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Purpose:The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab ± vincristine in patients with relapsed/refractory aggressive B-NHL.Patients and Methods:Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 + 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/BCL2 IHC was performed on available archival tissue.Results:Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n = 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non–germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL).Conclusions:The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.

Immunohistochemical staining of Bcl2, cMyc, Ki67, and CD3 in DLBCL subtype representative tumor samples (same as Supplementary Figure S1). Note that AD091967 is positive for both Bcl2 and cMyc. Cases AB189717, AD550620, and AE575816 show high proliferation rates (80%, 80%, 60%) Scale bars represent 50 µm.

Extranodal marginal zone lymphoma (EMZL) is a heterogeneous non-Hodgkin lymphoma. No consensus exists regarding the standard-of-care in patients with advanced-stage disease. Current recommendations are largely adapted from follicular lymphoma, for which bendamustine with rituximab (BR) is an established approach. We analyzed the safety and efficacy of frontline BR in EMZL using a large international consortium. We included 237 patients with a median age of 63 years (range, 21-85). Most patients presented with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (n = 228; 96.2%), stage III/IV (n = 179; 75.5%), and intermediate (49.8%) or high (33.3%) Mucosa Associated Lymphoid Tissue International Prognosis Index (MALT-IPI). Patients received a median of 6 (range, 1-8) cycles of BR, and 20.3% (n = 48) received rituximab maintenance. Thirteen percent experienced infectious complications during BR therapy; herpes zoster (4%) was the most common. Overall response rate was 93.2% with 81% complete responses. Estimated 5-year progression-free survival (PFS) and overall survival (OS) were 80.5% (95% CI, 73.1% to 86%) and 89.6% (95% CI, 83.1% to 93.6%), respectively. MALT-IPI failed to predict outcomes. In the multivariable model, the presence of B symptoms was associated with shorter PFS. Rituximab maintenance was associated with longer PFS (hazard ratio = 0.16; 95% CI, 0.04-0.71; P = .016) but did not impact OS. BR is a highly effective upfront regimen in EMZL, providing durable remissions and overcoming known adverse prognosis factors. This regimen is associated with occurrence of herpes zoster; thus, prophylactic treatment may be considered.

Histiocytic neoplasms are rare hematologic disorders accounting for less than 1% of cancers of the soft tissue and lymph nodes. Clinical presentation and prognosis of these disorders can be highly variable, leading to challenges for diagnosis and optimal management of these patients. Treatment often consists of systemic therapy, and recent studies support use of targeted therapies for patients with these disorders. Observation (“watch and wait”) may be sufficient for select patients with mild disease. These NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with the most common histiocytic disorders: Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease.

Acquired angioedema due to C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is rare and is associated with underlying lymphoproliferative diseases. C1-INH deficiency may be due to neoplastic over-consumption of C1-INH and the generation of anti-C1-INH autoantibodies. Uncovering an occult malignancy can lead to earlier oncology referral and improvement of angioedema after treatment of the underlying lymphoproliferative disorder. We characterized seven patients with C1-INH-AAE that highlights the importance of recognizing the association between C1-INH-AAE and underlying malignancy. In acute attacks, patients may be resistant to C1-INH therapy due to the presence of anti-C1-INH autoantibodies or rapid complement consumption, and may respond better to icatibant or ecallantide, which directly affect bradykinin. Treatment of the underlying malignancy also improves AAE-C1-INH symptoms and supports the role of lymphoproliferative B cells in AAE-C1-INH pathophysiology. Monitoring levels of C4, C1-INH function and level, and C1q may be predictive of AAE-C1-INH control and be used as surrogates for treatment efficacy. With close monitoring, low-dose danazol can be effective for long-term prophylaxis. Annual evaluation in AAE-C1-INH is recommended if an underlying malignancy is not found, as angioedema may precede the development of malignancy by several years. Our single-center study has aided in standardization of comprehensive AAE-C1-INH diagnosis, treatment, and monitoring strategies towards future therapeutic clinical trials.

Older AML patients have low remission rates and poor survival outcomes with standard chemotherapy. Microtransplantation (MST) refers to infusion of allogeneic hematopoietic stem cells without substantial engraftment. MST has been shown to improve clinical outcomes compared with chemotherapy alone. This is the first trial reporting on broad correlative studies to define immunologic mechanisms of action of MST in older AML patients. Older patients with newly diagnosed AML were eligible for enrollment, receiving induction chemotherapy with cytarabine (100 mg/m2) on days 1-7 and idarubicin (12 mg/m2) on days 1-3 (7 + 3). MST was administered 24 hours later. Patients with complete response (CR) were eligible for consolidation with high dose cytarabine (HiDAC) and a second cycle of MST. Responses were evaluated according to standard criteria per NCCN. Immune correlative studies were performed. Sixteen patients were enrolled and received 7 + 3 and MST (median age 73 years). Nine (56%) had high-risk and seven (44%) had standard-risk cytogenetics. Ten episodes of CRS were observed. No cases of GVHD or treatment-related mortality were reported. Event-free survival (EFS) was 50% at 6 months and 19% at 1 year. Overall survival (OS) was 63% at 6 months and 44% at 1 year. Donor microchimerism was not detected. Longitudinal changes were noted in NGS, TCR sequencing, and cytokine assays. Addition of MST to induction and consolidation chemotherapy was well tolerated in older AML patients. Inferior survival outcomes in our study may be attributed to a higher proportion of very elderly patients with high-risk features. Potential immunologic mechanisms of activity of MST include attenuation of inflammatory cytokines and emergence of tumor-specific T cell clones.

