Publications by authors named "Selina M Luger"

104 Publications

Posttraumatic stress disorder (PTSD) symptoms in patients with acute myeloid leukemia (AML).

Cancer 2021 Mar 25. Epub 2021 Mar 25.

Harvard Medical School, Boston, Massachusetts.

Background: Patients with acute myeloid leukemia (AML) receiving intensive chemotherapy face a life-threatening illness, isolating hospitalization, and substantial physical and psychological symptoms. However, data are limited regarding risk factors of posttraumatic stress disorder (PTSD) symptoms in this population.

Methods: The authors conducted a secondary analysis of data from 160 patients with high-risk AML who were enrolled in a supportive care trial. The PTSD Checklist-Civilian Version was used to assess PTSD symptoms at 1 month after AML diagnosis. The Brief COPE and the Functional Assessment of Cancer Therapy-Leukemia were to assess coping and quality of life (QOL), respectively. In addition, multivariate regression models were constructed to assess the relation between PTSD symptoms and baseline sociodemographic factors, coping, and QOL.

Results: Twenty-eight percent of patients reported PTSD symptoms, describing high rates of intrusion, avoidance, and hypervigiliance. Baseline sociodemographic factors significantly associated with PTSD symptoms were age (B = -0.26; P = .002), race (B = -8.78; P = .004), and postgraduate education (B = -6.30; P = .029). Higher baseline QOL (B = -0.37; P ≤ .001) and less decline in QOL during hospitalization (B = -0.05; P = .224) were associated with fewer PTSD symptoms. Approach-oriented coping (B = -0.92; P = .001) was associated with fewer PTSD symptoms, whereas avoidant coping (B = 2.42; P ≤ .001) was associated with higher PTSD symptoms.

Conclusions: A substantial proportion of patients with AML report clinically significant PTSD symptoms 1 month after initiating intensive chemotherapy. Patients' baseline QOL, coping strategies, and extent of QOL decline during hospitalization emerge as important risk factors for PTSD, underscoring the need for supportive oncology interventions to reduce the risk of PTSD in this population.
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http://dx.doi.org/10.1002/cncr.33524DOI Listing
March 2021

Comparison of CALGB 10403 (Alliance) and COG AALL0232 toxicity results in young adults with acute lymphoblastic leukemia.

Blood Adv 2021 Jan;5(2):504-512

University of Chicago Comprehensive Cancer Center, Chicago, IL.

Adolescents and young adults (AYAs) with acute lymphoblastic leukemia have improved outcomes when treated with pediatric-inspired regimens. CALGB 10403 was the largest prospective study to evaluate the feasibility of using a pediatric regimen in AYAs with acute lymphoblastic leukemia up to 40 years of age. This article presents the toxicity events observed in the CALGB 10403 study and compares these toxicities vs those observed among AYAs treated on the same arm of the companion Children's Oncology Group (COG) AALL0232 study. Toxicities in CALGB 10403 were similar to those observed in COG AALL0232. Some grade 3 to 4 adverse events were more often reported in CALGB 10403 compared with COG AALL0232 (hyperglycemia, hyperbilirubinemia, transaminase elevation, and febrile neutropenia). Adverse events correlated with body mass index ≥30 kg/m2 and some with increasing age. The mortality rate in CALGB 10403 was low (4%) and similar to that in the COG AALL0232 trial. A caveat to this analysis is that only 39% of CALGB 10403 patients completed all planned protocol treatment. In COG AALL0232, although 74% of patients aged <18 years completed treatment, only 57% of patients aged ≥18 years completed treatment. This scenario suggests that issues associated with age and treating physician may be a factor. Due to its improved survival rates compared with historical controls, the CALGB 10403 regimen is now a standard of care. The hope is that the rate of protocol completion will increase as more familiarity is gained with this regimen. These trials were registered at www.clinicaltrials.gov as #NCT00558519 (CALGB 10403) and #NCT00075725 (COG AALL0232).
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http://dx.doi.org/10.1182/bloodadvances.2020002439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839367PMC
January 2021

Rapid fluorescence in situ hybridisation optimises induction therapy for acute myeloid leukaemia.

