Chaos theory is presented for counselors working with clients experiencing life transitions. It is proposed as a model that considers disorder, unpredictability, and lack of control as normal parts ...of transition processes. Nonlinear constructs from physics are adapted for use in counseling. The model provides a method clients can use to reconstruct their own alternative life narratives, a framework in which life stories are understood, and a means to facilitate cocreation of adaptive interventions.
The syntheses of the 2′-deoxy and 2′,3′-dideoxynucleosides of 2,8-diaza-3-deazainosine and the 2′,3′-dideoxynucleoside of 2-aza-3-deazainosine were achieved and the pathways leading to these novel ...nucleosides are described. The preparation of the 2′,3′-dideoxynucleoside (1) of 2-aza-3-deazainosine involved deoxygenation of the 2′-deoxy-3′-imidazolide intermediate with n-Bu3SnH and AIBN. The latter nucleoside was synthesized from the known 2′-deoxy derivative of 2-aza-3-deazainosine. The three-step synthesis of 1 from the 2′-deoxy analogue was accomplished in 40% overall yield. Rather than synthesize the corresponding 2′,3′-dideoxynucleoside (2) of 2,8-diaza-3-deazainosine in the same manner, i.e. deoxygenation of the 2′-deoxynucleoside, a more cost-effective route was chosen. This pathway involved reductive cleavage of the 5′-protected, 2′,3′-thiocarbonate derivative to furnish a mixture of the 2′- and 3′-deoxy isomers. This mixture was not separated, but was deoxygenated by the aforementioned imidazolide method. Using this methodology, 2 was prepared in 23% overall yield from 2,8-diaza-3-deazainosine. Nucleosides 1 and 2 were evaluated for antiretroviral activity and were found to be inactive.
Background:
Myelofibrosis (MF), particularly Intermediate‐2 (Int‐2) or High‐Risk disease, is a life‐threatening disease for which the Janus Kinase inhibitor (JAKi), ruxolitinib, is currently the only ...approved therapy. Currently, there is no approved or effective therapy for patients (pts) who lack or lose response to ruxolitinib, and these pts have a notably poor prognosis (median overall survival OS 12–14 mo) (Kuykendall et al Ann Hematol 2018; Newberry et al Blood 2017). Imetelstat, a 13‐mer oligonucleotide that specifically targets the RNA template of human telomerase, is a potent competitive inhibitor of telomerase enzymatic activity. In a Phase 2 study of imetelstat (2 doses) in JAKi‐relapsed/refractory (R/R) Int‐2 or High‐Risk MF (MYF2001; NCT02426086), spleen volume reduction and total symptom score improvements and median OS of 29.9 mo (95% CI 22.8, NE) were observed in the 9.4 mg/kg arm (Mascarenhas et al ASH 2018 #685).
Aims:
To further assess the potential OS benefit of imetelstat, pts treated with 9.4 mg/kg in MYF2001 were compared to a closely matched patient population from real‐world data (RWD), treated contemporaneously.
Methods:
MYF2001 pts had MF that was R/R to JAKi, defined as documented progressive disease (PD) during or after JAKi treatment. For the historical control, external RWD were collected from a single‐center study which included 114 pts who had discontinued ruxolitinib. A closely matched cohort was identified using the guidelines for inclusion and exclusion criteria as defined in MYF2001 protocol and consisted of pts with MF who had discontinued JAKi due to lack or loss of response and were subsequently treated with best available therapy (BAT) at the Moffitt Cancer Center.
OS was measured from the time of JAKi discontinuation to death or censored at last follow‐up. To improve comparability, propensity score weighting approaches using average treatment effect for overlap population (ATO) and stabilized inverse probability treatment weighting (sIPTW) methods were used for critical baseline covariates (age, platelet count, time from diagnosis to JAKi discontinuation, JAKi duration, spleen size, sex, DIPSS score, ECOG, MF type, transfusion status, JAK2 mutation). Sensitivity analyses (to address early deaths post JAKi discontinuation observed in the RWD and the impact of subsequent transplant on OS) were explored to enhance the robustness of the results.
Results:
57 pts (treated with imetelstat 9.4 mg/kg) from MYF2001 and 38 pts treated with BAT from RWD (median follow‐up, 23 and 43 mo, respectively) were analyzed with improved balanced baseline covariates after propensity score adjustment. Overlap weighting results (ATO) are summarized in the Figure, showing a 65% lower risk of death with imetelstat vs BAT (hazard ratio HR, 0.35; 95% CI 0.18, 0.68; P = 0.0019). Sensitivity analysis results were consistent with the primary findings. With sIPTW, median OS was 30.69 mo (95% CI 25.2, not estimable) with imetelstat vs 12.04 mo (95% CI 9.5, 16.6) with BAT (HR, 0.33; 95% CI 0.18, 0.61; P = 0.0003), with 12‐mo OS rates of 85% and 52%, respectively and 24‐mo OS rates of 66% and 24%, respectively.
Summary/Conclusion:
These analyses showed that treatment with imetelstat was associated with a lower risk of death compared to BAT in closely matched pts with Int‐2 or High‐Risk MF after JAKi failure. Despite the limitations of such comparative analyses, this bridging of RWD with clinical trial data suggests favorable OS of imetelstat treatment in this very poor‐prognosis population and warrants further evaluation.
This doctoral research paper proposes an action-based model of leadership to assist with selecting and implementing various leadership theories given the context of a situation. Grounded in ...Contingency Theory and the Cognitive Affective Personality System, the Cognitive Behavioral Leadership Action Model utilizes a theoretical understanding that the context of a situation and how one encodes a leadership experience can help to define the most significant approach to leading. Additionally, this theoretical model uses aspects of Cognitive Behavioral Therapy to establish a new method of observing, thinking, leading, and reflecting. The goal of this study is to propose a novel way of leading that can assist leaders with the mental operation that takes place when implementing a leadership theory and reflecting on the success of the approach.