Introduction: There is no standard induction therapy in extranodal marginal zone lymphoma (EMZL); current guidelines borrow from follicular lymphoma, where bendamustine and rituximab (BR) is an accepted standard. The data on BR in EMZL is limited (Rummel MJ et al. Lancet 2013 & Salar A et al. Blood 2017), so we explored BR activity as part of an international consortium. Methods: This retrospective analysis involved 11 cancer centers from US and Italy. We included patients with EMZL treated with frontline BR (1/2008 to 12/2019). Expert pathology review was performed by each participating institution following the 2016 WHO classification. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier and associations with prognostic factors were assessed by log-rank test, univariable (UVA) and multivariable (MVA) Cox regression. MVA Cox models were constructed by selecting variables significant univariately. Results: 136 patients were identified; however, 18 patients with EMZL only located in bone marrow (BM) were excluded from this analysis to prevent possible inclusion of lymphoplasmacytic lymphoma. Thus, 118 patients were included in this study. Patient characteristics comprised median age of 61.5 years (range 21 to 85 years), women: 56.8%, ECOG performance status 0-1: 86%, stage III-IV: 79.7%, no B symptoms: 81.4%, normal LDH: 75.4%, BM involvement: 25.4%, and MALT-IPI score < 2: 63.6%. Most common extranodal (EN) sites were lung (22%), gastric (13.6%), ocular (11%), soft tissue (10.2%), salivary gland (10%), and gastrointestinal non-gastric (7.6%). Most patients presented with 1 or 2 EN sites (48.3% and 30.5%, respectively). Majority of patients (83.9%) had < 4 nodal sites. Paraprotein was positive in 27 of 80 (33.7%) patients with majority harboring IgM. The median number of BR cycles was 6 (range 1 to 6). Consolidation with radiation therapy was performed in 6% of the patients. Treatment response was determined by PET/CT in 70% and CT scans in the rest. The response to treatment was as follows: CR: 96 (81.4%), PR: 13 (11%), SD: 2 (1.7%), PD: 4 (3.4%), and unknown: 3 (2.5%) patients. No differences in response rate were observed by EN location. The incidence of infectious complications was 14% including herpes zoster (25%), pneumonia (18.7%) and influenza (18.7%). No treatment-related mortality was observed. Rituximab maintenance was implemented in 17% (n= 20) of the patients for a median duration of 11 (range 1 to 46) months. Biopsy-proven transformation to diffuse large B cell lymphoma occurred in 5.9% of the patients. Patients with lymphoma transformation had a higher mean SUV on diagnostic PET/CT (13.48 vs 7.77, P= 0.037, respectively). Secondary malignancies were observed in 6% of the patients with 1 case of acute myeloid leukemia. With a median follow up of 2.85 (range 0.08 to 9.45) years, the estimated 5-years PFS (Figure 1) and OS (Figure 2) were 72.3% (95%CI 59.3-81.8%) and 85.6% (95%CI 75.0-92.0%), respectively. No survival difference was observed between patients achieving CR or PR followed or not by rituximab maintenance, but the number of patients receiving maintenance was small. Similarly, no survival differences were observed in patients with gastric EMZL compared to non-gastric locations or by MALT-IPI score risk category. In both UVA and MVA analyses, variables associated with shorter survival were ECOG performance status ≥2 and failure to achieve CR (for MVA: ECOG PS ≥ 2 (HR: 6.56, P=0.006) and failure to achieve CR (HR: 5.35 P Conclusion: This study represents the largest analysis to date evaluating the activity and safety of BR in untreated EMZL. BR is a highly effective platform in upfront treatment of EMZL with majority of the patients achieving complete and durable remissions. ECOG PS ≥ 2 and failure to achieve CR were identified as prognostic factors associated with worse outcome in BR treated patients. High incidence of herpes zoster infection was observed in this study which has not been previously reported. In addition, increased median PFS and lower incidence of infectious complications was observed in this study compared to prior reports. Disclosures Alderuccio: ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Inovio Pharmaceuticals: Other: Family member; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member; Oncinfo: Honoraria; OncLive: Honoraria; Puma Biotechnology: Other: Family member; Foundation Medicine: Other: Family member. Beaven:Tessa Therapeutics: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; LoxoOncology: Research Funding; MorphoSysAb: Research Funding; Roche: Research Funding. Shouse:Kite Pharma: Honoraria, Speakers Bureau. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Castillo:TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Kymera: Consultancy; Abbvie: Research Funding; Janssen: Consultancy, Research Funding. Voorhees:AstraZeneca: Research Funding. Martin:Regeneron: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy. Kamdar:Roche: Research Funding. Herrera:AstraZeneca: Research Funding; Karyopharm: Consultancy; Immune Design: Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding. Friedberg:Roche: Other: Travel expenses; Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Portola Pharmaceuticals: Consultancy; Kite Pharmaceuticals: Research Funding; Bayer: Consultancy; Astellas: Consultancy; Seattle Genetics: Research Funding. Zinzani:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lossos:Seattle Genetics: Consultancy, Other; Stanford University: Patents & Royalties; Janssen Scientific: Consultancy, Other; Verastem: Consultancy, Honoraria; Janssen Biotech: Honoraria; NCI: Research Funding.

Purpose This study aimed to evaluate whether higher doses of consolidation radiation therapy (RT), which have been traditionally recommended for osseous sites in diffuse large B-cell lymphoma (DLBCL), are still necessary. Methods and materials Patients with DLBCL with osseous involvement treated with first-line chemotherapy followed by consolidation RT between 1995 and 2016 were reviewed. The primary endpoint was 5-year freedom from local recurrence, estimated using the Kaplan-Meier method. Outcomes based on the RT dose received were also assessed. Results A total of 51 patients were identified. The most common chemotherapy regimens were rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (80%) and cyclophosphamide, doxorubicin, vincristine, and prednisone (12%) with a median of 6 cycles (range, 3-8 cycles). After chemotherapy, 82% of patients achieved a complete response (CR), and 18% achieved a partial response (PR). All patients in PR were deemed appropriate for consolidation RT. The median dose was 29 Gy (24 Gy for CR; 36 Gy for PR). After a median follow-up of 86 months, 8 patients relapsed, with 2 relapses in the RT field after consolidation RT of 30 and 39.6 Gy, respectively. Overall, the 5-year freedom from local recurrence was 96% (95% confidence interval [CI], 91%-100%), disease-free survival was 76% (95% CI, 65%-89%), and overall survival was 86% (95% CI, 76%-96%). No dose-response relationship was observed. Conclusions In patients with DLBCL with osseous involvement who achieved a CR after first-line chemotherapy, 20 to 30 Gy of consolidation RT led to high rates of local control. Higher doses should be reserved for patients in PR.

Thrombotic microangiopathy (TMA) is a rare disorder characterized by microvascular injury and occlusion resulting in tissue ischemia and dysfunction. TMA occurs in a variety of settings including cocaine use. Although cocaine is widely used in the United States, cocaine-associated TMA is only rarely reported. Therefore, other factors may predispose cocaine users to the development of TMA. Emerging evidence indicates that cocaine activates complements. Therefore, complement activation may contribute to the development of cocaine-induced TMA. Here, we report a cocaine user who presented with renal failure. Renal biopsy demonstrated TMA. Laboratory tests revealed reduced serum complement C3 and normal complement C4 levels indicative of alternative complement activation. We postulate that complement activation is involved in the pathogenesis of cocaine-induced TMA.

e20060 Background: Hemophagocytic Lymphohistiocytosis (HLH) is a systemic inflammation disorder secondary to immune dysregulation. Patients may present with fevers, splenomegaly, bone marrow failure, and hemophagocytosis, among other clinical and laboratory findings. Lymphoma Associated HLH (LA-HLH) is a puzzling diagnosis given both conditions overlapping presentation. There are currently no established treatment guidelines for LA-HLH. Methods: We conducted a retrospective search of the tumor registry and pathology database at the University of Miami/Jackson Memorial Hospital to identify adult patients with the combined diagnosis of Lymphoma and HLH between January 2008 and July 2018. Results: Data from nine LA-HLH patients were identified and reviewed. Median age was 53 years (range 19-73), with 78% of cases of Hispanic origin. Lymphoma subtypes consisted of six T-cell/NK-cell neoplasms - 2 Peripheral T-cell Lymphomas (PTCL), NOS; 2 EBV+ Extranodal NK/T-Cell Lymphomas; 1 EBV+, CD8+, PTCL, NOS; 1 EBV+, Post-Transplant Lymphoproliferative Disorder-Anaplastic Large Cell Lymphoma, ALK negative (PTLD ALCL ALK-); and three B-cell neoplasms - 1 EBV+ DLBCL; 2 DLBCL, NOS. HLH and Lymphoma were diagnosed simultaneously in 6/9 cases. Hemophagocytosis phenomena was demonstrated in 7/9 cases. Treatment consisted of combined HLH and Lymphoma therapies in 4 cases, while Lymphoma directed therapy was applied to four patients; another case was treated with a modified version of the HLH-1994 protocol. Overall, a total of five cases were exposed to HLH-directed regimens (HLH-1994/2004). Three patients had refractory LA-HLH and entered hospice care, whereas another 3 cases succumbed to treatment-related complications. Of the seven cases that were evaluable for Lymphoma response, four cases (57%) achieved CR, and three of them (43%) were alive with no evidence of recurrence at 10, 16, and 52 months as of last contact. Conclusions: Herein, we describe our unique experience of an LA-HLH case series in a predominantly Hispanic population in South Florida. The diagnosis is challenging, often delayed, and the prognosis is dismal in refractory cases despite currently available rescue therapies. Furthermore, we describe for the first time the association between HLH and PTLD ALCL.

Purpose: The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab ± vincristine in patients with relapsed/refractory aggressive B-NHL. Patients and Methods: Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 + 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/BCL2 IHC was performed on available archival tissue. Results: Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n = 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non–germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL). Conclusions: The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.

