Publications by authors named "John P Leonard"

242 Publications

Racial disparities in diabetes care among incident breast, prostate, and colorectal cancer survivors: a SEER Medicare study.

J Cancer Surviv 2021 Mar 4. Epub 2021 Mar 4.

Weill Cornell Medicine, New York, NY, USA.

Background: Many cancer survivors with co-morbid diabetes receive less diabetes management than their non-cancer counterparts. We sought to determine if racial/ethnic disparities exist in recommended diabetes care within 12 months of an incident breast, prostate, or colorectal cancer diagnosis. Because co-morbid diabetes decreases long-term survival, identifying predictors of guideline-concordant diabetes care is important.

Methods: Using the Surveillance, Epidemiology, and End Results cancer registry linked to Medicare claims, we included beneficiaries aged 67+ years with diabetes and incident, non-metastatic breast, prostate, or colorectal cancer between 2008 and 2013. Primary outcomes were diabetes care services 12 months after diagnosis: (1) HbA1c test, (2) eye exam, and (3) low-density lipoprotein (LDL) test. Using modified Poisson models with robust standard errors, we examined each outcome separately.

Results: We included 34,643 Medicare beneficiaries with both diabetes and cancer. Mean age at diagnosis was 76.1 (SD 6.2), 47.2% were women; 35% had breast, 24% colorectal, and 41% prostate cancer. In the 12 months after incident cancer diagnosis, 82.4% received an HbA1c test, 55.3% received an eye exam, 77.8% had an LDL test, and 42.0% received all three tests. Compared to non-Hispanic Whites, Blacks were 3% (95% CI 0.95-0.98) less likely to receive a HbA1c test, 10% (95% CI 0.89-0.92) less likely to receive a LDL test, and 8% (95% 0.89-0.95) less likely to receive an exam eye. Blacks and Hispanics were 16% (95% CI 0.81-0.88) and 7% (0.88-0.98) less likely to receive all three tests, after accounting for confounders. Racial/ethnic differences persisted across cancer types.

Conclusion: Blacks and Hispanics with breast, prostate, and colorectal cancer and diabetes received less diabetes care after cancer diagnosis compared to non-Hispanic Whites. Differences were not explained by socio-economic factors or clinical need.

Implications For Cancer Survivors: Our findings are concerning given the high prevalence of diabetes and poor cancer outcomes among racial/ethnic minorities. The next step in this line of inquiry is to determine why minorities are less likely to receive comprehensive diabetes care in order to develop targeted strategies to increase receipt of appropriate diabetes management for these vulnerable populations.
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http://dx.doi.org/10.1007/s11764-021-01003-zDOI Listing
March 2021

Evaluation of the prognostic utility of bone marrow biopsy in diffuse large B-Cell lymphoma in the SEER-Medicare dataset.

Leuk Lymphoma 2021 Feb 25:1-14. Epub 2021 Feb 25.

Department of Hematology and Oncology, NewYork-Presbyterian Hospital/Weill Cornell Medical College, New York, NY, USA.

Positron emission tomography-computed tomography (PET-CT) has become the primary modality for staging in diffuse large B-cell lymphoma (DLBCL), whereas the role of staging bone marrow biopsy (BMB) has become less clear. In this analysis, we included 7,005 DLBCL patients in SEER-Medicare who received either PET-CT without BMB (PET-CT w/o BMB), CT with BMB (CT w/ BMB), or both PET-CT and BMB (PET-CT w/ BMB). The proportion of patients undergoing PET-CT increased across years of diagnosis, while the proportion undergoing CT or BMB decreased. In a fully adjusted Cox proportional hazards model, PET-CT w/ BMB was associated with a marginally superior OS compared to PET-CT w/o BMB. Notably, the association between PET-CT w/ BMB and OS was strongest in patients ≤70 years, but was not present when looking at individual stage of diagnosis. Overall, these data do not provide sufficient support to eliminate staging BMB in patients who undergo PET-CT.
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http://dx.doi.org/10.1080/10428194.2021.1889540DOI Listing
February 2021

Sequential intensive chemotherapy followed by autologous or allogeneic transplantation for refractory lymphoma.

Leuk Lymphoma 2021 Feb 13:1-15. Epub 2021 Feb 13.

Weill Cornell Medicine/New York-Presbyterian Hospital, New York, NY, USA.

We evaluate the safety of bendamustine as a bridge to stem cell transplantation (SCT) in patients with relapsed/refractory lymphoma and residual disease after salvage therapy. Thirty-four subjects without complete responses (CR) received bendamustine 200 mg/m/day for 2 days followed 14 days later by SCT. Sixteen subjects in partial remission (PR) with maximal FDG-PET SUVs ≤8 prior to bendamustine received autologous SCT, while 13 with suboptimal responses were allografted. Five subjects did not proceed to transplant. No bendamustine toxicities precluded transplantation and no detrimental effect on engraftment or early treatment-related mortality (TRM) was attributable to bendamustine. At 1 year, 75% of auto-recipients and 31% of allo-recipients were alive with CR. Two subjects in the autologous arm developed therapy-related myeloid neoplasia (t-MN). In conclusion, a bendamustine bridge to SCT can be administered without early toxicity to patients with suboptimal responses to salvage chemotherapy. However this approach may increase the risk of t-MN. (NCT02059239). Supplemental data for this article is available online at here.
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http://dx.doi.org/10.1080/10428194.2021.1881516DOI Listing
February 2021

Addition of Lenalidomide to R-CHOP Improves Outcomes in Newly Diagnosed Diffuse Large B-Cell Lymphoma in a Randomized Phase II US Intergroup Study ECOG-ACRIN E1412.

J Clin Oncol 2021 Feb 8:JCO2001375. Epub 2021 Feb 8.

Division of Hematology, Mayo Clinic, Rochester, MN.

