Publications by authors named "David L Porter"

141 Publications

Vitamin D deficiency after allogeneic hematopoietic cell transplantation promotes T-cell activation and is inversely associated with an EZH2-ID3 signature.

Transplant Cell Ther 2021 Sep 28. Epub 2021 Sep 28.

Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, New York. Electronic address:

Vitamin D promotes a shift from a proinflammatory to a more tolerogenic immune state in allogeneic hematopoietic cell transplant (HCT) recipients. The dominant mechanism responsible for this shift has not been elucidated. We took a multifaceted approach to evaluating the clinical and immunologic impact of low vitamin D levels in 53 HCT recipients. We used 28-plex flow cytometry for immunophenotyping, serum cytokine levels, T-cell cytokine production, and T-cell whole genome transcription. The median day-30 vitamin D level was 20 ng/mL, and deficiency was common in younger patients undergoing myeloablative transplantation. Low vitamin D levels were associated with a high CD8/Treg ratio, increased serum levels and T-cell production of proinflammatory cytokines, and a gene expression signature of unrestrained T-cell proliferation and epigenetic modulation through the PRC2/EZH2 complex. Immunophenotyping confirmed a strong association between high levels of vitamin D and an activated EZH2 signature, characterized by overexpression of ID3, which has a role in effector T-cell differentiation. Our findings demonstrate the critical role of vitamin D in modulating T-cell function in human GVHD and identify a previously undescribed interaction with EZH2 and ID3, which may impact effector differentiation and has implications to cell therapies and other forms of cancer immunotherapy. © 20XX American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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http://dx.doi.org/10.1016/j.jtct.2021.09.017DOI Listing
September 2021

BET bromodomain protein inhibition reverses chimeric antigen receptor extinction and reinvigorates exhausted T cells in chronic lymphocytic leukemia.

J Clin Invest 2021 08;131(16)

Center for Cellular Immunotherapies.

Chimeric antigen receptor (CAR) T cells have induced remarkable antitumor responses in B cell malignancies. Some patients do not respond because of T cell deficiencies that hamper the expansion, persistence, and effector function of these cells. We used longitudinal immune profiling to identify phenotypic and pharmacodynamic changes in CD19-directed CAR T cells in patients with chronic lymphocytic leukemia (CLL). CAR expression maintenance was also investigated because this can affect response durability. CAR T cell failure was accompanied by preexisting T cell-intrinsic defects or dysfunction acquired after infusion. In a small subset of patients, CAR silencing was observed coincident with leukemia relapse. Using a small molecule inhibitor, we demonstrated that the bromodomain and extra-terminal (BET) family of chromatin adapters plays a role in downregulating CAR expression. BET protein blockade also ameliorated CAR T cell exhaustion as manifested by inhibitory receptor reduction, enhanced metabolic fitness, increased proliferative capacity, and enriched transcriptomic signatures of T cell reinvigoration. BET inhibition decreased levels of the TET2 methylcytosine dioxygenase, and forced expression of the TET2 catalytic domain eliminated the potency-enhancing effects of BET protein targeting in CAR T cells, providing a mechanism linking BET proteins and T cell dysfunction. Thus, modulating BET epigenetic readers may improve the efficacy of cell-based immunotherapies.
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http://dx.doi.org/10.1172/JCI145459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363276PMC
August 2021

Impact of Conditioning Intensity and Genomics on Relapse After Allogeneic Transplantation for Patients With Myelodysplastic Syndrome.

JCO Precis Oncol 2021 25;5. Epub 2021 Jan 25.

Laboratory of Myeloid Malignancies, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.

Purpose: Patients with myelodysplastic syndrome (MDS) are at risk of relapse after allogeneic hematopoietic cell transplantation. The utility of ultra-deep genomic testing to predict and the impact of conditioning intensity to prevent MDS relapse are unknown.

Methods: Targeted error-corrected DNA sequencing was performed on preconditioning blood samples from patients with MDS (n = 48) from the Blood and Marrow Transplant Clinical Trials Network 0901 phase III randomized clinical trial, which compared outcomes by allogeneic hematopoietic cell transplantation conditioning intensity in adult patients with < 5% marrow myeloblasts and no leukemic myeloblasts in blood on morphological analysis at the time of pretransplant assessment. Clinical end points (53-month median follow-up) included transplant-related mortality (TRM), relapse, relapse-free survival (RFS), and overall survival (OS). Of the 48 patients examined, 14 experienced TRM, 23 are relapse-free, and 11 relapsed, of which 7 died.

Results: Using a previously described set of 10 gene regions, 42% of patients (n = 20) had mutations detectable before random assignment to reduced intensity conditioning (RIC) or myeloablative conditioning (MAC). Testing positive was associated with increased rates of relapse (3-year relapse, 40% 11%; = .022) and decreased OS (3-year OS, 55% 79%, = .045). In those testing positive, relapse rates were higher (3-year relapse, 75% 17%; = .003) and RFS was lower (3-year RFS, 13% 49%; = .003) in RIC versus MAC arms. Testing additional genes, including those associated with MDS, did not improve prognostication.

Conclusion: This study provides evidence that targeted DNA sequencing in patients with MDS before transplant can identify those with highest post-transplant relapse rates. In those testing positive, random assignment to MAC lowered but did not eliminate relapse risk.
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http://dx.doi.org/10.1200/PO.20.00355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140814PMC
January 2021

Leucovorin Rescue After Methotrexate Graft-Versus-Host Disease Prophylaxis Shortens the Duration of Mucositis, Time to Neutrophil Engraftment, and Hospital Length of Stay.