A phase II trial of R-MACLO-IVAM followed by thalidomide maintenance for mantle cell lymphoma (MCL) demonstrated promising progression-free survival (PFS) and overall survival (OS) rates. Thalidomide maintenance was associated with significant toxicity and was subsequently modified to rituximab maintenance. Herein, we present updated results and follow-up. Two sequential phase II trials included chemotherapy-naive patients with MCL up to 75 years old. Four cycles of R-MACLO-IVAM chemotherapy were delivered as previously described. Patients who achieved complete responses (CR) were eligible for thalidomide or rituximab maintenance therapy. Among 36 patients enrolled, the MCL International Prognostic Index (MIPI) was low in 53%, intermediate in 36% and high in 11%. Thirty-five patients completed at least 2 cycles of chemotherapy; 34 (94%) achieved a CR. After a median follow-up of 74.4 months, the 5-year PFS was 51% (95% CI 33–68%) and the 5-year OS was 85% (95% CI 73–97%). Two deaths occurred during the chemotherapy phase due to disease progression and neutropenic sepsis, respectively. One patient developed secondary acute myeloid leukemia after 7 years. R-MACLO-IVAM chemotherapy is effective for patients with newly diagnosed MCL. Am. J. Hematol. 90:E111–E116, 2015. © 2015 Wiley Periodicals, Inc.

Post-transplant lymphoproliferative disorder (PTLD) develops in 1-3% of liver transplant recipients and no consensus exists about therapeutic management. From 2006 to 2016, 1489 liver transplants were performed at our institution with 20 patients (incidence 1.3%) developing PTLD. Hepatitis C virus (HCV) was the leading cause (n = 10) of liver transplant in PTLD patients. Diffuse large B-cell lymphoma was the most frequent histologic subtype (n = 17), and we report our experience in the management of these patients. Patients were treated with frontline immunochemotherapy without immunosuppression reduction. All evaluable patients achieved a complete remission. Statistically significant decreased survival was identified in HCV-positive patients. Six patients (60%) exhibited increases in HCV RNA levels during therapy. Four patients (40%) developed graft failure and three of them (30%) died from liver dysfunction. This is the first study providing evidence of decreased survival in HCV-positive PTLD patients after liver transplant receiving immunochemotherapy.

Intestinal obstruction after liver transplant is a rare complication, with diverse clinical manifestations. Intestinal adhesion is the most common cause. However, internal hernia, abdominal wall hernia, and neoplasm are also reported. Intussusception is another rare cause of intestinal obstruction, which has been reported primarily in pediatric patients. Herein, we report a case of intestinal obstruction from intussusception in an adult liver transplant patient associated with post-transplant lymphoproliferative disorder.

Thrombotic thrombocytopenia purpura (TTP) is a severe multisystem disorder characterized by fever, microangiopathic hemolytic anemia, thrombocytopenia, neurologic symptoms, and impaired renal function. Platelet counts are usually diminished, whereas the bone marrow shows a large number of megakaryocytes indicating peripheral destruction and consumption of platelets. Coagulation studies in patients with TTP are normal or slightly elevated, which helps differentiate this entity from disseminated intravascular coagulation. The peripheral smear shows an abundance of schistocytes, reticulocytes, and, at times, nucleated red blood cells. Serum lactate dehydrogenase and indirect bilirubin are elevated as a result of mechanical destruction of red blood cells. Legionella pneumophila has been identified as a relatively common cause of both community-acquired and hospital-acquired pneumonia. An association between Legionella and TTP has only been cited once in the literature. Here we present a case of severe TTP with concurrent Legionella infection. Our patient presented with the classic clinical findings of TTP and an ADAMTS13 level of less than 5% associated with an inhibitor. After a 3-week treatment course with plasma exchange, steroids, and antibiotics, he had complete clinical recovery and his ADAMTS13 level increased to greater than 75%.

Extranodal marginal zone B-cell lymphoma is the most common orbital tumour. We conducted a retrospective analysis to examine: (i) the impact of initial presentation and staging on outcome and (ii) response to various treatment modalities and the effect of the latter on recurrence. Ninety patients with primary ocular adnexal marginal zone lymphoma (POAML) diagnosed at our institution between 1984 and 2009 were studied. POAML was associated with monoclonal gammopathy (13%) at presentation. Most POAML patients (86%) presented with Ann-Arbor stage I disease. Radiotherapy led to excellent local control, but relapses occurred in 18% of Ann-Arbor stage I patients during a median follow-up of 5 years. Local relapses, including secondary central nervous system (CNS) involvement, were observed in patients receiving radiation doses

Plasmablastic lymphoma (PBL), initially characterized as an aggressive lymphoma arising in the jaw and oral mucosa in HIV-infected patients, was recently reported to occur with extraoral manifestations, heterogeneous histologic findings, and variable association with immunodeficiency states. We reviewed clinical, morphologic, and immunophenotypic features of 13 cases of PBL to determine whether these different subtypes represent distinct morphologic and clinical entities. Two distinct subtypes of PBL were identified and classified as oral and extraoral PBL. The oral PBLs were strongly associated with HIV infection and commonly demonstrated plasmablastic morphologic features without plasmacytic differentiation. Extraoral PBLs tended to occur in patients with underlying non–HIV-related immunosuppression and universally demonstrated plasmacytic differentiation. The patients with oral PBL demonstrated better overall survival compared with patients with extraoral PBL (P = .02). Our findings suggest that PBL with oral and extraoral manifestation represent 2 distinct clinicopathologic entities.

Primary intraocular lymphoma (PIOL) is a rare, aggressive malignancy involving the retina, vitreous or optic nerve head, without (isolated PIOL) or with central nervous system (CNS) involvement. While isolated PIOL may initially manifest unilaterally, the majority (80–90%) of patients eventually develop bilateral disease, and 60–85% progress in the CNS within 2–3 years of initial diagnosis, limiting median survival to only 3 years (Freeman et al, 1987). The optimal treatment for PIOL is controversial and data on the therapy and outcome of isolated PIOL is limited to retrospective case reports or mostly small series with heterogeneous patient populations and treatment approaches (Akpek et al, 1999, Grimm et al, 2007, Hoffman et al, 2003, Jahnke et al, 2006). In November 2005, the University of Miami Sylvester Comprehensive Cancer Center lymphoma programme team decided to use a combination of binocular external beam radiation therapy and systemic chemotherapy containing high-dose methotrexate (modified de Angelis regimen) (Abrey et al, 2000) in all patients with newly diagnosed isolated PIOL. Our design aimed to eliminate ocular disease by binocular radiation, and to use concomitant/sequential chemotherapy to eradicate potential microscopic brain disease, which may be responsible for later relapse. Patients were not enrolled in a clinical trial, but were followed and data collected prospectively. This report presents our experience using this approach. All patients underwent diagnostic pars plana vitrectomy with cytology, immunocytochemistry, flow cytometry and gene rearrangement studies. Staging evaluation, which included computerized tomography scans of chest, abdomen and pelvis, brain magnetic resonance imaging (MRI) scan, lumbar puncture, bone marrow biopsy and aspiration, showed no systemic lymphoma. Radiation therapy of 30–40 (median 36) Gy was given at 1.8–2.0 Gy per fraction to both eyes and orbits including the optic nerve and conus. Chemotherapy consisted of methotrexate 3.5 g/m2 i.v. over 4 h, followed by Leucovorin rescue (15 mg i.v. every 8 h), Vincristine 2 mg i.v. push and Procarbazine 100 mg/m2/day p.o. for 7 days (odd cycles only), given every 2 weeks for 6 cycles. Patients underwent follow-up evaluation every 3–6 months and annual surveillance brain MRI. Complete response was defined as complete disappearance of lymphomatous infiltrates on post-treatment ophthalmological examination. Overall survival (OS) was calculated from pathological diagnosis until date of death from any cause or last follow-up. Kaplan Meier survival curves were constructed, censoring patients at the time of death or last follow-up. This study was approved by our institutional review board, in accordance with the declaration of Helsinki. Patient characteristics, clinical and pathological findings, treatment and follow-up data are summarized in Table I. As illustrated in Figure 1a, five patients initially received radiation therapy, followed by chemotherapy, with partial overlap in 3 patients. One patient was first treated with chemotherapy due to personal preference, but thereafter completed a course of ocular radiation therapy. All six patients (4 male, 2 female, median age 61.5 years) completed therapy without major interruptions, delays or side effects and achieved a complete remission (CR). We did not observe any adverse ocular effects during concomitant administration of chemo- and radiotherapy. During median follow-up of 44 (range 10–51) months, one patient developed parenchymal brain relapse and died 21 months after initial diagnosis (Figure 1b), while the remaining 5 patients have maintained CR for a median of 40 months (range 5–47 months). Three patients developed radiation-induced cataract and vascular retinopathy with median latency of 11.5 months (range 5–16 months) after radiation therapy. No other treatment-related long-term side effects have been observed. Figure 1 Treatment and outcome of PIOL patients. (A) Treatment sequence of radiation therapy (XRT) and chemotherapy in 6 patients with PIOL; (B) Overall Survival of 6 patients with isolated PIOL treated with a combination of binocular external beam radiation therapy ... Table I Clinical features, treatment, and outcome of 6 patients with primary intraocular lymphoma (PIOL) Historically, binocular radiation therapy of 30–45 Gy has been the mainstay of treatment for PIOL, yielding response rates of 60–97%, with frequent complete remissions and long-term local control. However, this treatment modality has only minimal impact on OS (Margolis et al, 1980), because CNS relapse occurs in almost all patients after a median of 37 (11 to 84) months, with median survival of 12 to 20 months, thus limiting 5-year OS after radiotherapy to 10 to 29% (Peterson et al, 1993). Systemic chemotherapy offers the possibility of preventing CNS recurrence and potentially treating the intraocular disease. However, the latter may be difficult, since high-dose intravenous methotrexate, the single most effective agent in the treatment of PCNSL, has been shown to achieve therapeutic, albeit lower concentrations in the vitreous (median 3.4 μM) than in the aqueous humor and cerebrospinal fluid 4 h after administration of 8 g/m2 as a 4-h infusion – a very high dose with significant risk for potentially serious side effects (Batchelor et al, 2003). Moreover, only seven of nine patients with therapeutic drug levels (1 μM or greater) responded to therapy and intraocular relapse occurred in three patients, indicating that chemotherapy with high-dose methotrexate as a single modality may not be sufficient for the treatment of PIOL. We also observed persistence of PIOL in one of our patients (Patient 6) who was first treated with chemotherapy, but subsequently received ocular radiation, resulting in CR. In a retrospective study from the Memorial Sloan Kettering Cancer Center (Hormigo et al, 2004), eight patients with isolated PIOL were treated with different systemic chemotherapy regimens – most containing either high-dose methotrexate at 3.5 g/m2 and/or high-dose cytarabine at 3 g/m2 or higher - and ocular radiation therapy. Six of eight patients (75%) achieved a CR. Five of eight patients (63%) developed progressive disease in the CNS after a median of 10 months (range 8–25 months), while the other 3 patients remained in CR for a median of 44 months (range 6–47 months). While this approach was similar to ours, it produced inferior results. The total dose, fractionation and sequencing of radiation therapy with chemotherapy that was not uniform, were not specified and may account for the observed difference in outcome compared to our patients. However, considering the small patient numbers, it is possible that these differences are due to chance. To our knowledge, we present the first report in the literature using a uniform and highly effective treatment approach in a series of patients with isolated PIOL. Further studies of this promising combination regimen in larger cohorts of patients with isolated PIOL are needed.