Purpose: Lenalidomide combined with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (R2CHOP) in untreated diffuse large B-cell lymphoma (DLBCL) has shown promising activity, particularly in the activated B-cell-like (ABC) subtype. Eastern Cooperative Oncology Group (ECOG)-ACRIN trial E1412 was a randomized phase II study comparing R2CHOP versus R-CHOP in untreated DLBCL.

Patients And Methods: Patients with newly diagnosed DLBCL, stage II bulky-IV disease, International Prognostic Index (IPI) ≥ 2, and ECOG performance status ≤ 2 were eligible and randomly assigned 1:1 to R2CHOP versus R-CHOP for six cycles. Tumors were analyzed using the NanoString Lymph2Cx for cell of origin. The primary end point was progression-free survival (PFS) in all patients with the co-primary end point of PFS in ABC-DLBCL. Secondary end points included overall response rate (ORR), complete response (CR) rate, and overall survival (OS).

Results: Three hundred forty-nine patients were enrolled; 280 patients (145 R2CHOP and 135 R-CHOP) were evaluable: 94 were ABC-DLBCL, 122 germinal center B-cell-like-DLBCL, 18 unclassifiable, and 46 unknowns. Baseline characteristics were well-balanced between arms, and the median age was 66 (range, 24-92); 70% of patients had stage IV disease; 34%, 43%, and 24% had IPI 2, 3, and 4 or 5, respectively. Myelosuppression was more common in the R2CHOP arm. The ORR and CR rate were 92% and 68% in R-CHOP and 97% ( = .06) and 73% ( = .43) in the R2-CHOP arm, respectively. The median follow-up was 3.0 years; R2CHOP was associated with a 34% reduction in risk of progression or death versus R-CHOP (hazard ratio [HR], 0.66 95% CI, 0.43 to 1.01) and 3-year PFS of 73% versus 61%, one-sided = .03, and an improvement in OS (83% and 75% at 3 years; HR, 0.67; one-sided = .05). The PFS HR for R2CHOP was 0.67 for ABC-DLBCL, one-sided = .1.

Conclusion: In this signal-seeking study, the addition of lenalidomide to R-CHOP (R2CHOP) improved outcomes in newly diagnosed DLBCL including patients with ABC-DLBCL.
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http://dx.doi.org/10.1200/JCO.20.01375DOI Listing
February 2021

Clinical and biological subtypes of B-cell lymphoma revealed by microenvironmental signatures.

Cancer Discov 2021 Feb 4. Epub 2021 Feb 4.

Division of Hematology and Medical Oncology, Weill Cornell Medical College and New York Presbyterian Hospital

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogenous disease. Transcriptomic and genetic characterization of DLBCL have increased the understanding of its intrinsic pathogenesis and provided potential therapeutic targets. However, the role of the microenvironment in DLBCL biology remains less understood. Here, we performed a transcriptomic analysis of the microenvironment of 4,655 DLBCLs from multiple independent cohorts and described four major lymphoma microenvironment categories that associate with distinct biological aberrations and clinical behavior. We also found evidence of genetic and epigenetic mechanisms deployed by cancer cells to evade microenvironmental constrains of lymphoma growth; supporting the rationale for implementing DNA hypomethylating agents in selected DLBCL patients. In addition, our work uncovered new therapeutic vulnerabilities in the biochemical composition of the extracellular matrix that were exploited to decrease DLBCL proliferation in pre-clinical models. This novel classification provides a roadmap for the biological characterization and therapeutic exploitation of the DLBCL microenvironment.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0839DOI Listing
February 2021

Safety and efficacy of navitoclax, a BCL-2 and BCL-X inhibitor, in patients with relapsed or refractory lymphoid malignancies: results from a phase 2a study.

Leuk Lymphoma 2020 Nov 25:1-9. Epub 2020 Nov 25.

George Washington University, Washington, DC, USA.

Navitoclax, a novel BCL-2 and BCL-X inhibitor, demonstrated promising antitumor activity in the dose-escalation part of a phase 1/2a study (NCT00406809) in lymphoid tumors. Herein, we report the continued safety and efficacy results of the phase 2a portion. Twenty-six adult patients with relapsed/refractory follicular lymphoma ( = 11, Arm A) and other relapsed/refractory lymphoid malignancies ( = 15, Arm B) were enrolled. Navitoclax administration schedule consisted of a 150-mg 7-day lead-in dose followed by 250-mg daily dosing with the option to further increase to 325 mg after 14 days if the 250-mg dose was tolerated. All patients experienced at least 1 treatment-related adverse event (TRAE). Seventeen (65.4%) patients reported grade 3/4 TRAEs; thrombocytopenia (38.5%) and neutropenia (30.8%) were the most common. Two patients reported serious AEs; none were fatal (no deaths occurred within 30 days of last dose of study drug). The objective response rate (complete and partial) was 23.1% (6/26; Arm A: 9.1%, Arm B: 33.3%). Median progression-free survival and time to progression were identical: 4.9 months (95% CI: 3.0, 8.2); median overall survival: 24.8 months (95% CI could not be computed). Navitoclax monotherapy has an acceptable safety profile and meaningful clinical activity in a minority of patients with relapsed/refractory lymphoid malignancies.
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http://dx.doi.org/10.1080/10428194.2020.1845332DOI Listing
November 2020

Laboratory Workup of Lymphoma in Adults.

Am J Clin Pathol 2021 01;155(1):12-37

Department of Medicine, Odette Cancer Centre/Sunnybrook Health Sciences Centre, Toronto, Canada.

Objectives: The diagnostic workup of lymphoma continues to evolve rapidly as experience and discovery lead to the addition of new clinicopathologic entities and techniques to differentiate them. The optimal clinically effective, efficient, and cost-effective approach to diagnosis that is safe for patients can be elusive, in both community-based and academic practice. Studies suggest that there is variation in practice in both settings.

