Publications by authors named "Thomas E Lew"

12 Publications

  • Page 1 of 1

T-cell replete allogeneic stem cell transplant for mantle cell lymphoma achieves durable disease control, including against TP53-mutated disease.

Bone Marrow Transplant 2021 Jul 20. Epub 2021 Jul 20.

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

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http://dx.doi.org/10.1038/s41409-021-01418-3DOI Listing
July 2021

How I treat chronic lymphocytic leukemia after venetoclax.

Blood 2021 Apr 19. Epub 2021 Apr 19.

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

Venetoclax-based regimens have expanded the therapeutic options for patients with chronic lymphocytic leukemia (CLL), frequently achieving remissions with undetectable measurable residual disease (uMRD) and facilitating time-limited treatment without utilizing chemotherapy. Although response rates are high and durable disease control is common, longer-term follow-up of patients with relapsed and refractory (RR) disease, especially in the presence of TP53 aberrations, demonstrates frequent disease resistance and progression. Although the understanding of venetoclax resistance remains incomplete, progressive disease (PD) is typified by oligoclonal leukemic populations with distinct resistance mechanisms, including BCL2 mutations, upregulation of alternative BCL2 family proteins and genomic instability. Although most commonly observed in heavily pre-treated patients with disease refractory to fludarabine and harboring complex karyotype (CK), Richter transformation (RT) presents a distinct and challenging manifestation of venetoclax resistance. For patients with progressive CLL after venetoclax, treatment options include B-cell receptor pathway inhibitors (BCRis), allogeneic stem cell transplantation (SCT), chimeric antigen receptor (CAR) T-cells, and venetoclax re-treatment for those with disease relapsing after time-limited therapy. However, data to inform clinical decisions for these patients are limited. We review the biology of venetoclax resistance and outline an approach to the common clinical scenarios encountered after venetoclax-based therapy that will increasingly confront practising clinicians.
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http://dx.doi.org/10.1182/blood.2020008502DOI Listing
April 2021

Rehabilitation in patients with lymphoma: An overview of Systematic Reviews.

J Rehabil Med 2021 Mar 17;53(3):jrm00163. Epub 2021 Mar 17.

Department of Rehabilitation Medicine, The Royal Melbourne Hospital, 34-54 Poplar Road Parkville, Victoria, Australia. E-mail:

Objective: To evaluate existing evidence from published systematic reviews for the effectiveness of rehabilitation interventions in patients with lymphoma.

Data Sources: A comprehensive literature search was conducted using medical/health science databases up to 1 October 2020. Bibliographies of pertinent articles, journals and grey literature were searched.

Data Extraction And Synthesis: Two reviewers independently selected and reviewed potential reviews for methodological quality and graded the quality of evidence for outcomes using validated tools. Any discrepancies were resolved by final group consensus.

Results: Twelve systematic reviews (n = 101 studies, 87,132 patients with lymphoma) evaluated 3 broad categories of rehabilitation interventions (physical modalities, nutrition and complementary medicine). Most reviews were of moderate-to-low methodological quality. The findings suggest: moderate-quality evidence for exercise programmes for improved fatigue and sleep disturbance; low-quality evidence for exercise therapy alone and qigong/tai chi for improved symptoms and overall quality of life, and an inverse association between sunlight/ultraviolet radiation exposure and incidence of non-Hodgkin's lymphoma; and very low-quality evidence for beneficial effects of yoga for sleep disturbances. Association between physical activity and lymphoma risk is indistinct.

Conclusion: Despite a range of rehabilitation modalities used for patients with lymphoma, high-quality evidence for many is sparse. Beneficial effects of exercise programmes were noted for fatigue, psychological symptoms and quality of life. More research with robust study design is required to determine the effective rehabilitation approaches.
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http://dx.doi.org/10.2340/16501977-2810DOI Listing
March 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

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

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

A case of multi-drug resistant ESBL-producing Shigella sonnei acute acalculous cholecystitis and gastroenteritis in a returned traveller.

J Travel Med 2018 08;25(1)

Alfred Health, Melbourne, Victoria, Australia.

The first case of Shigella-associated acalculous cholecystitis is described. A 27-year-old woman presented to hospital with diarrhoea and acute acalculous cholecystitis one day after return to Australia from Vietnam. Her feces culture grew multi-drug resistant ESBL-producing Shigella sonnei and she improved with antimicrobial therapy and intravenous fluids.
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http://dx.doi.org/10.1093/jtm/tay029DOI Listing
August 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

Early serum creatinine accurately predicts acute kidney injury post cardiac surgery.

BMC Nephrol 2017 Mar 16;18(1):93. Epub 2017 Mar 16.

