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Article ; Online: Clinical experiences with venetoclax and other pro-apoptotic agents in lymphoid malignancies: lessons from monotherapy and chemotherapy combination.

Lew, Thomas E / Seymour, John F

2022 Volume 15, Issue 1, Page(s) 75

Abstract: BH3-mimetics are a novel drug class of small molecule inhibitors of BCL2 family proteins which restore apoptosis in malignant cells. The only currently approved BH3-mimetic, the selective BCL2 inhibitor venetoclax, is highly efficacious in chronic ... ...

Abstract	BH3-mimetics are a novel drug class of small molecule inhibitors of BCL2 family proteins which restore apoptosis in malignant cells. The only currently approved BH3-mimetic, the selective BCL2 inhibitor venetoclax, is highly efficacious in chronic lymphocytic leukemia and has rapidly advanced to an approved standard of care in frontline and relapsed disease in combination with anti-CD20 monoclonal antibodies. In this context, tumour lysis syndrome and myelosuppression are the most commonly encountered toxicities and are readily manageable with established protocols. Venetoclax is active in other lymphoid malignancies including several B cell non-Hodgkin lymphomas, acute lymphoblastic leukemia and multiple myeloma, with the highest intrinsic sensitivity observed in mantle cell lymphoma and Waldenstrom macroglobulinemia. Venetoclax combination with standard regimens in follicular lymphoma, multiple myeloma and aggressive B cell neoplasms has shown some promise, but further studies are required to optimize dose and scheduling to mitigate increased myelosuppression and infection risk, and to find validated biomarkers of venetoclax sensitivity. Future research will focus on overcoming venetoclax resistance, targeting other BCL2 family members and the rational design of synergistic combinations.
MeSH term(s)	Adult ; Antineoplastic Agents ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use ; Humans ; Lymphoma, B-Cell/drug therapy ; Multiple Myeloma/drug therapy ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Sulfonamides/pharmacology ; Sulfonamides/therapeutic use
Chemical Substances	Antineoplastic Agents ; Bridged Bicyclo Compounds, Heterocyclic ; Proto-Oncogene Proteins c-bcl-2 ; Sulfonamides ; venetoclax (N54AIC43PW)
Language	English
Publishing date	2022-06-03
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2429631-4
ISSN	1756-8722 ; 1756-8722
ISSN (online)	1756-8722
ISSN	1756-8722
DOI	10.1186/s13045-022-01295-3
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Article ; Online: Health-related quality of life for patients with chronic lymphocytic leukaemia - A critical outcome measure in the era of highly effective therapies.

Lew, Thomas E / Anderson, Mary Ann

British journal of haematology

2022 Volume 197, Issue 4, Page(s) 394–396

MeSH term(s)	Bridged Bicyclo Compounds, Heterocyclic ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/therapy ; Outcome Assessment, Health Care ; Quality of Life ; Sulfonamides
Chemical Substances	Bridged Bicyclo Compounds, Heterocyclic ; Sulfonamides
Language	English
Publishing date	2022-03-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.18118
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Article ; Online: How I treat chronic lymphocytic leukemia after venetoclax.

Lew, Thomas E / Tam, Constantine S / Seymour, John F

Blood

2021 Volume 138, Issue 5, Page(s) 361–369

Abstract: Venetoclax-based regimens have expanded the therapeutic options for patients with chronic lymphocytic leukemia (CLL), frequently achieving remissions with undetectable measurable residual disease and facilitating time-limited treatment without ... ...

Abstract	Venetoclax-based regimens have expanded the therapeutic options for patients with chronic lymphocytic leukemia (CLL), frequently achieving remissions with undetectable measurable residual disease and facilitating time-limited treatment without chemotherapy. Although response rates are high and durable disease control is common, longer-term follow-up of patients with relapsed and refractory disease, especially in the presence of TP53 aberrations, demonstrates frequent disease resistance and progression. Although the understanding of venetoclax resistance remains incomplete, progressive disease 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 pretreated patients with disease refractory to fludarabine and harboring complex karyotype, Richter transformation presents a distinct and challenging manifestation of venetoclax resistance. For patients with progressive CLL after venetoclax, treatment options include B-cell receptor pathway inhibitors, allogeneic stem cell transplantation, chimeric antigen receptor T cells, and venetoclax retreatment 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 practicing clinicians.
MeSH term(s)	Allografts ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use ; Drug Resistance, Neoplasm ; Hematopoietic Stem Cell Transplantation ; Humans ; Immunotherapy, Adoptive ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell/therapy ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Sulfonamides/therapeutic use ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	BCL2 protein, human ; Bridged Bicyclo Compounds, Heterocyclic ; Proto-Oncogene Proteins c-bcl-2 ; Sulfonamides ; TP53 protein, human ; Tumor Suppressor Protein p53 ; venetoclax (N54AIC43PW)
Language	English
Publishing date	2021-03-04
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2020008502
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Article ; Online: Promises and pitfalls of targeted agents in chronic lymphocytic leukemia.

