Publications by authors named "Mary Ann Anderson"

55 Publications

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

Blood 2021 Jun 3. Epub 2021 Jun 3.

Department of Hematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital; University of Melbourne, 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, then 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 on study and could be re-treated with VenR upon progression. Median follow-up for all patients (N=49) was 5.3 years. Five-year rates for overall survival, progression-free survival, and duration of response were 86% (95% CI, 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 re-treated 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. ClinicalTrials.gov ID: NCT01682616.
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http://dx.doi.org/10.1182/blood.2020009578DOI Listing
June 2021

Review of Venetoclax in CLL, AML and Multiple Myeloma.

J Pers Med 2021 May 24;11(6). Epub 2021 May 24.

Department of Haematology, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.

Venetoclax is a highly selective and effective B-cell lymphoma-2 (BCL-2) inhibitor, which is able to reinstate the apoptotic potential of cancer cells. With its full repertoire yet to be explored, it has changed the therapeutic landscape in haematological malignancies, and most particularly chronic lymphocytic leukaemia (CLL), acute myeloid leukaemia (AML) and multiple myeloma (MM). In CLL, it has shown remarkable efficacy both as monotherapy and in combination therapy. Based on data from MURANO and CLL14 studies, fixed-duration combination therapy of venetoclax with anti-CD20 antibody is now the standard of care in numerous countries. In AML, although of limited efficacy as a single agent, venetoclax combination therapy has demonstrated encouraging outcomes including rapid, durable responses and acceptable toxicity, particularly in the older, unfit patient population. Multiple myeloma with translocation (t)(11;14) harbours high BCL-2/ myeloid cell leukaemia sequence-1 (MCL-1) and BCL-2/BCL-XL ratio and is, therefore, particularly suited for venetoclax-based therapy. Despite a wide ranging and evolving clinical role in these diseases, venetoclax treatment is not curative and, over time, clonal evolution and disease relapse appear to be the norm. While a variety of distinct resistance mechanisms have been identified, frequently emerging in a sub-clonal pattern, the full picture is yet to be characterised. Further illumination of the complex interplay of various factors is needed to pave the way for rational combination therapies aimed at circumventing resistance and improving durability of disease control. Serial molecular studies can aid in identification of new prognostically significant and/or targetable mutations.
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http://dx.doi.org/10.3390/jpm11060463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225137PMC
May 2021

CAR-T cell therapy: practical guide to routine laboratory monitoring.

Pathology 2021 Apr 5;53(3):408-415. Epub 2021 Mar 5.

Clinical Hematology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, Vic, Australia; Centre of Excellence in Cellular Immunotherapy, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia; Division of Blood Cells and Blood Cancer, The Walter and Eliza Hall Institute, Parkville, Vic, Australia. Electronic address:

Chimeric antigen receptor (CAR)-T cell therapy is a genetically-modified cellular immunotherapy that has a current established role in the treatment of relapsed/refractory B-cell acute lymphoblastic leukaemia and diffuse large B-cell lymphoma, with emerging utility in a spectrum of other haematological and solid organ malignancies. It is associated with a number of characteristic toxicities, most notably cytokine release syndrome and neurotoxicity, for which laboratory testing can aid in the prediction of severity and in monitoring. Other toxicities, such as cytopenias/marrow hypoplasia, hypogammagloblinaemia and delayed immune reconstitution are recognised and require monitoring due to the implications for infection risk and prophylaxis. The detection or quantitation of circulating CAR-T can be clinically useful, and is achieved through both direct methods, if available, or indirect/surrogate methods. It is important that the laboratory is informed of the CAR-T therapy and target antigen whenever tissue is collected, both for response assessment and investigation of possible relapse, so that the expression of the relevant antigen can be assessed, in order to distinguish antigen-positive and -negative relapses. Finally, the measurement of circulating tumour DNA has an evolving role in the surveillance of malignancy, with evidence of its utility in the post-CAR-T setting, including predicting patients who will inevitably experience frank relapse, potentially allowing for pre-emptive therapy.
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http://dx.doi.org/10.1016/j.pathol.2021.02.002DOI Listing
April 2021

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

Tumor lysis syndrome: still the Achilles heel of venetoclax in treatment of CLL?

