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The prognostic relevance of diagnosis to treatment interval (DTI) in patients with newly diagnosed mantle cell lymphoma (MCL) is unknown. Hence, we sought to evaluate the impact of DTI on outcomes in MCL using 3 large datasets (1) the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource, (2) patients enrolled in the ALL Age Asthma Cohort/CALGB 50403, and (3) a multisitecohort of patients with MCL. Patients were a priori divided into 2 groups, 0 to 14 days (short DTI) and 15 to 60 days (long DTI). The patients in whom observation was deemed appropriate were excluded. One thousand ninety-seven patients newly diagnosed with MCL and available DTI were included in the study. The majority (73%) had long DTI (n=797). Patients with short DTI had worse eastern cooperative oncology group performance status (ECOG PS ≥2), higher lactate dehydrogenase, bone marrow involvement, more frequent B symptoms, higher MCL International Prognostic Index (MIPI ≥6.2), and were less likely to receive intensive induction therapy than long DTI group. The median progression-free survival (2.5 years vs 4.8 years, p

The treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has significantly evolved in recent years. Targeted therapy with Bruton’s tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors has emerged as an effective chemotherapy-free option for patients with previously untreated or relapsed/refractory CLL/SLL. Undetectable minimal residual disease after the end of treatment is emerging as an important predictor of progression-free and overall survival for patients treated with fixed-duration BCL-2 inhibitor-based treatment. These NCCN Guidelines Insights discuss the updates to the NCCN Guidelines for CLL/SLL specific to the use of chemotherapy-free treatment options for patients with treatment-naïve and relapsed/refractory disease.

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.

Introduction We designed a multicenter, phase Ib dose-escalation trial of carfilzomib with bendamustine and rituximab in patients with relapsed/refractory non-Hodgkin lymphoma ( NCT02187133 ) in order to improve the response rates of this difficult-to-treat population. Chemoimmunotherapy with bendamustine and rituximab has shown activity in a variety of lymphomas, and proteasome inhibitors have demonstrated pre-clinical synergy and early clinical activity in this population. The objectives were to determine the maximum tolerated dose of carfilzomib and the preliminary efficacy of this combination. Patients and Methods The protocol followed a 3+3 design of carfilzomib dose escalation combined with standard doses of bendamustine and rituximab. Patients were treated for up to 6 cycles with an interim positron emission tomography/computed tomography after cycle 3. Results Ten patients were treated on the dose-escalation phase. The study was terminated at a carfilzomib dose of 56 mg/m2, and the maximum tolerated dose was not reached. The most common grade 3/4 adverse event was thrombocytopenia. There was 1 dose-limiting toxicity observed, grade 3 febrile neutropenia, and there were no treatment-related deaths. The overall response rate was 40% (complete response rate, 30%), with a median duration of response of 12 months and a median progression-free survival of 2.1 months. Conclusion Carfilzomib in combination with bendamustine and rituximab is a safe and well-tolerated treatment for patients with relapsed/refractory non-Hodgkin lymphoma. Preliminary data indicate that this combination may have efficacy with an acceptable side effect profile in this heavily pre-treated patient population with limited treatment options.

Background More than one-half of high-risk patients with relapsed/refractory (rr) diffuse large B-cell lymphoma (DLBCL) relapse after autologous hematopoietic cell transplantation (auto-HCT). In this phase II study, we investigate the long-term outcomes of high-risk patients with rrDLBCL receiving intensive consolidation therapy (ICT) with OVA (ofatumumab, etoposide, and high-dose cytarabine) prior to auto-HCT. Patients and Methods The primary endpoints were the ability of OVA to mobilize peripheral stem cells and the 2-year progression-free survival (PFS) rate following OVA. Secondary endpoints included safety, 2-year overall survival (OS), impact of cell of origin (COO), and the prognostic utility of next-generation sequencing minimal residual disease (MRD) testing. We simultaneously retrospectively assessed the outcomes of DLBCL patients who underwent ICT with a similar regimen at our institution. Results Twenty-seven patients received salvage chemotherapy, with a response rate of 25% in patients with germinal center B-cell (GCB)-DLBCL versus 92% in patients with non-GCB-DLBCL (P = .003). Nineteen responding patients underwent ICT with OVA (100% successful stem cell mobilization). The 2-year PFS and OS rate was 47% and 59%, respectively, with no difference based on COO. Similar findings were observed when the study and retrospective cohorts were combined. Neutropenia was the most common toxicity (47%). MRD-negative patients at the completion of salvage had a median OS of not reached versus 3.5 months in MRD-positive patients (P = .02). Conclusions OVA followed by auto-HCT is effective and safe for high-risk rrDLBCL. Patients with GCB-DLBCL had a lower response to salvage chemotherapy, but no difference in outcomes based on COO was seen after auto-HCT. MRD testing in the relapsed setting was predictive of long-term survival.

Objectives We sought to examine the natural history of geriatric assessment (GA) and quality of life (QOL) domains among adults age ≥ 50 years undergoing autologous hematopoietic cell transplantation (autoHCT). Materials and Methods A QOL tool and cancer-specific GA were completed before autoHCT in patients ≥50 years, and at 100 days, six months, and one year post-transplant. Results One hundred eighty-four patients completed the pre-transplant QOL/GA assessment, 169 (92%) completed the 100-day assessment, 162 (88%) completed the six-month assessment, and 145 (79%) completed the twelve-month assessment. Functional status, as measured by instrumental activities of daily living (IADL), decreased from baseline to day 101 (mean change −0.42 points, 95% CI, −0.75 to −0.09, p = 0.01) but returned to baseline by one year. Physical function as measured by Medical Outcomes Study-Physical Health (MOS-PH) increased by mean of 3.27 points (95% CI, −0.02 to 6.56, p = 0.05) by one year. Physician-rated KPS improved by one year, but patient-rated KPS did not. No QOL metric deteriorated from baseline. Baseline factors predictive of IADL and MOS-PH as measured over time included comorbidities and disease status at transplant. IADL and MOS-PH as measured over time were not significantly associated with age. Conclusions AutoHCT for adults age ≥ 50 years resulted in an initial decrease in functional status, with subsequent improvement back to baseline by one year. Physical health and QOL measures were improved or unchanged over time. AutoHCT is well tolerated in well selected older patients, using patient reported geriatric metrics as outcomes.

A subset of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients develop Richter transformation (RT), classically resulting in diffuse large B-cell lymphoma (RT-DLBCL); however, a minority of cases result in Hodgkin lymphoma (RT-HL). RT-HL can be of type 1 or 2. RT-HL1 consists of Hodgkin-Reed Sternberg (HRS) cells in a background of CLL, and RT-HL2 has HRS cells in the typical inflammatory background of classical HL (CHL). Here we describe a rare case of CLL with an increased number of HRS-like cells which evolved to Epstein–Barr virus (EBV)-positive DLBCL over 2 years. The patient was a 48-year-old man who initially presented with right inguinal lymphadenopathy and was found to have both CLL/SLL and HSV lymphadenitis, which was then treated with valacyclovir and acyclovir prophylaxis. Approximately 1 year later, he developed diffuse lymphadenopathy with CLL and scattered EBV-positive HRS-like cells, consistent with RT-HL1, for which he received rituximab. After 3 months, he again developed diffuse lymphadenopathy with worsening symptoms. The patient was diagnosed with EBV-positive DLBCL by lymph node biopsy and responded well to 6 cycles of R-CHOP. This is the first case of CLL with RT-HL1 predating RT-DLBCL. While RT-HL1 and RT-DLBCL have been described previously, the potential for an association between these entities is cryptic. As more cases are reported, this relationship can be studied in greater detail.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are characterized by a progressive accumulation of leukemic cells in the peripheral blood, bone marrow, and lymphoid tissues. Treatment of CLL/SLL has evolved significantly in recent years because of the improved understanding of the disease biology and the development of novel targeted therapies. In patients with indications for initiating treatment, the selection of treatment should be based on the disease stage, patient's age and overall fitness (performance status and comorbid conditions), and cytogenetic abnormalities. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

Immunochemotherapy followed by autologous transplant (ASCT) in CALGB/Alliance 59909 achieved a median progression-free survival (PFS) in mantle cell lymphoma (MCL) of 5 years, but late recurrences occurred. We evaluated tolerability and efficacy of adding post-transplant bortezomib consolidation (BC) or maintenance (BM) to this regimen in CALGB/Alliance 50403, a randomized phase II trial. Following augmented-dose R-CHOP/ methotrexate, high-dose cytarabine-based stem cell mobilization, cyclophosphamide/carmustine/etoposide (CBV) autotransplant, and rituximab, patients were randomized to BC (1.3 mg/m2 IV days 1, 4, 8, 11 of a 3-week cycle for four cycles) or BM (1.6 mg/m2 IV once weekly × 4 every 8 weeks for 18 months) beginning day 90. The primary endpoint was PFS, measured from randomization for each arm. Proliferation signature, Ki67, and postinduction minimal residual disease (MRD) in bone marrow were assessed. Of 151 patients enrolled; 118 (80%) underwent ASCT, and 102 (68%) were randomized. Both arms met the primary endpoint, with median PFS significantly greater than 4 years (P < .001). The 8-year PFS estimates in the BC and BM arms were 54.1% (95% CI 40.9%-71.5%) and 64.4% (95% 51.8%-79.0%), respectively. Progression-free survival was significantly longer for transplanted patients on 50403 compared with those on 59909. Both the PFS and OS were significantly better for those who were MRD-negative post-induction. The high risk proliferation signature was associated with adverse outcome. Both BM and BC were efficacious and tolerable, although toxicity was significant. The comparison between studies 50403 and 59909 with long-term follow up suggests a PFS benefit from the addition of BC or BM post- transplant.

