Kooperativer Bibliotheksverbund

In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 29 ( 2011-07-19), p. 11983-11988

Abstract: High-throughput sequencing technology enables population-level surveys of human genomic variation. Here, we examine the joint allele frequency distributions across continental human populations and present an approach for combining complementary aspects of whole-genome, low-coverage data and targeted high-coverage data. We apply this approach to data generated by the pilot phase of the Thousand Genomes Project, including whole-genome 2–4× coverage data for 179 samples from HapMap European, Asian, and African panels as well as high-coverage target sequencing of the exons of 800 genes from 697 individuals in seven populations. We use the site frequency spectra obtained from these data to infer demographic parameters for an Out-of-Africa model for populations of African, European, and Asian descent and to predict, by a jackknife-based approach, the amount of genetic diversity that will be discovered as sample sizes are increased. We predict that the number of discovered nonsynonymous coding variants will reach 100,000 in each population after ∼1,000 sequenced chromosomes per population, whereas ∼2,500 chromosomes will be needed for the same number of synonymous variants. Beyond this point, the number of segregating sites in the European and Asian panel populations is expected to overcome that of the African panel because of faster recent population growth. Overall, we find that the majority of human genomic variable sites are rare and exhibit little sharing among diverged populations. Our results emphasize that replication of disease association for specific rare genetic variants across diverged populations must overcome both reduced statistical power because of rarity and higher population divergence.

Type of Medium: Online Resource

ISSN: 0027-8424 , 1091-6490

URL: Article

DOI: 10.1073/pnas.1019276108

Language: English

Publisher: Proceedings of the National Academy of Sciences

Publication Date: 2011

detail.hit.zdb_id: 209104-5

detail.hit.zdb_id: 1461794-8

SSG: 11

SSG: 12

In: Genome Medicine, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2022-10-13)

Abstract: The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. Methods Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid, or late gestation lethal. We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes. We explored a gene similarity approach for novel gene discovery and investigated unsolved cases from the 100,000 Genomes Project. Results We found that genes in the early gestation lethal category have distinct characteristics and are enriched for genes linked with recessive forms of inherited metabolic disease. We identified several genes sharing multiple features with known biallelic forms of inborn errors of the metabolism and found signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes in patients recruited under this disease category. We highlight two novel gene candidates with phenotypic overlap between the patients and the mouse knockouts. Conclusions Information on the developmental period at which embryonic lethality occurs in the knockout mouse may be used for novel disease gene discovery that helps to prioritise variants in unsolved rare disease cases.

Type of Medium: Online Resource

ISSN: 1756-994X

URL: Article

DOI: 10.1186/s13073-022-01118-7

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 2484394-5

In: European Journal of Haematology, Wiley, Vol. 111, No. 1 ( 2023-07), p. 96-102

Abstract: To describe the incidence of cardiotoxicity in patients with anthracycline exposure who subsequently receive EPOCH for non‐Hodgkin lymphoma (NHL). Methods We conducted a retrospective cohort study of adults with anthracycline exposure who subsequently received EPOCH for NHL at Memorial Sloan Kettering Cancer Center. The primary outcome was cumulative incidence of arrhythmia, heart failure (HF), left ventricular (LV) dysfunction, or cardiac death. Results Among 140 patients, most had diffuse large B‐cell lymphoma. Inclusive of EPOCH, median cumulative doxorubicin‐equivalent dose was 364 mg/m 2 ; exposure was 400 mg/m 2 or higher in 41%. With median 36‐month follow‐up, 23 cardiac events were noted in 20 patients. Cumulative incidence of cardiac events at 60 months was 15% (95% confidence interval [CI]: 9%–21%). When limited to LV dysfunction/HF, cumulative incidence at 60 months was 7% (95% CI: 3%–13%), with most events occurring after the first year. Univariate analysis indicated only history of cardiac disease and dyslipidemia to be associated with cardiotoxicity; no other risk factors, including cumulative anthracycline dose, were identified. Conclusions In this retrospective cohort, representing the largest experience in this setting with extended follow‐up, cumulative incidence of cardiac events was low. Rates of LV dysfunction or HF were particularly low, suggesting infusional administration may mitigate risk despite prior exposure.

