Publications by authors named "Craig A Portell"

25 Publications

  • Page 1 of 1

Outcomes of Burkitt lymphoma with central nervous system involvement: evidence from a large multi-center cohort study.

Haematologica 2021 Feb 4. Epub 2021 Feb 4.

Lifespan Cancer Institute, Alpert Medical School of Brown University, Providence, RI.

Central nervous system (CNS) involvement in Burkitt lymphoma (BL) poses a major therapeutic challenge, and the relative ability of contemporary regimens to treat CNS involvement remains uncertain. We described prognostic significance of CNS involvement and incidence of CNS recurrence/progression after contemporary immunochemotherapy using real-world clinicopathologic data on adults with BL diagnosed between 2009 and 2018 across 30 US institutions. We examined associations between baseline CNS involvement, patient characteristics, complete response (CR) rates, and survival. We also examined risk factors for CNS recurrence. Nineteen percent (120/641) of patients (age 18-88 years) had CNS involvement. It was independently associated with HIV infection, poor performance status, involvement of ≥2 extranodal sites, or bone marrow involvement. First-line regimen selection was unaffected by CNS involvement (P=0.93). Patients with CNS disease had significantly lower rates of CR (59% versus 77% without; P.
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http://dx.doi.org/10.3324/haematol.2020.270876DOI Listing
February 2021

Burkitt Lymphoma International Prognostic Index.

J Clin Oncol 2021 Jan 27:JCO2003288. Epub 2021 Jan 27.

Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.

Purpose: Burkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches.

Methods: We derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019.

Results: In the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively.

Conclusion: The BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.
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http://dx.doi.org/10.1200/JCO.20.03288DOI Listing
January 2021

Outcomes of COVID-19 in patients with CLL: a multicenter international experience.

Blood 2020 09;136(10):1134-1143

Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.

Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive ("watch and wait"), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi's; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi's at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi's in COVID-19 are needed to provide definitive evidence of benefit.
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http://dx.doi.org/10.1182/blood.2020006965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472711PMC
September 2020

Burkitt lymphoma in the modern era: real-world outcomes and prognostication across 30 US cancer centers.

Blood 2021 Jan;137(3):374-386

Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL.

We examined adults with untreated Burkitt lymphoma (BL) from 2009 to 2018 across 30 US cancer centers. Factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate Cox models. Among 641 BL patients, baseline features included the following: median age, 47 years; HIV+, 22%; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to 4, 23%; >1 extranodal site, 43%; advanced stage, 78%; and central nervous system (CNS) involvement, 19%. Treatment-related mortality was 10%, with most common causes being sepsis, gastrointestinal bleed/perforation, and respiratory failure. With 45-month median follow-up, 3-year PFS and OS rates were 64% and 70%, respectively, without differences by HIV status. Survival was better for patients who received rituximab vs not (3-year PFS, 67% vs 38%; OS, 72% vs 44%; P < .001) and without difference based on setting of administration (ie, inpatient vs outpatient). Outcomes were also improved at an academic vs community cancer center (3-year PFS, 67% vs 46%, P = .006; OS, 72% vs 53%, P = .01). In multivariate models, age ≥ 40 years (PFS, hazard ratio [HR] = 1.70, P = .001; OS, HR = 2.09, P < .001), ECOG PS 2 to 4 (PFS, HR = 1.60, P < .001; OS, HR = 1.74, P = .003), lactate dehydrogenase > 3× normal (PFS, HR = 1.83, P < .001; OS, HR = 1.63, P = .009), and CNS involvement (PFS, HR = 1.52, P = .017; OS, HR = 1.67, P = .014) predicted inferior survival. Furthermore, survival varied based on number of factors present (0, 1, 2 to 4 factors) yielding 3-year PFS rates of 91%, 73%, and 50%, respectively; and 3-year OS rates of 95%, 77%, and 56%, respectively. Collectively, outcomes for adult BL in this real-world analysis appeared more modest compared with results of clinical trials and smaller series. In addition, clinical prognostic factors at diagnosis identified patients with divergent survival rates.
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http://dx.doi.org/10.1182/blood.2020006926DOI Listing
January 2021

Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK Inhibition as an Effective Strategy.

Clin Cancer Res 2020 Jul 20;26(14):3589-3596. Epub 2020 Mar 20.