The Aim Of This Review Is To: develop an evidence-based guideline for the preanalytic phase of testing, focusing on specimen requirements for the diagnostic evaluation of lymphoma.

Methods: The American Society for Clinical Pathology, the College of American Pathologists, and the American Society of Hematology convened a panel of experts in the laboratory workup of lymphoma to develop evidence-based recommendations. The panel conducted a systematic review of the literature to address key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, recommendations were derived based on the available evidence, the strength of that evidence, and key judgments as defined in the GRADE Evidence to Decision framework.

Results: Thirteen guideline statements were established to optimize specimen selection, ancillary diagnostic testing, and appropriate follow-up for safe and accurate diagnosis of indolent and aggressive lymphoma.

Conclusions: Primary diagnosis and classification of lymphoma can be achieved with a variety of specimens. Application of the recommendations can guide decisions about specimen suitability, diagnostic capabilities, and correct utilization of ancillary testing. Disease prevalence in patient populations, availability of ancillary testing, and diagnostic goals should be incorporated into algorithms tailored to each practice environment.
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http://dx.doi.org/10.1093/ajcp/aqaa191DOI Listing
January 2021

Laboratory Workup of Lymphoma in Adults: Guideline From the American Society for Clinical Pathology and the College of American Pathologists.

Arch Pathol Lab Med 2021 Mar;145(3):269-290

The Department of Medicine, Odette Cancer Centre/Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (Cheung).

Context.—: The diagnostic workup of lymphoma continues to evolve rapidly as experience and discovery led to the addition of new clinicopathologic entities and techniques to differentiate them. The optimal clinically effective, efficient, and cost-effective approach to diagnosis that is safe for patients can be elusive, in both community-based and academic practice. Studies suggest that there is variation in practice in both settings.

Objective.—: To develop an evidence-based guideline for the preanalytic phase of testing, focusing on specimen requirements for the diagnostic evaluation of lymphoma.

Design.—: The American Society for Clinical Pathology, the College of American Pathologists, and the American Society of Hematology convened a panel of experts in the laboratory workup of lymphoma to develop evidence-based recommendations. The panel conducted a systematic review of literature to address key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation approach, recommendations were derived based on the available evidence, strength of that evidence, and key judgements as defined in the Grading of Recommendations Assessment, Development, and Evaluation Evidence to Decision framework.

Results.—: Thirteen guideline statements were established to optimize specimen selection, ancillary diagnostic testing, and appropriate follow-up for safe and accurate diagnosis of indolent and aggressive lymphoma.

Conclusions.—: Primary diagnosis and classification of lymphoma can be achieved with a variety of specimens. Application of the recommendations can guide decisions on specimen suitability, diagnostic capabilities, and correct use of ancillary testing. Disease prevalence in patient populations, availability of ancillary testing, and diagnostic goals should be incorporated into algorithms tailored to each practice environment.
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http://dx.doi.org/10.5858/arpa.2020-0261-SADOI Listing
March 2021

Biomarkers for Risk Stratification in Patients With Previously Untreated Follicular Lymphoma Receiving Anti-CD20-based Biological Therapy.

Am J Surg Pathol 2021 Mar;45(3):384-393

Cleveland Clinic, Cleveland, OH.

Follicular lymphoma (FL) is an indolent B-cell neoplasm of germinal center origin. Standard treatment regimens consist of anti-CD20 therapy with or without chemotherapy. While high response rates to initial therapy are common, patients ultimately relapse or have progressive disease. Clinical risk factors such as the Follicular Lymphoma International Prognostic Index (FLIPI) have been identified, but there is a need for prognostic and predictive biomarkers. We studied markers of lymphoma cells and tumor microenvironment by immunohistochemistry in tissue samples from patients enrolled in 1 of 4 phase 2 trials of anti-CD20-based biological therapy for previously untreated grades 1 to 2 or 3A FL. Results were correlated with progression-free survival (PFS) and PFS status at 24 months. The 4 trials included 238 patients (51.1% male, median age: 55 y) with stage III, IV, or bulky stage II disease. By FLIPI, 24.6% had low-risk, 56.8% had intermediate-risk, and 18.6% had high-risk disease. The outcome differed significantly for patients treated with lenalidomide and rituximab (CALGB 50803) compared with the other 3 trials (median: PFS not reached vs. 3.0 y, hazard ratio=3.47, 95% confidence interval: 2.11-5.72); therefore, data were stratified by clinical trial (CALGB 50803 vs. all others) and adjusted for FLIPI risk group. Among 154 patients with available tissue, interfollicular BCL6 positivity, interfollicular CD10 positivity, and elevated Ki67 proliferation index ≥30% within neoplastic follicles were each associated with inferior PFS and a high risk of the early event by PFS status at 24 months. We identify promising biomarkers for FL risk stratification that warrant further validation in phase 3 trials.
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http://dx.doi.org/10.1097/PAS.0000000000001609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878306PMC
March 2021

Efficacy and safety results from CheckMate 140, a phase 2 study of nivolumab for relapsed/refractory follicular lymphoma.

Blood 2021 Feb;137(5):637-645

Mayo Clinic, Rochester, MN.

Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, showed promising activity in relapsed or refractory (R/R) follicular lymphoma (FL) in a phase 1 study. We conducted a phase 2 trial to further evaluate its efficacy and safety in patients with R/R FL and to explore biomarkers of response. Patients with R/R FL and at least 2 prior lines of therapy, each containing a CD20 antibody or an alkylating agent, were treated with nivolumab 3 mg/kg every 2 weeks. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Biomarker analyses included gene expression profiling and multiplex immunofluorescence studies of pretreatment tumor samples. A total of 92 patients were treated. After a minimum follow-up of 12 months, ORR was 4% (4 of 92 patients). Median progression-free survival (PFS) was 2.2 months (95% confidence interval [CI], 1.9-3.6 months). Median duration of response was 11 months (95% CI, 8-14 months). Exploratory analyses suggested that responders had significantly higher proportion of CD3+ T cells in the tumor microenvironment than nonresponders, but no significant differences in PD-1 or programmed death-ligand 1 expression were observed. High expression of a set of tumor-associated macrophage genes was associated with reduced PFS (hazard ratio, 3.28; 95% CI, 1.76-6.11; P = .001). The safety profile was consistent with previous reports of nivolumab. In conclusion, nivolumab monotherapy was associated with very limited activity in patients with R/R FL. Better understanding of the immune biology of this disease may facilitate the development of effective checkpoint-based strategies. This trial was registered at www.clinicaltrials.gov as #NCT02038946.
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http://dx.doi.org/10.1182/blood.2019004753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869188PMC
February 2021

Mantle Cell Lymphoma: Biologic Insights to Bedside Impact.

Authors:
John P Leonard

Hematol Oncol Clin North Am 2020 Oct 30;34(5):xiii-xiv. Epub 2020 Jul 30.

Weill Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA. Electronic address:

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http://dx.doi.org/10.1016/j.hoc.2020.07.001DOI Listing
October 2020

Hematology and oncology clinical care during the coronavirus disease 2019 pandemic.

CA Cancer J Clin 2020 09 14;70(5):349-354. Epub 2020 Jul 14.

Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York.

New York City has been at the epicenter of the coronavirus disease 2019 (COVID-19) pandemic that has already infected over a million people and resulted in more than 70,000 deaths as of early May 2020 in the United States alone. This rapid and enormous influx of patients into the health care system has had profound effects on all aspects of health care, including the care of patients with cancer. In this report, the authors highlight the transformation they underwent within the Division of Hematology and Medical Oncology as they prepared for the COVID-19 crisis in New York City. Under stressful and uncertain conditions, some of the many changes they enacted within their division included developing a regular line of communication among division leaders to ensure the development and implementation of a restructuring strategy, completely reconfiguring the inpatient and outpatient units, rapidly developing the ability to perform telemedicine video visits, and creating new COVID-rule-out and COVID-positive clinics for their patients. These changes allowed them to manage the storm while minimizing the disruption of important continuity of care to their patients with cancer. The authors hope that their experiences will be helpful to other oncology practices about to experience their own individual COVID-19 crises.
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http://dx.doi.org/10.3322/caac.21627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404745PMC
September 2020

Positron Emission Tomography-Directed Therapy for Patients With Limited-Stage Diffuse Large B-Cell Lymphoma: Results of Intergroup National Clinical Trials Network Study S1001.

J Clin Oncol 2020 09 13;38(26):3003-3011. Epub 2020 Jul 13.

Division of Hematology/Oncology, Wilmot Cancer Institute, University of Rochester, Rochester, NY.

Purpose: Diffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)-directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity.

Methods: Patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received 3 cycles of standard R-CHOP therapy and underwent a centrally reviewed interim PET/computed tomography scan (iPET). Those with a negative iPET proceeded with 1 additional cycle of R-CHOP, whereas those with a positive iPET received involved field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy.

Results: Of 158 patients enrolled, 132 were eligible and 128 underwent iPET, which was positive in 14 (11%) of the patients. With a median follow-up of 4.92 years (range, 1.1-7.7 years), only 6 patients progressed and 3 died as a result of lymphoma. Eleven patients died as a result of nonlymphoma causes at a median age of 80 years. The 5-year progression-free survival estimate was 87% (95% CI, 79% to 92%) and the OS estimate was 89% (95% CI, 82% to 94%), with iPET-positive and iPET-negative patients having similar outcomes.

Conclusion: To our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best NCTN results in this disease subset. With PET-directed therapy, 89% of the patients with a negative iPET received R-CHOP × 4, and only 11% had a positive iPET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP × 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.
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http://dx.doi.org/10.1200/JCO.20.00999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479758PMC
September 2020

Longitudinal Toxicity over Time (ToxT) analysis to evaluate tolerability: a case study of lenalidomide in the CALGB 50401 (Alliance) trial.

Lancet Haematol 2020 Jun;7(6):e490-e497

Alliance Statistics and Data Center, Mayo Clinic, Scottsdale, AZ, USA.

Evaluation of tolerability is increasingly relevant for patients with haematological malignancies treated with chronically administered therapies. Adverse events from these agents might affect the ability of patients to tolerate treatment over time. Conventional toxicity tables that include the incidence of high-grade adverse events, defined by the Common Terminology Criteria for Adverse Events, do not provide information on the time profile of these adverse events or reflect the continuous, lower grade symptomatic toxicities that are particularly relevant to treatment tolerability for patients living with indolent disease. Modern approaches to the evaluation and reporting of toxicity that capture the tolerability of treatment to the patient are imperative. In this Viewpoint, we present a focused, pilot, and longitudinal Toxicity over Time analysis of adverse events from lenalidomide and lenalidomide with rituximab in patients with follicular lymphoma treated in the CALGB 50401 (Alliance; NCT00238238) trial to define the trajectory of adverse events and quantify the burden of continuous, low-grade events. Toxicity over Time analyses provided clinically relevant descriptions of neutropenia and fatigue trajectories caused by lenalidomide that were not identified by standard analysis of the maximum grade events defined by the Common Terminology Criteria for Adverse Events. Systematic, rigorous incorporation of patient-reported outcomes in clinical trials will be crucial to our understanding of the tolerability of chronically administered therapies in patients with haematological malignancies.
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http://dx.doi.org/10.1016/S2352-3026(20)30067-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457391PMC
June 2020

Potential impact of consolidation radiation therapy for advanced Hodgkin lymphoma: a secondary analysis of SWOG S0816.