Type of Medium: Online Resource

ISSN: 0902-4441 , 1600-0609

URL: Issue

URL: Article

DOI: 10.1111/ejh.v111.1

DOI: 10.1111/ejh.13971

Language: English

Publisher: Wiley

Publication Date: 2023

detail.hit.zdb_id: 2027114-1

In: Cancer, Wiley, Vol. 124, No. 14 ( 2018-07-15), p. 3025-3036

Abstract: This is the first and largest study to date of patients with hematologic malignancies who received chemotherapy in the intensive care unit (ICU) at a US tertiary cancer center. These data can assist oncology and critical care teams when discussing goals of care and prognosticating outcomes of patients who receive chemotherapy in the ICU and in dealing with the triage of scarce ICU resources.

Type of Medium: Online Resource

ISSN: 0008-543X , 1097-0142

URL: Issue

URL: Article

DOI: 10.1002/cncr.v124.14

DOI: 10.1002/cncr.31409

Language: English

Publisher: Wiley

Publication Date: 2018

detail.hit.zdb_id: 1479932-7

detail.hit.zdb_id: 2599218-1

detail.hit.zdb_id: 2594979-2

detail.hit.zdb_id: 1429-1

In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 21, No. 12 ( 2021-12), p. 873-878

Type of Medium: Online Resource

ISSN: 2152-2650

URL: Article

DOI: 10.1016/j.clml.2021.07.024

Language: English

Publisher: Elsevier BV

Publication Date: 2021

detail.hit.zdb_id: 2540998-0

detail.hit.zdb_id: 2193618-3

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1644-1644

Abstract: Introduction Belantamab mafodotin is an antibody drug conjugate targeting B-cell maturation antigen (BCMA) on plasma cells and was the first BCMA-targeted drug approved by the FDA. Single agent effect was around 31-34% in a recent phase II study (Lonial et al, Lancet Oncology 2020). Side effects, including keratopathy and reduced visual acuity, necessitate dose reduction and dose delays that may limit efficacy. Patients enrolled on clinical trials, however, often do not reflect a real-world population due to eligibility criteria that limit comorbidities and include wash-out periods not typical of clinical practice. The aim of this study was to assess response rates, dose modifications, and frequency of ocular adverse events in patients treated with belantamab mafodotin in a real-world setting. Methods All patients treated with commercial drug belantamab mafodotin at Memorial Sloan Kettering Cancer Center since October 2020 were included in the study. Descriptive statistics were used to assess patient characteristics, response rates, and rate of adverse events. Results Forty-two relapsed/refractory multiple myeloma patients were treated with belantamab mafodotin between October 2020 and the data cut off July 2021, including 55% (N=23) women; median age was 67 years. Twelve patients had been included in the Expanded Access Program with belantamab mafodotin prior to transitioning to commercial drug. Thirty patients (71%) had high risk cytogenetics, including gain 1q, t(4;14), t(14;16), t(14;20), complex karyotype, and MYC-translocations. Patients had been treated with a median of 7 (range 4-14) prior lines of therapy. All patients had received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. Eleven patients had received a BCMA-targeted agent in clinical trials, including bi-specific antibodies, chimeric antigen receptor (CAR) T cells, and one patient had received prior trial therapy with belantamab mafodotin. Patients received a median of 3 cycles (range 1-17) of belantamab mafodotin. The majority, 95% (N=40) as single agent, while two patients were treated with belantamab mafodotin in combination with other standard myeloma treatments. The overall response rate (ORR) in all patients was 43%; 18/42 patients. Of these, 7 achieved a partial response (PR); 5 patients achieved a very good partial response (VGPR), 4 patients achieved