Background: Chimeric antigen receptor T-cell (CAR T) immunotherapy is an evolving treatment for relapsed/ refractory non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). There is a growing need to elucidate the infectious complications of BCMA- and CD19-directed CAR T therapy. We performed a single-center retrospective analysis of infection outcomes up to 1-year post BCMA and CD19-directed CAR T treatment. Methods: All patients treated at our institution with a BCMA-directed CAR T therapy for MM or with a CD19-directed CAR T for NHL from 2018-2020 were analyzed for risk factors for infection and infectious complications. Bacterial, viral and fungal infections were recorded if there was a microbiologic or histopathologic diagnosis or if clinical suspicion for infection required empiric treatment. Infection severity was classified as mild, moderate, severe, life-threatening, or fatal as previously described (Young et al. 2016, van Burnik et al. 2007). Infections were identified from the day of the first CAR T-cell infusion up to 1 year after infusion. Observation of infections was terminated at the time of disease progression, initiation of next therapy, or death, whichever occurred first. Fisher's exact test and Wilcoxon rank-sum test were used to compare between cohorts. Poisson mixed effects model with a subject-specific random intercept and an offset to account for the duration at risk was used to identify risk factors for infections. Results: Of the 104 subjects in this study, 55 patients (53%) had MM treated with BCMA CAR T and 49 patients (47%) had NHL treated with CD19 CAR T. Median number of prior therapies was 6 (4 - 9) in the BCMA cohort and 3 (2-4) in the CD19 cohort (Table 1). Prior to starting lymphodepleting (LD) chemotherapy, most patients did not have IgG< 400, ALC< 200, or ANC< 500. Almost all the patients were on antibacterial (99%), antiviral (99%) and antifungal (92%) prophylaxis (ppx), with 18%, 90% and 9% of patients starting this before LD chemotherapy, respectively. Median follow-up time was 5.8 months (95% CI: 4.2-6.4). In total, there were 87 infection events (48 bacterial, 33 viral, and 6 fungal) observed in 56 patients (54%), with 47 infections in 29 (53%) patients in the BCMA CAR T cohort and 40 infections in 27 (55%) patients in the CD19 CAR T cohort (p =0.9). The BCMA cohort had 19 bacterial (40%) vs 29 bacterial (73%) in CD19 cohort (p=0.005), while BCMA cohort had 25 viral (53%) vs 8 viral (20%) in CD19 cohort (p=0.002). Fungal infection rates were comparable between BCMA and CD19 cohorts, 3 (6%) vs 3 (8%) respectively (p=1). Among the infections that occurred, 20 (23%) were high severity occurring in 16 patients (15%) of the overall cohort. Four high severity infections (5%) occurred in 3 patients (5%) in the BCMA cohort while 16 high severity infections (18%) occurred in 13 patients (27%) in the CD19 cohort (p < 0.001) (Figure 1). The BCMA cohort had higher rates of respiratory infections (68% vs 50%, p=0.1), while the CD19 cohort had higher rates of bloodstream infections (15% vs 2%, p=0.05) and gastrointestinal infections (10% vs 0%, p=0.04). The rates of grade (Gr) 3-4 neutropenia and IgG < 300 in both the cohorts at various time points post CAR T were comparable. At 9-12 months, Gr 3-4 neutropenia was 7% vs 8% (p=1) and IgG < 300 was 7% vs 33% (p=0.1) for the BCMA and CD19 cohorts respectively. Adjusting for time periods, risk factors for development of infections were use of steroids (incidence rate ratio [IRR] 1.6, 95% CI: 1.1-2.5, p=0.03) and post CAR T hypogammaglobulinemia (IgG < 600) (IRR =2.1, 95% CI: 1.2-3.9, p=0.02). Conclusions: This retrospective study is one of the largest studies to date comparing the post CAR T infections rates between BCMA and CD19 directed CAR T treated patients. While the incidence of infection, use of antimicrobial ppx, and rates of Gr 3-4 neutropenia and hypogammaglobulinemia were comparable between BCMA and CD19 CAR T cohorts, viral infections were more common post BCMA CAR T while bacterial infections were more frequent post CD19 CAR T. Use of steroids as well as post CAR T hypogammaglobulinemia are possible risk factors for development of infections. Further studies are needed to examine the infectious complications post-CAR T treatment, characterize the underlying risk factors, and to establish appropriate prophylactic approaches in patients undergoing CD19- and BCMA-directed CAR T therapy. Disclosures Fakhri: University of California San Francisco: Current Employment. Ai:Nurix Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics, Kymera: Membership on an entity's Board of Directors or advisory committees. Martin:Seattle Genetics: Research Funding; GSK: Consultancy; Sanofi: Research Funding; AMGEN: Research Funding; Janssen: Research Funding. Wolf:Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Shah:BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. Andreadis:Genentech: Other: Spouse Employee (salary and stock); Novartis: Research Funding; Celgene/Juno: Research Funding; Amgen: Research Funding; Merck: Research Funding; Gilead/Kite: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Astellas: Other: Advisor; Seattle Genetics: Other: Advisor; Karyopharm: Other: Advisor; Incyte: Other. Wong:GSK: Research Funding; Amgen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Roche: Research Funding; Janssen: Research Funding; Fortis: Research Funding.

EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is a preferred regimen for HIV-non-Hodgkin lymphomas (HIV-NHLs), which are frequently Epstein-Barr virus (EBV) positive or human herpesvirus type-8 (HHV-8) positive. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. We performed a randomized phase 2 study in 90 patients (45 per study arm) with aggressive HIV-NHLs, using dose-adjusted EPOCH (plus rituximab if CD20+), alone or with 300 mg vorinostat, administered on days 1 to 5 of each cycle. Up to 1 prior cycle of systemic chemotherapy was allowed. The primary end point was complete response (CR). In 86 evaluable patients with diffuse large B-cell lymphoma (DLBCL; n = 61), plasmablastic lymphoma (n = 15), primary effusion lymphoma (n = 7), unclassifiable B-cell NHL (n = 2), and Burkitt lymphoma (n = 1), CR rates were 74% vs 68% for EPOCH vs EPOCH-vorinostat (P = .72). Patients with a CD4+ count

We set out to assess feasibility and safety of allogeneic hematopoietic cell transplant in 17 persons with HIV in a phase II prospective multicenter trial. The primary endpoint was 100-day nonrelapse mortality (NRM). Patients had an 8/8 HLA-matched related or at least a 7/8 HLA-matched unrelated donor. Indications for transplant were acute leukemia, myelodysplasia, and lymphoma. Conditioning was myeloablative or reduced intensity. There was no NRM at 100 days. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 41%. At 1 year, overall survival was 59%; deaths were from relapsed/progressive disease (n = 5), acute GVHD (n = 1), adult respiratory distress syndrome (n = 1), and liver failure (n = 1). In patients who achieved complete chimerism, cell-associated HIV DNA and inducible infectious virus in the blood were not detectable. Blood and Marrow Transplant Clinical Trials Network 0903/AIDS Malignancy Consortium 080 was registered at www.clinicaltrials.gov (no. NCT01410344).

Introduction We report the results of a phenotypic and functional analysis of immune reconstitution in HIV(+) patients treated with allogeneic hematopoietic stem cell transplant (allo-HSCT), in comparison with HIV(+) autologous transplant (auto-HSCT) recipients, HIV(-) auto-HSCT recipients and healthy controls (HCs). Methods Blood samples were collected at days 56, 180 and 365 post-transplant from HIV(+) allo-ASCT recipients (n=17, BMT-CTN-0903/AMC-080 trial), HIV(+) auto-SCT recipients (n=36, BMT-CTN-0803/AMC-071 trial) and HIV(-) auto-SCT recipients (n=30, NCT00569309/OSU-07044 trial), and at 1 time point from 71 HCs. Five-color flow cytometry was performed on whole blood. Principal component analysis (PCA) examined global differences across 18 immune cell subsets between all subject cohorts. Wilcoxon rank-sum tests compared median absolute and proportionate cell counts. Feature importance score analysis (FIS) identified contributions of 100 immune cell populations to differences between HIV(+) cohorts and HCs. Functional responsiveness of HIV(+) allo-HSCT recipients' T cells to stimulation with CD3- and CD28-directed antibodies, NK cells to stimulation with IL-12+IL-18 and monocytes to stimulation with lipopolysaccharide (LPS) was assessed by mass cytometry on peripheral blood mononuclear cells (n=2) and compared to HCs (n=2). Results PCA showed that immunomes of HIV(+) allo-HSCT recipients and HIV(+) auto-HSCT recipients clustered together at all time points. HIV(-) auto-SCT recipients and HCs clustered together and away from the HIV(+) cohorts. FIS identified 13 cell subsets that defined the difference between HIV(+) allo-HSCT recipients (all visits) and HCs and 11 immune cell subsets that defined the difference between HIV(+) auto-HSCT recipients (all visits) and HCs; in each comparison, activated CD3+/HLA-DR+ T cells had the greatest impact on the difference between composite HIV(+) and HC immunomes. At 1 year, both HIV(+) transplant recipient cohorts had higher absolute numbers of activated T cells, effector T cells and CD8+ T cells than HCs and lower numbers of CD4+ T cells, naive T cells, and activated NK cells compared to HCs (p Conclusion Chronic HIV infection confers pro-inflammatory immune characteristics on phenotypic and functional profiling of the cellular immunome of stem cell transplant recipients, irrespective of allogeneic or autologous stem cell donor source.

Background The California End of Life Option Act (EOLOA), which legalized physician-assisted death (PAD), became effective in 2016. The EOLOA does not require a mental health consultation in all cases nor does it state the standards for the mental health assessment. University of California, San Francisco Medical Center (UCSFMC) policy makers decided to require a mental health assessment of all patients seeking PAD under the EOLOA. Objectives The Department of Psychiatry was tasked with developing a standard protocol for the mental health assessment of patients seeking PAD. Methods Members of the consultation-liaison (C-L) service developed a document to guide members in completing the mental health evaluations for patients requesting PAD. Results A committee at UCSFMC developed a clinical protocol informed by the law with an additional local expectation of an evaluation by a psychiatrist or clinical psychologist. The C-L psychiatry group at UCSF developed a standard protocol for the psychiatric assessment for use by clinicians performing these assessments. Attention to the cognitive, mood, and decisional capacity status pertinent to choosing PAD is required under the clinical guidance document. Case vignettes of 6 patients evaluated for PAD are presented. Conclusions The local adoption of the California EOLOA by UCSFMC requires a mental health assessment of all patients requesting EOL services at UCSF. The clinical guideline for these assessments was locally developed, informed by the literature on EOL in other jurisdictions where it has already been available.