Pulmonary marginal zone lymphoma is a rare disease arising from bronchial-associated lymphoid tissue (BALT). There is limited information on clinical presentation, natural history and treatment of this type of lymphoma. We conducted a retrospective review of patients with biopsy-proven BALT lymphoma treated at our institution and patients from the surveillance epidemiology and end results (SEER) database. Twenty-one patients (median age 57) with disease stage IE (n = 10) and IV (n = 11), were treated at our institution. Initial management included observation (n = 4), surgery (n = 5), combination chemotherapy (n = 7), single-agent rituximab (n = 3) and radioimmunotherapy (n = 2). Complete remission was observed in 10, partial remission in 3, stable disease in 7, and disease progression in 1 patient. With a median follow-up of 20 months, Kaplan-Meier estimates for progression-free and overall survival (OS) at 80 months were 90% and 95%, respectively. We identified 326 patients (59% females and 41% males; median age 68 [30 to 85) with BALT lymphoma in the SEER database. Fifty-five per cent had stage IE, 10% stage IIE, 3% stage IIIE, and 22% stage IV disease. After a median follow-up of 35 months, median OS was 112 months, and disease-specific median survival was not reached. At 90 months, disease-specific survival was 85% (CI 77-92) with no significant differences in outcome between patients presenting with different stages. Our single institution experience and review of the SEER database, confirm the indolent features and favourable outcome of this rare disease.

A phase II trial of R-MACLO-IVAM followed by thalidomide maintenance for mantle cell lymphoma (MCL) demonstrated promising progression-free survival (PFS) and overall survival (OS) rates. Thalidomide maintenance was associated with significant toxicity and was subsequently modified to rituximab maintenance. Herein we present updated results and follow-up. Two sequential phase II trials included chemotherapy-naïve patients with MCL up to 75 years old. Four cycles of R-MACLO-IVAM chemotherapy were delivered as previously described. Patients who achieved complete responses (CR) were eligible for thalidomide or rituximab maintenance therapy. Among 36 patients enrolled, the mantle cell lymphoma International Prognostic Index (MIPI) was low in 53%, intermediate in 36% and high in 11%. Thirty-five patients completed at least 2 cycles of chemotherapy; 34 (94%) achieved a CR. After a median follow-up of 74.4 months, the 5-year PFS was 51% (95% CI 33% – 68%) and the 5-year OS was 85% (95% CI 73% – 97%). Two deaths occurred during the chemotherapy phase due to disease progression and neutropenic sepsis respectively. One patient developed secondary acute myeloid leukemia after 7 years. R-MACLO-IVAM chemotherapy is effective for patients with newly diagnosed MCL.

The best upfront therapy for patients with non-gastric extranodal marginal zone lymphomas (MZLs) is not defined. We assessed the safety and efficacy of radioimmunotherapy with 90yttrium (90Y) ibritumomab tiuxetan as upfront therapy in MZL (NCT00453102). A total of 16 patients were enrolled, 81% with advanced-stage disease and 44% with bulky disease. The overall response rate (ORR) at 12 weeks post-therapy was 87.5% (90% confidence interval [CI]: 65.6–97.7%), including a complete response in eight (50%), complete response unconfirmed in one (6%) and partial response in five (31%) patients. With a median follow-up of 65.6 months (range 4.0–96.5), the median progression-free survival (PFS) was 47.6 months (range 4.0–93.3) and median overall survival (OS) was not reached. The 5-year PFS was 40% (90% CI: 19.9–59.5%) and 5-year OS was 71.8% (90% CI: 46.8–86.5%). Overall, 90Y ibritumomab tiuxetan was well tolerated and led to long-term responses and PFS rates.

Interactions between human haematopoietic and bone marrow stromal cells are governed by complex carbohydrate-mediated adhesion processes. In order to evaluate corresponding carbohydrate-binding sites on human myelo- and erythropoietic cells which were able to react with mono- or oligosaccharides, we established an immunocytochemical double-staining assay. In a first step, cell lineages were visualized using Lewisx (CD15) or glycophorin C-specific monoclonal antibodies. The second step included polyacrylamide-conjugated carbohydrate structures. According to our results, the carbohydrate-binding potential of granulopoietic cells increased during the process of maturation, contrasting a reduction of carbohydrate-binding sites on erythroid precursor cells during differentiation. With respect to previous in vitro studies, these findings shed some light on certain aspects of bone marrow homing as well as on the trafficking of mature cellular elements into circulation. It is tempting to speculate that carbohydrate-mediated adhesion mechanisms may be involved in the various functional defects of progenitor cells in chronic myelogenic leukaemia, especially regarding their complex interactions with the marrow microenvironment.