Br J Haematol 2020 12 10;191(5):935-938. Epub 2020 Sep 10.

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

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http://dx.doi.org/10.1111/bjh.17082DOI Listing
December 2020

Lenalidomide-Epoetin Alfa Versus Lenalidomide Monotherapy in Myelodysplastic Syndromes Refractory to Recombinant Erythropoietin.

J Clin Oncol 2021 Mar 13;39(9):1001-1009. Epub 2021 Jan 13.

Leukemia Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY.

Purpose: Impaired response to erythropoietin underlies ineffective erythropoiesis and anemia in myelodysplastic syndromes (MDS). We investigated whether treatment with lenalidomide (LEN), which augments erythropoietin receptor signaling in vitro, can restore and improve hemoglobin response to epoetin (EPO) alfa in patients with lower-risk, non-del(5q) MDS who have anemia that is refractory to or have low probability of benefit from treatment with recombinant erythropoietin.

Methods: In a phase III, US intergroup trial, we randomly assigned patients to receive either LEN and EPO alfa or LEN alone following stratification by serum erythropoietin concentration and prior erythropoietin treatment.

Results: A total of 195 evaluable patients were randomly assigned: 99 patients to the LEN-EPO alfa cohort and 96 to LEN alone. After four cycles of treatment, the primary end point of major erythroid response (MER) was significantly higher (28.3%) with the combination compared with LEN alone (11.5%) ( = .004). Among 136 patients who completed 16 weeks of study treatment, 38.9% and 15.6% achieved MER, respectively ( = .004). Additionally, minor erythroid response was achieved in 18.2% and 20.8% of patients, for an overall erythroid response rate of 46.5% versus 32.3%. Among LEN nonresponders, 38 crossed over to the addition of EPO alfa with 10 patients (26.3%) achieving a MER. Responses to the combined treatment were highly durable with a median MER duration of 23.8 months compared with 13 months with LEN alone.

Conclusion: LEN restores sensitivity to recombinant erythropoietin in growth factor-insensitive, lower-risk, non-del(5q) MDS, to yield a significantly higher rate and duration of MER compared with LEN alone (funded by the National Cancer Institute; E2905 ClinicalTrials.gov identifier: NCT02048813).
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http://dx.doi.org/10.1200/JCO.20.01691DOI Listing
March 2021

Consolidation Therapy for Acute Myeloid Leukemia: Defining a Benchmark.

Authors:
Selina M Luger

J Clin Oncol 2021 Mar 7;39(8):870-875. Epub 2021 Jan 7.

Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Journal Journal of Clinical Oncology,
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http://dx.doi.org/10.1200/JCO.20.03142DOI Listing
March 2021

Effectiveness of Integrated Palliative and Oncology Care for Patients With Acute Myeloid Leukemia: A Randomized Clinical Trial.

JAMA Oncol 2021 Feb;7(2):238-245

Massachusetts General Hospital, Boston.

Importance: Patients with acute myeloid leukemia (AML) receiving intensive chemotherapy experience substantial decline in their quality of life (QOL) and mood during their hospitalization for induction chemotherapy and often receive aggressive care at the end of life (EOL). However, the role of specialty palliative care for improving the QOL and care for this population is currently unknown.

Objective: To assess the effect of integrated palliative and oncology care (IPC) on patient-reported and EOL outcomes in patients with AML.

Design, Setting, And Participants: We conducted a multisite randomized clinical trial of IPC (n = 86) vs usual care (UC) (n = 74) for patients with AML undergoing intensive chemotherapy. Data were collected from January 2017 through July 2019 at 4 tertiary care academic hospitals in the United States.

Interventions: Patients assigned to IPC were seen by palliative care clinicians at least twice per week during their initial and subsequent hospitalizations.

