Publications by authors named "Philip Thompson"

355 Publications

Ibrutinib Plus Venetoclax for First-line Treatment of Chronic Lymphocytic Leukemia: A Nonrandomized Phase 2 Trial.

JAMA Oncol 2021 Jun 10. Epub 2021 Jun 10.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston.

Importance: Oral targeted therapies have advanced the treatment of chronic lymphocytic leukemia (CLL). These therapies include Bruton tyrosine kinase inhibitors, used as monotherapy, and the Bcl-2 inhibitor venetoclax, typically combined with the CD20 monoclonal antibody. Preclinical studies have shown synergy between Bruton tyrosine kinase inhibitors and the Bcl-2 inhibitor venetoclax.

Objective: To examine the rate of complete remission, complete remission with incomplete count recovery, and bone marrow-undetectable measurable residual disease (U-MRD) after treatment with the combination of ibrutinib and venetoclax.

Design, Setting, And Participants: A single-center, phase 2 nonrandomized trial enrolled patients from August 17, 2016, to June 5, 2018. Participants included previously untreated patients with CLL who met International Workshop on CLL 2008 criteria for treatment indication. Patients were required to have at least 1 of the following features: del(17p), TP53-mutated CLL, del(11q), unmutated immunoglobulin heavy-chain variable gene, or age 65 years or older.

Interventions: Therapy consisted of ibrutinib, 420 mg/d, monotherapy for 3 cycles, thereafter combined with venetoclax (standard weekly dose ramp-up to 400 mg/d) for a total of 24 cycles of combination treatment. Responses were assessed at serial points according to International Workshop on CLL 2008 criteria. Measurable residual disease (MRD) was assessed by multicolor flow cytometry with a sensitivity of 10-4.

Main Outcomes And Measures: Outcomes included complete remission, complete remission with incomplete count recovery, and bone marrow U-MRD rate.

Results: Eighty patients (57 [71%] men) were treated; median age was 65 years (range, 26-83 years). The median follow-up for all 80 patients was 38.5 months (range, 5.6-51.1 months). Five patients discontinued the study during the ibrutinib monotherapy phase; the remaining 75 patients received combination therapy. On an intent-to-treat analysis of combined treatment, 45 (56%) patients achieved bone marrow U-MRD remission at 12 cycles and 53 (66%) patients achieved bone marrow U-MRD remission at 24 cycles. Overall, 60 (75%) patients achieved bone marrow U-MRD remission as their best response. Responses were seen across all high-risk subgroups, independent of the immunoglobulin heavy-chain variable gene mutation status, fluorescence in situ hybridization category, or TP53 mutation. The 3-year progression-free survival was 93%, and 3-year overall survival was 96%. No patient had CLL progression; 2 patients developed Richter transformation.

Conclusions And Relevance: The findings of this study suggest that combination therapy with ibrutinib and venetoclax might be beneficial for previously untreated patients with CLL. Remissions appeared to be durable during a follow-up of more than 3 years, with activity seen across high-risk disease subgroups, including those with del(17p)/TP53-mutated CLL.

Trial Registration: ClinicalTrials.gov Identifier: NCT02756897.
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http://dx.doi.org/10.1001/jamaoncol.2021.1649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193546PMC
June 2021

Lipophilic Salts and Lipid-Based Formulations: Enhancing the Oral Delivery of Octreotide.

Pharm Res 2021 Jun 7. Epub 2021 Jun 7.

Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.

Purpose: Successful oral peptide delivery faces two major hurdles: low enzymatic stability in the gastro-intestinal lumen and poor intestinal membrane permeability. While lipid-based formulations (LBF) have the potential to overcome these barriers, effective formulation of peptides remains challenging. Lipophilic salt (LS) technology can increase the apparent lipophilicity of peptides, making them more suitable for LBF.

Methods: As a model therapeutic peptide, octreotide (OCT) was converted to the docusate LS (OCT.DoS), and compared to the commercial acetate salt (OCT.OAc) in oral absorption studies and related in vitro studies, including parallel artificial membrane permeability assay (PAMPA), Caco-2, in situ intestine perfusion, and simulated digestion in vitro models. The in vivo oral absorption of OCT.DoS and OCT.OAc formulated in self-emulsifying drug delivery systems (SEDDS) was studied in rats.

Results: LS formulation improved the solubility and loading of OCT in LBF excipients and OCT.DoS in combination with SEDDS showed higher OCT absorption than the acetate comparator in the in vivo studies in rats. The Caco-2 and in situ intestine perfusion models indicated no increases in permeability for OCT.DoS. However, the in vitro digestion studies showed reduced enzymatic degradation of OCT.DoS when formulated in the SEDDS formulations. Further in vitro dissociation and release studies suggest that the enhanced bioavailability of OCT from SEDDS-incorporating OCT.DoS is likely a result of higher partitioning into and prolonged retention within lipid colloid structures.

