Publications by authors named "Andrew W Roberts"

156 Publications

Reimbursement Policies for Diabetes Prevention Program (DPP): Implications for Racial and Ethnic Health Disparities.

Kans J Med 2021 1;14:234-237. Epub 2021 Sep 1.

Department of Population Health, University of Kansas School of Medicine, Kansas City, KS.

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http://dx.doi.org/10.17161/kjm.vol1415125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415384PMC
September 2021

Trajectories of glycemic control with clinical pharmacy specialist management of veterans with type 2 diabetes.

Res Social Adm Pharm 2021 Aug 26. Epub 2021 Aug 26.

University of Kansas School of Pharmacy, Department of Pharmacy Practice, Lawrence, KS, United States.

Background: Improved control of glycemic control likely lowers the risk of diabetes complications and clinical pharmacy specialist (CPS) services can improve glycemic control. Though the pattern of control may also matter in terms of outcomes.

Objectives: The objective of this study was to examine the longitudinal trajectories of HbA1c among a large population of Veterans with type 2 diabetes who received CPS-led diabetes management.

Methods: This is an observational, multicenter cohort study of Veterans with type-2 diabetes managed by CPSs between 7/1/2013 and 7/1/2017 with baseline glycosylated hemoglobin (HbA1c) level ≥8%. Two years of HbA1c measurements were used to group patients into distinct patterns of HbA1c trajectories over time using group-based trajectory modeling. Characteristics associated with successful HbA1c trajectories and association of assigned trajectories with all-cause and diabetes-related hospitalizations were analyzed using logistic regression.

Results: A total of 4119 Veterans were included and able to be successfully segmented into six distinct HbA1c trajectory groups over time: High Gradually Decreasing (n = 325, 7.9%), Moderate Early Decline (n = 1692, 41.1%), Large Early Decline (n = 231, 5.6%), Uncontrolled Stable (n = 1468, 35.6%), Early Decline/Subsequent Increase (n = 266, 6.5%), and Very Uncontrolled Stable (n = 137, 3.3%). The distinguishing factor between successful and less successful trajectories appears to be the progress made within the first six months of pharmacist management.

Conclusions: Significant variability exists in the pattern of glycemic control over time of type 2 diabetes patients managed by clinical pharmacy specialists. Limited resources should be first prioritized to managing patients with very elevated HbA1c and into the first six months of CPS management.
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http://dx.doi.org/10.1016/j.sapharm.2021.08.010DOI Listing
August 2021

Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition.

Blood Adv 2021 Oct;5(20):4054-4058

Department of Clinical Haematology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Covalent Bruton tyrosine kinase inhibitors (BTKi's) and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL), especially those with biologically adverse disease. Patients with CLL resistant to their first targeted agent (TA) can be effectively treated with the alternative class. However, relapses are expected with second-line TA therapy, and the clinical challenge of double class-resistant disease is now emerging with increasing frequency. To define the characteristics and outcomes of patients with double class-resistant disease, we retrospectively analyzed 17 patients who developed progressive disease (PD) on both TA classes for CLL (venetoclax, then BTKi, n=12; BTKi, then venetoclax, n = 5). The cohort was heavily pretreated (median lines of prior therapy, 4) and enriched for adverse disease genetics (complex karyotype, 12 of 12 tested [100%]; del(17p)/TP53 mutations, 15 of 17 [88%]). The median time to progression on prior venetoclax was 24 months (range, 6-94 months) and was 25 months (range, 1-55 months) on prior BTKi. Progression on second-line TA was manifest as progressive CLL in 11 patients and as Richter transformation in 6. The median overall survival after progression on second-line TA was 3.6 months (95% confidence interval, 2-11 months). Patients with double class-resistant CLL have a dismal prognosis, representing a group of high unmet need.
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http://dx.doi.org/10.1182/bloodadvances.2021005083DOI Listing
October 2021

Health costs of women with chronic overlapping pain conditions by opioid and complementary and integrative health use.

Health Serv Res 2021 Aug 28. Epub 2021 Aug 28.

Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Objective: To estimate differences in average annual health care expenditures of adult women with chronic overlapping pain conditions (COPCs) by pain treatment modality as follows: (1) no long-term opioid or complementary and integrative health (CIH) use; (2) CIH only use; (3) long-term opioid only use; and (4) long-term opioid and CIH use.

Data Source: Cross-sectional Medical Expenditure Panel Survey data (2012-2016).

Study Design: We estimated differences between average annual expenditures of adult women with COPCs by their use of long-term opioids and CIH modalities. Generalized linear regression with a log link function was used to estimate adjusted marginal effects in annual expenditures. The distribution family was chosen based on Modified Park Tests. We controlled for pain severity, patient demographic characteristics, physical limitations, comorbidities, mental health, insurance status, physical therapy use, and census region. We also employed propensity-score based marginal mean weighting through stratification to balance our treatment groups on observed covariates.

Data Collection/extraction Methods: We identified adult women (>17 years) with one or more self-reported COPC using 3-digit International Classification of Diseases (ICD)-9/10-Clinical Modification (CM) codes (N = 9169) and categorized their use of CIH and long-term opioids.

Principal Findings: Compared to women without long-term opioid or CIH use, CIH only use was significantly associated with lower inpatient expenditures (-$947 [-$1699, -$196]; p-value < 0.01), higher office-based expenditures ($1345 [$944, $1746]; p-value < 0.001), and higher patient out-of-pocket expenditures ($628 [$409, $848]; p-value < 0.001). Long-term opioid use, alone or in combination with CIH, was significantly associated with higher expenditures (p-value < 0.05) in total and across all utilization categories compared to women without any long-term opioid or CIH use.

Conclusions: Our results indicate that CIH treatment approaches for chronic pain have the potential to be utilized without increasing overall costs. Future research should further examine the role of CIH modalities in achieving cost-effective pain management that reduces avoidable opioid use.
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http://dx.doi.org/10.1111/1475-6773.13875DOI Listing
August 2021

BCL2 and MCL1 inhibitors for hematologic malignancies.