Main Outcomes And Measures: Patients completed the 44-item Functional Assessment of Cancer Therapy-Leukemia scale (score range, 0-176) to assess QOL; the 14-item Hospital Anxiety and Depression Scale (HADS), with subscales assessing symptoms of anxiety and depression (score range, 0-21); and the PTSD Checklist-Civilian version to assess posttraumatic stress disorder (PTSD) symptoms (score range, 17-85) at baseline and weeks 2, 4, 12, and 24. The primary end point was QOL at week 2. We used analysis of covariance adjusting and mixed linear effect models to evaluate patient-reported outcomes. We used Fisher exact test to compare patient-reported discussion of EOL care preferences and receipt of chemotherapy in the last 30 days of life.

Results: Of 235 eligible patients, 160 (68.1%) were enrolled; of the 160 participants, the median (range) age was 64.4 (19.7-80.1) years, and 64 (40.0%) were women. Compared with those receiving UC, IPC participants reported better QOL (adjusted mean score, 107.59 vs 116.45; P = .04), and lower depression (adjusted mean score, 7.20 vs 5.68; P = .02), anxiety (adjusted mean score, 5.94 vs 4.53; P = .02), and PTSD symptoms (adjusted mean score, 31.69 vs 27.79; P = .01) at week 2. Intervention effects were sustained to week 24 for QOL (β, 2.35; 95% CI, 0.02-4.68; P = .048), depression (β, -0.42; 95% CI, -0.82 to -0.02; P = .04), anxiety (β, -0.38; 95% CI, -0.75 to -0.01; P = .04), and PTSD symptoms (β, -1.43; 95% CI, -2.34 to -0.54; P = .002). Among patients who died, those receiving IPC were more likely than those receiving UC to report discussing EOL care preferences (21 of 28 [75.0%] vs 12 of 30 [40.0%]; P = .01) and less likely to receive chemotherapy near EOL (15 of 43 [34.9%] vs 27 of 41 [65.9%]; P = .01).

Conclusions And Relevance: In this randomized clinical trial of patients with AML, IPC led to substantial improvements in QOL, psychological distress, and EOL care. Palliative care should be considered a new standard of care for patients with AML.

Trial Registration: ClinicalTrials.gov Identifier: NCT02975869.
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http://dx.doi.org/10.1001/jamaoncol.2020.6343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747042PMC
February 2021

Herpes zoster during arsenic trioxide therapy for acute promyelocytic leukemia.

Leuk Lymphoma 2021 03 26;62(3):696-702. Epub 2020 Oct 26.

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

Historically, arsenic exposure has been associated with herpes zoster (HZ) infection, however the risk is not well characterized in arsenic trioxide (ATO) treated patients with acute promyelocytic leukemia (APL). We aimed to characterize the risk of HZ in 112 ATO treated patients with APL with and without antiviral prophylaxis (AVP). HZ occurred in 13/112 (11.6%) within 6 months of completing ATO, including one case of HZ encephalitis. AVP reduced the incidence of HZ (17.5% vs. 4.1%, RR 0.24 [95% CI 0.05-1.0,  = .025]) with a number needed to treat of 7.7. HZ despite AVP occurred later than HZ in patients without AVP (7.8 vs. 2.3 months from starting ATO,  = .11). Older age and prior HZ increased the risk of HZ in patients not receiving AVP. Routine AVP should be considered in patients with APL receiving ATO, particularly in older patients and those with a history of HZ.
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http://dx.doi.org/10.1080/10428194.2020.1838507DOI 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

Incorporation of extracorporeal photopheresis into a reduced intensity conditioning regimen in myelodysplastic syndrome and aggressive lymphoma: results from ECOG 1402 and 1902.

Transfusion 2020 Aug 12;60(8):1867-1872. Epub 2020 Jul 12.

Genentech Inc, San Francisco, California.

Background: Extracorporeal photopheresis (ECP) is an immunomodulatory cellular therapy which has been shown to induce a tolerogenic state in patients with acute and chronic graft-vs-host disease. ECOG-ACRIN explored the activity of ECP as a part of a reduced intensity conditioning regimen in two multicenter trials in patients with MDS (E1902) and lymphomas (E1402). While both studies closed before completing accrual, we report results in 23 patients (17 MDS and 6 lymphoma).