Conclusion: The combination of LS and LBF enhanced the in vivo oral absorption of OCT primarily via the protective effect of LBF sheltering the peptide from gastrointestinal degradation.
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http://dx.doi.org/10.1007/s11095-021-03063-3DOI Listing
June 2021

Response to Comment on Trophic strategy and bleaching resistance in reef-building corals.

Sci Adv 2021 Jun 2;7(23). Epub 2021 Jun 2.

The Swire Institute of Marine Science and the School of Biological Sciences, University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China.

Recently, we published a novel method used to assess the trophic niches of different coral species and demonstrated that their nutrition varied considerably, with some species highly dependent on their photosynthetic algal symbionts and others able to feed on plankton to meet energetic requirements. Adjustments to the use of this tool are necessary when it is applied to other scientific questions and symbiotic organisms. We respond to a comment highlighting a risk of bias in the methods, discuss suggested adjustments, and propose further refinements to improve method robustness.
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http://dx.doi.org/10.1126/sciadv.abi8666DOI Listing
June 2021

Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) regimen for chronic lymphocytic leukemia (CLL) with mutated IGHV and without TP53 aberrations.

Leukemia 2021 May 18. Epub 2021 May 18.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Chemoimmunotherapy with combined fludarabine, cyclophosphamide and rituximab (FCR) has been an effective treatment for patients with chronic lymphocytic leukemia (CLL). We initiated a phase II trial for previously untreated patients with CLL with mutated IGHV and absence of del(17p)/TP53 mutation. Patients received ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for three cycles. Patients who achieved complete remission (CR)/CR with incomplete count recvoery (CRi) with marrow undetectable measurable residual disease (U-MRD) received additional nine cycles of ibrutinib with three cycles of obinutuzumab; all others received nine additional cycles of ibrutinib and obinutuzumab. Patients in marrow U-MRD remission after cycle 12 discontinued all treatment, including ibrutinib. Forty-five patients were treated. The median follow-up is 41.3 months. Among the total 45 treated patients, after three cycles, 38% achieved CR/CRi and 87% achieved marrow U-MRD. After cycle 12, the corresponding numbers were 67% and 91%, respectively. Overall, 44/45 (98%) patients achieved marrow U-MRD as best response. No patient had CLL progression. The 3-year progression-free survival (PFS) and overall survival (OS) were 98% and 98%, respectively. Per trial design, all patients who completed cycle 12 discontinued ibrutinib, providing for a time-limited therapy. Grade 3-4 neutropenia and thrombocytopenia occurred in 58% and 40% patients, respectively. The iFCG regimen with only 3 cycles of chemotherapy is an effective, time-limited regimen for patients with CLL with mutated IGHV and without del(17p)/TP53 mutation.
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http://dx.doi.org/10.1038/s41375-021-01280-8DOI Listing
May 2021

Clinical and molecular characteristics and treatment patterns of adolescent and young adult patients with chronic lymphocytic leukaemia.

Br J Haematol 2021 May 10. Epub 2021 May 10.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Chronic lymphocytic leukaemia (CLL) rarely presents in adolescent and young adult (AYA) patients (patients aged 15-39 years). Disease characteristics and outcomes of AYA patients with CLL are not well understood, particularly in the era of novel oral targeted therapies. We analysed outcomes of 227 AYA patients with CLL diagnosed in the last two decades and evaluated at our institution. Median time to first treatment (TTFT) was 2·2 years, and five- and 10-year overall survival (OS) were 90% and 78%, respectively. Pre-treatment elevated beta 2-microglobulin, advanced Rai stage, del(11q) or del(17p) by FISH, unmutated IGHV and CD38 positivity were associated with both shorter TTFT and OS. Within the subgroup of patients who received oral targeted therapy at any time, del(11q) or del(17p) and complex karyotype were associated with shorter OS. First-line treatment choice was significantly associated with time to second treatment (P < 0·001). Patients harbouring del(11q) or del(17p) experienced shorter time to Richter transformation and were more likely to undergo an allogeneic stem cell transplant. There was a significant association between age and both OS and time to Richter transformation. Our study is the first analysis of AYA patients with CLL with a large number of patients treated with oral targeted therapies.
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http://dx.doi.org/10.1111/bjh.17498DOI Listing
May 2021

Reduced Expression in Lung Fibroblasts from Patients with IPF Is Not Mediated by Promoter Methylation or Mir155.

Biomedicines 2021 Apr 30;9(5). Epub 2021 Apr 30.

Institute for Respiratory Health, Nedland 6009, WA, Australia.