Although the use of geriatric assessment (GA) in the allogeneic hematopoietic cell transplantation (HCT) setting has been reported, few studies have evaluated the impact of patient-reported function on autologous HCT (autoHCT) outcomes. In this study, GA, including the administration of Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) quality of life tool, was performed in 184 patients age ≥50 years (median age, 61 years; range, 50 to 75 years) before autoHCT. Associations among GA findings, quality of life metrics, and post-transplantation outcomes were evaluated using Cox regression. Indications for autoHCT included multiple myeloma (73%), non-Hodgkin lymphoma (20%), and other disorders (7%). The median progression-free survival (PFS) was 28 months, whereas the median overall survival (OS) was not reached. In unadjusted analysis, both PFS and OS were significantly associated with 5 GA components: limitation in instrumental activities of daily living, patient-reported Karnofsky Performance Status (KPS), and the Physical, Functional, and BMT subscale scores of the FACT-BMT. In multivariate analysis, 3 components—limitation in instrumental activities of daily living, patient-reported KPS, and FACT-BMT Physical subscale—remained predictive of both PFS and OS when adjusted for age, provider-reported KPS, disease status, and HCT comorbidity index. In older adults undergoing autoHCT, limitation in any 1 of 3 patient-reported measures of functional status was independently associated with inferior PFS and OS, even after adjusting for known prognostic factors.

In 2014, autologous hematopoietic cell transplant (autoHCT) was removed from the National Comprehensive Cancer Network guidelines as a recommended treatment for patients with intermediate-risk AML in first complete remission (CR1). We reviewed the outcomes of all patients with intermediate-risk AML treated with autoHCT in CR1 at our institution. Of 334 patients who underwent autoHCT for AML between 1988 and 2013, 133 patients with intermediate-risk AML in CR1 were identified. Cytogenetics were diploid in 97 (73%). With a median follow-up of 4.1 years (range 0.1-17), median overall survival (OS) is 6.7 years; at 5 years post-transplant, 59% of patients remain alive and 43% remain relapse-free. Forty-eight percent of relapsing patients proceeded to salvage alloHCT. Our findings demonstrate that nearly half of patients with intermediate-risk AML in CR1 achieve sustained remissions, and that salvage alloHCT is feasible in those who relapse. AutoHCT therefore remains a reasonable option for intermediate-risk patients with AML in CR1.

Patients with the most common aggressive AIDS-related non-Hodgkin lymphomas can expect improved outcomes approaching those of immunocompetent patients in the contemporary era. When treated with appropriate antilymphoma therapy, these improvements apply to every subgroup of patients, including those with low CD4 counts and high-risk disease. Background We undertook the present analysis to examine the shifting influence of prognostic factors in HIV-positive patients diagnosed with aggressive non-Hodgkin lymphoma (NHL) over the last two decades. Patients and methods We carried out a pooled analysis from an existing database of patients with AIDS-related lymphoma. Individual patient data had been obtained prior from prospective phase II or III clinical trials carried out between 1990 until 2010 in North America and Europe that studied chemo(immuno)therapy in HIV-positive patients diagnosed with AIDS-related lymphomas. Studies had been identified by a systematic review. We analyzed patient-level data for 1546 patients with AIDS-related lymphomas using logistic regression and Cox proportional hazard models to identify the association of patient-, lymphoma-, and HIV-specific variables with the outcomes complete response (CR), progression-free survival, and overall survival (OS) in different eras: pre-cART (1989–1995), early cART (1996–2000), recent cART (2001–2004), and contemporary cART era (2005–2010). Results Outcomes for patients with AIDS-related diffuse large B-cell lymphoma and Burkitt lymphoma improved significantly over time, irrespective of baseline CD4 count or age-adjusted International Prognostic Index (IPI) risk category. Two-year OS was best in the contemporary era: 67% and 75% compared with 24% and 37% in the pre-cART era (P Conclusions Our results demonstrate a significant improvement of CR rate and survival for all patients with AIDS-related lymphomas. Effective HIV-directed therapies reduce the impact of HIV-related prognostic factors on outcomes and allow curative antilymphoma therapy for the majority of patients with aggressive NHL.

Diffuse large B-cell lymphoma (DLBCL) is an AIDS-defining, aggressive lymphoid neoplasm in which normal lymph node architecture is replaced by sheets of large, atypical lymphoid cells. It is thought to arise from mature B-cells and is comprised of large, non-cleaved centroblasts and immunoblasts with abundant cytoplasm and prominent nucleoli. As the most common form of non-Hodgkin lymphoma (NHL) in both HIV-positive and HIV-negative individuals, there is an increasing appreciation of its morphologic, genetic, and biologic heterogeneity.

Hairy cell leukemia (HCL) is a rare type of indolent B-cell leukemia, characterized by symptoms of fatigue and weakness, organomegaly, pancytopenia, and recurrent opportunistic infections. Classic HCL should be considered a distinct clinical entity separate from HCLvariant (HCLv), which is associated with a more aggressive disease course and may not respond to standard HCL therapies. Somatic hypermutation in the IGHV gene is present in most patients with HCL. The BRAF V600E mutation has been reported in most patients with classic HCL but not in those with other B-cell leukemias or lymphomas. Therefore, it is necessary to distinguish HCLv from classic HCL. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of classic HCL.

While the International Prognostic Index is commonly used to predict outcomes in immunocompetent patients with aggressive B-cell non-Hodgkin lymphomas, HIV-infection is an important competing risk for death in patients with AIDS-related lymphomas. We investigated whether a newly created prognostic score (AIDS-related lymphoma International Prognostic Index) could better assess risk of death in patients with AIDS-related lymphomas. We randomly divided a dataset of 487 patients newly diagnosed with AIDS-related lymphomas and treated with rituximab-containing chemoimmunotherapy into a training (n=244) and validation (n=243) set. We examined the association of HIV-related and other known risk factors with overall survival in both sets independently. We defined a new score (AIDS-related lymphoma International Prognostic Index) by assigning weights to each significant predictor [age-adjusted International Prognostic Index, extranodal sites, HIV-score (composed of CD4 count, viral load, and prior history of AIDS)] with three risk categories similar to the age-adjusted International Prognostic Index (low, intermediate and high risk). We compared the prognostic value for overall survival between AIDS-related lymphoma International Prognostic Index and age-adjusted International Prognostic Index in the validation set and found that the AIDS-related lymphoma International Prognostic Index performed significantly better in predicting risk of death than the age-adjusted International Prognostic Index (P=0.004) and better discriminated risk of death between each risk category (P=0.015 vs. P=0.13). Twenty-eight percent of patients were defined as low risk by the ARL-IPI and had an estimated 5-year overall survival (OS) of 78% (52% intermediate risk, 5-year OS 60%; 20% high risk, 5-year OS 50%).

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. Results: Of 86 evaluable patients, 64 had DLBCL (34 GCB-type and 27 ABC-type), 15 plasmablastic lymphoma (PBL), and 7 primary effusion lymphoma (PEL) [Table 1]. Fifty-one (59%) patients were treatment naïve, whereas 35 (41%) had been pre-treated with one cycle of CHOP-like or EPOCH prior to enrollment. Grade 4 neutropenia was more frequent for VOR-EPOCH than for EPOCH (47% vs. 20%), and also grade 4 thrombocytopenia more frequent for VOR-EPOCH (29% vs 2%). The two regimens had similar rates of febrile neutropenia (18% vs. 16%). CR rates were also comparable for the two regimens (68% vs. 74%) [1-sided P=0.72] (Table 1). Median HIV plasma RNA generally decreased in both arms. No significant differences were observed in T-cell subsets or size of the latent HIV reservoir between arms. Treatment outcomes did not differ significantly across NHL subtypes or EBV status (Table 1), nor with pre-protocol systemic therapy (Table 2). Overall CR rates were 45% in patients with CD4+ counts of 50-100 cells/mm3, 63% with 100-199 cells/mm3, and 85% in patients with >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 ( Conclusion: This prospective trial demonstrated that EPOCH-based chemotherapy was broadly efficacious against aggressive HIV-NHLs, including high risk subtypes (ABC DLBCL, PBL, and PEL). However, a 5-day course of VOR given with each chemotherapy cycle failed to improve outcomes. Consistent with prior reports in HIV-uninfected patients with DLBCL, a DTI of ≥15 days was associated with better clinical outcomes than a shorter DTI. A strategy of permitting pre-protocol therapy was useful in facilitating accrual and was used in about 40% of study participants without compromising clinical outcomes. Disclosures Baiocchi: Prelude: Consultancy. Noy:Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. OffLabel Disclosure: Vorinostat is being tested in combination with chemotherapy for HIV-associated B-cell lymphoma