Transplant Cell Ther 2021 05 5;27(5):431.e1-431.e8. Epub 2021 Feb 5.

Blood and Marrow Transplant and Cellular Therapy Program, Abramson Cancer Center, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; Division of Hematology and Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

Oropharyngeal mucositis (OPM) is common following conditioning for allogeneic hematopoietic cell transplantation (alloHCT) and results in pain, functional status decline, need for nutritional support, infections, and prolonged length of stay (LOS). Methotrexate (MTX) graft-versus-host disease (GVHD) prophylaxis exacerbates OPM and slows hematopoietic engraftment, which may prolong LOS. Previous studies have demonstrated reduced OPM and more rapid engraftment when leucovorin (LCV) is added following MTX GVHD prophylaxis, yet this practice is controversial. The primary objective of this study was to determine if the routine addition of LCV to MTX GVHD prophylaxis impacted the duration of grade 2 to 4 OPM. Secondary objectives included determination of the incidence of grade 2 to 4 and grade 3 to 4 OPM, time to engraftment, ability to receive all four planned MTX doses, use of total parenteral nutrition (TPN), use of patient-controlled analgesia (PCA), LOS, incidence of acute or chronic GVHD, relapse-free survival (RFS), and overall survival (OS). This single-center, retrospective cohort study compared alloHCT outcomes for 46 adult patients who received MTX 15 mg/m day +1; MTX 10 mg/m days +3, +6, and +11 (15-10-10-10); and LCV following days +3, +6, and +11 MTX compared to historical controls who did not. Patients who received myeloablative conditioning (MAC) and matched related donor (MRD) or matched unrelated donor (MUD) alloHCT were included. The addition of LCV resulted in significant reductions in the duration of grade 2 to 4 OPM (median, 6 days versus 10.5 days; P = .0004), duration of TPN (7 days versus 16 days; P = .001), PCA use (16% versus 39%; P = .0001), time to neutrophil engraftment (median, 18 versus 20 days; P = .008), and LOS (median, 27.5 versus 31 days; P = .017) compared to historical controls. Patients who received routine LCV had similar incidences of grade 2 to 4 acute GVHD (30% versus 28%; relative risk [RR], 1.08; 95% confidence interval [CI], .57 to 2.03; P = 1.0), grade 3 or 4 acute GVHD (2% versus 7%; RR, .33; 95% CI, .04 to 3.09; P = .62) and chronic GVHD (37% versus 30%; RR, 1.21; 95% CI, .67 to 2.16; P = .66) compared to historical controls. Graft failure occurred in 2% of patients in each group. In a multivariable logistic regression analysis, RFS was similar in the LCV group compared to historical controls (HR, .86; 95% CI, .24 to 1.2; P = .13); however, OS was improved in patients who received LCV (HR, .33; 95% CI, .13 to .83; P = .01). In patients undergoing MAC MRD/MUD alloHCT with four planned doses of MTX GVHD prophylaxis (15-10-10-10), LCV was associated with reduced duration of grade 2 to 4 OPM, faster neutrophil engraftment, reduced utilization of TPN and PCA, and shortened LOS compared to historical controls not receiving routine LCV. These benefits were apparent without an increased risk of acute or chronic GVHD or adverse effect on RFS. LCV improved OS; however, it is unclear if this was due to the intervention or an unmeasured confounder. A randomized, prospective trial of LCV prophylaxis in patients receiving MAC alloHCT and MTX 15-10-10-10 GVHD prophylaxis is warranted to confirm our findings.
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http://dx.doi.org/10.1016/j.jtct.2021.01.028DOI Listing
May 2021

Myeloablative versus Reduced-Intensity Conditioning for Hematopoietic Cell Transplantation in Acute Myelogenous Leukemia and Myelodysplastic Syndromes-Long-Term Follow-Up of the BMT CTN 0901 Clinical Trial.

Transplant Cell Ther 2021 06 26;27(6):483.e1-483.e6. Epub 2021 Feb 26.

Duke University, Durham, North Carolina.

Several prospective randomized trials comparing conditioning intensity before allogeneic hematopoietic cell transplantation (HCT) have been performed, with conflicting results. Although reduced-intensity conditioning (RIC) leads to lower treatment-related mortality (TRM), this is offset by higher rates of relapse. Long-term follow-up of randomized comparative trials are limited. Here we present long-term follow-up of a randomized comparison of myeloablative conditioning (MAC) compared with RIC before HCT for acute myelogenous leukemia (AML) or myelodysplasia (MDS). Long-term comparative analyses of overall survival, relapse, and relapse-free survival were performed. Patients age 18 to 65 years with <5% marrow myeloblasts were randomized to receive MAC (n = 135) or RIC (n = 137), followed by HCT from an HLA-matched donor. The primary endpoint of the trial was an 18-month pointwise comparison of overall survival. The analyses were performed using a proportional hazards model. The median follow-up of the entire cohort was 51 months. At 4 years, the transplant-related mortality (TRM) was 25.1% for MAC, compared with 9.9% for RIC (P < .001). Patients who received RIC had a significantly higher risk of relapse compared to those who received MAC (hazard ratio [HR], 4.06; 95% CI, 2.59 to 6.35; P < 0.001). Among the patients who relapsed after HCT, postrelapse survival was similar at 3 years (24% for MAC and 26% for RIC). Overall survival was superior for patients who received MAC compared to those who received RIC (HR, 1.54; 95% CI, 1.07 to 2.2; P = .03). Our data show that patients who received MAC were at higher risk of late TRM compared with those who received RIC; however, because of the exceedingly high rates of relapse in the RIC arm, overall survival remained significantly better for patients who received MAC. Among patients with MDS or AML eligible for either MAC or RIC regimens, long-term follow up demonstrates a survival advantage for patients who received MAC.
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http://dx.doi.org/10.1016/j.jtct.2021.02.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217373PMC
June 2021

CCR5-edited CD4+ T cells augment HIV-specific immunity to enable post-rebound control of HIV replication.