The interleukin (IL)-6 family of cytokines and exaggerated signal transducer and activator of transcription (STAT)3 signaling is implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis, but the mechanisms regulating STAT3 expression and function are unknown. Suppressor of cytokine signaling (SOCS)1 and SOCS3 block STAT3, and low SOCS1 levels have been reported in IPF fibroblasts and shown to facilitate collagen production. Fibroblasts and lung tissue from IPF patients and controls were used to examine the mechanisms underlying SOCS1 down-regulation in IPF. A significant reduction in basal mRNA in IPF fibroblasts was confirmed. However, there was no difference in the kinetics of activation, and methylation of SOCS1 in control and IPF lung fibroblasts was low and unaffected by 5'-aza-2'-deoxycytidine' treatment. is a target of microRNA-155 and although microRNA-155 levels were increased in IPF tissue, they were reduced in IPF fibroblasts. Therefore, SOCS1 is not regulated by gene methylation or microRNA155 in these cells. In conclusion, we confirmed that IPF fibroblasts had lower levels of SOCS1 mRNA compared with control fibroblasts, but we were unable to determine the mechanism. Furthermore, although SOCS1 may be important in the fibrotic process, we were unable to find a significant role for SOCS1 in regulating fibroblast function.
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http://dx.doi.org/10.3390/biomedicines9050498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147237PMC
April 2021

A New Turn in Peptide-Based Imaging Agents: Foldamers Afford Improved Theranostics Targeting Cholecystokinin-2 Receptor-Positive Cancer.

J Med Chem 2021 04 7;64(8):4841-4856. Epub 2021 Apr 7.

Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia.

Proteins adopt unique folded secondary and tertiary structures that are responsible for their remarkable biological properties. This structural complexity is key in designing efficacious peptides that can mimic the three-dimensional structure needed for biological function. In this study, we employ different chemical strategies to induce and stabilize a β-hairpin fold of peptides targeting cholecystokinin-2 receptors for theranostic application (combination of a targeted therapeutic and a diagnostic companion). The newly developed peptides exhibited enhanced folding capacity as demonstrated by circular dichroism (CD) spectroscopy, ion-mobility spectrometry-mass spectrometry, and two-dimensional (2D) NMR experiments. Enhanced folding characteristics of the peptides led to increased biological potency, affording four optimal Ga-68 labeled radiotracers ([Ga]Ga-, [Ga]Ga-) targeting CCK-2R. In particular, [Ga]Ga- and [Ga]Ga- presented improved metabolic stability, enhanced cell internalization, and up to 6 fold increase in tumor uptake. These peptides hold great promise as next-generation theranostic radiopharmaceuticals.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02213DOI Listing
April 2021

Prognostic factors for progression in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in complete molecular response within 3 months of therapy with tyrosine kinase inhibitors.

Cancer 2021 Apr 1. Epub 2021 Apr 1.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: The achievement of a 3-month complete molecular response (CMR) is a major prognostic factor for survival in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). However, 25% of patients relapse during therapy with tyrosine kinase inhibitors (TKIs).

Methods: The authors reviewed 204 patients with Ph-positive ALL who were treated between January 2001 and December 2018 using the combination of hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus a TKI (imatinib, 44 patients [22%]; dasatinib, 88 patients [43%]; or ponatinib, 72 patients [35%]). Progression-free survival (PFS) was defined as the time from the start date of therapy to the date of relapse, death, or last follow-up. Overall survival (OS) was defined as the time from the start date of therapy to the date of death or last follow-up.

Results: Overall, a 3-month CMR was observed in 57% of patients, including 32% of those who received imatinib, 52% of those who received dasatinib, and 74% of those who received ponatinib. The median follow-up was 74 months (imatinib, 180 months; dasatinib, 106 months; ponatinib, 43 months). Among 84 patients in 3-month CMR, 17 (20%) proceeded to undergo allogeneic stem cell transplantation (ASCT). The 5-year PFS and OS rates were 68% and 72%, respectively. By multivariate analysis, ponatinib therapy was the only significant favorable independent factor predicting for progression (P = .028; hazard ratio, 0.388; 95% CI, 0.166-0.904) and death (P = .042; hazard ratio, 0.379; 95% CI, 0.149-0.966). ASCT was not a prognostic factor for PFS and OS by univariate analysis.

Conclusions: In patients with Ph-positive ALL, ponatinib is superior to other types of TKIs in inducing and maintaining a CMR, thus preventing disease progression. ASCT does not improve outcome once a 3-month CMR is achieved.
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http://dx.doi.org/10.1002/cncr.33529DOI Listing
April 2021

Prognostic value of measurable residual disease after venetoclax and decitabine in acute myeloid leukemia.

Blood Adv 2021 04;5(7):1876-1883

Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX.