Introduction. Our previous flow cytometry-based comparison of HIV(+) and HIV(-) autologous hematopoietic stem cell transplant (auto-HSCT) recipient immunomes at 56, 180 and 365 days post-transplant to each other and to healthy controls (HCs) showed that both sets of auto-HSCT recipient immunomes approached HCs over time, but retained significant differences. HIV(+), but not HIV(-), auto-AHCT recipients retained pro-inflammatory features consistent with chronic HIV infection. Here, we report the results of a quantitative and functional analysis of immune reconstitution in HIV(+) patients treated with allogeneic hematopoietic stem cell transplant (allo-HSCT), in comparison with HIV(+) auto-HSCT recipients and HCs. Methods. Blood samples were collected for analysis at days 56, 180 and 365 post-transplant from HIV(+) transplant recipients and at 1 time point from HCs. Whole blood analysis was performed by five-color flow cytometry across 100 immune marker combinations. Comparisons were made between HIV(+) allo-HSCT recipients (n=17, acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, Hodgkin and non-Hodgkin lymphoma that received myeloablative or reduced intensity conditioning on the BMT-CTN-0903/AMC-080 trial), HIV(+) auto-HSCT recipients (n=36, aggressive B cell non-Hodgkin lymphoma or Hodgkin lymphoma that received myeloablative conditioning on the BMT-CTN-0803/AMC-071 trial) and 71 HCs. Unsupervised principal component analysis (PCA) examined differences in immune cell proportions, identified by flow cytometry across 100 cell subsets at each time point. Wilcoxon rank-sum tests compared median absolute counts and median proportions of cell subsets. An independent feature importance score analysis (FIS) identified contributions of immune cell populations expressing specific immune marker combinations to the differences between HIV(+) auto-HSCT recipients, HIV(+) allo-HSCT recipients and HCs. Functional responsiveness of HIV(+) allo-HSCT recipients' T cells to stimulation with CD3- and CD28-directed antibodies, NK cells to stimulation with IL-12 and IL-18 and monocytes to stimulation with lipopolysaccharide (LPS) was assessed in a preliminary mass cytometry on peripheral blood mononuclear cells isolated at the same time points (n=2) and compared to HCs (n=2). Results. PCA showed that immunomes of HIV(+) allo-HSCT recipients and HIV(+) auto-HSCT recipients clustered together with each other, but away from HCs at all time points throughout the post-transplant year. FIS identified: 1) 13 cell subsets that defined the difference between HIV(+) allo-HSCT recipients (all visits) and HCs, and 2) 11 immune cell subsets that defined the difference between HIV(+) auto-HSCT recipients (all visits) and HCs; in both of these comparisons, activated CD3+/HLA-DR+ T cells had the greatest impact on the difference between HIV(+) and HC immunomes. At 1 year, both HIV(+) transplant recipient cohorts had higher absolute numbers of activated T cells, effector T cells and CD8+ T cells than HCs (Wilcoxon rank-sum test, p Conclusion. Chronic HIV infection confers the pro-inflammatory immune features on the phenotypic and functional profiling of the T lymphocyte immunome of stem cell transplant recipients, irrespective of allogeneic or autologous stem cell donor source. Disclosures Devine: Bristol Myers: Other: Grant for monitoring support & travel support; Kiadis Pharma: Other: Protocol development (via institution); Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Noy:Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Hofmeister:Celgene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Navarro:Atara Biotherapeutics: Employment, Equity Ownership. Behbehani:Fluidigm corporation: Other: Travel funding. Lozanski:Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding; Stemline Therapeutics Inc.: Research Funding; Genentec: Research Funding. Baiocchi:Prelude: Consultancy.

Background Despite advances in therapy, relapsed or refractory (RR) non-Hodgkin lymphoma (NHL) remains a major treatment challenge. Preclinical data support the activity of proteasome inhibitors against lymphoma through multiple mechanisms including activation of the endoplasmic reticulum (ER) stress response and reduction in the threshold for apoptosis in response to chemotherapy. Clinically, proteasome inhibiton with bortezomib added to bendamustine yielded promising results in patients (pts) with indolent NHL with limited additional toxicity. Compared to bortezomib, carfilzomib is a more target specific and potent proteasome inhibitor with less neurotoxicity. We embarked on a multicenter, phase 1b dose escalation trial to assess the combination of carfilzomib with bendamustine and rituximab in pts with RR aggressive or indolent NHL. Methods The primary objective of the study is to determine the maximum tolerated dose (MTD) and recommended phase II dose of carfilzomib when combined with bendamustine and rituximab. The secondary objective is to evaluate the preliminary antitumor activity of the combination in select NHL histologies. Correlative studies examine markers of ER stress and apoptosis in response to treatment. Here we report the preliminary results of the dose escalation phase expected to be completed in Fall 2019. We followed a standard 3+3 design with escalation of the carfilzomib dose in 4 dose level cohorts combined with bendamustine dosed at 90 mg/m2 IV on Days 1 and 2 and Rituximab dosed at 375 mg/m2 IV on Day 9 of cycle 1 and Day 1 of subsequent cycles. Initially, carfilzomib was dosed twice a week with dose level 1 at 15 mg/m2 IV on days 1,2,8,9, 15, and 16. Subsequently, we explored weekly dosing schedules with carfilzomib at 36 mg/m2 (dose level 2), 56 mg/m2 (dose level 3), and 70 mg/m2 (dose level 4) on days 9 and 16 with a 20 mg/m2 starting dose on day 2. Dose limiting toxicity (DLT) was defined as Gr4 or specific Gr3 events attributable to the combination. Pts are treated for up to 6 cycles with an interim PET/CT after cycle 3. Results To date, 10 pts have been treated on the dose escalation phase with one patient currently on study treatment. Overall, 5 pts had diffuse large B-cell lymphoma (DLBCL), 3 mantle cell lymphoma (MCL), 1 follicular lymphoma (FL), and 1 marginal zone lymphoma (MZL). Pts received a median of 3 prior lines of therapy. Four pts were treated on dose level 1, 3 on dose level 2, and 3 on dose level 3. Treatment-emergent Grade 2-4 adverse events included thrombocytopenia in 1 pt (Gr 4), neutropenia in 1 pt (Gr 4), febrile neutropenia in 1 pt (Gr 3), culture negative fevers in 1 pt (Gr 3), nausea/vomiting in 2 pts (Gr 2 and 3), other GI toxicities in 1 pt (Gr 2), lower back pain in 1 pt (Gr 2), arthralgias in 1 pt (Gr 2), and cerebrevoascular ischemia in 1 pt (Gr 2). Two pts had treatment related-SAEs (Gr3 culture negative fevers; Gr 3 febrile neutropenia and Gr 3 vomiting) at dose level 2 and 3 respectively. One patient experienced DLT (Gr 3 febrile neutropenia) at dose level 3. There were no treatment related deaths. Of 10 evaluable pts to date, the overall response rate (ORR) is 40% with 3 pts achieving complete remission (one with FL, one with DLBCL and one with MCL) and one pt with MCL achieving a partial remission. The responder with FL had relapsed disease after achieving prior complete remission with rituximab and bendamustine alone. For the 9 pts who completed study treatment, median duration of treatment was 2.4 months, median progression free survival was 1.9 months and median overall survival was 11.6 months. The median duration of response for the 3 responders who completed therapy was 21.8 months. Conclusion Carfilzomib in combination with bendamustine and rituximab is a safe and well-tolerated treatment for pts with RR NHL. The MTD has not been reached and enrollmemt continues, with dose escalation phase anticipated to complete in Fall 2019. Preliminary data indicate that this combination may have efficacy with an acceptable side effect profile in this heavily pre-treated patient population with limited treatment options. Disclosure: This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program with general research support provided by Amgen. Disclosures Tuscano: Spectrum: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Honoraria; Amgen: Honoraria; Takada: Research Funding; Abbvie: Research Funding; Genentech: Research Funding. Wieduwilt:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen, Leadiant, Merck, Servier: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Reata Pharmaceuticals: Equity Ownership. Andreadis:Genentech: Equity Ownership, Other: Spouse is Employee; Novartis: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy.

Human herpesvirus 8 (HHV8) is a gamma herpesvirus associated with Kaposi sarcoma, multicentric Castleman disease, and primary effusion lymphoma, lymphoproliferative diseases that are most commonly observed in immunocompromised individuals. The viral genome expresses genes responsible for inhibition of apoptosis, cell cycle entry, and angiogenesis. Viral homologs of human regulatory genes are expressed, providing stimuli for angiogenesis, B-cell proliferation, and immune evasion. Variations in expression of these factors give rise to the 3 known HHV8-associated malignancies. Identification of these pathogenetic mechanisms has led to exploration of targeted treatment approaches for all 3 of these disorders with success in Kaposi sarcoma and multicentric Castleman disease; primary effusion lymphoma remains a clinical challenge.

Limited comparative data exist for the treatment of HIV-associated non-Hodgkin lymphoma. We analyzed pooled individual patient data for 1546 patients from 19 prospective clinical trials to assess treatment-specific factors (type of chemotherapy, rituximab, and concurrent combination antiretroviral [cART] use) and their influence on the outcomes complete response (CR), progression free survival (PFS), and overall survival (OS). In our analysis, rituximab was associated with a higher CR rate (odds ratio [OR] 2.89; P < .001), improved PFS (hazard ratio [HR] 0.50; P < .001), and OS (HR 0.51; P < .0001). Compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), initial therapy with more dose-intense regimens resulted in better CR rates (ACVBP [doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisolone]: OR 1.70; P < .04), PFS (ACVBP: HR 0.72; P = .049; "intensive regimens": HR 0.35; P < .001) and OS ("intensive regimens": HR 0.54; P < .001). Infusional etoposide, prednisone, infusional vincristine, infusional doxorubicin, and cyclophosphamide (EPOCH) was associated with significantly better OS in diffuse large B-cell lymphoma (HR 0.33; P = .03). Concurrent use of cART was associated with improved CR rates (OR 1.89; P = .005) and trended toward improved OS (HR 0.78; P = .07). These findings provide supporting evidence for current patterns of care where definitive evidence is unavailable.

Purpose Concerns regarding neurocognitive toxicity of whole-brain radiotherapy (WBRT) have motivated development of alternative, dose-intensive chemotherapeutic strategies as consolidation in primary CNS lymphoma (PCNSL). We performed a multicenter study of high-dose consolidation, without WBRT, in PCNSL. Objectives were to determine: one, rate of complete response (CR) after remission induction therapy with methotrexate, temozolomide, and rituximab (MT-R); two, feasibility of a two-step approach using high-dose consolidation with etoposide plus cytarabine (EA); three, progression-free survival (PFS); and four, correlation between clinical and molecular prognostic factors and outcome. Patients and Methods Forty-four patients with newly diagnosed PCNSL were treated with induction MT-R, and patients who achieved CR received EA consolidation. We performed a prospective analysis of molecular prognostic biomarkers in PCNSL in the setting of a clinical trial. Results The rate of CR to MT-R was 66%. The overall 2-year PFS was 0.57, with median follow-up of 4.9 years. The 2-year time to progression was 0.59, and for patients who completed consolidation, it was 0.77. Patients age > 60 years did as well as younger patients, and the most significant clinical prognostic variable was treatment delay. High BCL6 expression correlated with shorter survival. Conclusion CALGB 50202 demonstrates for the first time to our knowledge that dose-intensive consolidation for PCNSL is feasible in the multicenter setting and yields rates of PFS and OS at least comparable to those of regimens involving WBRT. On the basis of these encouraging results, an intergroup study has been activated comparing EA consolidation with myeloablative chemotherapy in this randomized trial in PCNSL, in which neither arm involves WBRT.