Leuk Lymphoma 2020 10 4;61(10):2286-2288. Epub 2020 Aug 4.

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

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http://dx.doi.org/10.1080/10428194.2020.1802454DOI Listing
October 2020

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

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

Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations.

Nat Commun 2019 06 3;10(1):2385. Epub 2019 Jun 3.

Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.

Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 antagonist has revealed emergence of a drug-selected BCL-2 mutation (G101V) in some patients failing therapy. To understand the molecular basis of this acquired resistance we describe the crystal structures of venetoclax bound to both BCL-2 and the G101V mutant. The pose of venetoclax in its binding site on BCL-2 reveals small but unexpected differences as compared to published structures of complexes with venetoclax analogues. The G101V mutant complex structure and mutant binding assays reveal that resistance is acquired by a knock-on effect of V101 on an adjacent residue, E152, with venetoclax binding restored by a E152A mutation. This provides a framework for considering analogues of venetoclax that might be effective in combating this mutation.
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http://dx.doi.org/10.1038/s41467-019-10363-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547681PMC
June 2019

Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia.

Cancer Discov 2019 03 4;9(3):342-353. Epub 2018 Dec 4.

Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia.

The BCL2 inhibitor venetoclax induces high rates of durable remission in patients with previously treated chronic lymphocytic leukemia (CLL). However, despite continuous daily treatment, leukemia recurs in most patients. To investigate the mechanisms of secondary resistance, we analyzed paired pre-venetoclax and progression samples from 15 patients with CLL progression enrolled on venetoclax clinical trials. The novel Gly101Val mutation in BCL2 was identified at progression in 7 patients, but not at study entry. It was first detectable after 19 to 42 months of therapy, and its emergence anticipated clinical disease progression by many months. Gly101Val reduces the affinity of BCL2 for venetoclax by ∼180-fold in surface plasmon resonance assays, thereby preventing the drug from displacing proapoptotic mediators from BCL2 in cells and conferring acquired resistance in cell lines and primary patient cells. This mutation provides new insights into the pathobiology of venetoclax resistance and provides a potential biomarker of impending clinical relapse. SIGNIFICANCE: Why CLL recurs in patients who achieve remission with the BCL2 inhibitor venetoclax has been unknown. We provide the first description of an acquired point mutation in BCL2 arising recurrently and exclusively in venetoclax-treated patients. The mutation reduces venetoclax binding and is sufficient to confer resistance...
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http://dx.doi.org/10.1158/2159-8290.CD-18-1119DOI Listing
March 2019

Dynamic molecular monitoring reveals that SWI-SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma.

Nat Med 2019 01 19;25(1):119-129. Epub 2018 Nov 19.

Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and nonresponders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1-p24.3 loss and/or mutations in components of the SWI-SNF chromatin-remodeling complex were present in all patients with primary resistance and two-thirds of patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored, providing concurrent information on treatment response and tumor evolution. Functional modeling demonstrated that compromise of the SWI-SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a model for real-time assessment of innovative targeted therapies.
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http://dx.doi.org/10.1038/s41591-018-0243-zDOI Listing
January 2019

Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma.

N Engl J Med 2018 03;378(13):1211-1223

From the Peter MacCallum Cancer Centre, Melbourne, VIC (C.S.T., M.A.A., R.A., S.H., R.J.H., K.B., G.T., J.D.I., M.B., D.W., S.L., S.-J.D., M.A.D., J.F.S., A.W.R.), and the Victorian Comprehensive Cancer Centre (C.S.T., M.A.A., R.A., S.H., R.J.H., K.B., D.W., S.-J.D., M.A.D., J.F.S., A.W.R.), the Faculty of Medicine (C.S.T., R.J.H., S.-J.D., M.A.D., J.F.S., A.W.R.) and Centre for Cancer Research (S.-J.D., M.A.D.), University of Melbourne, the Department of Clinical Haematology and Bone Marrow Transplantation, the Royal Melbourne Hospital (C.S.T., M.A.A., K.B., J.F.S., A.W.R.), and the Division of Cancer and Haematology, Walter and Eliza Hall Institute of Medical Research (M.A.A., A.W.R.), Parkville, VIC - all in Australia; and the University Hospital of Schleswig-Holstein, Kiel (C.P.), and Klinikum der Universität, Ludwig-Maximilian University of Munich, Munich (M.D.) - both in Germany.

