- Email: [email protected]
Novel Therapeutic Options in CML
Extended Abstract: 060-CML-03
Novel Therapeutic Options in CML Abstract Tyrosine kinase inhibitors (TKIs) have turned chronic myeloid leukemia (CML) from a life-threatening malignancy worth the risk of an allogeneic stem cell transplant into a chronic condition. For most patients with chronic phase CML (CP-CML) life expectancy is now dictated by co-morbidities. As a result treatment paradigms for CML are changing, with more emphasis on quality of life, avoidance of long-term TKI toxicities and treatment free remission (TFR) as the key therapy objective rather than overall survival (OS). Despite these advances there is still a minority of patients who are either diagnosed with accelerated or blast phase CML or who fail first line TKI therapy and have reduced OS compared to matched control populations. The past year has seen advances in CML therapy in several areas. (1) Bosutinib, a second generation (2G) TKI, was approved for second-line therapy several years ago. In comparison with imatinib, and 2G TKIs dasatinib and nilotinib, bosutinib lacks activity against platelet-derived growth factor receptor (PDGFR) and KIT, two kinases thought to account for some of the adverse events (AEs) observed with TKIs, including fluid retention. An initial phase 3 trial in newly diagnosed patients with CP-CML (BELA study) comparing bosutinib 500mg daily vs. imatinib 400mg daily had failed to demonstrate a difference in the primary endpoint (complete cytogenetic response), due to excess treatment discontinuations in the experimental arm. Another phase 3 trial (BFORE study) using 400 mg bosutinib vs. 400 mg imatinib has reported improved rates of major molecular response (MMR) in the experimental arm, suggesting that bosutinib may be approved for frontline therapy. As MMR rates are comparable to the other second generation (2G) TKIs dasatinib and nilotinib, bosutinib’s place in the CML algorithm will be determined by AEs and tolerability, particularly cardiovascular (CV) toxicity. As such toxicity may have long latency, only long-term follow-up will be able to clarify whether bosutinib’s CV toxicity is closer to other 2G TKIs or the ‘safe option’ imatinib. While all currently approved TKIs target the catalytic site, functioning essentially as ATP competitors, a novel principle is emerging in the form of ABL001 (asciminib). This novel molecule binds to the myristoyl pocket, an allosteric regulatory site, mimicking the physiological mechanism of ABL1 autoinhibition. ABL001, due to its unique mechanism of action, has few off target effects, and is active against the catalytic site BCR-ABL1 mutants characteristic of clinical resistance to currently approved TKIs, including the T315I mutant. An ongoing phase 1 clinical trial in CP-, AP- and BP-CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has demonstrated considerable activity for ABL001 as a single agent, but also in combination with other TKIs, with generally good tolerability. Responses seem to vary according to BCR-ABL1 genotype, with more limited activity against T315I. This is not easy to explain mechanistically, but suggests that ponatinib, the only approved TKI
Michael Deininger, MD, PhD University of Utah, Salt Lake City, 84112, USA [email protected]
Keywords Tyrosine kinase inhibitor, Allosteric inhibitor, Treatment free remission, Major molecular response, Deep molecular response S105
with activity against T315I, may remain an important option for this subgroup of patients, even after a potential approval of ABL001 in the future. ABL001 represents a new mechanistic paradigm and may enrich the therapeutic armamentarium as a single agent or in combination. (2) TFR is increasingly recognized as the new therapy goal in CML. While guidelines thus far recommended to attempt TFR only within clinical trials, in 2017 the National Comprehensive Cancer Network (NCCN) has published a set of conditions for selection of patients suitable for a trial of TFR, recognizing the need to provide guidance for an intervention that is increasingly common in the community. Long-term follow-up of the STIM study, initially published in 2010, showed that TRF was surprisingly stable at approximately 40%, with no recurrences beyond those published in the first report. Several successful TFR studies were reported that used more lenient criteria to include patients [such as deep molecular response (DMR; a 4-log or more reduction of BCR-ABL1 transcripts) rather than MR4.5] or less strict criteria to diagnose recurrence, such as loss of MMR rather than loss of DMR. Additionally similar results are emerging for