Abstract:With the advent of targeted therapies for chronic lymphocytic leukemia (CLL), treatment choice has expanded and patients are living longer. Careful consideration is needed regarding treatment duration and sequence, how best to meet patients' needs, balancing toxicities while improving long-term survival and maximizing depth of response. This review addresses these considerations and discusses current targeted treatment dilemmas. Targeted therapies have dramatically transformed the CLL treatment landscape. Two … Show more
“…With a fixed-duration approach, Bcl-2i venetoclax can achieve deep remissions, resulting in high rates of uMRD in treatment-naive and r/r CLL patients [ 31 , 43 , 44 ]. In contrast, BTKi such as ibrutinib and acalabrutinib seldom achieve a complete remission or uMRD status but still produce high ORR, long-term disease control, and survival benefits [ 50 ]. Ongoing studies are now evaluating the clinically complimentary activity of BTKi and Bcl-2i as combination therapies [ 31 , 50 ].…”
Section: Treatmentmentioning
confidence: 99%
“…In contrast, BTKi such as ibrutinib and acalabrutinib seldom achieve a complete remission or uMRD status but still produce high ORR, long-term disease control, and survival benefits [ 50 ]. Ongoing studies are now evaluating the clinically complimentary activity of BTKi and Bcl-2i as combination therapies [ 31 , 50 ]. The treatment combination of BTKi (ibrutinib) and Bcl-2i (venetoclax) in first-line [ 51 ] and r/r [ 52 ] treatment settings in clinical trials showed a high uMRD rate of 36% in r/r CLL patients [ 52 ] and 61% in untreated high-risk and older patients with CLL [ 51 ].…”
In recent years, considerable progress has been made in the standard treatment for chronic lymphocytic leukaemia (CLL) due to the availability of new potent drugs. However, the majority of data on CLL were derived from Western populations, with limited studies and guidelines on the management of CLL from an Asian population perspective. This consensus guideline aims to understand treatment challenges and suggest appropriate management approaches for CLL in the Asian population and other countries with a similar socio-economic profile. The following recommendations are based on a consensus by experts and an extensive literature review and contribute towards uniform patient care in Asia.
“…With a fixed-duration approach, Bcl-2i venetoclax can achieve deep remissions, resulting in high rates of uMRD in treatment-naive and r/r CLL patients [ 31 , 43 , 44 ]. In contrast, BTKi such as ibrutinib and acalabrutinib seldom achieve a complete remission or uMRD status but still produce high ORR, long-term disease control, and survival benefits [ 50 ]. Ongoing studies are now evaluating the clinically complimentary activity of BTKi and Bcl-2i as combination therapies [ 31 , 50 ].…”
Section: Treatmentmentioning
confidence: 99%
“…In contrast, BTKi such as ibrutinib and acalabrutinib seldom achieve a complete remission or uMRD status but still produce high ORR, long-term disease control, and survival benefits [ 50 ]. Ongoing studies are now evaluating the clinically complimentary activity of BTKi and Bcl-2i as combination therapies [ 31 , 50 ]. The treatment combination of BTKi (ibrutinib) and Bcl-2i (venetoclax) in first-line [ 51 ] and r/r [ 52 ] treatment settings in clinical trials showed a high uMRD rate of 36% in r/r CLL patients [ 52 ] and 61% in untreated high-risk and older patients with CLL [ 51 ].…”
In recent years, considerable progress has been made in the standard treatment for chronic lymphocytic leukaemia (CLL) due to the availability of new potent drugs. However, the majority of data on CLL were derived from Western populations, with limited studies and guidelines on the management of CLL from an Asian population perspective. This consensus guideline aims to understand treatment challenges and suggest appropriate management approaches for CLL in the Asian population and other countries with a similar socio-economic profile. The following recommendations are based on a consensus by experts and an extensive literature review and contribute towards uniform patient care in Asia.
“…Clinical management of chronic lymphocytic leukemia (CLL) patients has been transformed by the introduction of targeted therapies that disrupt tumor microenvironmental signals, leading to enhanced survival rates of poor-prognostic patients, highlighting a potential curative strategy [ 1 ]. However, these treatments are not suitable for all CLL patients and the development of drug resistance has been demonstrated [ 2 , 3 ].…”
Targeted deletion of Raptor, a component of mechanistic target of rapamycin complex 1 (mTORC1), reveals an essential role for mTORC1 in initiation/maintenance of leukemia in a CLL model, resulting from a failure for haemopoietic stem/progenitor cells (HSPCs) to commit to the B cell lineage. Induction of Raptor-deficiency in NSG mice transplanted with Mx1-Raptor CLL progenitor cells (PKCα-KR-transduced HSPCs) after disease establishment revealed a reduction in CLL-like disease load and a significant increase in survival in the mice. Interestingly in an aggressive CLL-like disease model, rapamycin treatment reduced disease burden more effectively than AZD2014 (dual mTORC1/2 inhibitor), indicating a skew towards mTORC1 sensitivity with more aggressive disease. Rapamycin, but not ibrutinib, efficiently targeted the eEF2/eEF2K translation elongation regulatory axis, downstream of mTORC1, resulting in eEF2 inactivation through induction of eEF2T56 phosphorylation. mTOR inhibitor treatment of primary patient CLL cells halted proliferation, at least in part through modulation of eEF2K/eEF2 phosphorylation and expression, reduced protein synthesis and inhibited expression of MCL1, Cyclin A and Cyclin D2. Our studies highlight the importance of translation elongation as a driver of disease progression and identify inactivation of eEF2 activity as a novel therapeutic target for blocking CLL progression.
“…The clinical management of chronic lymphocytic leukemia (CLL) patients has been transformed by the introduction of targeted therapies that disrupt tumor microenvironmental signals, leading to enhanced survival rates of poor-prognostic patients, highlighting a potential curative strategy ( 1 ). However, these treatments are not suitable for all CLL patients, and the development of drug resistance has been demonstrated ( 2, 3 ).…”
The precise role of mechanistic target of rapamycin complex 1 (mTORC1) during chronic lymphocytic leukemia (CLL) pathogenesis remains to be elucidated. Targeted deletion of mTORC1 component Raptor in adult mice reveals that mTORC1 function is essential for initiation and maintenance of CLL. Raptor-deficient bone marrow-derived PKCα-KR transduced haemopoietic progenitors failed to generate a CLL-like disease in vitro, due to an inability to overcome the mTORC1-mediated block in B cell lineage commitment. Induction of Raptor-deficiency in NSG mice transplanted with Mx1-Raptor BM-derived PKCα-KR transduced cells after disease was established, revealed a reduced CLL-like disease load and a significant increase in survival in the mice. Interestingly in mice transplanted with an aggressive CLL-like disease, rapamycin treatment reduced disease burden more effectively than AZD2014 (dual mTORC1/2 inhibitor), indicating a skew towards mTORC1 sensitivity with more aggressive leukemic disease. Rapamycin efficiently targeted the translation elongation axis eEF2/eEF2K downstream of mTORC1, resulting in eEF2 inactivation through induction of eEF2T56 phosphorylation. Rapamycin treatment of primary CLL cells halted proliferation, modulated eEF2K/eEF2 phosphorylation and inhibited MCL1 expression. Our studies demonstrate that mTORC1 plays an essential role in leukemia progression in vitro and in vivo in our CLL mouse model, with evidence for increased rapamycin sensitivity in aggressive secondary CLL transplants. Furthermore, the suppression of translation elongation through inactivation of eEF2 may offer a novel therapeutic target for blocking CLL progression.
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