Study Design And Methods: Patients received 2 days of ECP followed by pentostatin 4 mg/m2 /day for two consecutive days, followed by 600 cGy of total body irradiation prior to stem cell infusion. Immunosuppression for aGVHD was infusional cyclosporine A or tacrolimus and methotrexate on day +1, +3, with mycophenolate mofetil starting on day 100 for chronic GVHD prophylaxis.

Results: All patients engrafted, with median time to neutrophil and platelet engraftment of 15-18 days and 10-18 days respectively. Grade 3 or 4 aGVHD occurred in 13% and chronic extensive GVHD in 30%.

Conclusions: These studies demonstrate that ECP/pentostatin/TBI is well tolerated and associated with adequate engraftment of neutrophils and platelets in patients with lymphomas and MDS.
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http://dx.doi.org/10.1111/trf.15798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606221PMC
August 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

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

At three years, patients with acute lymphoblastic leukaemia are still at risk for relapse. Results of the international MRC UKALLXII/ECOG E2993 trial.

Br J Haematol 2020 10 27;191(1):37-43. Epub 2020 Mar 27.

University College London, London, UK.

Late relapse [>3 years from complete remission (CR)] in acute lymphoblastic leukaemia (ALL), is unusual. Data from the MRC UKALLXII/ECOG E2993 trial are presented to evaluate the incidence and characteristics of late relapse in adult ALL. Of 1,909 patients, 1,752 (92%) achieved CR and among these 757 (43·2%) relapsed; 691 (91·3%) within three years and 66 (8·7%) beyond. Among these 66 patients, median time to relapse was 47 (37-144) months. Relapse beyond three years occurred in 3·8% of all who achieved CR. The cumulative risk of relapse was 40%, 43% and 45% at three, five and ten years respectively. Out of the 1 752 patients who achieved CR, 11·7% underwent autologous and 40·6% allogeneic transplant, while in CR1. Of the autologous patients, 43·2% relapsed early and 3·4% relapsed late. However, among the allogeneic patients, 13·2% relapsed early and only 1·3% late. The five-year overall survival from relapse was 5·8% and 20% in the early and late relapse patients respectively. In conclusion, late relapse in adults with ALL is not uncommon, and is associated with better outcome after relapse compared to early relapse.
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http://dx.doi.org/10.1111/bjh.16616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687130PMC
October 2020

Rapid Donor Identification Improves Survival in High-Risk First-Remission Patients With Acute Myeloid Leukemia.

JCO Oncol Pract 2020 06 27;16(6):e464-e475. Epub 2020 Jan 27.

Fred Hutchinson Cancer Research Center, Seattle, WA.

Purpose: Patients with acute myeloid leukemia with high-risk cytogenetics in first complete remission (CR1) achieve better outcomes if they undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy alone. However, only approximately 40% of such patients typically proceed to HCT.

Methods: We used a prospective organized approach to rapidly identify donors to improve the allogeneic HCT rate in adults with high-risk acute myeloid leukemia in CR1. Newly diagnosed patients had cytogenetics obtained at enrollment, and those with high-risk cytogenetics underwent expedited HLA typing and were encouraged to be referred for consultation with a transplantation team with the goal of conducting an allogeneic HCT in CR1.

Results: Of 738 eligible patients (median age, 49 years; range, 18-60 years of age), 159 (22%) had high-risk cytogenetics and 107 of these patients (67%) achieved CR1. Seventy (65%) of the high-risk patients underwent transplantation in CR1 ( < .001 compared with the historical rate of 40%). Median time to HCT from CR1 was 77 days (range, 20-356 days). In landmark analysis, overall survival (OS) among patients who underwent transplantation was significantly better compared with that of patients who did not undergo transplantation (2-year OS, 48% 35%, respectively [ = .031]). Median relapse-free survival after transplantation in the high-risk cohort who underwent transplantation in CR1 (n = 70) was 11.5 months (range, 4-47 months), and median OS after transplantation was 14 months (range, 4-44 months).

Conclusion: Early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donor led to a CR1 transplantation rate of 65% in the high-risk group, which, in turn, led to an improvement in OS when compared with the OS of patients who did not undergo transplantation.
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http://dx.doi.org/10.1200/JOP.19.00133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291544PMC
June 2020

Wide variation in use and interpretation of gene mutation profiling panels among health care providers of patients with myelodysplastic syndromes: results of a large web-based survey.