J Clin Invest 2021 04;131(7)

Department of Microbiology and Center for Cellular Immunotherapies.

BackgroundWe conducted a phase I clinical trial that infused CCR5 gene-edited CD4+ T cells to determine how these T cells can better enable HIV cure strategies.MethodsThe aim of trial was to develop RNA-based approaches to deliver zinc finger nuclease (ZFN), evaluate the effect of CCR5 gene-edited CD4+ T cells on the HIV-specific T cell response, test the ability of infused CCR5 gene-edited T cells to delay viral rebound during analytical treatment interruption, and determine whether individuals heterozygous for CCR5 Δ32 preferentially benefit. We enrolled 14 individuals living with HIV whose viral load was well controlled by antiretroviral therapy (ART). We measured the time to viral rebound after ART withdrawal, the persistence of CCR5-edited CD4+ T cells, and whether infusion of 10 billion CCR5-edited CD4+ T cells augmented the HIV-specific immune response.ResultsInfusion of the CD4+ T cells was well tolerated, with no serious adverse events. We observed a modest delay in the time to viral rebound relative to historical controls; however, 3 of the 14 individuals, 2 of whom were heterozygous for CCR5 Δ32, showed post-viral rebound control of viremia, before ultimately losing control of viral replication. Interestingly, only these individuals had substantial restoration of HIV-specific CD8+ T cell responses. We observed immune escape for 1 of these reinvigorated responses at viral recrudescence, illustrating a direct link between viral control and enhanced CD8+ T cell responses.ConclusionThese findings demonstrate how CCR5 gene-edited CD4+ T cell infusion could aid HIV cure strategies by augmenting preexisting HIV-specific immune responses.REGISTRATIONClinicalTrials.gov NCT02388594.FundingNIH funding (R01AI104400, UM1AI126620, U19AI149680, T32AI007632) was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). Sangamo Therapeutics also provided funding for these studies.
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http://dx.doi.org/10.1172/JCI144486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011906PMC
April 2021

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of lymphoma.

J Immunother Cancer 2020 12;8(2)

Department of Medicine Section of Hematology/Oncology, University of Chicago, Chicago, Illinois, USA

The recent development and clinical implementation of novel immunotherapies for the treatment of Hodgkin and non-Hodgkin lymphoma have improved patient outcomes across subgroups. The rapid introduction of immunotherapeutic agents into the clinic, however, has presented significant questions regarding optimal treatment scheduling around existing chemotherapy/radiation options, as well as a need for improved understanding of how to properly manage patients and recognize toxicities. To address these challenges, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts in lymphoma to develop a clinical practice guideline for the education of healthcare professionals on various aspects of immunotherapeutic treatment. The panel discussed subjects including treatment scheduling, immune-related adverse events (irAEs), and the integration of immunotherapy and stem cell transplant to form recommendations to guide healthcare professionals treating patients with lymphoma.
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http://dx.doi.org/10.1136/jitc-2020-001235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768967PMC
December 2020

Immunotherapy with cells.

Hematology Am Soc Hematol Educ Program 2020 12;2020(1):590-597

Lymphoma Program and Cell Therapy and Transplant Program, Hematology-Oncology Division, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.

Both older and newer cell therapies have demonstrated impressive responses in otherwise poor-prognosis lymphomas. Consequently, cellular therapy now plays a major role in the management of many non-Hodgkin lymphomas. In this article, we examine the role of chimeric antigen receptor (CAR) T cells, allogeneic stem cell transplantation, and virus-directed T cells for treatment of lymphomas. We review the current indications for CAR T cells and discuss our clinical approach to selecting and treating patients with aggressive B-cell lymphomas to receive CD19-directed CAR T cells. In addition, we highlight newer cell therapies and provide an overview of promising future approaches that have the potential to transform immunotherapy with cells to treat lymphomas.
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http://dx.doi.org/10.1182/hematology.2020000174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727576PMC
December 2020

Diagnostic biomarkers to differentiate sepsis from cytokine release syndrome in critically ill children.

Blood Adv 2020 10;4(20):5174-5183

Division of Hematology and Oncology, Children's Hospital of Philadelphia, Philadelphia, PA.