TFR after 2G TKIs, suggesting that TFR may become a reality for 20-30% of patients. More follow-up is clearly needed, as community-based trials such as the EuroSKI trial, show a slow attrition of the TRF curve rather than a plateau, indicating that continued monitoring will be essential to avoid recurrence of overt CML. In countries with highly fragmented medical care systems and lack of comprehensive coverage (such as the US) this may be challenging and could eventually lead to impaired outcomes. Interestingly, approximately 25% of patient undergoing TFR experience a TKI withdrawal syndrome, perhaps due to reactivation of mast cells that had been suppressed by the TKI’s anti-KIT activity. TFR is the ultimate answer to long-term TKI toxicities and TKI-associated reduced quality of life, in addition to reducing the costs of medical care. Much effort is being directed in identifying clinical parameters or biomarkers to predict successful TFR, but thus far only longer duration of TKI exposure and longer duration of DMR have been mostly consistent across the different studies. This provides indirect support for the ‘attrition theory’ of TKI-based eradication of CML. Additionally detailed analyses of immune parameters revealed associations between TRF and higher numbers of NK cells and/or lower numbers of T-suppressor cells, but these correlations are too weak to inform clinical decisions. (3) Patients who fail to achieve DMR or experience recurrence upon TKI discontinuation require long-term TKI therapy. Although many pathways have been implicated in the persistence of residual CML despite continued exposure to TKIs, this has not been translated into clinical progress. Currently active studies include combination of TKIs with JAK kinase inhibitors and pioglitazone, amongst others. Experience has that trials combining TKIs with additional agents are difficult to recruit into, reflecting the excellent OS survival of patients on TKIs alone and their limited willingness to accept inconvenience and potentially additional AEs for the uncertain prospect of improving their response and achieve TFR. Better pre-clinical models that more faithfully reflect clinical CML will be needed to improve this situation and achieve ‘functional cure’ in the majority of patients. With all the progress in CML, much work remains to be done.
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Novel Therapeutic Options in CML Abstract Tyrosine kinase inhibitors (TKIs) have turned chronic myeloid leukemia (CML) from a life-threatening malignancy worth the risk of an allogeneic stem cell transplant into a chronic condition. For most patients with chronic phase CML (CP-CML) life expectancy is now dictated by co-morbidities. As a result treatment paradigms for CML are changing, with more emphasis on quality of life, avoidance of long-term TKI toxicities and treatment free remission (TFR) as the key therapy objective rather than overall survival (OS). Despite these advances there is still a minority of patients who are either diagnosed with accelerated or blast phase CML or who fail first line TKI therapy and have reduced OS compared to matched control populations. The past year has seen advances in CML therapy in several areas. (1) Bosutinib, a second generation (2G) TKI, was approved for second-line therapy several years ago. In comparison with imatinib, and 2G TKIs dasatinib and nilotinib, bosutinib lacks activity against platelet-derived growth factor receptor (PDGFR) and KIT, two kinases thought to account for some of the adverse events (AEs) observed with TKIs, including fluid retention. An initial phase 3 trial in newly diagnosed patients with CP-CML (BELA study) comparing bosutinib 500mg daily vs. imatinib 400mg daily had failed to demonstrate a difference in the primary endpoint (complete cytogenetic response), due to excess treatment discontinuations in the experimental arm. Another phase 3 trial (BFORE study) using 400 mg bosutinib vs. 400 mg imatinib has reported improved rates of major molecular response (MMR) in the experimental arm, suggesting that bosutinib may be approved for frontline therapy. As MMR rates are comparable to the other second generation (2G) TKIs dasatinib and nilotinib, bosutinib’s place in the CML algorithm will be determined by AEs and tolerability, particularly cardiovascular (CV) toxicity. As such toxicity may have long latency, only long-term follow-up will be able to clarify whether bosutinib’s CV toxicity is closer to other 2G TKIs or the ‘safe option’ imatinib. While all currently approved TKIs target the catalytic site, functioning essentially as ATP competitors, a novel principle