Leuk Lymphoma 2020 06 6;61(6):1455-1464. Epub 2020 Feb 6.

Department of Internal Medicine, Section of Hematology, Yale School of Medicine, New Haven, CT, USA.

Next-generation sequencing (NGS) is increasingly employed for diagnosis, risk stratification, and management of patients with myelodysplastic syndrome (MDS). We aimed to describe beliefs and practice patterns among providers who treat MDS patients with respect to the utility of NGS in diagnosis, risk stratification, prognosis, and treatment decisions at various points along the disease trajectory, response assessment, and development of institutional guidelines for MDS-specific molecular profiling. Using a 23-question web-based survey in May-June 2018, we identified a widespread use of molecular profiling with MDS-specific panels ( = 53; 39%) and general panels including MDS-related genes ( = 63; 47%), with the majority done at diagnosis (92%). We found substantial variations in genes tested in assays, providers beliefs, practices, testing logistics, and interpretation of results, and recognized multiple challenges limiting a wider utilization of molecular profiling. High-quality data are needed to develop evidence-based guidelines for the role of NGS in the care of MDS patients.
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http://dx.doi.org/10.1080/10428194.2020.1723013DOI Listing
June 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
February 2020

Acute myeloid leukemia: How to treat the fit patient over age 75?

Authors:
Selina M Luger

Best Pract Res Clin Haematol 2019 12 19;32(4):101105. Epub 2019 Oct 19.

Leukemia Program, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, 12th Floor South Pavilion, Philadelphia, PA, 19104, USA. Electronic address:

Survival rates for patients with acute myeloid leukemia (AML) older than 75 years are still quite dismal. Recent approvals, therefore, of two agents specifically to treat older patients-glasdegib and venetoclax-have created excitement among the medical community. Clinical data, particularly complete response (CR) rates and CR with incomplete hematologic recovery (CRi), look quite promising and are reviewed here. Yet the question remains whether fit elderly patients should receive combination therapy containing the newer agents, particularly since intensive chemotherapy remains the only treatment that has demonstrated the ability to achieve long-term disease-free survival.
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http://dx.doi.org/10.1016/j.beha.2019.101105DOI Listing
December 2019

Longitudinal targeted next-generation sequencing in a patient with acute myeloid leukaemia.

Br J Haematol 2019 09 17;186(6):801. Epub 2019 Jun 17.

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

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http://dx.doi.org/10.1111/bjh.16048DOI Listing
September 2019

Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia.

Cancer Discov 2019 08 14;9(8):1050-1063. Epub 2019 May 14.

Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.

Gilteritinib is a potent and selective kinase inhibitor with single-agent clinical efficacy in relapsed/refractory -mutated acute myeloid leukemia (AML). In this context, however, gilteritinib is not curative, and response duration is limited by the development of secondary resistance. To evaluate resistance mechanisms, we analyzed baseline and progression samples from patients treated on clinical trials of gilteritinib. Targeted next-generation sequencing at the time of AML progression on gilteritinib identified treatment-emergent mutations that activate RAS/MAPK pathway signaling, most commonly in or Less frequently, secondary -F691L gatekeeper mutations or fusions were identified at progression. Single-cell targeted DNA sequencing revealed diverse patterns of clonal selection and evolution in response to FLT3 inhibition, including the emergence of mutations in -mutated subclones, the expansion of alternative wild-type subclones, or both patterns simultaneously. These data illustrate dynamic and complex changes in clonal architecture underlying response and resistance to mutation-selective tyrosine kinase inhibitor therapy in AML. SIGNIFICANCE: Comprehensive serial genotyping of AML specimens from patients treated with the selective FLT3 inhibitor gilteritinib demonstrates that complex, heterogeneous patterns of clonal selection and evolution mediate clinical resistance to tyrosine kinase inhibition in -mutated AML. Our data support the development of combinatorial targeted therapeutic approaches for advanced AML...
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http://dx.doi.org/10.1158/2159-8290.CD-18-1453DOI Listing
August 2019

Maintenance therapy in acute myeloid leukemia: What is the future?