Chimeric antigen receptor (CAR) T-cells directed against CD19 have drastically altered outcomes for children with relapsed and refractory acute lymphoblastic leukemia (r/r ALL). Pediatric patients with r/r ALL treated with CAR-T are at increased risk of both cytokine release syndrome (CRS) and sepsis. We sought to investigate the biologic differences between CRS and sepsis and to develop predictive models which could accurately differentiate CRS from sepsis at the time of critical illness. We identified 23 different cytokines that were significantly different between patients with sepsis and CRS. Using elastic net prediction modeling and tree classification, we identified cytokines that were able to classify subjects as having CRS or sepsis accurately. A markedly elevated interferon γ (IFNγ) or a mildly elevated IFNγ in combination with a low IL1β were associated with CRS. A normal to mildly elevated IFNγ in combination with an elevated IL1β was associated with sepsis. This combination of IFNγ and IL1β was able to categorize subjects as having CRS or sepsis with 97% accuracy. As CAR-T therapies become more common, these data provide important novel information to better manage potential associated toxicities.
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http://dx.doi.org/10.1182/bloodadvances.2020002592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594400PMC
October 2020

Cytokine release syndrome and neurotoxicity following CAR T-cell therapy for hematologic malignancies.

J Allergy Clin Immunol 2020 11 6;146(5):940-948. Epub 2020 Aug 6.

Division of Cellular Therapy and Stem Cell Transplant, Hospital of the University of Pennsylvania, Philadelphia, Pa; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa.

Chimeric antigen receptor T cells are a new and exciting immunotherapeutic approach to managing cancer, with impressive efficacy but potentially life-threatening inflammatory toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Patients with severe CRS may develop capillary leak syndrome and disseminated intravascular coagulation, with a cytokine signature similar to that of macrophage activation syndrome/hemophagocytic lymphohistiocytosis. Moderate-to-severe CRS is managed with the IL-6 receptor antagonist tocilizumab with or without corticosteroids, with questions remaining regarding the optimal management of nonresponders. ICANS is an inflammatory neurotoxicity typically occurring after CRS and characterized by impaired blood-brain barrier integrity. Symptoms of encephalopathy range from mild confusion and aphasia to somnolence, obtundation, and in some cases seizures and cerebral edema. ICANS is currently managed with corticosteroids; however, the optimal dose and duration remain to be determined. Little information is available to guide the management of patients with steroid-refractory ICANS. Numerous cytokine-targeted therapies have been proposed to manage these inflammatory toxicities, but few clinical data are available. Management of inflammatory toxicities of chimeric antigen receptor T cells often requires multidisciplinary management and intensive care, during which allergists and immunologists may encounter patients with these unique toxicities.
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http://dx.doi.org/10.1016/j.jaci.2020.07.025DOI Listing
November 2020

Venous thromboembolism following pegaspargase in adults receiving antithrombin supplementation.

Leuk Lymphoma 2020 09 1;61(9):2200-2207. Epub 2020 Jun 1.

Department of Medicine, Hematology-Oncology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

Pegaspargase (PEG) increases venous thromboembolism (VTE) in acute lymphoblastic leukemia (ALL) potentially due to depletion of anticoagulation factors, including antithrombin (AT). The benefit and cost of AT supplementation in adults is unclear. We aimed to characterize VTE incidence and risk factors following AT and determine the characteristics and costs of supplementation. Fifty-three adults received PEG and AT. VTE occurred in 21% (grade ≥3 8%). T cell ALL and patients receiving prednisone during induction were at highest risk. Repeat AT levels post supplementation were subtherapeutic forty-four percent of the time. A median of 18 days elapsed between PEG and two sequential therapeutic AT levels despite supplementation. Patients received a median of 2 AT doses per PEG dose at a median cost of $11,145. VTE remains common in adults despite AT supplementation. More aggressive AT supplementation may reduce VTE but warrant prospective evaluation given the significant cost.
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http://dx.doi.org/10.1080/10428194.2020.1765239DOI Listing
September 2020

Advances in CAR T Therapy for Hematologic Malignancies.

Pharmacotherapy 2020 08 3;40(8):741-755. Epub 2020 Jun 3.

Division of Hematology/Oncology, Cell Therapy and Transplant, Perelman School of Medicine and the Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

The introduction of chimeric antigen receptor T-cell (CAR T) therapy has resulted in a paradigm shift in the management of relapsed/refractory B-cell malignancies. Patients with acute lymphoblastic leukemia and non-Hodgkin's lymphoma who had exhausted all meaningful treatment options now have an opportunity for long-term remission and possibly cure. CAR T is rapidly expanding into the treatment paradigm for multiple myeloma with approvals expected in the near future. CAR T for chronic lymphocytic leukemia may not be far behind, while CAR T studies in Hodgkin lymphoma and acute myeloid leukemia are ongoing. Such therapeutic success brings challenges in toxicity management related to cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Our understanding of these unique syndromes is evolving, with predictive models and additional treatment strategies on the horizon. This review aims to summarize the progress of CAR T therapeutics within malignant hematology thus far and highlight ongoing advances in the field.
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http://dx.doi.org/10.1002/phar.2414DOI Listing
August 2020

Chimeric Antigen Receptor T Cell Therapy During the COVID-19 Pandemic.

Biol Blood Marrow Transplant 2020 07 14;26(7):1239-1246. Epub 2020 Apr 14.