Leuk Lymphoma 2020 10 26;61(10):2442-2447. Epub 2020 May 26.

Department of Medicine, Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA.

The role of radiotherapy (RT) in the management of advanced Hodgkin Lymphoma (HL) is inadequately defined in this era of functional imaging with PET scan. SWOG-S0816 treated advanced stage Hodgkin lymphoma patients with ABVD+/- escBEACOPP and no RT. We queried whether RT might have benefited patients in S0816 who would have met the GHSG-HD15 criteria for RT by simulating RT use as per HD15 criteria of PET + residual disease ≥2.5 cm. Receiver-operating-characteristics analyses were performed by varying disease-control rates within radiation fields and size cutoffs for residual disease. Among the 49 PET3+ S0816 patients, RT would have raised the 2-year PFS from 30.6% to 50.2-58.1% using three residual disease cutoffs (1.5, 2.0 and 2.5 cm) and assuming 80 and 90% in-field control rates . Although there may be improvement in PFS as size cutoff point is lowered, consequential toxicities from RT require further definition to assess relative benefits.
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http://dx.doi.org/10.1080/10428194.2020.1768388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704391PMC
October 2020

Effects of sun angle, lunar illumination, and diurnal temperature on temporal movement rates of sympatric ocelots and bobcats in South Texas.

PLoS One 2020 23;15(4):e0231732. Epub 2020 Apr 23.

East Foundation, San Antonio, Texas, United States of America.

Sympatric ocelots (Leopardus pardalis) and bobcats (Lynx rufus) in South Texas show substantial overlap in body size, food habits, and habitat use. Consequently, we explore whether temporal niche partitioning may explain ocelot and bobcat coexistence. We investigated the influence of sun angle, lunar illumination, and maximum diurnal temperature on temporal movement rates of sympatric ocelots (n = 8) and bobcats (n = 6) using a combination of high-frequency GPS locations and bi-axial accelerometer data. We demonstrated that accelerometer data could be used to predict movement rates, providing a nearly continuous measure of animal activity and supplementing GPS locations. Ocelots showed a strong nocturnal activity pattern with the highest movement rates at night whereas bobcats showed a crepuscular activity pattern with the highest movement rates occurring around sunrise and sunset. Although bobcat activity levels were lower during the day, bobcat diurnal activity was higher than ocelot diurnal activity. During warmer months, bobcats were more active on nights with high levels of lunar illumination. In contrast, ocelots showed the highest nocturnal activity levels during periods of low lunar illumination. Ocelots showed reduced diurnal activity on hotter days. Our results indicate that ocelot and bobcat coexistence in South Texas can be partially explained by temporal niche partitioning, although both felids showed periods of overlapping activity during nocturnal and crepuscular periods.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231732PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179910PMC
July 2020

Lenalidomide in follicular lymphoma.

Blood 2020 06;135(24):2133-2136

Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX.

Lenalidomide is an immunomodulatory drug approved in the United States for use with rituximab in patients with relapsed/refractory follicular lymphoma. We reviewed data from trials addressing the safety and efficacy of lenalidomide alone and in combination with rituximab as a first-line therapy and as a treatment of patients with relapsed/refractory follicular lymphoma. Lenalidomide-rituximab has been demonstrated to be an effective chemotherapy-free therapy that improves upon single-agent rituximab and may become an alternative to chemoimmunotherapy.
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http://dx.doi.org/10.1182/blood.2019001751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290094PMC
June 2020

Prognostic value of interim FDG-PET in diffuse large cell lymphoma: results from the CALGB 50303 Clinical Trial.

Blood 2020 06;135(25):2224-2234

Department Medicine, Washington University School of Medicine, St. Louis, MO.

As part of a randomized, prospective clinical trial in large cell lymphoma, we conducted serial fluorodeoxyglucose positron emission tomography (FDG-PET) at baseline, after 2 cycles of chemotherapy (interim PET [i-PET]), and at end of treatment (EoT) to identify biomarkers of response that are predictive of remission and survival. Scans were interpreted in a core laboratory by 2 imaging experts, using the visual Deauville 5-point scale (5-PS), and by calculating percent change in FDG uptake (change in standardized uptake value [ΔSUV]). Visual scores of 1 through 3 and ΔSUV ≥66% were prospectively defined as negative. Of 524 patients enrolled in the parent trial, 169 agreed to enroll in the PET substudy and 158 were eligible for final analysis. In this selected population, all had FDG-avid disease at baseline; by 5-PS, 55 (35%) remained positive on i-PET and 28 (18%) on EoT PET. Median ΔSUV on i-PET was 86.2%. With a median follow-up of 5 years, ΔSUV, as continuous variable, was associated with progression-free survival (PFS) (hazard ratio [HR] = 0.99; 95% confidence interval [CI], 0.97-1.00; P = .02) and overall survival (OS) (HR, 0.98; 95% CI, 0.97-0.99; P = .03). ΔSUV ≥66% was predictive of OS (HR, 0.31; 95% CI, 0.11-0.85; P = .02) but not PFS (HR, 0.47; 95% CI, 0.19-1.13; P = .09). Visual 5-PS on i-PET did not predict outcome. ΔSUV, but not visual analysis, on i-PET predicted OS in DLBCL, although the low number of events limited the statistical analysis. These data may help guide future clinical trials using PET response-adapted therapy. This trial was registered at www.clinicaltrials.gov as #NCT00118209.
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http://dx.doi.org/10.1182/blood.2019003277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316220PMC
June 2020

Bortezomib consolidation or maintenance following immunochemotherapy and autologous stem cell transplantation for mantle cell lymphoma: CALGB/Alliance 50403.

Am J Hematol 2020 06 6;95(6):583-593. Epub 2020 Apr 6.

Hematology-Oncology, MedStar Georgetown University Hospital, Washington, District of Columbia, USA.