Semin Hematol 2019 04 28;56(2):102-109. Epub 2018 Aug 28.

Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Electronic address:

Relapse remains the primary obstacle to long-term survival in patients with acute myeloid leukemia (AML) who achieve a remission following standard induction and consolidation therapy. Although allogeneic hematopoietic stem cell transplantation decreases the risk of relapse for many patients, relapse is common even among these patients. A number of approaches to maintenance therapy for AML have been studied with the goal of finding an agent with a tolerable side effect profile that may be given to patients in remission, typically for a prolonged period of time, in order to decrease the risk of relapse. Numerous trials that evaluated cytotoxic agents as maintenance therapy did not find any improvement in survival, but more recent studies of alternative approaches to maintenance including immunomodulation, epigenetic reprogramming, and targeted agents have been much more promising. In this article, we review the current evidence for various maintenance strategies for AML including immunotherapy, hypomethylating agents, and targeted therapies, particularly FLT3 inhibitors. We also discuss promising emerging approaches to maintenance for AML, including the incorporation of measurable residual disease assessment.
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http://dx.doi.org/10.1053/j.seminhematol.2018.08.006DOI Listing
April 2019

Relapsed T Cell ALL: Current Approaches and New Directions.

Curr Hematol Malig Rep 2019 04;14(2):83-93

Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Purpose Of Review: Patients with relapsed T cell acute lymphoblastic leukemia (T-ALL) have limited therapeutic options and a poor prognosis. Although a variety of salvage chemotherapy regimens may be used, response rates are unsatisfactory. This article summarizes current approaches and promising emerging strategies for the treatment of relapsed T-ALL.

Recent Findings: Although nelarabine is the only agent approved specifically for T-ALL, recent studies have identified a variety of genetic alterations and signaling pathways that are critical in its pathogenesis. Based on these findings, a number of small-molecule inhibitors and other targeted therapies are being studied for relapsed T-ALL, including gamma-secretase inhibitors, BCL-2 inhibitors, cyclin-dependent kinase inhibitors, and mTOR inhibitors. In addition, pre-clinical studies of chimeric antigen receptor T cells targeting CD5 and CD7 as well as the monoclonal antibody daratumumab have shown promising results for T-ALL. Relapsed T-ALL currently remains challenging to treat, but recent pre-clinical studies of targeted and immunotherapeutic agents have shown encouraging results. A number of clinical trials investigating these approaches for T-ALL are currently underway.
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http://dx.doi.org/10.1007/s11899-019-00501-3DOI Listing
April 2019

The relationship between clinical trial accrual volume and outcomes in acute myeloid leukemia: A SWOG/ECOG-ACRIN study (S0106 and E1900).

Leuk Res 2019 03 17;78:29-33. Epub 2019 Jan 17.

The University of Alabama at Birmingham, Birmingham, AL, United States.

Purpose: To study whether institutional clinical trial accrual volume affects clinical outcomes of younger (age less than 61 years) patients with acute myeloid leukemia.

Patients And Methods: We investigated the impact of clinical trial accrual on response rates, early mortality and survival in patients with AML enrolled between 2002 and 2009 into two parallel cooperative group clinical trials SWOG S0106/ECOG-ACRIN E1900. Institutions were classified as low- (LAIs) (≤ 9 enrolled patients) or high-accruing institutions (HAIs) (≥10 enrolled patients). Fisher's exact text and logistic regression analysis were used to analyze the response and early mortality rates. The effect of accrual volume on survival was analyzed by log-rank tests and Cox regression models.

Results: A total of 1252 patients from 152 institutions were included in the final analyses. The median clinical trial registrations in HAIs was 19 patients (range, 10 to 92) versus 3 (range, 1 to 9) patients in LAIs. In multivariate analyses, HAIs, as a quantitative covariate, was associated with improved complete remission rates (odds ratio (OR) 1.08, p = 0.0051), but no improvement median overall survival (HR 0.97, p = 0.065) or median event-free (hazard ratio (HR) 0.97, p = 0.05). Early mortality rates were similar between cohorts and academic affiliation had no impact on response rates or survival.