Hematopoietic Cellular Therapy Program, Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL. Electronic address:

The SARS-CoV-2 coronavirus (COVID-19) pandemic has significantly impacted the delivery of cellular therapeutics, including chimeric antigen receptor (CAR) T cells. This impact has extended beyond patient care to include logistics, administration, and distribution of increasingly limited health care resources. Based on the collective experience of the CAR T-cell Consortium investigators, we review and address several questions and concerns regarding cellular therapy administration in the setting of COVID-19 and make general recommendations to address these issues. Specifically, we address (1) necessary resources for safe administration of cell therapies; (2) determinants of cell therapy utilization; (3) selection among patients with B cell non-Hodgkin lymphomas and B cell acute lymphoblastic leukemia; (4) supportive measures during cell therapy administration; (5) use and prioritization of tocilizumab; and (6) collaborative care with referring physicians. These recommendations were carefully formulated with the understanding that resource allocation is of the utmost importance, and that the decision to proceed with CAR T cell therapy will require extensive discussion of potential risks and benefits. Although these recommendations are fluid, at this time it is our opinion that the COVID-19 pandemic should not serve as reason to defer CAR T cell therapy for patients truly in need of a potentially curative therapy.
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http://dx.doi.org/10.1016/j.bbmt.2020.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194685PMC
July 2020

Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia.

J Clin Oncol 2020 09 16;38(25):2862-2871. Epub 2020 Apr 16.

Cell Therapy and Transplant Program, Division of Hematology-Oncology, Department of Medicine, Philadelphia, PA.

Purpose: To describe long-term outcomes of anti-CD19 chimeric antigen receptor T (CART) cells in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Methods: Between January 2013 and June 2016, 42 patients with relapsed or refractory CLL were enrolled in this study and 38 were infused with anti-CD19 CART cells (CART-19). Of these, 28 patients were initially randomly assigned to receive a low (5 × 10) or high (5 × 10) dose of CART-19, and 24 were evaluable for response assessment. After an interim analysis, 10 additional patients received the selected (high) dose and of these, eight were evaluable for response. Patients were followed for a median 31.5 months (range, 2 to 75 months).

Results: At 4 weeks, the complete and overall responses for the 32 evaluable patients were 28% (90% CI, 16% to 44%) and 44% (90% CI, 29% to 60%), respectively. The median overall survival (OS) for all patients was 64 months; there was no statistically significant difference between low- and high-dose groups ( = .84). Regardless of dose, prolonged survival was observed in patients who achieved a CR versus those who did not ( = .035), with median OS not reached in patients with CR versus 64 months in those without CR. The median progression-free survival was 40.2 months in patients with CR and 1 month in those without a CR ( < .0001). Toxicity was comparable in both dose groups.

Conclusion: In patients with advanced CLL, a 5 × 10 dose of CART-19 may be more effective than 5 × 10 CART-19 at inducing CR without excessive toxicity. Attainment of a CR after CART-19 infusion, regardless of cell dose, is associated with longer OS and progression-free survival in patients with relapsed CLL.
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http://dx.doi.org/10.1200/JCO.19.03237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265376PMC
September 2020

Risk of invasive fungal infections in patients with high-risk MDS and AML receiving hypomethylating agents.

Am J Hematol 2020 07 4;95(7):792-798. Epub 2020 May 4.

Division of Hematology-Oncology/Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Invasive fungal infections (IFI) are a significant source of morbidity and mortality for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Given the heterogeneity of the population receiving hypomethylating agents (HMA), it is difficult for clinicians to accurately assess their patients' risk of infection. Literature on the incidence of IFI following HMA is limited to several studies of azacitidine. The primary objective of this retrospective study was to establish the incidence of IFI in HMA treated AML/MDS patients at a large U.S. comprehensive cancer center. Secondary objectives included comparing incidence of IFI among pre-specified subgroups to identify potential risk factors for IFI. Two hundred three patients with AML, intermediate to very high risk MDS or chronic myelomonocytic leukemia who received at least two cycles of HMA were included. The incidence of IFI, as defined by the European Organization for Research and Treatment of Cancer / Invasive Fungal Infections Cooperative Group criteria, was 9.6%, with 20 IFI diagnosed following HMA (three proven, four probable, 13 possible). Among the proven cases of IFI, molds included Scedosporium and Fusarium spp. Eleven patients who developed IFIs were neutropenic upon initiating HMA. The majority (17/20) of infections occurred during the first four cycles. Given this incidence, mold-active prophylaxis can be considered in patients who are neutropenic at the start of therapy.
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http://dx.doi.org/10.1002/ajh.25808DOI Listing
July 2020

Impact of Conditioning Intensity of Allogeneic Transplantation for Acute Myeloid Leukemia With Genomic Evidence of Residual Disease.

J Clin Oncol 2020 04 20;38(12):1273-1283. Epub 2019 Dec 20.

Duke University, Durham, NC.

Purpose: Patients with acute myeloid leukemia (AML) in remission remain at risk for relapse even after allogeneic hematopoietic cell transplantation (alloHCT). AML measurable residual disease (MRD) status before alloHCT has been shown to be prognostic. Whether modulation of the intensity of the alloHCT conditioning regimen in patients with AML who test positive for MRD can prevent relapse and improve survival is unknown.

Methods: Ultra-deep, error-corrected sequencing for 13 commonly mutated genes in AML was performed on preconditioning blood from patients treated in a phase III clinical trial that randomly assigned adult patients with myeloid malignancy in morphologic complete remission to myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC).