a complete response (CR) and 1 patient achieved a stringent CR (Table 1). Median duration of response for patients in the ORR cohort was 11 months (95% confidence interval: 9.1-not reached). Three patients achieved a minimal response (MR), 6 patients had stable disease (SD), and 1 patient was not evaluable for response assessment. After a median follow up of 7.5 months, 14 patients had progressive disease and 10 patients had died. Sixteen patients continued on belantamab mafodotin therapy at the time of data cutoff, July 31 st 2021. In a separate analysis of patients not included in the Expanded Access Program, the ORR was 33%; 5 achieved a PR, 4 patients VGPR, 1 patient CR. Two patients achieved a MR, 3 patients had SD, and 14 patients had progressive disease. Twenty-seven patients (64%) had any grade of ocular toxicity on ophthalmology exam. Using the Keratopathy and Visual Acuity (KVA) scale, 12 patients had grade 1 keratopathy, 7 had grade 2, and 8 had grade 3 keratopathy. Fourteen patients had presence of corneal microcysts. Eighteen patients experienced a decline in best corrected visual acuity (BCVA); 10 patients had grade 1, 5 had grade 2, and 3 patients had grade 3 decline in BCVA. The dose of belantamab mafodotin was reduced from the starting dose of 2.5 mg/kg to 1.92 mg/kg in 17 patients: 16 patients due to ocular toxicity and 1 patient due to baseline cytopenia. Additionally, one or more doses were delayed in 9 patients due to keratopathy; the majority of patients (N=8) were able to continue therapy with maintained response on a lower dose after the delay. Conclusion In this heavily pre-treated multiple myeloma population, the ORR was 33-43% which is similar or better than reported in a recent phase II study. The rate of ocular toxicity (64% keratopathy) was also comparable to previous reports. These data demonstrate encouraging results for belantamab mafodotin treatment in the real-world setting with responses and toxicities comparable to clinical trial subjects. Additional patients and updated follow up will be reported at the meeting. Figure 1 Figure 1. Disclosures Hultcrantz: Intellisphere LLC: Consultancy; Curio Science LLC: Consultancy; Daiichi Sankyo: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding. Peterson: GlaxoSmithKline: Consultancy. Hassoun: Celgene, Takeda, Janssen: Research Funding. Korde: Medimmune: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Mailankody: Bristol Myers Squibb/Juno: Research Funding; Jansen Oncology: Research Funding; Physician Education Resource: Honoraria; Plexus Communications: Honoraria; Fate Therapeutics: Research Funding; Takeda Oncology: Research Funding; Allogene Therapeutics: Research Funding; Evicore: Consultancy; Legend Biotech: Consultancy. Landau: Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genzyme: Honoraria. Shah: Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Lahoud: MorphoSys: Membership on an entity's Board of Directors or advisory committees. Scordo: McKinsey & Company: Consultancy; Angiocrine Bioscience: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; i3 Health: Other: Speaker. Landgren: Celgene: Research Funding; Janssen: Other: IDMC; Janssen: Research Funding; Janssen: Honoraria; Amgen: Honoraria; Amgen: Research Funding; Takeda: Other: IDMC; GSK: Honoraria. Giralt: CELGENE: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; JANSENN: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees. Lesokhin: Trillium Therapeutics: Consultancy; Behringer Ingelheim: Honoraria; bristol myers squibb: Research Funding; Genetech: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding; pfizer: Consultancy, Research Funding; Serametrix, Inc: Patents & Royalties.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-153443

