Publications by authors named "Noelle V Frey"

53 Publications

Relapsed ALL: CAR T vs transplant vs novel therapies.

Authors:
Noelle V Frey

Hematology Am Soc Hematol Educ Program 2021 12;2021(1):1-6

Cell Therapy and Transplant Program, Abramson Cancer Center, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.

Chimeric antigen receptor T-cell therapy targeting CD19 (CART19) has expanded the treatment options for patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). The approval of tisagenlecleucel for pediatric and young adult patients with r/r ALL has allowed broader access for some patients, but the treatment of older adults is available (at the time of this writing) only within a clinical trial. High remission rates have been consistently observed with varied CART19 products and treatment platforms, but durability of remissions and thus the potential role of a consolidative allogeneic stem cell transplant (SCT) is more uncertain and likely to vary by product and population treated. The immunologic characteristics of CARTs that confer high response rates also account for the life-threatening toxicities of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, the severity of which also varies by patient and disease characteristics and product. Further considerations informing a decision to treat include feasibility of leukapheresis and timeline of manufacture, alternative treatment options available, and the appropriateness of a potential consolidative allogeneic SCT. Advances in the field are under way to improve rate and duration of responses and to mitigate toxicity.
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http://dx.doi.org/10.1182/hematology.2021000225DOI Listing
December 2021

Characterization of Pericarditis following Allogeneic Hematopoietic Cell Transplantation.

Transplant Cell Ther 2021 Nov 30;27(11):934.e1-934.e6. Epub 2021 Jul 30.

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

Pericarditis is an uncommon cardiac complication following allogeneic hematopoietic cell transplantation (alloHCT), with limited data characterizing its incidence, presentation, and management. The etiology of pericarditis in this setting is poorly understood and may include conditioning-related toxicity, infection, or graft-versus-host disease (GVHD). The objective of the present study was to characterize the clinical presentation, management, and outcomes of post-alloHCT pericarditis observed at a single center. This retrospective case-control study of consecutive adults undergoing alloHCT over 5 years was conducted to identify patients who developed pericarditis. Pericarditis was diagnosed using clinical, electrocardiography, and echocardiography findings. Identified cases were compared with a cohort of patients who underwent alloHCT during the same period but did not develop pericarditis. A total of 620 patients underwent alloHCT over the 5-year period, 20 of whom developed pericarditis (3.2% incidence). One patient had a pre-alloHCT history of pericarditis. All but 3 patients had received anthracycline therapy and 1 patient had received chest irradiation before undergoing alloHCT. Patients with pericarditis were more likely than patients without pericarditis to have received total body irradiation (odds ratio [OR], 4.57; P = .003) or cyclophosphamide (OR, 2.35; P = .07) as conditioning or GVHD prophylaxis. Fourteen patients experienced their initial episode of pericarditis before day +100 post-alloHCT, with a median time to onset at day +7. Six patients had their initial episode on day +100 or later, with a median time to onset at day +268. Only 1 patient had active, previously diagnosed GVHD, and 3 patients were on systemic steroid therapy at the time of pericarditis diagnosis. Pericarditis was treated primarily with colchicine (median duration 91 days). Seven episodes of recurrence occurred in 5 patients. Two patients experienced cardiac tamponade following their initial diagnosis, and 3 developed tamponade at recurrence. Recurrence was more common in patients who received no or <90 days of colchicine compared with those who received ≥90 days (45.5% vs 0%; P = .02). No cardiac-related deaths occurred. Overall survival was 85% at a median follow-up of 30 months post-alloHCT. Pericarditis occurred in 3.2% of patients in this single-center study, with cases observed both before and after day +100 and some cases occurring ≥1 year after alloHCT. Colchicine was an effective intervention, with ≥90 days of treatment associated with reduced recurrence. Pericarditis should be considered in patients presenting with chest pain following alloHCT.
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http://dx.doi.org/10.1016/j.jtct.2021.07.025DOI Listing
November 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

Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells.

Nat Med 2021 05 22;27(5):842-850. Epub 2021 Apr 22.

Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

While CD19-directed chimeric antigen receptor (CAR) T cells can induce remission in patients with B cell acute lymphoblastic leukemia (ALL), a large subset relapse with CD19 disease. Like CD19, CD22 is broadly expressed by B-lineage cells and thus serves as an alternative immunotherapy target in ALL. Here we present the composite outcomes of two pilot clinical trials ( NCT02588456 and NCT02650414 ) of T cells bearing a 4-1BB-based, CD22-targeting CAR in patients with relapsed or refractory ALL. The primary end point of these studies was to assess safety, and the secondary end point was antileukemic efficacy. We observed unexpectedly low response rates, prompting us to perform detailed interrogation of the responsible CAR biology. We found that shortening of the amino acid linker connecting the variable heavy and light chains of the CAR antigen-binding domain drove receptor homodimerization and antigen-independent signaling. In contrast to CD28-based CARs, autonomously signaling 4-1BB-based CARs demonstrated enhanced immune synapse formation, activation of pro-inflammatory genes and superior effector function. We validated this association between autonomous signaling and enhanced function in several CAR constructs and, on the basis of these observations, designed a new short-linker CD22 single-chain variable fragment for clinical evaluation. Our findings both suggest that tonic 4-1BB-based signaling is beneficial to CAR function and demonstrate the utility of bedside-to-bench-to-bedside translation in the design and implementation of CAR T cell therapies.
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http://dx.doi.org/10.1038/s41591-021-01326-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451032PMC
May 2021

CAR T in adult ALL: When and for whom?

Best Pract Res Clin Haematol 2021 03 13;34(1):101256. Epub 2021 Feb 13.

Cell Therapy and Transplant Program, Abramson Cancer Center, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Chimeric antigen receptor T cell therapy targeting CD19 (CART19) has shown remarkable results in patients with relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (ALL). In patients 25 years of age or younger CART19 therapy is an accepted standard of care, while the treatment of older adults is less straight forward and possible only in the context of a clinical trial. Treatment of older patients with CAR T cells requires careful consideration of overall treatment goals, suitability of a consolidative hematopoietic stem cell transplant (HSCT), alternative treatment options, patient risk profile, and anticipated responses and toxicities of the specific CAR T cell products available. Here we use patient guided examples to inform approaches to care.
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http://dx.doi.org/10.1016/j.beha.2021.101256DOI Listing
March 2021

Tacrolimus induced pseudogout following allogeneic hematopoietic cell transplant.

J Oncol Pharm Pract 2021 Apr 20;27(3):771-775. Epub 2020 Aug 20.

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

Introduction: Crystalline arthritis (CA), characterized by acute joint pain and erythema secondary to calcium pyrophosphate deposition (CPPD, or pseudogout) or monosodium urate crystals (gout), is a potentially underreported complication following allogeneic hematopoietic cell transplant (alloHCT). Graft-versus-host disease prophylaxis with calcineurin inhibitors (CNIs) causes hypomagnesemia and hyperuricemia, resulting in CA. CA related to tacrolimus has yet to be characterized following alloHCT.

Case Report: We retrospectively reviewed records of 450 consecutive patients undergoing alloHCT and identified 15 (3.3% incidence) who developed CA on tacrolimus. Large joints were involved in 10 (66.7%) patients, all patients had recent hypomagnesemia, and no patient had hyperuricemia, suggesting CPPD was the most likely etiology. Eleven (73.3%) patients received systemic corticosteroids; 6 as initial therapy and 5 added to or substituted for colchicine in the setting of slow or inadequate response. The median duration of corticosteroid therapy was 6 days, however 2 patients (13.3%) required prolonged maintenance due to recurrence. Eleven (73.3%) patients received colchicine; 9 as initial therapy and 2 added to or substituted for corticosteroids in the setting of slow or inadequate response. The median duration of colchicine therapy was 18 days. The median time to symptom resolution was 21 days.

