Antibody-Drug Conjugate αEGFR-E-P125A Reduces Triple-negative Breast Cancer Vasculogenic Mimicry, Motility, and Metastasis through Inhibition of EGFR, Integrin, and FAK/STAT3 Signaling.

Primary tumor growth and metastasis in triple-negative breast cancer (TNBC) require supporting vasculature, which develop through a combination of endothelial angiogenesis and vasculogenic mimicry (VM), a process associated with aggressive metastatic behavior in which vascular-like structures are lined by tumor cells. We developed αEGFR-E-P125A, an antibody-endostatin fusion protein that delivers a dimeric, mutant endostatin (E-P125A) payload that inhibits TNBC angiogenesis and VM in vitro and in vivo. To characterize the mechanisms associated with induction and inhibition of VM, RNA sequencing (RNA-seq) of MDA-MB-231-4175 TNBC cells grown in a monolayer (two-dimensional) was compared with cells plated on Matrigel undergoing VM [three-dimensional (3D)]. We then compared RNA-seq between TNBC cells in 3D and cells in 3D with VM inhibited by αEGFR-E-P125A (EGFR-E-P125A). Gene set enrichment analysis demonstrated that VM induction activated the IL6-JAK-STAT3 and angiogenesis pathways, which were downregulated by αEGFR-E-P125A treatment.Correlative analysis of the phosphoproteome demonstrated decreased EGFR phosphorylation at Y1069, along with decreased phosphorylation of focal adhesion kinase Y397 and STAT3 Y705 sites downstream of α5ß1 integrin. Suppression of phosphorylation events downstream of EGFR and α5ß1 integrin demonstrated that αEGFR-E-P125A interferes with ligand-receptor activation, inhibits VM, and overcomes oncogenic signaling associated with EGFR and α5ß1 integrin cross-talk. In vivo, αEGFR-E-P125A treatment decreased primary tumor growth and VM, reduced lung metastasis, and confirmed the inhibition of signaling events observed in vitro. Simultaneous inhibition of EGFR and α5ß1 integrin signaling by αEGFR-E-P125A is a promising strategy for the inhibition of VM, tumor growth, motility, and metastasis in TNBC and other EGFR-overexpressing tumors. SIGNIFICANCE: αEGFR-E-P125A reduces VM, angiogenesis, tumor growth, and metastasis by inhibiting EGFR and α5ß1 integrin signaling, and is a promising therapeutic agent for TNBC treatment, used alone or in combination with chemotherapy.

Inhibition of Vasculogenic Mimicry and Angiogenesis by an Anti-EGFR IgG1-Human Endostatin-P125A Fusion Protein Reduces Triple Negative Breast Cancer Metastases.

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited therapeutic options. Metastasis is the major cause of TNBC mortality. Angiogenesis facilitates TNBC metastases. Many TNBCs also form vascular channels lined by tumor cells rather than endothelial cells, known as 'vasculogenic mimicry' (VM). VM has been linked to metastatic TNBC behavior and resistance to anti-angiogenic agents. Epidermal growth factor receptor (EGFR) is frequently expressed on TNBC, but anti-EGFR antibodies have limited efficacy. We synthesized an anti-EGFR antibody-endostatin fusion protein, αEGFR IgG1-huEndo-P125A (αEGFR-E-P125A), designed to deliver a mutant endostatin, huEndo-P125A (E-P125A), to EGFR expressing tumors, and tested its effects on angiogenesis, TNBC VM, and motility in vitro, and on the growth and metastasis of two independent human TNBC xenograft models in vivo. αEGFR-E-P125A completely inhibited the ability of human umbilical vein endothelial cells to form capillary-like structures (CLS) and of TNBC cells to engage in VM and form tubes in vitro. αEGFR-E-P125A treatment reduced endothelial and TNBC motility in vitro more effectively than E-P125A or cetuximab, delivered alone or in combination. Treatment of TNBC with αEGFR-E-P125A was associated with a reduction in cytoplasmic and nuclear ß-catenin and reduced phosphorylation of vimentin. αEGFR-E-P125A treatment of TNBC xenografts in vivo inhibited angiogenesis and VM, reduced primary tumor growth and lung metastasis of orthotopically implanted MDA-MB-468 TNBC cells, and markedly decreased lung metastases following intravenous injection of MDA-MB-231-4175 lung-tropic TNBC cells. Combined inhibition of angiogenesis, VM, and TNBC motility mediated by αEGFR-E-P125A is a promising strategy for the prevention of TNBC metastases.

