Objective: To provide the clinician with an update and the current status and future direction of approved immune checkpoint inhibitors (ICIs) in oncology. Data Sources: A PubMed search from January ...1, 1966 to March 13, 2015 was performed using the key terms ipilimumab, pembrolizumab, lambrolizumab, nivolumab, immune checkpoint inhibitor, MDX-010, MDX-101, BMS-734016, MK-3475, SCH 900475, MDX-1106, BMS-936558, ONO-4538, CTLA-4, PD-1, or PD-L1 and cancer, oncology, or neoplasm. Additional references were identified from the investigators’ personal files, recent oncology meetings, review articles, clinical guidelines, and package inserts. Study Selection and Data Extraction: All English-language clinical trials assessing the safety and efficacy of ipilimumab, nivolumab, and pembrolizumab in cancer were considered. The PubMed search resulted in 215 trials; 33 met inclusion criteria. A further 28 trials were identified from the above sources; 61 trials from 2005 to 2015 were included. We consolidated and clarified treatment recommendations for the management of immune-related adverse events (irAEs), assessed response criteria, and calculated the clinical utility of leading tumor profiling options. Data Synthesis: Ipilimumab and nivolumab, but not pembrolizumab, have an overall survival (OS) advantage over chemotherapy first line in unresectable/metastatic melanoma. Nivolumab has an OS advantage versus chemotherapy in second-line squamous non-small-cell lung cancer. Data in other settings are promising. Nivolumab and pembrolizumab are better tolerated than ipilimumab. Further validation of response criteria is needed. Tumor profiling to predict clinical benefit is premature but promising. Conclusions: The treatment landscape in oncology is quickly evolving with the advent of ICIs.
Ipilimumab is a standard treatment for metastatic melanoma, but immune-related adverse events (irAEs) are common and can be severe. We reviewed our large, contemporary experience with ipilimumab ...treatment outside of clinical trials to determine the frequency of use of systemic corticosteroid or anti-tumor necrosis factor α (anti-TNFα) therapy and the effect of these therapies on overall survival (OS) and time to treatment failure (TTF).
We reviewed retrospectively the medical records of patients with melanoma who had received treatment between April 2011 and July 2013 with ipilimumab at the standard dose of 3 mg/kg. We collected data on patient demographics, previous and subsequent treatments, number of ipilimumab doses, irAEs and how they were treated, and overall survival.
Of the 298 patients, 254 (85%) experienced an irAE of any grade. Fifty-six patients (19%) discontinued therapy because of an irAE, most commonly diarrhea. Overall, 103 patients (35%) required systemic corticosteroid treatment for an irAE; 29 (10%) also required anti-TNFα therapy. Defining TTF as either starting a new treatment or death, estimated median TTF was 5.7 months. Twelve percent of patients experienced long-term disease control without receiving additional antimelanoma therapy. OS and TTF were not affected by the occurrence of irAEs or the need for systemic corticosteroids.
IrAEs are common in patients treated with ipilimumab. In our experience, approximately one-third of ipilimumab-treated patients required systemic corticosteroids, and almost one-third of those required further immune suppression with anti-TNFα therapy. Practitioners and patients should be prepared to treat irAEs and should understand that such treatment does not affect OS or TTF.
Azacitidine + venetoclax, decitabine + venetoclax, and low-dose cytarabine + venetoclax are now standard treatments for newly diagnosed older or unfit patients with acute myeloid leukemia (AML). ...Although these combinations are also commonly used in relapsed or refractory AML (RR-AML), clinical and molecular predictors of response and survival in RR-AML are incompletely understood. We retrospectively analyzed clinical and molecular characteristics and outcomes for 86 patients with RR-AML who were treated with venetoclax combinations. The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 24%, and the overall response rate was 31% with the inclusion of a morphologic leukemia-free state. Azacitidine + venetoclax resulted in higher response rates compared with low-dose cytarabine + venetoclax (49% vs 15%; P = .008). Median overall survival (OS) was 6.1 months, but it was significantly longer with azacitidine + venetoclax compared with low-dose cytarabine + venetoclax (25 vs 3.9 months; P = .003). This survival advantage of azacitidine + venetoclax over low-dose cytarabine + venetoclax persisted when patients were censored for subsequent allogeneic stem cell transplantation (8.1 vs 3.9 months; P = .035). Mutations in NPM1 were associated with higher response rates, whereas adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 were associated with worse OS. Relapse was driven by diverse mechanisms, including acquisition of novel mutations and an increase in cytogenetic complexity. Venetoclax combination therapy is effective in many patients with RR-AML, and pretreatment molecular characteristics may predict outcomes. Trials that evaluate novel agents in combination with venetoclax therapy in patients with RR-AML that have adverse risk genomic features are warranted.