In order to isolate and enrich bone marrow mononuclear phagocytes, we performed magnetic-activated cell sorting using beads coupled to a monoclonal antibody directed against the monocyte/macrophage surface molecule CD14. Co-localization of antigens in single cells was achieved by combining an alkaline phosphatase--anti-alkaline phosphatase and an avidin--biotin complex immunoassay, avoiding the use of peroxidase. Bone marrow macrophages were first labelled by the monoclonal antibody PG-M1 (anti-CD68). Subsequently, cytoplasmic and/or surface double staining by the monoclonal antibodies against HLA-DR and Mac-2 antigen or the lectin GSA-I-B4 was carried out. Whereas HLA-DR was co-expressed by the great majority of PG-M1+ macrophages (84.9% +/- 6.9%), only a subpopulation exhibited Mac-2 (69.9% +/- 5.9%) antigen or galactoside structures detected by GSA-I-B4 (65.0% +/- 6.7%). The latter result differed only slightly from the percentage of GSA-I-B+4 macrophages determined in a previous comparative immunomorphometrical study. Therefore, using our method of isolation and enrichment by magnetic-activated cell sorting, only a negligible portion of macrophages is apparently stimulated, as shown by GSA-I-B4 staining. This methodology seems to be a valuable tool for further studies on the monocyte--macrophage system. © 1998 Chapman & Hall

Sunitinib, a new vascular endothelial growth factor receptor inhibitor, has demonstrated activity in renal cell carcinoma and is now widely used in the palliative treatment of patients with metastatic renal cell carcinoma. It is generally well tolerated but has been associated with a low incidence of grade 3 and 4 toxicities including fatigue, diarrhea, anorexia, mucositis, skin toxicity, immune thrombocytopenic purpura, hypertension, hypothyroidism, cytopenias, and decreased cardiac ejection fraction. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is a rare condition that is severe and may be fatal. Several medications have been implicated in causing TTP-HUS including clopidogrel, mitomycin C, cisplatin. In this report, we describe a case of atypical HUS-microangiopathic hemolytic anemia during treatment with sunitinib in a patient with metastatic renal cell carcinoma. To our knowledge, this is the fourth case of microangiopathic hemolytic anemia associated with sunitinib described in the literature and the first case with fatal outcome despite treatment with plasmapheresis, dialysis, and withdrawal of sunitinib.

Plasmablastic lymphoma (PBL), initially characterized as an aggressive lymphoma arising in the jaw and oral mucosa in HIV-infected patients, was recently reported to occur with extraoral manifestations, heterogeneous histologic findings, and variable association with immunodeficiency states. We reviewed clinical, morphologic, and immunophenotypic features of 13 cases of PBL to determine whether these different subtypes represent distinct morphologic and clinical entities. Two distinct subtypes of PBL were identified and classified as oral and extraoral PBL. The oral PBLs were strongly associated with HIV infection and commonly demonstrated plasmablastic morphologic features without plasmacytic differentiation. Extraoral PBLs tended to occur in patients with underlying non-HIV-related immunosuppression and universally demonstrated plasmacytic differentiation. The patients with oral PBL demonstrated better overall survival compared with patients with extraoral PBL (P = .02). Our findings suggest that PBL with oral and extraoral manifestation represent 2 distinct clinicopathologic entities.

Primary central nervous system lymphoma (PCNSL) accounts for approximately 4% of all primary brain tumors and has a poor prognosis in both immunocompetent as well as in immunocompromised patients. We conducted a retrospective analysis to examine the clinical characteristics and prognostic factors in HIV-negative and HIV-positive patients with PCNSL and to assess the effect of highly active antiretroviral therapy (HAART) therapy on the outcome of HIV-positive patients. Patients diagnosed with PCNSL between 1999 and 2008 at our institution were divided into two groups based on their HIV status. Their demographic and clinical characteristics were compared using the chi-square test. Kaplan-Meier survival curves were constructed employing the univariate log-rank test. Multivariate analyses of survival were performed by Cox proportional hazards models incorporating the prognostic factors identified in the univariate log rank test. Forty-one HIV-positive patients and 45 HIV-negative patients were identified. HIV-positive patients were younger, more likely to present with seizures and elevated serum LDH levels. There were significant differences in complete remission (CR) rates (P = 0.010) and overall survival (OS) (P = 0.034) in favor of the HIV-negative group. In the HIV-positive group, OS was better in patients with KPS > 70 and patients who received HAART, but remained inferior to that in the HIV-negative patients. HIV-positive patients had a worse prognosis compared to HIV-negative patients despite similar clinical characteristics. Better performance status (KPS > 70) and treatment with HAART conferred better OS in HIV-positive patients.

Primary or secondary central nervous system (CNS) involvement by marginal zone B-cell lymphoma (MZBCL) is rare. A retrospective analysis of patients was done with MZBCL involving the CNS, diagnosed and treated at our institution between 2004 and 2010. We identified 10 MZBCL patients with primary (six) or secondary (four) CNS involvement. Five patients presented with primary dural lymphoma and were treated with surgical resection, whole-brain radiation, or systemic chemotherapy. Only one patient had CNS relapse 5 years later. A single patient with primary intraocular lymphoma achieved clinical remission with ocular radiotherapy and systemic chemotherapy. Four patients had ocular MZBCL within 5 years of the initial diagnosis of primary ocular adnexal MZBCL and primary splenic MZBCL. There was no evidence of local recurrence in all but one who developed systemic relapse after 3 years of follow-up. Primary or secondary CNS involvement by MZBCL display indolent clinical behavior and have a generally favorable prognosis, underlining the importance of their differentiation from aggressive lymphomas that more commonly involve the CNS.

Rituximab is a chimeric anti-CD20 monoclonal antibody widely used in the treatment of B-cell non-Hodgkin lymphomas (NHL). Most adverse effects are due to infusion-related reactions, and severe respiratory complications are rare. We retrospectively reviewed clinical data and serial imaging studies of five patients with NHL treated with rituximab-containing chemotherapy who developed new pulmonary abnormalities on routine follow-up FDG-PET/CT imaging. None of the patients had pulmonary lymphoma or other pulmonary disease before therapy and all remained asymptomatic during follow-up. New pulmonary interstitial FDG-uptake was detected on follow-up FDG-PET/CT between 1 and 3 months post-treatment, preceded computed tomography abnormalities in one case, and persisted for several months. FDG uptake was linear, subpleural with maximum Standardized uptake value (SUV) from 2.0 to 5.84. Rituximab-containing chemotherapy for NHL may be associated with asymptomatic late pulmonary toxicity characterised by a distinct FDG uptake pattern. Awareness of this finding is important and should not be confused with lymphoma.

Lymphomas of the ocular adnexa are a heterogeneous group of malignancies, composing approximately 1% to 2% of non-Hodgkin lymphomas (NHLs) and 8% of extranodal lymphomas. The most common subtype, accounting for up to 80% of cases of primary ocular adnexal lymphoma, is marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) type. In the recent past, there have been significant advances in our understanding of the clinical characteristics, morphology and phenotype, etiology, pathogenesis, diagnosis, natural history, treatment approaches, outcome, and prognostic factors of this disease entity. Novel immunologic and molecular techniques have aided in the distinction between MALT lymphoma and other lymphoproliferative disorders and led to the identification of tissue markers of prognostic significance. Modern imaging modalities provide invaluable tools for accurate staging and treatment planning. Besides radiotherapy and chemotherapy, a variety of new treatment options have emerged in the management of patients with ocular adnexal MALT lymphoma, especially monoclonal antibody therapy and antibiotic therapy against Chlamydia psittaci, which has been associated with the pathogenesis of ocular adnexal lymphomas in some parts of the world. In this review, we present a state-of-the-art summary of ocular adnexal MALT lymphomas.

High-dose chemotherapy with autologous SCT has become standard of care for patients with relapsed aggressive non-Hodgkin's lymphoma (NHL). To improve safety and efficacy of this treatment, new conditioning regimens are being developed. We retrospectively reviewed clinical data of patients with relapsed NHL treated at our institution with i.v. BU and CY (BU/CY) as conditioning regimen for autologous SCT between January 2000 and April 2005. We identified 43 patients (24 men, 19 women, median age 50) with diffuse large B-cell lymphoma (n=28), follicular lymphoma (n=8), mantle cell lymphoma (n=4) and peripheral T-cell lymphoma (n=3). Following salvage chemotherapy, there were 26 complete responses, 13 partial responses and 4 stable diseases. Median time to neutrophil and platelet recovery was 11 and 13.5 days, respectively. Treatment-related toxicities included nausea/vomiting, diarrhea and mucositis. The 100-day mortality was 9%: sepsis (n=1), pneumonia (n=1) and hepatic veno-occlusive disease (n=2). Twenty-one patients were followed until death and twenty-one surviving patients were followed for a median of 29 months (range 0.4-76). Three-year estimates of event-free survival, progression-free survival and overall survival were 35, 39 and 43%, respectively. We conclude that i.v. BU/CY is a safe and effective conditioning regimen for autologous SCT in relapsed NHL.