Establishing the diagnosis of focal brain lesions in patients with unexplained neurologic symptoms represents a challenge. The goal of this study is to provide evidence supporting functional roles for CXC chemokine ligand (CXCL)13 and interleukin (IL)-10 in central nervous system (CNS) lymphomas and to evaluate the utility of each as prognostic and diagnostic biomarkers. We demonstrate for the first time that elevated CXCL13 concentration in cerebrospinal fluid (CSF) is prognostic and that CXCL13 and CXCL12 mediate chemotaxis of lymphoma cells isolated from CNS lymphoma lesions. Expression of the activated form of Janus kinase 1 supported a role for IL-10 in prosurvival signaling. We determined the concentration of CXCL13 and IL-10 in CSF of CNS lymphoma patients and control cohorts including inflammatory and degenerative neurologic disease in a multicenter study involving 220 patients. Bivariate elevated CXCL13 plus IL-10 was 99.3% specific for primary and secondary CNS lymphoma, with sensitivity significantly greater than reference standard CSF tests. These results identify CXCL13 and IL-10 as potentially important biomarkers of CNS lymphoma that merit further evaluation and support incorporation of CXCL13 and IL-10 into diagnostic algorithms for the workup of focal brain lesions in which lymphoma is a consideration.

Background. The optimal therapeutic approach for patients with AIDS-related primary central nervous system lymphoma (AR-PCNSL) remains undefined. While its incidence declined substantially with combination antiretroviral therapy (cART), AR-PCNSL remains a highly aggressive neoplasm for which whole brain radiotherapy (WBRT) is considered a standard first-line intervention. Methods. To identify therapy-related factors associated with favorable survival, we first retrospectively analyzed outcomes of AR-PCNSL patients treated at San Francisco General Hospital, a public hospital with a long history of dedicated care for patients with HIV and AIDS-related malignancies. Results were validated in a retrospective, multicenter analysis that evaluated all newly diagnosed patients with AR-PCNSL treated with cART plus high-dose methotrexate (HD-MTX). Results. We provide evidence that CD4+ reconstitution with cART administered during HD-MTX correlates with long-term survival among patients with CD4 Conclusion. Long-term disease-free survival can be achieved in AR-PCNSL, even among those with histories of opportunistic infections, limited access to health care, and medical non-adherence. Given this, as well as the long-term toxicities of WBRT, we recommend that integration of cART plus first-line HD-MTX be considered for all patients with AR-PCNSL.

Autologous hematopoietic cell transplant (AHCT) for HIV-infected patients is largely limited to centers with HIV-specific expertise. The Blood and Marrow Transplant Clinical Trials Network 0803/AIDS Malignancy Consortium 071 trial is a multicenter phase 2 study of AHCT for patients with HIV-related lymphoma (HRL). Eligible patients had chemotherapy-sensitive relapsed/persistent HRL, were >15 years of age, and had treatable HIV infection. Patients were prepared using carmustine, etoposide, cytarabine, and melphalan and received consistent management of peritransplant antiretroviral treatment. The primary endpoint was 1-year overall survival. Forty-three patients were enrolled; 40 underwent AHCT. Pretransplant HIV viral load was undetectable (

Improved outcomes have recently been reported for rituximab (R) plus rituximab plus infusional etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH) chemotherapy in patients with human immunodeficiency virus (HIV)-associated, aggressive B-cell, non-Hodgkin lymphoma (NHL). The objective of the current analysis was to assess whether patient selection or other factors contributed to this improvement and to identify patients who are at the greatest risk for lethal toxicity.The authors performed a pooled analysis of 2 consecutive trials that included 150 patients with HIV-associated NHL who received either R-CHOP (n = 99; Acquired Immunodeficiency Syndrome [AIDS] Malignancy Consortium Trial 010 [AMC010]) or R-EPOCH (n = 51; AMC034). Age-adjusted International Prognostic Index (aaIPI), CD4 count at lymphoma diagnosis (100/μL vs ≥100/μL), and treatment (R-CHOP vs R-EPOCH) were included as variables in a multivariate logistic regression model for complete response (CR) and in a Cox proportional hazards regression models for event-free survival (EFS) and overall survival (OS).Features that were associated significantly with an improved CR rate and improved EFS and OS included a low aaIPI score and a baseline CD4 count ≥100/μL. When the analysis was adjusted for aaIPI and CD4 count, patients who received concurrent R-EPOCH had improved EFS (hazard ratio [HR] 0.40; 95% confidence intervals [CI], 0.23, 0.69; P.001) and OS (HR, 0.38; 95% CI, 0.21, 0.69; P.01). Treatment-associated death occurred significantly more often in patients with CD4 counts50/μL (37% vs 6%; P.01).The current analysis provided additional level 2 evidence supporting the use of concurrent R-EPOCH in patients with HIV-associated lymphoma and a CD4 count50/μL, and the results support the design of an ongoing phase 3 trial comparing concurrent R-EPOCH with R-CHOP in immunocompetent patients with diffuse large B-cell lymphoma (National Clinical Trial no. NCT00118209).

PURPOSE Urgency to initiate therapy has to be weighed against the time required for screening and consenting to enroll a patient onto a clinical trial. Exclusion of patients with rapidly progressive or symptomatic disease may lead to selection of patients with less aggressive disease. We recently identified that a short diagnosis to treatment interval (DTI) is associated with adverse clinical factors and inferior outcome in patients with diffuse large B-cell lymphoma (DLBCL) (Maurer et al, JCO 2018); shorter time to treatment was also found to be associated with outcome in other aggressive lymphomas, including mantle cell lymphoma (MCL), in the National Cancer Database (Olszewski et al, BJH 2018). Here we assess the association of DTI with clinical variables and outcome in MCL from an observational cohort with validation in patients enrolled on an NCTN clinical trial. PATIENTS AND METHODS Newly diagnosed patients with MCL were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER), now a subcohort of the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study. Patients initially managed with observation were excluded. DTI was defined as the time in days from date of first lymphoma-containing biopsy to the initiation of therapy. Associations of DTI with clinical factors and outcome were examined using a 14 day split based on the previous MER study of DTI in DLBCL. Odds ratios (OR) and Cox model hazard ratios (HR) are reported. Outcome was assessed using event-free survival (EFS) where events were defined as progression/relapse, initiation of new anti-lymphoma therapy, or death due to any cause. A validation cohort was assembled from patients enrolled in CALGB (Alliance) clinical trial 50403. Protocol therapy was high dose chemotherapy with autologous hematopoietic stem cell transplantation (ASCT) consolidation and post-ASCT rituximab followed by bortezomib as either consolidation or maintenance. DTI was defined as time from diagnosis to study registration and outcome was assessed using progression-free survival (PFS) as defined on the clinical trial. RESULTS 271 patients with MCL enrolled in the MER from 2002-2015 and initiated treatment within 100 days of diagnosis. Median age at diagnosis was 64 years (range 36-76), 211 (78%) were male, and 92% were stage III-IV; MIPI was Low (41%), Intermediate (36%) and High (23%). Induction therapy was R-CHOP based (50%), B-R based (16%), HyperCVAD based (8%), 2-CDA based (11%), and other (15%). Median EFS of the cohort was 41 months (95% CI: 34-46). Median DTI was 26 days (IQR: 14-38) and 28% enrolled within 14 days of diagnosis, exhibiting a longer DTI than DLBCL patients enrolled in the MER during the same time period. Short DTI (0-14 days) was associated with adverse clinical factors including ECOG PS 2-4 (OR=5.74, 95% CI: 2.51-13.1, p0.30). Short DTI was also associated with inferior EFS (HR=1.78, 95% CI: 1.27-2.49, p=0.0008) which remained significant after adjusting for MIPI score (HR=1.72, 95% CI: 1.23-2.41, p=0.0016). In the validation cohort, 144 patients enrolled on 50403 within 100 days of diagnosis from 2006-2010. Median age at diagnosis was 59 years (range 29-69), 77% were male, and 97% were stage III-IV; MIPI was Low (51%), Intermediate (31%) and High (17%). Median PFS of the cohort was 84 months (95% CI: 50-109). Median DTI was 35 days (IQR: 22-46) and 11% enrolled within 14 days of diagnosis. Short DTI (0-14 days) was associated with PS (OR=9.00, 95% CI: 1.18-69.0, p=0.034) and) higher MIPI score (OR=2.09, 95% CI: 1.08-4.04, p=0.029) but not elevated LDH (OR=1.27, 95% CI: 0.43-3.74, p=0.66). Short DTI was associated with inferior PFS (HR=2.21, 95% CI:1.19-4.09, p=0.011) which remained clinically significant after adjusting for MIPI score (HR=1.85, 95% CI: 0.98-3.47, p=0.056). CONCLUSION A short diagnosis-to-treatment interval is strongly associated with adverse clinical factors and poor outcome in newly diagnosed MCL in the MER. Clinical trials are encouraged to facilitate enrollment of patients with short DTI to avoid potential selection bias. Support: U01 CA195568, P50 CA097274, U10CA180821, U10CA180882; ClinicalTrials.gov Identifier: NCT00310037 (CALGB 50403) Figure. Figure. Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Kaplan:Bayer Pharmaceuticals: Consultancy. Cohen:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Takeda: Research Funding. Martin:Gilead: Consultancy; Kite: Consultancy; Seattle Genetics: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; Bayer: Consultancy. Kahl:Abbvie: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Acerta: Consultancy; Juno: Consultancy; Celgene: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; CTI: Consultancy; ADC Therapeutics: Consultancy. Bartlett:ImaginAB: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Merck & Co: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Affimed: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Millennium: Research Funding; Genentech: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cerhan:Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding. Leonard:Karyopharm: Consultancy; Biotest: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Novartis: Consultancy; AstraZeneca: Consultancy; Juno: Consultancy; BMS: Consultancy; Sutro: Consultancy; MEI Pharma: Consultancy; Genentech/Roche: Consultancy; Celgene: Consultancy; Gilead: Consultancy; United Therapeutics: Consultancy.