Immunochemotherapy followed by autologous transplant (ASCT) in CALGB/Alliance 59909 achieved a median progression-free survival (PFS) in mantle cell lymphoma (MCL) of 5 years, but late recurrences occurred. We evaluated tolerability and efficacy of adding post-transplant bortezomib consolidation (BC) or maintenance (BM) to this regimen in CALGB/Alliance 50403, a randomized phase II trial. Following augmented-dose R-CHOP/ methotrexate, high-dose cytarabine-based stem cell mobilization, cyclophosphamide/carmustine/etoposide (CBV) autotransplant, and rituximab, patients were randomized to BC (1.3 mg/m IV days 1, 4, 8, 11 of a 3-week cycle for four cycles) or BM (1.6 mg/m IV once weekly × 4 every 8 weeks for 18 months) beginning day 90. The primary endpoint was PFS, measured from randomization for each arm. Proliferation signature, Ki67, and postinduction minimal residual disease (MRD) in bone marrow were assessed. Of 151 patients enrolled; 118 (80%) underwent ASCT, and 102 (68%) were randomized. Both arms met the primary endpoint, with median PFS significantly greater than 4 years (P < .001). The 8-year PFS estimates in the BC and BM arms were 54.1% (95% CI 40.9%-71.5%) and 64.4% (95% 51.8%-79.0%), respectively. Progression-free survival was significantly longer for transplanted patients on 50403 compared with those on 59909. Both the PFS and OS were significantly better for those who were MRD-negative post-induction. The high risk proliferation signature was associated with adverse outcome. Both BM and BC were efficacious and tolerable, although toxicity was significant. The comparison between studies 50403 and 59909 with long-term follow up suggests a PFS benefit from the addition of BC or BM post- transplant.
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http://dx.doi.org/10.1002/ajh.25783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486983PMC
June 2020

Diabetes care management patterns before and after a cancer diagnosis: A SEER-Medicare matched cohort study.

Cancer 2020 04 30;126(8):1727-1735. Epub 2020 Jan 30.

Division of General Internal Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York.

Background: Diabetes places patients with cancer at an increased risk of infections, hospitalizations, and mortality. The objective of the current study was to characterize diabetes care management patterns among patients with cancer in the year before and, separately, after cancer diagnosis. The authors hypothesized that diabetes care declines after a diagnosis of cancer.

Methods: The Surveillance, Epidemiology, and End Results (SEER) cancer registry linked to Medicare claims data was used. The authors included diabetic beneficiaries aged ≥65 years who were diagnosed with incident, nonmetastatic breast, prostate, or colorectal cancer between 2008 and 2013. Controls were diabetic Medicare beneficiaries in SEER regions who did not have cancer. Cases were matched to controls based on age, sex, Charlson Comorbidity Index, and diabetes severity. Primary outcomes were diabetes care received over 12 months: 1) hemoglobin A1c testing; 2) eye examination; and 3) low-density lipoprotein testing. Using a difference-in-difference (DID) approach, the authors examined use differences 12 months before to after diagnosis for patients with cancer and controls. To avoid capturing testing related to diagnosis and not diabetes management, the authors implemented a 90-day washout period (45 days before and/or after diagnosis).

Results: A total of 32,728 diabetic patients with cancer and 32,728 matched noncancer controls were included. After diagnosis, patients with cancer were found to have modest, but significantly lower, rates of diabetes care use compared with controls. Patients with cancer had greater declines in hemoglobin A1c testing (DID, 2.4%; 95% CI, 1.7%-3.0%), low-density lipoprotein testing (DID, 4.3%; 95% CI, 3.6%-5.0%), and receipt of all diabetes indicators (DID, 2.7%; 95% CI, 1.8%-3.5%) 12 months before to after diagnosis.

Conclusions: Compared with controls, less diabetes care use was observed among patients with cancer in the year after diagnosis. Understanding and addressing the reasons for this may improve outcomes in this population.
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http://dx.doi.org/10.1002/cncr.32728DOI Listing
April 2020

Lymphoma Study Titles on ClinicalTrials.gov Lack Details Necessary for Study Identification.

Clin Lymphoma Myeloma Leuk 2020 02 21;20(2):e82-e86. Epub 2019 Nov 21.

Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY. Electronic address:

Background: ClinicalTrials.gov is used by clinicians and patients to identify clinical trials. We assessed the ease with which users could identify relevant trials related to lymphoma using the short and official titles. We hypothesized that lymphoma titles frequently lack important information.

Materials And Methods: We performed 2 searches on ClinicalTrials.gov. The first search was performed before June 2017, when ClinicalTrials.gov underwent updates to improve usability. The second was performed after 2017. We assessed whether the short and official titles of each trial provided information on the study phase, eligible disease status, lymphoma histologic subtype, study intervention, primary objective, and the presence of randomization and placebo control.

Results: Of the pre-overhaul lymphoma trials, the official versus short titles included information regarding study intervention (99% vs. 96%), study phase (82% vs. 14%), lymphoma histologic subtype (78% vs. 72%), disease status (46% vs. 35%), randomization (13% vs. 2%), presence of placebo (6% vs. 2%), and primary objective (38% vs. 26%). Of the post-overhaul trials, the official versus short titles included information regarding study intervention (97% vs. 96%), lymphoma histologic subtype (83% vs. 78%), study phase (78% vs. 8%), disease status (64% vs. 50%), primary objective (38% vs. 23%), presence of placebo (11% vs. 0%), and randomization (18% vs. 0%).

Conclusion: The official titles were more informative than were the short titles on ClinicalTrials.gov. However, the short and official titles both often lacked the basic information needed to understand a clinical trial. This has persisted despite updates to the platform. These results highlight the need for standardization of the format and content included in study titles.
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http://dx.doi.org/10.1016/j.clml.2019.11.011DOI Listing
February 2020

Illness Understanding and Advance Care Planning in Patients with Advanced Lymphoma.