Department of Haematology, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.

Purpose: Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood.

Experimental Design: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies].

Results: We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve ( = 130), and 81% were idelalisib naïve ( = 263). ORR to BTKi was 84% ( = 44) in BTKi-naïve patients versus 54% ( = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.

Conclusions: For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3815DOI Listing
July 2020

Outcomes in patients with aggressive B-cell non-Hodgkin lymphoma after intensive frontline treatment failure.

Cancer 2020 01 30;126(2):293-303. Epub 2019 Sep 30.

Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown.

Methods: Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy.

Results: In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse <12 months from completion of first-line therapy) experienced inferior median PFS (2.8 vs 23 months; P < .001) and OS (6 months vs not reached; P < .001) compared with patients with late treatment failure. Although the 17% of patients with early failure who achieved a complete response to second-line immunochemotherapy experienced prolonged survival, this outcome could not be predicted by clinicopathologic features at the start of second-line immunochemotherapy.

Conclusions: Patients with early treatment failure after intensive first-line immunochemotherapy experience poor outcomes after receiving standard second-line immunochemotherapy. The use of standard-of-care or experimental therapies currently available in the third-line setting and beyond should be investigated in the second-line setting for these patients.
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http://dx.doi.org/10.1002/cncr.32526DOI Listing
January 2020

Treatment of Refractory ALK Rearranged Anaplastic Large Cell Lymphoma With Alectinib.

Clin Lymphoma Myeloma Leuk 2019 06 11;19(6):e247-e250. Epub 2019 Mar 11.

Division of Hematology/Oncology, University of Virginia, Charlottesville, VA.

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http://dx.doi.org/10.1016/j.clml.2019.03.001DOI Listing
June 2019

Maintenance rituximab or observation after frontline treatment with bendamustine-rituximab for follicular lymphoma.

Br J Haematol 2019 02 21;184(4):524-535. Epub 2018 Dec 21.

Washington University School of Medicine, Saint Louis, MO, USA.

Bendamustine (B) with rituximab (R) is a standard frontline treatment for medically fit follicular lymphoma (FL) patients. The safety and efficacy of maintenance rituximab (MR) after BR induction has not been formally compared to observation for FL, resulting in disparate practice patterns. Prospective trials have shown benefit of MR after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), yet recent data from the GALLIUM study comparing outcomes of patients treated with chemotherapy with R or obinutuzumab (G) showed higher than anticipated fatal adverse events with BR/BG. In order to assess the efficacy and tolerability of MR after BR, we retrospectively collected data on 640 newly diagnosed patients treated with FL. We found that patients who achieved partial remission (PR) after ≥4 cycles of BR had improved duration of response (DOR) with MR vs. no maintenance, whereas those in complete remission did not. These findings were confirmed in a validation cohort. In the entire study population, the known fatal adverse event rate after BR was 2·5% and did not significantly differ in those receiving MR versus no maintenance. [Correction added on 14 January 2019, after online publication: The preceding sentence has been corrected in this current version.] Within the limitations inherent to retrospective analysis, these data suggest that FL patients with a PR to BR experience prolongation of remission with MR with an acceptable safety profile.
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http://dx.doi.org/10.1111/bjh.15720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486816PMC
February 2019

Revised Dose Ramp-Up to Mitigate the Risk of Tumor Lysis Syndrome When Initiating Venetoclax in Patients With Mantle Cell Lymphoma.

J Clin Oncol 2018 Oct 25:JCO1800359. Epub 2018 Oct 25.

Matthew S. Davids, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Gottfried von Keudell, Yale School of Medicine, New Haven, CT; Craig A. Portell, University of Virginia Health System, Charlottesville, VA; Jonathon B. Cohen, Winship Cancer Institute of Emory University, Atlanta, GA; David C. Fisher, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Francine Foss, Yale School of Medicine, New Haven, CT; Andrew W. Roberts, Royal Melbourne Hospital and University of Melbourne, Melbourne, Victoria, Australia; John F. Seymour, Royal Melbourne Hospital, Peter MacCallum Cancer Centre, and University of Melbourne, Melbourne, Victoria, Australia; Rod A. Humerickhouse, AbbVie, Chicago, IL; and Constantine S. Tam, Royal Melbourne Hospital, Peter MacCallum Cancer Centre, St Vincent's Hospital, and University of Melbourne, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1200/JCO.18.00359DOI Listing
October 2018

The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL.