Introduction: Aggressive chemo-immunotherapy followed by peripheral blood stem cell autografting (ASCT) in CALGB (Alliance) 59909 achieved a median progression-free survival (PFS) in MCL of 5 years (Damon et al JCO, 2009), but late recurrences occurred. Using the CALGB 59909 treatment backbone, we evaluated tolerability and efficacy of adding post-transplant bortezomib consolidation (BC) or maintenance (BM)in a randomized phase II trial. Interim results of CALGB (Alliance) 50403 were previously presented (ASH 2015) demonstrating 5 yr PFS 70% and 69% for the BM and BC arms respectively. We now report final 8 year follow up results from this trial and compare outcomes to CALGB 59909, which differed from CALGB 50403 only by the absence of post-transplant bortezomib. Methods: The primary endpoint was PFS measured from randomization for each treatment arm. Induction therapy was with 2-3 cycles of augmented R-CHOP (2000 mg/m2 cyclophosphamide) and methotrexate (300 mg/m2) followed by high-dose cytarabine/etoposide/rituximab(R)/filgrastim (EAR) stem cell mobilization and cyclophosphamide/carmustine/etoposide (CBV) ASCT. After 2 doses of post-transplant R, patients were randomized to BC (1.3 mg/ m2 IV days 1, 4, 8, 11 of a 3-week cycle for 4 cycles) or BM (1.6 mg/m2 IV weekly x4 every 8 weeks for 18 months) beginning at approximately day 90. Minimal residual disease (MRD) was analyzed using patient-specific PCR probes for the bcl-1 / IgH junction or the IgH CDR3 region. Results: 151 patients were enrolled from 10/2006 - 6/2010 at 14 sites; 147 who received treatment are included in this analysis. Median age was 59 years (29-69); stage II (2.7%), III (11.6%), IV (85.0%); MIPI low (52.4%), intermediate (30.6%), high (17.0%); blastoid histology (12.9%); bone marrow involvement (81.0%); Ki67 was evaluated in 86 and was >30% in 17.4% of patients. 118 (80%) underwent ASCT and 102 (68%) were randomized. Most withdrawals (45) were for progression (10) or adverse events (AEs) (19) including 4 treatment-related deaths. Fifty-two patients were randomized to BM and 50 to BC. Following randomization, 34 (65%) completed BM and 33 (66%) completed BC. Withdrawal for AEs occurred in 14 (28%) of BC and 7 (13%) of BM patients (p = 0.09), most for cytopenias or peripheral neuropathy. With a median follow-up 7.8 years from randomization (8.3 from registration), the median PFS from randomization for the BM arm was not reached and was 8.9 years (95% CI 7.2 to not reached) for the BC arm. Both arms had median PFS significantly greater than the null hypothesis setting median PFS to 4 years (p < 0.001; 1-sided test of exponential parameter)The 8-year PFS estimates in the BM and BC arms were 77% (95% CI 66-90%) and 58% (95% CI 44-76%), respectively. Among all 147 patients treated on CALGB 50403, 8-year PFS from time of registration was 43.6% (35.6-53.3%). PFS from registration was not significantly extended in CALGB 50403 compared with CALGB 59909 (log rank p=0.24), but using a landmark analysis from time of transplant, PFS was significantly extended in CALGB 50403 (log rank p=0.005)(fig 1). Baseline patient characteristics in the two studies were not significantly different. In CALGB 50403, 8-year PFS from registration by MIPI was 52.0% (95% CI 41.1-66.0%) in MIPI low risk, 37.5% (95% CI 25.3-55.4%) in intermediate risk, and 28.2% (95% CI 13.7-57.9%) in high-risk. Bone marrow MRD results were collected for 42 patients post-induction therapy; 8-year PFS estimates were 80.2% (95% CI 62.2-100%) (n=17) and 43.2% (95% CI 27.3-68.2%) (n=25) for MRD-negative and MRD-positive patients, respectively (p=0.009). Conclusions: Induction chemotherapy followed by ASCT and either BC or BM was efficacious and tolerable, although BC was associated with more withdrawals for toxicity. PFS was not significantly different between BC and BM. The comparison between studies 50403 and 59909 with long-term follow up continues to suggest a PFS benefit from the addition of BC or BM among patients undergoing transplant. This did not translate into a PFS benefit from time of study enrollment possibly due to the higher pre-transplant dropout rate in 50403. MRD-negativity following induction chemo-immunotherapy is highly associated with improved PFS and the role of ASCT in post-induction MRD-negative patients is currently under investigation in a randomized clinical trial. Support: U10CA180821, U10CA180882, U24CA196171; ClinicalTrials.gov Identifier: NCT00310037 Disclosures Kaplan: Bayer Pharmaceuticals: Consultancy. Maurer:Celgene: Research Funding; Morphosys: Research Funding; Nanostring: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Bartlett:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Blum:Acerta: Consultancy; Astra-Zeneca: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Humanigen: Consultancy, Honoraria; Research to Practice: Speakers Bureau; Bristol-Myers Squibb: Other: Data safety and monitoring board. Leonard:AstraZeneca: Consultancy; Juno: Consultancy; BMS: Consultancy; ADC Therapeutics: Consultancy; Gilead: Consultancy; Biotest: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; MEI Pharma: Consultancy; Celgene: Consultancy; United Therapeutics: Consultancy; Sutro: Consultancy; Genentech/Roche: Consultancy; Pfizer: Consultancy; Bayer: Consultancy. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy.

10030Background: The optimal means of assessing fitness for AutoHCT in older adults with hematologic malignancies is unknown. Few studies have evaluated the impact of patient reported function on A...

Purpose To determine the relative frequency with which Kaposi's sarcoma–associated herpesvirus/HHV-8 (KSHV) DNA is detected in peripheral-blood mononuclear cells (PBMCs) and in plasma of patients with AIDS-KS and AIDS-associated non-Hodgkin's lymphoma (NHL; AIDS-NHL); to determine whether the presence of viral DNA in plasma reflects lysis of tumor cells or reflects the presence of viremia (ie, virion-encapsidated DNA); and to determine the effect of lymphoma therapy on KSHV DNA. Patients and Methods Samples were obtained from patients enrolled in AIDS Malignancy Consortium clinical trials and from healthy donors. Real time PCR was used to quantify KSHV DNA in peripheral blood mononuclear cells (PBMC) and plasma. DNase digestion and fragment size determination studies were used to characterize the DNA detected. Results In patients with AIDS-KS, KSHV DNA was detected in PBMC (54%) and in plasma (62%). In patients with AIDS-NHL, KSHV DNA was detected in PBMC (19%) and in plasma (22%). Median copy numbers also differed. KSHV DNA in plasma appeared to be encapsidated. In six patients with AIDS-NHL who were treated with chemotherapy (with or without rituximab), KSHV copy number declined in PBMC and in plasma. Conclusion KSHV DNA is sometimes detected in PBMC or in plasma of patients with AIDS-NHL without KS. Among patients with KSHV DNA detected in PBMC or in plasma, copy number does not distinguish between patients with AIDS-NHL and AIDS-KS. KSHV DNA in plasma likely reflects viremia and not simply lysis of tumor or other KSHV-infected cells. KSHV DNA copy number in PBMC and in plasma declined with lymphoma-directed cytotoxic chemotherapy in each of the six patients studied.

Intensive chemotherapy for human immunodeficiency virus (HIV)-associated non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) has resulted in durable remissions in a substantial proportion of patients. High-dose chemotherapy and autologous stem cell transplantation (AuSCT), moreover, has resulted in sustained complete remissions in selected patients with recurrent chemosensitive disease. Based on a favorable experience with dose-reduced high-dose busulfan, cyclophosphamide, and AuSCT for older patients with non-HIV–associated aggressive lymphomas, an AIDS Malignancy Consortium multicenter trial was undertaken using the same dose-reduced busulfan and cyclophosphamide preparative regimen with AuSCT for recurrent HIV-associated NHL and HL. Of the 27 patients in the study, 20 received an AuSCT. The median time to achievement of an absolute neutrophil count (ANC) of ≥ 0.5×10 9 /L was 11 days (range, 9-16 days). The median time to achievement of an unsupported platelet count of ≥ 20×10 9 /L was 13 days (range, 6-57 days). One patient died on day +33 posttransplantation from hepatic veno-occlusive disease (VOD) and multiorgan failure. No other fatal regimen-related toxicity occurred. Ten of 19 patients (53%) were in complete remission at the time of their day +100 post-AuSCT evaluation. Of the 20 patients, 10 were alive and event-free at a median of 23 weeks post-AuSCT. Median overall survival (OS) was not reached by 13 of the 20 patients alive at the time of last follow-up. This multi-institutional trial demonstrates that a regimen of dose-reduced high-dose busulfan, cyclophosphamide, and AuSCT is well tolerated and is associated with favorable disease-free survival (DFS) and OS probabilities for selected patients with HIV-associated NHL and HL.