Results: No mutations were detected in 32% of MAC and 37% of RIC recipients; these groups had similar survival (3-year overall survival [OS], 56% 63%; = .96). In patients with a detectable mutation (next-generation sequencing [NGS] positive), relapse (3-year cumulative incidence, 19% 67%; < .001) and survival (3-year OS, 61% 43%; = .02) was significantly different between the MAC and RIC arms, respectively. In multivariable analysis for NGS-positive patients, adjusting for disease risk and donor group, RIC was significantly associated with increased relapse (hazard ratio [HR], 6.38; 95% CI, 3.37 to 12.10; < .001), decreased relapse-free survival (HR, 2.94; 95% CI, 1.84 to 4.69; < .001), and decreased OS (HR, 1.97; 95% CI, 1.17 to 3.30; = .01) compared with MAC. Models of AML MRD also showed benefit for MAC over RIC for those who tested positive.

Conclusion: This study provides evidence that MAC rather than RIC in patients with AML with genomic evidence of MRD before alloHCT can result in improved survival.
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http://dx.doi.org/10.1200/JCO.19.03011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164487PMC
April 2020

CD19-targeting CAR T cell immunotherapy outcomes correlate with genomic modification by vector integration.

J Clin Invest 2020 02;130(2):673-685

Department of Microbiology.

Chimeric antigen receptor-engineered T cells targeting CD19 (CART19) provide an effective treatment for pediatric acute lymphoblastic leukemia but are less effective for chronic lymphocytic leukemia (CLL), focusing attention on improving efficacy. CART19 harbor an engineered receptor, which is delivered through lentiviral vector integration, thereby marking cell lineages and modifying the cellular genome by insertional mutagenesis. We recently reported that vector integration within the host TET2 gene was associated with CLL remission. Here, we investigated clonal population structure and therapeutic outcomes in another 39 patients by high-throughput sequencing of vector-integration sites. Genes at integration sites enriched in responders were commonly found in cell-signaling and chromatin modification pathways, suggesting that insertional mutagenesis in these genes promoted therapeutic T cell proliferation. We also developed a multivariate model based on integration-site distributions and found that data from preinfusion products forecasted response in CLL successfully in discovery and validation cohorts and, in day 28 samples, reported responders to CLL therapy with high accuracy. These data clarify how insertional mutagenesis can modulate cell proliferation in CART19 therapy and how data on integration-site distributions can be linked to treatment outcomes.
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http://dx.doi.org/10.1172/JCI130144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994131PMC
February 2020

Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia.

J Clin Oncol 2020 02 9;38(5):415-422. Epub 2019 Dec 9.

Division of Hematology Oncology, Abramson Cancer Center, Cell Therapy and Transplant, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

Purpose: The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults. We report outcomes for adults with r/r ALL treated with an optimized CTL019 dosing and CRS management strategy.

Methods: Adults with r/r B-cell ALL received CTL019 in 1 of 2 trials. Patients received lymphodepletion followed by CTL019 as either a one-time infusion or fractionated infusions split over 3 days (day 1, 10%; day 2, 30%; day 3, 60%), which allowed for day 2 and day 3 doses to be held for early CRS. Total planned CTL019 dose varied with adaptive protocol modifications in response to efficacy and CRS toxicity.

Results: Thirty-five adults with r/r ALL received CTL019 in 1 of 3 dosing cohorts. The low-dose cohort (n = 9) received single or fractionated dosing and had manageable toxicity with a 33% complete remission (CR) rate. In the high-dose single infusion cohort, 3 of 6 patients with refractory CRS concurrent with culture-positive sepsis died, and 3 achieved CR. The 20 patients in the high-dose fractionated (HDF) cohort had a 90% CR rate and manageable CRS. The HDF cohort had the highest survival, with a 2-year overall survival of 73% (95% CI, 46% to 88%) and event-free survival of 49.5% (95% CI, 21% to 73%).

Conclusion: Fractionated dosing of CTL019 with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL.
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http://dx.doi.org/10.1200/JCO.19.01892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312030PMC
February 2020

Innovation and Access at the Mercy of Payment Policy: The Future of Chimeric Antigen Receptor Therapies.

J Clin Oncol 2020 02 1;38(5):384-387. Epub 2019 Nov 1.

University of Pennsylvania, Philadelphia, PA.

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http://dx.doi.org/10.1200/JCO.19.01691DOI Listing
February 2020

Clinical utilization of Chimeric Antigen Receptor T-cells (CAR-T) in B-cell acute lymphoblastic leukemia (ALL)-an expert opinion from the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT).

Bone Marrow Transplant 2019 11 15;54(11):1868-1880. Epub 2019 May 15.

Department of Haematological Medicine, King's College, London, UK.

On August 30, 2017, the U.S. Food and Drug Administration (US-FDA) approved tisagenlecleucel (KYMRIAH, Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor-T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring and disease assessments. To address these issues, experts representing the American Society for Blood and Marrow Transplant (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), the International Society of Cell and Gene Therapy (ISCT), and the Foundation for the Accreditation of Cellular Therapy (FACT), formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.
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http://dx.doi.org/10.1038/s41409-019-0451-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268756PMC
November 2019

Management of giant cell hepatitis associated with chronic lymphocytic leukemia - a case series and review of the literature.

Cancer Biol Ther 2019 15;20(8):1136-1140. Epub 2019 May 15.

c CLL Program, Leukemia Service , Memorial Sloan- Kettering Cancer Center , New York , NY , USA.