•In patients with RR-AML, venetoclax combination therapy resulted in responses in 31% of patients and a median OS of 6.1 months.•NPM1 mutations predicted higher response rates; adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 predicted worse OS.
Display omitted
Blinatumomab Buie, Larry W.; Pecoraro, Joshua J.; Horvat, Troy Z. ...
Annals of Pharmacotherapy,
09/2015, Letnik:
49, Številka:
9
Book Review, Journal Article
Recenzirano
Objective: To review the clinical pharmacology, efficacy, and safety of blinatumomab for the treatment of pediatric and adult precursor B-cell acute lymphoblastic leukemia (B-ALL). Data Sources: A ...literature search of EMBASE (1947 to April 2015), Medline (1946 to April 2015), PubMed (1996 to April 2015), the U.S. National Institutes of Health Clinicaltrials.gov, the Food and Drug Administration, and relevant meeting abstracts was conducted using the terms blinatumomab, BiTE, bispecific T-cell engager, MT103, MEDI-538, and Blincyto. Study Selection/Data Extraction: Human and animal studies describing the pharmacology, pharmacokinetics and pharmacodynamics, efficacy, and safety of blinatumomab for precursor B-ALL were identified. Data Synthesis: Blinatumomab is a first-in-class bispecific T-cell engager (BiTE) antibody derived from a B-lineage specific antitumor mouse monoclonal antibody that binds to both CD19 of B-cells and CD3 of T-cells. A pivotal phase II trial demonstrated that response rates were high in a refractory or relapsed patient population, with 43% achieving complete remission (CR). Median relapse-free survival was 5.9 months for those with CR or CR with incomplete hematological recovery. Median overall survival was 6.1 months, and 60% of patients achieved minimal residual disease (MRD) negativity. The most common adverse events included pyrexia, neurological events, headache, febrile neutropenia, peripheral edema, nausea, hypokalemia, constipation, and anemia. Conclusions: Blinatumomab is a novel BiTE therapeutic monoclonal antibody that has shown promising results in patients with relapsed or refractory ALL or those achieving a CR with persistent MRD. Phase III clinical trials should define the optimal place in therapy of blinatumomab.
Objective: To review the pharmacology, efficacy, and safety of venetoclax for treatment of lymphoid malignancies. Data Sources: A literature search was performed of PubMed and MEDLINE databases (2005 ...to September 2016), abstracts from the American Society of Hematology and the American Society of Clinical Oncology, and ongoing studies from clinicaltrials.gov. Searches were performed utilizing the following key terms: venetoclax, ABT-199, GDC-199, obatoclax, GX15-070, BCL-2 inhibitor, navitoclax, ABT-263, and Venclexta. Study Selection/Data Extraction: Studies of pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of venetoclax in lymphoid malignancies were identified. Data Synthesis: Recently, treatment of B-cell lymphoproliferative disorders has shifted from conventional cytotoxic chemotherapy to novel small-molecule inhibitors. The advent of recently Food and Drug Administration–approved oral agents ibrutinib and idelalisib has shifted the paradigm of chronic lymphocytic leukemia (CLL) treatment; however, complete remission is uncommon, and the outcome for patients progressing on these treatments remains poor. Attention has been focused on a novel target, the B-cell lymphoma-2 protein (BCL-2), which serves an essential role in regulation of apoptosis. Venetoclax has demonstrated efficacy in multiple subtypes of lymphoid malignancies, including patients with relapsed/refractory CLL harboring deletion 17p, with an overall response rate of nearly 80%. Venetoclax is generally well tolerated, with the significant adverse effect being tumor lysis syndrome, for which there are formal management recommendations. Conclusion: Venetoclax has demonstrated promising results in relapsed/refractory lymphoid malignancies, with an acceptable adverse effect profile. As the role of BCL-2 inhibition in various malignancies becomes further elucidated, venetoclax may offer benefit to a myriad other patient populations.