R-MACLO-IVAM regimen followed by maintenance therapy induces durable remissions in untreated mantle cell lymphoma - Long term follow up results.

We present long-term combined results of two clinical trials implementing R-MACLO-IVAM induction followed by thalidomide or rituximab maintenance in 44 patients with untreated mantle cell lymphoma (MCL). The first 22 patients (UM-MCL1 ClinicalTrials.gov identifier NCT00450801) received maintenance with thalidomide (200 mg daily until relapse/intolerable toxicity) and a subsequent cohort of 22 patients (UM-MCL2 ClinicalTrials.gov identifier NCT00878254) received rituximab (375 mg/m2 IV weekly × 4, repeated every 6 months for 3 years). Considering all 44 patients, 41 (93.2%) achieved complete response (CR), two (4.5%) partial response (PR), and one (2.3%) was not evaluated for response. With a median follow up of 7.2 years (range < 1 month to 16 years), the 5-year progression-free survival (PFS) was 55.6% (95% CI: 38.9%-69.4%) and median PFS 7.9 years (95% CI: 3.7-11 years). The 5-year OS was 83.3% (95% CI: 68.1%-91.7%) and median OS was not reached. Patients with blastic variant (n = 6) had a 5-year PFS and OS of 20.8% and 60%, respectively. Myelosuppression was the most common adverse event during immunochemotherapy. Long-term treatment-related mortality was 6.8%. Note, R-MACLO-IVAM followed by maintenance therapy is an effective regimen to induce long-term remission in MCL without need for consolidation with ASCT.

Short survival and frequent transformation in extranodal marginal zone lymphoma with multiple mucosal sites presentation.

Between 11 and 37% of extranodal marginal zone lymphoma (EMZL) patients present with disease involvement in multiple mucosal sites (MMS). We analyzed 405 EMZL patients seen between 1995 and 2017: 265 (65.4%) patients presented with stage I disease, 49 of 309 (15.8%) patients with bone marrow involvement, and 35 of 328 (10.7%) patients with monoclonal gammopathy (MG). Forty-three (10.6%) patients had MMS presentation, which was more frequently seen in patients aged >60 years (55.8%). Five (17.9%) of 28 MMS patients had MG. MMS patients commonly exhibited the International Prognostic Index (IPI) >2 (79.1%), Follicular Lymphoma International Prognostic Index (FLIPI) >2 (39.5%), and Mucosa-Associated Lymphoid Tissue Lymphoma International Prognostic Index (MALT-IPI) 2-3 (60.5%). Both MMS presentation and MG were associated with shorter survival univariately. In multivariable Cox regression models, shorter progression-free survival (PFS) and overall survival (OS) were observed in patients with MMS (hazard ratio [HR] = 3.08 and 2.92, respectively), age ≥60 years (HR = 1.52 and 2.45, respectively), and in patients who failed to attain a complete remission following initial therapy (HR = 3.27 and 2.13, respectively). Elevated lactate dehydrogenase was associated with shorter PFS (HR = 1.92), while anemia (HR = 2.46) was associated with shortened OS. MALT-IPI ≥2 (HR = 2.47 and 4.75), FLIPI >2 (HR = 1.65 and 2.09), and IPI >2 (HR = 2.09 and 1.73) were associated with shorter PFS and OS, respectively. Higher grade transformation (HGT) occurred in 11 (25.6%) MMS patients with a 5-year cumulative incidence of 13.2% (95% CI 4.7-26.1%). EMZL patients with MMS presentation represent a novel clinical subset associated with shorter PFS, OS, and higher incidence of HGT that needs novel therapeutic approaches.

Risk Factors for Transformation to Higher-Grade Lymphoma and Its Impact on Survival in a Large Cohort of Patients With Marginal Zone Lymphoma From a Single Institution.