Background: Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma. Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. Preclinical models predict synergy in combination.

Methods: We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events. The primary end point was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in blood.

Results: The study included 24 patients with relapsed or refractory mantle-cell lymphoma (23 patients) or previously untreated mantle-cell lymphoma (1 patient). Patients were 47 to 81 years of age, and the number of previous treatments ranged from none to six. Half the patients had aberrations of TP53, and 75% had a high-risk prognostic score. The complete response rate according to computed tomography at week 16 was 42%, which was higher than the historical result of 9% at this time point with ibrutinib monotherapy (P<0.001). The rate of complete response as assessed by positron-emission tomography was 62% at week 16 and 71% overall. MRD clearance was confirmed by flow cytometry in 67% of the patients and by ASO-PCR in 38%. In a time-to-event analysis, 78% of the patients with a response were estimated to have an ongoing response at 15 months. The tumor lysis syndrome occurred in 2 patients. Common side effects were generally low grade and included diarrhea (in 83% of the patients), fatigue (in 75%), and nausea or vomiting (in 71%).

Conclusions: In this study involving historical controls, dual targeting of BTK and BCL2 with ibrutinib and venetoclax was consistent with improved outcomes in patients with mantle-cell lymphoma who had been predicted to have poor outcomes with current therapy. (Funded by Janssen and others; AIM ClinicalTrials.gov number, NCT02471391 .).
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http://dx.doi.org/10.1056/NEJMoa1715519DOI Listing
March 2018

Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax.

Blood 2017 06 4;129(25):3362-3370. Epub 2017 May 4.

Department of Clinical Haematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Parkville, Australia.

The BCL2 inhibitor venetoclax achieves responses in ∼79% of patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (RR-CLL/SLL), irrespective of risk factors associated with poor response to chemoimmunotherapy. A limitation of this targeted therapy is progressive disease (PD) in some patients. To define the risk factors for progression, the clinicopathological features of PD, and the outcomes for patients after venetoclax failure, we analyzed 67 heavily pretreated patients on 3 early phase clinical trials. Investigations at progression included positron emission tomography scan and biopsy. Twenty-five (37%) patients manifested PD on therapy: 17 with Richter transformation (RT) and 8 with progressive CLL/SLL. RT occurred significantly earlier (median 7.9 months) than progressive CLL (median 23.4 months) ( = .003). Among patients who received the recommended phase 2 dose of venetoclax or higher (≥400 mg/d), fludarabine refractoriness and complex karyotype were associated with progression (hazard ratio 7.01 [95% confidence interval 1.7-28.5]; = .002 and 6.6 [1.5-29.8]; = .005, respectively), whereas del(17p) and/or mutation were not ( = .75). Median postprogression survival was 13 (<1-49.9) months. Bruton tyrosine kinase inhibitors were active in progressive CLL, but outcomes were mixed. Patients with disease that is fludarabine refractory or who have complex cytogenetics should have occult RT excluded before initiating venetoclax therapy.
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http://dx.doi.org/10.1182/blood-2017-01-763003DOI Listing
June 2017

Venous thromboembolism management practices and knowledge of guidelines: a survey of Australian haematologists and respiratory physicians.

Intern Med J 2017 Apr;47(4):436-446

Department of Respiratory and Sleep Medicine, Royal Melbourne Hospital, Melbourne, Victoria, Australia.

Background: Current international clinical practice guidelines do not adequately address all clinical scenarios in the management of venous thromboembolism (VTE), and no comprehensive Australian guidelines exist.

Aims: To identify areas of uncertainty in VTE management and whether self-reported practice is consistent with guidelines.

Methods: We conducted an Australian cross-sectional online survey consisting of 53 questions to investigate doctors' VTE management practices. The survey was distributed to consultant and trainee/registrar haematologists and respiratory physicians with the aid of participating medical societies.

Results: A total of 71 haematologists and 110 respiratory physicians responded to the survey. The majority of survey respondents were 31-50-years old and worked in teaching hospitals and in the acute care setting. Under-treatment was reported for high-risk pulmonary embolism (PE) and duration of anticoagulation for first-episode unprovoked PE (32 and 83% respectively). Over-treatment was reported in areas of thrombolysis for intermediate-risk PE (16%) and duration of anticoagulation for first-episode provoked PE (41%). Uncertainty and variations in doctors' management approaches were also found.