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3127-3127

Abstract: Background. Prior studies consistently show that the use of maintenance therapy after completion of combination therapy translates into longer progression-free survival (PFS) in patients with multiple myeloma. Some studies show that maintenance therapy prolongs overall survival (OS). Typically, maintenance therapy is used in the setting of newly diagnosed multiple myeloma; however, emerging data suggest that (at least a subset of) patients in the early relapse setting, for example those who achieve MRD negativity, may also be candidates for maintenance therapy integrated with careful disease monitoring. Currently, lenalidomide is considered the standard of care for maintenance; however, there is only limited published data on long-term use, with respect to the ability to sustain MRD negativity, mechanisms of relapse, and late toxicities. We were motivated to develop a study focusing on long-term lenalidomide maintenance therapy and to study clinical and correlative data. Here, we report on sustained MRD negativity and clinical tolerability. Methods. This single arm, phase 2 was designed to enroll 100 evaluable patients. Per protocol, maintenance therapy with lenalidomide 10 mg is given days 1-21 on a 28-day cycle. The initial study design had a total duration of 36 months; it was subsequently extended with additional 24 months (i.e., total of 60 months). Per standard procedures for protocol amendments, patients were offered to re-consent for the extension. Per protocol, patients underwent bone marrow biopsies and aspirates as well as PET/CT exams at baseline, annually, at progression/end of treatment; blood work was done every 3 months. Bone marrow and blood samples were banked longitudinally per the research protocols. Based on practical considerations, the study was statistically powered for the primary end-point progression-free survival, which provided sufficient numbers of samples for the planned correlative assays focusing on MRD testing, genomic characterization of detectable disease, and profiling of the bone marrow microenvironment. All these assays were conducted in serial samples collected over time and assessed in relation to clinical outcomes. Results. A total of 100 evaluable patients meeting eligibility criteria were enrolled (63% males) between September 2015 and January 2019. Baseline characteristics include median age 63 years (range 38-86 years) and median ECOG score 1 (range 0-1). At the submission of this abstract, the median number of cycles delivered is currently 26 (range 1 to 48); 86 patients have completed 12 or more cycles, 57 patients have completed 24 or more cycles, and 29 patients have completed 36 or more cycles. MRD testing had been completed at least once in all patients. Thirty-four patients were MRD negative at enrollment. At median followup time of 28 months (range 3.4 to 45.6), 15/100 (15%) patients have progressed. Considering the entire follow-up time from initial MRD negativity to last follow-up on study, we found 39 (of 85 tested; 46%) and 25 (of 57 tested; 44%) to have evidence of 1 and 2 years sustained MRD negativity, respectively. Only 19 patients were tested for MRD at 3 years and 16 (84%) had sustained MRD negativity. Toxicities (grade 3) include neutrophil count decrease (N=9), hypertension (N=3), diarrhea (N=2), lung infection (N=2), and rash maculo-papular (N=2), and toxicities (grade 4) include sepsis (N=2) and platelet count decrease (N=1). The most common 1/2 toxicities were diarrhea (N=51), fatigue (N=33), and upper respiratory infection (N=23). Among evaluable patients, dose reductions of lenalidomide due to toxicities and tolerability issues were done in 6 (6%) patient. Conclusions. Among evaluable patients who were treated with lenalidomide 10 mg maintenance therapy days 1-21 on a 28-day cycle on this study, at a median followup of 28 months, we found 46% and 44% to have evidence of 1 and 2 years sustained MRD negativity, respectively. Currently, 19 patients have been tested for MRD at 3 years; 16 (84%) show evidence of 3 years sustained MRD negativity. The toxicity profile was in accord with prior studies and tolerability was quite good reflected in only 6 patients requiring dose reductions due to toxicities. Correlative assays focusing on mechanisms of sustained MRD negativity in this study are presented in a separate abstract at this meeting. Disclosures Landgren: Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC. Lesokhin:Genentech: Research Funding; GenMab: Consultancy, Honoraria; Janssen: Research Funding; Serametrix Inc.: Patents & Royalties; Juno: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Hassoun:Janssen: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Landau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Ho:Invivoscribe, Inc.: Honoraria. Roshal:Physicians' Education Resource: Other: Provision of services; Celgene: Other: Provision of Services; Auron Therapeutics: Equity Ownership, Other: Provision of services. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-125842