Department of Nephrology, Monash Medical Centre, Level 3, Block E, 246 Clayton Rd, Clayton, VIC, 3168, Australia.

Background: Acute Kidney Injury (AKI) is a well recognized complication of cardiac surgery. It is associated with significant morbidity and mortality. The aims of our study are twofold; 1. To define the incidence of AKI post cardiac surgery. 2. To identify pre-morbid and operative risk factors for developing AKI and to determine if immediate post operative serum creatinine (IPOsCr) accurately predicts the development of AKI.

Methods: We prospectively studied 196 consecutive patients undergoing elective (on-pump) cardiac surgery. Baseline patient characteristics, including medical co-morbidities, proteinuria, procedural data and kidney function (serum creatinine (sCr) were collected. Internationally standardised criteria for AKI were used (sCr >1.5 times baseline, elevation in sCr >26.4 μmmol/L (0.3 mg/dl). Measurements were collected pre-operatively, within 2 h of surgical completion (IPOsCr) and daily for two days. Logistic regression was used to assess predictive factors for AKI including IPOsCr. Model discrimination was assessed using ROC AUC curves.

Results: Forty (20.4%) patients developed AKI postoperatively. Hypertension (OR 2.64, p = 0.02), diabetes (OR 2.25, p = 0.04), proteinuria (OR 2.48, p = 0.02) and a lower baseline eGFR (OR 0.74, p = 0.002) were associated with AKI in univariate analysis. A multivariate logistic model with preoperative and surgical factors (age, gender, eGFR, proteinuria, hypertension, diabetes and type of cardiac surgery) demonstrated moderate discrimination for AKI (ROC AUC 0.76). The addition of IPOsCr improved model discrimination for AKI (AUC 0.82, p = 0.07 versus baseline AUC) and was independently associated with AKI (OR 7.17; 95% CI 1.27-40.32; p = 0.025).

Conclusions: One in 5 patients developed AKI post cardiac surgery. These patients have significantly increased morbidity and mortality. IPOsCr is significantly associated with the development of AKI, providing a cheap readily available prognostic marker.
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http://dx.doi.org/10.1186/s12882-017-0504-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353965PMC
March 2017

Dose-reduced fludarabine, cyclophosphamide and rituximab is well tolerated in older patients with chronic lymphocytic leukemia and has preserved therapeutic efficacy.

Leuk Lymphoma 2016 May 20;57(5):1044-53. Epub 2015 Nov 20.

b Department of Hematology , Peter MacCallum Cancer Centre , East Melbourne , Australia ;

Despite its efficacy in prospective trials, full dose fludarabine, cyclophosphamide and rituximab (FCR) may be too toxic for elderly patients with chronic lymphocytic leukemia (CLL) in clinical practice. We retrospectively reviewed the impact of dose reductions in FCR therapy on the outcomes of 42 consecutive patients aged 65-87 (median 72) years. Despite a median cumulative fludarabine dose reduction of 50% from full dose, the objective response and complete response rates were 86% and 38% respectively (frontline 94%/59%; previously treated 80%/24%). Dose reductions of 25-75% were not significantly associated with inferior progression free survival compared to minimal reductions (≤25%) (p=0.49), and did not preclude deep responses, including six cases (14%) of minimal residual disease negativity. Although hematological and infectious toxicities were common, treatment limiting adverse effects were infrequent. Dose attenuated FCR appears to have preserved efficacy and may be a viable therapeutic option for elderly patients with CLL.
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http://dx.doi.org/10.3109/10428194.2015.1096353DOI Listing
May 2016

Rasburicase causing severe oxidative hemolysis and methemoglobinemia in a patient with previously unrecognized glucose-6-phosphate dehydrogenase deficiency.

Acta Haematol 2013 11;130(4):254-9. Epub 2013 Jul 11.

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

Rasburicase is frequently used in tumor lysis syndrome (TLS). Although it is very well tolerated, it can cause severe oxidative hemolytic anemia and methemoglobinemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. We report another case of rasburicase-induced methemoglobinemia in a patient with previously unrecognized G6PD deficiency and review the cases of methemoglobinemia and oxidative hemolysis reported in the literature to date. Patients from ethnicities in which G6PD deficiency is prevalent at high risk of TLS should be screened for G6PD deficiency prior to administration of rasburicase where practical. Asymptomatic decrease in oxygen saturation by oximetry and cyanosis are signs of methemoglobinemia; patients recover with conservative measures including supplemental oxygen and packed red cell transfusion.
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http://dx.doi.org/10.1159/000351048DOI Listing
January 2014
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