Discussion: Patients on tacrolimus following alloHCT presenting with acute joint pain and erythema should be evaluated for CPPD. Hypomagnesemia secondary to CNIs is likely the precipitating factor for CPPD in this population. Patients can effectively be managed with systemic corticosteroids and/or colchicine, however prolonged duration of treatment and even maintenance may be necessary. Based on the Naranjo Algorithm, CPPD secondary to tacrolimus induced hypomagnesemia is a possible adverse drug event, with a score of 3-4.
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http://dx.doi.org/10.1177/1078155220951241DOI Listing
April 2021

Cardiovascular Effects of CAR T Cell Therapy: A Retrospective Study.

JACC CardioOncol 2020 Jun 16;2(2):193-203. Epub 2020 Jun 16.

Division of Cardiovascular Diseases, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, United States.

Background: Anti-CD19 chimeric antigen receptor (CAR) T cell (CART19) therapy holds great promise in the treatment of hematological malignancies. A high occurrence of cardiac dysfunction has been noted in children treated with CART19 therapy.

Objectives: We aimed to define the occurrence of major cardiovascular events (MACE) in adult patients treated with CART19 cells and assess the relationships between clinical factors, echocardiographic parameters, laboratory values, and cardiovascular outcomes.

Methods: Baseline clinical, laboratory and echocardiographic parameters were collected in 145 adult patients undergoing CART19 cell therapy. MACE included cardiovascular death, symptomatic heart failure, acute coronary syndrome, ischemic stroke and de novo cardiac arrhythmia. Baseline parameters associated with MACE were identified using Cox proportional cause-specific hazards regression analysis.

Results: Thirty-one patients had MACE (41 events) at a median time of 11 days (Q1-Q3:6-151 days) after CART19 cell infusion. The median follow-up period was 456 days (Q1-Q3: 128-1214 days). Sixty-one patients died. Cytokine release syndrome (CRS) occurred 176 times in 104 patients; the median time to CRS was 6 days (Q1-Q3: 1-8 days). The Kaplan-Meier estimates for MACE and CRS at 30 days were 17% and 53% respectively. The KM estimates for survival at 1 year was 71%. Multivariable Cox proportional cause-specific hazards regression analysis determined that baseline creatinine and Grade 3 or 4 CRS were independently associated with MACE.

Conclusion: Patients treated with CART19 are at an increased risk of MACE and may benefit from cardiovascular surveillance. Further large prospective studies are needed to confirm the incidence and risk factors predictive of MACE.
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http://dx.doi.org/10.1016/j.jaccao.2020.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413146PMC
June 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

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

Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction.

Cancer Discov 2020 04 30;10(4):552-567. Epub 2020 Jan 30.

Division of Hematology/Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy (CART19) occurs in 10% to 20% of patients with acute lymphoblastic leukemia (ALL); however, the mechanisms of this resistance remain elusive. Using a genome-wide loss-of-function screen, we identified that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T-cell cytotoxicity that permitted antigen persistence and was subsequently magnified by the induction of CAR T-cell functional impairment. These findings were validated using samples from two CAR T-cell clinical trials in ALL, where we found that reduced expression of death receptor genes was associated with worse overall survival and reduced T-cell fitness. Our findings suggest that inherent dysregulation of death receptor signaling in ALL directly leads to CAR T-cell failure by impairing T-cell cytotoxicity and promoting progressive CAR T-cell dysfunction. SIGNIFICANCE: Resistance to CART19 is a significant barrier to efficacy in the treatment of B-cell malignancies. This work demonstrates that impaired death receptor signaling in tumor cells causes failed CART19 cytotoxicity and drives CART19 dysfunction, identifying a novel mechanism of antigen-independent resistance to CAR therapy..
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http://dx.doi.org/10.1158/2159-8290.CD-19-0813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416790PMC
April 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

Paraneoplastic Focal Segmental Glomerulosclerosis Associated With Acute Lymphocytic Leukemia.

Kidney Int Rep 2019 Oct 25;4(10):1494-1498. Epub 2019 Jun 25.

Renal, Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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http://dx.doi.org/10.1016/j.ekir.2019.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829180PMC
October 2019

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

Hodgkin lymphoma patients have an increased incidence of idiopathic acquired aplastic anemia.