Objective: To review the pharmacology, efficacy, and safety of Food and Drug Administration approved and promising immunotherapy agents used in the treatment of acute lymphoblastic leukemia (ALL). ...Data Sources: A literature search was performed of PubMed and MEDLINE databases (1950 to July 2017) and of abstracts from the American Society of Hematology and the American Society of Clinical Oncology. Searches were performed utilizing the following key terms: rituximab, blinatumomab, inotuzumab, ofatumumab, obinutuzumab, Blincyto, Rituxan, Gazyva, Arzerra, CAR T-cell, and chimeric antigen receptor (CAR). Study Selection/Data Extraction: Studies of pharmacology, clinical efficacy, and safety of rituximab, ofatumumab, obinutuzumab, inotuzumab, blinatumomab, and CAR T-cells in the treatment of adult patients with ALL were identified. Data Synthesis: Conventional chemotherapy has been the mainstay in the treatment of ALL, producing cure rates of approximately 90% in pediatrics, but it remains suboptimal in adult patients. As such, more effective consolidative modalities and novel therapies for relapsed/refractory disease are needed for adult patients with ALL. In recent years, anti-CD20 antibodies, blinatumomab, inotuzumab, and CD19-targeted CAR T-cells have drastically changed the treatment landscape of B-cell ALL. Conclusion: Outcomes of patients with relapsed disease are improving thanks to new therapies such as blinatumomab, inotuzumab, and CAR T-cells. Although the efficacy of these therapies is impressive, they are not without toxicity, both physical and financial. The optimal sequencing of these therapies still remains a question.
Highlights • Ten patients were switched to Erwinia asparaginase after pegaspargase intolerance. • After switching to Erwinia asparaginase, no hypersensitivity reactions occurred. • No patient ...developed clinically relevant asparaginase-related toxicities. • No relapses occurred in patients switched to Erwinia asparaginase in CR1. • Erwinia asparaginase can administered, despite prior pegaspargase intolerance
Introduction: Blinatumomab is a bispecific T-cell engaging monoclonal antibody, linking CD19+ B-cells with CD3+ T-cells. Blinatumomab has shown pronounced clinical benefit in relapsed/refractory ...(R/R) B-ALL patients. A common toxicity is cytokine release syndrome (CRS), which includes a constellation of symptoms related to systemic inflammatory response. No available conclusive data suggests that cytokine elevation predicts response to therapy, neurotoxicity, or severity of CRS. C-reactive protein (CRP) is currently used as a surrogate for IL-6 bioactivity. To this end, we sought to determine if there is an association between CRP and ferritin levels and development of CRS, neurotoxicity, and response in patients receiving blinatumomab.
Methods: This IRB approved, single-center, retrospective study at Memorial Sloan Kettering Cancer Center included adult patients with R/R B-ALL treated with blinatumomab between 1/1/11 and 12/31/16. Patients without appropriate follow up were excluded. Patients were identified via electronic medical records and an internal pharmacy database. CRS was graded using the criteria outlined by Lee et al (Lee DW, et al. Blood. 2014 Jul 10;124(2):188-95). Continuous variables were summarized with medians, interquartile ranges (IQR: 25th and 75th percentiles), or ranges. Categorical variables were summarized with frequencies and percentages. Comparisons between groups were evaluated using the Wilcoxon rank sum test or Fisher's exact test for continuous and categorical variables, respectively. Maximum change in CRP or ferritin was calculated for each patient as the difference between peak value and baseline value of each respective biomarker.
Results: A total of 25 patients were included. Median age was 51.7 years, with a predominant female population (56%). Eight patients (32%) had extramedullary disease at baseline; 12 patients (48%) had >50% bone marrow blasts at the time of treatment with blinatumomab. 14 patients (56%) experienced CRS during cycle 1, with ten grade 1 events and four grade 2 events. Among 11 patients who started cycle 2, two patients experienced CRS, one grade 1 and one grade 2 event. In cycle 1, median time to onset of CRS was one day (range, 0-9). Median baseline CRP was 0.94 mg/dl (range, 0.05-33.3), and days to peak CRP was two days (range, 0 - 13). Median peak CRP was significantly increased (p=0.001) in patients with CRS (20.6, IQR 17.1-31.9) compared to patients without CRS (5.2, IQR 1.7-12.0). In addition, median absolute peak ferritin level and incremental change in ferritin from baseline in cycle 1 significantly correlated to CRS (p=0.03 and 0.023, respectively). The presence of >50% blasts at pretreatment was not associated with increased incidence of CRS. Neurotoxicity was documented in six patients (24%) during cycle 1, with a median onset of nine days from the start of therapy (range, 1-23). Patients with neurotoxicity had a significantly shorter time to peak CRP, with a median of two vs. three days (p=0.031). Baseline and peak ferritin level in cycle 1 were significantly increased in patients with neurotoxicity (p=0.044 and 0.026, respectively). Eleven patients (44%) achieved a complete response and 14 patients (56%) had refractory disease. Responders were found to have significantly lower baseline CRP (p=0.008) and lower baseline ferritin values (p=0.03). No grade 4 or 5 CRS was observed and no patient discontinued therapy due to CRS.