PURPOSE: Given the paucity of data on higher-grade transformation (HGT) to aggressive lymphoma in patients with marginal zone lymphoma (MZL), we report on a large cohort of patients, identify risk factors, and determine HGT impact on overall survival (OS). METHODS: We analyzed 453 patients with biopsy-proven MZL seen at our institution between 1995 and 2016. Kaplan-Meier, Cox proportional hazards regression, and competing risk methods were used in analyses of time-to-event outcomes. RESULTS: Thirty-four patients (7.5%) had biopsy-proven HGT to diffuse large B-cell lymphoma, including seven (21%) diagnosed at the time of initial MZL diagnosis. Among 27 incident patients, median time to HGT was 29 months (range, 1.3 to 135 months). Higher risk of HGT was observed in those with nodal/splenic MZL (subdistribution hazard ratio [SHR], 2.60; P = .023). On multivariable competing risk analysis, elevated lactate dehydrogenase (SHR, 2.71), more than four nodal sites (SHR, 2.97), and failure to achieve complete remission (CR) after initial treatment (SHR, 3.76) conveyed significantly higher risk for HGT ( P < .02). International Prognostic Index (IPI), Follicular Lymphoma IPI, and Mucosa-Associated Lymphoid Tissue Lymphoma IPI were only significant predictors of HGT univariably. Patients with HGT had shorter OS (5-year rate, 65% v 86%; P < .001). Patients who presented with HGT within 12 months since MZL diagnosis had shorter OS than those with HGT at MZL diagnosis combined with those with HGT more than 12 months later (4-year rate, 43% v 81%, P < .001). Non-CR and higher scores of IPI, Follicular Lymphoma IPI, and Mucosa-Associated Lymphoid Tissue Lymphoma IPI were the main significant predictors for shorter progression-free survival and OS. CONCLUSION: Failure to achieve CR after initial treatment, elevated lactate dehydrogenase, and more than four nodal sites at the time of MZL diagnosis are the main predictors of increased risk of HGT. Patients with HGT have shorter OS.

Dabrafenib and Trametinib Treatment for Erdheim-Chester Disease With Brain Stem Involvement.

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis characterized by infiltration of organs by CD68+ and CD1a- lipid-laden histiocytes, including the central nervous system in more than a third of patients. Molecular analysis of ECD samples has demonstrated the prevalence of BRAF V600E mutations as high as 54%. Recently, vemurafenib became the only Food and Drug Administration-approved treatment for patients with ECD who carry the BRAF V600E mutation. However, dabrafenib has been suggested to have greater brain distribution. We describe a 44-year-old female patient treated from August of 2015 through November 2017. She presented with a 2-year history of light-headedness, fatigue, and vertigo. She was moderately dysmetric, diffusely hyperreflexic, and dysarthric in the bilateral upper and lower extremities. Her gait was wide-based. She had dysarthria and nystagmus on horizontal gaze bilaterally. Magnetic resonance imaging showed an extensive area of increased T2/fluid-attenuated inversion recovery signal in the brain stem, enhancement in the pons and midbrain, and thickening of the pituitary stalk. Positron emission tomography/computed tomography (PET/CT) and whole-body technetium Tc99m bone scintigraphy showed intense symmetrical radiotracer uptake in the distal femur and tibia bilaterally, which was biopsied. Immunohistochemistry was negative for BRAF V600E, but genomic sequencing revealed the mutation. The patient received combination therapy with dabrafenib and trametinib. Her nystagmus, dysarthria, dysmetria, and gait improved remarkably. Subsequent PET/CT and magnetic resonance imaging showed complete resolution of all radiographic evidence of disease. In this case report, we demonstrate the success of a combination therapy with dabrafenib and trametinib.

Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma.

This pivotal phase 2 study evaluated the safety and efficacy of brentuximab vedotin in patients with relapsed or refractory (R/R) systemic anaplastic large cell lymphoma (ALCL). After a median observation period of approximately 6 years from first treatment, we examined the durability of remission, progression-free survival (PFS), overall survival (OS), and safety outcomes of patients treated on this trial. Among all enrolled patients (n = 58), no progressions were observed beyond 40 months, and median OS was not reached. Patients with a complete response (CR), as assessed by the investigator (38 of 58, 66%), continued to demonstrate improved outcomes with neither median OS nor PFS reached. Of the 38 CR patients, 16 received a consolidative stem cell transplant (SCT) with median PFS not reached. Among patients who were on-study and in remission at study closure, 16 patients had not received any new treatment after single-agent brentuximab vedotin other than consolidative SCT. Among this subset of 16 patients, 8 received SCT, and the remaining 8 patients (14% of all enrolled patients) remained in sustained remission without consolidative SCT or any new anticancer therapy. Thirty-three patients experienced peripheral neuropathy, among whom, the majority (30 of 33, 91%) had experienced resolution or improvement at their last assessment. These final results, which demonstrated a high rate of peripheral neuropathy resolution, and durable remissions in a subset of patients with relapsed or refractory systemic ALCL, provide evidence that single-agent brentuximab vedotin may be a potentially curative treatment option. This trial was registered at www.clinicaltrials.gov as #NCT00866047.