is emerging in the form of ABL001 (asciminib). This novel molecule binds to the myristoyl pocket, an allosteric regulatory site, mimicking the physiological mechanism of ABL1 autoinhibition. ABL001, due to its unique mechanism of action, has few off target effects, and is active against the catalytic site BCR-ABL1 mutants characteristic of clinical resistance to currently approved TKIs, including the T315I mutant. An ongoing phase 1 clinical trial in CP-, AP- and BP-CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has demonstrated considerable activity for ABL001 as a single agent, but also in combination with other TKIs, with generally good tolerability. Responses seem to vary according to BCR-ABL1 genotype, with more limited activity against T315I. This is not easy to explain mechanistically, but suggests that ponatinib, the only approved TKI
Michael Deininger, MD, PhD University of Utah, Salt Lake City, 84112, USA [email protected]
Keywords Tyrosine kinase inhibitor, Allosteric inhibitor, Treatment free remission, Major molecular response, Deep molecular response S105
with activity against T315I, may remain an important option for this subgroup of patients, even after a potential approval of ABL001 in the future. ABL001 represents a new mechanistic paradigm and may enrich the therapeutic armamentarium as a single agent or in combination. (2) TFR is increasingly recognized as the new therapy goal in CML. While guidelines thus far recommended to attempt TFR only within clinical trials, in 2017 the National Comprehensive Cancer Network (NCCN) has published a set of conditions for selection of patients suitable for a trial of TFR, recognizing the need to provide guidance for an intervention that is increasingly common in the community. Long-term follow-up of the STIM study, initially published in 2010, showed that TRF was surprisingly stable at approximately 40%, with no recurrences beyond those published in the first report. Several successful TFR studies were reported that used more lenient criteria to include patients [such as deep molecular response (DMR; a 4-log or more reduction of BCR-ABL1 transcripts) rather than MR4.5] or less strict criteria to diagnose recurrence, such as loss of MMR rather than loss of DMR. Additionally similar results are emerging for TFR after 2G TKIs, suggesting that TFR may become a reality for 20-30% of patients. More follow-up is clearly needed, as community-based trials such as the EuroSKI trial, show a slow attrition of the TRF curve rather than a plateau, indicating that continued monitoring will be essential to avoid recurrence of overt CML. In countries with highly fragmented medical care systems and lack of comprehensive coverage (such as the US) this may be challenging and could eventually lead to impaired outcomes. Interestingly, approximately 25% of patient undergoing TFR experience a TKI withdrawal syndrome, perhaps due to reactivation of mast cells that had been suppressed by the TKI’s anti-KIT activity. TFR is the ultimate answer to long-term TKI toxicities and TKI-associated reduced quality of life, in addition to reducing the costs of medical care. Much effort is being directed in identifying clinical parameters or biomarkers to predict successful TFR, but thus far only longer duration of TKI exposure and longer duration of DMR have been mostly consistent across the different studies. This provides indirect support for the ‘attrition theory’ of TKI-based eradication of CML. Additionally detailed analyses of immune parameters revealed associations between TRF and higher numbers of NK cells and/or lower numbers of T-suppressor cells, but these correlations are too weak to inform clinical decisions. (3) Patients who fail to achieve DMR or experience recurrence upon TKI discontinuation require long-term TKI therapy. Although many pathways have been implicated in the persistence of residual CML despite continued exposure to TKIs, this has not been translated into clinical progress. Currently active studies include combination of TKIs with JAK kinase inhibitors and pioglitazone, amongst others. Experience has that trials combining TKIs with additional agents are difficult to recruit into, reflecting the excellent OS survival of patients on TKIs alone and their limited willingness to accept inconvenience and potentially additional AEs for the uncertain prospect of improving their response and achieve TFR. Better pre-clinical models that more faithfully reflect clinical CML will be needed to improve this situation and achieve ‘functional cure’ in the majority of patients. With all the progress in CML, much work remains to be done.
S106