Blood 2018 12 4;132(23):2446-2455. Epub 2018 Oct 4.

Department III of Internal Medicine, University Hospital Ulm, Ulm, Germany; and.

Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphatidylinositol 3-kinase δ and γ (PI3K-δ,γ) being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can promote B-cell proliferation and survival in clonal B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients. We report here the results of DUO, a global phase 3 randomized study of duvelisib vs ofatumumab monotherapy for patients with relapsed or refractory (RR) CLL/SLL. Patients were randomized 1:1 to oral duvelisib 25 mg twice daily (n = 160) or ofatumumab IV (n = 159). The study met the primary study end point by significantly improving progression-free survival per independent review committee assessment compared with ofatumumab for all patients (median, 13.3 months vs 9.9 months; hazard ratio [HR] = 0.52; < .0001), including those with high-risk chromosome 17p13.1 deletions [del(17p)] and/or mutations (HR = 0.40; = .0002). The overall response rate was significantly higher with duvelisib (74% vs 45%; < .0001) regardless of del(17p) status. The most common adverse events were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough on the duvelisib arm, and neutropenia and infusion reactions on the ofatumumab arm. The DUO trial data support duvelisib as a potentially effective treatment option for patients with RR CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02004522.
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http://dx.doi.org/10.1182/blood-2018-05-850461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284216PMC
December 2018

Risk of Major Bleeding with Ibrutinib.

Clin Lymphoma Myeloma Leuk 2018 11 1;18(11):755-761. Epub 2018 Aug 1.

Division of Hematology-Oncology, Department of Medicine and Cancer Center, University of Virginia Health System, Charlottesville, VA.

Background: The Bruton tyrosine kinase inhibitor, ibrutinib, is an effective therapy against mature B-cell malignancies. Although generally well tolerated, serious bleeding emerged during developmental clinical trials as an unexpected, although uncommon, adverse event. As the use of ibrutinib increases outside of the clinical trial setting and in patients with more comorbidities, the rate of major bleeding could be greater.

Materials And Methods: A retrospective analysis the data from all patients at our center and its regional clinics who had been prescribed ibrutinib from January 2012 to May 2016 were reviewed for demographic data, comorbid illnesses, bleeding events, and concurrent medications.

Results: We identified 70 patients. Bleeding of any grade occurred in 56% of patients, mostly grade 1 to 2 bruising and epistaxis. Major bleeding, defined as grade ≥ 3, occurred in 19% of patients, greater than previously reported. Anemia (hemoglobin < 12 g/dL; hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.4-18.2; P = .02) and an elevated international normalized ratio (> 1.5; HR, 9.5; 95% CI, 2.7-33.5; P < .01) at ibrutinib initiation were associated with an increased risk of major bleeding. Of those with major bleeding, most patients were also taking an antiplatelet agent (70%), an anticoagulant (17%), or a CYP 3A4 inhibitor (7%), with 13% taking both antiplatelet and anticoagulant medications. The use of both antiplatelet and anticoagulant therapy significantly increased the risk of a major bleed event (HR, 19.2; 95% CI, 2.3-166.7; P < .01).

Conclusion: The results of the present study have demonstrated a greater rate of major bleeding with ibrutinib use in a standard clinical setting than previously reported. Patients with anemia or an elevated international normalized ratio or requiring anticoagulant and/or antiplatelet medications during ibrutinib therapy have a significantly increased risk of major bleeding. Careful consideration of the risks and benefits for this population is needed. The combination of antiplatelet and anticoagulation medications with ibrutinib therapy is of particular concern.
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http://dx.doi.org/10.1016/j.clml.2018.07.287DOI Listing
November 2018

Novel therapies for relapsed/refractory mantle cell lymphoma.

Best Pract Res Clin Haematol 2018 03 20;31(1):105-113. Epub 2017 Nov 20.