Blood 2021 Sep;138(13):1120-1136

Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

BCL2 and MCL1 are commonly expressed prosurvival (antiapoptotic) proteins in hematologic cancers and play important roles in their biology either through dysregulation or by virtue of intrinsic importance to the cell-of-origin of the malignancy. A new class of small-molecule anticancer drugs, BH3 mimetics, now enable specific targeting of these proteins in patients. BH3 mimetics act by inhibiting the prosurvival BCL2 proteins to enable the activation of BAX and BAK, apoptosis effectors that permeabilize the outer mitochondrial membrane, triggering apoptosis directly in many cells and sensitizing others to cell death when combined with other antineoplastic drugs. Venetoclax, a specific inhibitor of BCL2, is the first approved in class, demonstrating striking single agent activity in chronic lymphocytic leukemia and in other lymphoid neoplasms, as well as activity against acute myeloid leukemia (AML), especially when used in combination. Key insights from the venetoclax experience include that responses occur rapidly, with major activity as monotherapy proving to be the best indicator for success in combination regimens. This emphasizes the importance of adequate single-agent studies for drugs in this class. Furthermore, secondary resistance is common with long-term exposure and often mediated by genetic or adaptive changes in the apoptotic pathway, suggesting that BH3 mimetics are better suited to limited duration, rather than continuous, therapy. The success of venetoclax has inspired development of BH3 mimetics targeting MCL1. Despite promising preclinical activity against MYC-driven lymphomas, myeloma, and AML, their success may particularly depend on their tolerability profile given physiological roles for MCL1 in several nonhematologic tissues.
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http://dx.doi.org/10.1182/blood.2020006785DOI Listing
September 2021

Trends in Medicare Part D coverage of generics with equivalent brand-name drugs.

Am J Manag Care 2021 07;27(7):283-288

Department of Health Policy, Vanderbilt University School of Medicine, 2525 West End Ave, Ste 1203, Nashville, TN 37203. Email:

Objectives: To evaluate whether increased placement of generic drugs on higher cost-sharing tiers in Medicare Part D is associated with coverage of multisource brand-name drugs, plan type, or product characteristics.

Study Design: Descriptive study of Medicare Prescription Drug Formulary Files.

Methods: We analyzed plan coverage and tiering of brand-name drugs and matched generics from 2013-2019. We compared tiering changes and estimated out-of-pocket spending by tier for all Part D plans and by plan type (Medicare Advantage prescription drug [MA-PD] vs stand-alone prescription drug plan [PDP]) for covered generic drugs. Finally, we identified the generic products commonly placed on higher tiers in 2019 and categorized them based on clinical characteristics.

Results: Across 5,220,488 plan-product combinations in 2019, 76.4% of generic drug observations reflected coverage on Part D plan formularies, compared with only 12.1% of brand-name drugs. Between 2013 and 2019, the share of observations reflecting covered generics on lower tiers decreased from 76.8% to 53.9%, whereas the share on higher tiers increased from 7.5% to 28.0%. MA-PD plans were more likely than PDPs to place generic drugs on lower tiers, even among plan sponsors offering both plan types. Despite these trends, higher tier placement does not appear to be related to more generous coverage of brand-name products. Instead, in 2019, 70% of high-tier generics had multiple formulations, required heightened clinical monitoring, or had head-to-head treatment options available.

Conclusions: Although Part D plans have increasingly placed covered generic drugs on higher formulary tiers over time, this may be partly explained by a drug's clinical profile and availability of substitutes rather than preferred brand-name drug coverage.
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http://dx.doi.org/10.37765/ajmc.2021.88701DOI Listing
July 2021

Cereblon pathway biomarkers and immune profiles in patients with myeloma receiving post-ASCT lenalidomide maintenance (LEOPARD).

Leuk Lymphoma 2021 Jul 15:1-11. Epub 2021 Jul 15.

Malignant Haematology and Stem Cell Transplantation, Alfred Hospital, Melbourne, Australia.

LEOPARD was a single arm, phase II study of lenalidomide (LEN) and alternate day prednisolone maintenance in patients with newly diagnosed multiple myeloma (MM) following autologous stem cell transplantation (ASCT). Sixty patients were enrolled. Estimated median potential follow-up was 44 m, median PFS was 38.3 m, median OS was not reached (landmark 36 m OS: 71.4%). Correlative immunohistochemistry performed on pre-ASCT trephines demonstrated high MM tumor cereblon (total/cytoplasmic) was associated with superior OS ( = .045,  = .031, respectively), whereas high c-Myc was associated with inferior PFS ( = .04). Patients with high cereblon (total/nuclear) were more likely to improve depth of response, whereas patients with high c-Myc were less likely, suggesting alternative/more effective post-ASCT strategies for patients with high c-Myc need identification. Peripheral blood immune profiling (mass cytometry) informed a more sustained response to LEN maintenance, demonstrating enrichment of activated/cytotoxic NK cells and cytotoxic T cells in patients with durable responses, contrasting with enrichment of B-regs in early relapsers.
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http://dx.doi.org/10.1080/10428194.2021.1948030DOI Listing
July 2021

Efficacy of venetoclax plus rituximab for relapsed CLL: 5-year follow-up of continuous or limited- duration therapy.

Blood 2021 Sep;138(10):836-846

Department of Hematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.