Conclusion: Our data shows there is an association between changes in biomarkers (CRP and ferritin) and development of CRS, and suggests frequent monitoring of these biomarkers may be useful in predicting patients at risk for CRS and neurotoxicity, possibly leading to earlier intervention. Considering the infrequent CRS events documented in cycle 2, our results raise the question of the required admission for patients in cycle 2. Due to a small sample size and retrospective nature of this study, these findings need to be examined prospectively to confirm the association of these biomarkers with blinatumomab-associated toxicities and inform monitoring guidelines.
Display omitted
Horvat:Agios: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Park:Amgen: Consultancy.
Introduction: Severe pegaspargase hypersensitivity during first-line therapy for acute lymphoblastic leukemia (ALL) occurs in 1.8-5.9% of patients (Oncaspar package insert; Douer D, et al. J Clin ...Oncol 2014;32:905-911). Erwinia asparaginase is the preferred therapeutic alternative as it retains excellent activity in patients with Escherichia coli asparaginase or pegaspargase antibodies (Willer A, et al. Blood 2011;118:5774-82; Plourde PV, et al. Pediatr Blood Cancer 2014;61:1232-38; Salzer WL, et al. Blood 2013;122:507-14; Zalewska-Szewczyk B, et al. Clin Exp Med 2009;9:113-16). Furthermore, pegaspargase desensitization may not prevent recurrence of severe allergy (Sahiner UM, et al. Pediatr Int 2013;55:531-33). The risk for allergy and other common asparaginase-related adverse effects exists with Erwinia asparaginase, however most data is from pediatric reports. The aim of this study was to assess the safety and feasibility of using Erwinia asparaginase in adult ALL patients with previous pegaspargase hypersensitivity or intolerance.
Methods: This is a single-center retrospective analysis of eight adult ALL patients who received Erwinia asparaginase after intolerance to pegaspargase between November 2011 and July 2015. Toxicities were graded using the Common Terminology Criteria for Adverse Events version 4.0. The Memorial Sloan Kettering Investigational Review Board granted an exemption from IRB review.
Results: The eight patients received a total of 29 cycles (median 3 cycles each, range 1-6) as part of various pediatric-inspired chemotherapy regimens. Each cycle consisted of Erwinia asparaginase 25,000 units/m2 intramuscularly every 48 hours (either including or excluding weekends). Corticosteroid premedication was given with 52 of 170 total Erwinia asparaginase doses. The median age was 33 years (range 23-72), 7 (87.5%) were males, 75% had B-cell ALL, and 25% had T-cell ALL. Seven patients received Erwinia asparaginase while in first complete remission (CR1) and only one as part of second-line therapy. Patients received a median of 2 prior doses of pegaspargase (range 1-4) before switching to Erwinia asparaginase for either grade 3/4 anaphylaxis (n=6), urticaria/pruritus (n=1), or grade 4 hyperbilirubinemia (n=1). Six patients received all intended cycles, 1 patient was lost to follow up after 1 cycle, and 1 patient was still receiving treatment at the time of analysis. No hypersensitivity reactions occurred and no patient developed arterial or venous thrombosis. Laboratory adverse effects are reported in table 1. One patient died from disease (the 1 patient that received Erwinia asparaginase as part of second-line therapy), 1 patient died in a motor vehicle accident while in first remission, and six patients are still alive and in first remission at 7.5-29.6 months from diagnosis. No morphologic relapses have occurred in patients in first remission (n=7) at a follow up of 4.9-26.4 months after switching to Erwinia asparaginase.
Conclusions: Replacing pegaspargase with Erwinia asparaginase after hypersensitivity allowed all patients to continue asparaginase therapy without hypersensitivity. Adverse effects with Erwinia asparaginase were limited to laboratory abnormalities of minimal clinical consequence. In contrast to the known high rate of hepatoxicity in adults treated with pegaspargase, no high grade liver toxicity was seen. In light of the critical role of asparaginase in ALL therapy, our preliminary observations suggest that asparagine depletion with Erwinia asparaginase can proceed as scheduled despite pegaspargase intolerance. Within our small cohort undergoing first-line therapy, relapse did not occur after transitioning to this therapeutic alternative.
Table 1Laboratory abnormalities by gradeGrade 1Grade 2Grade 3Grade 4AST7000ALT7200TBILI1000Amylase2000Lipase1100Triglycerides3431Fibrinogen2610Total231341*Laboratory abnormalities were counted per event, not per patient
Douer:Gilead: Consultancy.
PDF