PLoS One 2019 5;14(4):e0215021. Epub 2019 Apr 5.

Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, United States of America.

Idiopathic acquired aplastic anemia (AA) is a rare lymphocyte-mediated bone marrow aplasia. No specific mechanisms or triggers of AA have been identified. We recently observed several patients who developed AA after Hodgkin lymphoma (HL). We hypothesized that the co-occurrence of HL and AA is not random and may be etiologically significant. To test this hypothesis, we determined the incidence of AA in HL patients at our institution. We identified four patients with co-occurring HL and AA, with the incidence of AA in HL patients >20-fold higher compared to the general population. We identified 12 additional patients with AA and HL through a systematic literature review. Of the 16 total patients,15 (93.8%) developed AA after or concurrent with a HL diagnosis. None of the patients had marrow involvement by HL. Five of 15 patients were in complete remission from HL at the time of AA diagnosis, and six had a concurrent presentation with no prior cytotoxic therapy, with diagnostic timeframe information unavailable for four patients. The median interval between HL diagnosis and AA onset was 16 months, ranging from concurrent to 14 years after a HL diagnosis. The median survival after AA diagnosis was 14 months (range: 1 month to 20 years). Our results show that patients with HL have a higher incidence of AA compared to the general population and suggest that HL-related immune dysregulation may be a risk factor for AA. Better recognition and management of AA in HL patients is needed to improve outcomes in this population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215021PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450628PMC
December 2019

Chimeric antigen receptor T cells for acute lymphoblastic leukemia.

Authors:
Noelle V Frey

Am J Hematol 2019 05 22;94(S1):S24-S27. Epub 2019 Mar 22.

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

Chimeric antigen receptor (CAR) modified T cells targeted to CD19 have resulted in unprecedented remission rates for adult and pediatric patients with relapsed and refractory B cell acute lymphoblastic leukemia (ALL). With regulatory approval for tisagenlecleucel and many other agents under active investigation, the use of CAR T cells for ALL continues to expand. While some remissions from anti-CD19 CAR T cells are durable without a consolidative allogeneic stem cell transplantation, CD19 positive and negative relapses remain a significant concern fueling investigations into the biology of CAR T cell persistence and the development of CARTs that target more than 1 antigen. The treatment related toxicities of cytokine release syndrome and neurologic events are potentially life threatening but recent advances have improved understanding and management strategies. This review summarizes outcomes for patients with ALL treated with CD19-CAR T cells while exploring the field's challenges and future directions.
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http://dx.doi.org/10.1002/ajh.25442DOI Listing
May 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

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

Oral Vancomycin Prophylaxis Is Highly Effective in Preventing Clostridium difficile Infection in Allogeneic Hematopoietic Cell Transplant Recipients.

Clin Infect Dis 2019 05;68(12):2003-2009

Blood and Marrow Transplantation Program, Abramson Cancer Center and the Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.

Background: Clostridium difficile infection (CDI) is a leading cause of infectious complications in allogeneic hematopoietic cell transplant recipients (alloHCT). We sought to evaluate whether prophylactic oral vancomycin reduces the incidence of CDI in alloHCT recipients.

Methods: We conducted a retrospective cohort study to examine the effectiveness of CDI prophylaxis with oral vancomycin, as compared to no prophylaxis, in 145 consecutive adult alloHCT recipients at the University of Pennsylvania between April 2015 and November 2016. Patients received oral vancomycin 125 mg twice daily, starting on admission and continuing until discharge. The primary outcome of interest was the association between oral vancomycin prophylaxis and CDI diagnosis. Secondary outcomes included graft-versus-host disease (GVHD) and relapse.

Results: There were no cases of CDI in patients that received prophylaxis (0/90, 0%), whereas 11/55 (20%) patients who did not receive prophylaxis developed CDI (P < .001). Oral vancomycin prophylaxis was not associated with a higher risk of acute, grades 2-4 GVHD (subhazard ratio [sHR] 1.59; 95% confidence interval [CI] 0.88-2.89; P = .12), acute, grades 3-4 GVHD (sHR 0.65; 95% CI 0.25-1.66; P = .36), or acute, grades 2-4 gastrointestinal GVHD (sHR 1.95; 95% CI 0.93-4.07; P = .08) at day 180 post-transplant. No associations between oral vancomycin and relapse or survival were observed.