Conclusion: This survey demonstrated significant over-treatment, under-treatment and variability in the practice of VTE management. The findings highlight the need for the development and implementation of national guidelines for the management of VTE in Australia.
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http://dx.doi.org/10.1111/imj.13382DOI Listing
April 2017

Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma.

J Clin Oncol 2017 Mar 17;35(8):826-833. Epub 2017 Jan 17.

Matthew S. Davids, Dana-Farber Cancer Institute, Boston, MA; Andrew W. Roberts, John F. Seymour, and Mary Ann Anderson, University of Melbourne; Andrew W. Roberts and Mary Ann Anderson, Royal Melbourne Hospital and Eliza Hall Institute of Medical Research; and John F. Seymour, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; John M. Pagel, Swedish Cancer Institute, Seattle, WA; Brad S. Kahl, Washington University Medical School, St Louis, MO; William G. Wierda, University of Texas MD Anderson Cancer Center, Houston, TX; Soham Puvvada, University of Arizona, Tucson, AZ; Thomas J. Kipps, University of California San Diego, San Diego, CA; Ahmed Hamed Salem, Martin Dunbar, Ming Zhu, Jeremy A. Ross, Lori Gressick, Monali Desai, Su Young Kim, Maria Verdugo, Rod A. Humerickhouse, and Gary B. Gordon, AbbVie, Chicago, IL; Ahmed Hamed Salem, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; Franklin Peale, Genentech, South San Francisco, CA; John F. Gerecitano, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center, New York, NY.

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.
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http://dx.doi.org/10.1200/JCO.2016.70.4320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455685PMC
March 2017

Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study.

Lancet Oncol 2017 Feb 13;18(2):230-240. Epub 2017 Jan 13.

Victorian Comprehensive Cancer Centre, Parkville, Melbourne, VIC, Australia; Faculty of Medicine, University of Melbourne, Parkville, Melbourne, VIC, Australia; Department of Clinical Haematology and BMT, The Royal Melbourne Hospital, Parkville, Melbourne, VIC, Australia; Division of Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, VIC, Australia.

Background: Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab.

Methods: Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200-600 mg) and then monthly rituximab commenced (375 mg/m in month 1 and 500 mg/m in months 2-6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616.

Findings: Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1-2 toxicities included upper respiratory tract infections (in 28 [57%] of 49 patients), diarrhoea (27 [55%]), and nausea (25 [51%]). Grade 3-4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 [53%]), thrombocytopenia (eight [16%]), anaemia (seven [14%]), febrile neutropenia (six [12%]), and leucopenia (six [12%]). The most common serious adverse events were pyrexia (six [12%]), febrile neutropenia (five [10%]), lower respiratory tract infection, and pneumonia (each three [6%]). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66-91) and 89% (95% CI 72-96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax.

Interpretation: A substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination offers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies.

Funding: AbbVie Inc and Genentech Inc.
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http://dx.doi.org/10.1016/S1470-2045(17)30012-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316338PMC
February 2017

Transformed Lymphoma.

Hematol Oncol Clin North Am 2016 Dec;30(6):1317-1332

Department of Haematology, Peter MacCallum Cancer Centre, Parkville 3050, Australia; Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Australia.

Transformed lymphoma is a complex syndrome that encompasses an array of different underlying low-grade lymphoproliferative conditions transforming into more aggressive disease as manifest by morphologic, clinical, and genetic features. Over the last decade, advances in chemoimmunotherapy have led to new options. Knowledge surrounding the genetic changes driving the process of transformation is leading to novel targeted therapies. This article focuses on the transformation of chronic lymphocytic leukemia and follicular lymphoma into diffuse large B-cell lymphoma.
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http://dx.doi.org/10.1016/j.hoc.2016.07.012DOI Listing
December 2016

The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism.

Blood 2016 06 11;127(25):3215-24. Epub 2016 Apr 11.

Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia; Department of Clinical Hematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Parkville, VIC, Australia;

BCL2 blunts activation of the mitochondrial pathway to apoptosis, and high-level expression is required for chronic lymphocytic leukemia (CLL) survival. Venetoclax (ABT-199) is a small-molecule selective inhibitor of BCL2 currently in clinical trials for CLL and other malignancies. In conjunction with the phase 1 first-in-human clinical trial of venetoclax in patients with relapsed or refractory CLL (M12-175), we investigated the mechanism of action of venetoclax in vivo, explored whether in vitro sensitivity assays or BH3 profiling correlated with in vivo responses in patients, and determined whether loss of TP53 function affected responses in vitro and in vivo. In all samples tested, venetoclax induced death of CLL cells in vitro at concentrations achievable in vivo, with cell death evident within 4 hours. Apoptotic CLL cells were detected in vivo 6 or 24 hours after a single 20-mg or 50-mg dose in some patients. The extent of mitochondrial depolarization by a BIM BH3 peptide in vitro was correlated with percentage reduction of CLL in the blood and bone marrow in vivo, whereas the half lethal concentration derived from standard cytotoxicity assays was not. CLL cell death in vitro and the depth of clinical responses were independent of deletion of chromosome 17p, TP53 mutation, and TP53 function. These data provide direct evidence that venetoclax kills CLL cells in a TP53-independent fashion by inhibition of BCL2 in patients and support further assessment of BH3 profiling as a predictive biomarker for this drug.
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http://dx.doi.org/10.1182/blood-2016-01-688796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920022PMC
June 2016

Current challenges and novel treatment strategies in double hit lymphomas.

Ther Adv Hematol 2016 Feb;7(1):52-64

Department of Clinical Hematology and Bone Marrow Transplant, Royal Melbourne Hospital, Parkville, Australia.

High-grade B-cell lymphomas with recurrent chromosomal break points have been termed 'double hit lymphoma' (DHL). The most commonly seen DHL is diffuse large B-cell lymphoma (DLBCL) with t(14;18) and t(8;14) or t(8;22) resulting in overexpression of BCL2 and MYC, respectively. The increased proliferation due to MYC overexpression, without the ability for an apoptotic brake as a result of BCL2 overexpression, results in 'the perfect storm of oncogenesis'. Thus this disease presents a number of diagnostic and therapeutic challenges for the hematologist. The first and foremost challenge is to recognize the DHL. As different morphological entities can be affected it is incumbent on pathologists and clinicians to maintain a high index of suspicion especially in disease that appears unusually aggressive or refractory to therapy. Diagnosis by fluorescence in situ hybridization (FISH) is a sensitive and specific method for detection of the disease but is time-consuming and expensive. While detection by immunohistochemistry (IHC) is sensitive and correlates with survival, standardized methods for this are not widely agreed upon. The second and equally important challenge in DHL is optimizing clinical outcome in a group of patients for whom the prognosis is widely regarded as poor. While improvements have been achieved by dose escalating standard chemotherapeutic regimens, many patients continue to do badly. Furthermore as a disease of aging many patients are unsuitable for dose-intensive chemotherapy regimens. There are now multiple novel targeted agents in various stages of clinical development that offer hope for better outcomes without undue toxicity. Among the most exciting of these developments include specific inhibitors of both BCL2 and MYC.
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http://dx.doi.org/10.1177/2040620715608091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713886PMC
February 2016

Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia.

N Engl J Med 2016 Jan 6;374(4):311-22. Epub 2015 Dec 6.

From the Department of Clinical Haematology and the Bone Marrow Transplantation Unit, Royal Melbourne Hospital (A.W.R., M.A.A.), the Division of Cancer and Haematology, Walter and Eliza Hall Institute of Medical Research (A.W.R., M.A.A.), and the Victorian Comprehensive Cancer Centre (A.W.R., J.F.S.), Parkville, VIC, and the University of Melbourne (A.W.R., J.F.S.) and Peter MacCallum Cancer Centre (J.F.S.), Melbourne, VIC - all in Australia; Dana-Farber Cancer Institute, Boston (M.S.D., J.R.B.); the Swedish Medical Center, Seattle (J.M.P.); Washington University, St. Louis (B.S.K.); University of Arizona, Tucson (S.D.P.); Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (J.F.G.); University of California, San Diego, San Diego (T.J.K.); AbbVie, North Chicago, IL (L.G., S.W., M.D., M.Z., M.B.D., E.C., S.H.E., R.A.H.); and University of Texas M.D. Anderson Cancer Center, Houston (W.G.W.).