Assessment of measurable residual disease (MRD) provides prognostic information in acute myeloid leukemia (AML). However, the utility of MRD with venetoclax-based lower intensity regimens is unknown. We analyzed the prognostic value of achieving a negative MRD in older/"unfit" patients with AML receiving first-line therapy with 10-day decitabine and venetoclax. MRD was evaluated in bone marrow specimens using multicolor flow cytometry (sensitivity 0.1%). Ninety-seven patients achieving either a complete remission (CR) or CR with incomplete hematologic recovery (CRi) or morphologic leukemia-free state were included. Median age was 72 years (interquartile range, 68-78 years), and 64% had adverse-risk AML. Eighty-three patients achieved CR/CRi, and 52 (54%) became MRD negative. Median time to becoming MRD negative was 2.0 months (interquartile range, 0.9-3.1 months). Patients becoming MRD negative by 2 months had longer relapse-free survival (RFS) compared with those remaining MRD positive (median RFS, not reached vs 5.2 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.12-0.78; P = .004), longer event-free survival (EFS) (median EFS, not reached vs 5.8 months; HR, 0.25; 95% CI, 0.12-0.55; P < .001), as well as longer overall survival (OS) (median OS, 25.1 vs 7.1 months; HR, 0.23; 95% CI, 0.11-0.51; P < .001). Patients achieving an MRD-negative CR had longer OS compared with those with an inferior response (median OS, 25.1 vs 11.6 months; HR, 0.33; 95% CI, 0.19-0.58; P < .0005). Patients becoming MRD negative within 1 month had an improved OS compared with MRD-positive patients (median OS, 25.1 vs 3.4 months; HR, 0.15; 95% CI, 0.03-0.64; P < .0001). Differential impact of MRD status on survival outcomes persisted at a later 4-month time point of evaluation. In conclusion, MRD-negative status at 1, 2, and 4 months after starting therapy confers significantly better survival in older/unfit patients with AML receiving first-line therapy with 10-day decitabine and venetoclax. This trial was registered at www.clinicaltrials.gov as #NCT03404193.
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http://dx.doi.org/10.1182/bloodadvances.2020003717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045494PMC
April 2021

Phase 2 study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia.

Haematologica 2021 Mar 18. Epub 2021 Mar 18.

UC San Diego Moores Cancer Center, San Diego, CA.

B-cell receptor signalling inhibition by targeting Bruton tyrosine kinase (BTK) is effective in treating chronic lymphocytic leukemia (CLL). The BTK inhibitor ibrutinib may be intolerable for some patients. Acalabrutinib is a more selective BTK inhibitor that may be better tolerated by patients who are intolerant to ibrutinib. A phase 2 study of acalabrutinib was conducted in patients with relapsed/refractory CLL who were ibrutinib-intolerant and had continued disease activity. Intolerance was defined as having discontinued ibrutinib due to persistent grade 3/4 adverse events (AEs) or persistent/recurrent grade 2 AEs despite dose modification/interruption. Patients received oral acalabrutinib 100 mg twice daily until disease progression or intolerance. Sixty patients were treated. Overall response rate to acalabrutinib was 73% and three patients (5%) achieved complete remission. At median follow-up of 35 months, the median progressionfree and overall survival were not reached; 24-month estimates were 72% and 81%, respectively. The most frequent AEs with acalabrutinib were diarrhea (53%), headache (42%), contusion (40%), dizziness (33%), upper respiratory tract infection (33%), and cough (30%). Most common reasons for acalabrutinib discontinuation were progressive disease (23%) and AEs (17%). Most patients with baseline samples (49/52; 94%) and all with on-treatment samples (3/3; 100%) had no detectable BTK and/or PLCG2 mutations. Acalabrutinib is effective and tolerable in most patients with relapsed/refractory CLL who are intolerant of ibrutinib. Acalabrutinib may be useful for patients who may benefit from BTK inhibitor therapy but are ibrutinib intolerant.
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http://dx.doi.org/10.3324/haematol.2020.272500DOI Listing
March 2021

The multi-kinase inhibitor TG02 induces apoptosis and blocks B-cell receptor signaling in chronic lymphocytic leukemia through dual mechanisms of action.

Blood Cancer J 2021 Mar 13;11(3):57. Epub 2021 Mar 13.

Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

The constitutive activation of B-cell receptor (BCR) signaling, together with the overexpression of the Bcl-2 family anti-apoptotic proteins, represents two hallmarks of chronic lymphocytic leukemia (CLL) that drive leukemia cell proliferation and sustain their survival. TG02 is a small molecule multi-kinase inhibitor that simultaneously targets both of these facets of CLL pathogenesis. First, its inhibition of cyclin-dependent kinase 9 blocked the activation of RNA polymerase II and transcription. This led to the depletion of Mcl-1 and rapid induction of apoptosis in the primary CLL cells. This mechanism of apoptosis was independent of CLL prognostic factors or prior treatment history, but dependent on the expression of BAX and BAK. Second, TG02, which inhibits the members of the BCR signaling pathway such as Lck and Fyn, blocked BCR-crosslinking-induced activation of NF-κB and Akt, indicating abrogation of BCR signaling. Finally, the combination of TG02 and ibrutinib demonstrated moderate synergy, suggesting a future combination of TG02 with ibrutinib, or use in patients that are refractory to the BCR antagonists. Thus, the dual inhibitory activity on both the CLL survival pathway and BCR signaling identifies TG02 as a unique compound for clinical development in CLL and possibly other B cell malignancies.
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http://dx.doi.org/10.1038/s41408-021-00436-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956145PMC
March 2021

Macrocyclic peptidomimetics as inhibitors of insulin-regulated aminopeptidase (IRAP).