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 18-19

Abstract: Background. Consensus from prior studies shows that the use of maintenance therapy after completion of combination therapy leads to longer progression-free survival (PFS) for patients with multiple myeloma with some studies showing an overall survival (OS) benefit. Currently, lenalidomide is the standard of care; however, there are limited published data on long-term use regarding ability to sustain minimal residual disease (MRD)-negativity and late toxicities. We were motivated to develop a study focusing on continuous, induction-agnostic lenalidomide maintenance with integration of clinical and correlative data. Here, we report formal results of this phase II study with focus on MRD dynamics and tolerability. Methods. This single arm, phase II trial enrolled 100 evaluable patients. Lenalidomide 10 mg is given days 1-21 on a 28-day cycle. Per protocol, patients underwent bone marrow biopsies and aspirates as well as PET/CT at baseline, annually, at progression/end of study; blood work was done every 3 months. The study was statistically powered for the primary endpoint of PFS at 36 months. Correlative assays included MRD testing (10-color single-tube flow cytometry and IGHV sequencing; sensitivity ≤10-5), genomic characterization of detectable disease, and profiling of the bone marrow microenvironment performed on serially banked samples. Results. 100 evaluable patients were enrolled (63% males) between September 2015 and January 2019. Baseline characteristics include median age 63 years (range 38-87 years) and median ECOG score 1 (range 0-1). Prior to enrollment, 22 (30%) patients had high-risk FISH/SNP signature defined as one or more of: 1q+, t(4;14), t(14;16), t(14;20), and 17p- and 48 patients had undergone autologous hematopoietic cell transplantation (AHCT). At abstract submission, median cycles delivered is 39 (range 9-62). 74% of patients have completed ³24 cycles and 55% have completed ³36 cycles. Overall PFS at 36 months was 77% (95% CI: 0.69-0.87) and PFS at 60 months was 63% (95% CI: 0.51-0.78). All patients had MRD testing at least once. 46% were MRD-negative at enrollment. 7 patients who were MRD+ at enrollment converted to MRD-negative. At median follow up 39.4 months (range 7-56 months), 20/100 patients (20%) have progressed. In consideration of the entire follow-up time from initial MRD-negativity, 44 (of 95 tested; 46%) and 37 (of 73 tested; 51%) achieved sustained MRD-negativity at 1 and 2 years, respectively. 22 patients were MRD-negative at 3 years (of 51 tested; 43%). Among those who sustained MRD-negativity for 2 years, with median follow-up of 19 months past the 2-year landmark analysis (max 120 months), there were no progression events. Age, induction regimen, and MRD status at enrollment were the only significant variables associated with PFS regardless of cytogenetic risk or transplant status. At 1 and 2-year landmark analysis, MRD-negativity superseded all else as the most significant factor associated with PFS with HR 0.06(p=0.0004) and HR 1/Inf (p=0.015), respectively. Toxicities (grade 3) included neutrophil count decrease (20%), hypertension (3%), diarrhea (3%), lung infection (2%), and maculo-papular rash (2%), and toxicities (grade 4) include sepsis (2%) and platelet count decrease (7%). The most common non-grade 3/4 toxicities were diarrhea (55%), fatigue (36%), and upper respiratory infection (30%). 7% developed a secondary malignancy on study: 3 adenocarcinoma, 1 squamous cell carcinoma, 1 CMML, 1 MDS, 1 ALL, and 1 glioblastoma. One evaluable patient required dose reduction due to toxicities/tolerability. Conclusions. This prospective study of continuous lenalidomide maintenance, agnostic to induction regimen or AHCT usage, was designed to evaluate the dynamics of MRD-negativity in relation to PFS. It expands on the importance of MRD as a predictor of outcome and illustrates how continuous maintenance therapy can deepen and sustain MRD-negative responses achieved with modern combination therapy. For this cohort, MRD-negativity at each landmark profoundly outweighed the impact of all other variates. Among those who had sustained MRD-negativity at 2 years (37% of the cohort), regardless of MRD status at enrollment, none have had progression events at median 43 months. Our results support cross-sectional MRD testing as a surrogate endpoint for drug approval, and the use of longitudinal MRD tracking in clinical management. Disclosures Korde: Amgen: Research Funding; Astra Zeneca: Other: Advisory Board. Lesokhin:Genentech: Research Funding; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; BMS: Consultancy, Honoraria, Research Funding. Smith:Precision Biosciences: Consultancy; Bristol Myers Squibb: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics: Consultancy. Shah:Physicians Education Resource: Honoraria; Celgene/BMS: Research Funding. Mailankody:Physician Education Resource: Honoraria; PleXus Communications: Honoraria; Takeda Oncology: Research Funding; Janssen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding. Hultcrantz:Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding. Hassoun:Takeda: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Scordo:McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Other: Ad-hoc advisory board. Chung:Genentech: Research Funding. Shah:Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Thoren:Sebia: Research Funding; The Binding Site: Research Funding. Ho:Invivoscribe, Inc.: Honoraria. Dogan:AbbVie: Consultancy; EUSA Pharma: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy; Corvus Pharmaceuticals: Consultancy; Physicians Education Resource: Consultancy; Roche: Consultancy, Research Funding; National Cancer Institute: Research Funding. Giralt:MILTENYI: Consultancy, Research Funding; ACTINUUM: Consultancy, Research Funding; KITE: Consultancy; OMEROS: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding; TAKEDA: Research Funding. Landgren:Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Seattle Genetics: Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Seattle Genetics: Research Funding; Karyopharma: Research Funding; Merck: Other; Adaptive: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-140152