Background: New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells.

Methods: We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day.

Results: The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%.

Conclusions: Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.).
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http://dx.doi.org/10.1056/NEJMoa1513257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7107002PMC
January 2016

Ability emotional intelligence of nurse managers in the Midwestern United States.

Asia Pac J Oncol Nurs 2015 Apr-Jun;2(2):82-88

Department of Biobehavioral Nursing Science, College of Nursing, University of Illinois at Chicago, Chicago, IL, USA.

Objective: The aim of this study was to describe the emotional intelligence (EI) and examine the corresponding demographic characteristics of front-line Nurse Managers in acute care settings.

Methods: This quantitative descriptive study was conducted in eight acute care hospitals in the Midwestern United States. The Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) was used to measure the EI of 87 front-line Nurse Managers. Demographic characteristics of the participants were captured on a second tool, the Nurse Manager Demographic Characteristics questionnaire. Descriptive and inferential statistics were used for analysis.

Results: Significant correlations were found between the perceiving and using branches of the model and total EI score and nurses certified in a specialty. No significant correlations were found between EI and graduate education, age, years in management, percentage of time in management or number of direct reports. Considerations for future research are discussed.

Conclusions: Opportunity exists to develop EI in front-line Nurse Managers.
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http://dx.doi.org/10.4103/2347-5625.155733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123481PMC
December 2016

BCL2 inhibition in double hit lymphoma.

Leuk Lymphoma 2015 Jul 21;56(7):1928-9. Epub 2015 Jan 21.

Division of Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research , Parkville , Australia.

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http://dx.doi.org/10.3109/10428194.2014.987769DOI Listing
July 2015

Targeting BCL2 for the treatment of lymphoid malignancies.

Semin Hematol 2014 Jul 15;51(3):219-27. Epub 2014 May 15.

The Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia; The Department of Clinical Haematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Parkville, Victoria, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; The Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia. Electronic address:

The failure of apoptosis (programmed cell death) underpins the development of many tumors and often renders them resistant to cytotoxic therapies. In hematologic malignancies, this impairment of apoptosis is often caused by overexpression of the pro-survival protein BCL2. Because abnormally high levels of BCL2 sustain these tumors, there has been much interest in targeting BCL2 as a novel approach to treating various hematologic malignancies. One such approach is the development of BH3 mimetic compounds, small molecules that mimic the action of the BH3-only proteins, natural antagonists of BCL2 and its pro-survival relatives. These compounds act by restoring the ability of a cell to undergo apoptotic cell death. Some of them have shown very encouraging results in early-phase clinical trials that are currently underway, particularly in patients with chronic lymphocytic leukemia and some non-Hodgkin lymphomas, diseases marked by BCL2 overexpression. In this review, we discuss the rationale behind targeting BCL2, highlight the recent findings from clinical trials, and pinpoint the next steps in the clinical development of this interesting and promising class of targeted agents, particularly for the treatment of lymphoid malignancies.
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http://dx.doi.org/10.1053/j.seminhematol.2014.05.008DOI Listing
July 2014

A comparison of survey methods in studies of the nurse workforce.

Nurse Res 2013 Mar;20(4):22-7

Mennonite College of Nursing, Illinois State University, United States.

Aim: To compare and contrast postal and internet surveys in studies of nurse workforces.

Background: There is little research that examines the advantages and disadvantages of different surveys in studies of nurse workforces.

Data Sources: Previous studies that used different approaches to disseminate surveys.

Discussion: There are advantages and disadvantages to using postal or internet surveys for nurse workforce studies.

Conclusion: Factors researchers may wish to consider in selecting survey methods include research topic, costs, coverage, timing and the characteristics of potential respondents.

Implications For Research/practice: Response rate, data quality and adequate coverage of the population being studied can be optimised if the researcher selects an appropriate survey method.
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http://dx.doi.org/10.7748/nr2013.03.20.4.22.e286DOI Listing
March 2013

BH3 mimetic therapy: an emerging and promising approach to treating chronic lymphocytic leukemia.