Giant cell hepatitis (GCH) is a rare diagnosis in adults that is found in 0.25% of liver biopsies. GCH has been associated with multiple causes including drugs (6-mercaptopurine, methotrexate), toxins, viruses and autoimmune. GCH has been described in few patients with chronic lymphocytic leukemia (CLL). Here we describe three patients diagnosed with GCH thought to be related to underlying CLL and its management. All of our patients were treated with a combination of immunosuppression as well as CLL-directed therapy to address CLL and concomitant liver disease. GCH is a rare manifestation of active CLL and should be ruled out with prompt liver biopsy in patients with CLL with persistent transaminitis without another attributable cause. Prompt treatment of GCH with immunosuppression is required to prevent long-term liver toxicity. If transaminitis does not improve with immunosuppression alone, the addition of CLL directed therapy should be considered in patients who carry this diagnosis to prevent long-term liver toxicity.
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http://dx.doi.org/10.1080/15384047.2019.1598763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628867PMC
August 2020

Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8 T cells and impede CAR T-cell efficacy.

Blood 2019 07 10;134(1):44-58. Epub 2019 May 10.

Department of Hematology, Cancer Center Amsterdam.

In chronic lymphocytic leukemia (CLL), acquired T-cell dysfunction impedes development of effective immunotherapeutic strategies, through as-yet unresolved mechanisms. We have previously shown that CD8 T cells in CLL exhibit impaired activation and reduced glucose uptake after stimulation. CD8 T cells in CLL patients are chronically exposed to leukemic B cells, which potentially impacts metabolic homeostasis resulting in aberrant metabolic reprogramming upon stimulation. Here, we report that resting CD8 T cells in CLL have reduced intracellular glucose transporter 1 (GLUT1) reserves, and have an altered mitochondrial metabolic profile as displayed by increased mitochondrial respiration, membrane potential, and levels of reactive oxygen species. This coincided with decreased levels of peroxisome proliferator-activated receptor γ coactivator 1-α, and in line with that, CLL-derived CD8 T cells showed impaired mitochondrial biogenesis upon stimulation. In search of a therapeutic correlate of these findings, we analyzed mitochondrial biogenesis in CD19-directed chimeric antigen receptor (CAR) CD8 T cells prior to infusion in CLL patients (who were enrolled in NCT01747486 and NCT01029366 [https://clinicaltrials.gov]). Interestingly, in cases with a subsequent complete response, the infused CD8 CAR T cells had increased mitochondrial mass compared with nonresponders, which positively correlated with the expansion and persistence of CAR T cells. Our findings demonstrate that GLUT1 reserves and mitochondrial fitness of CD8 T cells are impaired in CLL. Therefore, boosting mitochondrial biogenesis in CAR T cells might improve the efficacy of CAR T-cell therapy and other emerging cellular immunotherapies.
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http://dx.doi.org/10.1182/blood.2018885863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022375PMC
July 2019

Accelerating chimeric antigen receptor therapy in chronic lymphocytic leukemia: The development and challenges of chimeric antigen receptor T-cell therapy for chronic lymphocytic leukemia.

Am J Hematol 2019 05 23;94(S1):S10-S17. Epub 2019 Mar 23.

Cell Therapy and Transplant Program, Division of Hematology-Oncology, Perelman School of Medicine and Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.

Studies of chimeric antigen receptor (CAR) T-cell therapy in chronic lymphocytic leukemia (CLL) have demonstrated the potential to produce deep remissions-and possibly cures-in some patients with heavily pretreated, high-risk, relapsed, and refractory disease. Unfortunately, most clinical trials of CAR T cells in CLL report complete responses only in the minority of patients, although recent studies have begun to elucidate the factors most predictive of response. These studies have suggested strategies for optimizing CAR T-cell fitness as well as the pre-existing host immune response, approaches that will likely lead to improvements in the efficacy of CAR T cells in CLL. Treating patients earlier in the course of their disease or using combination therapies with CAR T cells may further enhance efficacy. In this review, we summarize the existing literature on CAR T cell therapy in CLL, discuss mechanisms of response and resistance, and describe challenges facing the field.
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http://dx.doi.org/10.1002/ajh.25457DOI Listing
May 2019

Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203).

Lancet Haematol 2019 Mar;6(3):e132-e143

Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA.

Background: Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial.

Methods: In this prospective multicentre phase 2 trial, adult patients aged 18-75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1·3 mg/m intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day -3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m intravenous bolus on day 1 and 10 mg/m intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0·05 mg/kg twice daily (or oral equivalent) starting on day -3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5-15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3-4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037.

Findings: Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0·72 (90% CI 0·54-0·94; p=0·044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0·98 (0·76-1·27; p=0·92) for tacrolimus, methotrexate, and bortezomib, and 1·10 (0·86-1·41; p=0·49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13%) had grade 3 and 67 (73%) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11%) had grade 3 and 68 (76%) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20%) had grade 3 and 63 (68%) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84%] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82%] for tacrolimus, methotrexate, and bortezomib; and 78 [85%] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47%], 44 [49%], and 43 [47%], respectively).

Interpretation: Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial.

Funding: US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.
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http://dx.doi.org/10.1016/S2352-3026(18)30221-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503965PMC
March 2019

Clinical Utilization of Chimeric Antigen Receptor T Cells in B Cell Acute Lymphoblastic Leukemia: An Expert Opinion from the European Society for Blood and Marrow Transplantation and the American Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2019 03 18;25(3):e76-e85. Epub 2018 Dec 18.

Department of Haematological Medicine, King's College, London, United Kingdom.