Lew, Thomas E / Anderson, Mary Ann / Seymour, John F

Cancer drug resistance (Alhambra, Calif.)

2020 Volume 3, Issue 3, Page(s) 415–444

Abstract: Targeted agents have significantly improved outcomes for patients with chronic lymphocytic leukemia, particularly high-risk subgroups for whom chemoimmunotherapy previously offered limited efficacy. Two classes of agent in particular, the Bruton tyrosine ...

Abstract	Targeted agents have significantly improved outcomes for patients with chronic lymphocytic leukemia, particularly high-risk subgroups for whom chemoimmunotherapy previously offered limited efficacy. Two classes of agent in particular, the Bruton tyrosine kinase inhibitors (e.g., ibrutinib) and the B-cell lymphoma 2 inhibitor, venetoclax, induce high response rates and durable remissions in the relapsed/refractory and frontline settings. However, maturing clinical data have revealed promises and pitfalls for both agents. These drugs induce remissions and disease control in the majority of patients, often in situations where modest efficacy would be expected with traditional chemoimmunotherapy approaches. Unfortunately, in the relapsed and refractory setting, both agents appear to be associated with an inevitable risk of disease relapse and progression. Emerging patterns of resistance are being described for both agents but a common theme appears to be multiple sub-clonal drivers of disease progression. Understanding these mechanisms and developing effective and safe methods to circumvent the emergence of resistance will determine the longer-term utility of these agents to improve patients' quality and length of life. Rational drug combinations, optimised scheduling and sequencing of therapy will likely hold the key to achieving these important goals.
Language	English
Publishing date	2020-05-23
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2578-532X
ISSN (online)	2578-532X
DOI	10.20517/cdr.2019.108
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Article ; Online: Rehabilitation in patients with lymphoma: An overview of Systematic Reviews.

Amatya, Bhasker / Khan, Fary / Lew, Thomas E / Dickinson, Michael

Journal of rehabilitation medicine

2021 Volume 53, Issue 3, Page(s) jrm00163

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Humans ; Lymphoma/rehabilitation ; Quality of Life/psychology
Language	English
Publishing date	2021-03-17
Publishing country	Sweden
Document type	Journal Article ; Systematic Review
ZDB-ID	2039427-5
ISSN	1651-2081 ; 1651-2235 ; 0891-060X ; 1650-1977
ISSN (online)	1651-2081 ; 1651-2235
ISSN	0891-060X ; 1650-1977
DOI	10.2340/16501977-2810
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Article ; Online: Ruxolitinib bridging therapy to allogeneic SCT for high-risk refractory subcutaneous panniculitis-like T-cell lymphoma.

Watson, Leisa R / Lew, Thomas E / Fox, Lucy C / Khot, Amit / van der Weyden, Carrie

Leukemia & lymphoma

2022 , Page(s) 1–5

Language	English
Publishing date	2022-09-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	1042374-6
ISSN	1029-2403 ; 1042-8194
ISSN (online)	1029-2403
ISSN	1042-8194
DOI	10.1080/10428194.2022.2118537
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Article ; Online: Venetoclax-rituximab is active in patients with BTKi-exposed CLL, but durable treatment-free remissions are uncommon.

Lew, Thomas E / Bennett, Rory / Lin, Victor S / Whitechurch, Ashley / Handunnetti, Sasanka M / Marlton, Paula / Shen, Yandong / Mulligan, Stephen P / Casan, Joshua / Blombery, Piers / Tam, Constantine S / Roberts, Andrew W / Seymour, John F / Thompson, Philip A / Anderson, Mary A

Blood advances

2024 Volume 8, Issue 6, Page(s) 1439–1443

MeSH term(s)	Humans ; Rituximab/therapeutic use ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Neoplasm Recurrence, Local ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use ; Sulfonamides
Chemical Substances	Rituximab (4F4X42SYQ6) ; venetoclax (N54AIC43PW) ; Bridged Bicyclo Compounds, Heterocyclic ; Sulfonamides
Language	English
Publishing date	2024-01-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2023011327
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Article ; Online: Treatment approaches for patients with TP53-mutated mantle cell lymphoma.

Lew, Thomas E / Minson, Adrian / Dickinson, Michael / Handunnetti, Sasanka M / Blombery, Piers / Khot, Amit / Anderson, Mary Ann / Ritchie, David / Tam, Constantine S / Seymour, John F

The Lancet. Haematology

2023 Volume 10, Issue 2, Page(s) e142–e154

Abstract: Mantle cell lymphoma is an uncommon subtype of lymphoma characterised by clinical and biological heterogeneity. Although most patients with mantle cell lymphoma have durable responses after chemoimmunotherapy, there is a need to prospectively identify ... ...