RSC Med Chem 2020 Feb 8;11(2):234-244. Epub 2020 Jan 8.

Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences , Parkville , Victoria 3052 , Australia . Email:

Macrocyclic analogues of the linear hexapeptide, angiotensin IV (AngIV) have proved to be potent inhibitors of insulin-regulated aminopeptidase (IRAP, oxytocinase, EC 3.4.11.3). Along with higher affinity, macrocycles may also offer better metabolic stability, membrane permeability and selectivity, however predicting the outcome of particular cycle modifications is challenging. Here we describe the development of a series of macrocyclic IRAP inhibitors with either disulphide, olefin metathesis or lactam bridges and variations of ring size and other functionality. The binding mode of these compounds is proposed based on molecular dynamics analysis. Estimation of binding affinities (Δ) and relative binding free energies (ΔΔ) with the linear interaction energy (LIE) method and free energy perturbation (FEP) method showed good general agreement with the observed inhibitory potency. Experimental and calculated data highlight the cumulative importance of an intact N-terminal peptide, the specific nature of the macrocycle, the phenolic oxygen and the C-terminal functionality.
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http://dx.doi.org/10.1039/c9md00485hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412577PMC
February 2020

Venetoclax with decitabine vs intensive chemotherapy in acute myeloid leukemia: A propensity score matched analysis stratified by risk of treatment-related mortality.

Am J Hematol 2021 03 24;96(3):282-291. Epub 2020 Dec 24.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Hypomethylating agents (HMA) with venetoclax is a new standard for older/unfit patients with acute myeloid leukemia (AML). However, it is unknown how HMA with venetoclax compare to intensive chemotherapy (IC) in patients who are "fit" or "unfit" for IC. We compared outcomes of older patients with newly diagnosed AML receiving 10-day decitabine with venetoclax (DEC10-VEN) vs IC. DEC10-VEN consisted of daily venetoclax with decitabine 20 mg/m for 10 days for induction and decitabine for 5 days as consolidation. The IC cohort received regimens containing cytarabine ≥1 g/m /d. A validated treatment-related mortality score (TRMS) was used to classify patients at high-risk or low-risk for TRM with IC. Propensity scores were used to match patients to minimize bias. Median age of the DEC10-VEN cohort (n = 85) was 72 years (range 63-89) and 28% patients were at high-risk of TRM with IC. The comparator IC group (n = 85) matched closely in terms of baseline characteristics. DEC10-VEN was associated with significantly higher CR/CRi compared to IC (81% vs 52%, P < .001), and lower rate of relapse (34% vs 56%, P = .01), 30-day mortality (1% vs 24%, P < .01), and longer overall survival (OS; 12.4 vs 4.5 months, HR = 0.48, 95%CI 0.29-0.79, P < .01). In patients at both at high-risk and low-risk of TRM, DEC10-VEN showed significantly higher CR/CRi, lower 30-day mortality, and longer OS compared to IC. Patients at both high-risk and low-risk of TRM had comparable outcomes with DEC10-VEN. In conclusion, DEC10-VEN offers better outcomes compared to intensive chemotherapy in older patients with newly diagnosed AML, particularly in those at high-risk of TRM.
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http://dx.doi.org/10.1002/ajh.26061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128145PMC
March 2021

Is There an Interplay Between the Functional Domains of IRAP?

Front Cell Dev Biol 2020 29;8:585237. Epub 2020 Sep 29.

Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.

As a member of the M1 family of aminopeptidases, insulin regulated aminopeptidase (IRAP) is characterized by distinct binding motifs at the active site in the C-terminal domain that mediate the catalysis of peptide substrates. However, what makes IRAP unique in this family of enzymes is that it also possesses trafficking motifs at the N-terminal domain which regulate the movement of IRAP within different intracellular compartments. Research on the role of IRAP has focused predominantly on the C-terminus catalytic domain in different physiological and pathophysiological states ranging from pregnancy to memory loss. Many of these studies have utilized IRAP inhibitors, that bind competitively to the active site of IRAP, to explore the functional significance of its catalytic activity. However, it is unknown whether these inhibitors are able to access intracellular sites where IRAP is predominantly located in a basal state as the enzyme may need to be at the cell surface for the inhibitors to mediate their effects. This property of IRAP has often been overlooked. Interestingly, in some pathophysiological states, the distribution of IRAP is altered. This, together with the fact that IRAP possesses trafficking motifs, suggest the localization of IRAP may play an important role in defining its physiological or pathological functions and provide insights into the interplay between the two functional domains of the protein.
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http://dx.doi.org/10.3389/fcell.2020.585237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550531PMC
September 2020

IRAP Inhibitors: M1-Aminopeptidase Family Inspiration.

Front Pharmacol 2020 25;11:585930. Epub 2020 Sep 25.

Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.