Background: Marginal zone lymphomas (MZLs) account for 10% to 17% of all non-Hodgkin lymphomas (NHLs). Eradication of Helicobacter pylori (HP) is considered the initial therapy of choice for localized HP-positive gastric MALT and radiation is commonly used for other localized MALT or nodal MZL. While radiotherapy in localized MALT and nodal MZLs frequently results in long term local control and prolonged progression-free survival (PFS), it is not always feasible. Consensus guidelines on the best upfront therapy for patients with non-gastric MALT and disseminated extranodal MZLs are absent. Considering the excellent local control of MZLs with radiotherapy, targeted delivery of radiation by radioimmunotherapy may be the preferential approach for patients with untreated disseminated MZL. Based on this premise, we designed a single center Phase II clinical trial to examine 90Y Ibritumomab in the upfront treatment of patients with Marginal Zone Lymphoma. Methods: Eligible patients were 18 years and older with a diagnosis of untreated, histologically proven CD20-positive marginal zone lymphoma of all stages, including extranodal and nodal MZL variants. Patients with HP-negative and patients with HP-positive gastric MALT lymphoma who did not respond to antibiotic therapy were also eligible. Additional inclusion criteria were: measurable disease (at least one lymph node or tumor mass 2 cm in any axis), Eastern Cooperative Oncology (ECOG) performance status of 0, 1 or 2 and adequate bone marrow (neutrophils >1.5x109/L; platelets >100x109/L), hepatic and renal functions. Treatment consisted of intravenous rituximab 250 mg/m² on day 1 with appropriate premedications. On Day 8, patients received a second dose of rituximab 250 mg/m² prior to 0.4 mCi/kg (14.8 MBq/kg) of 90Y ibritumomab tiuxetan administered as a 10-minute intravenous push. Response assessment was made at week 12 post therapy by CT scan and physical examination. Patients underwent follow up with regular clinical reviews and CT scans of the neck, chest, abdomen, and pelvis every 3 months for the first 2 years and then every 6 months for an additional 3 years. Results: Between June 2006 and January 2014, 16 patients were enrolled. The median age was 62 years with a range of 37 to 84 years. The ORR at week 12 post treatment was 87.5% (14 of 16 patients) with a 90% confidence interval of 65.6% to 97.7%. The responses comprised of CR in 8 (50%), CRu in 1 (6%) and PR in 5 (31%) patients. A total of 2 patients (13%) were defined as having stable disease at week 12 restaging. With a median follow up of 65.6 months (range 4.0-96.5), the median PFS was 47.6 months (range 4.0-93.3) for all patients (Figure 1A), with median PFS of 47.6 months (range 4.0-74.2) for patients achieving CR. Of the 16 treated patients, 4 died (25%). None of the deaths was directly attributed to MZL and 2 patients died while being in continuous CR. Median OS by Kaplan-Meier method for all the patients was not attained (Figure 1B). The 5-year PFS was 40% (90% CI: 19.9% - 59.5%) and 5-year OS was 71.8% (90% CI: 46.8% - 86.5%). The principal toxicity was hematological. Reversible grade 3 or 4 neutropenia occurred in 8 of 16 (50%) of patients, median duration 21 days (range 9-69 days). Reversible grade 3 or 4 thrombocytopenia was observed in 5 of 16 (31.3%) patients with a median duration of 28 days (range 13-42 days). Grade 4 anemia occurred in one (6.3%) patient and lasted for 15 days. Later adverse non-hematological events were typically mild and self-limiting. Conclusion: Our phase-II trial suggests that one single injection of 90Y ibritumomab tiuxetan may be a valid therapeutic option for front-line therapy of patients with MALT lymphoma, producing response rates similar to those achieved with immunochemotherapy treatment regimens. Further evaluation of this therapeutic approach in a prospective, preferentially randomized, multi-institutional clinical trial is needed. Figure 1A Figure 1A. Figure 1B Figure 1B. Disclosures No relevant conflicts of interest to declare.

Primary testicular lymphoma (PTL) is a rare entity with distinct natural history and inferior outcome compared to nodal and other extranodal diffuse large B-cell lymphoma (DLBCL). This lymphoma is ...

We thank Drs Ponzoni et al for their interest in our review on extranodal marginal zone lymphoma of the ocular adnexa (OAML) and would like to express our point of view regarding the comments the authors are raising on the association between Chlamydophila psittaci (Cp) and OAML. As illustrated in

Background Amplification and/or over-expression of the mitotic Aurora A kinase (AAK) have been reported in a variety of tumors. The investigational, selective, AAK inhibitor MLN8237 (alisertib) has shown signs of anti-tumor activity in pts with hematologic malignancies including aggressive non-Hodgkin lymphoma (NHL). Over-expression of AAK leads to resistance to microtubule targeted agents such as vincristine (V) and inhibiting AAK leads to synergy in the presence of these agents (Mahadevan D et al. CCR 2012). The combination of MLN8237 (M) + rituximab (R) ± V has shown synthetic lethality in pre-clinical B-NHL mouse models (ibid) supporting clinical evaluation of this combination; we report the safety and recommended phase 2 dose (RP2D) from the phase 1 clinical data of this MR ± V combination in pts with aggressive B-NHL. Methods Adults with CD20+ B-NHL after 1–4 prior regimens (including ASCT) and ECOG PS 0–2 were eligible. In part 1 (MR), pts received one dose level of M 50 mg BID days 1–7 + R 375 mg/m2 IV day 1 in 21-day cycles (up to 8) in combination, followed by single agent M. In part 2 (MRV), M dose escalation followed a 3+3 design (M starting dose: ∼50% of MR RP2D [30mg BID] days 1–7 + R 375 mg/m2 IV on day 1 + V 1.4 mg/m2 [max, 2 mg] IV on days 1 and 8 of 21-day cycle). The RP2D was determined as the dose level at which Results As of 16 July 2013, 35 pts were enrolled (28 DLBCL, 1 transformed follicular, 1 Burkitt, and 5 mantle cell) with data entered for 32 pts (21 male) at time of data cut-off (part 1, n=13; part 2, n=19 [MLN8237: 30 mg, n=4; 40 mg n=12; 50 mg, n=3]). 1 pt in the MR cohort and 8 pts in the MRV cohorts continue on treatment. Pt demographics, exposure, and safety data are shown in the table. MR was well tolerated with 1 DLT; therefore M 50 mg BID x 7 d + R 375mg/m2 was the recommended regimen for this doublet. For the MRV triplet the RP2D was M 40 mg BID. Common grade (G) ≥3 drug-related AEs across the cohorts included: thrombocytopenia, leukopenia, neutropenia, fatigue and anemia. To date, 26 pts have discontinued treatment (15 progressive disease [PD], 5 AEs [including 2 unrelated deaths, unrelated G4 T7 spinal cord mass and compression, G1 related pulmonary fibrosis, G2 unrelated cough and dysphagia], 3 symptomatic deterioration, 2 other, 1 withdrawal by subject). An additional unrelated, on-study death occurred in a pt who had discontinued treatment due to PD. At the MR RP2D combination, MLN8237 median Tmax was 2 hr and geometric mean steady-state AUC0-12hr was 18,960 nM*hr (n=11, CV: 61.2%), which is consistent with what was achieved in M single agent at 50 mg BID. Assessment of the effect of MLN8237 on vincristine PK is ongoing. 12 pts administered MR were response evaluable; 1 50 y male pt with DLBCL had a complete response (CR), 2 pts had partial response (PR) including one 79 y male pt with DLBCL ongoing at 29 cycles, and 5 pts had stable disease (SD) for up to 13 cycles. 8 MRV pts are currently response evaluable (M 30 mg, n=3; 40 mg, n=5); one 78 y male pt with DLBCL in the 30 mg cohort had CR; at the RP2D (40 mg BID cohort) one 71 y male with non- germinal center B-cell-like DLBCL and having progressed following prior transplant had CR; one 66 y male pt with large B-cell had PR, 5 pts had SD. Response assessments are pending for 5 pts. Enrollment continues to the MRV RP2D to complete the required number of PK-evaluable pts. Conclusions MR ± V is overall well tolerated and has shown preliminary anti-tumor activity in pts with relapsed/refractory B-cell lymphomas. Disclosures: Off Label Use: Use of the investigational agent MLN8237 in combination in patients with aggressive B-cell NHL. Persky:Millennium: The Takeda Oncology Company: Research Funding. Mahadevan:Novartis: Honoraria; Millennium: The Takeda Oncology Company: Honoraria. Miller:Spectrum: Research Funding; Abbott Laboratories: Research Funding. Hayslip:Celgene: Research Funding. Park:TEVA: Research Funding; Seattle Genetics, Inc.: Research Funding. Ruan:Seattle Genetics, Inc.: Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Rosen:Disney Family Cancer Center: Research Funding. Padmanabhan Iyer:Millennium: The Takeda Oncology Company: Research Funding. Zhang:Takeda Pharmaceutical Company Ltd.: Equity Ownership; Millennium: The Takeda Oncology Company: Employment. Zhou:Millennium: The Takeda Oncology Company: Employment. Dansky Ullmann:Millennium: The Takeda Oncology Company: Employment. Leonard:Millennium: The Takeda Oncology Company: Employment, Equity Ownership.