Department of Hematology/Oncology, University of Virginia, USA. Electronic address:

Mantle cell lymphoma is an aggressive Non-Hodgkin's lymphoma that is considered incurable with standard therapies. Most patients treated with frontline immunochemotherapy relapse within a few years and do not usually respond to salvage chemotherapy. Persistent activation of the B-cell receptor pathway is critical to the pathogenesis of mantle cell lymphoma. Inhibition of Bruton's tyrosine kinase, an essential B-cell receptor pathway component with ibrutinib has shown clinical activity and has changed how MCL is treated in the relapsed/refractory setting. However, resistance to ibrutinib is common and response is limited. Novel agents targeting the B-cell receptor pathway along with therapies outside of the pathway will be reviewed in this article. Ongoing and future studies will better define how these agents should be utilized in the ever-changing treatment landscape of mantle cell lymphoma.
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http://dx.doi.org/10.1016/j.beha.2017.10.010DOI Listing
March 2018

Microenvironmental agonists generate phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL.

Blood Adv 2017 Jun;1(14):933-946

Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, United States.

resistance and rapid recurrence often characterize responses of B-cell malignancies to ibrutinib (IBR), indicating a need to develop drug combinations that block compensatory survival signaling and give deeper, more durable responses. To identify such combinations, we previously performed a combinatorial drug screen and identified the Bcl-2 inhibitor venetoclax (VEN) as a promising partner for combination with IBR in Mantle Cell Lymphoma (MCL). We have opened a multi-institutional clinical trial to test this combination. However, analysis of primary samples from patients with MCL as well as chronic lymphocytic leukemia (CLL) revealed unexpected heterogeneous resistance even to the IBR+VEN combination. In the current study, we demonstrate that resistance to the combination can be generated by microenvironmental agonists: IL-10, CD40L and, most potently, CpG-oligodeoxynucleotides (CpG-ODN), which is a surrogate for unmethylated DNA and a specific agonist for TLR9 signaling. Incubation with these agonists caused robust activation of NF-κB signaling, especially alternative NF-κB, which led to enhanced expression of the anti-apoptotic proteins Mcl-1, Bcl-xL, and survivin, thus decreasing dependence on Bcl-2. Inhibitors of NF-κB signaling blocked overexpression of these anti-apoptotic proteins and overcame resistance. Inhibitors of Mcl-1, Bcl-xL, or survivin also overcame this resistance, and showed synergistic benefit with the IBR+VEN combination. We conclude that microenvironmental factors, particularly the TLR9 agonist, can generate resistance to the IBR+VEN combination in CLL and MCL cells. This signaling pathway presents targets for overcoming drug resistance induced by extrinsic microenvironmental factors in diverse B-cell malignancies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637393PMC
http://dx.doi.org/10.1182/bloodadvances.2016004176DOI Listing
June 2017

Orbital mantle cell lymphoma presenting as myasthenia gravis.

Orbit 2017 Dec 18;36(6):365-369. Epub 2017 Aug 18.

a Department of Ophthalmology , University of Virginia , Charlottesville , Virginia , USA.

A 69-year-old man, previously treated with pyridostigmine for myasthenia gravis (manifesting as ptosis and diplopia) was evaluated for several concomitant bilateral anterior orbital masses. Imaging revealed 3 discrete, solid masses within and around the orbits. An incisional biopsy demonstrated atypical lymphocytes positive for CD20 and Cyclin-D1, consistent with mantle cell lymphoma. The patient received induction chemotherapy with a rituximab-based regimen. He experienced resolution of his diplopia and ptosis after one cycle of chemotherapy and achieved complete remission of the orbital masses and myasthenia symptoms after 6 cycles. Myasthenia gravis is most commonly associated with thymoma, but may also be observed with other malignancies. Recognition that orbital lymphoma may coexist with myasthenia gravis will help in expediting the diagnosis of future cases and in guiding treatment decisions.
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http://dx.doi.org/10.1080/01676830.2017.1337202DOI Listing
December 2017

Implementation of a Model-Based Design in a Phase Ib Study of Combined Targeted Agents.

Clin Cancer Res 2017 Dec 21;23(23):7158-7164. Epub 2017 Jul 21.

Division of Translational Research & Applied Statistics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia.