The insulin regulated aminopeptidase (IRAP) has been proposed as an important therapeutic target for indications including Alzheimer's disease and immune disorders. To date, a number of IRAP inhibitor designs have been investigated but the total number of molecules investigated remains quite small. As a member the M1 aminopeptidase family, IRAP shares numerous structural features with the other M1 aminopeptidases. The study of those enzymes and the development of inhibitors provide key learnings and new approaches and are potential sources of inspiration for future IRAP inhibitors.
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http://dx.doi.org/10.3389/fphar.2020.585930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546331PMC
September 2020

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial.

Lancet Haematol 2020 Oct 5;7(10):e724-e736. Epub 2020 Sep 5.

Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Venetoclax combined with hypomethylating agents is a new standard of care for newly diagnosed patients with acute myeloid leukaemia (AML) who are 75 years or older, or unfit for intensive chemotherapy. Pharmacodynamic studies have suggested superiority of the longer 10-day regimen of decitabine that has shown promising results in patients with high-risk AML in phase 2 trials. We hypothesised that venetoclax with 10-day decitabine could have improved activity in patients with newly diagnosed AML and those with relapsed or refractory AML, particularly in high-risk subgroups.

Methods: This single centre, phase 2 trial was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). The study enrolled older patients (aged >60 years) with newly diagnosed AML, not eligible for intensive chemotherapy; secondary AML (progressed after myelodysplastic syndrome or chronic myelomonocytic leukaemia); and relapsed or refractory AML. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 3 or less, white blood cell count less than 10 × 10 per L, and adequate end-organ function. Patients with favourable-risk cytogenetics (eg, t[15;17] or core-binding factor AML) or who had received previous BCL2-inhibitor therapy were excluded. Patients received decitabine 20 mg/m intravenously for 10 days with oral venetoclax 400 mg daily for induction, followed by decitabine for 5 days with daily venetoclax for consolidation. The primary endpoint was overall response rate. The secondary endpoints analysed within this report include safety, overall survival, and duration of response, in keeping with recommendations of European LeukemiaNet 2017 guidelines. All patients who received at least one dose of treatment were eligible for safety and response assessments. The trial was registered on ClinicalTrials.gov (NCT03404193) and continues to accrue patients.

Findings: Between Jan 19, 2018, and Dec 16, 2019, we enrolled 168 patients; 70 (42%) had newly diagnosed AML, 15 (9%) had untreated secondary AML, 28 (17%) had treated secondary AML, and 55 (33%) had relapsed or refractory AML. The median age was 71 years (IQR 65-76) and 30% of patients had ECOG performance status of 2 or higher. The median follow-up for all patients was 16 months (95% CI 12-18; actual follow-up 6·5 months; IQR 3·4-12·4). The overall response rate was 74% (125 of 168 patients; 95% CI 67-80) and in disease subgroups were: 89% in newly diagnosed AML (62 of 70 patients; 79-94), 80% in untreated secondary AML (12 of 15 patients; 55-93), 61% in treated secondary AML (17 of 28 patients; 42-76), and 62% in relapsed or refractory AML (34 of 55 patients; 49-74). The most common treatment-emergent adverse events included infections with grades 3 or 4 neutropenia (n=79, 47%) and febrile neutropenia (n=49, 29%). 139 (83%) of 168 patients had serious adverse events, most frequently neutropenic fever (n=63, 38%), followed by pneumonia (n=17, 10%) and sepsis (n=16, 10%). The 30-day mortality for all patients was 3·6% (n=6, 95% CI 1·7-7·8). The median overall survival was 18·1 months (95% CI 10·0-not reached) in newly diagnosed AML, 7·8 months (2·9-10·7) in untreated secondary AML, 6·0 months (3·4-13·7) in treated secondary AML, and 7·8 months (5·4-13·3) relapsed or refractory AML. The median duration of response was not reached (95% CI 9·0-not reached) in newly diagnosed AML, 5·1 months (95% CI 0·9-not reached) in untreated secondary AML, not reached (95% CI 2·5-not reached) in previously treated secondary AML, and 16·8 months (95% CI 6·6-not reached) in relapsed or refractory AML.

Interpretation: Venetoclax with 10-day decitabine has a manageable safety profile and showed high activity in newly diagnosed AML and molecularly defined subsets of relapsed or refractory AML. Future larger and randomised studies are needed to clarify activity in high-risk subsets.

Funding: US National Institutes of Health and National Cancer Institute.
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http://dx.doi.org/10.1016/S2352-3026(20)30210-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549397PMC
October 2020

BTK Inhibitors and Chemoimmunotherapy for CLL.

Authors:
Philip Thompson

Clin Lymphoma Myeloma Leuk 2020 09;20 Suppl 1:S22-S24

Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas, 77030, United States. Electronic address:

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http://dx.doi.org/10.1016/S2152-2650(20)30449-3DOI Listing
September 2020

The effect of temperature on physiology, toxicity and toxin content of the benthic dinoflagellate Coolia malayensis from a seasonal tropical region.

Water Res 2020 Oct 3;185:116264. Epub 2020 Aug 3.