Anti-CD20-interleukin-21 fusokine targets malignant B cells via direct apoptosis and NK-cell-dependent cytotoxicity.

In spite of newly emerging therapies and the improved survival of patients with non-Hodgkin lymphoma (NHL), relapses or primary refractory disease are commonly observed and associated with dismal prognosis. Although discovery of the anti-CD20 antibody rituximab has markedly improved outcomes in B-cell NHL, rituximab resistance remains an important obstacle to successful treatment of these tumors. To improve the efficacy of CD20-targeted therapy, we fused interleukin 21 (IL-21), which induces direct lymphoma cytotoxicity and activates immune effector cells, to the anti-CD20 antibody (αCD20-IL-21 fusokine). We observed substantially enhanced IL-21R-mediated signaling by the fusokine compared with native IL-21 at equimolar concentrations. Fusokine treatment led to direct apoptosis of lymphoma cell lines and primary tumors that otherwise were resistant to native IL-21 treatment. In addition to direct cytotoxicity, the fusokine enhanced NK cell activation, effector functions, and interferon γ production, resulting in greater antibody-dependent cell-mediated cytotoxicity compared with IL-21 and/or anti-CD20 antibody treatments. Further, the αCD20-IL-21 fusokine stabilizes IL-21 and prolongs its half-life. In vivo αCD20-IL-21 therapy resulted in a significant tumor control in the rituximab-resistant A20-huCD20 tumors. Collectively, the dual functional ability of the αCD20-IL-21 fusokine to induce direct apoptosis and activate immune effector cells may provide benefit over existing treatments for NHL.

Clofazimine Enteropathy: A Rare and Underrecognized Complication of Mycobacterial Therapy.

Clofazimine-induced crystal-storing histiocytosis is a rare complication of treatment previously reported in dermatology literature as a complication of leprosy therapy. We report a case of disseminated Mycobacterium abscessus requiring treatment with high-dose oral clofazimine resulting in enteropathy in a patient who presented with abdominal pain, malnutrition, and melena.

B cell regulation of the anti-tumor response and role in carcinogenesis.

The balance between immune effector cells such as T cells and natural killer cells, and immunosuppressive Treg cells, dendritic, myeloid and monocytic sub-populations in the tumor microenvironment acts to calibrate the immune response to malignant cells. Accumulating evidence is pointing to a role for B cells in modulating the immune response to both solid tumors and hematologic cancer. Evidence from murine autoimmune models has defined B regulatory cell (Breg) subsets that express cytokines such as IL-10, TGF-ß, and/or express immune regulatory ligands such as PD-L1, which can suppress T cell and/or natural killer cell responses. Multiple murine tumor models exhibit decreased tumor growth in B cell deficient or B cell depleted mice. In several of these models, B cells inhibit T cell mediated tumor immunity and/or facilitate conversion of T cells to CD4(+)CD25(+)FoxP3(+) T regs, which act to attenuate the innate and/or adaptive antitumor immune response. Mechanisms of suppression include the acquisition of inhibitory ligand expression, and phosphorylation of Stat3, and induction of IL-10 and TGF-ß, resulting in a Breg phenotype. Breg suppressive activity may affect diverse cell subtypes, including T effector cells, NK cells, myeloid derived suppressor cells (MDSC) and/or tumor associated macrophages. B cells may also directly promote tumorigenesis through recruitment of inflammatory cells, and upregulation of pro-angiogenic genes and pro-metastatic collagenases. Breg infiltration has now been identified in a variety of solid tumor malignancies including but not limited to ovarian, gastric, non-small cell lung cancer, pancreatic, esophageal, head and neck, and hepatocellular carcinomas. Increasing evidence suggests that recruitment of B cells and acquisition of suppressive activity within the tumor bed may be an important mechanism through which B cells may modulate innate and/or adaptive anti-tumor immunity. B cell depletion in the clinic using anti-CD20 antibodies and/or inhibitors of BTK and/or other signaling pathways, may be a useful strategy for augmenting the anti-tumor immune response.

Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma.

