Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in ...mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.
Introduction
Cytogenetic analysis is important for stratifying patients with various neoplasms. We explored the use of targeted next generation sequencing (NGS) in detecting chromosomal structural ...abnormalities or copy number variations (CNVs) in patients with myeloid neoplasms.
Methods
Plasma cell-free DNA (cfDNA) from 2821 myeloid or lymphoid neoplasm patients were collected. cfDNA was sequenced using a 275 gene panel. CNVkit software was used for analyzing and visualizing CNVs. Cytogenetic data from corresponding bone marrow (BM) samples was available on 89 myeloid samples.
Results
Of the 2821 samples, 1539 (54.5%) showed evidence of mutations consistent with the presence of neoplastic clones in circulation. Of these 1539 samples, 906 (59%) showed abnormalities associated with myeloid neoplasms and 633 (41%) with lymphoid neoplasms. Chromosomal structural abnormalities in cfDNA were detected in 146 (16%) myeloid samples and 76 (12%) lymphoid samples. Upon comparison of the myeloid samples with 89 BM patients, NGS testing was able to reliably detect chromosomal gain or loss, except for fusion abnormalities. When cytogenetic abnormalities were classified according to prognostic classes, there was a complete (100%) concordance between cfDNA NGS data and cytogenetic data.
Conclusions
This data shows that liquid biopsy using targeted NGS is reliable in detecting chromosomal structural abnormalities in myeloid neoplasms. In specific circumstances, targeted NGS may be reliable and efficient to provide adequate information without the need for BM biopsy considering broad mutation profiling can be obtained through adequate sequencing within the same test. Overall, this study supports the use of liquid biopsy for early diagnosis and monitoring of patients with myeloid neoplasms.
In PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase ...inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270.
Abstract
Background: The development of tyrosine kinase inhibitors (TKIs) has dramatically changed the landscape of chronic myelogenous leukemia (CML) treatment. Dosing of TKIs is based on the phase ...of disease at presentation, but is not altered based on body surface area (BSA), gender, or other patient characteristics. Although TKIs are generally well tolerated, lower grade hematologic and non-hematologic toxicities are not infrequent. Inability to maintain dosing during the first year of therapy (missing as few as 10% of doses per month) has been associated with lower rates of major molecular response (MMR), which might have survival implications and/or prevent treatment-free remission attempts. While the package insert of three TKIs (imatinib, dasatinib, nilotinib) commonly used in first line therapy provides specific dose-reduction instructions for hematologic toxicity, only nilotinib has recommendations for non-hematologic toxicities. Long-term outcome data on the effects of dose-reduction of TKI therapy based on toxicity is lacking. Furthermore, there is little data on risk factors for TKI intolerance. Thus, we sought to identify characteristics of patients requiring dose reductions as a part of first-line TKI treatment for chronic phase CML who successfully achieved an MMR 4 or greater as well to determine the long-term outcome of these patients in a retrospective fashion.
Methods: Using electronic medical records, we identified patients seen at the John Theurer Cancer Center for treatment of newly diagnosed chronic phase CML between November 1, 2012 and July 1, 2016 who had successfully achieved an MMR 4 or greater. These records were screened for individuals requiring chronic dose reductions as part of first-line treatment for chronic phase CML. We identified 35 consecutive patients that were able to tolerate full dose TKI therapy per package insert. This control group was used to determine risk factors for TKI intolerance compared to patients that required dose reduction.
Results: A total of 20 patients were identified who achieved an MMR 4 or greater and required long-term dose reduction of first-line TKI therapy with a median follow up of 48.5 months (range 18.7-172.6). The median time on full dose therapy prior to dose reduction was 7.7 months (range 0-40.2). The median time spent on reduced dose therapy was 43.5 months (range 12.1-159.0). The time to MMR was 8.3 months (1.8-40.2). The majority of patients remained in MMR 4 despite maintenance on dose reduction. Median progression free survival (PFS), as defined by loss of MMR, of dose-reduced patients had not yet been reached. One, two, and three year PFS rates were 100%, 95.0%, and 88.7% respectively. When compared to the control group of patients tolerating front line therapy at full-dose, patients requiring dose reduction were more likely to be female: 80% vs 46% (P=0.028) and have a lower BSA: 1.78 versus 2.03 mg/m2 (P=0.0014). Other variables including age, TKI, Sokol score, and performance status were similar in both groups.
Discussion: Among patients who achieved MMR4 or greater on first-line therapy, we noted that female sex and lower BSA were risk factors for TKI dose reduction. Based on the available control group, it cannot be determined if either of these are independent variables. This retrospective analysis demonstrates many patients are able to successfully achieve and maintain a deep molecular response with reduced doses of TKI therapy and perhaps provides justification for dose reduction to increase compliance and maximize treatment tolerability. The majority of patients remained in MMR4 despite dose reductions.