State Key Laboratory of Marine Pollution, City University of Hong Kong, Hong Kong, China; Research Centre for the Oceans and Human Health, City University of Hong Kong Shenzhen Research Institute, Shenzhen, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, China.

Coolia malayensis is one of the commonly found benthic dinoflagellates in Hong Kong which can produce biotoxins and threaten the early life stages of marine invertebrates. Seawater temperature has been recognized as one of the primary environmental factors that affect the formation of harmful algal blooms. The present study evaluated the responses of C. malayensis, including growth, toxicity and toxin content (putative analogues of okadaic acid and azaspiracids), after exposure to a range of seven different temperatures (i.e., 16°C, 18°C, 20°C, 22°C, 24°C, 26°C, and 28°C). The highest algal density and specific growth rate were recorded at 24°C. Significantly higher F/F (maximum quantum yield of PSII) and total phaeo-pigment values were observed in the exponential growth phase at 28°C. The toxicity of the algal extract, which was assessed by the lethality rate of Artemia larvae, increased with temperature. The highest toxin content was detected at the second highest temperature treatment, i.e., 26°C. Overall, temperature had significant effects on the physiological activities and toxicity of C. malayensis. This study has raised attention to the potentially increasing risks posed by toxic benthic dinoflagellates during heat waves in coastal waters.
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http://dx.doi.org/10.1016/j.watres.2020.116264DOI Listing
October 2020

Obesity, Sex, Race, and Early Onset Hypertension: Implications for a Refined Investigation Strategy.

Hypertension 2020 09 3;76(3):859-865. Epub 2020 Aug 3.

From the Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Freeman Road, United Kingdom (P.T., I.L., C.T., N.S., T.E.).

Investigation for secondary causes is recommended in early onset hypertension. However, obesity is associated with higher blood pressure (BP), so investigation for alternative secondary causes may not be necessary in all obese patients. We sought to define a rational approach to investigation across strata of age, body mass index (BMI) sex and race, based on BP distributions in the US National Health and Nutrition Examination Surveys 2005 to 2016. The majority (71% [95% CI, 59%-79%] and 64% [95% CI, 57%-69%] by European and US definitions respectively) of early onset hypertension cases were attributable to BP distribution shifts accompanying obesity and male sex. Male versus female sex, BMI>40 versus 18.2
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15557DOI Listing
September 2020

Disrupting the platelet internal membrane via PI3KC2α inhibition impairs thrombosis independently of canonical platelet activation.

Sci Transl Med 2020 07;12(553)

Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia.

Arterial thrombosis causes heart attacks and most strokes and is the most common cause of death in the world. Platelets are the cells that form arterial thrombi, and antiplatelet drugs are the mainstay of heart attack and stroke prevention. Yet, current drugs have limited efficacy, preventing fewer than 25% of lethal cardiovascular events without clinically relevant effects on bleeding. The key limitation on the ability of all current drugs to impair thrombosis without causing bleeding is that they block global platelet activation, thereby indiscriminately preventing platelet function in hemostasis and thrombosis. Here, we identify an approach with the potential to overcome this limitation by preventing platelet function independently of canonical platelet activation and in a manner that appears specifically relevant in the setting of thrombosis. Genetic or pharmacological targeting of the class II phosphoinositide 3-kinase (PI3KC2α) dilates the internal membrane reserve of platelets but does not affect activation-dependent platelet function in standard tests. Despite this, inhibition of PI3KC2α is potently antithrombotic in human blood ex vivo and mice in vivo and does not affect hemostasis. Mechanistic studies reveal this antithrombotic effect to be the result of impaired platelet adhesion driven by pronounced hemodynamic shear stress gradients. These findings demonstrate an important role for PI3KC2α in regulating platelet structure and function via a membrane-dependent mechanism and suggest that drugs targeting the platelet internal membrane may be a suitable approach for antithrombotic therapies with an improved therapeutic window.
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http://dx.doi.org/10.1126/scitranslmed.aar8430DOI Listing
July 2020

Improving Membrane Permeation in the Beyond Rule-of-Five Space by Using Prodrugs to Mask Hydrogen Bond Donors.

ACS Chem Biol 2020 08 20;15(8):2070-2078. Epub 2020 Jul 20.

Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.

A wide range of drug targets can be effectively modulated by peptides and macrocycles. Unfortunately, the size and polarity of these compounds prevents them from crossing the cell membrane to reach target sites in the cell cytosol. As such, these compounds do not conform to standard measures of drug-likeness and exist in beyond the rule-of-five space. In this work, we investigate whether prodrug moieties that mask hydrogen bond donors can be applied in the beyond rule-of-five domain to improve the permeation of macrocyclic compounds. Using a cyclic peptide model, we show that masking hydrogen bond donors in the natural polar amino acid residues (His, Ser, Gln, Asn, Glu, Asp, Lys, and Arg) imparts membrane permeability to the otherwise impermeable parent molecules, even though the addition of the masking group increases the overall compound molecular weight and the number of hydrogen bond acceptors. We demonstrate this strategy in PAMPA and Caco2 membrane permeability assays and show that masking with groups that reduce the number of hydrogen-bond donors at the cost of additional mass and hydrogen bond acceptors, a donor-acceptor swap, is effective.
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http://dx.doi.org/10.1021/acschembio.0c00218DOI Listing
August 2020

Structure-Interaction Relationship of Polymyxins with the Membrane of Human Kidney Proximal Tubular Cells.

