and B-2 microglobulin were all normal. A whole body computerized tomography (CT) scan revealed diffuse adenopathy above and below the diaphragm. An excisional node biopsy showed grade 3A nodular FL. The Ki-67 labeling index was 40-50%. A bone marrow biopsy showed a small focus of para-trabecular CD20+ lymphoid aggregates. She received 6 cycles of bendamustine (90 mg/m2 days +1 and + 2) and rituximab (375 mg/m2 on day+2) with each cycle delivered every 4 weeks. A follow up CT scan at completion of therapy showed a partial response with resolution of axillary adenopathy and a dramatic shrinkage of the large retroperitoneal nodes. 18 months later she had crampy abdominal pain in the absence of B symptoms. Positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro- D-glucose integrated with CT (18F-FDG PET/CT) scan showed widespread adenopathy, diffuse splenic involvement and substantial marrow involvement. Biopsy of a 2.4 cm right axillary node (SUVmax of 16.1) showed involvement by grade 3A FL with a predominant nodular pattern of growth. A bone marrow biopsy once again showed only a small focus of FL. She received idelalisib (150 mg twice daily), and rituximab (375 mg/m2, monthly) beginning May, 2015. After 4 cycles, a repeat CT scan showed a complete radiographic response. Idelalisib was subsequently held while she received corticosteroids for immune-mediated colitis. A month later she restarted idelalisib with a 50% dose reduction. Two weeks later she returned to clinic complaining of bilateral hip and low lumbar discomfort but no B symptoms. A restaging 18F-FDG PET/CT in January of 2016 showed dramatic marrow uptake. A bone marrow aspirate showed sheets of tumor cells representing a spectrum from intermediate sized cells with lymphoblastic features to very large atypical cells with multiple nucleoli. Two distinct histologies were present; one remained consistent with the patient's known FL with a predominant nodular pattern and the other consistent with HT (The large atypical cells expressed PAX5, CD10, BCL2, and cMYC, and were negative for CD20, MPO, CD34, CD30, and BCL6). Focal areas showed faint, heterogeneous expression of terminal deoxynucleotidyl transferase (TdT) best seen on the clot section. Ki67 proliferation index was high (4+/4). FISH analysis showed two populations with MYC amplification and/or rearrangement, and no evidence of BCL6 rearrangement; a karyotype analysis showed a complex abnormal female karyotype with t (14; 18) and multiple structural and numerical abnormalities. She started dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) with concomitant prophylactic intrathecal methotrexate and cytarabine. She had but a short lived response before dying in hospice from progressive lymphoma. Whether idelalisib could provide a microenvironment for selection of more aggressive clones needs to be addressed. Our patient's clinical course is confounded by the incorporation of idelalisib while being further complicated by the complexity of HT and the mechanisms in which first-line chemotherapy regimens impact DHL. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Both HIV+ Hodgkin and non-Hodgkin lymphomas have higher rates of latent infection by the gamma-herpesviruses (GHVs), Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpes virus (KSHV), than corresponding lymphomas in the HIV-seronegative population. Bortezomib, a proteasome inhibitor, induces lytic activation of both EBV and KSHV. Lytic activation of GHVs latently infecting lymphoma cells is hypothesized to beneficial both for direct tumor cell lysis as well as increased cytotoxic immune response due to viral lytic gene products. Furthermore, preclinical studies found proteasome inhibition impairs HIV infectivity via preservation of human anti-retroviral APOBEC3G, suggesting a novel therapeutic strategy to control HIV. Given that therapy of relapsed or refractory HIV-associated lymphoma (R/R-HAL) results in modest rates of remission, we sought to capitalize on the high viral association within HAL using an oncolytic strategy with bortezomib. Objectives: The primary objective of this study was to evaluate safety and overall response rate (ORR) of R/R-HAL to bortezomib combined with ifosfamide, carboplatin, etoposide +/- rituximab (ICE/R). The secondary objectives of this study were to estimate the impact of bortezomib on lytic activation of EBV and KSHV, using peripheral blood mononuclear cell (PBMC) viral loads, and on HIV using single copy plasma viral loads; to report overall survival at 1 year (1yr-OS); and to correlate EBV and KSHV viral load changes with lymphoma response. Methods: A 3+3 dose escalation design with a 7-day lead-in period of bortezomib alone prior to bortezomib + ICE/R allowed for assessment of early effects of bortezomib on viral loads. Bortezomib was given intravenously on day 1 and 8 of each cycle at one of 4 dose levels: 0.7, 1, 1.3 or 1.5 mg/m2. Standard dose ICE +/- R began day 8 of cycle 1 (28-day cycle); ICE +/- R began day 1 of all subsequent cycles (21-day cycle). Rituximab was included in the regimen only for CD20+ lymphoma. Binomial proportions were used to estimate ORR. The product-limit (Kaplan-Meier) method was used to estimate 1yr-OS. The Wilcoxon signed rank test was used to evaluate changes in viral loads. Results: Twenty-three subjects were enrolled from 7 sites within the AIDS Malignancy Consortium (AMC). More than 90% of enrolled subjects were men and half were minorities; at baseline, 20/23 were on antiretroviral therapy, median CD4 count was 315/µL and median HIV viral load was undetectable. Mean age was 50 years. Over half of subjects had stage IV HAL; the majority had diffuse large B-cell lymphoma (DLBCL) (n=15), 2 had primary effusion (PEL), 3 had plasmablastic and 2 had Hodgkin lymphoma. Figure 1 summarizes grade 3-4 toxicities of the 22 subjects evaluable for adverse events during the dose-limiting toxicity period (cycles 1+2). The maximum tolerated dose was not reached at the highest dose cohort studied (bortezomib 1.5mg/m2). Responses occurred in 14/22 subjects initiating protocol therapy: 5 complete and 9 partial responses (PR). Of the 20 subjects who completed 2 or more cycles, the ORR was 80%. Nine of the responders underwent auto-hematopoietic stem cell transplant after protocol therapy. 1yr-OS was 55%. After bortezomib alone, median values of EBV PBMC viral load measured on day 8 were 2x greater than baseline. However, paired analysis did not confirm significant change in this small sample (n=16 evaluable), and there was no correlation found between change in EBV viral load and response. The 2 subjects with known KSHV+ lymphoma (PEL) each had more than a 1-log increase in day 8 KSHV viral load compared with baseline. Both of these subjects attained a PR from protocol therapy. Conclusions: Addition of bortezomib to ICE/R in R/R HAL is feasible with ORR (80%) and 1yr-OS (55%) comparing very favorably with a prior AMC retrospective report of ICE/R in R/R HAL (n=31, ORR 32%, 1yr-OS 38%, Bayraktar 2012). Evaluation of data collected from individual subjects suggests GHV lytic activation may occur with bortezomib alone. However, the lower bortezomib dose levels used to treat the bulk of study subjects and the limited study sample size limit our power to confirm this conclusion. We plan to further explore the effects of proteasome inhibition on GHVs. Evaluation of the impact of bortezomib on HIV replication is pending and will be presented at the meeting. Disclosures Reid: Millennium: Research Funding. Sparano:Takeda: Research Funding.