Presented here are the 5-year end-of-study results from the pivotal phase 2 trial of brentuximab vedotin in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) after failed hematopoietic autologous stem cell transplantation. At 5 years, the overall patient population (N = 102) had an estimated overall survival (OS) rate of 41% (95% confidence interval [CI]: 31-51) and progression-free survival (PFS) rate of 22% (95% CI: 13-31). Patients who achieved a complete response (CR) to brentuximab vedotin (N = 34) had estimated OS and PFS rates of 64% (95% CI: 48-80%) and 52% (95% CI: 34-69%), respectively. The median OS and PFS were not reached in CR patients, with 13 patients (38% of all CR patients) remaining in follow-up and in remission at study closure. Of the 13 patients, 4 received consolidative hematopoietic allogeneic stem cell transplant, and 9 (9% of all enrolled patients) remain in sustained CR without receiving any further anticancer therapy after treatment with brentuximab vedotin. Of the patients who experienced treatment-emergent peripheral neuropathy, 88% experienced either resolution (73%) or improvement (14%) in symptoms. These 5-year follow-up data demonstrate that a subset of patients with R/R HL who obtained CR with single-agent brentuximab vedotin achieved long-term disease control and may potentially be cured. The trial was registered at www.clinicaltrials.gov as #NCT00848926.

Mammary-tumor-educated B cells acquire LAP/TGF-ß and PD-L1 expression and suppress anti-tumor immune responses.

B lymphocytes play a role in inhibiting the immune response against certain tumors, but the underlying mechanisms are poorly understood. EMT-6 mammary tumors grow well in wild-type (WT) mice but show reduced growth in B-cell-deficient µ(-/-) BALB/c mice (BCDM). WT mice demonstrate extensive B-cell infiltration into the tumor bed, reduced CD8(+) T cell and CD49(+) NK cell infiltration, and markedly reduced cytolytic T-cell response relative to BCDM. Expression of LAP/TGF-ß1, CD80, CD86 and PD-L1 is significantly increased in tumor-infiltrating B cells (TIL-B) relative to splenic B cells. LAP/TGF-ß1 expression on TIL-B progressively increased from 5.4±1.7% on day 8 to 43.1±6.1% by day 21 post tumor implantation. Co-culture of EMT-6 tumor cells with Naive-B cells ex vivo generated B cells (EMT6-B) with a similar immunophenotype to TIL-B. Purified TIL-B, or in-vitro-generated EMT6-B suppressed CD4(+), CD8(+) and CD4(+)CD25(-) T-cell proliferation, and Th1 cytokine secretion, and also suppressed purified NK-cell proliferation in response to IL-15, compared to naive splenic B cells. Acquired B regulatory function required direct tumor cell: B-cell contact, and was partially reversed by antibody to TGF-ß or PD-L1, leading to tumor rejection in vivo B-cell acquisition of a suppressive phenotype following tumor infiltration may result in profound inhibition of T-cell anti-tumor responses.

Regulatory B cells in anti-tumor immunity.

Advances in understanding of the immune microenvironment have highlighted the role of immunosuppressive T cell, myeloid, dendritic and monocytic sub-populations in inhibition of the anti-tumor immune response. The role of B cells in modulating the immune response to solid tumors as well as lymphoid malignancies is less well understood. Murine models of autoimmune disease have defined B regulatory cell (Breg) subsets with immune suppressive activity, including B cell subsets that express IL-10, and transforming growth factor-ß, which can facilitate T regulatory cell recruitment and expansion. Multiple murine tumor models point to the existence of similar immune suppressive B cell sub-populations that can migrate into tumor deposits and acquire an immune suppressive phenotype, which then leads to attenuation of the local anti-tumor immune response. Other murine models of viral or chemically induced skin carcinogenesis have identified a pivotal role for B cells in promoting inflammation and carcinogenesis. While many human solid tumors demonstrate significant B cell infiltration and/or tertiary lymphoid structure formation, the functional properties of tumor-infiltrating B cells and their effects on immunity are poorly understood. Recent successes in early Phase I/II trials using anti-checkpoint inhibitor antibodies such as nivolumab or pidilizumab directed against PD-1 in the setting of Hodgkin's and non-Hodgkin's lymphomas validate the therapeutic utility of reversing B cell-mediated immune suppression. Further studies to define Breg subsets, and mechanisms of suppression, may provide new avenues for modulation of the immune response and meaningful therapeutic intervention in both lymphoid and solid tumors.

Updated survival analysis of two sequential prospective trials of R-MACLO-IVAM followed by maintenance for newly diagnosed mantle cell lymphoma.

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 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.