We report long-term follow-up of the phase 1b study of venetoclax and rituximab (VenR) in patients with relapsed chronic lymphocytic leukemia (CLL), including outcomes with continuous or limited-duration therapy. Patients received venetoclax daily (200-600 mg) and rituximab over 6 months and then received venetoclax monotherapy. Patients achieving complete response (CR), CR with incomplete marrow recovery (CRi), or undetectable minimal residual disease (uMRD) assessed by flow cytometry (<10-4 cutoff) were allowed, but not required, to discontinue therapy, while remaining in the study and could be retreated with VenR upon progression. Median follow-up for all patients (N = 49) was 5.3 years. Five-year rates (95% CI) for overall survival, progression-free survival, and duration of response were 86% (72-94), 56% (40-70), and 58% (40-73), respectively. Of the 33 deep responders (CR/CRi or uMRD), 14 remained on venetoclax monotherapy (continuous therapy), and 19 stopped venetoclax therapy (limited-duration therapy) after a median of 1.4 years. Five-year estimates of ongoing response were similar between continuous (71%; 95% CI, 39-88) or limited-duration therapy (79% [49-93]). Six of 19 patients in the latter group had subsequent disease progression, all >2 years off venetoclax (range, 2.1-6.4). Four patients were retreated with VenR, with partial responses observed in the 3 evaluable to date. VenR induced deep responses that were highly durable with either continuous or limited-duration therapy. Retreatment with VenR induced responses in patients with CLL progression after discontinuing therapy. Continuous exposure to venetoclax in deep responders does not appear to provide incremental benefit.
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http://dx.doi.org/10.1182/blood.2020009578DOI Listing
September 2021

Long-term Follow-up of Patients with Relapsed or Refractory Non-Hodgkin Lymphoma Treated with Venetoclax in a Phase I, First-in-Human Study.

Clin Cancer Res 2021 Sep 3;27(17):4690-4695. Epub 2021 Jun 3.

Department of Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.

Purpose: We previously reported a 44% overall response rate (ORR) with the oral BCL-2 inhibitor venetoclax in a phase I study of relapsed/refractory non-Hodgkin lymphoma (NHL). Complete response (CR) was observed in patients with mantle cell lymphoma [(MCL), 21%, = 6/28] and follicular lymphoma [(FL), 17%, = 5/29], and partial response (PR) noted in several patients with Waldenström macroglobulinemia (WM), and marginal zone lymphoma (MZL). Here, we report the long-term outcomes of these four cohorts.

Patients And Methods: All patients ( = 106) received venetoclax monotherapy in dose cohorts of 200 to 1,200 mg daily until disease progression or unacceptable toxicity. ORR, progression-free survival (PFS), duration of response (DoR), and adverse events (AEs) were evaluated.

Results: At a median follow-up of 38.5 months (range, 30.0-46.5), the median PFS for all 106 patients was 5.4 [95% confidence interval (CI), 3.5-8.4] months (FL, 10.8; MCL, 11.3; MZL, 21.2; and WM, 30.4). The median DoR was 14.9 (95% CI, 9.7-27.6) months (FL, 26.6; MCL, 15.7; MZL, 20.1; and WM, 25.3). Achievement of CR versus PR predicted longer DoR in both MCL (31.5 vs. 10.1 months) and FL (37.6 vs. 9.7 months). All grade hematologic AEs were infrequent: neutropenia (19%), anemia (19%), and thrombocytopenia (17%), with no new cytopenias after 2 years on therapy. Nonhematologic AEs included nausea (49%), diarrhea (46%), fatigue (44%), with decreased incidence after 1 year.

Conclusions: Venetoclax monotherapy has a manageable safety profile and achieves durable responses in a subset of patients with FL, MCL, WM, and MZL, particularly in those who achieve CR. Further research is warranted on combination strategies to enhance the durability of response to venetoclax.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4842DOI Listing
September 2021

Predictors of Chronic Opioid Use: A Population-level Analysis of North Carolina Cancer Survivors Using Multi-Payer Claims.

J Natl Cancer Inst 2021 Apr 20. Epub 2021 Apr 20.

Yale School of Public Health, New Haven, CT.

Background: No population-based studies have examined chronic opioid use among cancer survivors who are diverse with respect to diagnosis, age group, and insurance status.

Methods: We conducted a retrospective cohort study using North Carolina (NC) cancer registry data linked with claims from public and private insurance (2006-2016). We included adults with non-metastatic cancer who had no prior chronic opioid use (N = 38,366). We used modified Poisson regression to assess the adjusted relative risk of chronic opioid use in survivorship (>90-day continuous supply of opioids in the 13-24 months following diagnosis) associated with patient characteristics.

Results: Only 3.0% of cancer survivors in our cohort used opioids chronically in survivorship. Predictors included younger age (adjusted risk ratio [aRR], 50-59 vs 60-69 = 1.23, 95% confidence interval [CI] = 1.05-1.43), baseline depression (aRR = 1.22, 95% CI = 1.06-1.41) or substance use (aRR = 1.43, 95% CI = 1.15-1.78) and Medicaid (aRR vs Private = 1.93, 95% CI = 1.56-2.40). Survivors who used opioids intermittently (vs not at all) before diagnosis were twice as likely to use opioids chronically in early survivorship (aRR = 2.62, 95% CI = 2.28-3.02). Those who used opioids chronically (vs intermittently or not at all) during active treatment had a nearly 17-fold increased likelihood of chronic use in survivorship (aRR = 16.65, 95 CI = 14.30-19.40).

Conclusions: Younger and low-income survivors, those with baseline depression or substance use, and those who require chronic opioid therapy during treatment are at increased risk for chronic opioid use in survivorship. Our findings point to opportunities improve assessment of psychosocial histories and to engage patients in shared decision-making around long-term pain management, when chronic opioid therapy is required during treatment.
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http://dx.doi.org/10.1093/jnci/djab082DOI Listing
April 2021

Intact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias.

Blood 2021 May;137(20):2721-2735

The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.