BACKGROUND. Matrix metalloproteinases (MMPs) are overexpressed in Kaposi sarcoma (KS). The safety and efficacy of a novel, orally bioavailable MMP inhibitor, BMS-275291, was evaluated in patients with human immunodeficiency virus-associated KS and the correlation between changes in the percentage of apoptotic cells in tumor biopsies and response was explored. METHODS. Cohorts of 6 patients were to be treated with BMS-275291. The initial cohort received 1200 mg once a day; subsequent doses were to be escalated to 600 mg twice daily and 1200 mg twice daily, or decreased to 600 mg/day. Tumor biopsies for apoptosis assays were collected pretreatment and on Day 29. Prospectively defined dose level adjustments were to be based on dose-limiting toxicity (DLT), tolerability, changes in the percentage of apoptotic cells, and treatment response. RESULTS. Sixteen patients were enrolled; 15 received the study drug and could be evaluated. The median duration of treatment was 20 weeks (range, 3–54 weeks). A dose of 1200 mg once a day was well tolerated but induced only 1 response. A DLT occurred in 3 patients treated with 600 mg twice daily, and included grade 3 fatigue, grade 3 allergic reaction, and grade 3 arthralgias; 2 responses were noted at this dose level (toxicity was graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]). Based on predetermined endpoints, the trial was closed after accrual of 15 treated patients. Assessment of biologic response for dose escalation/de-escalation decisions utilizing the apoptosis assay was not feasible. CONCLUSIONS. BMS-275291 given at a dose of 600 mg twice daily induced unacceptable toxicity. The better-tolerated schedule of 1200 mg once a day demonstrated inadequate efficacy in patients with human immunodeficiency virus-associated KS. The apoptosis assay was not helpful in predicting response. Cancer 2008. © 2008 American Cancer Society.

Plasmablastic lymphoma (PBL) is an aggressive CD20 negative diffuse large B cell lymphoma over-represented in patients with HIV infection. CD45 expression is weak, but immunoglobulin genes are rearranged and plasma cell markers are expressed.[1] In 1997, 95% of the cases were reported to be from HIV + patients, all with oral cavity involvement, 68% stage I. In this pre-HAART era report, 9//11 patients with follow-up died within a year of diagnosis. Most other case reports and case series have typically described poor survival for patients with PBL, particularly those infected with HIV,[2] while others were more optimistic.[3] We sought to characterize patients with PBL diagnosed and treated solely in the HAART era. We identified 12 patients with newly diagnosed PBL treated at the AIDS Malignancy Consortium (AMC) sites from 1999 to 2008. This retrospective analysis suggests these patients had better outcomes than those identified pre-HAART, perhaps due to use of aggressive chemotherapy made possible because of better supportive care and antiretroviral therapy. All AMC sites, which participated in this retrospective review were queried for cases of PBL diagnosed from 1998–2008. Two of the authors (AC and AN) reviewed the pathology reports for the criteria for plasmablastic lymphoma described in the 2008 WHO Classification.[4] Twelve cases from 9 AMC sites were included in this study. Descriptive statistics were computed for demographic and clinical characteristics. Overall survival (OS) was calculated from date of initial diagnosis to death or last follow-up. Kaplan-Meier estimates of 1-year survival were computed. All AMC sites had an Institutional Review Board waiver of authorization. Baseline clinical characteristics at study entry are presented in Table 1. The median CD4 + count at HIV diagnosis was 256 cells/uL (range 45–750) and was lower at initial PBL diagnosis with a median of 136 cells/uL (range of 2–514). Sixty-seven percent of the patients had had a prior opportunistic infection. Most (58%) of patients were not on HAART at lymphoma diagnosis, however, they had all previously taken HAART at some point. Of 7 patients not on HAART, 6 started HAART, typically at diagnosis or chemoimmunotherapy initiation. Stage at initial diagnosis was I (25%), II (25%), III (0%) and IV (50%). Four of 7 patients with extranodal disease had more than one site of involvement. Extranodal sites of disease at initial diagnosis included bone without bone marrow (4), bone marrow (1), liver (2), kidney (2), sinus (1), cerebrospinal fluid (1), colon (1), skin (1), adrenal (1), nasopharynx (1) and stomach (1). Table 1 Clinical characteristics at study entry of 12 HIV-positive patients with initial diagnosis of plasmablastic lymphoma. Surprisingly, no patients had oral involvement. LDH was elevated in 5/8 where the value was known. The International Prognostic Index could not be calculated for the group as a whole as performance status assessment data was not available in one third of the patients. Not all cases had uniform immunophenotypic data available [Table 1]. As per the definition of plasmablastic lymphoma, all 12 cases tested were negative for the B cell marker CD20. Similarly, markers of terminal B cell differentiation, CD138 and MUM-1/IFR4, were positive in 6/6 cases and in 4/4 cases tested, respectively Epstein-Barr virus (EBV) was present in 8/8 cases based on in situ hybridization (EBER). At initial diagnosis, 10/12 patients received chemotherapy, although HAART alone was attempted without success in one patient. Treatment was CHOP on a 14 day cycle (n=1) [5] or 21 day cycle (n=3), [6] (cyclophosphamide, doxorubicin, vincristine, prednisone), infusional CDE (n=1), (cyclophosphamide, doxorubicin, etoposide); [7] infusional EPOCH (n=2) (cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone),[8,9] or other (n=5). The other therapies included EPOCH with high dose methotrexate and zidovudine, either alternating (n=2), or sequential (n=2). Three patients with stage I/II disease received radiation in combination with chemotherapy. Two of the ten treated patients experienced grade 3/4 toxicity. No patient died of treatment. One patient experienced grade 3/4 fatigue, anemia, thrombocytopenia, febrile neutropenia, nausea, vomiting, diarrhea, and weight loss, and the other patient experienced renal insufficiency. Responses were complete (CR) in 7, partial (PR) in 2 and refractory in 1. CRs were seen with CHOP (n=4), EPOCH (n=2), and EPOCH alternating with high dose methotrexate and zidovudine (n=1). PRs were seen after EPOCH alternating with high dose methotrexate and zidovudine (n=2). The one patient treated with CDE had refractory disease. Overall survival is shown in Fig. 1. At a median follow up of 73 weeks (range, 40–165), the median survival was not reached. The one-year survival was 66.7% (SE, 13.6). No patients died in the follow up period after year one. Figure 1 Survival of plasmablastic lymphoma patients. We report the first case series of plasmablastic lymphoma patients, under the care of dedicated HIV malignancy oncologists in a consortium setting, diagnosed and treated exclusively in the HAART era. In this study we demonstrate relatively long disease free survival despite earlier reports showing nearly all HIV + patients with PBL were destined to die from progressive lymphoma. In the initial, pre-HAART study of PBL by Delecluse, et al.[1] 9 of the 11 patients died within 16 months of diagnosis including 3 patients with stage I disease treated with external beam radiation, poly-chemotherapy or a combination of both. In the HAART era, intensive treatment of aggressive lymphomas, such as Burkitt and diffuse large B cell lymphoma, can result in CR and long-term survival for HIV infected patients.[9–11] Cohort studies suggest that plasmablastic lymphoma has an inferior survival to Burkitt and DLBCL.[12] We demonstrate that PBL may be curable, even in patients with higher stage disease and more extranodal involvement compared to the cases described by Delecluse, et al. where the disease was primarily localized to the jaw in the majority of patients. Recently, Ibrahim et al. reported in abstract form, their single institution experience with 25 patients during the HAART era.[13] Similar to our study, only 32% were on HAART and the median CD4 + cell count was 87cells/uL. Only 76% received chemotherapy, with EPOCH being the most common treatment choice (56%), and 28% received radiotherapy. The response rate was 84% and the median OS observed in all patients who received chemotherapy was 11.6 months (range, 2–63 months). Those who were treated with EPOCH demonstrated a better median overall survival (17 months) compared to those treated with CHOP and CHOP-like regimens (7 months, p=0.04). Castillo et al. reviewed 112 cases in the literature and noted a median overall survival of 15 months with a 3 year OS of only 25%. In contrast, Cattaneo et al. reported their single institution experience of 13 patients treated during the HAART era with a 67% 3 year OS.[14] 15 patients were treated, all with CHOP or CHOP-like regiments, with involved field consolidation in seven. Five received high dose therapy with autologus stem cell transplant as first CR consolidation. The initial goal of this AMC retrospective study was to identify which first line therapy might be the most promising for HIV positive patients with plasmablastic lymphoma. The rarity of this lymphoma resulted in a very small cohort, possibly as a result of incomplete retrieval from institutional databases. In this regard, we were unable to draw specific conclusions due to the sample size, the disparate number of lymphoma regimens, and the retrospective nature of the study. However, it is notable that CR was achieved with CHOP or EPOCH based regimens. The literature on regimens more intensive than CHOP is inconsistent. Two earlier retrospective studies did not demonstrate an advantage of therapies more intensive than CHOP for PBL.[15,16] Loghavi et al. noted a series of 50 patients (20 HIV+) tended to have a better OS with CHOP than hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) (p=0.078).[17] Nonetheless, many experts do consider CHOP inadequate and favor intensive therapies including EPOCH.[18] As an aside, we cannot comment on the efficacy of HAART therapy alone, as only one patient was treated with this strategy with disease progression. In addition to intensive chemotherapy, it is probable that our patients fared better than those in the pre- HAART era due in part to better supportive care and more robust immune status. However, we cannot be certain, as the median CD4 + cell count of 256 cells/uL at initial PBL diagnosis was relatively low. Moreover, 59% had had a prior opportunistic infection and only 29% were on HAART at PBL diagnosis. Currently Clinical Trials Support Unit (CTSU) 9177 is prospectively studying EPOCH therapy for patients diagnosed with PBL irrespective of HIV status. Given the biologic similarity to multiple myeloma, drug classes like immune modulatory agents (IMiDs) and protease inhibitors [19] might also be promising agents for future study. The nearly ubiquitous finding of Epstein Barr in tumor tissue (11of 12 evaluable cases in our study) may provide a rationale for viral-based strategies. Finally, the role for autologous stem cell transplant in the setting of relapsed/refractory disease is also worthy of exploration.