Background There is ample data for the response rates and clinical outcomes for patients with newly diagnosed multiple myeloma (MM) treated with first-line lenalidomide and dexamethasone (LEN/DEX). Phase II and III studies have reported objective response rates (ORR) in the range of 70-90%. However, extrapolating from clinical trials to ‘real world' clinical practice is sometimes difficult. This is particularly so when it comes to large city hospital systems such as Jackson Memorial Hospital (JMH) in Miami, Florida. JMH is the third-largest public hospital and third-largest teaching hospital in the United States. Patients are primarily uninsured or insured through Medicaid. Additionally, one might surmise, that for a medication like LEN- with a relatively narrow therapeutic index, high cost, and cumbersome prescribing/dispensing requirements- outcomes in the ‘real world' might be inferior to those cited in clinical study. We endeavored to explore such outcomes in JMH to determine whether the benefits of this high cost drug in this setting are concordant with published data. Methods We conducted a retrospective analysis of all patients enrolled into the Celgene patient assistance program and prescribed LEN from January 1, 2010 through July 30, 2013 at JMH. We identified 96 patients enrolled into this program, 35 patients received LEN/DEX as first-line therapy for MM and are evaluable for this analysis. The primary end-point for analysis was response at 4 months. Results Medical records of 35 patients were reviewed. The mean age was 59 (46-75), majority of patients were female (60%), and 29% were black. Consistent with our patient population, 71.4% of patients were Hispanic, 44% were uninsured, and 64% had Medicaid. IgG (60%) was the most common heavy chain involved while 3 patients had light chain disease only. The majority of patients (88.6%) had stage III disease by the Durie-Salmon criteria, and 37.1% had ISS stage III disease. Cytogenetic studies were evaluable in 30 patients: 66.7% were standard-risk, 30% intermediate-risk and 3.3 % high-risk according to mSMART risk classification. At 4-month follow-up, 26 (74.3%) patients had an OR: 6 (17.1%) patients had CR, 7 (20%) had VGPR, and 13 (37.1%) had PR. 6 (17.1%) patients had progressive disease, change in therapy, or were lost to follow-up. There were no documented deep venous thromboses, a known risk of LEN therapy. Only 8 patients (23%) underwent autologous stem cell transplant following primary therapy. Conclusion Responses with upfront LEN/DEX in MM at JMH, were relatively similar to published data in large clinical studies. This provides support for the extrapolation of data from well supported clinical trials at fully-resourced medical institutions, for an oral chemotherapy drug with significant potential toxicities and logistical barriers, to a primarily Medicaid patient population in a county hospital. Disclosures: No relevant conflicts of interest to declare.

Abstract 1622 Background: Contemporary therapy for mantle cell lymphoma (MCL) in fit patients usually consists of an induction phase followed by autologous stem cell transplantation (SCT). We previously reported a phase II trial of intensive chemotherapy induction with R-MACLO-IVAM followed by thalidomide maintenance and demonstrated promising progression-free survival (PFS) and overall survival (OS) rates without SCT (Lossos et al, Leuk Lymph 2010). We subsequently modified the protocol to utilize rituximab maintenance instead of thalidomide. Herein we present updated results and follow-up for the patients treated on this trial. Methods: This was a prospective single-arm phase II trial conducted at the University of Miami with IRB approval. Eligible patients were chemotherapy-naïve and had a confirmed diagnosis of MCL using WHO criteria, age 18–75 years, ECOG PS 0–2, adequate organ function and no history of HIV or prior cancer. Pretreatment staging include CT and PET scans, endoscopy, colonoscopy and bone marrow biopsy. Cycle 1 consisted of R-MACLO (rituximab, methotrexate, doxorubicin, cyclophosphamide and vincristine) followed by G-CSF. When the ANC was >1.5×109/L, cycle 2 with R-IVAM (rituximab, ifosfamide, mesna, etoposide and cytarabine) was begun, followed by G-CSF, as previously reported. Fourteen days after ANC recovery from cycle 2, cycles 3 and 4 were given in identical fashion to 1 and 2. Four weeks after ANC recovery from cycle 4, patients were re-staged and responses were assessed by standard criteria. Patients who achieved complete responses (both radiologically and pathologically) were eligible for the maintenance phase. The first 22 patients were treated with thalidomide maintenance (target daily dose of 200mg); the protocol was subsequently modified to utilize rituximab maintenance at a dose of 375 mg/m2 IV weekly × 4 weeks, repeated every 6 months. Maintenance therapy was continued until MCL relapse or intolerable toxicity. OS was calculated from the date of diagnosis to the date of death or last follow up. PFS was calculated from date of diagnosis until the date of pathological evidence of recurrence or death. Data were summarized using descriptive statistics and survival was analyzed using the Kaplan-Meier method. Results: Between June 2004 and June 2012, 32 patients were enrolled, 22 on the first phase and 10 after the amendment to rituximab maintenance. All patients were evaluable for toxicity and 31 were evaluable for response. Median age was 56.5 years (range 39–73). All subjects had at least stage III disease with bone marrow involvement in 84% and gastrointestinal involvement in 38%. Distribution according to MIPI: low 28%; intermediate 38%; high 34%. All patients had diffuse variant except 2 with blastic variant. Twenty-eight patients completed all 4 cycles of therapy; treatment was stopped in 2 after 3 cycles, and in one after 2 cycles, and 1 died during cycle 1. Of the 31 patients completing 2 cycles of chemotherapy, 29 (94%) achieved a complete response (CR) and 2 had a partial response (PR). After a median follow-up of 54.9 months, the 5-year PFS was 69% (95% CI 51% – 82%) and the 5-year OS was 88% (95% CI 72% – 95%) [Fig 1 & 2]. Lower MIPI group (low vs intermediate vs high) was associated with longer PFS (log rank p = 0.007) and longer OS (log rank p = 0.036) [Fig 3 & 4]. Nine patients relapsed and 5 died; 1 died from sepsis on cycle 1; 1 died in CR at 38 months from non-small cell lung cancer diagnosed 19 months after MCL and the other 3 died from relapsed MCL after 22, 24 and 60 months respectively. Seven of the 9 patients who relapsed were treated with rituximab and bendamustine and one underwent an allogeneic SCT. Toxicities during the chemotherapy phase for the last 10 patients were similar to what was previously published for the first 22 patients, with the exception of lower renal toxicity since the dose of methotrexate was reduced to a total of 4.2 g/m2 instead of 6.7 g/m2 prior to the amendment. The toxicities during the thalidomide maintenance phase were similar to what was previously reported. For the 10 patients who received rituximab maintenance, there were no unexpected toxicities during the maintenance phase. Conclusions: R-MACLO-IVAM results in a high overall response rate (94% CR and 6% PR) and a low relapse rate after over 4.5 years of median follow-up. The median PFS and OS still have not been reached. These results compare favorably with regimens that include upfront SCT. Disclosures: No relevant conflicts of interest to declare.