Selective targeting of BCL-2 with the BH3-mimetic venetoclax has been a transformative treatment for patients with various leukemias. TP-53 controls apoptosis upstream of where BCL-2 and its prosurvival relatives, such as MCL-1, act. Therefore, targeting these prosurvival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL-2 has produced clinically relevant responses in blood cancers with aberrant TP-53. However, in our study, TP53-mutated or -deficient myeloid and lymphoid leukemias outcompeted isogenic controls with intact TP-53, unless sufficient concentrations of BH3-mimetics targeting BCL-2 or MCL-1 were applied. Strikingly, tumor cells with TP-53 dysfunction escaped and thrived over time if inhibition of BCL-2 or MCL-1 was sublethal, in part because of an increased threshold for BAX/BAK activation in these cells. Our study revealed the key role of TP-53 in shaping long-term responses to BH3-mimetic drugs and reconciled the disparate pattern of initial clinical response to venetoclax, followed by subsequent treatment failure among patients with TP53-mutant chronic lymphocytic leukemia or acute myeloid leukemia. In contrast to BH3-mimetics targeting just BCL-2 or MCL-1 at doses that are individually sublethal, a combined BH3-mimetic approach targeting both prosurvival proteins enhanced lethality and durably suppressed the leukemia burden, regardless of TP53 mutation status. Our findings highlight the importance of using sufficiently lethal treatment strategies to maximize outcomes of patients with TP53-mutant disease. In addition, our findings caution against use of sublethal BH3-mimetic drug regimens that may enhance the risk of disease progression driven by emergent TP53-mutant clones.
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http://dx.doi.org/10.1182/blood.2020010167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138548PMC
May 2021

Medicaid prescription limits and their implications for naloxone accessibility.

Drug Alcohol Depend 2021 01 17;218:108355. Epub 2020 Oct 17.

Division of Pharmaceutical Outcomes and Policy, UNC Eshelman School of Pharmacy, One University Heights, CB# 2125, Asheville, NC 28804, USA. Electronic address:

Background: Expanding access to and utilization of naloxone is a vitally important harm reduction strategy for preventing opioid overdose deaths, particularly in vulnerable populations like Medicaid beneficiaries. The objective of this study was to characterize the landscape of monthly prescription fill limit policies in Medicaid programs and their potential implications for expanding naloxone use for opioid overdose harm reduction.

Methods: A cross-sectional, multi-modal online and telephonic data collection strategy was used to identify and describe the presence and characteristics of monthly prescription fill limit policies across state Medicaid programs. Contextual characteristics were described regarding each state's Medicaid enrollment, opioid prescribing rates, and overdose death rates. Data collection and analysis occurred between February and May 2020.

Results: Medicaid-covered naloxone fills are currently subject to monthly prescription fill limit policies in 10 state Medicaid programs, which cover 20 % of the Medicaid population nationwide. Seven of these programs are located in states ranking in the top 10 highest per-capita opioid prescribing rates in the country. However, 8 of these programs are located in states with opioid overdose death rates below the national average.

Conclusions: Medicaid beneficiaries at high risk of opioid overdose living in states with monthly prescription fill limits may experience significant barriers to obtaining naloxone. Exempting naloxone from Medicaid prescription limit restrictions may help spur broader adoption of naloxone for opioid overdose mortality prevention, especially in states with high opioid prescribing rates. Achieving unfettered naloxone coverage in Medicaid is critical as opioid overdoses and Medicaid enrollment increase amid the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568500PMC
January 2021

Therapeutic development and current uses of BCL-2 inhibition.

Authors:
Andrew W Roberts

Hematology Am Soc Hematol Educ Program 2020 12;2020(1):1-9

Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Clinical Haematology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, Australia; Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Australia; and Victorian Comprehensive Cancer Centre, Melbourne, Australia.

B-cell lymphoma 2 (BCL2) is a key protein regulator of apoptosis. It is variably highly expressed in many hematological malignancies, providing protection from cell death induced by oncogenic and external stresses. Venetoclax is the first selective BCL2 inhibitor, and the first of a new class of anticancer drug (BH3-mimetics) to be approved for routine clinical practice, currently in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). To help understand the potential and limitations of this therapy, this brief review will touch on the history of development of venetoclax, dissect its mechanism of action, and summarize critical evidence for its approved use in the management of patients with CLL and AML. It will also consider recent data on mechanisms of resistance and explore concepts pertinent to its future development based on key lessons learned to date.
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http://dx.doi.org/10.1182/hematology.2020000154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727569PMC
December 2020

Immune recovery in patients with mantle cell lymphoma receiving long-term ibrutinib and venetoclax combination therapy.

Blood Adv 2020 10;4(19):4849-4859

ACRF Translational Research Laboratory, Royal Melbourne Hospital, Melbourne, VIC, Australia.

Combination venetoclax plus ibrutinib for the treatment of mantle cell lymphoma (MCL) has demonstrated efficacy in the relapsed or refractory setting; however, the long-term impact on patient immunology is unknown. In this study, changes in immune subsets of MCL patients treated with combination venetoclax and ibrutinib were assessed over a 4-year period. Multiparameter flow cytometry of peripheral blood mononuclear cells showed that ≥12 months of treatment resulted in alterations in the proportions of multiple immune subsets, most notably CD4+ and CD8+ effector and central memory T cells and natural killer cells, and normalization of T-cell cytokine production in response to T-cell receptor stimulation. Gene expression analysis identified upregulation of multiple myeloid genes (including S100 and cathepsin family members) and inflammatory pathways over 12 months. Four patients with deep responses stopped study drugs, resulting in restoration of normal immune subsets for all study parameters except myeloid gene/pathway expression, suggesting long-term combination venetoclax and ibrutinib irreversibly affects this population. Our findings demonstrate that long-term combination therapy is associated with immune recovery in MCL, which may allow responses to subsequent immunotherapies and suggests that this targeted therapy results in beneficial impacts on immunological recovery. This trial was registered at www.clinicaltrials.gov as #NCT02471391.
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http://dx.doi.org/10.1182/bloodadvances.2020002810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556128PMC
October 2020

Response to Strassels and Durham.

J Natl Cancer Inst 2020 12;112(12):1280

Department of Population Health and Department of Anesthesiology, University of Kansas Medical Center (KUMC), Kansas City, KS, USA.