Conclusions: Prophylaxis with oral vancomycin is highly effective in preventing CDI in alloHCT recipients without increasing the risk of graft-versus-host disease or disease relapse. Further evaluation via a prospective study is warranted.
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http://dx.doi.org/10.1093/cid/ciy822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541731PMC
May 2019

Tocilizumab for the treatment of severe steroid-refractory acute graft-versus-host disease of the lower gastrointestinal tract.

Bone Marrow Transplant 2019 02 24;54(2):212-217. Epub 2018 May 24.

Blood and Marrow Transplantation Program, Abramson Cancer Center and the Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Steroid-refractory (SR) acute gastrointestinal (GI) graft-versus-host disease (GVHD) is associated with significant mortality in allogeneic hematopoietic cell transplantation recipients. We retrospectively evaluated the efficacy of tocilizumab for the treatment of SR biopsy-proven acute lower GI GVHD in 16 consecutive adult transplant recipients between October 2015 and July 2016. Tocilizumab 8 mg/kg was administered every 2 weeks until achievement of complete response, defined as resolution of all manifestations of GI GVHD, or until patients had progression or initiation of other therapy. Ten of 16 patients (62.5%; 95% CI, 0.39-82) achieved a complete response after a median time of 11 days (range, 2-28 days) from tocilizumab initiation. The median time to response onset (improvement in stage by at least 1) was 1 day (range, 1-4 days). Tocilizumab was administered at a median of 9 days (range, 3-75 days) from GVHD diagnosis and 10 days (range, 3-75 days) from initiation of high-dose steroids. At a median follow-up of 7.6 months (range, 0.8-27.7 months) from initiation of tocilizumab, 6/16 (37.5%) patients are alive and free of their underlying hematologic malignancy. Tocilizumab appears to be a highly active agent for the treatment of severe SR lower GI acute GVHD.
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http://dx.doi.org/10.1038/s41409-018-0236-zDOI Listing
February 2019

Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia.

Nat Med 2018 05 30;24(5):563-571. Epub 2018 Apr 30.

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Tolerance to self-antigens prevents the elimination of cancer by the immune system. We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response. Transcriptomic profiling revealed that CAR T cells from complete-responding patients with CLL were enriched in memory-related genes, including IL-6/STAT3 signatures, whereas T cells from nonresponders upregulated programs involved in effector differentiation, glycolysis, exhaustion and apoptosis. Sustained remission was associated with an elevated frequency of CD27CD45ROCD8 T cells before CAR T cell generation, and these lymphocytes possessed memory-like characteristics. Highly functional CAR T cells from patients produced STAT3-related cytokines, and serum IL-6 correlated with CAR T cell expansion. IL-6/STAT3 blockade diminished CAR T cell proliferation. Furthermore, a mechanistically relevant population of CD27PD-1CD8 CAR T cells expressing high levels of the IL-6 receptor predicts therapeutic response and is responsible for tumor control. These findings uncover new features of CAR T cell biology and underscore the potential of using pretreatment biomarkers of response to advance immunotherapies.
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http://dx.doi.org/10.1038/s41591-018-0010-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117613PMC
May 2018

Sirolimus enhances remission induction in patients with high risk acute myeloid leukemia and mTORC1 target inhibition.

Invest New Drugs 2018 08 2;36(4):657-666. Epub 2018 Apr 2.

Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1's kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML. Methods Flow cytometric measurements of ribosomal protein S6 phosphorylation (pS6) were performed before and during sirolimus treatment to determine whether mTORC1 inhibition enriched for chemotherapy response. Results In 51 evaluable subjects, the overall response rate (ORR) to the combination regimen was 47% (95% confidence interval 33-61%, 33% CR, 2% CRi, 12% PR) and similar toxicity to historic experience with MEC alone. 37 subjects had baseline pS6 measured pre-sirolimus, of whom 27 (73%) exhibited mTORC1 activity. ORR was not significantly different between subjects with and without baseline mTORC1 activity (52% vs 40%, respectively, p = 0.20). The ORR among subjects with baseline target activation and mTORC1 inhibition during therapy was 71% (12/17) compared to 20% (2/10) in subjects without target inhibition. Conclusions Fixed, whole blood pS6 by flow cytometry may be a predictive biomarker for clinical response to mTORC1 inhibitor-based regimens. These data provide clinical confirmation that mTORC1 activation mediates chemotherapy resistance in patients with AML.
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http://dx.doi.org/10.1007/s10637-018-0585-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060002PMC
August 2018

Higher Donor Apheresis Blood Volumes Are Associated with Reduced Relapse Risk and Improved Survival in Reduced-Intensity Allogeneic Transplantations with Unrelated Donors.

Biol Blood Marrow Transplant 2018 06 2;24(6):1203-1208. Epub 2018 Feb 2.

Blood and Marrow Transplantation Program and Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY. Electronic address:

Allogeneic hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) offers a curative option for patients with hematologic malignancies who are unable to undergo myeloablative conditioning, but its success is limited by high rates of relapse. Several studies have suggested a role for T cell doses in peripheral blood stem cell grafts in RIC HSCT. Because T cell dose is typically not known until after the collection, and apheresis blood volume is easily modifiable, we hypothesized that higher donor apheresis blood volumes would improve transplantation outcomes through an effect on graft composition. Thus, we analyzed the relationships between apheresis volume, graft composition, and transplantation outcomes in 142 consecutive patients undergoing unrelated donor allogeneic RIC HSCT. We found that apheresis volume ≥15 L was associated with a significantly decreased risk of relapse (adjusted hazard ratio [aHR], .48; 95% confidence interval [CI], .28 to .84]; P = .01) and improved relapse-free survival (aHR, .56; 95% CI, .35 to .89; P = .02) and overall survival (aHR, .55; 95% CI, .34 to .91; P = .02). A high apheresis volume was not associated with increased rates of acute or chronic graft-versus-host disease. These results demonstrate that an apheresis volume of at least 15 L is independently predictive of improved transplantation outcomes after RIC allogeneic HSCT.
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http://dx.doi.org/10.1016/j.bbmt.2018.01.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993582PMC
June 2018

The promise of chimeric antigen receptor T cells (CARTs) in leukaemia.

Br J Haematol 2017 04 15;177(1):13-26. Epub 2016 Dec 15.

Department of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA, USA.

The success of genetically engineered T cells that express chimeric antigen receptors (CARTs) has been a momentous step forward in harnessing the potent cancer fighting abilities of the immune system. The efficacy seen in relapsed/refractory (r/r) acute lymphoblastic leukaemia (ALL), not only by inducing remission, but also in maintaining long-term disease control, has been unprecedented. While the foundation for this approach has been firmly set in place, continued development will improve the efficacy, toxicity and applicability to other malignancies of this new class of 'living drugs'. In this review, we provide a comprehensive overview of the most current clinical trial data in both acute and chronic leukaemias, and discuss some of the potential ways to enhance the activity and safety of CART therapy going forward.
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http://dx.doi.org/10.1111/bjh.14475DOI Listing
April 2017

Cytokine release syndrome with novel therapeutics for acute lymphoblastic leukemia.

Hematology Am Soc Hematol Educ Program 2016 Dec;2016(1):567-572

Abramson Cancer Center, Hospital of the University of Pennsylvania, Philadelphia, PA.