Abstract 1752 Background: Post-transplant lymphoproliferative disease (PTLD) represents a major complication after solid organ transplantation, associated with high morbidity and mortality. Few, mostly small retrospective case series have reported on the clinical features, treatment and outcome of PTLD after liver transplantation, and the optimal treatment approach remains controversial. At our institution, the management of PTLD was not standardized until 2006, when a dedicated lymphoma team for PTLD treatment was formed and adopted a uniform approach based on histologic phenotype. In this approach, monoclonal diffuse large B-cell lymphoma (DLBCL) occurring post transplant was treated aggressively with immunochemotherapy. Methods: We retrospectively analyzed the clinical data of all adult patients who developed PTLD following liver transplantation at our institution between 1988 and 2010. We also compared the outcomes of patients with the most common PTLD histology - DLBCL - treated before 2006 (era 1) and thereafter (era 2). Results: We identified 26 patients (m=18, f=8) with median age of 60 (range 15–80). Underlying liver diseases included hepatitis C (n=9), non-alcoholic steatohepatitis (n=3), alcoholic cirrhosis (n=3), biliary atresia (n=3), autoimmune hepatitis (n=3), cryptogenic cirrhosis (n=2), hepatitis B (n=1), fulminant hepatic failure (n=1) and congenital syndrome (n=1). Acute transplant rejection that required additional immunosuppressive therapy was observed in 16 (62%). Median latency of PTLD after liver transplantation was 39 (range 1–192) months. Eight patients (31%) presented with early PTLD, i.e. within one year after transplantation. Histologic entities included DLBCL (n=16), polymorphic lymphoplasmacytic infiltrate (n=4), marginal zone lymphoma (n=1), Burkitt lymphoma (n=1), Hodgkin lymphoma (n=1) and plasmacytoma (n=1). Tissue staining for EBER was positive in 4/21 evaluated cases (19%). The majority of patients (65%) presented with stage IV disease, and all but one (96%) manifested with extranodal disease. Median IPI score was 3. Initial treatment approaches in patients diagnosed and treated in era 1 (n=13) included reduction or discontinuation of immunosuppression alone (n=2) or in combination with antiviral agents (n=2) and Rituximab (n=7). Two patients died before initiation of therapy. Complete remission to first-line therapy was observed in 3 and partial remission in 4 patients evaluated for response. Six patients in this group died from progressive disease (n=1), infectious complications (n=3), hemorrhagic stroke (n=1) and unknown cause (n=1). Among patients diagnosed and treated in era 2 (n=13), eleven received chemotherapy with or without Rituximab without reduction of immunosppression, one patient was on “watch and wait” for asymptomatic splenic marginal zone lymphoma and another patient decided to seek treatment elsewhere and was lost to follow-up. Eleven patients in this group (1 patient with plasmacytoma of the liver and 10 with DLBCL, including 1 case of primary CNS lymphoma) were evaluable for response and all achieved a complete remission. After a median follow-up period of 28.5 months for surviving patients, the 3-year overall survival (OS) and progression-free survival (PFS) for all patients were 73% and 71%, respectively. One- and 3-year OS was 60% and 51%, respectively, for patients treated in era 1 and 100% for patients treated in era 2 (p=0.01), with 1- and 3-year PFS of 51% in era 1 and 91% in era 2, respectively (p=0.03). Patients with DLBCL histology treated in era 1 had 1- and 3-year OS of 40% and 20% (median 11 months), respectively, while those treated in era 2 had 1- and 3-year OS of 100% (p=0.001), with corresponding 1 and 3-year PFS of 20% (median 8 months) and 90%, respectively (p=0.004). Conclusion: Our study is one of the largest ever published on PTLD in adult liver transplant recipients. The majority of these patients present with aggressive histologies and high risk features. An aggressive immunochemotherapeutic approach by experienced and dedicated lymphoma and liver transplant teams may benefit post-transplant patients with DLBCL and lead to outcomes similar to those observed in the non-transplant setting. Disclosures: No relevant conflicts of interest to declare.

e18539 Background: Plasmablastic lymphoma (PBL) was initially characterized as an aggressive subtype of NHL most frequently arising in the jaw and oral cavity in patients with HIV infection, accoun...

e12502 Background: Primary central nervous system lymphoma (PCNSL) accounts for approximately 4% of all primary brain tumors and has a poor prognosis in both immunocompetent as well as in immunocom...

19508 Background: Pulmonary marginal zone lymphoma (BALT lymphoma) is a rare disease. Few small case series suggest an indolent course with favorable outcome; however, there is limited information on clinical presentation, natural history and treatment of this type of lymphoma. Methods: We conducted a retrospective review of patients with biopsy-proven BALT lymphoma diagnosed between 1994 and 2007 and treated at our institution, and patients from the Surveillance Epidemiology and End Results (SEER) database diagnosed between 1988 and 2003. Results: Twenty-one patients, 11 male and 10 female, with a median age of 57, were identified at our institution. Disease stage was IE (n=10) and IV (n=11), including 7 with extrapulmonary involvement. Initial management included observation (n=4), surgery (n=5), combination chemotherapy (n=7), single-agent rituximab (n=3) and radioimmunotherapy (n=2). Following first- line treatment, complete remission was observed in 10, partial remission in 3, stable disease in 7, an...

18508 Background: High-dose chemotherapy followed by autologous stem cell transplanatation has become standard of care for patients with relapsed, chemosensitive non-Hodgkin’s lymphoma (NHL). In an effort to improve safety and efficacy of this therapeutic approach, new conditioning regimens are being developed. Methods: We retrospectively reviewed the clinical data of 44 consecutive patients with relapsed NHL who had been treated with intravenous Busulfan and Cyclophosphamide (BU/CY) as conditioning regimen for autologous stem cell transplantation between January 2000 and April 2005. Busulfan was administered at a total dose of 3.2 mg/kg on days -7 to -4 (given in two or four divided doses), followed by Cyclophosphamide at a dose of 120 mg/kg intravenously on days -3 and -2. We determined treatment-related morbidity and mortality, event-free survival (EFS, defined as time period between transplantation and occurrence of serious morbidity, disease relapse, disease progression, or death), disease-free survival (DFS), and overall survival (OS). Results: The distribution by histologic type of the 44 patients was as follows: 29 diffuse large B-cell lymphoma, 8 follicular lymphoma, 4 mantle cell lymphoma, and 3 peripheral T-cell lymphoma. Median age was 50 (range 20 to 68 years). At the time of transplantation, 27 patients had attained a complete response (CR or CRu) to salvage chemotherapy, 13 had achieved a partial response, and 4 had stable disease. Median time to neutrophil recovery post transplantation was 11 days. Treatment-related toxicities included nausea/vomiting (77%), diarrhea (43%), and mucositis (66%), which were mild in the majority of cases. Neutropenic fever occurred in 82% of patients. The 100-day mortality rate was 4 (9%) of patients: sepsis (n=1), pneumonia (n=1), and hepatic veno-occlusive disease (n=2). After a median follow-up of 52 months, 3-year Kaplan-Meier estimates of EFS, DFS, and OS were 35%, 41% and 44% respectively. Conclusions: Intravenous BU/CY is a safe and effective conditioning regimen as part of autologous transplantation for relapsed NHL. Our outcomes are comparable to those of other published regimens. Further investigation of this treatment approach is warranted. No significant financial relationships to disclose.