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http://dx.doi.org/10.1093/jnci/djaa146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735774PMC
December 2020

Association of Current Opioid Use With Serious Adverse Events Among Older Adult Survivors of Breast Cancer.

JAMA Netw Open 2020 09 1;3(9):e2016858. Epub 2020 Sep 1.

Department of Population Health, University of Kansas Medical Center, Kansas City.

Importance: National efforts to improve safe opioid prescribing focus on preventing misuse, overdose, and opioid use disorder. This approach overlooks opportunities to better prevent other serious opioid-related harms in complex populations, such as older adult survivors of cancer. Little is known about the rates and risk factors for comprehensive opioid-related harms in this population.

Objective: To determine rates of multiple opioid-related adverse drug events among older adults who survived breast cancer and estimate the risk of these events associated with opioid use in the year after completing cancer treatment.

Design, Setting, And Participants: This retrospective cohort study used 2007 to 2016 Surveillance, Epidemiology and End Results-Medicare data from fee-for-service Medicare beneficiaries with first cancer diagnosis of stage 0 to III breast cancer at age 66 to 90 years from January 1, 2008, through December 31, 2015, who completed active breast cancer treatment. Data were analyzed from October 31, 2019, to June 10, 2020.

Exposures: Repeated daily measure indicating possession of any prescription opioid supply in Medicare Part D prescription claims.

Main Outcomes And Measures: Adjusted risk ratios (aRRs), estimated using modified Poisson generalized estimating equation models, for adverse drug events related to substance misuse (ie, diagnosed opioid abuse, dependence, or poisoning), other adverse drug events associated with opioid use (ie, gastrointestinal events, infections, falls and fractures, or cardiovascular events), and all-cause hospitalization associated with opioid supply the prior day, controlling for patient characteristics.

Results: Among 38 310 women included in the study (mean [SD] age, 74.3 [6.3] years), there were 0.010 (95% CI, 0.008-0.011) adverse drug events related to substance misuse per 1000 person-days, 0.237 (95% CI, 0.229-0.245) other adverse drug events associated with opioid use per 1000 person-days, and 0.675 (95% CI, 0.662-0.689) all-cause hospitalizations per 1000 person-days. Opioid use was associated with increased risk of adverse drug events related to substance misuse (aRR, 14.62; 95% CI, 9.69-22.05; P < .001), other adverse drug events related to opioid use (aRR, 2.50; 95% CI, 2.11-2.96; P < .001), and all-cause hospitalization (aRR, 2.77; 95% CI, 2.55-3.02; P < .001). In a dose-response effect, individuals with high daily opioid doses had consistently higher risks of all study outcomes compared with individuals who had low opioid doses. Compared with days with no opioid exposure, the risk of any adverse drug event related to substance misuse was 3.4-fold higher for individuals with a current opioid supply ≥50 mg morphine equivalent dose per day (aRR, 3.40; 95% CI, 2.47-4.68; P < .001), while the risk was 2.3-fold higher for individuals with 1 to 49 mg morphine equivalent dose per day (aRR, 2.29; 95% CI, 1.89-2.77; P < .001).

Conclusions And Relevance: These findings suggest that among older adults who survived breast cancer, continued prescription opioid use in the year after completing active cancer treatment was associated with an immediate increased risk of a broad range of serious adverse drug events related to substance misuse and other adverse drug events associated with opioid use. Clinicians should consider the comprehensive risks of managing cancer pain with long-term opioid therapy.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.16858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492912PMC
September 2020

Opioid Use Disorder and Overdose in Older Adults With Breast, Colorectal, or Prostate Cancer.

J Natl Cancer Inst 2021 04;113(4):425-433

Department of Population Health Sciences, Duke University School of Medicine; Duke Cancer Institute, Durham, NC, USA.

Background: Despite high rates of opioid therapy, evidence about the risk of preventable opioid harms among cancer survivors is underdeveloped. Our objective was to estimate the odds of opioid use disorder (OUD) and overdose following breast, colorectal, or prostate cancer diagnosis among Medicare beneficiaries.

Methods: We conducted a retrospective cohort study using 2007-2014 Surveillance, Epidemiology, and End Results-Medicare data for cancer survivors with a first cancer diagnosis of stage 0-III breast, colorectal, or prostate cancer at age 66-89 years between 2008 and 2013. Cancer survivors were matched to up to 2 noncancer controls on age, sex, and Surveillance, Epidemiology, and End Results region. Using Firth logistic regression, we estimated adjusted 1-year odds of OUD or nonfatal opioid overdose associated with a cancer diagnosis. We also estimated adjusted odds of OUD and overdose separately and by cancer stage, prior opioid use, and follow-up time.

Results: Among 69 889 cancer survivors and 125 007 controls, the unadjusted rates of OUD or nonfatal overdose were 25.2, 27.1, 38.9, and 12.4 events per 10 000 patients in the noncancer, breast, colorectal, and prostate samples, respectively. There was no association between cancer and OUD. Colorectal survivors had 2.3 times higher odds of opioid overdose compared with matched controls (adjusted odds ratio = 2.33, 95% confidence interval  = 1.49 to 3.67). Additionally, overdose risk was greater in those with more advanced disease, no prior opioid use, and preexisting mental health conditions.

Conclusions: Opioid overdose was a rare, but statistically significant, outcome following stage II-III colorectal cancer diagnosis, particularly among previously opioid-naïve patients. These patients may require heightened screening and intervention to prevent inadvertent adverse opioid harms.
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http://dx.doi.org/10.1093/jnci/djaa122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023814PMC
April 2021

Zanubrutinib for the treatment of patients with Waldenström macroglobulinemia: 3 years of follow-up.

Blood 2020 10;136(18):2027-2037

Haematology Department, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.