In recent years, investigators have recognized the rigidity of single-agent, safety-only, traditional designs, rendering them ineffective for conducting contemporary early-phase clinical trials, such as those involving combinations and/or biological agents. Novel approaches are required to address these research questions, such as those posed in trials involving targeted therapies. We describe the implementation of a model-based design for identifying an optimal treatment combination, defined by low toxicity and high efficacy, in an early-phase trial evaluating a combination of two oral targeted inhibitors in relapsed/refractory mantle cell lymphoma. Operating characteristics demonstrate the ability of the method to effectively recommend optimal combinations in a high percentage of trials with reasonable sample sizes. The proposed design is a practical, early-phase, adaptive method for use with combined targeted therapies. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of a melanoma helper peptide vaccine plus novel adjuvant combinations. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712236PMC
December 2017

The role of infectious agents, antibiotics, and antiviral therapy in the treatment of extranodal marginal zone lymphoma and other low-grade lymphomas.

Curr Treat Options Oncol 2015 Jun;16(6):28

Division of Hematology and Oncology, University of Virginia School of Medicine, PO Box 800716, Charlottesville, VA, 22908-0716, USA.

Opinion Statement: There is strong evidence to corroborate the association with Helicobacter pylori (Hp) to gastric extranodal marginal zone lymphoma (ENMZL) and hepatitis C virus (HCV) to splenic/nodal marginal zone lymphoma. Koch's postulates generally hold for these two associations and eradication of the infectious agent is well supported. Hp eradication (HPE) is recommended as front-line therapy for early stage gastric ENMZL regardless of Hp status. Complete response (CR) rate for Hp-negative patients is not as high as for Hp-positive patients; however, the benign nature of HPE and high rates of salvage allow this strategy to be safe while sparing some Hp-negative patients from systemic therapy or radiation. Similarly for HCV-seropositive patients, treatment with antivirals should be strongly considered as first-line for those who do not require immediate cytoreductive therapy or at some point even after completing chemoimmunotherapy. The controversy regarding the role for antibiotics is greatest for primary ocular adnexal lymphoma (POAL). Considering the low incidence of Chlamydia psittaci (Cp) infection with OAL and the challenges to reliably identifying Cp, we typically do not consider doxycycline in POAL treatment. Involved-field radiotherapy (IFRT) remains the treatment of choice for most with unilateral POAL. However, if reliable detection of Cp is available and Cp is identified, patients with unilateral low tumor stage POAL who do not require immediate radiotherapy could be considered for doxycycline as front-line treatment. Other infectious associations to indolent lymphomas have been made, including Borrelia borgdorferi (Bb) in cutaneous lymphoma and Campylobacter in immunoproliferative small intestinal disease (IPSID), but these associations are not as strong and primary treatment targeting the infectious agents is not recommended.
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http://dx.doi.org/10.1007/s11864-015-0344-6DOI Listing
June 2015

Clinical characteristics of 95 patients with ocular adnexal and uveal lymphoma: treatment outcomes in extranodal marginal zone subtype.

Clin Lymphoma Myeloma Leuk 2014 Jun 15;14(3):203-10. Epub 2013 Nov 15.

Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.

Background: Lymphoma rarely presents in the ocular adnexa but is usually extranodal marginal zone (ENMZ) lymphoma when it does. Involved-field radiotherapy (IFRT) is the standard of care for unilateral disease, but the optimal management of more extensive disease is unclear.

Patients And Methods: We retrospectively evaluated the clinical characteristics and outcomes of 95 patients with ocular adnexal lymphoma (OAL) or uveal lymphoma treated or diagnosed at our institution. All patients identified were included in the risk factor analysis for progression-free survival (PFS). The initial treatment-related outcomes were assessed for ENMZ OAL only (n = 62).

Results: With a median follow-up of 32 months, significant risk factors for PFS after initial treatment were age (hazard ratio, 1.33; 95% confidence interval, 1.02-1.74), female gender (hazard ratio, 2.04; 95% confidence interval, 1.04-4.00), and a history of lymphoma (hazard ratio, 2.31; 95% confidence interval, 1.12-4.78). In ENMZ, IFRT was associated with improved PFS (median, 5.4 years; P < .001). Progression occurred in 7 of 39 (23%), with 6 of the 7 (86%) at systemic sites. Single-agent rituximab was typically used for bilateral ocular or systemic presentations of ENMZ OAL. Progression occurred in 7 of 11 (64%), with no progression at systemic sites. All progression events in those initially treated with rituximab occurred in the ocular adnexa.