J Palliat Med 2020 06 18;23(6):832-837. Epub 2019 Oct 18.

Department of Medicine, Weill Cornell Medicine, New York, New York, USA.

The prognosis of an aggressive lymphoma can change dramatically following failure of first-line treatment. This sudden shift is challenging for the promotion of illness understanding and advance care planning (ACP). Yet, little is known about illness understanding and ACP in patients with aggressive lymphomas. To examine illness understanding, rates of engagement in ACP, and reasons for lack of ACP engagement in patients with advanced B cell lymphomas. Cross-sectional observational study. Patients ( = 27) with aggressive B cell lymphomas that relapsed after first- or second-line treatment treated at a single urban academic medical center. Participants were administered structured surveys by trained staff to obtain self-report measures of illness understanding (i.e., aggressiveness, terminality, curability) and ACP (i.e., discussions of care preferences, completion of advance directives). The majority of patients reported discussing curability (92.6%), prognosis (77.8%), and treatment goals (88.9%) with their medical team. Yet, less than one-third of patients reported being terminally ill (29.6%) and having incurable disease (22.2%). Most patients had a health care proxy (81.5%) and had decided about do-not-resuscitate status (63%), but the majority had not completed a living will (65.4%) or discussed their care preferences with others (55.6%). The accuracy of lymphoma patients' illness understanding following first-line treatment is difficult to determine due to the potential for cure following transplant. However, this study suggests that a large proportion of patients with advanced B cell lymphomas may underestimate the severity of their illness, despite discussing illness severity with their medical team. Providing patients with information on prognosis, and the ACP process may increase engagement in ACP.
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http://dx.doi.org/10.1089/jpm.2019.0311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249459PMC
June 2020

New developments in the treatment of follicular lymphoma.

Authors:
John P Leonard

Rinsho Ketsueki 2019 ;60(9):1199-1204

Division of Hematology and Medical Oncology, Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital.

The treatment of follicular lymphoma (FL) continues to evolve. Those patients who present with minimal symptoms often are observed without therapy until significant progression occurs. When treatment is needed, initial options include single agent rituximab (R, anti-CD20), or various forms of chemoimmunotherapy including either R or the newer anti-CD20 monoclonal antibody obinutuzumab (O), with or without maintenance administration. Recent data suggest that the immunomodulatory agent lenalidomide can also be effective in combination with rituximab in both the upfront and relapsed setting. Patients with recurrent disease are frequently treated with chemoimmunotherapy or phosphoinositol-3-kinase (PI3K) inhibitors. Current information suggests that the most important prognostic feature of FL is the presence or absence of early progression (within 2 years of initial treatment/diagnosis). Ongoing efforts are focused on biomarkers to optimally match treatment to patient populations and further improve clinical outcomes.
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http://dx.doi.org/10.11406/rinketsu.60.1199DOI Listing
October 2019

Reply to T.M. Weis et al.

J Clin Oncol 2019 11 18;37(31):2953. Epub 2019 Sep 18.

Nancy L. Bartlett, MD, Washington University School of Medicine, St Louis, MO; Wyndham H. Wilson, MD, PhD, National Institutes of Health, Bethesda, MD; and John P. Leonard, MD, Weill Medical College of Cornell University, New York, NY.

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http://dx.doi.org/10.1200/JCO.19.01617DOI Listing
November 2019

Phase I Study of the Novel Enhancer of Zeste Homolog 2 (EZH2) Inhibitor GSK2816126 in Patients with Advanced Hematologic and Solid Tumors.

Clin Cancer Res 2019 12 30;25(24):7331-7339. Epub 2019 Aug 30.

Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom.

Purpose: Enhancer of zeste homolog 2 (EZH2) activity is dysregulated in many cancers.

Patients And Methods: This phase I study determined the safety, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of the intravenously administered, highly selective EZH2 inhibitor, GSK2816126, (NCT02082977). Doses of GSK2816126 ranged from 50 to 3,000 mg twice weekly, and GSK2816126 was given 3-weeks-on/1-week-off in 28-day cycles. Eligible patients had solid tumors or B-cell lymphomas with no available standard treatment regimen.

Results: Forty-one patients (21 solid tumors, 20 lymphoma) received treatment. All patients experienced ≥1 adverse event (AE). Fatigue [22 of 41 (53.7%)] and nausea [20 of 41 (48.8%)] were the most common toxicity. Twelve (32%) patients experienced a serious AE. Dose-limiting elevated liver transaminases occurred in 2 of 7 patients receiving 3,000 mg of GSK2816126; 2,400 mg was therefore established as the MTD. Following intravenous administration of 50 to 3,000 mg twice weekly, plasma GSK2816126 levels decreased biexponentially, with a mean terminal elimination half-life of approximately 27 hours. GSK2816126 exposure (maximum observed plasma concentration and area under the plasma-time curve) increased in a dose-proportional manner. No change from baseline in H3K27me3 was seen in peripheral blood mononuclear cells. Fourteen of 41 (34%) patients had radiological best response of stable disease, 1 patient with lymphoma achieved a partial response, 21 of 41 (51%) patients had progressive disease, and 5 patients were unevaluable for antitumor response.

Conclusions: The MTD of GSK2816126 was established at 2,400 mg, but the dosing method and relatively short half-life limited effective exposure, and modest anticancer activity was observed at tolerable doses.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-4121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377921PMC
December 2019

A Human Stem Cell Model of Fabry Disease Implicates LIMP-2 Accumulation in Cardiomyocyte Pathology.

Stem Cell Reports 2019 08 1;13(2):380-393. Epub 2019 Aug 1.