Inhibitors of Bruton's tyrosine kinase (BTK) have established therapeutic activity in patients with Waldenström macroglobulinemia (WM). Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 1/2 study in patients with WM who were either treatment-naïve (TN) or had relapsed/refractory (R/R) disease. Patients had disease requiring treatment per International Workshop on Waldenström Macroglobulinemia (IWWM) criteria. Treatment was 160 mg of oral zanubrutinib twice daily (n = 50) or 320 mg once daily (n = 23). Efficacy endpoints included overall response rate (ORR) and very good partial response/complete response (VGPR/CR) rates per IWWM-6 criteria (with modification of VGPR definition published previously). Between September 2014 and March 2018, 77 patients (24 TN and 53 R/R) began treatment. At a median follow-up of 36.0 months for patients with R/R disease and 23.5 months for TN, 72.7% remained on treatment. Reasons for treatment discontinuation included any adverse events in 13.0% of patients (1 treatment related), disease progression (10.4%), and other (3.9%). The ORR was 95.9%, and the VGPR/CR rate was 45.2%, which increased over time: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24 months. Estimated 3-year progression-free survival rate was 80.5%, and overall survival rate was 84.8%. Adverse events of interest included contusion (32.5%, all grade 1), neutropenia (18.2%), major hemorrhage (3.9%), atrial fibrillation/flutter (5.2%), and grade 3 diarrhea (2.6%). Long-term treatment with single-agent zanubrutinib resulted in deep and durable responses in some patients with WM. The safety profile of long-term zanubrutinib therapy in these patients was acceptable. This trial was registered at www.clinicaltrials.gov as #NCT02343120.
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http://dx.doi.org/10.1182/blood.2020006449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596846PMC
October 2020

Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy.

J Clin Oncol 2020 10 20;38(30):3506-3517. Epub 2020 Jul 20.

Department of Haematology, The Alfred Hospital, Melbourne, Victoria, Australia.

Purpose: The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax has an emerging role in acute myeloid leukemia (AML), with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients. The tolerability and efficacy of venetoclax in combination with intensive chemotherapy in AML is unknown.

Patients And Methods: Patients with AML who were ≥ 65 years (≥ 60 years if monosomal karyotype) and fit for intensive chemotherapy were allocated to venetoclax dose-escalation cohorts (range, 50-600 mg). Venetoclax was administered orally for 14 days each cycle. During induction, a 7-day prephase/dose ramp-up (days -6 to 0) was followed by an additional 7 days of venetoclax combined with infusional cytarabine 100 mg/m on days 1-5 and idarubicin 12 mg/m intravenously on days 2-3 (ie, 5 + 2). Consolidation (4 cycles) included 14 days of venetoclax (days -6 to 7) combined with cytarabine (days 1-2) and idarubicin (day 1). Maintenance venetoclax was permitted (7 cycles). The primary objective was to assess the optimal dose schedule of venetoclax with 5 + 2.

Results: Fifty-one patients with a median age of 72 years (range, 63-80 years) were included. The maximum tolerated dose was not reached with venetoclax 600 mg/day. The main grade ≥ 3 nonhematologic toxicities during induction were febrile neutropenia (55%) and sepsis (35%). In contrast to induction, platelet recovery was notably delayed during consolidation cycles. The overall response rate (complete remission [CR]/CR with incomplete count recovery) was 72%; it was 97% in de novo AML and was 43% in secondary AML. During the venetoclax prephase, marrow blast reductions (≥ 50%) were noted in -, -, and -mutant AML.

Conclusion: Venetoclax combined with 5 + 2 induction chemotherapy was safe and tolerable in fit older patients with AML. Although the optimal postremission therapy remains to be determined, the high remission rate in de novo AML warrants additional investigation (ANZ Clinical Trial Registry No. ACTRN12616000445471).
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http://dx.doi.org/10.1200/JCO.20.00572DOI Listing
October 2020

Palliative Care's Role Managing Cancer Pain During the Opioid Crisis: A Qualitative Study of Patients, Caregivers, and Clinicians.

J Pain Symptom Manage 2020 12 6;60(6):1127-1135.e2. Epub 2020 Jul 6.

Division of Palliative Medicine, Department of Internal Medicine, University of Kansas School of Medicine, Kansas City, Kansas, USA; Department of History and Philosophy of Medicine, University of Kansas School of Medicine, Kansas City, Kansas, USA.

Context: Patients with cancer face symptoms because of disease and treatment, and pain is common and complex. The opioid crisis may complicate patients' and clinicians' experiences of managing pain in cancer care.

Objectives: In our study of perceptions and experiences with palliative care (PC) at an outpatient cancer center, we examined communication around symptom management throughout cancer care, and pain and its management emerged as particularly salient. The objective of this article is to describe, from the perspectives of patients, caregivers, and oncology health care professionals, the role of PC in navigating the complicated dynamics of pain management amidst the opioid crisis.

Methods: A qualitative descriptive study with grounded theory components was designed to investigate experiences with and perceptions of specialist PC and symptom management, including pain. Interviews were audiorecorded and transcribed, and focused coding identified themes related to pain and pain management from all three perspectives.

Results: About 44 patients, caregivers, and non-PC health care professionals completed interviews. Patients with cancer and their caregivers had many concerns about pain management and were specifically concerned about opioid use and stigma. For patients, PC improved pain management and helped to destigmatize appropriate pain management. Oncology clinicians reported that partnering with PC facilitated complex pain management and also provided moral support around difficult opioid recommendations for patients.

Conclusion: PC offers the potential to uniquely support both patients and other oncology professionals in optimally navigating the complexity around pain management for cancer care in the midst of the opioid crisis.
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http://dx.doi.org/10.1016/j.jpainsymman.2020.06.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680449PMC
December 2020

Cotargeting BCL-2 and MCL-1 in high-risk B-ALL.

Blood Adv 2020 06;4(12):2762-2767

Centre for Cancer Research, University of Melbourne, Parkville, Melbourne, Australia.