Conclusion: The results of the present study have confirmed IFRT as the standard for unilateral ENMZ OAL. Single-agent rituximab was an effective agent for bilateral ocular or systemic ENMZ OAL, particularly for systemic control, but ocular progression should be closely monitored. Combined modality therapy should be studied further in bilateral and systemic ENMZ OAL.
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http://dx.doi.org/10.1016/j.clml.2013.10.011DOI Listing
June 2014

Uveal lymphoma: clinical features, diagnostic studies, treatment selection, and outcomes.

Ophthalmology 2014 Jan 18;121(1):334-341. Epub 2013 Oct 18.

Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Objective: To describe the clinical features, ancillary diagnostic studies, and treatment selection in a cohort of patients with uveal lymphoma.

Design: Retrospective clinical review.

Participants: A total of 22 patients (34 affected eyes) diagnosed with uveal lymphoma between 1997 and 2013.

Methods: Data were collected regarding patient characteristics, clinical features on ophthalmic examination, ancillary imaging studies, and primary treatment selection.

Main Outcome Measures: Relapse defined as lymphoma recurrence in the initial site of presentation, the contralateral eye, or other systemic site and overall survival.

Results: Fifteen patients were male (68.2%). Median age at diagnosis was 68.0 years. The choroid was involved in 21 cases (95.5%), and 1 case (4.5%) was ciliochoroidal. Other ocular adnexal structures were affected in 13 patients (59.1%), including the conjunctiva in 4 (18.2%), the orbit in 7 (31.8%), and both the conjunctiva and orbit in 2 (9.1%). Bilateral disease was present in 12 patients (54.5%). The most common presenting symptom was decreased vision in 15 patients (68.2%). The median delay in diagnosis was 4.0 months. Yellow-white choroidal infiltrates were observed on fundus examination in 34 eyes (100.0%) with corresponding hypofluorescence in 100% of cases when indocyanine green angiography was performed. Infiltrates were located anterior to the arcades (67.6%), most commonly in a diffuse (32.4%) or superotemporal (32.4%) distribution. B-scan ultrasonography detected extrascleral extension in 22 patients (75.9%) with a pattern of crescentic thickening in 19 (86.4%). Extranodal marginal zone lymphoma was the predominant (76.2%) histologic subtype. External beam radiotherapy (72.7%) was most commonly chosen for primary treatment. Systemic imaging at the time of diagnosis revealed that the majority of cases (77.3%) were localized to the eye; none of the patients developed new systemic disease (median follow-up, 30.3 months).

Conclusions: Uveal lymphoma has distinctive clinical features. Overlap with ocular adnexal structures is common, and ancillary imaging is essential for evaluating the full extent of ocular disease and presence of systemic involvement.
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http://dx.doi.org/10.1016/j.ophtha.2013.09.004DOI Listing
January 2014

The phosphatidylinositol 3-kinases (PI3K) inhibitor GS-1101 synergistically potentiates histone deacetylase inhibitor-induced proliferation inhibition and apoptosis through the inactivation of PI3K and extracellular signal-regulated kinase pathways.

Br J Haematol 2013 Oct 25;163(1):72-80. Epub 2013 Jul 25.

Clinical Pathology, Institute of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA.

Previously, we showed that inhibition of the protein kinase C β (PKCβ)/AKT pathway augments engagement of the histone deacetylase inhibitor (HDI)-induced apoptosis in lymphoma cells. In the present study, we investigated the cytotoxicity and mechanisms of cell death induced by the delta isoform-specific phosphatidylinositide 3-kinase (PI3K) inhibitor, GS-1101, in combination with the HDI, panobinostat (LBH589) and suberoylanilide hydroxamic acid (SAHA). Lymphoma cell lines, primary non-Hodgkin Lymphoma (NHL) and chronic lymphocytic leukaemia (CLL) cells were simultaneously treated with the HDI, LBH589 and GS-1101. An interaction of the LBH589/GS-1101 combination was formally examined by using various concentrations of LBH589 and GS-1101. Combined treatment resulted in a synergistic inhibition of proliferation and showed synergistic effect on apoptotic induction in all tested cell lines and primary NHL and CLL cells. This study indicates that interference with PI3K signalling dramatically increases HDI-mediated apoptosis in malignant haematopoietic cells, possibly through both AKT-dependent or AKT- independent mechanisms. Moreover, the increase in HDI-related apoptosis observed in PI3K inhibitor-treated cells appears to be related to the disruption of the extracellular signal-regulated kinase (ERK) signalling pathway. This study provides a strong rational for testing the combination of PI3K inhibitors and HDI in the clinic.
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http://dx.doi.org/10.1111/bjh.12498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784300PMC
October 2013

Novel targeted therapies in acute lymphoblastic leukemia.