Leuk Lymphoma 2013 May 1;54(5):909-11. Epub 2013 Feb 1.

Division of Cancer and Hematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

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http://dx.doi.org/10.3109/10428194.2013.769223DOI Listing
May 2013

What level of knowledge do elementary school teachers possess concerning the care of children with asthma? A pilot study.

J Pediatr Nurs 2012 Oct 25;27(5):523-7. Epub 2011 Aug 25.

University of Illinois, Chicago, IL, USA.

A self-report questionnaire was used to assess the level of knowledge among a convenience sample of 34 elementary school teachers in a rural school district in Illinois. The questionnaire addressed general asthma knowledge and management, including signs and symptoms, triggers, and treatment. The results suggest a knowledge deficit among this sample of elementary school teachers; the average score was 75%. Teachers with an increased exposure/experience with asthma scored significantly higher than did those with limited exposure. Implications of these findings for schools in rural areas are discussed.
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http://dx.doi.org/10.1016/j.pedn.2011.07.004DOI Listing
October 2012

Comparison of pulse oximetry measures in a healthy population.

Medsurg Nurs 2012 Mar-Apr;21(2):70-5; quiz 76

University of Illinois at Chicago, Moline, IL, USA.

In this study finger and ear oximetry readings of 89 healthy persons were compared. The findings do not support the common nursing practice of using a finger sensor to obtain a pulse oximetry reading from an individual's ear if the finger is not usable.
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July 2012

Rapid response team in a rural hospital.

Clin Nurse Spec 2012 Mar-Apr;26(2):95-102

College of Nursing, University of Illinois at Chicago, Illinois, USA.

Purpose/objectives: The objective of this study was to explore the nurses' knowledge and perceptions of the Rapid Response Team (RRT).

Design: This study was of a prospective, quantitative, descriptive design.

Setting: The setting was a 175-bed rural community nonteaching regional hospital.

Sample: Fifty-seven nurses participated, resulting in a 90.4% response.

Methods: Data were collected through distribution of an adapted survey termed Rapid Response Team Survey; the tool consisted of 3 parts.

Findings: The mean knowledge score was average. A "physician positive" response to the calling of an RRT was not particularly important; a "physician negative" response to calling the RRT was even less important. Knowledge of the RRT criteria and the understanding of the call criteria were important. Knowledge of the process for calling the RRT and how to call were less important to this group.

Conclusions: Although the nurses were able to identify that changes in the patient's condition had occurred, weakness existed in recognition that those changes required rapid intervention through the calling of the RRT. The nurses positively perceived the RRT and the hospital's commitment to it. The nurses generally did not allow physician response to impact their willingness to call the RRT.

Implications: The results of this study suggest that education is needed on early identification of the unstable patient and the early insidious signs seen in diseases such as sepsis.
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http://dx.doi.org/10.1097/NUR.0b013e31824590fbDOI Listing
April 2012

An overview of job embeddedness.

J Prof Nurs 2011 Sep-Oct;27(5):320-7

Mennonite College of Nursing at Illinois State University, Normal, IL 61790-5810, USA.

Nursing turnover in health care organizations is a considerable problem that needs to be reframed within the context of "nurse retention" and "job embeddedness" (JE). A construct from the business literature, JE has been associated with "retention" or "antiwithdrawal." Conversely, turnover encompasses the process of quitting. This distinction is significant. JE represents a mediating construct between various "on-the-job" (organizational) factors, "off-the-job" (community) factors, and employee retention. This article presents an overview of JE including the dimensions, the related concepts of turnover and retention, and associated research. JE may be used to develop specific nurse-retention strategies following careful organizational and community assessment. With the current and looming nursing shortage, perhaps it is time for health care institutions to consider the adaptation of JE tenets.
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http://dx.doi.org/10.1016/j.profnurs.2011.04.004DOI Listing
January 2012

Nurses' knowledge and attitudes regarding pain assessment and intervention.

Medsurg Nurs 2011 Jan-Feb;20(1):7-11

University of Illinois at Chicago, College of Nursing, Chicago, IL, USA.

Registered nurses were queried about their knowledge and attitudes regarding pain management. Results suggest knowledge of pain management principles and interventions is insufficient.
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April 2011