Sanofi, Translational Sciences Unit, Sanofi, 13 quai Jules Guesdes, 94400 Vitry-sur-Seine, France. Electronic address:

Here, we have used patient-derived induced pluripotent stem cell (iPSC) and gene-editing technology to study the cardiac-related molecular and functional consequences of mutations in GLA causing the lysosomal storage disorder Fabry disease (FD), for which heart dysfunction is a major cause of mortality. Our in vitro model recapitulated clinical data with FD cardiomyocytes accumulating GL-3 and displaying an increased excitability, with altered electrophysiology and calcium handling. Quantitative proteomics enabled the identification of >5,500 proteins in the cardiomyocyte proteome and secretome, and revealed accumulation of the lysosomal protein LIMP-2 and secretion of cathepsin F and HSPA2/HSP70-2 in FD. Genetic correction reversed these changes. Overexpression of LIMP-2 directly induced the secretion of cathepsin F and HSPA2/HSP70-2, implying causative relationship, and led to massive vacuole accumulation. In summary, our study has revealed potential new cardiac biomarkers for FD, and provides valuable mechanistic insight into the earliest pathological events in FD cardiomyocytes.
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http://dx.doi.org/10.1016/j.stemcr.2019.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700557PMC
August 2019

Five-year follow-up of SWOG S0816: limitations and values of a PET-adapted approach with stage III/IV Hodgkin lymphoma.

Blood 2019 10;134(15):1238-1246

Division of Hematology/Oncology, University of Rochester, Rochester NY.

Patients with advanced-stage Hodgkin lymphoma (HL) demonstrated excellent 2-year progression-free survival (PFS) after receiving positron emission tomography (PET)-adapted therapy on SWOG S0816. Patients received 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Patients achieving complete response (CR) on PET scan following cycle 2 of ABVD (PET2) continued 4 additional cycles of ABVD. Patients not achieving CR on PET2 were switched to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for 6 cycles. After a median follow-up of 5.9 years, a subset of 331 eligible patients with central review of PET2 was analyzed. PET2 was negative in 82% and positive in 18%. For all patients, the estimated 5-year PFS and OS was 74% (95% confidence interval [CI], 69%-79%) and 94% (95% CI, 91%-96%), respectively. For PET2- and PET2+ patients, the 5-year PFS was 76% (95% CI, 70%-81%) and 66% (95% CI, 52%-76%), respectively. Seven (14%) and 6 (2%) patients reported second cancers after treatment with eBEACOPP and ABVD, respectively (P = .001). Long-term OS of HL patients treated on S0816 remains high. Nearly 25% of PET2- patients experienced relapse events, demonstrating limitations ABVD therapy and of the negative predictive value of PET2. In PET2+ patients who received eBEACOPP, PFS was favorable, but was associated with a high rate of second malignancies compared with historical controls. Our results emphasize the importance of long-term follow-up, and the need for more efficacious and less toxic therapeutic approaches for advanced-stage HL patients. This trial was registered at www.clinicaltrials.gov as #NCT00822120.
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http://dx.doi.org/10.1182/blood.2019000719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788007PMC
October 2019

Evaluation of a REDCap-based Workflow for Supporting Federal Guidance for Electronic Informed Consent.

AMIA Jt Summits Transl Sci Proc 2019 6;2019:163-172. Epub 2019 May 6.

Information Technologies & Services Department, Weill Cornell Medicine, New York, NY.

Adoption of electronic informed consent (eConsent) for research remains low despite evidence of improved patient comprehension, usability, and workflow processes compared to paper. At our institution, we implemented an eConsent workflow using REDCap, a widely used electronic data capture system. The goal of this study was to evaluate the extent to which the REDCap eConsent solution adhered to federal guidance for eConsent. Of 29 requirements derived from sixteen recommendations from the United States Office for Human Research Protections (OHRP) and Food and Drug Administration (FDA), the REDCap eConsent solution supported 24 (86%). To the best of our knowledge, this is among the first studies to evaluate an eConsent approach's support for federal guidance. Findings suggest use of REDCap may help other institutions overcome barriers to eConsent adoption, and that OHRP and FDA expand guidance to recommend eConsent solutions integrate with enterprise clinical and research information systems.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6568140PMC
May 2019

Substrate Reduction Therapy for Sandhoff Disease through Inhibition of Glucosylceramide Synthase Activity.

Mol Ther 2019 08 4;27(8):1495-1506. Epub 2019 Jun 4.

Sanofi, 49 New York Avenue, Framingham, MA 01701, USA. Electronic address:

Neuronopathic glycosphingolipidoses are a sub-group of lysosomal storage disorders for which there are presently no effective therapies. Here, we evaluated the potential of substrate reduction therapy (SRT) using an inhibitor of glucosylceramide synthase (GCS) to decrease the synthesis of glucosylceramide (GL1) and related glycosphingolipids. The substrates that accumulate in Sandhoff disease (e.g., ganglioside GM2 and its nonacylated derivative, lyso-GM2) are distal to the drug target, GCS. Treatment of Sandhoff mice with a GCS inhibitor that has demonstrated CNS access (Genz-682452) reduced the accumulation of GL1 and GM2, as well as a variety of disease-associated substrates in the liver and brain. Concomitant with these effects was a significant decrease in the expression of CD68 and glycoprotein non-metastatic melanoma B protein (Gpnmb) in the brain, indicating a reduction in microgliosis in the treated mice. Moreover, using in vivo imaging, we showed that the monocytic biomarker translocator protein (TSPO), which was elevated in Sandhoff mice, was normalized following Genz-682452 treatment. These positive effects translated in turn into a delay (∼28 days) in loss of motor function and coordination, as measured by rotarod latency, and a significant increase in longevity (∼17.5%). Together, these results support the development of SRT for the treatment of gangliosidoses, particularly in patients with residual enzyme activity.
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http://dx.doi.org/10.1016/j.ymthe.2019.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697407PMC
August 2019