Abstract	Mantle cell lymphoma is an uncommon subtype of lymphoma characterised by clinical and biological heterogeneity. Although most patients with mantle cell lymphoma have durable responses after chemoimmunotherapy, there is a need to prospectively identify high-risk subsets of patients for whom disease control with standard chemotherapy will be short lived. Among the available prognostic factors, TP53 mutations are uniquely informative owing to their strong association with early disease progression and death among patients receiving conventional chemoimmunotherapy, with the highest negative prognostic value compared with other established risk indicators, including the mantle cell lymphoma international prognostic index, histological features, elevated Ki-67, and other genetic lesions. The poor outcomes for patients with TP53-mutated mantle cell lymphoma receiving chemoimmunotherapy and second-line Bruton tyrosine kinase inhibitors represent an urgent need for alternative approaches. In this Review, we synthesise the available data to inform the management of this high-risk subset of patients and present a treatment strategy prioritising clinical trials and early use of cellular therapies.
MeSH term(s)	Humans ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Immunotherapy ; Lymphoma, Mantle-Cell/drug therapy ; Lymphoma, Mantle-Cell/genetics ; Patients ; Prognosis ; Tumor Suppressor Protein p53/genetics
Chemical Substances	TP53 protein, human ; Tumor Suppressor Protein p53
Language	English
Publishing date	2023-02-01
Publishing country	England
Document type	Journal Article ; Review
ISSN	2352-3026
ISSN (online)	2352-3026
DOI	10.1016/S2352-3026(22)00355-6
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Article ; Online: Allogeneic stem cell transplantation achieves long-term remissions in mantle cell lymphoma, including in

Lew, Thomas E / Cliff, Edward R Scheffer / Dickinson, Michael / Tam, Constantine S / Seymour, John F / Blombery, Piers / Bajel, Ashish / Ritchie, David / Khot, Amit

Leukemia & lymphoma

2023 Volume 64, Issue 11, Page(s) 1792–1800

Abstract: Cytarabine-containing chemoimmunotherapy followed by autologous transplantation and rituximab maintenance achieves durable remissions for most patients with mantle cell lymphoma (MCL). However, patients ... ...

Abstract	Cytarabine-containing chemoimmunotherapy followed by autologous transplantation and rituximab maintenance achieves durable remissions for most patients with mantle cell lymphoma (MCL). However, patients with
MeSH term(s)	Adult ; Humans ; Lymphoma, Mantle-Cell/therapy ; Lymphoma, Mantle-Cell/drug therapy ; Neoplasm Recurrence, Local ; Hematopoietic Stem Cell Transplantation/adverse effects ; Rituximab/therapeutic use ; Transplantation, Autologous ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Stem Cell Transplantation ; Tumor Suppressor Protein p53/genetics
Chemical Substances	Rituximab (4F4X42SYQ6) ; TP53 protein, human ; Tumor Suppressor Protein p53
Language	English
Publishing date	2023-08-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	1042374-6
ISSN	1029-2403 ; 1042-8194
ISSN (online)	1029-2403
ISSN	1042-8194
DOI	10.1080/10428194.2023.2241095
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Article ; Online: Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for pirtobrutinib cross-resistance.

Blombery, Piers / Thompson, Ella R / Lew, Thomas E / Tiong, Ing Soo / Bennett, Rory / Cheah, Chan Y / Lewis, Katharine Louise / Handunnetti, Sasanka M / Tang, Chloe Pek Sang / Roberts, Andrew / Seymour, John F / Tam, Constantine S

Blood advances

2022 Volume 6, Issue 20, Page(s) 5589–5592

Abstract: The covalent Bruton's tyrosine kinase inhibitors (BTKis) are highly effective for the treatment of chronic lymphocytic leukemia (CLL). The dominant resistance mechanism observed with the BTKi ibrutinib is the development of BTK Cys481 codon mutations. ... ...

Abstract	The covalent Bruton's tyrosine kinase inhibitors (BTKis) are highly effective for the treatment of chronic lymphocytic leukemia (CLL). The dominant resistance mechanism observed with the BTKi ibrutinib is the development of BTK Cys481 codon mutations. Whether a similar resistance mutation profile exists for the newer-generation, more selective BTKi zanubrutinib is unknown. In samples referred for diagnostic next-generation sequencing in patients with progressive CLL, we observed an enrichment in the kinase-dead BTK Leu528Trp mutation in patients treated with zanubrutinib compared with ibrutinib (54%; 7 of 13 vs 4%; 1 of 24, P = .001). We describe 2 patients with BTK Leu528Trp mutations who showed clinical cross-resistance and progressive enrichment of the BTK Leu528Trp mutation over time when treated with the noncovalent BTKi pirtobrutinib. Both patients subsequently responded to venetoclax-based treatment. In summary, we have identified an enrichment of the BTK Leu528Trp mutation arising in patients treated with zanubrutinib that may impart cross-resistance to the noncovalent inhibitor pirtobrutinib and therefore may have implications for sequencing of these treatments in CLL.
MeSH term(s)	Agammaglobulinaemia Tyrosine Kinase ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Mutation ; Piperidines ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Pyrazoles ; Pyrimidines
Chemical Substances	Piperidines ; Protein Kinase Inhibitors ; Pyrazoles ; Pyrimidines ; zanubrutinib (AG9MHG098Z) ; Agammaglobulinaemia Tyrosine Kinase (EC 2.7.10.2)
Language	English
Publishing date	2022-07-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2022008325
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