On August 30, 2017 the US Food and Drug Administration approved tisagenlecleucel (Kymriah; Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present, ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring, and disease assessments. To address these issues experts representing the American Society for Blood and Marrow Transplant, the European Society for Blood and Marrow Transplantation, the International Society of Cell and Gene Therapy, and the Foundation for the Accreditation of Cellular Therapy formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.
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http://dx.doi.org/10.1016/j.bbmt.2018.12.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335749PMC
March 2019

Chimeric antigen receptor (CAR) T therapies for the treatment of hematologic malignancies: clinical perspective and significance.

J Immunother Cancer 2018 12 4;6(1):137. Epub 2018 Dec 4.

Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.

Chimeric Antigen Receptor (CAR) T cell therapies - adoptive T cell therapies that have been genetically engineered for a new antigen-specificity - have displayed significant success in treating patients with hematologic malignancies, leading to three recent US Food and Drug Administration approvals. Based on the promise generated from these successes, the field is rapidly evolving to include new disease indications and CAR designs, while simultaneously reviewing and optimizing toxicity and management protocols. As such, this review provides expert perspective on the significance and clinical considerations of CAR T cell therapies in order to provide timely information to clinicians about this revolutionary new therapeutic class.
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http://dx.doi.org/10.1186/s40425-018-0460-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278156PMC
December 2018

Early positron emission tomography/computed tomography as a predictor of response after CTL019 chimeric antigen receptor -T-cell therapy in B-cell non-Hodgkin lymphomas.

Cytotherapy 2018 12 29;20(12):1415-1418. Epub 2018 Oct 29.

Lymphoma Program at the Abramson Cancer Center and the Division of Hematology-Oncology Perelman School of Medicine, University of Pennsylvania, Pennsylvania, USA.

Molecular imaging with F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is an established modality for response assessment in patients with lymphoma undergoing treatment. However, patients treated with novel immunotherapies may have false-positive PET/CT findings due to tumor site and systemic inflammation. In particular, treatment with autologous chimeric antigen receptor modified T-cells redirected at CD19 (CTL019 CAR-T cells) is often complicated by "cytokine release syndrome" (CRS) due to a severe systemic inflammatory reaction. Infiltration of tumors by activated CTL019 cells may impact radiographic and functional imaging findings. The role of PET/CT in patients treated with CTL019 has not previously been described. We performed a pilot, single-arm, prospective study to explore the utility of early PET/CT in patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) undergoing treatment with CTL019 CAR-T cells. Patients had PET/CT prior to CTL019 infusion and then early PET/CT at 1 month after treatment. The primary outcome was the amount/change in metabolically active tumor volume (MTV) and FDG uptake. We enrolled seven patients (DLBCL, three; FL, four). Six of 7 had baseline PET/CT with active disease. On post-treatment PET/CT, three patients had no residual MTV, two patients had a decrease in MTV and two patients had an increase in MTV. The three patients with no residual MTV all remain in remission >2 years post-treatment. The patients with less than complete response all subsequently relapsed. Development of CRS did not confound PET/CT findings. In patients with DLBCL and FL receiving CTL019 CAR-T cells, early PET/CT may predict response to this novel immunotherapy.
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http://dx.doi.org/10.1016/j.jcyt.2018.10.003DOI Listing
December 2018

Extended CCR5 Blockade for Graft-versus-Host Disease Prophylaxis Improves Outcomes of Reduced-Intensity Unrelated Donor Hematopoietic Cell Transplantation: A Phase II Clinical Trial.

Biol Blood Marrow Transplant 2019 03 10;25(3):515-521. Epub 2018 Oct 10.

Abramson Cancer Center and Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Graft-versus-host disease (GVHD) remains the most common treatment-related complication after allogeneic hematopoietic cell transplantation (allo-HCT). Lymphocyte migration plays a critical role in the pathogenesis of GVHD. A previous phase I/II trial demonstrated that CCR5 blockade with maraviroc in the first 30days after allo-HCT resulted in a low incidence of early acute GVHD, primarily in visceral organs, but with no impact on late acute or chronic GVHD. We conducted a phase II trial to examine the efficacy of an extended course of maraviroc, administered through post-transplantation day +90 in addition to standard prophylaxis in 37 recipients of reduced-intensity-conditioned unrelated donor allo-HCT performed to treat hematologic malignancies. Extended maraviroc treatment was safe and feasible. The primary study endpoint, day +180 rate of grade II-IV acute GVHD, was 22 ± 7%, liver GVHD was not observed, and gut GVHD was uncommon. The day +180 rate of grade III-IV acute GVHD was 5 ± 4%. The 1-year rate of moderate to severe chronic GVHD was 8 ± 5% and that of disease relapse was 30 ± 8%. Overall survival at 1 year was 70 ± 8%. Compared with the previously studied short course of maraviroc, the extended course resulted in a significantly higher GVHD-free, relapse-free survival (adjusted hazard ratio [HR], .45; 95% confidence interval [CI], .25 to .82; P = .009) and overall survival (adjusted HR, .48; 95% CI, .24 to .96; P = .037). A combined analysis of both trials showed that high maraviroc trough concentrations on the day of hematopoietic cell infusion were associated with lower rates of acute GVHD. An extended course of maraviroc after reduced-intensity-conditioned unrelated donor allo-HCT is safe and effective in preventing acute and chronic GVHD and is associated with favorable survival.
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http://dx.doi.org/10.1016/j.bbmt.2018.09.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445759PMC
March 2019
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