Leuk Lymphoma 2014 Apr 28;55(4):737-48. Epub 2013 Aug 28.

Division of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic , Cleveland, OH , USA.

Chemotherapy alone cures only 25-45% of adult patients with acute lymphoblastic leukemia (ALL), making novel treatment agents and strategies desperately needed. The addition of monoclonal antibodies (rituximab, alemtuzumab, epratzumab) to chemotherapy has demonstrated encouraging results in patients with newly diagnosed and relapsed ALL. The anti-CD22 immunoconjugate, inotuzumab ozogamicin, and the anti-CD19 BiTE(®) antibody, blinatumomab, have demonstrated impressive single agent activity in patients with relapsed or refractory B-ALL. Early reports of chimeric antigen receptor therapies have been promising in patients with relapsed ALL. Other agents targeting NOTCH1, FLT3, the proteasome and DNA methylation are early in development. These new agents hope to improve the outcome of ALL therapy with less toxicity. The challenge going forward will be to find safe and effective combinations and determine where in the treatment schema these agents will be most effective in ALL therapy.
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http://dx.doi.org/10.3109/10428194.2013.823493DOI Listing
April 2014

Clinical and pharmacologic aspects of blinatumomab in the treatment of B-cell acute lymphoblastic leukemia.

Clin Pharmacol 2013 12;5(Suppl 1):5-11. Epub 2013 Apr 12.

Leukemia Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.

Acute lymphoblastic leukemia (ALL) in adults remains a challenging disease to treat, and novel therapies are needed. Precursor-B ALL comprises 80% of cases, and the CD19 antigen is expressed in nearly all precursor-B ALL patients. Bispecific T-cell-engaging antibodies are novel bioengineered proteins. The bispecific T-cell-engaging antibody blinatumomab engages polyclonal T cells to CD19-expressing B cells. By binding to both CD3 and CD19, blinatumomab physically brings these T cells in close proximity to malignant B cells and potentiates T-cell-induced cytotoxic cell kill. Blinatumomab requires continuous intravenous infusion due to its short half-life, the need for continuous exposure for the drug to exert sufficient efficacy, and lessened toxicity. A phase II trial of B-cell ALL patients with persistent or relapsed minimal residual disease demonstrated an 80% rate of complete molecular remission. Cytokine-release syndrome and central nervous system events, such as seizures and encephalopathy, are reversible toxicities. Promising results in B-cell ALL with minimal residual disease have led to further evaluation of this drug in newly diagnosed and relapsed B-cell ALL.
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http://dx.doi.org/10.2147/CPAA.S42689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3650887PMC
May 2013

Ocular adnexal lymphoma: assessment of a tumor-node-metastasis staging system.

Ophthalmology 2013 Sep 9;120(9):1915-9. Epub 2013 May 9.

Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.

Purpose: To assess distribution, correlations, and prognostic effect of tumor (T), node (N), and metastasis (M) staging on relapse and survival.

Design: Retrospective clinical review.

Participants: Sixty-three patients diagnosed with primary ocular adnexal lymphoma (OAL) between January 1986 and November 2011.

Methods: Complete ocular examination and systemic evaluation were performed. Patients were staged according to the American Joint Committee on Cancer (AJCC) seventh edition tumor-node-metastasis (TNM) clinical staging system for OAL and followed every 6 to 12 months (median follow-up, 27.9 months).

Main Outcome Measures: Relapse defined as lymphoma recurrence in the initial site of presentation, the contralateral ocular adnexal structures, or other systemic site and overall survival.