Improving survival outcomes in adult B-cell acute lymphoblastic leukemia (B-ALL) remains a clinical challenge. Relapsed disease has a poor prognosis despite the use of tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome positive (Ph+ ALL) cases and immunotherapeutic approaches, including blinatumomab and chimeric antigen receptor T cells. Targeting aberrant cell survival pathways with selective small molecule BH3-mimetic inhibitors of BCL-2 (venetoclax, S55746), BCL-XL (A1331852), or MCL1 (S63845) is an emerging therapeutic option. We report that combined targeting of BCL-2 and MCL1 is synergistic in B-ALL in vitro. The combination demonstrated greater efficacy than standard chemotherapeutics and TKIs in primary samples from adult B-ALL with Ph+ ALL, Ph-like ALL, and other B-ALL. Moreover, combined BCL-2 or MCL1 inhibition with dasatinib showed potent killing in primary Ph+ B-ALL cases, but the BH3-mimetic combination appeared superior in vitro in a variety of Ph-like ALL samples. In PDX models, combined BCL-2 and MCL1 targeting eradicated ALL from Ph- and Ph+ B-ALL cases, although fatal tumor lysis was observed in some instances of high tumor burden. We conclude that a dual BH3-mimetic approach is highly effective in diverse models of high-risk human B-ALL and warrants assessment in clinical trials that incorporate tumor lysis precautions.
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http://dx.doi.org/10.1182/bloodadvances.2019001416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322969PMC
June 2020

Naloxone Prescribing Among Frequent Opioid Prescribers in Medicare Part D from 2013 to 2017: a Retrospective Study.

Authors:
Andrew W Roberts

J Gen Intern Med 2021 02 6;36(2):543-545. Epub 2020 May 6.

Department of Population Health, Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS, USA.

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http://dx.doi.org/10.1007/s11606-020-05872-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878639PMC
February 2021

BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax.

Blood 2020 06;135(25):2266-2270

Department of Clinical Haematology, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Highly active BTK inhibitors (BTKis) and the BCL2 inhibitor venetoclax have transformed the therapeutic landscape for chronic lymphocytic leukemia (CLL). Results of prospective clinical trials demonstrate the efficacy of venetoclax to salvage patients with disease progression on BTKis, but data on BTKi therapy after disease progression on venetoclax are limited, especially regarding durability of benefit. We retrospectively evaluated the records of 23 consecutive patients with relapsed/refractory CLL who received a BTKi (ibrutinib, n = 21; zanubrutinib, n = 2) after stopping venetoclax because of progressive disease. Median progression-free survival (PFS) and median overall survival after BTKi initiation were 34 months (range, <1 to 49) and 42 months (range, 2-49), respectively. Prior remission duration ≥24 months and attainment of complete remission or undetectable measurable residual disease on venetoclax were associated with longer PFS after BTKi salvage (P = .044 and P = .029, respectively). BTKi therapy achieved durable benefit for patients with the BCL2 Gly101Val venetoclax resistance mutation (estimated 24-month PFS, 69%). At a median survivor follow-up of 33 months (range, 2-53), 11 patients remained on BTKi and 12 had stopped therapy because of disease progression (n = 8) or toxicity (n = 4). Our findings indicate that BTKi therapy can provide durable CLL control after disease progression on venetoclax.
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http://dx.doi.org/10.1182/blood.2020004782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316215PMC
June 2020

Cancer survivorship and its association with perioperative opioid use for minor non-cancer surgery.

Support Care Cancer 2020 Dec 25;28(12):5763-5770. Epub 2020 Mar 25.

Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS, USA.

Purpose: Reducing high-risk prescription opioid use after surgery has become a key strategy in mitigating the opioid crisis. Yet, despite their vulnerabilities, we know little about how cancer survivors use opioids for non-cancer perioperative pain compared to those with no history of cancer. The purpose was to examine the association of cancer survivorship with the likelihood of receiving perioperative opioid therapy for non-cancer minor surgery.

Methods: Using 2007-2014 SEER-Medicare data for breast, colorectal, prostate, and non-cancer populations, we conducted retrospective cohort study of opioid-naïve Medicare beneficiaries who underwent one of six common minor non-cancer surgeries. Modified Poisson regression estimated the relative risk of receiving a perioperative opioid prescription associated with cancer survivorship compared to no history of cancer. Stabilized inverse probability of treatment weights were used to balance measurable covariates between cohorts.

Results: We included 1486 opioid-naïve older adult cancer survivors and 3682 opioid-naïve non-cancer controls. Cancer survivorship was associated with a 5% lower risk of receiving a perioperative opioid prescription (95% confidence interval: 0.89, 1.00; p = 0.06) compared to no history of cancer. Cancer survivorship was not associated with the extent of perioperative opioid exposure.

Conclusion: Cancer survivors were slightly less likely to receive opioid therapy for non-cancer perioperative pain than those without a history of cancer. It is unclear if this reflects a reduced risk of opioid-related harms for cancer survivors or avoidance of appropriate perioperative pain therapy. Further examination of cancer survivors' experiences with and attitudes about opioids may inform improvements to non-cancer pain management for cancer survivors.
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http://dx.doi.org/10.1007/s00520-020-05420-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529663PMC
December 2020

Targeting MCL-1 in hematologic malignancies: Rationale and progress.

Blood Rev 2020 11 21;44:100672. Epub 2020 Feb 21.

Gehr Family Center for Leukemia, City of Hope Medical Center, Duarte, CA, USA.

Myeloid cell leukemia sequence 1 (MCL-1) is an antiapoptotic protein that plays a key role in promoting cell survival in multiple myeloma (MM), acute myeloid leukemia (AML), and non-Hodgkin lymphoma (NHL). Overexpression of MCL-1 is associated with treatment resistance and poor prognosis; thus, MCL-1 inhibitors are rational therapeutic options for malignancies depending on MCL-1. Several MCL-1 inhibitors have entered clinical trials, including AZD5991, S64315, AMG 176, and AMG 397. A key area of investigation is whether MCL-1 inhibitors will complement the activity of BCL-2 inhibitors, such as venetoclax, and synergistically enhance anti-tumor efficacy when given in combination with other anti-cancer drugs. Another important question is whether a safe therapeutic window can be found for this new class of inhibitors. In summary, inhibition of MCL-1 shows potential as a treatment for hematologic malignancies and clinical evaluation of MCL-1 inhibitors is currently underway.
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http://dx.doi.org/10.1016/j.blre.2020.100672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442684PMC
November 2020

Deep profiling of apoptotic pathways with mass cytometry identifies a synergistic drug combination for killing myeloma cells.