HIV is associated with an excess risk for lymphoid malignancies. Although the risk of lymphoma has decreased in HIV-infected individuals in the era of effective combination antiretroviral therapy, it remains high. Treatment outcomes have improved due to improvements in HIV and cancer therapeutics for the common HIV-associated lymphomas. R-CHOP/R-EPOCH are the standard of care for HIV-associated diffuse large B-cell lymphoma. HIV-infected patients with Burkitt lymphoma and good performance status should receive dose-intensive regimens. HIV-infected patients with primary central nervous system lymphoma can respond favorably to high-dose methotrexate-based therapy. In many cases, treatment and expected outcomes for HIV-infected patients with either Hodgkin or non-Hodgkin's lymphomas are very similar to HIV-negative patients. There is currently no standard treatment for HIV-associated multicentric Castleman disease or primary effusion lymphoma. For those hematologic cancers in which transplantation is part of standard care, this modality should be considered an option in those with well-controlled HIV infection.

Lexical change in Yupik and Inuit languages was relatively slow until the period of widespread cultural change brought about by contact with Europeans over the past few centuries, probably because there had been little earlier contact with other language families. The colonial period brought various groups to the Arctic and different waves of language contact, primarily with Danish, French, English, and Russian. Lexical borrowing has been significant, and old borrowings, often the result of early trade, can be distinguished from later ones and often pertain to food, tobacco, tools, fabric and other areas where new goods were introduced. Later borrowings came about largely when European political structures were set up and may be less thoroughly integrated phonologically than older borrowings. Numbers of borrowings can be taken to reflect the extent of the foreign contact, as is clearly the case with Russian words in Alaskan languages, most numerous in Aleut, which had the most sustained Russian presence. New religious terms to describe Christianity came into the languages during the colonial period, sometimes as borrowings, but also as relexicalizations of old words pertaining to shamanism. A third means of lexical expansion is coinage, where new terms are invented based on native roots and suffixes. The languages and dialects may thus develop words for the same object or concept by borrowing from different European languages, by relexicalizing an old word, or by coining a new one, with a different result in each case. Different sources for new lexical items have resulted in an important level of differentiation among the languages, and this differentiation needs to be recognized., Le changement lexical des langues yupik et inuit a été relativement lent jusqu'à la période des vastes changements culturels engendrés par le contact avec les Européens au cours de ces derniers siècles, sans doute parce qu'il n'y avait eu, jusque là, que peu de contacts avec d'autres langues. La période coloniale a amené plusieurs groupes dans l'Arctique et différentes vagues de contacts de langues, principalement avec le danois, le français, l'anglais et le russe. L'emprunt lexical a été considérable et les premiers emprunts, souvent le résultat des tous premiers trocs, peuvent se distinguer des suivants et se rapportent souvent à la nourriture, au tabac, aux outils, aux tissus et aux autres domaines où de nouvelles denrées étaient introduites. Les emprunts plus tardifs sont apparus en grand nombre avec la mise en place des structures politiques européennes, et d'un point de vue phonologique, sont peut-être moins entièrement intégrés que les premiers. Nombre d'emprunts peuvent être présentés en tant que reflet de l'étendu du contact avec l'étranger comme c'est clairement le cas des langues d'Alaska qui contiennent des mots russes; les plus nombreux sont dans l'aléoute, langue parlée dans la région qui a connu une présence russe des plus importantes. De nouveaux termes religieux pour décrire le christianisme ont été introduits pendant la période coloniale, parfois comme emprunts mais aussi comme des relexicalisations de mots précédemment liés au chamanisme. Le néologisme est la troisième voie d'expansion lexicale où de nouveaux termes sont inventés, fondés sur les racines et les suffixes de la langue d'origine. Par conséquent, les langues et les dialectes peuvent développer des mots pour le même objet ou le même concept en empruntant aux langues européennes, en relexicalisant un mot ancien ou en créant un mot nouveau avec à chaque fois un résultat différent. Les différentes sources de ces nouveaux items lexicaux ont eu pour résultat un important niveau de différenciation parmi les langues et cette dernière se doit d'être identifiée.

PURPOSE OF REVIEW: Human immunodeficiency virus infection is associated with an increased risk of non-Hodgkin lymphoma. Even with a decrease in AIDS-defining illnesses after the advent of highly active antiretroviral therapy, HIV-associated non-Hodgkin lymphoma remains an important problem. RECENT FINDINGS: Low CD4+ T-lymphocyte count, disease stage, performance status, serum lactate dehydrogenase, and number of extranodal sites of disease are all important prognostic factors for HIV-non-Hodgkin lymphoma. Recent studies have examined the role of infusional chemotherapy, as well as immunotherapy, in the treatment of aggressive HIV-non-Hodgkin lymphoma, and autologous stem cell transplantation for relapsed or refractory HIV-non-Hodgkin lymphoma. New developments in the association of viral infection and pathogenesis of certain subtypes of HIV-non-Hodgkin lymphoma have also recently been reported. SUMMARY: Outcomes of HIV-non-Hodgkin lymphoma are improving with the routine use of highly active antiretroviral therapy and combination chemotherapy. For aggressive HIV-non-Hodgkin lymphoma, infusional chemotherapy regimens are well tolerated and lead to complete response in about 50-75% of cases and a 2-3 years overall survival of 40-60%. The potential benefit of adding rituximab to combination chemotherapy may be offset by infectious complications in severely immunosuppressed patients. HIV-associated Burkitt lymphoma should be treated with an intensive regimen rather than standard cyclophosphamide, doxorubicin, vincristine, prednisone-like chemotherapy. Autologous stem cell transplantation should be considered for selected patients with relapsed or refractory HIV-non-Hodgkin lymphoma.

Presentation of Case A 44-year-old man was seen in the clinic because of a right atrial mass. Six years earlier, the patient had been found to have Pneumocystis carinii pneumonia and human immunodeficiency virus (HIV) infection. He had returned to a satisfactory state of health with the use of highly active antiretroviral therapy. He did not have severe disabling symptoms from either the HIV infection or its management. Ten months before being seen in the clinic, he had an episode of substernal pain that lasted nine hours. An exercise stress test performed at another hospital did not provoke chest pain . . .

Although Hodgkin lymphoma (HL) is not considered an AIDSdefining malignancy, population-based studies have demonstrated an increased incidence of this disease in the setting of HIV infection. In a prospective cohort study of 11,112 individuals who were positive for HIV, with 71,687 patient-years of follow-up, the incidence of HL was 14 times higher than in the general population. In contrast to other HIV-associated malignancies that occur more commonly with severe immunocompromise, HL is associated with moderate immunologic impairment and the incidence actually seems to decline at CD4 lymphocyte counts of less than 200/ L. Although incidence rates for the AIDS-defining malignancies (Kaposi’s sarcoma, aggressive B-cell non-Hodgkin lymphoma [NHL]) have fallen, the incidence of HL may actually be increasing since the advent of combination antiretroviral therapy (cART), perhaps as a consequence of improvement in the level of immune function. However, the increased relative risk of HL is substantially lower than that observed for aggressive B-cell lymphoma. As a result of the small number of cases, studies investigating approaches to management of HIV-associated HL have been largely retrospective in design. For the more common AIDS-defining lymphomas, diffuse large B-cell lymphoma and Burkitt lymphoma, outcomes have improved dramatically in the 16 years since the introduction of active antiretroviral therapies, which have transformed HIV disease into a survivable chronic illness. Prospective studies in the pre-cART era demonstrated 2-year overall survival (OS) in the 10% to 20% range with complete remission (CR) rates of 35% to 50%, far inferior to those observed in non-HIV–associated lymphomas. Prognosis at that time was largely dependent on the severity of immunosuppression rather than on features of the lymphoma. This experience changed with the advent of cART such that now treatment outcomes using standard regimens such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone or dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab approach those observed in the non-HIV–infected population, with CR rates of 65% to 77% and 2-year OS rates of more than 60%. The International Prognostic Index (IPI) score seems to be a significant prognostic factor in patients treated with chemotherapy and concurrent cART. On the basis of the age-adjusted IPI score, the survival of patients in one trial using rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone was similar to that achieved by patients with aggressive lymphomas who were not infected with HIV. HL in the HIV-seropositive population is more likely to have mixed cellularity or lymphocyte-depleted histology and is almost always Epstein-Barr virus–associated. The majority of patients present with advanced-stage disease. Before the introduction of cART, treatment outcomes for HIV-HL were poor. In an Italian retrospective study of 114 patients with HIV-associated HL who received various standard chemotherapeutic regimens, the median OS was 15 months. Sixty percent died, 35% of those from opportunistic infection, 33% from HL, and 12% from both. As has been the case for aggressive B-cell lymphomas in patients with HIV infection, small retrospective and prospective studies have suggested improvement in outcome with the advent of cART. A retrospective study of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with cART in 62 patients with advanced-stage HIVassociated HL demonstrated a CR rate of 87% and 5-year OS of 76%. A prospective trial reported a CR rate of 81% and 2-year OS of 51% in 59 patients treated with the Stanford V regimen (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone) administered with antiretroviral therapy. The fact that only 10% of these patients received radiotherapy suggests that the regimen was either not delivered as designed or that the inclusion of patients with early-stage and low-bulk disease (factors associated with inferior outcome with this regimen) resulted in relatively disappointing outcomes. In the article that accompanies this editorial, the German HIV-Related Lymphoma Study Group presents data from the largest prospective trial ever conducted in patients with HIV-associated HL. In this study, 112 patients were allocated to treatment on the basis of stage and risk category. Those with early-stage favorable disease (IA/B or IIA/B) received two to four cycles of ABVD plus 30 Gy of involved-field radiotherapy. Patients with early-stage unfavorable disease received four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) at baseline or four cycles of ABVD followed by 30 Gy of involved-field radiotherapy if disease was 5 cm or residual disease was 2 cm. Those with advanced disease received eight cycles of BEACOPP with or without radiotherapy to sites 2.5 cm. Patients with advanced HIV disease, including Eastern Cooperative Oncology Group performance score 2, received ABVD. There were five toxic deaths: 4% with early favorable, 0% with early unfavorable, and 7% with advanced disease. CR rates were 96%, 100%, and 86% for these three groups, respectively, and 2-year PFS JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 33 NOVEMBER 2