Background:
There are limited treatment options for red blood cell (RBC) transfusion dependent (TD) LR (IPSS Low/Int‐1) MDS patients who are relapsed/refractory to ESAs. Imetelstat is a ...first‐in‐class telomerase inhibitor that targets cells with short telomeres and active telomerase, characteristics observed in some MDS patients across all disease stages. Preliminary results show that imetelstat is effective treatment in LR‐MDS patients inducing durable TI (Steensma et al ASH 2018 Abstr463).
Aims:
We report updated efficacy data with a median follow‐up of 12.1 months in 38 LR non‐del(5q) MDS patients, R/R to ESA and LEN/HMA naive from the open‐label, single‐arm Part 1 of IMerge, an ongoing phase 2/3 study (NCT02598661).
Methods:
Part 1 of the IMerge study included patients with LR MDS, who were heavily transfused (≥4U/8wks), were R/R to ESA or had sEPO >500 mU/mL. Imetelstat 7.5 mg/kg was administered IV every 4 weeks. The primary endpoint was 8‐week TI rate; key secondary endpoints included 24‐week TI rate, safety, duration of TI, and hematologic improvement (HI) rate. Among the initially enrolled patients, higher 8‐week TI rate was observed in the non‐del5q, LEN/HMA naive patients. Therefore, the study was amended to subsequently enroll only these patients. From a total of 57 patients enrolled in Part 1, 38 were non‐del(5q), LEN/HMA naïve patients (13 in the initial and 25 in the expansion cohort). Here we report long‐term efficacy, safety and biomarker data from these 38 patients.
Results:
Median baseline RBC transfusion burden was 8U/8weeks (range 4–14), 37% of the patients had IPSS Int‐1; 71% had WHO 2001 RARS or RCMD‐RS subtype and 32% with evaluable sEPO levels had baseline level >500 mU/mL.
As of 23 January 2019, median follow‐up was 12.1 months for the 38 patients, representing 30.4 and 11.6 months for the initial 13 and additional 25 patients, respectively. The 8‐week TI rate was 45% (17/38) and median TI duration was 8.5 months (range 1.8–32.4). Of the 17 responding patients, 10 (59%) remained transfusion free for over 24 weeks. The 8‐week TI rate did not differ based on the presence of ring sideroblasts or baseline sEPO levels. The 24‐week TI rate was 26% (10/38). Erythroid HI, defined as transfusion reduction by at least 4 units /8 weeks (IWG2006), was achieved in 68% (26/38) of the patients. The most frequently reported adverse events were manageable and reversible grade ≥3 cytopenias. 6/38 patients had IPSS‐R intermediate/poor cytogenetic risk. All 6 patents achieved 8‐week TI; 2/6 patients achieved partial cytogenetic response. Post treatment decrease in telomerase hTERT RNA level was observed in 25/34 (73.5%) patients with available sample. Among 7 patients with pre‐ and post‐treatment mutation analyses, six had SF3B1 mutations at baseline, and a decrease in the mutation VAF was observed in 2 patients that had longest TI duration on study.
Summary/Conclusion:
In high RBC transfusion burden patients with non‐del(5q) LR‐MDS R/R to ESA and naive to LEN/HMA, single‐agent imetelstat yielded 8‐week TI rate of 45%, with a median duration of 8.5 months (range 1.8–32.4). The 24‐week TI rate was 26%. HI‐E rate was 68%. All patients with IPSS‐R intermediate and poor cytogenetic risk responded. Biomarker analyses of telomerase activity and mutation allele burden indicate an effect on the malignant mutant clone. These data support Part 2 of IMerge, Phase 3 placebo‐controlled, randomized portion of the study, expected to open mid‐2019.
A solution phase synthesis for the preparation of libraries of 2-substituted phenylpropyl amines and amides was accomplished using dihydrocoumarins as a useful synthon in parallel synthesis. Resin ...quench methods were utilized in the purifications of the amides and a resin quench-capture method was utilized in metallo-organic reductions leading to the targeted phenylpropyl amines.
Graphic
The synthesis of
S
4-substituted nucleosides possessing the imidazo- and
v-triazolo4,5-
dpyridazine ring systems was undertaken and the compounds prepared were evaluated as inhibitors of nucleoside ...transport into human erythrocytes.
1-(2,3,5-Tri-O-
acetyl-β-
d-ribofuranosyl)
-v-
triazolo4,5-d
pyridazine-4(5H)-
thione
and
1-(2,3,5-tri-O-
acetyl-β-
d-ribofuranosyl)imidazo
4,5-d
pyridazine-4(5H)-
thione
were each synthesized by two different routes and served as precursors for the title analogues. The nitrobenzylmercaptopurine riboside (NBMPR) analogues,
4-(p-
nitrobenzylthio)-1-(β-
d-ribofuranosyl)imidazo
4,5-d
pyridazine
and
4-(p-
nitrobenzylthio)-1-(β-
d-ribofuranosyl)
-v-
triazolo4,5-d
pyridazine
, inhibited the transport of adenosine, but were approximately 4- and 28-fold less active, respectively, than NBMPR and nitrobenzylthioformycin, known potent and specific inhibitors of carrier-mediated transport.
Selected
S
4-substituted imidazo- and v-triazolo4,5-
dpyridazine nucleosides were prepared as nucleoside transport inhibitors.
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