ACS Infect Dis 2020 08 17;6(8):2110-2119. Epub 2020 Jul 17.

Biomedicine Discovery Institute, Infection & Immunity Program and Department of Microbiology, Monash University, Clayton, Melbourne, Victoria 3800, Australia.

Multidrug-resistant Gram-negative bacteria are a serious global threat to human health. Polymyxins are increasingly used in patients as a last-line therapy to treat infections caused by these life-threatening 'superbugs'. Unfortunately, polymyxin-induced nephrotoxicity is the major dose-limiting factor and understanding its mechanism is crucial for the development of novel, safer polymyxins. Here, we undertook the first all-atom molecular dynamics simulations of the interaction between four naturally occurring polymyxins A, B, M and colistin A (representative structural variations of the polymyxin core structure) and the membrane of human kidney proximal tubular cells. All polymyxins inserted spontaneously into the hydrophobic region of the membrane where they were retained, although their insertion abilities varied. Polymyxin A completely penetrated into the hydrophobic region of the membrane with a unique folded conformation, whereas the other three polymyxins only inserted their fatty acyl tails into this region. Furthermore, local membrane defects and increased water penetration were induced by each polymyxin, which may represent the initial stage of cellular membrane damage. Finally, the structure-interaction relationship of polymyxins was investigated based on atomic interactions at the cell membrane level. The hydrophobicity at positions 6/7 and stereochemistry at position 3 regulated the interactions of polymyxins with the cell membrane. Collectively, our results provide new mechanistic insights into polymyxin-induced nephrotoxicity at the atomic level and will facilitate the development of new-generation polymyxins.
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http://dx.doi.org/10.1021/acsinfecdis.0c00190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485602PMC
August 2020

Occupy BTK: the key to controlling CLL.

Blood 2020 07;136(1):4-6

The University of Texas MD Anderson Cancer Center.

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http://dx.doi.org/10.1182/blood.2020005877DOI Listing
July 2020

Incidence and characterization of fungal infections in chronic lymphocytic leukemia patients receiving ibrutinib.

Leuk Lymphoma 2020 10 12;61(10):2488-2491. Epub 2020 Jun 12.

Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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http://dx.doi.org/10.1080/10428194.2020.1775215DOI Listing
October 2020

Treating Leukemia in the Time of COVID-19.

Acta Haematol 2021 11;144(2):132-145. Epub 2020 May 11.

Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, USA,

The coronavirus disease 2019 (COVID-19) pandemic poses several challenges to the management of patients with leukemia. The biology of each leukemia and its corresponding treatment with conventional intensive chemotherapy, with or without targeted therapies (venetoclax, FLT3 inhibitors, IDH1/2 inhibitors, Bruton's tyrosine kinase inhibitors), introduce additional layers of complexity during COVID-19 high-risk periods. The knowledge about COVID-19 is accumulating rapidly. An important distinction is the prevalence of "exposure" versus "clinical infectivity," which determine the risk versus benefit of modifying potentially highly curative therapies in leukemia. At present, the rate of clinical infection is <1-2% worldwide. With a mortality rate of 1-5% in CO-VID-19 patients in the general population and potentially of >30% in patients with cancer, careful consideration should be given to the risk of COVID-19 in leukemia. Instead of reducing patient access to specialized cancer centers and modifying therapies to ones with unproven curative benefit, there is more rationale for less intensive, yet effective therapies that may require fewer clinic visits or hospitalizations. Here, we offer recommendations on the optimization of leukemia management during high-risk COVID-19 periods.
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http://dx.doi.org/10.1159/000508199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270066PMC
April 2021

Heterodimeric Analogues of the Potent Y1R Antagonist 1229U91, Lacking One of the Pharmacophoric C-Terminal Structures, Retain Potent Y1R Affinity and Show Improved Selectivity over Y4R.

J Med Chem 2020 05 16;63(10):5274-5286. Epub 2020 May 16.

Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia.

The cyclic dimeric peptide 1229U91 (GR231118) has an unusual structure and displays potent, insurmountable antagonism of the Y receptor. To probe the structural basis for this activity, we have prepared ring size variants and heterodimeric compounds, identifying the specific residues underpinning the mechanism of 1229U91 binding. The homodimeric structure was shown to be dispensible, with analogues lacking key pharmacophoric residues in one dimer arm retaining high antagonist affinity. Compounds also showed enhanced Y1R selectivity over Y4R compared to 1229U91.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00027DOI Listing
May 2020