McCloskey:Celgene Pharmaceuticals: Consultancy, Speakers Bureau; Takeda Pharmaceuticals: Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Amgen: Speakers Bureau; COTA: Equity Ownership. Stanislaus:Celgene Pharmaceuticals: Consultancy, Speakers Bureau; Takeda Pharmacetucals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Koprivnikar:Otsuka Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Consultancy, Speakers Bureau; Amgen Pharmaceuticals: Speakers Bureau; COTA: Equity Ownership.
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Anticoagulant management of cancer-associated thrombosis is challenging since this patient population is concurrently at an increased risk for bleeding. The use of direct oral anticoagulants ...(DOACs) dabigatran, rivaroxaban, apixaban is not recommended for the treatment of venous thromboembolism (VTE) in cancer patients since there is limited data in this patient population. Despite limited evidence for use, DOACs are commonly prescribed due to ease of administration and lack of required laboratory monitoring. The objective of this study was to evaluate the practice and safety patterns of the DOACs when used for VTE treatment in the oncology population at Hackensack University Medical Center (HackensackUMC).
This study was a retrospective chart review of adult cancer patients treated at HackensackUMC who received dabigatran, rivaroxaban, or apixaban for the treatment of VTE. The protocol was reviewed and approved by the Institutional Review Board. Patients were identified through a computer generated report of the DOACs which included patients on all inpatient adult oncology floors at HackensackUMC from January 2013 to October 2015. Patients were included in this study if they were 18 years of age or older, admitted to an oncology floor, receiving a DOAC for VTE treatment for at least 48 hours, and had active cancer. Patients were excluded from this study if they were receiving hemodialysis or receiving a DOAC exclusively for the indication of atrial fibrillation. The primary outcomes of this study included the percentage of patients who were receiving a DOAC dosage consistent with that of the package insert and the percentage of patients who experienced clinically significant bleeding. The secondary outcomes of this study included the percentage of patients who had their DOAC held for thrombocytopenia and high risk procedures. Descriptive statistics were used to analyze study outcomes.
Of the 126 patients screened, 39 patients were included. Thirty-five patients were on rivaroxaban and 4 patients were on apixaban (Table 1). Ten of 39 patients (26%) were not receiving a DOAC dosage consistent with that of the package insert. Of these 10 patients identified, the majority were receiving a lower DOAC dose than is recommended in the package insert. Our assumption is that these patients received a lower than recommended dose due to concerns for increased risk of bleeding. No patients experienced clinically significant bleeding. Four of 39 patients (10%) experienced a minor bleeding episode, all of which were gastrointestinal and/or genitourinary bleeds (Table 2). Four of 14 thrombocytopenic patients (29%) did not have their DOAC dose held for thrombocytopenia (none of which experienced a bleeding episode). All patients had their DOACs appropriately held for all procedures.
Increased education and awareness on manufacturer recommended dosing of DOACs is warranted for oncology prescribers. Despite the increased risk for bleeding in cancer patients, no clinically significant bleeding events were identified in our patient cohort. To our knowledge, this is the first study to evaluate the use of DOACs for VTE treatment in patients with cancer at a high risk for bleeding. This data suggests that the use of DOACs may be safe to use for VTE treatment in the oncology population. This study may provide foundation for larger, randomized, controlled trials to determine whether DOACs should be used for VTE treatment in cancer patients.
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Howlett:Eisai: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Sandoz: Honoraria; Teva: Speakers Bureau. McCloskey:Ariad: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau.