T-cell-engaging immunotherapies are exciting new approaches to treat patients with acute lymphoblastic leukemia (ALL). These unique agents, which include blinatumomab, a CD3/CD19 bispecific antibody, and chimeric antigen receptor (CAR) modified T cells targeted to CD19 have shown unprecedented remission rates in the relapsed, refractory ALL setting. Cytokine release syndrome (CRS), resulting from the high magnitude of immune activation by these therapies, is the most significant treatment-related toxicity. CRS manifests with fever and malaise and can progress to life-threatening capillary leak with hypoxia and hypotension. The clinical signs of CRS correlate with T-cell activation and high levels of cytokines, including interleukin 6 (IL-6). Tocilizumab, an anti-IL-6 receptor antagonist, is usually effective in the management of severe CRS induced by CAR T cells and has been adopted by most clinical trial programs. With blinatumomab administration, the goal has been to prevent CRS with corticosteroid premedication, disease cytoreduction, and dose adjustments. Collaborative efforts are underway to harmonize the definition and grading system of CRS to allow for better interpretation of toxicities across trials and allow for informed management algorithms.
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http://dx.doi.org/10.1182/asheducation-2016.1.567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142489PMC
December 2016

The Promise of Chimeric Antigen Receptor T-Cell Therapy.

Oncology (Williston Park) 2016 10;30(10):880-8, 890

Chimeric antigen receptors (CARs) are engineered molecules that can be introduced into T cells to enable them to target specific tumor antigens. CAR T cells targeting CD19 have shown promise in patients with relapsed and refractory B-cell neoplasms, including those with acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphomas. Notably, durable responses have been observed in patients who had not undergone consolidative stem cell transplant, a finding that correlates with reports of T-cell persistence and B-cell aplasia in studies of anti-CD19 treatment in vivo. Cytokine release syndrome, correlating with activation and expansion of T cells, and neurologic toxicity are the most significant treatment-related adverse effects. Efforts are underway to extend the benefits of immunotherapy with anti-CD19 CAR T cells to other targets and tumor types.
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October 2016

Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia.

Crit Care Med 2017 Feb;45(2):e124-e131

1Division of Critical Care Medicine, Department of Anesthesia and Critical Care, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 2Division of Oncology, Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 3Center for Cellular Immunotherapies, Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 4Department of Biostatistics and Epidemiology, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 5Division of Hematology-Oncology, Department of Medicine, Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

Objective: Initial success with chimeric antigen receptor-modified T cell therapy for relapsed/refractory acute lymphoblastic leukemia is leading to expanded use through multicenter trials. Cytokine release syndrome, the most severe toxicity, presents a novel critical illness syndrome with limited data regarding diagnosis, prognosis, and therapy. We sought to characterize the timing, severity, and intensive care management of cytokine release syndrome after chimeric antigen receptor-modified T cell therapy.

Design: Retrospective cohort study.

Setting: Academic children's hospital.

Patients: Thirty-nine subjects with relapsed/refractory acute lymphoblastic leukemia treated with chimeric antigen receptor-modified T cell therapy on a phase I/IIa clinical trial (ClinicalTrials.gov number NCT01626495).

Interventions: All subjects received chimeric antigen receptor-modified T cell therapy. Thirteen subjects with cardiovascular dysfunction were treated with the interleukin-6 receptor antibody tocilizumab.

Measurements And Main Results: Eighteen subjects (46%) developed grade 3-4 cytokine release syndrome, with prolonged fever (median, 6.5 d), hyperferritinemia (median peak ferritin, 60,214 ng/mL), and organ dysfunction. Fourteen (36%) developed cardiovascular dysfunction treated with vasoactive infusions a median of 5 days after T cell therapy. Six (15%) developed acute respiratory failure treated with invasive mechanical ventilation a median of 6 days after T cell therapy; five met criteria for acute respiratory distress syndrome. Encephalopathy, hepatic, and renal dysfunction manifested later than cardiovascular and respiratory dysfunction. Subjects had a median of 15 organ dysfunction days (interquartile range, 8-20). Treatment with tocilizumab in 13 subjects resulted in rapid defervescence (median, 4 hr) and clinical improvement.

Conclusions: Grade 3-4 cytokine release syndrome occurred in 46% of patients following T cell therapy for relapsed/refractory acute lymphoblastic leukemia. Clinicians should be aware of expanding use of this breakthrough therapy and implications for critical care units in cancer centers.
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http://dx.doi.org/10.1097/CCM.0000000000002053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452983PMC
February 2017
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