Conclusion: Clinical trial accrual volume, had an independent, albeit modest, impact on complete remission rates, but not on overall survival and event-free in younger patients with AML.
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http://dx.doi.org/10.1016/j.leukres.2019.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615032PMC
March 2019

A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403.

Blood 2019 04 18;133(14):1548-1559. Epub 2019 Jan 18.

University of Chicago Comprehensive Cancer Center, Chicago, IL.

Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children's Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for response. Median age was 24 years (range, 17-39 years). Use of the pediatric regimen was safe; overall treatment-related mortality was 3%, and there were only 2 postremission deaths. Median event-free survival (EFS) was 78.1 months (95% confidence interval [CI], 41.8 to not reached), more than double the historical control of 30 months (95% CI, 22-38 months); 3-year EFS was 59% (95% CI, 54%-65%). Median overall survival (OS) was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). Pretreatment risk factors associated with worse treatment outcomes included obesity and presence of the Philadelphia-like gene expression signature. Use of a pediatric regimen for AYAs with ALL up to age 40 years was feasible and effective, resulting in improved survival rates compared with historical controls. CALGB 10403 can be considered a new treatment standard upon which to build for improving survival for AYAs with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00558519.
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http://dx.doi.org/10.1182/blood-2018-10-881961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450431PMC
April 2019

A randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease.

Am J Hematol 2019 01 15;94(1):111-117. Epub 2018 Nov 15.

Hematology/Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.

To improve the outcome of relapsed/refractory acute myeloid leukemia (AML), a randomized phase II trial of three novel regimens was conducted. Ninety patients were enrolled and were in first relapse or were refractory to induction/re-induction chemotherapy. They were randomized to the following regimens: carboplatin-topotecan (CT), each by continuous infusion for 5 days; alvocidib (formerly flavopiridol), cytarabine, and mitoxantrone (FLAM) in a timed sequential regimen; or sirolimus combined with mitoxantrone, etoposide, and cytarabine (S-MEC). The primary objective was attainment of a complete remission (CR). A Simon two-stage design was used for each of the three arms. The median age of the patients in the FLAM arm was older at 62 years compared with 55 years for the CT arm and the S-MEC arm. The overall response was 14% in the CT arm (5/35, 90% CI 7%-35%), 28% in the FLAM arm (10/36, 90% CI, 16%-43%), and 16% in the S-MEC arm (3/19, 90% CI, 4%-36%). There were nine treatment-related deaths, seven of which occurred in the FLAM arm with four of these in elderly patients. We conclude that the FLAM regimen had an encouraging response rate and should be considered for further clinical development but should be used with caution in elderly patients.
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http://dx.doi.org/10.1002/ajh.25333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298814PMC
January 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

Very poor long-term survival in past and more recent studies for relapsed AML patients: The ECOG-ACRIN experience.

Am J Hematol 2018 Jun 15. Epub 2018 Jun 15.

Memorial Sloan Kettering Cancer, New York, New York.

This study examines the long-term OS of relapsed AML patients who were enrolled to 9 successive ECOG-ACRIN trials for newly diagnosed AML, during 1984-2008. The objectives were to examine whether there is a trend of improvement in the survival of relapsed AML patients in the more recent studies and to search for prognostic factors that are associated with long-term OS after relapse. A total of 3,012 patients were enrolled, 1,779(59.1%) achieved CR1 and of these, 58.9% relapsed. The median follow-up was 9.7 years. The median OS from relapse was 0.5 years and the 5-year OS was 10(±1)%. These results were similar even for the most recent studies. A multivariate model showed that age (p<0.001), cytogenetics at diagnosis, duration of CR1 (p<0.001) and undergoing allogeneic transplantation were significantly associated with OS from relapse. Even among patients who relapsed with better prognostic factors; age<40 and CR1>12 months, there was no significant OS difference between the studies (p=0.48). In conclusion, this large cohort appears to confirm that the survival of AML patients post-relapse continues to be dismal and has not improved during the past quarter of a century. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ajh.25162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699929PMC
June 2018

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

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