Cell Death Differ 2020 07 27;27(7):2217-2233. Epub 2020 Jan 27.

Baxter Laboratory for Stem Cell Biology, Stanford School of Medicine, Stanford, CA, USA.

Multiple myeloma is an incurable and fatal cancer of immunoglobulin-secreting plasma cells. Most conventional therapies aim to induce apoptosis in myeloma cells but resistance to these drugs often arises and drives relapse. In this study, we sought to identify the best adjunct targets to kill myeloma cells resistant to conventional therapies using deep profiling by mass cytometry (CyTOF). We validated probes to simultaneously detect 26 regulators of cell death, mitosis, cell signaling, and cancer-related pathways at the single-cell level following treatment of myeloma cells with dexamethasone or bortezomib. Time-resolved visualization algorithms and machine learning random forest models (RFMs) delineated putative cell death trajectories and a hierarchy of parameters that specified myeloma cell survival versus apoptosis following treatment. Among these parameters, increased amounts of phosphorylated cAMP response element-binding protein (CREB) and the pro-survival protein, MCL-1, were defining features of cells surviving drug treatment. Importantly, the RFM prediction that the combination of an MCL-1 inhibitor with dexamethasone would elicit potent, synergistic killing of myeloma cells was validated in other cell lines, in vivo preclinical models and primary myeloma samples from patients. Furthermore, CyTOF analysis of patient bone marrow cells clearly identified myeloma cells and their key cell survival features. This study demonstrates the utility of CyTOF profiling at the single-cell level to identify clinically relevant drug combinations and tracking of patient responses for future clinical trials.
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http://dx.doi.org/10.1038/s41418-020-0498-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308383PMC
July 2020

Undetectable peripheral blood MRD should be the goal of venetoclax in CLL, but attainment plateaus after 24 months.

Blood Adv 2020 01;4(1):165-173

Department of Clinical Haematology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, Australia.

The highly selective BCL2 inhibitor venetoclax achieves deep responses in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), including undetectable minimal residual disease (uMRD). We retrospectively reviewed 62 patients with CLL treated with venetoclax to investigate the performance of peripheral blood (PB) compared with bone marrow (BM) assessment of MRD; the kinetics, clinicopathological associations, and longer-term outcomes of uMRD attainment and recrudescence; and the ability of venetoclax dose escalation to deepen responses. Among 16 patients who achieved PB uMRD and had contemporaneous BM assessments, 13 (81%) had confirmed BM uMRD, and patients with PB uMRD had outcomes at least as favorable as those with BM uMRD for time to progression, overall survival, and MRD recrudescence. Excluding 2 patients lacking earlier assessment, the median time to PB uMRD was 18 (range, 5-26) months, with 90% of instances achieved by 24 months. There was no new PB uMRD attainment after 24 months without treatment intensification. The dominant association with earlier attainment of uMRD was concurrent rituximab (P = .012). Complex karyotype was associated with inferior uMRD attainment after 12 months of therapy (P = .015), and patients attaining uMRD whose disease harbored TP53 abnormalities demonstrated a trend toward earlier recrudescence (P = .089). Of patients who received venetoclax dose escalations, 4 (27%) of 15 achieved improvements in response. For patients with R/R CLL receiving venetoclax, PB uMRD commonly correlates with BM uMRD and is associated with a comparable longer-term prognosis. Concurrent rituximab augments uMRD attainment, but dose escalation and further treatment beyond 24 months infrequently deepen responses.
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http://dx.doi.org/10.1182/bloodadvances.2019000864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960473PMC
January 2020

Long-term opioid therapy definitions and predictors: A systematic review.

Pharmacoepidemiol Drug Saf 2020 03 18;29(3):252-269. Epub 2019 Dec 18.

Department of Population Health, University of Kansas Medical Center, Kansas City, KS, USA.

Purpose: This review sought to (a) describe definitions of long-term opioid therapy (LTOT) outcome measures, and (b) identify the predictors associated with the transition from short-term opioid use to LTOT for opioid-naïve individuals.

Methods: We conducted a systematic review of the peer-reviewed literature (January 2007 to July 2018). We included studies examining opioid use for more than 30 days. We classified operationalization of LTOT based on criteria used in the definitions. We extracted LTOT predictors from multivariate models in studies of opioid-naïve individuals.

Results: The search retrieved 5,221 studies, and 34 studies were included. We extracted 41 unique variations of LTOT definitions. About 36% of definitions required a cumulative duration of opioid use of 3 months. Only 17% of definitions considered consecutive observation periods, 27% used days' supply, and no definitions considered dose. We extracted 76 unique predictors of LTOT from seven studies of opioid-naïve patients. Common predictors included pre-existing comorbidities (21.1%), non-opioid prescription medication use (13.2%), substance use disorders (10.5%), and mental health disorders (10.5%).

Conclusions: Most LTOT definitions aligned with the chronic pain definition (pain more than 3 months), and used cumulative duration of opioid use as a criterion, although most did not account for consistent use. Definitions were varied and rarely accounted for prescription characteristics, such as days' supply. Predictors of LTOT were similar to known risk factors of opioid abuse, misuse, and overdose. As LTOT becomes a central component of quality improvement efforts, researchers should incorporate criteria to identify consistent opioid use to build the evidence for safe and appropriate use of prescription opioids.
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http://dx.doi.org/10.1002/pds.4929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058495PMC
March 2020
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