Results: There were 40 men (63.5%). The median age was 65 years (range, 24-85 years). The affected site was the conjunctiva in 27 patients (42.9%), orbit in 38 patients (60.3%), and eyelid in 3 patients (4.8%). The histologic subtype was extranodal marginal zone lymphoma (EMZL) in 51 patients (81.0%). A total of 14 patients (23.3%) had T1, 42 patients (70.0%) had T2, 1 patient (1.7%) had T3, and 3 patients (5.0%) had T4 disease. A total of 48 patients (82.8%) had N0 disease, and 10 patients (17.2%) had N1-4 disease. M stage was M0 in 47 patients (81.0%) and M1 in 11 patients (19.0%). With advanced T stage, there was an increase in both N1-4 (P = 0.045) and M1 disease (P = 0.041). M1 disease was greater among patients with N1-4 disease compared with N0 stage (50.0% vs. 12.5%, P = 0.003). Overall, 18 patients (28.6%) relapsed and 6 patients (9.5%) died. In Cox analysis, relapse was not associated with T stage (hazard ratio [HR], 1.14 per 1 level increase, P = 0.71), N stage (HR, 1.47; P = 0.51 N1-4 vs. N0), or M stage (HR, 1.22; P = 0.76 M1 vs. M0). T stage was not associated with survival (HR, 0.86; P = 0.81), whereas N1-4 had marginally worse survival than N0 (HR, 5.35; P = 0.07), and M1 had worse survival than M0 (HR, 9.27; P = 0.008).

Conclusions: The TNM staging system for primary OAL is useful for precise characterization of extent of local disease. Although T stage does not predict relapse or survival, N1-4 and M1 stages indicated less favorable survival.

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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http://dx.doi.org/10.1016/j.ophtha.2013.02.003DOI Listing
September 2013

Adult lymphoblastic lymphoma.

Cancer J 2012 Sep-Oct;18(5):432-8

Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH 44195, USA.

Adult lymphoblastic lymphoma (LBL) is an aggressive form of non-Hodgkin lymphoma occurring in predominantly adolescent and young adult men. Lymphoblastic lymphoma is rare, accounting for 1% to 2% of all non-Hodgkin lymphomas and is of T-cell phenotype in 90% of cases. Lymphoblastic lymphoma is morphologically indistinct from acute lymphoblastic leukemia (ALL). Both express their lineage-specific markers as well as terminal deoxynucleotidyl transferase. The differences are often made on clinical grounds. Lymphoblastic lymphoma is characterized by a predominantly nodal distribution of disease, often with a large mediastinal mass. Patients with less than 25% bone marrow involvement have typically been categorized as LBL rather than ALL, although this has not been applied consistently in the literature. Gene expression studies have identified differences in gene expression, with LBL expressing higher levels of genes associated with cytoskeleton, adhesion, angiogenesis, and chemotaxis than ALL. Although LBL and ALL can be distinct clinically, chemotherapy strategies are often very similar. Acute lymphoblastic leukemia regimens, which incorporate intensive multidrug induction, consolidation, delayed intensification, and maintenance, have been shown to be superior to standard lymphoma regimens. As central nervous system (CNS) relapse is common, CNS prophylaxis with high-dose chemotherapy and intrathecal therapy is also standard. The prophylactic use of CNS irradiation has declined with the introduction of chemotherapy regimens incorporating high doses of CNS-penetrating drugs such as cytarabine and methotrexate. The use of consolidative radiation to the mediastinum remains uncertain. High-dose chemotherapy followed by autologous or allogeneic transplantation as consolidation for patients in CR1 is controversial with modern intensive chemotherapy regimens, although transplantation has a proven role in the relapse setting.
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http://dx.doi.org/10.1097/PPO.0b013e31826b1232DOI Listing
April 2013

Antibody therapy for acute lymphoblastic leukemia.

Curr Hematol Malig Rep 2012 Jun;7(2):153-9

Division of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Advances in chemotherapy administration have made acute lymphoblastic leukemia (ALL) a curable disease; however, most patients will relapse, despite readily attaining a complete remission. Treatment of relapse has shown dismal results with little advances made in the recent decades. Antigenic-directed therapy of ALL can complement cytotoxic chemotherapy and has shown encouraging results. This review will evaluate four antigens in ALL (CD20, CD22, CD52, and CD19) and therapeutic strategies to target them. We will review the clinical and preclinical data surrounding rituximab, epratuzumab, inotuzumab ozogamicin, alemtuzumab, blinatumomab, and chimeric antigen receptor-modified T-cell therapy.
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http://dx.doi.org/10.1007/s11899-012-0120-7DOI Listing
June 2012