Small ponds ( ≤ 2 ha) are often a common landscape feature, but their ecology has been less well studied than that of lakes. Studies of some lakes and reservoirs show among-year repeatability in the ...seasonal abundance of different zooplankton (i.e., succession). For small ponds the seasonal dynamics of zooplankton community structure are relatively unstudied, as are any mechanisms underlying these dynamics. We took a community-level approach to studying the spring-summer abundance of zooplankton in two small Ohio ponds. In particular we wanted to know if repeatable patterns exist for zooplankton community structure in these ponds. We surveyed the spring-summer zooplankton communities in the ponds from 2001 to 2003 and used community-level ordination techniques (i.e., non-metric multidimensional scaling, NMDS) to characterize the assemblages. For both ponds the seasonal pattern of total zooplankton abundance differed significantly among years. We found that the proportional abundance of taxa across the season also varied among years. Elements of the zooplankton community, as described by the NMDS dimensions, showed among-year variation in the spring-summer trajectories that developed. Some of the variation in these zooplankton communities was associated with seasonal changes in water temperature. This among-year variation in the seasonal pattern of zooplankton community structure suggests that community dynamics in these small ponds may not be very repeatable. These complex dynamics of zooplankton thus challenges us to improve our characterization of zooplankton communities in small ponds such that we can better understand the factors that drive the patterns we observe.PUBLICATION ABSTRACT
Background
The addition of tyrosine kinase inhibitors (TKIs) to chemotherapy improves the prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Single agent ...blinatumomab, a bi-specific T-cell engaging CD3-CD19 antibody construct, is more effective than multi-agent chemotherapy in relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and successfully achieves minimal residual disease (MRD) negativity in MRD positive patients. Limited data is available on the safety and efficacy of these agents in combination and uncertainties remain regarding the optimal use of blinatumomab +TKIs. Dual therapy with blinatumomab and TKIs may offer a safe and effective treatment option for relapsed and refractory patients without the incorporation of chemotherapy.
Patients and Methods
We report our retrospective experience in 18 patients who received blinatumomab +TKI for relapsed/refractory (R/R) Ph+ ALL (n=14), MRD+ Ph+ ALL (n=2) and chronic myeloid leukemia in lymphoid blast crisis (CML-LBC) (n=2). Ten patients received ponatinib; 8 patients received second generation TKIs (dasatinib, n=5; nilotinib, n=2; bosutinib, n=1). Blinatumomab was administered according to the package insert and TKI was initiated on day 1. Median follow up was 15 months and median number of blinatumomab +TKI cycles was 2 (range, 1-5). The median age was 47 years (range, 22-77). The median number of prior therapies was 2 (range, 1-8) and the median number of prior TKIs was 2 (range 1-4). Preexisting T315I mutations were present in one third of patients and 5 patients had relapsed following allogeneic stem cell transplant (alloHSCT).
Results
Transient grade 2-3 transaminase elevation was observed in 3 patients (ponatinib=2, dasatinib=1). Cytokine Release syndrome was observed in 2 patients. Transient neurotoxicity was observed in 3 patients (1patient with grade 3). All grade 2 and 3 toxicities were observed during the first cycle and all patients were successfully able to complete induction with blinatumomab +TKI. One patient on dasatinib experienced a PICC-associated DVT. There were no other vascular events observed.
For patients with r/r disease the CR rate was 88% (14/16) with most of these remissions being MRD negative by flow and PCR (12/14). Both of the patients treated for MRD positivity achieved an MRD negative response. Among T315I mutated patients, 5/6 achieved a CR and 4/5 were MRD negative. The median time to remission was 35 days. The 1 year survival was 80% and the median overall survival following blinatumomab therapy was 45 months. Among 16 pts who achieved an initial response to blinatumomab +TKI, six have expired at the time of this analysis. At the time of relapse on combination therapy, 3/8 pts exhibited new T315I mutations. Of note, all of these were treated with blinatumomab in combination with a second generation TKI. All patients maintained their CD19 positivity at the time of relapse. Both pts with CML-LBC were able to move to a transplant following therapy with blinatumomab +TKI and both attained MRD negative status as measured by Bcr/Abl PCR values. In total, 10 patients treated with blinatumomab +TKI proceeded to alloHSCT, 7 of these are still alive. Median duration of response (DOR) was 5.1 months with maximum DOR of 23.3 months.
Discussion
While limited due to its retrospective nature and relatively small sample size, this data set begins to answer important regarding the safety and efficacy of blinatumomab +TKI. Combination therapy was effective at achieving rapid and deep responses in this refractory patient population. The toxicities observed with blinatumomab +TKI were in keeping with those seen with blinatumomab alone. However, care should be taken in regard to potential overlapping toxicities of TKIs and blinatumomab, such as hepatotoxicity. The study also suggests a role for blinatumomab treatment in patients with CML-LBC, a rare and difficult disease state to treat. The identification of T315I mutation at relapse in 40% of patients on blinatumomab +second generation TKIs supports further prospective studies with ponatinib and blinatumomab in combination. Finally, loss of C19, which has relevance with regards to the potential benefit of subsequent CD19-directed therapies such as chimeric antigen receptor T-cell therapy was not seen in patients treated with blinatumomab +TKI.
McCloskey:Jazz: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau; Novartis: Speakers Bureau. Gagnon:Amgen: Speakers Bureau. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; Bristol-Myers Squibb: Consultancy; COTA: Equity Ownership. Koprivnikar:Amgen: Speakers Bureau; Pfizer: Honoraria; Novartis: Speakers Bureau; Abbvie: Speakers Bureau.
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