Phase II study of (90)Y Ibritumomab tiuxetan (Zevalin) in patients with previously untreated marginal zone lymphoma.

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 (90)yttrium ((90)Y) 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, (90)Y ibritumomab tiuxetan was well tolerated and led to long-term responses and PFS rates.

Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma.

We present response and survival outcomes of a pivotal phase 2 trial of the antibody-drug conjugate brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma following autologous stem cell transplant (N = 102) after a median observation period of approximately 3 years. Median overall survival and progression-free survival were estimated at 40.5 months and 9.3 months, respectively. Improved outcomes were observed in patients who achieved a complete remission (CR) on brentuximab vedotin, with estimated 3-year overall survival and progression-free survival rates of 73% (95% confidence interval [CI]: 57%, 88%) and 58% (95% CI: 41%, 76%), respectively, in this group (medians not reached). Of the 34 patients who obtained CR, 16 (47%) remain progression-free after a median of 53.3 months (range, 29.0 to 56.2 months) of observation; 12 patients remain progression-free without a consolidative allogeneic stem cell transplant. Younger age, good performance status, and lower disease burden at baseline were characteristic of patients who achieved a CR and were favorable prognostic factors for overall survival. These results suggest that a significant proportion of patients who respond to brentuximab vedotin can achieve prolonged disease control. The trial was registered at www.clinicaltrials.gov as #NCT00848926.

Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies.

BACKGROUND: Brentuximab vedotin is a CD30-directed antibody-drug conjugate. Retreatment with brentuximab vedotin monotherapy was investigated in patients with CD30-positive Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (ALCL) who relapsed after achieving complete or partial remission (CR or PR) with initial brentuximab vedotin therapy in a previous study (ClinicalTrials.gov NCT00947856). METHODS: Twenty-one patients with HL and 8 patients with systemic ALCL were retreated; 3 patients with systemic ALCL were retreated twice. Patients generally received brentuximab vedotin 1.8 mg/kg intravenously approximately every 3 weeks over 30 minutes as an outpatient infusion. The primary objectives of this study were to assess safety and to estimate antitumor activity of brentuximab vedotin retreatment. RESULTS: The objective response rate was 60% (30% CR) in HL patients and 88% (63% CR) in systemic ALCL patients. The estimated median duration of response for patients with an objective response was 9.5 months (range, 0.0+ to 28.0+ months) at the time of study closure. Of the 19 patients with objective response, 7 patients had not had an event of disease progression or death at the time of study closure; duration of response for these patients ranged from 3.5 to 28 months. Of the 11 patients with CR, 45% had response durations of over 1 year.Adverse events (AEs) occurring in ≥25% of patients during the retreatment period were generally similar in type and frequency to those observed in the pivotal trials of brentuximab vedotin monotherapy, with the exception of peripheral neuropathy, which is known to have a cumulative effect. Grade 3 or higher events were observed in 48% of patients; these were generally transient and managed by dose modifications or delays. Deaths due to AEs occurred in 3 HL patients; none were considered to be related to brentuximab vedotin retreatment. DISCUSSION: With the exception of a higher rate of peripheral motor neuropathy, retreatment with brentuximab vedotin was associated with similar side effects seen in the pivotal trials. CONCLUSIONS: Retreatment with brentuximab vedotin monotherapy is associated with response rates in 68% (39% CR) of patients with relapsed HL and systemic ALCL. TRIAL REGISTRATION: United States registry and results database ClinicalTrials.gov NCT00947856.

Diagnosis and treatment of diffuse large B-cell lymphoma in an orangutan (Pongo pygmaeus).

Lymphoma is a common malignancy observed in companion animals. This type of naturally occurring neoplasia has been uncommonly reported in great apes. Diffuse large B-cell lymphoma was diagnosed in an 8-yr-old captive orangutan (Pongo pygmaeus) with gastrointestinal disease by histologic and immunohistochemical methodologies. The orangutan was treated with three cycles of combination chemotherapy (intravenous Rituxan, cyclophosphamide, doxorubicin, and vincristine). The primate has been in good health and exhibiting normal behaviors for more than 15 mo following treatment.

A case of catheter-related bloodstream infection caused by Mycobacterium phocaicum.

We present a patient with double hit Burkitt's like lymphoma who developed a catheter-related bloodstream infection due to Mycobacterium phocaicum that was identified by rpoB gene sequencing. His infection resolved with 7 weeks of antibiotics and port-a-cath removal.