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 10-10

Abstract: Introduction Part B of the modified Magrath regimen (ifosfamide, etoposide, and cytarabine; IVAC) with or without rituximab (R) is utilized as a standalone regimen in the management of relapsed/refractory Burkitt lymphoma and other non-Hodgkin lymphomas (NHL). There are no comparative or prospective data and a paucity of retrospective, non-comparative data to support use of this regimen. A small retrospective study described second-line IVAC use without R in a mixed cohort of patients with diffuse large B-cell lymphoma (DLBCL) or peripheral T-cell lymphoma, suggesting utility as a bridge to hematopoietic cell transplantation (HCT) (Pereira J, et al. Leuk Res. 2006 Jun;30(6):681-5). The activity of this regimen in B-cell NHL, particularly in conjunction with R, and its toxicity remain incompletely described. In this study, we describe our institutional experience with IVAC +/- R in relapsed/refractory B-cell NHL. Methods We reviewed all patients with relapsed/refractory B-cell NHL treated with IVAC +/- R between 1 January 2004 and 30 September 2019 at Memorial Sloan Kettering Cancer Center to assess efficacy and toxicity. Patients who received IVAC as part of sequential or alternating chemotherapy were excluded. Standard dosing consisted of ifosfamide 1500mg/m2 IV over 60min days 1-5, etoposide 60mg/m2 IV over 60min days 1-5, cytarabine 2000mg/m2 IV over 3 hours every 12 hours days 1-2, with or without rituximab 375mg/m2 IV day 0 or 1 in 21- to 28-day cycles (Lacasce A, et al. Leuk Lymphoma. 2004 Apr;45(4):761-7). Results Cohort and treatment characteristics are described in Table 1. Among 54 eligible patients (median age 51 years), 76% had DLBCL; 30% had lymphomatous central nervous system involvement at the time of initiating IVAC. Patients had received median 2 prior lines of therapy, with the last dose of the most recent line of therapy administered a median of 3 weeks prior to initiating IVAC. Patients received median 2 cycles of IVAC +/- R; 48% received IVAC-R. Prophylactic antimicrobials with cycle 1 were utilized in 94%. Most patients received herpesvirus- (81%) and Pneumocystis- (80%) directed prophylaxis; broad-spectrum prophylaxis with a fluoroquinolone was less common (24%). Primary granulocyte colony stimulating factor (GCSF) was utilized in 93% of patients with cycle 1; primary or secondary GCSF was utilized in 94% of cycles. Efficacy outcomes are described in Table 1. Objective response rate (ORR) among 46 evaluated patients was 48%; 17% achieved CR. ORR did not vary significantly between patients who did or did not receive R (58% vs 42%; p = 0.5) but was associated with number of IVAC cycles administered (among responders, 69% received 3-4 cycles while 31% received 1-2 cycles; p & lt; 0.001). At median follow-up of 22 months, median progression-free survival (PFS) and overall survival (OS) were 3.1 months and 4.9 months, respectively (Figure). In Cox proportional hazard regression analysis of survival, patients who received R with every cycle (p = 0.025) and received 3 or more cycles (p & lt; 0.001) experienced significantly longer PFS. Patients who achieved CR (p & lt; 0.001) or PR (p = 0.003), received R with every cycle (p & lt; 0.001), received 3 or more cycles (p & lt; 0.001), or underwent subsequent HCT or CAR-T cell therapy (p = 0.001) experienced significantly longer OS. Toxicity outcomes are described in Table 2. Grade ≥ 3 anemia (93%), neutropenia (94%), and thrombocytopenia (100%; all grade 4) were common, regardless of number of cycles received. Febrile neutropenia (FN) occurred in 65% of patients and complicated 47% of cycles; documented infection occurred in 44%. Risk of FN and infection did not appear to be influenced by use of antimicrobial or GCSF prophylaxis. Grade ≥ 3 elevations in AST/ALT or total bilirubin were uncommon (5.6% and 9.3%, respectively). Neurotoxicity attributed to cytarabine or ifosfamide occurred in 17% of patients and was usually low-grade; hemorrhagic cystitis occurred in one patient. In patients for whom cause of death was documented (n = 37), mortality was attributed to a treatment-related complication in 19%. Conclusion IVAC-R may be a useful bridging therapy for patients with relapsed/refractory B-cell NHL who are planned for HCT. However, its potential for profound hematologic toxicity and life-threatening complications despite prophylactic measures requires careful consideration of less toxic alternatives. Disclosures Straus: Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; Targeted Oncology: Consultancy, Speakers Bureau; Imedex, Inc.: Speakers Bureau; NY Lymphoma Rounds: Consultancy; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; OncLive: Speakers Bureau; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-134607

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: AIDS Research and Human Retroviruses, Mary Ann Liebert Inc, Vol. 11, No. 2 ( 1995-02), p. 203-209

Type of Medium: Online Resource

ISSN: 0889-2229 , 1931-8405

URL: Article

DOI: 10.1089/aid.1995.11.203

Language: English

Publisher: Mary Ann Liebert Inc

Publication Date: 1995

detail.hit.zdb_id: 1475767-9